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  Subjects -> ENVIRONMENTAL STUDIES (Total: 831 journals)
    - ENVIRONMENTAL STUDIES (760 journals)
    - POLLUTION (23 journals)
    - WASTE MANAGEMENT (9 journals)

ENVIRONMENTAL STUDIES (760 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: 1)
Acta Oecologica     Hybrid Journal   (Followers: 7)
Acta Regionalia et Environmentalica     Open Access  
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 12)
Advances in Ecological Research     Full-text available via subscription   (Followers: 33)
Advances in Environmental Chemistry     Open Access  
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 13)
Advances in Life Science and Technology     Open Access   (Followers: 7)
Aeolian Research     Hybrid Journal   (Followers: 2)
African Journal of Environmental Science and Technology     Open Access   (Followers: 2)
African Journal of Sustainable Development     Full-text available via subscription   (Followers: 3)
AGE     Hybrid Journal   (Followers: 4)
Age and Ageing     Hybrid Journal   (Followers: 54)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10)
Amazon's Research and Environmental Law     Open Access  
Ambiência     Open Access  
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Applied Sciences     Open Access   (Followers: 26)
American Journal of Environmental Engineering     Open Access   (Followers: 10)
American Journal of Environmental Protection     Open Access   (Followers: 5)
American Journal of Environmental Sciences     Open Access   (Followers: 11)
American Journal of Microbiology     Open Access   (Followers: 12)
American Naturalist     Full-text available via subscription   (Followers: 54)
Annals of GIS     Hybrid Journal   (Followers: 12)
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: 42)
Annual Review of Environment and Resources     Full-text available via subscription   (Followers: 14)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 27)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 10)
Applied and Environmental Soil Science     Open Access   (Followers: 10)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 12)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 24)
Aquatic Toxicology     Hybrid Journal   (Followers: 15)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 5)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 7)
Archives of Environmental Protection     Open Access   (Followers: 5)
Archives of Toxicology     Hybrid Journal   (Followers: 14)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 4)
Asian Journal of Earth Sciences     Open Access   (Followers: 17)
Asian Journal of Rural Development     Open Access   (Followers: 7)
Asian Review of Environmental and Earth Sciences     Open Access   (Followers: 1)
Atas de Saúde Ambiental - ASA     Open Access  
ATBU Journal of Environmental Technology     Open Access   (Followers: 1)
Atmospheric and Climate Sciences     Open Access   (Followers: 13)
Atmospheric Environment     Hybrid Journal   (Followers: 30)
Austral Ecology     Hybrid Journal   (Followers: 12)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 7)
Australasian Journal of Human Security, The     Full-text available via subscription   (Followers: 3)
Australian Journal of Environmental Education     Full-text available via subscription   (Followers: 9)
Avicenna Journal of Environmental Health Engineering     Open Access  
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 9)
Basic and Applied Ecology     Hybrid Journal   (Followers: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 40)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 31)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 21)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 5)
Bioremediation Journal     Hybrid Journal   (Followers: 4)
BioRisk     Open Access   (Followers: 2)
BMC Ecology     Open Access   (Followers: 16)
Boletín Semillas Ambientales     Open Access  
Boston College Environmental Affairs Law Review     Open Access   (Followers: 6)
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: 8)
Bulletin of the American Meteorological Society     Open Access   (Followers: 21)
Business, Peace and Sustainable Development     Full-text available via subscription   (Followers: 3)
Canadian Journal of Earth Sciences     Full-text available via subscription   (Followers: 6)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 14)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 11)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 15)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 11)
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   (Followers: 1)
Challenges in Sustainability     Open Access  
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 15)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 10)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 55)
Civil and Environmental Engineering     Open Access   (Followers: 4)
Civil And Environmental Engineering Reports     Open Access   (Followers: 2)
Civil and Environmental Research     Open Access   (Followers: 14)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 14)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 5)
Cleanroom Technology     Full-text available via subscription  
Climate Change Economics     Hybrid Journal   (Followers: 10)
Climate Policy     Hybrid Journal   (Followers: 28)
Coastal Engineering Journal     Hybrid Journal   (Followers: 1)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 10)
Computational Ecology and Software     Open Access   (Followers: 6)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 3)
Conservation and Society     Open Access   (Followers: 10)
Conservation Letters     Open Access   (Followers: 26)
Conservation Physiology     Open Access   (Followers: 1)
Conservation Science     Open Access   (Followers: 15)
Construction Innovation: Information, Process, Management     Hybrid Journal   (Followers: 12)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 4)
Creativity and Innovation Management     Hybrid Journal   (Followers: 65)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 10)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 20)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 5)
Current Environmental Health Reports     Hybrid Journal  
Current Forestry Reports     Hybrid Journal  
Current Opinion in Environmental Sustainability     Hybrid Journal   (Followers: 9)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 4)
Developments in Atmospheric Science     Full-text available via subscription   (Followers: 7)
Developments in Earth and Environmental Sciences     Full-text available via subscription   (Followers: 4)
Developments in Earth Surface Processes     Full-text available via subscription   (Followers: 3)
Developments in Environmental Modelling     Full-text available via subscription   (Followers: 6)
Developments in Environmental Science     Full-text available via subscription   (Followers: 6)
Developments in Integrated Environmental Assessment     Full-text available via subscription   (Followers: 4)
Disaster Prevention and Management     Hybrid Journal   (Followers: 16)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 11)
Duke Environmental Law & Policy Forum     Open Access   (Followers: 6)
E3S Web of Conferences     Open Access  
Earth and Environmental Science Transactions of the Royal Society of Edinburgh     Hybrid Journal   (Followers: 5)
Earth Interactions     Full-text available via subscription   (Followers: 11)
Earth Science Informatics     Hybrid Journal   (Followers: 3)
Earth System Science Data (ESSD)     Open Access   (Followers: 3)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 5)
Earthquake Science     Hybrid Journal   (Followers: 8)
EchoGéo     Open Access   (Followers: 1)
Ecohydrology     Hybrid Journal   (Followers: 9)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 2)
Ecologia Aplicada     Open Access  
Ecología en Bolivia     Open Access  
Ecological Applications     Full-text available via subscription   (Followers: 111)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecological Complexity     Hybrid Journal   (Followers: 7)
Ecological Indicators     Hybrid Journal   (Followers: 14)
Ecological Informatics     Hybrid Journal   (Followers: 4)
Ecological Management & Restoration     Hybrid Journal   (Followers: 13)
Ecological Modelling     Hybrid Journal   (Followers: 72)
Ecological Monographs     Full-text available via subscription   (Followers: 27)
Ecological Processes     Open Access   (Followers: 5)
Ecological Questions     Open Access   (Followers: 5)
Ecological Research     Hybrid Journal   (Followers: 8)
Ecological Restoration     Full-text available via subscription   (Followers: 19)
Ecologist, The     Full-text available via subscription   (Followers: 26)
Ecology     Full-text available via subscription   (Followers: 224)
Ecology and Evolution     Open Access   (Followers: 44)
Ecology Letters     Hybrid Journal   (Followers: 148)
Economics and Policy of Energy and the Environment     Full-text available via subscription   (Followers: 6)
Économie rurale     Open Access   (Followers: 1)
Ecoprint : An International Journal of Ecology     Open Access   (Followers: 2)
Ecopsychology     Hybrid Journal   (Followers: 6)
Ecosphere     Hybrid Journal   (Followers: 2)
Ecosystem Services     Hybrid Journal   (Followers: 6)
Ecosystems     Hybrid Journal   (Followers: 23)
Ecotoxicology     Hybrid Journal   (Followers: 9)
Ecotoxicology and Environmental Safety     Hybrid Journal   (Followers: 6)
Ecozon@ : European Journal of Literature, Culture and Environment     Open Access   (Followers: 3)
Ekologija     Open Access  
Electronic Green Journal     Open Access   (Followers: 5)
Elementa : Science of the Anthropocene     Open Access   (Followers: 1)
Empowering Sustainability International Journal     Open Access  
Energy & Environmental Science     Full-text available via subscription   (Followers: 17)
Energy and Environment Focus     Free   (Followers: 3)
Energy and Environment Research     Open Access   (Followers: 11)
Energy and Environmental Engineering     Open Access   (Followers: 3)
Engenharia Sanitaria e Ambiental     Open Access  
English Academy Review: Southern African Journal of English Studies     Hybrid Journal   (Followers: 5)
English Studies     Hybrid Journal   (Followers: 5)
Envigogika     Open Access  
Environment and Behavior     Hybrid Journal   (Followers: 13)
Environment and Development Economics     Hybrid Journal   (Followers: 26)
Environment and Ecology Research     Open Access   (Followers: 2)
Environment and Natural Resources Research     Open Access   (Followers: 7)
Environment and Planning A     Full-text available via subscription   (Followers: 36)
Environment and Planning B : Planning and Design     Full-text available via subscription   (Followers: 31)
Environment and Planning C : Government and Policy     Full-text available via subscription   (Followers: 29)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 38)
Environment and Pollution     Open Access   (Followers: 6)
Environment and Society : Advances in Research     Full-text available via subscription   (Followers: 6)
Environment International     Hybrid Journal   (Followers: 8)
Environment of Care News     Full-text available via subscription   (Followers: 1)
Environment Systems & Decisions     Hybrid Journal   (Followers: 2)
Environment, Development and Sustainability     Hybrid Journal   (Followers: 28)
Environment, Space, Place     Full-text available via subscription   (Followers: 2)
Environment: Science and Policy for Sustainable Development     Hybrid Journal   (Followers: 44)
Environmental & Engineering Geoscience     Full-text available via subscription   (Followers: 2)
Environmental & Socio-economic Studies     Open Access  
Environmental and Climate Technologies     Open Access   (Followers: 1)
Environmental and Molecular Mutagenesis     Hybrid Journal   (Followers: 1)
Environmental Bioindicators     Hybrid Journal   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)
Environmental Claims Journal     Hybrid Journal   (Followers: 1)
Environmental Communication: A Journal of Nature and Culture     Hybrid Journal   (Followers: 16)
Environmental Development     Hybrid Journal   (Followers: 3)
Environmental Education Research     Hybrid Journal   (Followers: 14)

        1 2 3 4 | Last

Journal Cover Basic & Clinical Pharmacology & Toxicology
  [SJR: 0.739]   [H-I: 62]   [9 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7835 - ISSN (Online) 1742-7843
   Published by John Wiley and Sons Homepage  [1598 journals]
  • Dietary Pyridoxine Protects against Stress and Maintains
           Immune‐Hematological Status in Chanos Chanos Exposed to Endosulfan
    • Authors: Neeraj Kumar; K. Ambasankar, KK Krishnani, Shashi Bhushan, PS Minhas
      Abstract: The amelioration effect of water‐soluble vitamin pyridoxine against stress was evaluated in Milkfish, Chanos chanos exposed to endosulfan. Two hundred and twenty‐five fish were distributed randomly into five treatments, each with three replicates. Four isocaloric and isonitrogenous diets with graded levels of pyridoxine feed were such as normal water and fed with control diet (En0/PY0), endosulfan‐treated water and fed with control diet (En/PY0), endosulfan‐treated water and fed with 50 (En/ PY 50 mg/kg), 75 (En/ PY 75 mg/kg) and 100 mg/kg (En/PY 100 mg/kg) pyridoxine supplemented feed. The endosulfan in treated water was maintained at a level of 1/40th of LC50 (0.52 ppb). The effect of dietary pyridoxine supplementation was studied in terms of antioxidative enzymes (catalase, superoxide dismutase, glutathione‐S‐transferase), stress markers (heat shock protein 70, caspase 3, cortisol, acetylcholine esterase, blood glucose), immuno‐hematological parameters (total protein, albumin, globulin and A/G ratio, NBT, RBC, WBC, Hb), gill histopathogy and a subsequent challenge study with Vibrio parahaemolyticus. The antioxidative enzymes, stress markers, albumin, A/G ratio were significantly (p
      PubDate: 2016-03-31T09:20:35.233192-05:
      DOI: 10.1111/bcpt.12589
  • S‐Nitrosothiols as Platforms for Topical Nitric Oxide Delivery
    • Authors: Marcelo Ganzarolli Oliveira
      Abstract: Nitric oxide (NO) is a small radical species involved in several fundamental physiological processes, including the control of vascular tone, the immune response and neuronal signalling. Endothelial dysfunction with decreased NO bioavailability is the underlying cause of several diseases and has led to the development of a wide range of systemic NO‐donor compounds to lower the blood pressure and control hypertensive crises. However, several potential therapeutic actions of NO, not related to the cardiovascular system, demand exclusively local actions. Primary S‐nitrosothiols (RSNOs) are endogenously found NO carriers and donors and have emerged as platforms for the localized delivery of NO in topical applications. Formulations for this purpose have evolved from low molecular weight RSNOs incorporated in polymeric films, hydrogels and viscous vehicles, to polymeric RSNOs where the SNO moiety is covalently bound to the polymer backbone. The biological actions displayed by these formulations include the increase of dermal vasodilation, the acceleration of wound healing, the killing of infectious microorganisms and analgesic action against inflammatory pain. This MiniReview focuses on the state of the art of experimental topical formulations for NO delivery based on S‐nitrosothiols and their potential therapeutic applications. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-30T21:10:36.798009-05:
      DOI: 10.1111/bcpt.12588
  • Bis‐(2‐ethylhexyl) Phthalate (DEHP) Increases Insulin
           Expression and Lipid Levels in Drosophila melanogaster
    • Abstract: Bis‐(2‐ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP‐contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP‐fed male flies had higher expression levels of an insulin‐like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long‐term DEHP feeding may induce diabetes‐like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-24T06:31:02.328639-05:
      DOI: 10.1111/bcpt.12587
  • Evaluation of Mutual Drug‐Drug Interaction within Geneva Cocktail
           for Cytochrome P450 Phenotyping using Innovative Dried Blood Sampling
    • Abstract: Cytochrome P450 (CYP) activity can be assessed using a ‘cocktail’ phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low‐dose probes with a low‐invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre‐treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail. In order to further validate this cocktail, in this study we have verified whether probe drugs contained in the latter cause mutual drug‐drug interactions. In a randomized, 4‐way, Latin‐square cross‐over study, 30 healthy volunteers received low‐dose caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam (a previously validated combination with no mutual drug‐drug interactions); fexofenadine alone; bupropion alone or all 7 drugs simultaneously (Geneva cocktail). Pharmacokinetic profiles of the probe drugs and their metabolites were determined in DBS samples using both conventional micropipette sampling and new microfluidic device allowing for self‐sampling. The 90% confidence intervals for the geometric mean ratios of AUCmetabolite/AUCprobe for CYP probes administered alone or within Geneva cocktail fell within the 0.8‐1.25 bioequivalence range indicating the absence of pharmacokinetic interaction. The same result was observed for the chosen phenotyping indices i.e. metabolic ratios at 2 hr (CYP1A2, CYP3A) or 3 hr (CYP2B6, CYP2C9, CYP2C19, CYP2D6) post‐cocktail administration. DBS sampling could successfully be performed using a new microfluidic device. In conclusion, Geneva cocktail combined with an innovative DBS sampling device can be used routinely as a test for simultaneous CYP phenotyping. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-24T06:30:44.86642-05:0
      DOI: 10.1111/bcpt.12586
  • A Regional DTC‐led Intervention to Reduce the Hospital Costs of
           Expensive HIV Drugs
    • Authors: Camilla Munk Mikkelsen; Stig Ejdrup Andersen
