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  Subjects -> ENVIRONMENTAL STUDIES (Total: 760 journals)
    - ENVIRONMENTAL STUDIES (687 journals)
    - POLLUTION (22 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (687 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: 2)
Acta Oecologica     Hybrid Journal   (Followers: 8)
Acta Regionalia et Environmentalica     Open Access  
Advances in Ecological Research     Full-text available via subscription   (Followers: 35)
Advances in Environmental Chemistry     Open Access   (Followers: 1)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 16)
Advances in Life Science and Technology     Open Access   (Followers: 9)
Aeolian Research     Hybrid Journal   (Followers: 5)
African Journal of Environmental Science and Technology     Open Access   (Followers: 2)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10)
Amazon's Research and Environmental Law     Open Access  
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Environmental Engineering     Open Access   (Followers: 14)
American Journal of Environmental Protection     Open Access   (Followers: 6)
American Journal of Environmental Sciences     Open Access   (Followers: 12)
American Journal of Microbiology     Open Access   (Followers: 12)
American Naturalist     Full-text available via subscription   (Followers: 56)
Annals of GIS     Hybrid Journal   (Followers: 16)
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: 44)
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: 25)
Aquatic Toxicology     Hybrid Journal   (Followers: 17)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 6)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 8)
Archives of Environmental Protection     Open Access   (Followers: 6)
Archives of Toxicology     Hybrid Journal   (Followers: 15)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 4)
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: 23)
Atmospheric Environment     Hybrid Journal   (Followers: 52)
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   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 9)
Basic and Applied Ecology     Hybrid Journal   (Followers: 16)
Behavioral Ecology     Hybrid Journal   (Followers: 42)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 32)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 22)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 5)
Bioremediation Journal     Hybrid Journal   (Followers: 5)
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: 9)
Bulletin of the American Meteorological Society     Open Access   (Followers: 27)
Business, Peace and Sustainable Development     Full-text available via subscription   (Followers: 4)
Canadian Journal of Earth Sciences     Full-text available via subscription   (Followers: 6)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 27)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 13)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 17)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 11)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
Cell Biology and Toxicology     Hybrid Journal   (Followers: 12)
Chain Reaction     Full-text available via subscription   (Followers: 1)
Challenges in Sustainability     Open Access   (Followers: 1)
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 17)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 12)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 56)
Civil and Environmental Engineering     Open Access   (Followers: 6)
Civil And Environmental Engineering Reports     Open Access   (Followers: 4)
Civil and Environmental Research     Open Access   (Followers: 15)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 17)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 5)
Cleanroom Technology     Full-text available via subscription   (Followers: 1)
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: 4)
Conservation and Society     Open Access   (Followers: 10)
Conservation Letters     Open Access   (Followers: 27)
Conservation Science     Open Access   (Followers: 15)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 4)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 11)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 21)
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: 10)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 4)
Developments in Atmospheric Science     Full-text available via subscription   (Followers: 9)
Developments in Earth and Environmental Sciences     Full-text available via subscription   (Followers: 5)
Developments in Earth Surface Processes     Full-text available via subscription   (Followers: 3)
Developments in Environmental Modelling     Full-text available via subscription   (Followers: 7)
Developments in Environmental Science     Full-text available via subscription   (Followers: 6)
Developments in Integrated Environmental Assessment     Full-text available via subscription   (Followers: 5)
Disaster Prevention and Management     Hybrid Journal   (Followers: 17)
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: 6)
Earth Interactions     Full-text available via subscription   (Followers: 11)
Earth Science Informatics     Hybrid Journal   (Followers: 3)
Earth System Science Data (ESSD)     Open Access   (Followers: 4)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 5)
Earthquake Science     Hybrid Journal   (Followers: 9)
EchoGéo     Open Access   (Followers: 1)
Ecohydrology     Hybrid Journal   (Followers: 9)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 3)
Ecologia Aplicada     Open Access  
Ecología en Bolivia     Open Access  
Ecological Applications     Full-text available via subscription   (Followers: 118)
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: 88)
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: 20)
Ecologist, The     Full-text available via subscription   (Followers: 26)
Ecology     Full-text available via subscription   (Followers: 228)
Ecology and Evolution     Open Access   (Followers: 46)
Ecology Letters     Hybrid Journal   (Followers: 153)
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: 24)
Ecotoxicology     Hybrid Journal   (Followers: 10)
Ecotoxicology and Environmental Safety     Hybrid Journal   (Followers: 7)
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   (Followers: 1)
Energy & Environmental Science     Full-text available via subscription   (Followers: 18)
Energy and Environment Focus     Free   (Followers: 4)
Energy and Environment Research     Open Access   (Followers: 11)
Energy and Environmental Engineering     Open Access   (Followers: 6)
Engenharia Sanitaria e Ambiental     Open Access  
Envigogika     Open Access  
Environment and Behavior     Hybrid Journal   (Followers: 12)
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: 38)
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: 30)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 38)
Environment and Pollution     Open Access   (Followers: 7)
Environment and Society : Advances in Research     Full-text available via subscription   (Followers: 6)
Environment International     Hybrid Journal   (Followers: 9)
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: 29)
Environment, Space, Place     Full-text available via subscription   (Followers: 3)
Environment: Science and Policy for Sustainable Development     Hybrid Journal   (Followers: 44)
Environmental & Engineering Geoscience     Full-text available via subscription   (Followers: 3)
Environmental & Socio-economic Studies     Open Access  
Environmental and Climate Technologies     Open Access   (Followers: 3)
Environmental and Molecular Mutagenesis     Hybrid Journal   (Followers: 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)
Environmental Engineering Science     Hybrid Journal   (Followers: 9)
Environmental Ethics     Hybrid Journal   (Followers: 6)
Environmental Evidence     Open Access   (Followers: 1)