      Abstract: In 2009, the regional Drug and Therapeutics Committee (DTC) began a series of meetings with lead specialists in infectious diseases. The role of the DTC was to engage clinicians and ensure commitment to prescribing the least expensive drugs among the clinically equivalent HAARTs (highly active antiretroviral therapy). DTC also led implementation of a national guideline. This study analyses the impact of this process on HAART consumption and expenditure. The HAART consumption and expenditure (2009‐2013) was compared to forecasts produced by exponential smoothing (2004‐2009). Abrupt switches between drug regimens coincided with the DTC‐led meetings.. Overall, HAART consumption rose 16%, while price per defined daily dose (DDD) fell 11% and the 2013 expenditure decreased 23%. The consumption of drugs addressed by the guideline rose 48%. Still, the 2013 expenditure was 41.5 million DKK (5.5 million €) (27%) lower than expected, reflecting a fall in price per DDD that coincided with the intervention. The consumption of drugs not addressed by the guideline rose 8.3%, while price per DDD fell 8.5% and the 2013 expenditure was 26.8 million DKK (3.6 million €) (19%) lower than expected. Despite a steadily increasing consumption, significant cost savings followed this DTC‐led intervention. This multifaceted approach might be applicable to changing the prescribing of other expensive drug classes. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-24T06:25:49.021485-05:
      DOI: 10.1111/bcpt.12585
  • Fenethylline (Captagon) Abuse. Local Problems from an Old Drug become
    • Authors: Maria Katselou; Ioannis Papoutsis, Panagiota Nikolaou, Samir Qammaz, Chara Spiliopoulou, Sotiris Athanaselis
      Abstract: Fenethylline is a theophylline derivative of amphetamine having stimulant effects similar to those of other amphetamine type derivatives. Fenethylline was used as medicament for hyperactivity disorders in children, narcolepsy and depression, but it has also been used as a drug of abuse under the common name of “captagon”. Unlike other drugs of abuse, the clandestine synthesis of fenethylline is simple, using inexpensive laboratory instrumentation and raw materials legal to obtain. A review of all the existing knowledge of fenethylline is reported, concerning its chemistry, synthesis, pharmacology and toxicology, legislation, its prevalence and use as drug of abuse, as well as its analysis in biological or seized samples. Published or reported captagon‐related cases and seizures are also presented. All the reviewed information was gathered through a detailed search of PubMed and the internet. The primary drug market for fenethylline (as captagon) has traditionally been countries located on the Arabian Peninsula but also North Africa since 2013. In Arab countries, millions of captagon tablets are seized every year which represents one‐third of global amphetamines seizures within a year. Furthermore, three out of four patients treated for drug problems in Saudi Arabia are addicted to amphetamines, almost exclusively in the form of captagon. Significant information on fenethylline is provided for pharmacologists, toxicologists and forensic pathologists. Fenethylline, although old, has recently been introduced to the drug market, especially in Arab countries. Continuous community alertness is needed to tackle this current growing phenomenon. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-23T01:21:26.797716-05:
      DOI: 10.1111/bcpt.12584
  • PKC Activation as a Potential Therapeutic Strategy in Alzheimer's Disease:
           Is there a Role for ELAV‐like Proteins'
    • Abstract: Alzheimer's disease (AD), the most common cause of dementia, is an irreversible and progressive neurodegenerative disorder. It affects predominantly brain areas that are critical for memory and learning and is characterised by two main pathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles. Protein kinase C (PKC) has been classified as one of the cognitive kinases controlling memory and learning. By regulating several signalling pathways involved in amyloid and tau pathologies, it also plays an inhibitory role in AD pathophysiology. Among downstream targets of PKC are the ELAV‐like RNA‐binding proteins that modulate the stability and/or the translation of specific target mRNAs involved in synaptic remodelling linked to cognitive processes. This MiniReview summarises the current evidence on the role of PKC and ELAV‐like proteins in learning and memory mechanisms, highlighting how their derangement can contribute to AD pathophysiology. This last aspect emphasizes the potential of pharmacological activation of PKC as a promising therapeutic strategy for the treatment of AD. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-21T21:05:32.684011-05:
      DOI: 10.1111/bcpt.12581
  • Factors Associated with the Combined Use of Antidepressants and
           Benzodiazepines in Major Depression: A Case‐Control Study
    • Authors: Izabela Fulone; Marcus Tolentino Silva, Luciane Cruz Lopes
      Abstract: The aim was to identify the factors associated with the combined use of antidepressants and benzodiazepines (BDZs) in patients with major depression. We conducted a case‐control study in the public health service of the city of São Paulo, Brazil. The participants were all patients being treated with antidepressants, who were diagnosed with major depression. Patients who received a combination of antidepressants and BDZs were classified as cases, and those who used only antidepressants, as controls. Data were obtained from a pharmacy database, medical records and interviews with the healthcare team. The association of predisposing factors for combined therapy was analysed using logistic regression analysis, and the odds ratios (ORs) and 95% Confidence Intervals (CI) were calculated. Of the 1,355 users of antidepressants, 265 had major depression, of whom 138 were cases and 127 were controls. The factors associated with combined use were age older than 35 years (OR 2.2, 95% CI 1.0 to 4.7), absence of co‐morbidities (OR 2.3, 95% CI 1.4 to 4.1), no use of other drugs (OR 1.9, 95% CI 1.1 to 3.3). Patients with combined use were more likely to exhibit inadequate prescribing, including inappropriate antidepressants (OR 4.7, 95% CI 2.2 to 9.9), inadequate dosages (OR3.62, 95% CI 1.4 to 9.6) and/or a non‐recommended duration (OR 66.6, 95% CI 18.4 to 240.7). The factors identified showed the groups most susceptible to combined use in this population, who in turn are more likely to receive inappropriate prescriptions. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-21T14:46:21.585961-05:
      DOI: 10.1111/bcpt.12582
  • Carnosic Acid‐combined Arsenic Trioxide Anti‐Leukaemia Cells
           in the Establishment of NB4/SCID Mouse Model
    • Abstract: Despite great improvement in the treatment outcome of APL, treatment failure still sometimes occurs due to the toxicity of arsenic trioxide (ATO). Damage to the heart and liver often occurs even when the dose is lower than the therapeutic dose. Based on the results of cell experiments in vitro in the present study, we investigated the synergistic activity of carnosic acid (CA) combined with ATO in the SCID mouse model of human promyelocytic leukemia in vivo. A NB4/SCID mouse model was established in the present study. The NB4/SCID mice were randomly divided into three treatment groups (CA alone, ATO alone and CA combined with ATO) and a control group based on factorial design. The evaluation indicators of the curative effect of the drugs included expressions of cleaved caspase‐3, PTEN, p27 gene mRNA and proteins by immunohistochemistry, flow cytometry and Western blot analysis. The survival time was compared between the four groups. The results indicated that verification of the NB4/SCID mouse model was confirmed by histopathological examination. Compared with mice treated by CA or ATO alone, the mice in the CA and ATO combined group had a higher rate of apoptosis, which was linked with expressions of cleaved caspase‐3, PTEN, p27 gene mRNA and proteins. Also, the mice with the longest survival time were those treated with the combination of CA and ATO. In conclusion, the results of the present study indicated that CA and ATO in combination have strong synergistic anti‐leukaemic effects on cell activity. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-21T14:36:16.815076-05:
      DOI: 10.1111/bcpt.12580
  • Early Discontinuation of Metformin in Individuals Treated with Inhibitors
           of Transporters of Metformin
    • Abstract: The aim of this study was to examine the risk of early discontinuation of metformin as a proxy for intolerance, associated with use of drugs known to inhibit transporters involved in metformin distribution. We analysed all incident users of metformin in Denmark between 2000 and 2012 (n = 132,221) and in a cohort of US patients (n = 296,903). Risk of early discontinuation of metformin was assessed using adjusted logistic regression for 28 drugs putatively inhibiting metformin transporters and 4 negative controls. Increased odds of early discontinuation of metformin was only associated with codeine, an inhibitor of organic cation transporter 1 in both cohorts (adjusted odds ratio (OR) in Danish cohort (95% CI): 1.13 (1.02‐1.26), adjusted OR in American cohort (95% CI): 1.32 (1.19‐1.47)). The remaining drugs were not associated with increased odds of early discontinuation and, surprisingly, four drugs were associated with a decreased risk. These findings indicate that codeine use may be associated with risk of early discontinuation of metformin and could be used as a basis for further investigation. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-19T05:27:01.176944-05:
      DOI: 10.1111/bcpt.12579
  • Tirapazamine has no Effect on Hepatotoxicity of Cisplatin and
           5‐Fluorouracil but Interacts with Doxorubicin Leading to Side
           Changes in Redox Equilibrium
    • Abstract: Tirapazamine is a hypoxia‐activated prodrug which was shown to exhibit up to 300‐fold greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the combined anti‐cancer therapy of tirapazamine with a routinely used anti‐cancer drug seems to be a promising solution. Because tirapazamine undergoes redox cycle transformation in the current study, the effect of tirapzamine on redox hepatic equilibrium, lipid status and liver morphology was evaluated in rats exposed to cisplatin, doxorubicin and 5‐fluorouracil. Rats were intraperitoneally injected with tirapazamine and a particular cytostatic. The animals were sacrificed and blood and liver were collected. Hepatic glucose, total cholesterol, triglycerides, NADH, NADPH glutathione and the activity of glucose‐6‐phosphate dehydrogenase were determined. Liver morphology and the immune expression of HMG‐CoA‐reductase were also assessed. Glucose, total cholesterol, triglycerides, bilirubin concentrations and the activity of aspartate and alanine aminotransferases were determined in the plasma. Tirapazamine displayed insignificant interactions with cisplatin and 5‐fluorouracil referring to hepatic morphology and biochemical parameters. However, tirapazamine interacts with doxorubicin, thus leading to side changes in redox equilibrium and lipid peroxidation, but those effects are not severe enough to exclude that drug combination from further studies. Thus, tirapazamine seems to be a promising agent in successive studies on anti‐cancer activity in similar schedules. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-17T09:32:20.76269-05:0
      DOI: 10.1111/bcpt.12576
  • Potential Future Pharmacological Treatment of Bladder Dysfunction
    • Abstract: In the last decades, a number of new antimuscarinic drugs have been introduced for treatment of the overactive bladder (OAB), defined symptomatically (OAB syndrome) or urodynamically (detrusor overactivity). Recently, three new drug principles have been approved for clinical use, the β3‐adrenoceptor agonist, mirabegron, the phosphodiesterase 5‐inhibitor, tadalafil, and the blocker of afferent and efferent nerves, botulinum toxin. However, new alternatives are continuously being explored. OAB is a filling disorder, and ATP is involved in the generation of afferent impulses. One way of blocking the ATP afferent pathway is through the use of P2X3 receptor antagonists. In animal models, this strategy appears to work very well, but whether it translates effectively to man remains to be established. Evidence suggests that components of the endocannabinoid system are involved in regulation of bladder function. Clinical studies of cannabinoid extracts on LUTS are scarce and essentially restricted to MS patients, and the results have so far not been convincing. Amplification of endocannabinoid activity by inhibiting their degradation via fatty acid amide hydrolase inhibitors may be an attractive approach, but no clinical experiences in OAB have been reported. Studies of the lower urinary tract have indicated that several transient receptor potential (TRP) channels, including TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1, are expressed in the bladder and may act as sensors of stretch and/or chemical irritation. Animal studies have shown that inhibition of these pathways can be effective for the reduction of bladder activity. However, the roles of these channels for normal function and in pathological states have not been established, and so far adverse effects (hyperthermia) have hampered development of antagonists. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-17T09:26:27.805879-05:
      DOI: 10.1111/bcpt.12577
  • Unintentional Pharmaceutical‐related Medication Errors caused by
           Laypersons reported to the Toxicological Information Centre in the Czech
    • Abstract: The purpose of the article was to study unintentional pharmaceutical‐related poisonings committed by laypersons that were reported to the Toxicological Information Centre (TIC) in the Czech Republic. Identifying frequency, sources, reasons and consequences of the medication errors in laypersons could help to reduce the overall rate of medication errors. Records of medication error inquiries from 2013 and 2014 were extracted from the electronic database and the following variables were reviewed: drug class, dosage form, dose, age of the subject, cause of the error, time interval from ingestion to the call, symptoms, prognosis at the time of the call and first aid recommended. Of the calls, 1,354 met the inclusion criteria. Among them, central nervous system affecting drugs (23.6%), respiratory drugs (18.5%) and alimentary drugs (16.2%), were the most common drug classes involved in the medication errors. The highest proportion of the patients was in the youngest age subgroup 0–5 y‐o (46%). The reasons for the medication errors involved the leaflet misinterpretation and mistaken dose (53.6%), mixing up medications (19.2%), attempting to reduce pain with repeated doses (6.4%), erroneous routes of administration (2.2%), psychiatric/elderly patients (2.7%), others (9.0%) or unknown (6.9%). A high proportion of children among the patients may be due to the fact that children's dosages for many drugs vary by their weight, and a lot of medications come in a variety of concentrations. Most overdoses could be prevented by safer labelling, proper cap closure systems for liquid products and medication reconciliation by both physicians and pharmacists. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-17T09:26:17.222528-05:
      DOI: 10.1111/bcpt.12578
  • Investigation of Toxic Effects of Mushroom Poisoning on the Cardiovascular
    • Abstract: Mushroom poisoning (MP) is a public health problem in many countries. It is well‐known that consumption of wild mushrooms may cause serious toxicity on renal, hepatic and brain functions. In the literature, however, studies investigating cardiotoxic effects of MP are rare. In this study, we evaluated laboratory and ECG findings of patients and sought for possible toxic effects of MP on the cardiovascular system. During a 2‐year period, 175 patients with MP were included in the study. The majority of the poisonings occurred in early summertime. The most common complaint was found to be nausea and vomiting followed by mental status alterations. Methods of treatment were mainly based on gastric lavage, activated charcoal and supportive therapy. The most common ECG abnormalities in the patients with MP were sinus tachycardia, sinus arrhythmia, ST/T inversion, 1st degree AV block and QT prolongation, respectively. Cardiac markers of the patients were found to be normal. Then, patients were divided into two subgroups according to symptom onset after consumption (less than 6 hr and more than 6 hr). When the two groups were compared, prevalence of tachycardia was significantly higher in Group II. Additionally, a correlation between interval between mushroom consumption and onset of symptoms was strongly correlated with blood pressure (BP). As this interval prolonged, BP of the patients tended to increase. In conclusion, according to our results, although mechanisms need to be clarified, MP causes hypertension and ECG alterations, particularly tachycardia in patients with late‐onset symptoms. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-08T01:07:12.298759-05:
      DOI: 10.1111/bcpt.12569
  • Neto2 Influences on Kainate Receptor Pharmacology and Function
    • Authors: Liwei Han; James R. Howe, Darryl S. Pickering
      Abstract: Neuropilin tolloid‐like protein 2 (Neto2) is an auxiliary subunit of kainate receptors (KARs). It specifically regulates KARs, e.g., slows desensitization and deactivation, increases the rate of recovery from desensitization, promotes modal gating and increases agonist sensitivity. Although the mechanism of Neto2 modulation is still unclear, gain‐of‐function results from the characterization of GluK1‐GluA2 chimeras indicate that the GluK1 sequences included in these chimeras (part or all of the TMD and part of the linkers between the TMDs and LBD) play a key role in Neto2 modulation of KAR. In addition, GluK2 M3‐S2 linkers and the D1‐D1 dimer interface were also recently identified to be important for Neto2 modulation and some studies suggested that Neto2's N–terminal regions, LDLa domain and the C‐terminal regions are important for its modulation of KARs. Although more studies are needed to confirm the roles of these domains and to identify all the domains and residues essential for KAR modulation, these results facilitate our understanding of Neto2 modulation at the structural level, which could potentially aid the development of novel therapies for the treatment of diseases that are associated with KARs, e.g., epilepsies, non–syndromic autosomal recessive mental retardation, schizophrenia and bipolar disorder. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-01T09:14:39.433717-05:
      DOI: 10.1111/bcpt.12575
  • The TRPA1 Activator Allyl Isothiocyanate (AITC) Contracts Human Jejunal
           Muscle: Pharmacological Analysis
    • Abstract: The contractile effect of AITC (300 μM) on human jejunal longitudinal strips was inhibited by the TRPA1 antagonist HC 030031 and atropine or scopolamine, but was insensitive to tetrodotoxin, purinoceptor antagonists or capsaicin desensitization. It is concluded that TRPA1 activation stimulates a cholinergic mechanism in a tetrodotoxin‐resistant manner. This article is protected by copyright. All rights reserved.