Environmental Fluid Mechanics     Hybrid Journal   (Followers: 3)
Environmental Forensics     Hybrid Journal   (Followers: 1)
Environmental Geosciences     Full-text available via subscription   (Followers: 4)
Environmental Geotechnics     Open Access   (Followers: 3)
Environmental Hazards     Hybrid Journal   (Followers: 2)
Environmental Health     Open Access   (Followers: 9)
Environmental Health Insights     Open Access   (Followers: 4)
Environmental Health Perspectives (EHP)     Open Access   (Followers: 14)
Environmental History     Hybrid Journal   (Followers: 21)

        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
  • 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
  • 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
  • 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
  • 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
  • Thermoresponsive polymers with LCST‐ or UCST‐type phase
           behaviour do not induce toxicity to human endothelial cells
    • Abstract: Thermoresponsive polymers have gained extensive attention as biomedical materials especially for targeted drug delivery systems. We have recently developed water‐soluble polypeptides based thermoresponsive polymers that exhibit lower critical solution temperature (LCST) or upper critical solution temperature (UCST) type phase behaviours. In this study, the toxicity of these polymers to human umbilical vein endothelial cells (HUVECs) was investigated to assess the safety and biocompatibility. Up to 100μg/ml thermoresponsive polymers did not induce cytotoxicity to HUVECs, showing as unaltered mitochondrial viability assessed as cell counting kit‐8 (CCK‐8) assay and membrane integrity assessed as lactate dehydrogenase (LDH) assay. Inflammatory response, assessed as the release of chemokines soluble monocyte chemotactic protein 1 (sMCP‐1) and interleukin‐8 (IL‐8) as well as cytokine IL‐6, was not significantly affected by the polymers. In addition, 1μM thapsigargin (TG), an endoplasmic reticulum (ER) stress inducer, significantly decreased mitochondrial viability, but did not affect membrane integrity or inflammatory response. The presence of thermoresponsive polymers with LCST‐ type phase behaviour did not further affect the effects of TG. In conclusion, the thermoresponsive polymers used in this study are not toxic to endothelial cells, and therefore could be further considered as safe materials for biomedical applications. This article is protected by copyright. All rights reserved.
  • Absorption of Bupivacaine after Administration of a Lozenge as Topical
           Treatment for Pain from Oral Mucositis
    • Abstract: The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5 mg, 10 mg, 25 mg and 50mg bupivacaine, respectively, was administered as single dose to 10 healthy invididuals and lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to 5 HNC patients. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the HNC patients, respectively, after administration. The plasma concentration‐time profiles of bupivacaine were fitted to pharmacokinetic models using non‐linear mixed effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two‐compartment distribution model with absorption transit compartments. All observed plasma concentrations were well below bupivacaine concentrations (2000‐2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was 2‐fold higher in HNC patients with oral mucositis grade 1‐2, and 3‐fold higher in HNC patients with oral mucositis grade 3‐4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for 5 days. The 25 mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every 2 hr for 16 hr a day, the lozengscan be administered with minimum risk of exceeding the toxic limit. This article is protected by copyright. All rights reserved.
  • Drug‐Mediated Gene Regulation of Vitamin D3 Metabolism in Primary
           Human Dermal Fibroblasts
    • Abstract: Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug‐mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25‐hydroxyvitamin D3 and 1α,25‐dihydroxyvitamin D3. The results demonstrate that primary dermal fibroblasts have an active vitamin D3 metabolising system. High incidence of low bone mineral density is a concern for HIV‐infected patients treated with antiretroviral drugs. Osteomalacia and severe vitamin D deficiency have been reported. We investigated whether drug‐mediated gene regulation could be a possible mechanism behind these adverse drug effects. Fibroblasts were treated with different drugs used in HIV therapy and the 1α,25‐dihydroxyvitamin D3 levels and relative mRNA‐levels for crucial enzymes were determined. Efavirenz, stavudine and ritonavir significantly down‐regulated the bioactivating CYP2R1 and up‐regulated the catabolic CYP24A1. The drugs reduced bioactivating enzyme activities and cellular levels of 1α,25‐dihydroxyvitamin D3. The current results indicate that effects on gene expression may lead to disturbed vitamin D metabolism and decreased cellular levels of active vitamin D3. The data are consistent with the impaired bone health in patients treated with certain antiretroviral drugs. This article is protected by copyright. All rights reserved.
  • N‐acetylcysteine in Acute Organophosphorus Pesticide 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 3 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.
  • Issue Information
  • Utility of Pilot Studies for Predicting Ratios and Intrasubject
           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 intrasubject 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 × 2 design with 12 volunteers 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 × 4 design with 8 volunteers were similar to those of the 2 × 2 design with 12 volunteers. 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 × 2 design with at least 12 volunteers.
  • 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 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.
  • 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.
  • 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. Co‐ordinated 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 constitutes 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 in 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 shares many similarities, the use of animal models will certainly provide further advances in the field.
  • Pharmacokinetic Profile of Oral Magnesium Hydroxide
    • Abstract: Despite the presumption of a beneficial effect of magnesium (Mg) supplementation on various diseases, little is known concerning the pharmacokinetics of Mg hydroxide. This study was designed to provide a pharmacokinetic profile of Mg hydroxide after a single oral dose. Ten healthy male adults participated in this cross‐over study with three 24‐hr study days. Interventions were: 1) none (baseline), 2) oral intake of three (3 x 360 mg) tablets of Mg hydroxide (Mablet®) and 3) IV bolus infusion of 2 g Mg sulphate (index drug). Blood samples were collected before the single dose, after (i.e. post treatment administration) 15, 30, 60, 90 and 120 min. – and after 3, 4, 6, 8, 12 and 24 hr. Urine was collected in four 6‐hr periods per study day. Blood (N=10) and urine (N=6) Mg were analysed by descriptive statistics. Bioavailability was 14.9% (CI: 8.3; 26.8), blood clearance was 5.1 L/hr (CI: 2.1; 17.0), apparent volume of distribution was 60.2 L (CI: 35.6; 102.0), elimination constant was 0.08 hr−1 (CI: 0.05; 0.14), half‐life was 8.3 hr (CI: 4.8; 14.1), Cmax was 0.11 mmol/L (CI: 0.07; 0.14), and AUC(0‐24) was 92.3 mmol/L x minutes (CI: 45.5; 139.1). Urine Mg excretion augmented by 17.7% (CI: 8.9; 35.0) from baseline. No severe side effects. Mg hydroxide demonstrates a 15% bioavailability, and it constitutes a clinically relevant option for oral Mg supplementation. No severe side effects were seen. This article is protected by copyright. All rights reserved.