      PubDate: 2016-03-01T09:12:22.056385-05:
      DOI: 10.1111/bcpt.12574
  • MyricetinSelectivelyInducesApoptosis on Cancerous Hepatocytes by
           directlyTargeting their Mitochondria
    • Authors: Enayatollah Seydi; Hamid Reza Rasekh, Ahmad Salimi, Zhaleh Mohsenifar, Jalal Pourahmad
      Abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer‐related death. In patients for whom HCC could not be detected early, current treatments show poor tolerance and low efficacy.So, alternative therapies with good efficacy are urgently needed. The aim of this research was to evaluate the selective apoptotic effects of myricetin(MYR), a flavonoid compound, on hepatocytes and mitochondria obtained from the liver of HCC rats.In this study, HCC induced by diethylnitrosamine (DEN), as an initiator, and 2‐acetylaminofluorene (2‐AAF), as a promoter. To confirm the HCC induction, serum levels of alpha‐fetoprotein (AFP), AST, AST and ALP and histopathological changes in the liver tissue were evaluated. Rat liver hepatocytes and mitochondria for evaluation of the selective cytotoxic effects of MYR were isolated, and mitochondrial and cellular parameters related to apoptosis signaling were then determined. Our results showed that MYR was able to induce cytotoxicity only in hepatocytes from the HCC but not from the untreated control group. Besides, MYR (12.5, 25 and 50 μM) induced a considerable increase in reactive oxygen species (ROS) level, mitochondrial swelling, mitochondrial membrane permeabilization (MMP) and cytochrome c release only in cancerous but not in untreated normal hepatocyte mitochondria. MYR selectively increased caspase‐3 activation and apoptotic phenotypes in HCC but not untreated normal hepatocytes.Finally, our finding underlines MYR as a promising therapeutic candidate against HCC and recommends the compound for further studies. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-25T09:50:18.602154-05:
      DOI: 10.1111/bcpt.12572
  • Inhibition of Protein Disulfide Isomerase in Thrombosis
    • Authors: Roelof H. Bekendam; Robert Flaumenhaft
      Abstract: This MiniReview addresses our current understanding of the mechanisms by which protein disulfide isomerase (PDI) mediates thrombus formation and discusses the potential of blocking thrombosis by targeting PDI. Thiol isomerases are ubiquitous oxidoreductases primarily localized to the endoplasmic reticulum (ER) where they serve a critical role in protein folding. PDI is the founding member of the thiol isomerase family. Although PDI is an essential intracellular enzyme, it can participate in pathological processes once released from cells. In particular, PDI serves a critical role in thrombus formation, the underlying cause of myocardial infarction and stroke. Both platelets and endothelial cells secrete PDI upon vascular injury. Secreted PDI appears to activate multiple extracellular substrates in the vasculature, enabling the initiation of thrombus formation. As an essential component of thrombus formation, extracellular PDI represents a new target for pharmacological inhibition of clinical thrombosis. Quercetin‐3‐rutinoside, a flavonol highly abundant in common foods, inhibits PDI and blocks thrombus formation both in vitro and in vivo. Such observations have prompted clinical trials targeting PDI in thrombotic diseases. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-25T09:33:51.713196-05:
      DOI: 10.1111/bcpt.12573
  • Elevated Carboxyhemoglobin Concentrations by Pulse CO‐Oximetry is
           Associated with Severe Aluminium Phosphide Poisoning
    • Abstract: In pulse CO‐oximetry of aluminium phosphide (ALP)‐poisoned patients, we discovered that carboxyhemoglobin (CO‐Hb) level was elevated. We aimed to determine whether a higher CO level was detected in patients with severe ALP poisoning and if this could be used as a prognostic factor in these patients. In a prospective case‐control study, 96 suspected cases of ALP poisoning were evaluated. In the ALP‐poisoned group, demographic characteristics, gastric and exhalation silver nitrate test results, average CO‐Hb saturation, methemoglobin saturation, and blood pressure and blood gas analysis until death/discharge were recorded. Severely poisoned patients were defined as those with systolic blood pressure ≤80 mmHg, pH ≤7.2, or HCO3 ≤15 meq/L or those who died, while patients with minor poisoning were those without any of these signs/symptoms. A control group (37 patients) was taken from other medically ill patients to detect probable effects of hypotension and metabolic acidosis on CO‐Hb and methemoglobin saturations. Of 96 patients, 27 died and 37 fulfilled the criteria for severe poisoning. All patients with carbon monoxide saturation >18% met the criteria to be included in the severe poisoning group and all with a SpCO >25% died. Concerning all significant variables in univariate analysis of severe ALP toxicity, the only significant variable which could independently predict death was carbon monoxide saturation. Due to high mortality rate and need for intensive care support, early prediction of outcome is vital for choosing an appropriate setting (ICU or ordinary ward). CO‐oximetry is a good diagnostic and prognostic factor in patients with ALP poisoning even before any clinical evidence of toxicity will develop. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-21T23:20:39.884279-05:
      DOI: 10.1111/bcpt.12571
  • 9‐Hydroxyrisperidone‐induced Hyperprolactinaemia in Thai
           Children and Adolescents with Autism Spectrum Disorder
    • Abstract: Although our previous study revealed an association between prolactin level and risperidone dosage, data regarding the plasma concentration of risperidone are lacking. Therefore, this study aimed to investigate any association between plasma drug concentrations of risperidone, 9‐hydroxyrisperidone and serum prolactin level in Thai children and adolescents with autism spectrum disorders (ASD). The individuals for this study were 103 children and adolescents with ASD (90 males and 13 females). In the 12th hour after the last risperidone dose, blood samples were collected for analysis. Serum prolactin, plasma risperidone and 9‐hydroxyrisperidone levels were measured. Patients’ clinical data were collected from medical records – age, weight, height, body mass index, dose of risperidone and duration of treatment. Serum prolactin level was significantly positively correlated with plasma 9‐hydroxyrisperidone level (rs = 0.355, P < 0.001). The median concentration of 9‐hydroxyrisperidone in individuals with hyperprolactinaemia (7.59 ng/ml; IQR 4.86‐15.55) was significantly higher than non‐hyperprolactinaemic individuals (5.18 ng/ml; IQR 2.10‐8.99) after risperidone treatment (P = 0.006). By multivariate analysis, high prolactin level was correlated to high 9‐hydroxyrisperidone level (P = 0.010). The results of this study showed that serum prolactin levels, especially in autistic individuals with hyperprolactinaemia during risperidone treatment, were significantly correlated with the level of 9‐hydroxyrisperidone. These results suggest that hyperprolactinaemia may develop during risperidone treatment. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-16T02:18:59.521889-05:
      DOI: 10.1111/bcpt.12570
  • Strategies for using Plagiarism Software in the Screening of Incoming
           Journal Manuscripts: Recommendations based on a recent Literature Survey
    • Authors: Jens Lykkesfeldt
      Abstract: In recent years, several online tools have appeared capable of identifying potential plagiarism in science. While such tools may help to maintain or even increase the originality and ethical quality of the scientific literature, no apparent consensus exists among editors on the degree of plagiarism or self‐plagiarism necessary to reject or retract manuscripts. In the present study, two entire volumes of published original papers and reviews from Basic & Clinical Pharmacology & Toxicology were retrospectively scanned for similarity in anonymized form using iThenticate software to explore measures to predictively identify true plagiarism and self‐plagiarism and to potentially provide guidelines for future screening of incoming manuscripts. Several filters were applied, all of which appeared to lower the noise from irrelevant hits. The main conclusions were that plagiarism software offers a unique opportunity to screen for plagiarism easily but also that it has to be employed with caution as automated or uncritical use is far too unreliable to allow a fair basis for judging the degree of plagiarism in a manuscript. This remains the job of senior editors. Whereas a few cases of self‐plagiarism that would not likely have been accepted with today's guidelines were indeed identified, no cases of fraud or serious plagiarism were found. Potential guidelines are discussed. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-15T03:13:53.599951-05:
      DOI: 10.1111/bcpt.12568
  • The role of nitric oxide and hydrogen sulfide in urinary tract function
    • Abstract: This MiniReview focuses on the role played by nitric oxide (NO) and hydrogen sulfide (H2S) in physiology of the upper and lower urinary tract. NO and H2S, together with carbon monoxide, belong to the group of gaseous autocrine/paracrine messengers or gasotransmitters, which are employed for intra‐ and inter‐cellular communication in almost all organ systems. Because they are lipid‐soluble gases, gaseous transmitters are not constrained by cellular membranes, so that their storage in vesicles for later release is not possible. Gasotransmitter signals are terminated by falling concentrations upon reduction of production that are caused by reacting with cellular components (essentially reactive oxygen species and NO), binding to cellular components or diffusing away. NO and, more recently, H2S have been identified as key mediators in neurotransmission of the urinary tract, involved in the regulation of ureteral smooth muscle activity and urinary flow ureteral resistance, as well as by playing a crucial role in the smooth muscle relaxation of bladder outlet region. Urinary bladder function is also dependent on integration of inhibitory mediators, such as NO, released from the urothelium. In the bladder base and distal ureter, the colocalization of neuronal NO synthase with substance P and calcitonin‐gene related peptide in sensory nerves, as well as the existence of a high nicotinamide adenine dinucleotide phosphate‐diaphorase activity in dorsal root ganglion neurons also suggests the involvement of NO as a sensory neurotransmitter. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-11T07:27:31.243861-05:
      DOI: 10.1111/bcpt.12565
  • Comparative evaluation of partial a2‐adrenoceptor agonist and pure
           a2‐adrenoceptor antagonist on the behavioural symptoms of withdrawal
           after chronic alcohol administration in mice
    • Authors: Shivani Arora; Divya Vohora
      Abstract: As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2‐adrenergic agonist, and Mirtazapine (MRT), an antagonist of a2 – adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, the present study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal‐induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose‐dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time, increased climbing and swimming time during abstinence. The effect was dose‐dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE, TSZ and decrease in SDL was observed in CLN‐treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol‐paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated with alcohol withdrawal. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-11T07:25:17.057799-05:
      DOI: 10.1111/bcpt.12566
  • Antinociceptive Interaction of Tramadol with Gabapentin in Experimental
           Mononeuropathic Pain
    • Abstract: Neurophathic pain is the result of injury to the nervous system, and different animal models have been established to meet the manifestations of neuropathy. The pharmacotherapy for neuropathic pain includes gabapentin and tramadol, but these are only partially effective when given alone. The aim of this study was to assess the antinociceptive interaction between both drugs using the isobolographic analysis and changes of the IL‐1β concentration in a mouse model of neuropathic pain (partial sciatic nerve ligation or PSNL). The i.p. administration of gabapentin (5 ‐100 mg/kg) or tramadol (12.5 ‐ 100 mg/kg), displayed a dose‐dependent antinociception in the hot plate assay of PSNL mice, and effects induced by gabapentin with tramadol were synergistic. Administration of gabapentin or tramadol reversed significantly the increase of the concentration of IL‐1β induced by PSNL either 7 or 14 days and their combination was significantly more potent in reverse the elevated concentration of IL‐1β. The synergism obtained by co‐administration of gabapentin and tramadol is proposed to result from action on different mechanisms in pain patways. Gabapentin or tramadol or their combination modulate the expression of pro‐inflammatory cytokine, IL‐1β, in a model of mice PSNL which could be due to an inhibition of glial function. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-11T07:25:04.178078-05:
      DOI: 10.1111/bcpt.12567
  • Reply to Pajoumand A, Hassanian‐Moghaddam H, Zamani N's Letter to
           the Editor Regarding Our Article ‘Adverse Events Associated with
           Flumazenil Treatment for the Management of Suspected Benzodiazepine
           Intoxication – A Systematic Review with Meta‐Analyses of
           Randomised Trials’
    • PubDate: 2016-02-09T21:36:00.411106-05:
      DOI: 10.1111/bcpt.12557
  • Antidepressant‐like Effect of Insulin in
           Streptozotocin‐induced Type 2 Diabetes Mellitus Rats
    • Authors: Caio C. Sestile; Jhonatan C. Maraschin, Marcel P. Rangel, Roberto K. N. Cuman, Elisabeth A. Audi
      Abstract: This study evaluated the antidepressant‐like effect of insulin comparing to sertraline and its association in streptozotocin (STZ)‐induced type 2 diabetes mellitus (T2DM) rats, submitted to the forced swim test (FST). Male Wistar rats were daily treated for 21 days with insulin (1 or 2 IU/kg, i.p.), with the selective serotonin reuptake inhibitor (SSRI), sertraline (10 mg/kg, i.p.) or with a combination of insulin (1 or 2 IU/kg, i.p.) and sertraline (10 mg/kg, i.p.), and submitted to the FST. We also evaluated the water and food intake, urine volume and weight gain of the rats. Rats treated with STZ showed impaired glucose tolerance. Chronic treatment with sertraline showed antidepressant‐like effect in non‐diabetic and diabetic rats. Furthermore, sertraline promoted lower weight gain in diabetic rats. Insulin reduced the immobility behaviour in T2DM rats with impaired glucose tolerance. In conclusion, our results showed that insulin has antidepressant‐like effect comparable to sertraline. Sertraline is effective as an antidepressant and reduces weight gain, which reinforces its superiority over other SSRIs in the treatment of major depression disorder in T2DM patients. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-09T05:42:51.258487-05:
      DOI: 10.1111/bcpt.12563
  • Neuroprotective Effect of Ginsenoside Rd on Spinal Cord Injury Rats
    • Authors: Lin Cong; Wenting Chen
      Abstract: In the present study, the neuroprotective effects of ginsenoside Rd (GS Rd) were evaluated in a rat model of spinal cord injury (SCI). Rats in SCI groups received a T8 laminectomy and a spinal contusion injury. GS Rd 12.5, 25 and 50 mg/kg were administered intraperitoneally one hour before the surgery and once daily for 14 days. Dexamethasone 1 mg/kg was administered as a positive control. Locomotor function was evaluated using the BBB score system. H&E and Nissl staining were performed to observe the histological changes of the spinal cord. Levels of MDA and GSH and activity of SOD were assessed to reflect the oxidative stress state. The production of TNF‐α, IL‐1β and IL‐1were assessed using ELISA kits to examine the inflammatory responses in the spinal cord. TUNEL staining was used to detect the cell apoptosis in the spinal cord. Western blot analysis was used to examine the expression of apoptotic‐associated proteins and MAPK proteins. The results demonstrated that GS Rd 25 and 50 mg/kg significantly improved the locomotor function of rats after SCI, reduced tissue injury and increased neuron survival in the spinal cord. Mechanically, GS Rd decreased MDA level, increased GSH level and SOD activity, reduced the production of pro‐inflammatory cytokines and prevented cell apoptosis. The effects were equivalent to that of dexamethasone. In addition, GS Rd effectively inhibited the activation of MAPK signalling pathway induced by SCI, which might be involved in the protective effects of GS Rd against SCI. In conclusion, GS Rd attenuates SCI‐induced secondary injury through reversing the redox state imbalance, inhibiting the inflammatory response and apoptosis in the spinal cord tissue. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-02T07:36:08.626541-05:
      DOI: 10.1111/bcpt.12562
  • Scaffold‐free Tissue Formation under Real and Simulated Microgravity
    • Authors: Ganna Aleshcheva; Johann Bauer, Ruth Hemmersbach, Lasse Slumstrup, Markus Wehland, Manfred Infanger, Daniela Grimm
      Abstract: Scaffold‐free tissue formation in microgravity is a new method in regenerative medicine and an important topic in Space Medicine. In this MiniReview, we focus on recent findings in the field of tissue engineering that were observed by exposing cells to real microgravity in Space or to devices simulating to at least some extent microgravity conditions on Earth (ground‐based facilities). Under both conditions – real as well as simulated microgravity – a part of the cultured cells of various populations detaches from the bottom of a culture flask. The cells form three‐dimensional (3D) aggregates resembling the organs from which the cells have been derived. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-30T09:06:04.480386-05:
      DOI: 10.1111/bcpt.12561
  • Vascular reactivity profile of novel KCa3.1‐selective
           positive‐gating modulators in the coronary vascular bed
    • Abstract: Opening of intermediate‐conductance calcium‐activated potassium channels (KCa3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KCa3.1 selective positive‐gating modulators, SKA‐111 and SKA‐121, to 1) evoke porcine endothelial cell KCa3.1 membrane hyperpolarization, 2) induce endothelium‐dependent and, particularly, endothelium‐derived hyperpolarization (EDH)‐type relaxation in porcine coronary arteries (PCA), and 3) influence coronary artery tone in isolated rat hearts. In whole‐cell patch‐clamp experiments on endothelial cells of PCA (PCAEC), KCa‐currents evoked by bradykinin (BK) were potentiated ≈7‐fold by either SKA‐111 or SKA‐121 (both at 1 μM), and were blocked by a KCa3.1 blocker, TRAM‐34. In membrane potential measurements, SKA‐111 and SKA‐121 augmented bradykinin‐induced hyperpolarization. Isometric tension measurements in large and small‐caliber PCA showed that SKA‐111 and SKA‐121 potentiated endothelium‐dependent relaxation with intact NO‐synthesis and EDH‐type relaxation to BK by ≈2‐fold. Potentiation of the BK response was prevented by KCa3.1 inhibition. In Langendorff‐perfused rat hearts, SKA‐111 potentiated coronary vasodilation elicited by BK. In conclusion, our data show that positive‐gating modulation of KCa3.1 channels improves BK‐induced membrane hyperpolarization and endothelium‐dependent relaxation in small and large PCA as well as in the coronary circulation of rats. Positive‐gating modulators of KCa3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-28T09:11:17.721818-05:
      DOI: 10.1111/bcpt.12560
  • Acute methanol poisoning: Prevalence and predisposing factors of
           haemorrhagic and non‐haemorrhagic brain lesions
    • Authors: Sergey Zakharov; Katerina Kotikova, Manuela Vaneckova, Zdenek Seidl, Olga Nurieva, Tomas Navratil, Blazena Caganova, Daniela Pelclova
      Abstract: The purpose was to study the prevalence and predisposing factors of brain lesions in survivors of acute methanol poisoning. Clinical data on 106 patients with methanol poisoning were collected during the Czech mass poisoning outbreak. Of 83 survivors, in 46 (55%) patients follow‐up examinations including magnetic resonance imaging of brain (MR) were performed 3–8 and 24–28 months after discharge from the hospital. Of 46 patients with a median age of 49 (interquartile range, IQR 35–57) years, 24 (52%) patients had a total of 40 abnormal brain findings with haemorrhagic lesions detected in 15 (33%) and non‐haemorrhagic lesions found in 9 (19%) patients. The patients with haemorrhagic brain lesions were more acidemic (lower arterial blood pH, higher base deficit) and had higher glycaemia and lactacidaemia on admission than those without haemorrhages (all p