  • Concentration‐Response Relationship of Hearing Impairment Caused by
           Quinine and Salicylate: Pharmacological Similarities but different
           molecular mechanisms
    • Abstract: This review has the purpose to summarise concentration‐effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine‐induced increase in hearing threshold and its recovery can be analysed according to “the psychophysical power function”. The power function is a special case of the Hill equation when the stimulus (e.g., a drug concentration) is exceedingly small compared with the concentration that would elicit a half maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence presence, magnitude and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self‐attained most comfortable speech level and the acoustic stapedius reflex are not affected, i.e. the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but using different molecular mechanisms. This article is protected by copyright. All rights reserved.
  • An Effective Machine Learning Approach for Prognosis of Paraquat Poisoning
           Patients Using Blood Routine Indexes
    • Abstract: The early identification of toxic paraquat (PQ) poisoning in patients critical to ensure timely and accurate prognosis. Though plasma PQ concentration has been reported as a clinical indicator of PQ poisoning, it is not commonly applied in practice due to the inconvenient necessary instruments and operation. In this study, we explored the use of blood routine indexes to identify the degree of PQ toxicity and/or diagnose PQ poisoning in patients via machine learning approach. Specifically, we developed a method based on support vector machine combined with the feature selection technique to accurately predict PQ poisoning risk status, then tested the method on 79 (42 male and 37 female; 41 living and 38 deceased) patients. The detection method was rigorously evaluated against a real‐world dataset to determine its accuracy, sensitivity and specificity. Feature selection was also applied to identify factors correlated with risk status, and results showed that there are significant differences in blood routine indexes between dead and living PQ‐poisoned individuals (p‐value < 0.01). Feature selection also showed that the most important correlated indexes are white blood cell and neutrophils. In conclusion, the toxicity or prognosis of PQ poisoning can be preliminarily ascertained by blood routine testing without PQ concentration data, representing an additional tool and innovative approach to assess prognosis of PQ poisoning. This article is protected by copyright. All rights reserved.
  • Antinociceptive and Anti‐Inflammatory Effects of Ketamine and the
           Relationship to its Antidepressant Action and GSK3 Inhibition
    • Abstract: Ketamine (KET), a NMDA antagonist, exerts an antidepressant effect at subanesthetic doses and possesses analgesic and anti‐inflammatory activities. We evaluated the involvement of KET antinociceptive and anti‐inflammatory effects with its antidepressant action. Male Swiss mice were subjected to formalin, carrageenan‐induced paw oedema and forced swimming tests, for assessing antinociceptive, anti‐inflammatory and antidepressant effects. The treatment groups were: control, KET (2, 5 and 10 mg/kg), lithium (LI: 5 mg/kg) and KET2+LI5 combination. Immunohistochemistry analyses (TNF‐alpha, iNOS, COX‐2 and GSK3) in oedematous paws were performed. KET5 and KET10 reduced licking times in neurogenic (22 and 38%) and inflammatory (67 and 78%) phases of the formalin test, respectively, as related to controls. While LI5 inhibited the 2nd phase by 24%, the licking time was inhibited by 26 and 59% in the KET2+LI5 group (1st and 2nd phases). Furthermore, oedema volumes were reduced by 37 and 45% in the KET5 and KET10 groups, respectively. Oedema reductions were 29% in the LI5 group and 48% in the KET2+LI5 group. In the forced swimming test, there were 23, 38 and 53% decreases of the immobility time in KET2, KET5 and KET10 groups, respectively. While LI5 caused no significant effect, decreases of 52% were observed with KET2+LI5. KET also decreased TNF‐alpha, iNOS, COX‐2 and GSK3 immunostainings in oedematous paws, effects intensified with KET2+LI5. We showed that KET presents antinociceptive and anti‐inflammatory effects associated to its antidepressant response. Furthermore, our results indicate the close involvement of GSK3 inhibition and blockade of inflammatory responses, in the antidepressant drug effect. This article is protected by copyright. All rights reserved.
  • In Vitro Effects of the Neolignan 2,3‐Dihydrobenzofuran against
           Leishmania Amazonensis
    • Abstract: Leishmaniasis is an infectious disease complex caused by a protozoa from the Leishmania genus, which presents a broad spectrum of clinical manifestations: cutaneous, mucocutaneous and visceral forms. The current treatments are unsatisfactory considering few drugs are available and present some level of toxicity. Many lignans and neolignans have been used for the development of new anti‐Leishmania drugs. The capability in vitro of the neolignan 2,3‐dihydrobenzofuran (2,3‐DBF), a commonly found constituent of propolis and other plants, to inhibit the growth of promastigote and macrophages‐internalized amastigote forms of Leishmania amazonensis was investigated. The cytotoxicity of this compound was assessed by MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide) test in Balb/c murine macrophages and human erythrocyte lysis assay. The 2,3‐DBF was active against promastigotes (IC50=1.042 μM) and amastigotes (IC50=1.43 μM) forms, indicating a potent anti‐leishmanial effect. There was no evidence of cytotoxicity to macrophages or erythrocytes at concentrations ranging from 13 to 0.5 μM, after 48 hr of exposure. The anti‐leishmanial activity is probably mediated by the activation of macrophages, since treatment with 2,3‐DBF increases both phagocytic and lysosomal activities, as well as the nitrite (NO2‐) levels. These results suggest that 2,3‐DBF may be a potential candidate for the development of a new promising anti‐leishmanial drug. Further studies are needed to determine its potential in vivo effect as well as additional mechanisms underlying the anti‐leishmanial and immunomodulatory activities. This article is protected by copyright. All rights reserved.
  • The pan‐Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal
           Excitability by Direct Action on Striatal Neurons In Vivo
    • Abstract: Central Kv7 (KCNQ) channels are voltage‐dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan‐Kv7 channel opener retigabine. The effect of retigabine likely involves inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c‐Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c‐Fos positive neurons following a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2=Kv7.3=Kv7.5>>Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo. This article is protected by copyright. All rights reserved.