      PubDate: 2016-01-25T06:30:40.823548-05:
      DOI: 10.1111/bcpt.12559
  • Utility of Pilot Studies for Predicting Ratios and Intra‐subject
           Variability in High Variability Drugs
    • Abstract: Pilot studies can be used to identify adequate test formulations for pivotal bioequivalence trials. The objective of this study was to evaluate the usefulness of pilot studies in predicting ratios and the intra‐subject coefficient of variation (CVw) for pivotal studies of high‐variability drugs. Seven cross‐over and replicate bioequivalence trials were selected. A hundred simulations of pilot studies were performed for different sample sizes and designs. The pharmacokinetic data of the selected formulations were analysed using WinNonLin based on an analysis of variance (ANOVA). The CVw was estimated using the formula recommended by the European Medicines Agency based on the mean square of the ANOVA. We calculated the predictivity index ± 10% and ± 20% of the real value. The predictivity index of ± 20% in the 2 x 2 design with 12 subjects was 100% for AUC0‐t ratio, 87% for Cmax ratio, 50% for the CVw of AUC0‐t and 52% for the CVw of Cmax. The results of the 4 x 4 design with 8 subjects were similar to those of the 2 x 2 design with 12 subjects. These results were worse for the predictivity index of ± 10% in both designs. Pilot studies do not seem useful for predicting sample size. However, they were very good for predicting the AUC0‐t ratio and good for predicting the Cmax ratio. The most adequate design for pilot studies seems to be the 2 x 2 design with at least 12 volunteers. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-25T06:30:28.605781-05:
      DOI: 10.1111/bcpt.12558
  • Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic
           Metabolizing Enzymes and Transporters in Rat Liver and Kidneys
    • Authors: Hesham M. Korashy; Mushtaq A. Ansari, Zaid H. Maayah, Faisal Imam, Mohd Raish, Ibraheem M. Attaf, Naif O. Alharbi, Badr Moraished
      Abstract: Sunitinib (SUN) is a multi‐targeted tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal and renal cancers. To date, very little is known about the effects of SUN on the expression of hepatic and renal xenobiotic metabolizing enzymes (XME) and transporters. The present study was designed to investigate the capacity of chronic SUN treatment to modulate the mRNA and protein expression levels of phase I cytochrome P450 (CYP), phase II and Phase III transporters in rat liver and kidneys. For this purpose, SUN (25, 50 and 100 mg/kg) was injected IP into Wistar albino rats for 30 days; thereafter, the mRNA and protein expression levels of several XME and transporters were determined by RT‐PCR and Western blot analysis, respectively. Real‐time PCR analysis showed that SUN significantly induced the hepatic and renal CYP1A1, 1A2, 1B1, 2E1 and 4F4, whereas inhibited CYP2C11 and 4A2. Furthermore, SUN specifically induced renal but not hepatic CYP2J3 and 3A2, while it induced only hepatic CYP4A1. With regard to Phase II, SUN induced hepatic GSTA1 and UGT1A and renal NQO1 and UGT1A mRNA levels, whereas it inhibited renal GST1A expression. On the other hand, both renal and hepatic P‐gp, MRP2, and BCRP transporters were significantly induced by SUN at the mRNA and protein expression levels. Importantly, these differential effects were associated with changes in oxidative stress genes and lipid peroxidation levels. In conclusion, SUN can serve as XME and transporters modulator, which potentially may counteract the efficacy of the treatment, adverse reactions and drug interactions in SUN treatment. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-21T09:37:38.800595-05:
      DOI: 10.1111/bcpt.12555
  • Cardiovascular Alterations during the Interictal Period in Awake and
           Pithed Amygdala‐Kindled Tats
    • Abstract: Epileptic seizures are often accompanied by increased sympathetic cardiovascular activity (even interictally), but it remains unknown whether this increased activity is of central and/or peripheral origin. Hence, this study investigated the cardiovascular alterations produced by amygdala kindling in awake and pithed Wistar rats. Blood pressure (BP) and heart rate (HR) were initially recorded by tail cuff plethysmography in awake control, sham‐operated and amygdala kindled rats before and 24 hr after the kindling process. The after‐discharge threshold (ADT) was measured under different conditions to correlate brain excitability with BP and HR in kindled rats. 24 hr after the last kindling seizure: (i) HR, systolic and diastolic BP were increased; and (ii) only higher HR values correlated with lower ADT values. 48 hr after the last kindled seizure, all rats were pithed and prepared for analysing the tachycardic, vasopressor and vasodepressor responses by: (i) stimulation of the sympathetic or sensory vasodepressor CGRPergic outflows (stimulus‐response curves; S–R curves); and (ii) intravenous injections of noradrenaline or α–CGRP (dose‐response curves; D‐R curves). Interestingly: (i) the tachycardic S‐R and D‐R curves were attenuated, whilst the CGRPergic S‐R and D‐R curves were potentiated in kindled rats; and (ii) the vasopressor noradrenergic S‐R and D‐R curves were not significantly different in all groups. Therefore, the kindling process may be associated with overstimulation in the central sympathetic and sensory outflows interictally, producing: (i) peripheral attenuation of cardiac sympathetic outflow and β‐adrenoceptor activity; and (ii) peripheral potentiation of vasodepressor sensory CGRPergic outflow and CGRP receptor activity. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-21T09:35:16.183192-05:
      DOI: 10.1111/bcpt.12556
  • N‐acetylcysteine in Acute Organophosphorus Pesticides Poisoning: A
           Randomized, Clinical Trial
    • Abstract: Organophosphorus poisoning is a major global health problem with hundreds of thousands of deaths each year. Research interest in N‐acetylcysteine has grown among increasing evidence of the role of oxidative stress in organophosphorus poisoning. We aimed to assess the safety and efficacy of N‐acetylcysteine as an adjuvant treatment in patients with acute organophosphorus poisoning. This was a randomized, controlled, parallel‐group trial on 30 patients suffering from acute organophosphorus poisoning, who were admitted to the Poison Control Center of Tanta University Emergency Hospital, Tanta, Egypt, between April and September, 2014. Interventions included oral N‐acetylcysteine (600 mg three times daily for three days) as an added treatment to the conventional measures versus only the conventional treatment. Outcome measures included mortality, total dose of atropine administered, duration of hospitalization and the need for ICU admission and/or mechanical ventilation. A total of 46 patients were screened and 30 were randomized. No significant difference was found between both groups regarding demographic characteristics and the nature or severity of baseline clinical manifestations. No major adverse effects to N‐acetylcysteine therapy were reported. Malondialdehyde significantly decreased and reduced glutathione significantly increased only in the NAC‐treated patients. The patients on NAC therapy required less atropine doses than those who received only the conventional treatment; however, the length of hospital stay showed no significant difference between both groups. The study concluded that the use of N‐acetylcysteine as an added treatment was apparently safe, and it reduced atropine requirements in patients with acute organophosphorus pesticide poisoning. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-20T06:25:41.365988-05:
      DOI: 10.1111/bcpt.12554
  • Modelling of the Effect of End‐Tidal Carbon Dioxide on Cerebral
           Oxygen Saturation in Beach Chair Position under General Anaesthesia
    • Abstract: Patients undergoing shoulder surgery in the beach chair position (BCP) under general anaesthesia may be at risk of cerebral desaturation. Increasing end‐tidal carbon dioxide (EtCO2) is the most convenient and powerful method for the management of cerebral desaturation. The purpose of this study was to investigate the quantitative relationship between EtCO2 and cerebral oxygen saturation (rSO2) and to identify the associated influencing factors. Fifty‐one patients undergoing arthroscopic shoulder surgery in the BCP under general anaesthesia completed this study. Desflurane and remifentanil were used, and EtCO2 was steadily increased and then decreased by adjusting the ventilator settings every 3 min. so that time lag of rSO2 response to EtCO2 changes could be delineated. Near‐infrared spectroscopy was used to monitor rSO2 response. An indirect response model was used to examine the relationship between EtCO2 and rSO2. To determine the relevant covariates, a stepwise approach was used. There was a linear relationship between rSO2 and EtCO2 with a slight delay in the peak of rSO2 relative to EtCO2. Increase in end‐tidal desflurane concentration led to a slower response of rSO2 to the changes of EtCO2 (P = 0.0002). The presence of diabetes mellitus reduced the reactivity of rSO2 to EtCO2 changes (P
      PubDate: 2016-01-20T03:26:10.750227-05:
      DOI: 10.1111/bcpt.12549
  • Ritonavir‐Induced Suicidal Death of Human Erythrocytes
    • Abstract: The antiviral drug ritonavir has been shown to trigger suicidal death or apoptosis of tumour cells and has thus been considered for the treatment of malignancy. In analogy to apopotosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored whether and how ritonavir induces eryptosis. To this end, flow cytometry was employed to estimate cell volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin‐V‐binding, [Ca2+]i from Fluo3‐fluorescence, abundance of reactive oxygen species (ROS) from 2’,7’‐dichlorodihydrofluorescein diacetate (DCFDA) fluorescence and ceramide abundance utilizing specific antibodies. As a result, a 48‐hr exposure of human erythrocytes to ritonavir significantly increased the percentage of annexin‐V‐binding cells (≥ 5 μg/ml), significantly decreased forward scatter (≥ 5 μg/ml), significantly increased Fluo3‐fluorescence (20 μg/ml), slightly, but significantly increased DCFDA fluorescence (20 μg/ml) and slightly, but significantly increased ceramide abundance (20 μg/ml). The effect of ritonavir on annexin‐V‐binding was significantly blunted but not fully abolished by removal of extracellular Ca2+. In conclusion, ritonavir triggers erythrocyte shrinkage and phosphatidylserine translocation at the erythrocyte cell membrane, an effect in part due to stimulation of Ca2+ entry, oxidative stress and ceramide. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-20T02:56:33.59138-05:0
      DOI: 10.1111/bcpt.12547
  • Changes in biliary levels of arginine and its methylated derivatives after
           hepatic ischaemia/reperfusion
    • Authors: Andrea Ferrigno; Laura Giuseppina Di Pasqua, Clarissa Berardo, Vittoria Rizzo, Plinio Richelmi, Mariapia Vairetti
      Abstract: Arginine (Arg) can be methylated to form symmetrical dimethylarginine (SDMA) and asymmetrical dimethylarginine (ADMA), the latter an endogenous inhibitor of nitric oxide synthase (NOS). SDMA is excreted in the urine, while ADMA is mainly subjected to degradation in the liver. Arg competes with ADMA and SDMA for cellular transport across cationic amino‐acid transporters (CATs). We evaluated the changes in serum, tissue and biliary levels of Arg, citrulline (Cit), ADMA and SDMA and the modifications in CATs after ischaemia‐reperfusion (I/R). Male Wistar rats were subjected to 30‐min. partial‐hepatic ischaemia or sham‐operated. After 60‐min. reperfusion, the concentrations of ADMA, SDMA, Arg and Cit in serum, tissue and bile were measured. Serum levels of AST, ALT and Alkaline Phosphatase (AP) levels were determined. mRNA of cationic transporter 2A (CAT‐2A) and 2B (CAT‐2B) were also quantified. An increase in ADMA and a decrease in SDMA were observed in bile at the end of reperfusion. On the contrary, lower tissue ADMA levels and higher SDMA levels were quantified. No serum changes in ADMA and SDMA were found. A decrease in Arg and an increase of Cit were detected in serum, bile and tissue after I/R. A marked increase in AST, ALT and AP levels in serum confirmed I/R injury. A decrease in mRNA transporter CAT‐2A but not in CAT‐2B was detected. This study supported a biliary CAT‐2B–dependent transport of ADMA and demonstrated, for the first time, that the liver is also responsible for the biliary excretion of SDMA into the bile. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-20T02:51:28.394595-05:
      DOI: 10.1111/bcpt.12540
  • Reduced Mechanical Stretch Induces Enhanced Endothelin B
           Receptor‐mediated Contractility via Activation of Focal Adhesion
           Kinase and Extra Cellular‐regulated Kinase 1/2 in Cerebral Arteries
           from Rat
    • Authors: Marianne N. P. Rasmussen; Stine Spray, Gry F. Skovsted, Karin Warfvinge, Majid Sheykhzade, Lars Edvinsson
      Abstract: Cerebral ischaemia results in enhanced endothelin B (ETB) receptor‐mediated contraction and receptor protein expression in the affected cerebrovascular smooth muscle cells (SMC). Organ culture of cerebral arteries is a method to induce similar alterations in ETB receptor expression. We hypothesize that rapid and sustained reduction in wall tension/stretch is a possible trigger mechanism for this vascular remodelling. Isolated rat middle cerebral artery (MCA) segments were incubated in a wire‐myograph with or without mechanical stretch, prior to assessment of their contractile response to the selective ETB receptor agonist sarafotoxin 6c. The involvement of extracellular regulated kinase (ERK) 1/2 and focal adhesion kinase (FAK) were studied by their specific inhibitors U0126 and PF‐228, respectively. Compared to their stretched counterparts, un‐stretched MCA segments showed a significantly increased ETB receptor‐mediated contractile response following 12 hr of incubation, which was attenuated by either U0126 or PF‐228. The functionally increased ETB‐mediated contractility could be attributed to two different mechanisms: 1) a difference in ETB receptor localization from primarily endothelial expression to SMC expression and 2) an increased calcium sensitivity of the SMCs due to an increased expression of the calcium channel transient receptor potential canonical 1. Collectively, our results present a possible mechanism linking lack of vessel wall stretch/tension to changes in ETB receptor‐mediated contractility via triggering of an early mechanosensitive signalling pathway involving ERK1/2 and FAK signalling. A mechanism likely to be an initiating factor for the increased ETB receptor‐mediated contractility found after cerebral ischaemia. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-19T01:34:30.983787-05:
      DOI: 10.1111/bcpt.12553
  • Efficacy and Safety of FospropofolFD Compared to Propofol When Given
           During the Induction of General Anaesthesia: A Phase II, Multicenter,
           Randomized, Parallel‐Group, Active‐Controlled,
           Double‐Blind, Double‐Dummy Study
    • Authors: Rong Liu; Chaozhi Luo, Jin Liu, Wensheng Zhang, Yan Li, Jing Xu
      Abstract: The present phase II study aimed to compare the efficacy and safety of fospropofol disodium for injection (FospropofolFD) and propofol when given during the induction of general anaesthesia in patients scheduled for elective surgery. FospropofolFD is a water‐soluble prodrug of propofol. Approved by the Ethical Committee, 240 participants aged 18–65 years were equally randomly allocated to receive an intravenous bolus of FospropofolFD 20 mg/kg or propofol 2 mg/kg without any anaesthetic pre‐treatment. The primary efficacy end‐point was the sedation success rate within 5 min. after administering investigational drugs (the sedation success is defined as obtaining Modified Observer's Assessment of Alertness/Sedation scale score of 1). All the participants completed the induction and intubation within 25 min. after administration. The sedation success rates within 5 min. after administration of FospropofolFD 20 mg/kg and propofol 2 mg/kg were 94.50% versus 100% in the intention‐to‐treat population and 95.10% versus 100% in the per‐protocol population, respectively. The non‐inferiority test obtained a P value less than 0.025, and the lower limits of the one‐sided 97.5% confidence interval were more than –0.09. This meant that FospropofolFD 20 mg/kg was considered non‐inferior to propofol 2 mg/kg for the primary efficacy end‐point. Compared with propofol 2 mg/kg, FospropofolFD 20 mg/kg had a slower sedation efficacy. No serious adverse events were observed in the two groups. The sedation success rate within 5 min. after administration of FospropofolFD 20 mg/kg was non‐inferior to propofol 2 mg/kg, and FospropofolFD 20 mg/kg can be used for the induction of general anaesthesia safely. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-19T01:29:22.572482-05:
      DOI: 10.1111/bcpt.12552
  • Impact of Olmesartan Medoxomil on Amiodarone‐ Induced Pulmonary
           Toxicity in Rats: Focus on Transforming Growth
    • Abstract: Amiodarone (AD) is one of the most frequently prescribed antiarrhythmic agents worldwide but its effectiveness is limited due to the development of pulmonary toxicity. Several lines of evidence have suggested that AT1 receptor antagonists can attenuate pulmonary fibrosis in different animal models. This study was performed to evaluate the effect of olmesartan medoxomil (OM) on lung injury induced in rats by AD which was assessed biochemically (hydroxyproline content, MDA level and SOD activity), histologically (Ashcroft criteria and Masson's trichrome stain) and immunohistochemically (TGF‐β1 expression in lung tissue). The expression levels of TGF‐β1 and type I collagen mRNA were also determined by quantitative real‐time polymerase chain reaction. Forty‐eight adult male rats were randomized into six equal groups; control group, OM control groups, AD group received 40 mg/kg/day, p.o. for four weeks to induce pulmonary injury in rats and OM‐treated groups received 0.6 and 6 mg/kg/day, p.o. concomitantly with AD for the same period. The results indicated that OM significantly decreased collagen deposition and hydroxyproline content, ameliorated pathological score and decreased the elevation in type I collagen and TGF‐ß1 mRNA expression in lung tissue. Furthermore, it attenuated the AD‐induced increase in the MDA level and increased SOD activity in lung tissue. It can be concluded that OM exerts a protective effect against AD‐induced lung damage in rats which is attributed to modulation of profibrogenic cytokine (TGF‐β1) and antioxidant effect. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-18T21:22:58.791657-05:
      DOI: 10.1111/bcpt.12551
  • Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic
           Inflammatory Pain in Mice
    • Abstract: Chemokines are chemotactic cytokines whose involvement in nociceptive processing is being increasingly recognised. Based on the previous description of the involvement of CC chemokine receptor type 1 (CCR1) in pathological pain, we have assessed the participation of CCR1 and its endogenous ligands CCL3 and CCL5 in hyperalgesia and allodynia in mice following acute inflammation with carrageenan and chronic inflammation with complete Freund's adjuvant (CFA). The subcutaneous administration of the CCR1 antagonist J113863 (3‐30 mg/kg; 30 min. before) dose‐dependently inhibited carrageenan‐ and CFA‐evoked thermal hyperalgesia and mechanical allodynia produced by CFA but not by carrageenan. The maximal dose of J113863 did not modify the increase in paw thickness induced by carrageenan or CFA. An almost ten‐fold augmentation of CCL3 levels was detected by ELISA assays in following both carrageenan and CFA paws but not in spinal cords of inflamed mice, whereas CCL5 concentrations remained unaltered. Accordingly, a marked increase of CCL3 mRNA expression was observed in inflamed paws, with CCL3 protein detected in neutrophils and macrophages by immunohistochemical experiments. The intraplantar administration of an anti‐CCL3 antibody (0.3‐3 μg) blocked thermal hyperalgesia in carrageenan‐ and CFA‐inflamed mice as well as CFA‐evoked mechanical allodynia. Our data suggest that the increased concentrations of CCL3 present in inflamed tissues can be involved in acute and chronic inflammatory hyperalgesia as well as in chronic mechanical allodynia, and that these hypernociceptive symptoms can be counteracted by its neutralization with an antibody or by the blockade of CCR1 receptors. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:40:37.416653-05:
      DOI: 10.1111/bcpt.12543
  • Antidepressant or Antipsychotic Overdose in the Intensive Care Unit
           ‐ Identification of Patients at Risk
    • Abstract: It is often advised that patients who have ingested an overdose of antidepressants (AD) or antipsychotics (AP) are monitored with continuous ECG for minimum of 12‐24 hr. These patients are often observed in an ICU. Our aim was to identify the number of patients with AD and/or AP overdose without adverse signs at hospital admission that turned out to need intensive care treatment. The effect of the antidepressants overdose risk assessment (ADORA) system was evaluated in patients with antidepressant as well as antipsychotic overdose. Our hypothesis was that patients with low ADORA do not need intensive care treatment. This retrospective study was conducted in adult patients admitted to the ICU at Odense University Hospital after an overdose with AP and/or AD between 1 January 2009 and 1 September 2014. Patients with predefined adverse signs in the emergency department were excluded due to obvious need of intensive care. Of the 157 patients included, 12 patients (8%) developed events during the ICU stay. Only 3 patients received intubation, vasoactive drugs and/or dialysis. None developed ventricular dysrhythmias. There were no fatalities. All the patients with low‐risk assessment by ADORA within the first 6 hr did not develop events within the first 24 hr after hospital admission. The vast majority of patients with AD and/or AP overdose and no adverse signs at admission did not require intensive care treatment. Low ADORA risk assessment identified patients with antidepressant as well as antipsychotic overdose who would not require initial intensive care treatment. This is the first time the ADORA system has been evaluated in patients with antidepressant as well as antipsychotic overdose. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:26:57.747019-05:
      DOI: 10.1111/bcpt.12541
  • Role of Aspirin and Dexamethasone against Experimentally Induced
           Depression in Rats
    • Authors: Shailendra Bhatt; Priyanka Shukla, Jibril Raval, Sunita Goswami
      Abstract: A large number of current studies indicate that inflammatory mediators may contribute to depression in experimental models as well as in human beings. Nevertheless, the subject, whether anti‐inflammatory treatments can prevent depression still remains controversial. In the present study, a chronic mild stress (CMS) model of male Sprague–Dawley rats was used to investigate the role of anti‐inflammatory drugs in the treatment of depression. All the animals in different groups, except the normal control group, were exposed to CMS procedure for 28 days and concurrently treated with aspirin (10 mg/kg, p.o.) dexamethasone (1mg/kg p.o.) and amitriptyline (10 mg/kg p.o., reference standard), respectively. Amitriptyline was also used in combination with aspirin and dexamethasone to inspect any synergistic effects. Tests performed towards the end of the study included Sucrose preference test, behavioural tests like forced swim test, elevated plus maze, light dark box, locomotor activity, and biochemical estimations like serum cortisol and brain neurotransmitters. Disease control group (CMS‐treated) produced significant depressive behaviour in rats. The animals treated with aspirin showed increased sucrose preference, decreased immobility time in forced swim test, decreased serum cortisol and increased brain serotonin levels signifying antidepressant action. In contrast, there was aggravation of depressive behaviour in rats treated with dexamethasone. Together, these findings suggest that aspirin can serve as a potential antidepressant both individually and as adjunctive agent in the treatment of depression. Inhibition of the inflammatory mediators during stress procedures or any other potential physiological and biochemical mechanisms may be involved in its antidepressant effect. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:16:26.965025-05:
      DOI: 10.1111/bcpt.12539
  • Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats
    • Authors: Mohamed A. Morsy; Gehan H. Heeba
      Abstract: Treatment with cisplatin is associated with dose‐limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β1‐adrenoceptor antagonist, exhibits vasodilatory and anti‐oxidative properties. The present study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as evidenced by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor‐alpha, caspase‐3, angiotensin II, and endothelin‐1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre‐treatment with Nω‐nitro‐L‐arginine methyl ester, the non‐specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin‐induced nephrotoxicity that is most likely through its antioxidant, anti‐inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin‐1 levels. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:02:10.143578-05:
      DOI: 10.1111/bcpt.12538
  • Effect of Statin Treatment on Plasma 4β‐Hydroxycholesterol
    • Abstract: The endogenous oxysterol 4β‐hydroxycholesterol may be used as a marker for the drug‐metabolizing enzymes cytochrome P450 3A (CYP3A). The primary aim of this study was to investigate the effect of statin treatment on plasma 4β‐hydroxycholesterol concentrations. Plasma samples from a previously performed clinical study where gallstone patients had been treated with placebo (n=6), 20 mg fluvastatin (n=9) or 80 mg atorvastatin (n=9) daily for 4 weeks were analysed. Hepatic CYP3A mRNA levels had previously been shown to be unchanged in all three treatment groups. Plasma 4β‐hydroxycholesterol did not change significantly (p=0.92) in the placebo group, but treatment with low‐dose fluvastatin or high‐dose atorvastatin resulted in reductions in plasma concentration of 10.7% (p
      PubDate: 2016-01-14T22:49:43.49538-05:0
      DOI: 10.1111/bcpt.12537
  • Effect of omeprazole and dextromethorphan on the urinary metabolic ratio
           of flurbiprofen
    • Abstract: Interindividual differences in drug response ‐ especially due to drug metabolism ‐ are among the most important reasons for severe adverse drug reactions (ADR) in patients. About 80% of drugs causing clinically relevant ADR are metabolized by polymorphic enzymes [1]. The most important human enzymes for oxidative drug metabolism belong to the cytochrome P450 (CYP) monooxygenase superfamily. Several CYP possess high levels of genetic polymorphism and can be induced or inhibited, thereby causing pronounced differences in interindividual enzyme activity and drug response. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:43:09.279088-05:
      DOI: 10.1111/bcpt.12536
  • Modelling of the Sedative Effects of Propofol in Patients undergoing
           Spinal Anaesthesia: A Pharmacodynamic Analysis
    • Authors: Go Un Roh; Youngsoon Kim, Sang Hee Ha, Kyu Hee Jeong, Sumin Choi, Dong Woo Han
      Abstract: Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect‐site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect‐site target‐controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3‐4] and deep sedation (OAA/S scores of 1‐2) were developed using Nonlinear Mixed Effects Modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce50 values for adequate and deep sedation were 0.94 and 1.52 μg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (P=0.0003). The simulated Ce50 values for adequate sedation in 20‐year‐old patients with a T12 sensory level and in 80‐year‐old patients with a T4 level were 1.63 and 0.53 μg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:30:48.794887-05:
      DOI: 10.1111/bcpt.12535
  • MicroRNAs in Bladder Outlet Obstruction: Relationship to Growth and Matrix
    • Abstract: The discovery of microRNAs (miRNAs), which are ~22 nucleotide RNAs that inhibit protein synthesis in a sequence‐specific manner and are present in a range of species, has born hope of new therapeutic strategies. miRNAs play important roles in development “Development” of what''and disease, but they remain poorly studied in uropathologies beyond cancer. Here, we discuss biological functions of miRNAs in the lower urogenital tract. A special focus is on miRNAs that change in bladder outlet obstruction (BOO). This is a condition that affects nearly one third of all men over 60 years and that involves growth and fibrosis of the urinary bladder. Animal models of BOO, such as that in rat, have been developed and they feature a massive 6‐fold bladder growth over 6 weeks. Using microarrays, we have charted the miRNAs that change during the time‐course of this process and identified several with important modulatory roles. We discuss known and predicted functions of miR‐1, miR‐29, miR‐30, miR‐132/212, miR‐204 and miR‐221, all of which change in BOO. The majority of the miRNA‐mediated influences in BOO are expected to favour growth. We also outline evidence that miR‐29 represents a key effector molecule in a generic response to mechanical distension that is designed to counteract exaggerated organ deformation via effects on matrix deposition and stiffness. We conclude that miRNAs play important roles in bladder remodelling and growth and that they may be targeted pharmacologically to combat diseases of the lower urinary tract. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:12:24.671191-05:
      DOI: 10.1111/bcpt.12534
  • Sulfated Polysaccharide Isolated from the Seaweed Gracilaria caudata
           Exerts an Antidiarrhoeal Effect in Rodents
    • Abstract: Diarrhoea is a significant health problem for children in developing countries that causes more than 1 million deaths annually. The present study aimed to evaluate the antidiarrhoeal effect of sulfated polysaccharide (PLS) from the alga Gracilaria caudata in rodents. For the evaluation, acute diarrhoea was induced in Wistar rats (150–200 g) by administration of castor oil (10 mg/kg). Then, different parameters, including enteropooling and gastrointestinal transit and its pharmacological modulation by opioid and cholinergic pathways were assessed using activated charcoal in Swiss Mice (25–30 g). Secretory diarrhoea was examined using cholera toxin (1 mg/loop)‐treated, isolated intestinal loops from Swiss mice (25–30 g), which were also used to examine fluid secretion, loss of chloride ions into the intestinal lumen, and absorption. In addition, a GM1‐dependent ELISA was used to evaluate the interaction between PLS, cholera toxin and the GM1 receptor. Pre‐treatment with PLS (10, 30, and 90 mg/kg) reduced foecal mass, diarrhoeal faeces and enteropooling. However, 90 mg/kg more effectively reduced these symptoms; therefore, it was used as the standard dose in subsequent experiments. Gastrointestinal transit was also reduced by PLS treatment via a cholinergic mechanism. Regarding the diarrhoea caused by cholera toxin, PLS reduced all study parameters, and the ELISA showed that PLS can interact with both the GM1 receptor and cholera toxin. These results show that PLS from G. caudata effectively improved the parameters observed in acute and secretory diarrhoea, which affects millions of people, and may lead to the development of a new alternative therapy for this disease. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:10:04.477163-05:
      DOI: 10.1111/bcpt.12531
  • Structural Studies of Nicotinic Acetylcholine Receptors: Using
           Acetylcholine Binding Protein as a Structural Surrogate
    • Authors: Azadeh Shahsavar; Michael Gajhede, Jette S. Kastrup, Thomas Balle
      Abstract: Nicotinic acetylcholine receptors (nAChRs) are members of the pentameric ligand‐gated ion channel superfamily that play important roles in control of neurotransmitter release in the central and peripheral nervous system. These receptors are important therapeutic targets for development of drugs against a number of mental health disorders and for marketed smoking cessation aids. Unfortunately, drug discovery has been hampered by difficulties in obtaining sufficiently selective compounds. Together with functional complexity of the receptors, this has made it difficult to obtain drugs with sufficiently high‐target to off‐target affinity ratios. The recent and on‐going progress in structural studies holds promise to help understand structure‐function relationships of nAChR drugs at the atomic level. This will undoubtedly lead to design of more efficient drugs with fewer side effects. As a high‐resolution structure of a nAChR is yet to be determined, structural studies are to a large extent based on acetylcholine binding proteins (AChBPs) that despite low overall sequence identity display high degree of conservation of overall structure and amino acids at the ligand‐binding site. Further, AChBPs reproduce relative binding affinities of ligands at nAChRs. Over the past decade, AChBPs have been used extensively as models for nAChRs and have aided the understanding of drug receptor interactions at nAChRs significantly. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T05:49:29.058086-05:
      DOI: 10.1111/bcpt.12528
  • Variability of Voriconazole Trough Levels in Haematological Patients:
           Influence of Co‐Medications with CYP Inhibitors and/or with CYP
           Inhibitors plus CYP Inducers
    • Authors: Piergiorgio Cojutti; Anna Candoni, Fabio Forghieri, Miriam Isola, Maria Elena Zannier, Sara Bigliardi, Mario Luppi, Renato Fanin, Federico Pea
      Abstract: Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of co‐medications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough levels (Cmin). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed‐effect regression analyses were performed to identify independent predictors of normalized Cmin. Among the 83 included patients, 35 had co‐medication with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin (n=199) was 2.4 mg/L with a wide range of distribution (< 0.2‐13.5 mg/L). Median (IQR) normalized voriconazole Cmin was significantly higher in presence of CYP inhibitors (4.20 mg/L, 3.23–5.51 mg/L) than either in absence of interacting co‐treatments (2.55 mg/L, 1.54–3.47 mg/L) or in presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19–3.09 mg/L). Presence of CYP inhibitors resulted highly significantly associated with Cmin > 5.5 mg/L (OR: 23.22, 95% CI: 3.01–179.09, P=0.003). No significant association emerged when CYP inhibitors were co‐administered with CYP inducers (OR: 3.53, 95% CI: 0.36–34.95, P=0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are co‐treated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T04:29:15.011925-05:
      DOI: 10.1111/bcpt.12530
  • Cardiovascular Drugs and Metformin Drug Dosage According to Renal Function
           in Non‐Institutionalized Elderly Patients
    • Abstract: Background Adaptation of drug dosage to kidney function is a common problem in general practice. Aim To describe adaptation of cardiovascular drugs and metformin according to renal function and its association with mortality with regard to metformin in a cohort of elderly patients. Design and Setting Ancillary study to the S.AGES cohort made up of patients over 65 years old managed by their general practitioner under real‐life conditions and followed up prospectively for 3 years. Methods The medications studied were digoxin, spironolactone and metformin. Adaptation of their daily dose according to renal function (eGFR according to CKD/EPI) was compared to that recommended in the summaries of product characteristics (SPCs) or international scientific societies (ISS). Results 900 patients were included, including 588 on metformin. At baseline, dose adjustment according to renal function was 100% and 87.6% (95%CI:82.6‐92.6) for patients on digoxin and spironolactone, respectively. For metformin, only 71.3% (95%CI:67.6‐74.9) or 78.1% (95%CI:74.7‐81.4) of patients had their dosage adapted at inclusion according to their renal function depending on whether the SPCs or ISS recommendations were considered. During the 3 year follow‐up period, 42/588 patients died (none from lactic acidosis). At inclusion, a metformin dosage not adapted for renal function according to ISS was not associated with an increase in all cause mortality (OR 1.7; 95%CI 0.6‐5.0, p=0.32). Conclusion Approximately one quarter of elderly patients treated with metformin do not have their dosage adapted for renal function according to ISS although there is no increase in mortality after follow‐up for 3 years. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:46:44.809687-05:
      DOI: 10.1111/bcpt.12526
  • Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse
           Intrauterine Environment and Modulated by a Post‐Weaning
           High‐Fat Diet
    • Authors: Barent N. DuBois; Jacob Pearson, Tahir Mahmood, Kent Thornburg, Ganesh Cherala
      Abstract: Adult individuals born with intrauterine growth restriction (IUGR) have physiological maladaptations that significantly increase risk of chronic disease. We hypothesized that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low protein diet (9% protein) to produce IUGR offspring. Offspring were weaned onto either laboratory chow (11% fat) or high‐fat diet (45% fat). Adult offspring (5 months old) were dosed with furosemide (10 mg/kg i.p.) and serum and urine collected. The overall exposure profile in IUGR males was significantly reduced due to a ~35% increase in both clearance and volume of distribution. Females appeared resistant to the IUGR phenotype. The effects of the high‐fat diet trended in the opposite direction to that of IUGR, with increased drug exposure due to decreases in both clearance (31% males, 46% females) and volume of distribution (24% males, 44% females), with a 10% longer half‐life in both genders. The alterations in furosemide pharmacokinetics and pharmacodynamics were explained by changes in the expression of renal organic anion transporters‐1 and ‐3, and sodium‐potassium‐chloride cotransporter‐2. In summary, this study suggests that IUGR and diet interact to produce sub‐populations with similar body weights but dissimilar pharmacokinetic profiles; this underlines the limitation of one‐size‐fits‐all dosing which does not account for physiological differences in body composition resulting from IUGR and diet. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:25:09.926587-05:
      DOI: 10.1111/bcpt.12523
  • Effect of the combination of ezetimibe and simvastatin on gluconeogenesis
           and oxygen consumption in the rat liver
    • Abstract: The aim of this work was to investigate the effects of chronic treatment with the combination ezetimibe/simvastatin on gluconeogenesis in rat liver. Rats were treated daily with the combination ezetimibe/simvastatin (10/40 mg/Kg) by oral gavage. To measure gluconeogenesis and the associated pathways, isolated perfused rat liver was used. In addition, subcellular fractions, such as microsomes and mitochondria, were used for complementary measures of enzymatic activities. Treatment with the combination simvastatin/ezetimibe resulted in a decrease of gluconeogenesis from pyruvate (‐62%). Basal oxygen consumption of the treated animals was higher (+22%) than the control rats, but the resulting oxygen consumption that occurred after pyruvate infusion was 43% lower in animals treated with the combination simvastatin/ezetimibe. Oxygen consumption in the livers from treated animals was completely inhibited by cyanide (electron transport chain inhibitor), but not by proadifen (cytochrome P450 inhibitor). Chronic treatment with ezetimibe/simvastatin decreased the activity of the key enzymes glucose‐6‐phosphatase and fructose‐1,6‐bisphosphatase by 59% and 45%, respectively, which is probably the major reason for the decreased gluconeogenesis seen in ezetimibe/simvastatin‐treated rats. It is also possible that part of the effect of this combination on gluconeogenesis and on the oxygen consumption is related to the impairment of mitochondrial energy transduction. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:10:11.399441-05:
      DOI: 10.1111/bcpt.12522
  • Evidence of Different Propofol Pharmacokinetics under Short and Prolonged
           Infusion Times in Rabbits
    • Abstract: Propofol is an anaesthetic widely used both in human beings and animals. However, the characterization of propofol pharmacokinetics (PK) is not well understood when long‐term infusions are used. The main objective of this study was to explore the pharmacokinetic behaviour of propofol in a rabbit model during short and prolonged propofol infusions and to develop an internally validated PK model, for propofol dose individualization in the rabbit for future use. Population 1 (P1) was constituted by seven New Zealand rabbits and was used to characterize the pharmacokinetic profile of propofol at short infusions. Animals were anaesthetized with a bolus of 20−1, followed by an infusion rate of 50−1.h−1 of propofol at 1%, which was then maintained for 30 min. A second rabbit population (P2, n=7) was sedated according to reflexes responses and Index of Consciousness values, for 20 consecutive hours using propofol 2% aiming at characterizing propofol behaviour at long‐term infusions. Clinical data and blood samples were collected at specific time‐points in both populations. Propofol plasma concentrations were determined by GC/IT‐MS1. The NONMEM VII software was used to evaluate the relationships between dose and plasma concentrations. A linear two‐compartment model with different central compartment volume and plasma clearance (separately modelled in the two populations) was the one that best described propofol concentrations. The time course of propofol plasma concentrations was well characterized by the PK model developed, which simultaneously accounts for propofol short‐ and long‐term infusions and can be used to optimize future PK studies in rabbits. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T02:02:39.298437-05:
      DOI: 10.1111/bcpt.12521
  • Sydnone 1: A Mesoionic Compound with Anti‐tumoural and Hematological
           Effects In Vivo
    • Abstract: The present study evaluated the anti‐tumour activity of the mesoionic compound sydnone 1 (Syd‐1) against Walker‐256 carcinosarcoma. Tumour cells were subcutaneously inoculated in the hind limb in male Wistar rats. The animals were orally treated for 12 days with Syd‐1 (75 mg•kg−1) or vehicle. At the end of treatment, considerable decreases in tumour volume and tumour weight were observed in treated animals. Samples of these tumours presented increases in apoptotic bodies and pro‐apoptotic protein expression (Bax and p53), while the expression of the anti‐apoptotic protein Bcl‐2 was reduced. A decrease in reduced glutathione levels and an increase in glutathione peroxidase activity were observed in tumour after Syd‐1 treatment. However, significant splenomegaly was evident in animals that received Syd‐1, most likely attributable to the induction of hemolysis. The present study demonstrated the anti‐tumour activity of Syd‐1 against Walker‐256 carcinosarcoma. Its mechanism of action is linked to the activation of apoptotic pathways that lead to tumour cell death. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-26T08:31:45.161482-05:
      DOI: 10.1111/bcpt.12545
  • Mechanisms Involved in Thromboxane A2‐induced Vasoconstriction of
           Rat Intracavernous Small Penile Arteries
    • Abstract: Diabetes is associated with erectile dysfunction and with hypercontractility in erectile tissue and this is in part ascribed to increased formation of thromboxane. Rho kinase (ROCK) is a key regulator of calcium sensitization and contraction in vascular smooth muscle. This study investigated the role of calcium and ROCK in contraction evoked by activation of the thromboxane receptors. Rat intracavernous penile arteries were mounted for isometric tension and intracellular calcium ([Ca2+]i) recording and corpus cavernosum for measurements of MYPT1 phosphorylation. In penile arteries, U46619 by activation of thromboxane receptors concentration‐dependently increased calcium and contraction. U46619‐induced calcium influx was blocked by nifedipine, a blocker of L‐type calcium channels, and by 2‐aminoethoxydiphenyl borate, a blocker of transient receptor potential (TRP) channels. Inhibitors of ROCK, Y27632 and glycyl‐H1152P, concentration‐dependently reduced U46619‐induced contraction, but only Y27632 reduced [Ca2+]i‐levels in the penile arteries activated with either high extracellular potassium or U46619. MYPT‐Thr850 phosphorylation in corpus cavernous strips was increased in response to U46619 through activation of TP receptors and was found to be a direct result of phosphorylation by ROCK. Y27632 induced less relaxation in mesenteric arteries, H1152P induced equipotent relaxations, and a protein kinase C inhibitor, Ro‐318220, failed to relax intracavernous penile arteries, but induced full relaxation in rat mesenteric arteries. Our findings suggest that U46619 contraction depends on Ca2+ influx through L‐type and TRP channels, and ROCK‐dependent mechanisms in penile arteries. Inhibition of the ROCK pathway is a potential approach for the treatment of erectile dysfunction associated with hypertension and diabetes. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-26T08:31:32.570507-05:
      DOI: 10.1111/bcpt.12544
  • Systematic Review and Meta‐Analysis: Macrolides and
           Amoxicillin/Clavulanate‐induced Acute Liver Injury
    • Abstract: Antibacterials are frequently associated with idiosyncratic drug‐induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta‐analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials. gov, Livertox and Toxline (1980‐2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non‐user comparator. We summarised the evidence with a random‐effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case‐control, one cohort and one case‐population studies) and 9 (case‐population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 (95% Confidence Interval [CI] 1.81‐4.47), p
      PubDate: 2015-12-26T08:31:20.834261-05:
      DOI: 10.1111/bcpt.12550
  • Varenicline and Nicotine Patch Therapies in Young Adults Motivated to Quit
           Smoking: A Randomised, Placebo‐controlled, Prospective Study
    • Authors: Anna Tuisku; Merita Salmela, Pentti Nieminen, Tuula Toljamo
      Abstract: This study compares the nicotine patch to placebo in young adult light smokers, and the nicotine patch to varenicline in heavy smokers. Volunteer daily smokers were recruited into a randomised, placebo‐controlled study via community media, colleges and the army (aged 18 to 26 years). Those subjects with light tobacco dependence were randomised to 1) placebo patch (n=86) and 2) nicotine patch 10 mg/16 hr for 8 weeks (n=94), and those with stronger dependence to 3) nicotine patch 15 mg/16 hr for 8 weeks (n=51) and 4) varenicline for 12 weeks (n=60). The primary outcome variable was self‐reported smoking abstinence at week 12. Secondary outcome variables were self‐reported smoking abstinence at weeks 4 and 26, and self‐reported abstinence verified by saliva cotinine level at week 12. The prevalence of self‐reported smoking abstinence did not differ statistically significantly in light smokers during the follow‐up (week 4: 19.8% for placebo patch and 26.6% for nicotine patch 10 mg/16 hr; week 12: 17.4% versus 23.4%; week 26: 15.1% versus 20.2%), but the groups of heavy smokers differed significantly for 12 weeks (week 4: 19.6% for nicotine patch 15 mg/16 hr and 73.3% for varenicline, p
      PubDate: 2015-12-26T08:21:31.600831-05:
      DOI: 10.1111/bcpt.12548
  • Physiology and Pharmacology of Ejaculation
    • Abstract: Ejaculation is the final stage of coitus in mammalian male and is mandatory for natural procreation. Two synchronized phases, emission and expulsion, form the ejaculatory response and involve specific organs and anatomical structures. The peripheral events leading to ejaculation are commanded by autonomic (sympathetic and parasympathetic) and somatic divisions of the nervous system. The autonomic and somatic motor efferents originate in spinal nuclei located in thoracolumbar and lumbosacral segments. Coordinated activation of autonomic and somatic spinal nuclei is orchestrated by a group of lumbar spinal interneurons defined as the spinal generator of ejaculation. The generator of ejaculation together with the autonomic and somatic spinal nuclei constitute a spinal network that is under the strong influence of stimulating or inhibiting genital sensory and supraspinal inputs. A brain circuitry dedicated to ejaculation has been delineated that is part of a more global network controlling other aspects of the sexual response. This circuitry includes discrete neuronal populations distributed in all divisions of the brain. The corollary to the expanded CNS network is the variety of neurotransmitter systems participating to the ejaculatory process. Among them, serotonin neurotransmission plays a key role and its targeting led to the development of the first registered pharmacological treatment of premature ejaculation in human beings. Critical gaps remain in the understanding of neurophysiopharmacology of ejaculation and management of ejaculatory disorders in human beings needs improvement. Because the ejaculatory response in laboratory animals and in human beings share many similarities, the use of animal models will certainly provide further advances in the field. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-26T08:21:10.176586-05:
      DOI: 10.1111/bcpt.12546
  • New 1,4‐Dihydropyridines Down‐regulate Nitric Oxide in Animals
           with Streptozotocin‐induced Diabetes Mellitus and Protect DNA
           against Peroxynitrite Action
    • Abstract: Diabetes mellitus (DM) and its complications cause numerous health and social problems throughout the world. Pathogenic actions of nitric oxide (NO) are responsible to a large extent for development of complications of DM. Search for compounds regulating NO production in DM patients is thus important for the development of pharmacological drugs. Dihydropyridines (1,4‐DHPs) are prospective compounds from this point of view. The goals of the present work were to study the in vivo effects of new DHPs on NO and reactive nitrogen and oxygen species production in a streptozotocin (STZ) ‐induced model of DM in rats and to study their ability to protect DNA against nocive action of peroxynitrite. STZ‐induced diabetes caused an increase of NO production in the liver, kidneys, blood and muscles, but by a decrease of NO in adipose tissue of STZ‐treated animals. Cerebrocrast treatment was followed by normalization of NO production in the liver, kidneys and blood. Two other DHPs, etaftorone and fenoftorone, were effective in decreasing NO production in kidneys, blood and muscles of diabetic animals. Furthermore, inhibitors of nitric oxide synthase (NOS) and an inhibitor of xanthine oxidoreductase (XOR) decreased NO production in kidneys of diabetic animals. Treatment with etaftorone decreased expression of inducible NOS and XOR in kidneys whereas it increased the expression of endothelial NOS. In vitro, the studied DHPs did not significantly inhibit the activities of NOS and XOR but affected the reactivity of peroxynitrite with DNA. These new DHPs thus appear of strong interest for treatment of DM complications. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-12T14:11:36.137923-05:
      DOI: 10.1111/bcpt.12542
  • Response to: Adverse Events Associated with Flumazenil Treatment for the
           Management of Suspected Benzodiazepine Intoxication ‐ A Systematic
           Review with Meta‐Analyses of Randomized Trials
    • PubDate: 2015-11-03T01:20:52.120292-05:
      DOI: 10.1111/bcpt.12498
  • The Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety
           and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator
    • Abstract: Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent for auto‒immune disorders. The impact of hepatic or renal impairment on the pharmacokinetics, safety and tolerability of ponesimod and its inactive metabolites, ACT‒204426 and ACT‒338375, was evaluated. Two separate single‒centre, open‒label studies with 32 (hepatic study) and 24 (renal study) male and female subjects were conducted. Hepatic impairment was based on the Child–Pugh classification and renal impairment was determined by creatinine clearance using the Cockcroft–Gault equation. Subjects with severe hepatic or renal impairment were to be matched (sex and body mass index) with healthy subjects. All subjects received a single dose of 10 mg ponesimod. For ponesimod, the ratio of geometric means of AUC0‒∞ for subjects with severe hepatic impairment versus healthy subjects was 3.07 (90% CI: 2.19, 4.32). For severely renally impaired subjects versus healthy subjects, this ratio was 1.14 (0.82, 1.58). Cmax and tmax values of ponesimod were comparable across all groups in both studies. Exposure to metabolites was increased in subjects with moderate or severe hepatic impairment as compared to healthy subjects. During the course of these studies, there were no clinically relevant abnormalities related to vital signs, 12‒lead electrocardiograms and clinical laboratory values. Sixteen adverse events (AEs) were reported, 12 of them of mild intensity. No AEs were considered to be treatment‒related. Overall, ponesimod was well tolerated. In subjects with renal function impairment, dose adjustment is not warranted, whereas the dose should be reduced in subjects with moderate and severe hepatic impairment. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-03T00:28:32.122303-05:
      DOI: 10.1111/bcpt.12516
  • Pharmacokinetics of the Experimental Non‐Nucleosidic DNA Methyl
           Transferase Inhibitor N‐Phthalyl‐L‐Tryptophan
           (RG 108) in Rats
    • Abstract: DNA methyl transferase (DNMT) inhibitors can re‐establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non‐nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non‐specific DNMT inhibitor N‐phthalyl‐L‐tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr post injection and RG 108 in plasma was measured by high‐performance liquid chromatography coupled to mass spectrometry. Trough levels and AUC were significantly higher with multiple dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (tmax, mean±SD) was 37.5±15 min, terminal plasma half‐life was approximately 3.7 hr (60% CI: 2.1 – 15.6 h), maximal plasma concentration (Cmax) 61.3±7.6 μM and area under the curve was 200±54 μmol*h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple dose administration regimens. Maximal tissue levels (Cmax in μmol/kg) were 6.9±6.7, 1.6±0.4 and 3.4±1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 μM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-02T23:52:44.74041-05:0
      DOI: 10.1111/bcpt.12514
  • A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of
           Vortioxetine in Patients with Major Depressive Disorder
    • Authors: Himanshu Naik; Serena Chan, Majid Vakilynejad, Grace Chen, Henrik Loft, Atul R. Mahableshwarkar, Johan Areberg
      Abstract: Vortioxetine is approved for treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure–response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and 2 generalised anxiety disorder studies of vortioxetine (3160 patients), and efficacy data (Montgomery‐Åsberg Depression Rating Scale [MADRS]) from 7 MDD studies (2537 patients), were used for development of PK and PK/Efficacy models. One‐ and two‐compartment models were evaluated as structural PK models, and linear and non‐linear (Emax) models were used to describe the relationship between average vortioxetine concentration at steady state (Cav) and change in MADRS score from baseline (ΔMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterised by a two‐compartment model with first‐order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/h and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F but the effect of each of these covariates was not considered clinically relevant, as they lead to ±26% change in area under the curve (AUC) or Cmax of vortioxetine. An Emax model best described the relationship between ΔMADRS and Cav. Half maximal effective concentration (EC50) and Emax estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterised the vortioxetine exposure–response relationship. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-02T23:52:36.230514-05:
      DOI: 10.1111/bcpt.12513
  • The Inhibitory Effect of Ciprofloxacin on the
           β‐Glucuronidase‐mediated Deconjugation of the Irinotecan
           Metabolite SN‐38‐G
    • Authors: Takaaki Kodawara; Takashi Higashi, Yutaka Negoro, Yukio Kamitani, Toshiaki Igarashi, Kyohei Watanabe, Hitoshi Tsukamoto, Ryoichi Yano, Mikio Masada, Hiromichi Iwasaki, Toshiaki Nakamura
      Abstract: The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. β‐Glucuronidase, an intestinal bacteria‐produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide‐conjugated drugs. In this study, we established an in vitro system to evaluate the β‐glucuronidase‐mediated deconjugation of the irinotecan metabolite SN‐38‐G to its active SN‐38 form and the effect of ciprofloxacin thereon. SN‐38 formation increased in a time‐dependent manner from 5 to 30 min. in the presence of β‐glucuronidase. Ciprofloxacin and phenolphthalein‐β‐d‐glucuronide (PhePG), a typical β‐glucuronidase substrate, significantly decreased SN‐38‐G deconjugation and, hence, SN‐38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN‐38‐G to SN‐38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose‐dependent inhibitory effect on the β‐glucuronidase‐mediated conversion of SN‐38‐G to SN‐38 with a half‐maximal inhibitory concentration (IC50) value of 83.8 μM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non‐competitive manner, respectively. These findings suggest that the reduction in the serum SN‐38 concentration following co‐administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN‐38 through the non‐competitive inhibition of intestinal β‐glucuronidase‐mediated SN‐38‐G deconjugation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-30T22:38:08.083807-05:
      DOI: 10.1111/bcpt.12511
  • Effect of Iron and Carbon Monoxide on Fibrinogenase‐like Degradation
           of Plasmatic Coagulation by Venoms of Six Agkistrodon Species
    • Authors: Vance G. Nielsen; Daniel T. Redford, Patrick K. Boyle
      Abstract: Annually, thousands suffer poisonous snake bite, often from defibrinogenating species. It has been demonstrated that iron and carbon monoxide change the ultrastructure of plasma thrombi and improve coagulation kinetics. Thus, the present investigation sought to determine if pre‐treatment of plasma with iron and carbon monoxide could attenuate venom‐mediated catalysis of fibrinogen obtained from Agkistrodon species with fibrinogenase activity. Human plasma was pre‐treated with ferric chloride (0‐10 μM) and carbon monoxide releasing molecule‐2 (CORM‐2, 0‐100 μM) prior to exposure to 0.5‐11 μg/ml of six different Agkistrodon species’ venom. The amount of venom used for experimentation needed to decrease coagulation function of one or more kinetic parameters by at least 50% of normal values for (e.g., half the normal speed of clot formation). Coagulation kinetics were determined with thrombelastography. All six snake venoms degraded plasmatic coagulation kinetics to a significant extent, especially prolonging the onset to clot formation and diminishing the speed of clot growth. Pre‐treatment of plasma with iron and carbon monoxide attenuated these venom‐mediated coagulation kinetic changes in a species‐specific manner, with some venom effects markedly abrogated while others were only mildly decreased. Further in vitro investigation of other pit viper venoms that possess fibrinogenolytic activity is indicated to identify species amenable to or resistant to iron and carbon monoxide‐mediated attenuation of venom‐mediated catalysis of fibrinogen. Lastly, future preclinical investigation with animal models (e.g., rabbit ear bleed model) is planned to determine if iron and carbon monoxide can be used therapeutically after envenomation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-15T01:15:39.393058-05:
      DOI: 10.1111/bcpt.12504
  • Triggering of Suicidal Erythrocyte Death by the Antibiotic Ionophore