  • Mechanisms of Action and Toxicity of the Mycotoxin Alternariol: A Review
    • Abstract: The mycotoxin alternariol (AOH) is produced by Alternaria fungi. It occurs naturally in foodstuffs and is frequently found as contaminant in fruit and grain products. Most information regarding AOH toxicity and the potential mechanisms involved comes from in vitro studies, as only very limited in vivo studies have been performed. AOH forms reactive oxygen species (ROS) and interacts with DNA topoisomerase, thereby generating both single (SSB) and double strand DNA beaks (DSB). This triggers various DNA damage response pathways. AOH causes a marked reduction in proliferation in mammalian cells due to cell cycle arrest often in the G2/M‐phase. Following an additional inhibition of cytokinesis, cells with abnormal nuclei as well as polyploidy are reported. In macrophages, AOH may increase autophagic activity and induce senescence. Furthermore, AOH is found to change the morphology and phenotype of various human macrophage cell models. Studies so far indicate that the AOH‐induced effects are primarily a result of DSB via its effects on topoisomerase activity. Thus, most probably there will be a threshold for the AOH‐induced effects, typically seen in the 5‐10 μM range. These in vitro mechanistic studies further support the in vivo studies suggesting low acute toxicity. However, a decreased immune response to infections and/or a disturbed balance of the adaptive immune system when exposed together with other mycotoxins cannot be excluded. This hypothesis needs to be further explored with proper in vivo studies. This article is protected by copyright. All rights reserved.
  • Do Diuretics have Antinociceptive Actions: Studies of Spironolactone,
           Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone
           and Morphine
    • Abstract: Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, e.g. via mineralocorticoid receptor antagonism. In co‐administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.) and morphine (3 mg/kg, s.c.) induced antinociception using tail‐flick and hot plate tests in male Sprague‐Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system. This article is protected by copyright. All rights reserved.
  • Geraniol Induces Anti‐nociceptive Effect in Mice Evaluated in
           Behavioural and Electrophysiological Models
    • Abstract: Geraniol (GER) is a monoterpene alcohol with various biochemical and pharmacological properties present in the essential oil of more than 160 species of herbs, (especially the Cymbopogon genus). In this study, we evaluated the anti‐nociceptive activity of GER in behavioural and electrophysiological in vitro experimental models of nociception using male Swiss mice. GER (12.5, 25 or 50 mg/kg i.p. and 50 or 200 mg/kg p.o.) reduced the number of writhes induced by acetic acid. The opioid antagonist naloxone (5 mg/kg s.c.) administered in mice subsequently treated with GER (25 mg/kg i.p.) did not reverse such anti‐nociceptive activity, suggesting a non‐opioid pathway for the mechanism of action. GER (12.5, 25 and 50 mg/kg i.p.) reduced paw licking time in the second phase of the formalin test. Also, in the glutamate test, GER when administered 50 mg/kg i.p. reduced paw licking time, probably modulating glutamatergic neurotransmission. GER blocked reversibly components of the compound action potential (CAP) recorded in isolated sciatic nerve in a dependent manner for concentration and drug exposure time: 1 mM to 120 min. for the first component and 0.6 mM to 90 min. for the second component. The IC50 was calculated for the peak‐to‐peak amplitude (PPA) at 0.48 ± 0.04 mM. The conduction velocity was also reduced by exposure to GER starting from the concentration of 0.3 mM for both components of the CAP. In conclusion, it is suggested that GER has anti‐nociceptive activity, especially in pain related to inflammation, and in part related to reduced peripheral nerve excitability. This article is protected by copyright. All rights reserved.
  • Human Hepatic HepaRG Cells Maintain an Organotypic Phenotype with High
           Intrinsic CYP450 Activity/Metabolism and Significantly Outperform Standard
           HepG2/C3A Cells for Pharmaceutical and Therapeutic Applications
    • Abstract: Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, inter‐donor functional variability and early phenotypic alterations of PHHs restrict their use; whilst standard cell lines such as HepG2 lack a substantial and variable set of liver‐specific functions such as CYP450 activity. Alternatives include the HepG2‐derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype. Human HepaRG cells are an alternative organotypic co‐culture model of hepatocytes and cholangiocytes reported to maintain in vivo‐like liver‐specific functions, including intact Phase 1‐3 drug metabolism. In this study, we compared C3A and human HepaRG cells using phenotypic profiling, CYP450 activity and drug metabolism parameters to assess their value as hepatic models for pre‐clinical drug testing or therapeutics. Compared with C3As, HepaRG co‐cultures, exhibit a more organotypic phenotype, including evidence of hepatic polarity with strong expression of CYP3A4, the major isoform involved in the metabolism of over 60% of marketed drugs. Significantly greater CYP450 activity and expression of CYP1A2, CYP2E1 and CYP3A4 genes in HepaRG cells (comparable with that of human liver tissue) was demonstrated. Moreover, HepaRG cells also preferentially expressed the hepatic integrin α5β1 – an important modulator of cell behaviour including growth and survival, differentiation and polarity. Drug metabolite profiling of phenacetin (CYP1A2) and testosterone (CYP3A4) using LC‐MS/MS and HPLC, respectively, revealed HepaRGs had more intact (Phase 1‐2) metabolism profile. Thus, HepaRG cells significantly outperform C3A cells for potential pharmaceutical and therapeutic applications. This article is protected by copyright. All rights reserved.