    • Abstract: The K+,H+ ionophore and antibiotic nigericin has been shown to trigger apoptosis and is thus considered for the treatment of malignancy. Cellular mechanisms involved include induction of oxidative stress, which is known to activate erythrocytic Ca2+ permeable unselective cation channels leading to Ca2+ entry, increase of cytosolic Ca2+ activity ([Ca2+]i) and subsequent stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. The present study explored whether and how nigericin induces eryptosis. Phosphatidylserine exposure at the cell surface was estimated from annexin‐V‐binding, cell volume from forward scatter, [Ca2+]i from Fluo3‐fluorescence, pHi from BCECF‐ fluorescence, ceramide abundance utilizing antibodies and reactive oxygen species (ROS) formation from DCFDA‐dependent fluorescence. A 48‐hr exposure of human erythrocytes to nigericin significantly increased the percentage of annexin‐V‐binding cells (0.1‐10 nM), significantly decreased forward scatter (0.1 ‐ 1 nM), significantly decreased cytosolic pH (0.1 ‐ 1 nM) and significantly increased Fluo3‐fluorescence (0.1 ‐ 10 nM). Nigericin (1 nM) slightly, but significantly, increased ROS, but did not significantly modify ceramide abundance. The effect of nigericin on annexin‐V‐binding was significantly blunted, but not abolished by removal of extracellular Ca2+. The nigericin‐induced increase of [Ca2+]i and annexin‐V‐binding was again significantly blunted but not abolished by the Na+/H+ exchanger inhibitor cariporide (10 μM). Nigericin triggers eryptosis, an effect paralleled by ROS formation, in part dependent on stimulation of Ca2+ entry, and involving the cariporide sensitive Na+/H+ exchanger. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-12T13:01:21.264667-05:
      DOI: 10.1111/bcpt.12503
  • Curcumin, Silybin‐Phytosome® and α‐R‐Lipoic
           Acid Mitigate Chronic Hepatitis in Rat by Inhibiting Oxidative Stress and
           Inflammatory Cytokines Production
    • Authors: Shimaa O. Ali; Hebatallah A. Darwish, Nabila A. Ismail
      Abstract: Chronic hepatitis is recognized as a worldwide health problem that gradually progresses towards cirrhosis and hepatocellular carcinoma. Despite the large number of experiments using animal models for allergic hepatitis, it is still difficult to produce a picture of chronic hepatitis. Therefore, the present study was conducted to introduce an animal model approximating to the mechanism of chronicity in human hepatitis. The study also aimed to examine the hepatoprotective effects of curcumin, silybin phytosome® and α‐R‐lipoic acid against thioacetamide (TAA)‐induced chronic hepatitis in rat model. TAA was administered intraperitoneally at a dose of 200 mg/kg 3 times weekly for 4 weeks. At the end of this period, a group of rats was killed to assess the development of chronic hepatitis in comparison to their respective control group. TAA administration was then discontinued and the remaining animals were subsequently allocated into four groups. Group 1 was left untreated whereas groups 2‐4 were allowed to receive daily oral doses of curcumin, silybin phytosome® or α‐R‐lipoic acid, respectively, for 7 weeks. Increases in hepatic levels of malondialdehyde associated with TAA administration were inhibited in groups receiving supplements. Furthermore, glutathione depletion, collagen deposition, macrophage activation, nuclear factor κappa‐B expression as well as tumour necrosis factor‐α and interleukin‐6 levels were significantly decreased in response to supplements administration. Serological analysis of liver function and liver histopathological examination reinforced the results. The above evidence collectively indicates that the antioxidant and anti‐inflammatory activities of curcumin, silybin phytosome® and α‐R‐lipoic acid may confer therapeutic efficacy against chronic hepatitis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-12T12:45:31.813166-05:
      DOI: 10.1111/bcpt.12502
  • The Effect of the Combined Use of Methylergonovine and Oxytocin during
           Caesarean Section in the Prevention of Postpartum Haemorrhage
    • Abstract: We aimed to show the benefit to patients of postpartum hemorrhage prophylaxis treatment and the effectiveness as a uterotonic agent of the combined use of methylergonovine and oxytocin infusion in the prevention of hemorrhage during and after caesarean section, by comparison with a control group which received oxytocin infusion only. Two groups of patients undergoing caesarean section at the same clinic were included in the study. A combination of methylergonovine and oxytocin was administered to the first group during the intraoperative and postoperative periods. The second group did not receive methylergonovine and was administered only with oxytocin infusion in the intraoperative and postoperative periods. Preoperative and postoperative hemogram readings were taken for all patients in each of the groups for comparison. No difference was found between the two groups with regard to mean ages and preoperative hemogram values. The decrease in postoperative hemoglobin values for the group administered with methylergonovine maleate and oxytocin was found to be significantly greater than for the group administered with oxytocin only. Results indicated that prophylactic methylergonovine treatment was clearly successful for the patients and no adverse side effects were found. The routine use of methylergonovine and oxytocin infusion in combination during the intraoperative period of caesarean section reduced the level of postpartum hemorrhage considerably. We believe that this procedure will also reduce the risk of uterine atony, but clearly prospective studies will be necessary in future to confirm this assumption. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-09T06:55:23.461715-05:
      DOI: 10.1111/bcpt.12500
  • A Potential Mechanism Underlying the Antidepressant Effect of Insulin
  • The First Decade with the Swedish Prescribed Drug Register – A
           Systematic Review of the Output in the Scientific Literature
    • Abstract: The aim of this study was to quantify and characterize the scientific output from the Swedish Prescribed Drug Register (SPDR) the first decade after its establishment. A systematic literature search was performed in Medline, EMBASE and PubMed (2005‐2014). Additional publications were identified by personal knowledge, reference lists, contact with active authors and a citation search in Web of Sciences. Publications using SPDR data were included in the analysis and characterized regarding study type, presence of patient‐level record‐linkage, target population and topic. A total of 719 publications were identified in the literature search and an additional 148 by other strategies. 338 studies fulfilled the inclusion criteria. The majority were analytic (n=166; 49.1%) or descriptive (n=100; 29.5%). The remaining studies focused on validation (n=20; 5.9%), health economics (n=16; 4.7%) or miscellaneous (n=36; 10.7%). The analytic studies investigating effects of drug exposure focused mainly on safety (n=46) and/or effectiveness (n=23). The first publications appeared in 2007 (n=6), and in 2014, 90 articles using SPDR were published. Over the years, linkage with other registers using the personal identity number increased (0% to 88.9% of the publications). The population was often selected by age (49.7%), condition (45.0%) and/or drug (22.8%) and concerned predominantly psychiatric (29.0%) and cardiovascular (20.4%) diseases. In conclusion, the present study illustrates that the establishment of a nationwide individual‐based register on dispensed prescription drugs facilitates an encouraging development of pharmacoepidemiological research, both regarding the number of publications and the scientific level of the analyses. This article is protected by copyright. All rights reserved.
  • Philippe Grandjean is the 2015 BCPT Nordic Prize Awardee
  • Validity of the Prescriber Information in the Danish National Prescription
    • Abstract: The aim of this study was to measure the validity of the prescriber information recorded in the Danish National Prescription Registry (DNPR). The prescriber information recorded in the pharmacies’ electronic dispensing system was considered to represent the prescriber information recorded in the DNPR. Further, the problem of validity of the prescriber information pertains only to non‐electronic prescriptions, as these are manually entered into the dispensing system. The recorded prescriber information was thus validated against information from a total of 2,000 non‐electronic prescriptions at five Danish community pharmacies. The validity of the recorded prescriber information was measured at the level of the individual prescriber and the prescriber type, respectively. The proportion of non‐electronic prescriptions with incorrect registrations was 22.4% (95% Confidence Interval (CI): 20.6‐24.3) when considering individual prescriber identifiers and 17.8% (95% CI: 16.1‐19.5) when considering prescriber type. When excluding prescriptions specifically registered as ‘missing prescriber identifier’, the proportions decreased to 9.5% (95% CI: 8.2‐11.0) and 4.1% (95% CI: 3.2‐5.1), respectively. The positive predictive values for the classification of prescriber types were in the range of 94.0%‐99.2%, while the sensitivity ranged between 64.6%‐91.8%. With a maximum of 14% non‐electronic prescriptions of all prescriptions in the DNPR in 2015, this corresponds to correct classification of prescriber types in the DNPR of at least 97.5%. The prescriber information in the DNPR was found to be valid, especially in recent years. Researchers should be aware of the low sensitivity towards prescriptions from private practicing specialists. This article is protected by copyright. All rights reserved.
  • Intravenous Lipid Emulsion as an Antidote for the Treatment of Acute
           Poisoning: A Bibliometric Analysis of Human and Animal Studies
    • Abstract: In recent years, there has been increasing interest in the role of intravenous lipid formulations as potential antidotes in patients with severe cardiotoxicity caused by drug toxicity. The aim of this study was to conduct a comprehensive bibliometric analysis of all human and animal studies featuring lipid emulsion as an antidote for the treatment of acute poisoning. The Scopus database search was performed on 5 February 2016 in order to analyse the research output related to intravenous lipid emulsion as an antidote for the treatment of acute poisoning. Research indicators used for analysis included total number of articles, date (year) of publication, total citations, value of the h‐index, document types, countries of publication, journal names, collaboration patterns and institutions. A total of 594 articles were retrieved from Scopus for the period of 1955‐2015. The percentage share of global intravenous lipid emulsion research output showed that research output was 85.86% in 2006–2015 with yearly average growth in this field of 51 articles per year. The USA, United Kingdom (UK), France, Canada, New Zealand, Germany, Australia, China, Turkey and Japan accounted for 449 (75.6%) of all the publications. The total number of citations for all documents was 9,333, with an average of 15.7 citations per document. The h‐index of the retrieved documents for lipid emulsion research as antidote for the treatment of acute poisoning was 49. The USA and the UK achieved the highest h‐indices, 34 and 14, respectively. New Zealand produced the greatest number of documents with international collaboration (51.9%) followed by Australia (50%) and Canada (41.4%) out of the total number of publications for each country. In summary, we found an increase in the number of publications in the field of lipid emulsion after 2006. The results of the current study demonstrate that the majority of publications in the field of lipid emulsion were published by high‐income countries. Researchers from institutions in the USA led scientific production on lipid emulsion research. There is an obvious need to promote a deeper engagement through international collaborative research projects and funding mechanisms. This article is protected by copyright. All rights reserved.
  • Effects of Osteoporosis‐Inducing Drugs on Vitamin D‐Related
           Gene Transcription and Mineralization in MG‐63 and Saos‐2
    • Abstract: Vitamin D3 is important for calcium and phosphate homeostasis. To exert its effects, vitamin D3 has to be enzymatically activated into 1,25D3 (1,25‐dihydroxyvitamin D3). Regulation by endogenous vitamin D metabolites of the activation and inactivation of 1,25D3 is important to maintain adequate amounts of active vitamin D3. Vitamin D deficiency and low bone mineral density have been linked to treatments with antiretroviral drugs and glucocorticoids. However, the causes of drug‐induced osteoporosis remain unclear. The antiretroviral drugs efavirenz and ritonavir as well as the glucocorticoid dexamethasone were included in this study. Their effects on transcription of vitamin D‐regulating enzymes in MG‐63 cells were investigated. Ritonavir and dexamethasone both induced transcription of CYP27B1, the enzyme responsible for formation of 1,25D3. Efavirenz, however, suppressed CYP27B1 expression. When administered together with endogenous vitamin D metabolites, dexamethasone and efavirenz counteracted the 1,25D3‐mediated up‐regulation of CYP24A1, which inactivates 1,25D3. This suggests that the drugs may interfere with local regulation of the vitamin D metabolizing system in osteoblasts. Studies on mineralization were performed in MG‐63 cells and Saos‐2 cells by measuring calcium concentrations accumulated over time. The effects of efavirenz, ritonavir and dexamethasone and/or vitamin D metabolites were examined. 1,25D3 induced mineralization in both cell lines. Efavirenz administered alone did not affect mineralization but abrogated the inducing effects of 1,25D3 on mineralization in both MG‐63 cells and Saos‐2 cells. In summary, the results suggest that antiretroviral drugs and glucocorticoids may adversely affect bone by interference with the vitamin D‐system in osteoblasts. This article is protected by copyright. All rights reserved.
  • Daunorubicin Down‐Regulates the Expression of Stem Cell Markers and
           Factors Involved in Stem Cell Migration and Homing in Rat Heart in
           Subchronic but not Acute Cardiomyopathy
    • Abstract: We tested the hypothesis that daunorubicin (DAU) cardiotoxicity alters expression of cytokines involved in stem cell migration and homing. Male Wistar rats were treated with daunorubicin to induce acute DAU cardiomyopathy (6x3 mg/kg, i.p., every 48 hr, DAU‐A) or subchronic DAU cardiomyopathy (15 mg/kg, i.v., DAU‐C). The left ventricle was catheterized. The animals were killed 48 hr (DAU‐A) and 8 weeks (DAU‐C) after the last dose of DAU. Expression of foetal genes (Nppa, Nppb), isomyosins (Myh6, Myh7), sources of oxidative stress (Abcb8, gp91phox), cytokines (Sdf‐1, Cxcr4, Scf, Vegf, Hgf, Igf‐1), markers of cardiac progenitor (c‐kit, Atnx‐1), endothelial progenitor (CD34, CD133) and mesenchymal (CD44, CD105) stem cells were determined by qRT‐PCR in left ventricular tissue. Reduced body weight, decreased left ventricular weight and function, elevated Nppa, Nppb, Myh7 were observed in both models. Myh6 decreased only in DAU‐C, which had a 35% mortality. Up‐regulated gp91phox and down‐regulated Abcb8 in DAU were present only in DAU‐C where we observed markedly decreased expressions of Scf and Vegf as well as expressions of stem cell markers. Down‐regulation of cytokines and stem cell markers may reflect impaired chemotaxis, migration and homing of stem cells and tissue repair in the heart in subchronic but not acute model of DAU cardiomyopathy. This article is protected by copyright. All rights reserved.
  • The Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonist
           Capsazepine Improves the Impaired Lung Mechanics during Endotoxemia
    • Abstract: Acute lung injury (ALI) caused by systemic inflammatory response remains a leading cause of morbidity and mortality in critically ill patients. Management of patients with sepsis is largely limited to supportive therapies, reflecting an incomplete understanding of the underlying pathophysiology. Furthermore, there have been limited advances in the treatments for ALI. In the present study, lung function and a histological analysis were performed to evaluate the impact of transient receptor potential vanilloid‐1 receptor (TRPV1) antagonist (capsazepine; CPZ) on the lipopolysaccharide (LPS)‐induced lung injury in mice. For this, adult mice pre‐treated with CPZ or vehicle received intraperitoneal injections of LPS or saline and 24 hr after, the mice were anaesthetized, and lung mechanics was evaluated. The LPS‐challenged mice exhibited substantial mechanical impairment, characterized by increases in respiratory system resistance, respiratory system elastance, tissue damping and tissue elastance. The pre‐treatment with CPZ prevented the increase in respiratory system resistance and decreased the increase in tissue damping during endotoxemia. In addition, mice pre‐treated with CPZ had an attenuated lung injury evidenced by reduction on collapsed area of the lung parenchyma induced by LPS. This suggests that the TRPV1 antagonist capsazepine has a protective effect on lung mechanics in ALI during endotoxemia and that it may be a target for enhanced therapeutic efficacy in ALI. This article is protected by copyright. All rights reserved.
  • Oxymatrine Induces Liver Injury through JNK Signalling Pathway Mediated by
           TNF‐α In Vivo
    • Abstract: Oxymatrine (OMT) is a traditional Chinese medicine monomer and has been used for the treatment of chronic viral hepatitis and many other diseases. We aimed to investigate whether OMT could induce hepatotoxicity in mice and explored preliminary mechanisms of toxic effects. Four male Institute for Cancer Research mice were randomly divided into four groups: control group, 40,160 and 320 mg/kg OMT‐treated group. OMT was orally administered once daily for seven days. The OMT‐treated group exhibited an improved liver index and increase in serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase,augmented liver histological injury, elevated levels of malonaldehyde and tumour necrosis factor alpha (TNF‐α) accompanied by activation of Caspase‐9/‐8/‐3, up‐regulated expressions of tumour necrosis factor receptor l (TNFR1), TNF receptor‐associated structure domain (TRADD) and phosphorylation of stress‐activated protein kinase/ c‐jun N‐terminal protein kinases (p‐SAPK/JNK). Altogether, these results suggest that OMT at a dose of 320 mg/kg leads to liver damage, and is related to the activation of JNK signalling pathway mediated by TNF‐α in mice liver. This article is protected by copyright. All rights reserved.
  • Neutrophil Recruitment and Articular Hyperalgesia in Antigen‐Induced
    • Abstract: The cholinergic anti‐inflammatory pathway (CAP) is a complex neuroimmune mechanism triggered by the central nervous system to regulate peripheral inflammatory responses. Understanding the role of CAP in the pathogenesis of rheumatoid arthritis (RA) could help develop new therapeutic strategies for this disease. Therefore, we investigated the participation of this neuro‐immune pathway on the progression of experimental arthritis. Using an antigen‐induced arthritis (AIA) model, we investigated in mice the effects of vagotomy or the pharmacological treatments with hexamethonium (peripheral nicotinic receptor antagonist), methyl‐atropine (peripheral muscarinic receptor antagonist) or neostigmine (peripheral acetylcholinesterase inhibitor) on AIA progression. Unilateral cervical vagotomy was performed one week before the immunization protocol with methylated bovine serum albumin (mBSA), while drug administration was conducted during the period of immunization. On day 21, 6 hr after the challenge with mBSA injection in the femur‐tibial joint, the local neutrophil migration and articular mechanical hyperalgesia were assessed. Herein, we observed that vagotomy or blockade of peripheral nicotinic (but not muscarinic) receptors exacerbated the clinical parameters of this disease. Moreover, peripheral acetylcholinesterase inhibition by neostigmine‐treatment promoted a reduction of neutrophil recruitment in the knee joint and articular hyperalgesia. Our results demonstrated that peripheral activation of CAP modulates experimental arthritis providing a preclinical evidence of a potential therapeutic strategy for RA. This article is protected by copyright. All rights reserved.