  • A Danish Survey of Antihistamine Use and Poisoning Patterns
    • Abstract: The first‐generation antihistamine, promethazine, became a prescription‐only drug in Denmark as of December 2014. First‐generation antihistamines are known to have a higher toxic potential than second‐generation antihistamines. The aim of this study was to provide a nationwide description of the antihistamine use and poisoning pattern from 2007 to 2013 in Denmark based on two independent databases. There were 1049 antihistamine exposures in the national, advisory telephone service specialized in poisonings, the Danish Poison and Information Centre (DPIC), and 456 exposures in the three registers used within the State Serum Institute of Denmark (SSI), a department under the Danish Ministry of Health dealing with research‐based health surveillance in Denmark. First‐generation antihistamines constitute 61% and 73% of antihistamine registrations in DPIC and SSI, respectively. Antihistamine exposures increased by 7 exposures/10,000 enquiries per year in DPIC and 6 admissions per year in SSI – this increase is not significant due to a sudden decrease in 2012. Intentional exposures constituted 65% in DPIC of which 82% was due to suicide attempts, and 78% of the involved antihistamines were first‐generation antihistamines. Accidental exposures constituted 33% of which 61% were due to play and 29% involved first‐generation antihistamines. Single antihistamine exposures constituted 65% of DPIC exposures of which 98% involved only one brand of antihistamine. Multi‐drug exposures constituted 35% of DPIC exposures with equally distributed coingestants. Hospitalization was recommended in 78% of DPIC exposures. Admissions required only one day of treatment in 91% of the SSI exposures. One of the 14 identified deaths in the SSI study population was directly related to antihistamine poisoning. Results support the limited disclosure of promethazine in Denmark and illustrate a generation‐specific pattern indicating a suspected replacement of promethazine with other first‐generation antihistamines. This article is protected by copyright. All rights reserved.
  • Silencing Op18/stathmin by RNA interference promotes the sensitivity of
           nasopharyngeal carcinoma cells to taxol and high grade differentiation of
           xenografted tumours in nude mice
    • Abstract: Nasopharyngeal carcinoma (NPC) is a refractory tumour, and chemotherapy is one of the primary treatment modalities. Oncoprotein 18 (Op18)/stathmin is a conserved small cytosolic phosphoprotein and highly expressed in tumours, which plays a vital role in maintaining the malignant phenotype of tumours. Taxol (fig. 1) is a clinically widely used chemotherapeutics agent for a broad range of taxol‐resistant tumours. This study showed that Op18/stathmin silencing by RNA interference (RNAi) combined taxol cooperatively improved cellular apoptosis in CNE1 cells mainly via initiating endogenous death receptor pathway, impaired the capabilities of cellular proliferation and cellular migration, down‐regulated the half maximal inhibitory concentration (IC50) of taxol, meanwhile, decreased the expression of the upstream extracellular regulated kinase 1 (ERK1) in vitro. Evidences also showed that taxol cytotoxicity was markedly augmented for Op18/stathmin RNAi in other NPC cells. In vivo animal experiments have demonstrated that early combination of Op18/stathmin silencing and taxol evidently inhibited tumourigenicity of CNE1 cells and growth of xenografted tumours in nude mice. Remarkably, silencing Op18/stathmin by RNAi still promoted transformation of late‐stage CNE1 cells in NPC‐xenografted tumours from moderately to highly differentiated, inhibited the pleiotropic cytokine interleukin 10 (IL‐10) autocrine by transplanted tumours. These findings suggest that silencing Op18/stathmin by RNAi promotes chemosensitization of NPC to taxol and reverses malignant phenotypes of NPC, which provides a new clue for treating drug‐resistant tumours. This article is protected by copyright. All rights reserved.
  • Apoptotic process induced by oxaliplatin in rat hippocampus causes memory
    • Abstract: Aspects of memory involved in cognitive mechanisms were investigated in rat after oxaliplatin (OX) chemotherapy using animal behavioural assessment of passive avoidance and social learning paradigms, which are both hippocampus‐sensitive. Rodents, previously subjected to two‐week OX treatment, showed passive avoidance and social learning impairment and apoptotic processes in hippocampus. Apoptosis rate significantly increased in cultured hippocampal cells exposed to OX at increasing doses, and this effect was dose‐dependent. Ex vivo experiments showed that cell damage and apoptosis were blocked in hippocampus from OX rats co‐treated with copper sulfate (CS) which precludes OX transport inside the cell. In vivo, passive avoidance and social learning impairment could not be observed in OX rats co‐administered with CS. Thus, a site of action of OX treatment on memory impairment appears to be located at the hippocampus. These findings strongly support that cellular damage induced by OX in rodent hippocampus underlies the weakening of some memory functions. This article is protected by copyright. All rights reserved.
  • Cyclophsopahmide‐induced Down‐Regulation of Uroplakin II in
           the Mouse Urinary Bladder Epithelium is Prevented by S‐Allyl
    • Abstract: The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP‐induced HC. In this study, we studied the modulatory effect of the thiol‐rich compound S‐allyl cysteine (SAC) on the mRNA level of uroplakin II by real‐time PCR and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)‐induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP‐induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulfonic acid (mesna) (40 mg/kg), a known thiol‐rich drug, SAC, which has been in clinical application, was found to be more efficacious in affording protection in urinary bladder tissues. Role or uroplakins in CP‐induced urinary bladder toxicity has not been well investigated. The present study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium. This article is protected by copyright. All rights reserved.
  • Neuromuscular Effects of Rocuronium Bromide in Patients in Statin Therapy
           for at least Three Months
    • Abstract: Statins cause skeletal muscle myopathy. However, the neuromuscular effects of non‐depolarizing neuromuscular blocking agent in patients in long‐term statin therapy remain unclear. Hence, we investigated the neuromuscular effects of rocuronium and muscle injury in patients in long‐term statin therapy. Eighteen statin users using statins for at least 3 months were included in the statin group and 18 non‐statin users were included in the non‐statin group. General anaesthesia was induced with intravenous midazolam, etomidate, sufentanil and rocuronium 0.9mg·kg‐1 (3ED95) for intubation. Anaesthesia was maintained with 1% propofol and remifentanil. The onset time and duration 10% T1 and 25% T1 of rocuronium was recorded. Blood samples were obtained before induction, and 5 min., 1 hr, 2 hr, 4 hr, 12 hr and 24 hr after rocuronium administration to measure creatine kinase (CK), myoglobin and potassium. Myalgia was determined at 2 hr and 24 hr after surgery. There were no significant differences in the basic clinical characteristics between the two groups. The onset time of the statin group was significantly shorter than that of the non‐statin group (p=0.02), while the duration 10% T1 and 25% T1 of the statin group was significantly longer than that of the non‐statin group (p=0.006; p=0.045). The myoglobin and CK concentrations increased after rocuronium administration as compared to baseline in both groups. CK concentration in the statin group was significantly higher than in the non‐statin group just at 24 hr (p=0.000003). However, myoglobin showed no significant difference between the two groups. The onset time of rocuronium decreases and its duration time increases in patients in long‐term statin therapy. This article is protected by copyright. All rights reserved.
  • Safety, Pharmacokinetics and Pharmacodynamics of the Selective
           Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy
    • Abstract: AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This paper reports the initial, first‐in‐man, single and repeat dose‐escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once‐daily treatment. Plasma exposure suggested dose proportional pharmacokinetics and dose‐related effects on 24‐hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (Osteocalcin, TRAP5b, DHEA‐S and 4βOH‐cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus‐pituitary‐adrenal (HPA) effects appeared to be marginally greater in the Japanese versus the Caucasian dominant study population. AZD5423, inhaled via nebulisation, can be used in healthy individuals at doses of at least 300 μg for two weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit risk ratio may be improved relative to conventional inhaled steroids. This article is protected by copyright. All rights reserved.
  • Paracelsus Revisited: The Dose Concept in a Complex World
    • Abstract: At the time that Paracelsus coined his famous dictum, “What is there that is not poison' All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison,” embryonic toxicology was a fairly focused discipline that mainly dealt with occupational poisonings and side effects of pharmaceuticals, such as mercury. While Paracelsus paved the way for the modern threshold concept and the no‐adverse effect level, modern‐day toxicology is now tussling with highly complex issues, such as developmental exposures, genetic predisposition and other sources of hypersusceptibility, multiple causes of underestimated toxicity, and the continuous presence of uncertainty, even in regard to otherwise well‐studied mercury compounds. Further, the wealth of industrial chemicals now challenges the “untested‐chemical assumption,” that the lack of documentation means that toxic potentials can be ignored. Unfortunately, in its ambition to provide solid evidence, toxicology has been pushed into almost endless replications, as evidenced by the thousands of toxicology publications every year that focus on toxic metals, including mercury, while less well‐known hazards are ignored. From a public health viewpoint, toxicology needs to provide better guidance on decision‐making under ever‐present uncertainty. In this role, we need to learn from the stalwart Paracelsus the insistence on relying on facts rather than authority alone to protect against chemical hazards. This article is protected by copyright. All rights reserved.
  • Prognostic Factors in Emergency Department Patients with
           Glyphosate‐Surfactant Intoxication: Point‐of‐Care
           Lactate Testing
    • Abstract: An increasing number of suicide attempts involve the ingestion of glyphosate surfactant; hence, clinical toxicologists may encounter severe cases of glyphosate‐surfactant intoxication. In several other clinical conditions, serum lactate is used to predict outcome. We investigated the relationship between lactate levels and 30‐day mortality from glyphosate‐surfactant poisoning. This retrospective analysis involved 232 patients who were admitted to the emergency department after acute glyphosate‐surfactant poisoning between January 2004 and June 2014. We used a receiver operating characteristic (ROC) curve to define the optimal cut‐off point for lactate levels. A Kaplan‐Meier 30‐day survival curve was then analysed in terms of the defined cut‐off level. We used multivariate Cox proportional hazards regression analysis to determine the risk factors for 30‐day mortality. Of the 232 patients, 29 died, yielding a case fatality rate of 12.5%. Lactate was significantly higher in non‐survivors (6.5±3.1 mmol/L) than in survivors (3.3±2.2 mmol/L; p 59 years, corrected QT interval > 495 ms and potassium > 5.5 mmol/L were independent risk factors for 30‐day mortality. Lactate is an independent predictor of 30‐day mortality in patients with glyphosate‐surfactant poisoning. Early measurement of lactate levels may be a simple and practical way to assess the severity of intoxication. This article is protected by copyright. All rights reserved.
  • Visfatin Triggers the Cell Motility of Non‐Small Cell Lung Cancer
           (NSCLC) via Up‐Regulation of Matrix Metalloproteinases (MMPs)
    • Abstract: High levels of visfatin are correlated with worse clinical prognosis of various cancers. Still, the effects and mechanisms of visfatin on progression of non‐small cell lung cancer (NSCLC) remain unclear. Our present study revealed that plasma levels of visfatin in NSCLC patients (585 ± 287 pg/ml) were significantly (p
  • The Role of the Mucosa in Normal and Abnormal Bladder Function
    • Abstract: The internal face of the detrusor smooth muscle wall of the urinary bladder is covered by a mucosa, separating muscle from the hostile environment of urine. However, the mucosa is more than a very low permeability structure and offers a sensory structure that monitors the extent of bladder filling and composition of the urine. The mucosa may be considered as a single functional structure and comprises a tight epithelial layer under which is a basement membrane and lamina propria. The latter region itself is a complex of afferent nerves, blood vessels, interstitial cells and in some species including human beings a muscularis mucosae. Stress on the bladder wall through physical or chemical stressors elicits release of chemicals, such as ATP, acetylcholine, prostaglandins and nitric oxide that modulate the activity of either afferent nerves or the muscular components of the bladder wall. The release and responses are graded so that the mucosa forms a dynamic sensory structure, and there is evidence that the gain of this system is increased in pathologies such as overactive bladder and bladder pain syndrome. This system therefore potentially provides a number of drug targets against these conditions, once a number of fundamental questions are answered. These include: how is mediator release regulated; what are the intermediate roles of interstitial cells that surround afferent nerves and blood vessels; and what is the mode of communication between urothelium and muscle – by diffusion of mediators or by cell‐to‐cell communication' This article is protected by copyright. All rights reserved.
  • Association of Oseltamivir Activation with Gender and Carboxylesterase 1
           Genetic Polymorphisms
    • Abstract: Oseltamivir, an inactive anti‐influenza virus prodrug, is activated (hydrolyzed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non‐genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1‐mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the ‐816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (P = 0.039) while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (P = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, ‐816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, P = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations. This article is protected by copyright. All rights reserved.