  • Association between Gene Polymorphisms and Pain Sensitivity Assessed in a
           Multi‐Modal Multi‐Tissue Human Experimental Model – An
           Explorative Study
    • Abstract: The genetic influence on sensitivity to noxious stimuli (pain sensitivity) remains controversial and needs further investigation. In the present study, the possible influence of polymorphisms in three opioid receptor (OPRM, OPRD and OPRK) genes, and the catechol‐O‐methyltransferase (COMT) gene on pain sensitivity in healthy participants were investigated. Catechol‐O‐methyltransferase has an indirect effect on the mu opioid receptor by changing its activity through an altered endogenous ligand effect. Blood samples for genetic analysis were withdrawn in a multi‐modal and multi‐tissue experimental pain model in 40 healthy participants aged 20‐65 years. Seventeen different single nucleotide polymorphisms in different genes (OPRM, OPRK, OPRD and COMT) were included in the analysis. Experimental pain tests included thermal skin stimulation, mechanical muscle and bone stimulation, and mechanical, electrical and thermal visceral stimulations. A cold pressor test was also conducted. DNA was available from 38 participants out of 40. Compared to non‐carriers of the COMT rs4680A allele, carriers reported higher bone pressure pain tolerance threshold (i.e., less pain) by up to 23.8% (P0.05). In conclusion, COMT rs4680 and OPRK rs6473799 polymorphisms seem to be associated with pain sensitivity. Thus, the findings support a possible genetic influence of on pain sensitivity. This article is protected by copyright. All rights reserved.
  • The ABCB1, rs9282564, AG and TT Genotypes and the COMT, rs4680, AA
           Genotype are less frequent in Deceased Patients with Opioid Addiction
           (DOA) than in Living Patients with Opioid Addiction (LOA)
    • Abstract: Sudden death due to acute intoxication occurs frequently in patients with opioid addiction (OA). In order to examine if certain genotypes were associated with this, we examined the frequencies of 29 SNPs located in candidate genes related to opioid pharmacology: ABCB1, OPRM1, UGT2B7, CYP3A5, CYP2B6, CYP2C19, CYP2D6, COMT, KCNJ6 and SCN9A in 274 deceased patients with OA (DOA), 309 living patients with OA (LOA) and in 394 healthy volunteers (HV). The main hypothesis of the study was that subjects homozygous for the variant 3435T in ABCB1 (rs1045642) occur more frequently in DOA than in LOA and HV because morphine and methadone more readily cross the blood‐barrier in these subjects due to a lower efflux transporter activity of the ABCB1 (p‐glycoprotein) transporter. Our results did not support this hypothesis, since no statistically significant difference (p=0.506) in the frequency of the TT genotype of rs1045642 was observed between the DOA, LOA and HV cohorts. However, for another ABCB1 variant, rs9282564, we found that the frequencies of the AG and TT genotypes were 13, 21 and 25% in DOA, LOA and HV, respectively, and after correcting for age, sex and multiple testing, the differences between DOA and LOA were statistically significantly different (p=0.027). The COMT rs4680 AA genotype frequencies were 25%, 35% and 31% in DOA, LOA and HV, respectively, and the difference between DOA and LOA was also statistically significant (p= 0.0028). In conclusion, this study generated two hypotheses suggesting possible associations of a reduced risk of death and carrying, respectively, the ABCB1 rs9282564 AG and TT genotypes and the COMT rs4680 AA genotype among patients with OA. These findings should be confirmed in independent cohorts, and if a causal relationship between these variants and fatal poisoning in OA is confirmed, then it may be possible at least in theory to personalize prevention of sudden death in this patient group. This article is protected by copyright. All rights reserved.
  • Iron Supplements and Magnesium Peroxide: An Example of a Hazardous
           Combination in Self‐Medication
    • Abstract: The use of self‐medication, which includes dietary supplements and over‐the‐counter drugs, is still on the rise, while safety issues are not well addressed yet. This especially holds for combinations. For example, iron supplements and magnesium peroxide both produce adverse effects via the formation of reactive oxygen species (ROS). This prompted us to investigate the effect of the combination of three different iron supplements with magnesium peroxide on ROS formation. Hydroxyl radical formation by the three iron supplements either combined with magnesium peroxide or alone, was determined by performing a deoxyribose assay. Free iron content of iron supplements was determined using FerroZine assay. To determine hydrogen peroxide formation by magnesium peroxide, a ferrous thiocyanate assay was performed. Finally, electron spin resonance spectroscopy (ESR) was performed to confirm the formation of hydroxyl radicals. Our results show that magnesium peroxide induces the formation of hydrogen peroxide. All three iron supplements induced the formation of the extremely reactive hydroxyl radical, although the amount of radicals formed by the different supplements differed. It was shown that combining iron supplements with magnesium peroxide increases radical formation. The formation of hydroxyl radicals after the combination was confirmed with ESR. All three iron supplements contained labile iron and induced the formation of hydroxyl radicals. Additionally, magnesium peroxide in water yields hydrogen peroxide, which is converted into hydroxyl radicals by iron. Hence, iron supplements and magnesium peroxide is a hazardous combination and exemplifies that more attention should be given to combinations of products used in self‐medication. This article is protected by copyright. All rights reserved.
  • Agmatine Reverses Sub‐Chronic Stress‐induced Nod‐like
           Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats
    • Abstract: The activation of Nod‐like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)‐1β and IL‐18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with anti‐stress, anxiolytic and antidepressant‐like effects. In the present study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. Rats were divided into three groups as stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine, significantly down‐regulated the gene expressions of all stress‐induced NLRP3 inflammasome components (NLRP3, NF‐κB, PYCARD, caspase‐1, IL‐1β and IL‐18) in the hippocampus and prefrontal cortex (PFC), and reduced pro‐inflammatory cytokine levels not only in both brain regions but also in serum. Stress‐reduced levels of IL‐4 and IL‐10, two major anti‐inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. Findings of the present study suggest that stress‐activated NLRP3 inflammasome and cytokine responses are reversed by acute administration of agmatine. Whether antidepressant‐like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression. This article is protected by copyright. All rights reserved.
  • False Prolongation of Prothrombin Time in the Presence of a High Blood
           Concentration of Daptomycin
    • Abstract: Prothrombin time (PT) can reportedly be falsely prolonged by the antimicrobial drug daptomycin (DAP), and concomitant use of phosphatidylglycerol (PG). Although high doses of DAP (>6 mg/kg/day) are recommended for severe infection and result in a high blood concentration, the extent to which high blood concentrations of DAP interfere with PT, in the presence or absence of PG, has yet to be determined when using the HemosIL RecombiPlasTin 2G (Werfen Japan, Tokyo, Japan). We examined the effects of high doses of DAP on PT by using this reagent. DAP (0–500 mg/L) was added to normal plasma and plasma with an already prolonged PT in the presence or absence of liposomal amphotericin B (L‐AMB, 5–50 mg/L) or COATSOME EL‐01 empty cationic liposomes (CS, 25–250 mg/L). Furthermore, we undertook a Monte Carlo simulation to calculate the probability of achieving DAP concentrations >100 mg/L, >200 mg/L and >500 mg/L 0–48 hr after administrating 6–12 mg/kg of DAP. Apparent PT increased with increasing DAP concentration, but neither L‐AMB nor CS appeared to further elevate PT when co‐administered with DAP. The probability of achieving DAP concentrations >100 mg/L and >200 mg/L increased with DAP dose. Higher doses of DAP than the approved dose caused false prolongation of PT. PT should be monitored carefully in patients taking high doses of DAP; ideally, PT should be measured at the trough blood concentration of DAP. Concomitant use of L‐AMB and CS did not generally further elevate PT when co‐administered with DAP. Accurate measurement of prothrombin time (PT) is essential for the proper investigation and management of blood coagulation function. It has recently been reported that daptomycin (DAP) causes false prolongation of PT in a DAP dose‐dependent manner when PT is measured using HemosIL RecombiPlasTin [1, 2] This article is protected by copyright. All rights reserved.
  • Evaluation of Polybrominated Diphenyl Ether Toxicity on HepG2 Cells
           ‐ Hexa‐brominated Congener (BDE‐154) is Less Toxic than
           Tetra‐Brominated Congener (BDE‐47)
    • Abstract: Apoptotic cell death is one of the main consequences of exposure to brominated flame retardants, including PBDEs. However, few of these compounds have had their potential toxicity investigated. BDE‐154 is one of the most poorly studied PBDE congeners, but its level in the environment and in biological fluids is rising. In addition, its chemical structure differs from the other congeners with well‐documented toxicity, so BDE‐154 may display a distinct toxicity pattern. This study has evaluated how BDE‐154 affects the human hepatoblastoma cell line (HepG2) and has looked into the impact of this congener on human health. In addition, this study has related the effects of BDE‐154 with the effects of BDE‐47 to clarify the mechanism of PBDE toxicity. The HepG2 cell line was exposed to BDEs for 24 and 48 hr and submitted to assays to examine proliferation, viability, mitochondrial membrane potential, reactive oxygen species accumulation, phosphatidilseryne exposure, nuclear fragmentation and evaluation of pro‐caspase 3, pro‐caspase 9, cytochrome c release, and apoptosis inductor factor release by western blot analysis. BDE‐154 induced mitochondrial damage and led to apoptotic death of HepG2 cells, but these effects were less intense than the effects promoted by BDE‐47. Unlike other extensively reported congeners, BDE‐154 was only toxic at the higher tested concentrations, whereas BDE‐47 cytotoxicity was evident even at lower concentrations. Hence, like the toxicity pattern of other classes of substances such as polychlorinated biphenyls, the toxicity pattern of BDEs also depends on their chemical structure and aromatic substituent. This article is protected by copyright. All rights reserved.
  • Issue Information
  • Measurement of Rhodamine 123 in Three‐Dimensional Organoids: A Novel
           Model for P‐Glycoprotein Inhibitor Screening
    • Abstract: P‐glycoprotein (P‐gp), as the most important efflux transporter in intestines, plays the key role to determine the bioavailability of many drugs. The three‐dimensional (3D) organoid model is suitable to imitate small intestinal epithelium. In this study, a rapid, sensitive and efficient method to measure rhodamine 123 (Rh123, P‐gp substrate) in 3D organoids was developed to analyse P‐gp‐mediated drug transport. Ultrasonic cell disruptor was used to smash the organoid, and automatic microplate reader was used for detecting the concentration of Rh123 (λex/λem=485 nm/520 nm). Moreover, verapamil, quinidine and mitotane were used to make validation about this newly developed approach. All three P‐gp inhibitors significantly inhibited the transport of Rh123 into 3D organoids. Therefore, the above‐mentioned method could serve as a new model for P‐gp inhibitor screening in a high‐throughput way. This article is protected by copyright. All rights reserved.
  • Comparative Study of Genotoxicity Induced by Six Different PBDEs
    • Abstract: Indiscriminate use of synthetic substances has led to environmental contamination and increasing human and animals exposure to harmful chemicals. Polybrominated Flame Retardants (PBDEs), which serve as non‐covalent additives that enhance the safety of a variety of commercial and consumer goods, are an important class among potentially damaging synthetic substances. Its use is very common in developing countries, including Brazil. In theory, 209 different PBDE congeners exist, and many are currently being used during the manufacture of several products. Unfortunately, PBDEs are easily released from the original products, promptly reaching the environment. Knowledge about the toxicological power of these substances is still limited, which has prevented environmental and regulatory authorities from conducting adequate risk assessments. This research addresses the genotoxic and mutagenic potential of PBDEs. The effects of HepG2 cells and Salmonella typhimurium exposure to six main representatives of PBDEs, namely tetrabromodiphenylether (BDE‐47), pentabromodiphenylether (BDE‐99 and ‐100), hexabromodiphenylether (BDE‐153 and ‐154), and decabromodiphenylether (BDE‐209), were evaluated. The comet assay revealed that all the assessed BDEs exerted genotoxic effects but induced no micronuclei formation in HepG2 cells. These BDEs had no significant mutagenic effects on the Salmonella typhimurium strains TA98 and TA100. Taken together, the results of the genomic instability assays showed that PBDEs can represent a risk to the health of directly and indirectly exposed population, because the assessed BDEs induce genotoxic effects in the HepG2 cell line. This article is protected by copyright. All rights reserved.
  • Optimized Animal Model of CTX‐induced Bone Marrow Suppression
    • Abstract: Myelosuppression is one of the serious side effects of anti‐cancer chemotherapeutic drugs that deteriorate the bodily functions of patients, thereby affecting the quality of life considerably. Prevention of myelosuppression in anti‐cancer chemotherapy is an important research topic. A stabilized chemotherapy‐induced myelosuppression animal model is necessary in experimental research. This study aimed to establish an optimized animal model of chemotherapy‐induced bone marrow suppression. After C57BL/6 mice were treated with intermediate‐ and high‐dose (25/50 mg/kg) cyclophosphamide (CTX) for 10 days, the body weight, changes of thymus and spleen, number of white blood cells (WBCs), red blood cells (RBCs), and platelets (PLTs) and changes of bone marrow in the mice were systematically evaluated at the next 2, 7 and 14 days. Our results demonstrated that CTX treatments could significantly decrease the body weight of mice, as well as the ratios of the weights of thymus and spleen to body weight. The physiological structures of thymus and spleen were destroyed by CTX treatments. The number of WBCs and RBCs significantly declined after CTX treatments; however, the number of PLTs increased. Moreover, the expression of Sca1 in bone marrow cells decreased on day 2 but increased on day 14. The expression of CD34 decreased in bone marrow cells after CTX treatments. In conclusion, mice models, with high‐dose CTX treatments for 10 days, can be an optimized animal model for chemotherapy‐induced bone marrow suppression. This article is protected by copyright. All rights reserved.
  • High Frequency of CYP2D6 Ultrarapid Metabolizer Genotype in the Finnish
    • Abstract: CYP2D6 participates in the biotransformation of many commonly used drugs. Large genetic variability in CYP2D6 results in a wide interindividual variability in the response to CYP2D6 substrate drugs. Previous studies have assessed the phenotype and genotype distributions of CYP2D6 in relatively small Finnish population samples. The aim of our study was to investigate the frequencies of CYP2D6 genotypes in a larger Finnish population cohort of 857 healthy volunteers. The volunteers were genotyped for 10 CYP2D6 genetic variants (*2, *3, *4, *5, *6, *9, *10, *17, *39, *41) and copy number variation using TaqMan genotyping assays and copy number assay targeting exon 9. CYP2D6 phenotypes were inferred from the genotype data with the classical and activity score methods. According to the classical method, a large majority of the study subjects were extensive metabolizers (EM; 87.3%; 95% confidence interval 84.9‐89.3%) and the second largest group was ultra‐rapid metabolizers (UM; 7.2%; 5.7%‐9.2%). Intermediate (IM) and poor metabolizers (PM) were in clear minority (3.0%; 2.1%‐4.4% and 2.3%; 1.5%‐3.6%, respectively). The activity score method yielded similar phenotype predictions. These results show that the frequency of UM genotype is higher and that of PM and IM genotype is lower in the Finnish population than in other North European populations. Accordingly, CYP2D6 genetic profile of the Finnish population differs from its geographically close neighbours, which has implications for the effective and safe use of drugs metabolized by CYP2D6. This article is protected by copyright. All rights reserved.
  • Bisphenol A Increases the Migration and Invasion of Triple Negative Breast
           Cancer Cells via Oestrogen‐related Receptor Gamma
    • Abstract: Triple‐negative breast cancer (TNBC) is characterized by great metastasis and invasion capability. Our present study revealed that nanomolar bisphenol A (BPA), one of the most ubiquitous endocrine disruptors, can increase wound closure and invasion of both MDA‐MB‐231 and BT‐549 cells. BPA treatment can increase protein and mRNA expression of matrix metalloprotease 2 (MMP‐2) and MMP‐9, while had no effect on the expression of vimentin (Vim) and fibronectin (FN) in TNBC cells. The expression of G protein‐coupled receptor (GPER), which has been suggested to mediate rapid oestrogenic signals, was not varied in BPA‐treated MDA‐MB‐231 and BT‐549 cells. Its inhibitor G15 also had no effect on BPA‐induced MMPs expression and cell invasion. Interestingly, BPA treatment can significantly increase the mRNA and protein expression of oestrogen‐related receptor γ (ERRγ), but not ERRα or ERRβ, in both MDA‐MB‐231 and BT‐549 cells. The knock‐down of ERRγ can markedly attenuate BPA‐induced expression of MMP‐2 and MMP‐9 in TNBC cells. BPA treatment can activate both ERK1/2 and Akt in TNBC cells. Both inhibitors of ERK1/2 (PD98059) and Akt (LY294002) can attenuate BPA‐induced ERRγ expression and cell invasion of MDA‐MB‐231 cells. Collectively, our data revealed that BPA can increase the expression of MMPs and in vitro motility of TNBC cells via ERRγ. Both activation of ERK1/2 and Akt participated in this process. Our study suggests that more attention should be paid to the roles of xenoestrogens such as BPA in the development and progression of TNBC. This article is protected by copyright. All rights reserved.
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