  • Curcumin Inhibits 5‐Fluorouracil‐induced Up‐regulation
           of CXCL1 and CXCL2 of the Colon Associated with Attenuation of Diarrhoea
    • Abstract: The compound 5‐fluorouracil (5‐FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C‐X‐C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5‐FU in mice. Curcumin has anti‐inflammatory, anti‐tumourand antioxidant properties. Therefore, we examined the effect of curcumin on 5‐FU‐induced diarrhoea development and CXCL1 and CXCL2 up‐regulation in the colon. Mice were given 5‐FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5‐FU and administered 30 min. before the administration of 5‐FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real‐time RT‐PCR. Curcumin reduced the 5‐FU‐induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up‐regulated by 5‐FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5‐FU application in vitro. The 5‐FU‐induced up‐regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay‐117082 and bortezomib, nuclear factor kappa B (NF‐κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element‐binding protein–histone acetyltransferase (HAT) inhibitor. In conclusion, these finding suggested that curcumin prevented the development of diarrhoea by inhibiting NF‐κB and HAT activation. This article is protected by copyright. All rights reserved.
  • Low‐Chlorinated Non‐Dioxin‐like PCBs Present in Blood
           and Breast Milk Induce Higher Levels of Reactive Oxygen Species in
           Neutrophil Granulocytes than Highly Chlorinated Congeners
    • Abstract: Despite their ban several decades ago, polychlorinated biphenyls (PCBs) still pose a health threat to human beings due to their persistent and accumulative nature and continued presence in the environment. Non‐dioxin‐like (NDL)‐PCBs have earlier been found to have effects on the immune system, including human neutrophil granulocytes. The aim of this study was to investigate differences between ortho‐chlorinated NDL‐PCBs with a low or high degree of chlorination in their capability to induce the production of reactive oxygen species (ROS) in human neutrophil granulocytes in vitro. We used some of the congeners occurring at the highest levels in blood, breast milk and food; PCB 52 representing the low chlorinated and PCB 180 the high chlorinated congeners. In addition, the extensively studied PCB 153 was included as a reference compound. ROS production was assessed with the luminol‐amplified chemiluminescence and DCF fluorescence assays. The involvement of intracellular signalling mechanisms was investigated using different pharmacological substances. At high concentrations (10‐20 μM), PCB 52 induced more ROS than PCB 153 and PCB 180. The role of extracellular signal regulated kinase (ERK) 1/2 and/or ERK 5 signalling in PCB‐induced ROS production was implicated through the reduction in ROS in the presence of the specific inhibitor U0126, whereas reduced ROS production after use of SB203580 and SP600125 indicated involvement of the p38 mitogen activated protein kinase (MAPK) and c‐Jun amino‐terminal kinase (JNK) pathways, respectively. In addition, the calcineurin inhibitor FK‐506, the intracellular calcium chelator BAPTA‐AM and the anti‐oxidant vitamin E reduced the levels of ROS. The intracellular signalling mechanisms involved in ROS production in human neutrophil granulocytes appeared to be similar for PCB 52, PCB 153 and PCB 180. Based on the results from the present and previous studies, we conclude that for abundant ortho‐chlorinated PCBs found in blood, low chlorinated congeners induce higher production of ROS in neutrophil granulocytes than highly chlorinated congeners. This could be relevant during acute exposure scenarios when high concentrations of PCBs are present. This article is protected by copyright. All rights reserved.
  • Human UDP‐Glucuronosyltransferases 1A1, 1A3, 1A9, 2B4 and 2B7 are
           Inhibited by Diethylstilbesterol
    • Abstract: Inhibition of UDP‐glucuronosyltransferases (UGT) can result in many undesired side effects. Diethylstilbestrol (DES), a synthetic oestrogen famous for its multiple toxicities, was once widely administered to women in high dosages and now still gains application in clinics. This study investigated in vitro inhibitory effects of DES on catalytic activities of human UGTs, aiming at disclosing new potential toxic mechanisms on the basis of interactions between DES and metabolizing enzymes. DES (10 μM) could decrease activities of UGT1A1, 1A3, 1A9, 2B4 and 2B7 in catalyzing 4‐Methylumbelliferon (4‐Mu) glucuronidation. Further kinetic analyses showed that inhibition of these UGTs followed competitive (UGT1A1 and 1A9), mixed (UGT1A3 and 2B4), and non‐competitive (UGT2B7) mechanisms, with Ki values ranging from 0.91 to 4.1 μM. The inhibition potentials of UGT1A9 and 2B7 in human liver microsomes (HLM) were further tested by employing propofol and zidovudine as probe substrates, respectively. The inhibition of human liver microsomal UGT1A9 followed mixed mechanism, with the Ki value of 3.5 μM and α of 4.1. On the other hand, DES displayed non‐competitive inhibition against UGT2B7 in HLM, with the Ki value of 9.8 μM. The risks of in vivo inhibition of human UGTs were also predicted by calculation of plasma C/Ki values. Results suggest that DES can trigger in vivo inhibition of UGT1A1, 1A3, 1A9, 2B4 and 2B7 after the intravenous administration in high doses. This article is protected by copyright. All rights reserved.
  • Effects of an Antimutagenic 1,4‐Dihydropyridine AV‐153 on
           Expression of Nitric Oxide Synthases and DNA Repair‐related Enzymes
           and Genes in Kidneys of Rats with a Streptozotocin Model of Diabetes
    • Abstract: Development of complications of diabetes mellitus (DM), including diabetic nephropathy, is a complex multi‐stage process, dependent on many factors including modification of nitric oxide (NO) production and impaired DNA repair. The goal of the present work was to study in vivo effects of a 1,4‐dihydropyridine AV‐153, known as antimutagene and DNA‐binder, on expression of several genes and proteins involved in NO metabolism and DNA repair in kidneys of rats with streptozotocin (STZ)‐induced model of DM. Transcription intensity was monitored by means of real‐time RT‐PCR and expression of proteins by immunohistochemistry. Development of DM significantly induced PARP1 protein expression, while AV‐153 (0.5 mg/kg) administration decreased it. AV‐153 increased expression of Parp1 gene in kidneys of both intact and diabetic animals. Expression of H2afx mRNA and γH2AX histone protein, a marker of DNA breakage, was not changed in diabetic animals, but AV‐153 up‐regulated expression of the gene without any impact on the protein expression. Development of DM was followed by a significant increase of iNOS enzyme expression, while AV‐153 down‐regulated the enzyme expression up to normal levels. iNos gene expression was also increased in diabetic animals, but unlike the protein, the expression of mRNA was enhanced by AV‐153 administration. Expression of both eNOS protein and eNos gene in kidneys was down‐regulated, and administration of AV‐153 normalized the expression level. Effects of the compound in kidneys of diabetic animals appear to be beneficial, as a trend for normalization of expression of NO synthases is observed. This article is protected by copyright. All rights reserved.
  • Impact of implementing a protocol on the perioperative management in
           patients treated with anti‐thrombotics admitted for hip fracture
           surgery: an observational study
    • Abstract: This study aimed to describe the impact of implementing a protocol on the perioperative management of patients admitted for hip fracture treated with anti‐thrombotics. A protocol was designed based on recommendations from the American College of Chest Physicians (ACCP). After its implementation (May 2012), information on anti‐thrombotic management was collected from admission to three months after surgery in retrospective (October 2011‐March 2012) and prospective (October 2012‐March 2013) cohorts. Patients’ thromboembolic risk was classified into high, moderate or low according to the ACCP categories. A total of 113 and 101 cases were included in the retrospective and prospective cohorts, respectively. No differences in age, gender, American Society of Anaesthesiology score or thrombotic risk categories were observed between cohorts. Most patients were treated with aspirin or triflusal (55.1 and 48.1% in each cohort, respectively), clopidogrel (24.5 and 26.6%) or acenocoumarol (16.3 and 20.2%). In moderate‐high thromboembolic risk patients, a higher rate of bridging therapy with full doses of enoxaparin (18.5% and 50%, p=0.04 before and 9.1% and 43.7%, p=0.02 after surgery) and a lower rate of aspirin discontinuation (76% and 55.3%, p=0.03) were observed in the prospective cohort. Both cohorts had a similar percentage of cases with bleeding (68.1 and 68.3%) and thrombotic events (11.5% and 13%). No differences in the timing between surgery and the discontinuation or resumption of anti‐thrombotics were noted. After protocol implementation, aspirin was less often stopped and bridging therapy with therapeutic doses of enoxaparin was used more often. However, interruption and resumption times of anti‐thrombotics remained almost unchanged. In order to achieve these goals, more efforts should be made to implement the protocol in clinical practice. This article is protected by copyright. All rights reserved.
  • Placental Growth Factor (PLGF) Triggers EMT‐like Changes in Rat Type
           II Alveolar Epithelial Cells: Activation of NFκB Signalling Pathway
    • Abstract: Epithelial‐to‐mesenchymal transition (EMT) occurs frequently in lung epithelium in response to damage stimuli, such as inflammation and oxidative stress. Our group has already found an excessive release of placental growth factor (PLGF) in hyperoxic lung injury in newborn rodents. Nonetheless, whether this increased PLGF plays a role in mediating EMT process of alveolar epithelial cells (AECs) is unclear and requires further investigation. In this study, primary type II AECs were first isolated for neonatal Sprague‐Dawley (SD) rats and treated with different doses (25 or 100 ng/ml) of recombinant PLGF for 48 hr. As compared to the untreated AECs, exogenous PLGF induced a reduction of E‐cadherin (a critical epithelial maker) and increases of vimentin and fibronectin (mesenchymal markers) in a dose‐dependent manner. The higher dose was more potent in promoting the EMT‐like changes in AECs. We also found that PLGF promoted the degradation of nuclear factor κB (NFκB) inhibitor (IκBα), induced phosphorylation of NFκB p65 at Ser 536 and enhanced p65 nuclear translocation in primary AECs. In addition, the NFκB inhibitor BAY 11‐7082 partly counteracted PLGF‐induced alterations of EMT‐related proteins in rat AECs. In summary, our study demonstrates that exogenous PLGF can induce EMT‐like changes in type II AECs at least partly by activating NFκB signalling transduction in vitro. PLGF may play a role in driving fibrotic lesions, and thus can be a promising target for lung diseases. This article is protected by copyright. All rights reserved.
  • Lipid Rescue – Efficacy and Safety Still Unproven
    • Abstract: Intralipid®, the soybean oil‐based nutritional lipid emulsion for intravenous administration, has maintained a remarkably safe record for more than 50 years. In conventional use, its rare adverse effects consist of pancreatitis, hepatic failure, dyspnoea and anaphylaxis, and these are usually due to overdose or too rapid infusion rate [1, 2]. Intralipid®, and other similar stable lipid emulsions have also pharmaceutical application as vehicles for various drugs such as diazepam, etomidate and propofol. This article is protected by copyright. All rights reserved.
  • Impact of Ageing on Serum Concentrations of Risperidone and its Active
           Metabolite in Patients with known CYP2D6 Genotype
    • Abstract: The aim of this study was to investigate the impact of ageing on serum concentrations of risperidone and 9‐hydroxyrisperidone in patients with known CYP2D6 genotype. We included retrospective therapeutic drug monitoring data from 464 genotyped patients with measured serum concentrations of risperidone and 9‐hydroxyrisperidone following oral administration. Patients were divided into two age subgroups, i.e. ≤65 (n=396) and >65 years (n=68), and dose‐adjusted concentrations (C:D ratios) were compared using multiple linear regression analyses with CYP2D6 genotype and gender as covariates. Moreover, absolute concentrations and prescribed daily doses were compared between age subgroups by simple, univariate Mann‐Whitney tests. Age had no effect on C:D ratio of risperidone (P>0.4), but C:D ratios of 9‐hydroxyrisperidone and risperidone + 9‐hydroxyrisperidone (total active moiety) were estimated to be 2.6‐ and 2.0‐fold higher in patients >65 versus ≤65 years (P65 years might be a particularly vulnerable subgroup of adverse effects. This article is protected by copyright. All rights reserved.
  • 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.
  • 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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