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  Subjects -> ENVIRONMENTAL STUDIES (Total: 768 journals)
    - ENVIRONMENTAL STUDIES (704 journals)
    - POLLUTION (22 journals)
    - WASTE MANAGEMENT (9 journals)

ENVIRONMENTAL STUDIES (704 journals)                  1 2 3 4 5 6 7 8 | Last

Acta Ecologica Sinica     Open Access   (Followers: 9)
Acta Limnologica Brasiliensia     Open Access   (Followers: 2)
Acta Oecologica     Hybrid Journal   (Followers: 9)
Acta Regionalia et Environmentalica     Open Access  
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 11)
Advances in Ecological Research     Full-text available via subscription   (Followers: 24)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 25)
Advances in Life Science and Technology     Open Access   (Followers: 5)
Aeolian Research     Hybrid Journal   (Followers: 1)
African Journal of Environmental Science and Technology     Open Access   (Followers: 2)
African Journal of Sustainable Development     Full-text available via subscription   (Followers: 3)
AGE     Hybrid Journal   (Followers: 4)
Age and Ageing     Hybrid Journal   (Followers: 23)
Agricultura Tecnica     Open Access   (Followers: 5)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10)
Ambiência     Open Access  
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
Ambiente & sociedade     Open Access   (Followers: 2)
American Journal of Applied Sciences     Open Access   (Followers: 27)
American Journal of Environmental Engineering     Open Access   (Followers: 6)
American Journal of Environmental Protection     Open Access   (Followers: 3)
American Journal of Environmental Sciences     Open Access   (Followers: 13)
American Journal of Microbiology     Open Access   (Followers: 13)
American Naturalist     Full-text available via subscription   (Followers: 36)
Annals of Environmental Science     Open Access   (Followers: 9)
Annals of GIS     Hybrid Journal   (Followers: 14)
Annals of Warsaw University of Life Sciences - SGGW. Land Reclamation     Open Access   (Followers: 2)
Annual Review of Ecology, Evolution, and Systematics     Full-text available via subscription   (Followers: 36)
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: 18)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 10)
Applied and Environmental Soil Science     Open Access   (Followers: 12)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 7)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 11)
Aquatic Ecology     Hybrid Journal   (Followers: 13)
Aquatic Toxicology     Hybrid Journal   (Followers: 17)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription   (Followers: 1)
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 5)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 10)
Archives of Environmental Protection     Open Access   (Followers: 4)
Archives of Toxicology     Hybrid Journal   (Followers: 10)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 1)
Asian Journal of Earth Sciences     Open Access   (Followers: 17)
Asian Journal of Rural Development     Open Access   (Followers: 9)
ATBU Journal of Environmental Technology     Open Access  
Atmospheric and Climate Sciences     Open Access   (Followers: 14)
Atmospheric Environment     Hybrid Journal   (Followers: 27)
Austral Ecology     Hybrid Journal   (Followers: 7)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 4)
Australasian Journal of Human Security, The     Full-text available via subscription   (Followers: 3)
Australian Journal of Environmental Education     Full-text available via subscription   (Followers: 6)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 6)
Basic and Applied Ecology     Hybrid Journal   (Followers: 13)
Behavioral Ecology     Hybrid Journal   (Followers: 33)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 27)
Biodegradation     Hybrid Journal   (Followers: 2)
Biodiversity     Hybrid Journal   (Followers: 17)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 3)
Bioremediation Journal     Hybrid Journal   (Followers: 5)
BioRisk     Open Access   (Followers: 2)
BMC Ecology     Open Access   (Followers: 15)
Boston College Environmental Affairs Law Review     Open Access   (Followers: 5)
Bothalia : African Biodiversity & Conservation     Open Access  
Built Environment     Full-text available via subscription   (Followers: 4)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 11)
Bulletin of the American Meteorological Society     Open Access   (Followers: 12)
Canadian Journal of Earth Sciences     Full-text available via subscription   (Followers: 6)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 12)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 12)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 17)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 10)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
CCLR - Carbon and Climate Law Review     Full-text available via subscription   (Followers: 2)
Cell Biology and Toxicology     Hybrid Journal   (Followers: 8)
Chain Reaction     Full-text available via subscription  
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 14)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 2)
Chemosphere     Hybrid Journal   (Followers: 10)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 18)
Civil and Environmental Research     Open Access   (Followers: 11)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 14)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 8)
Climate Change Economics     Hybrid Journal   (Followers: 16)
Climate Policy     Hybrid Journal   (Followers: 18)
Coastal Engineering Journal     Hybrid Journal   (Followers: 1)
Columbia Journal of Environmental Law     Free   (Followers: 7)
Computational Ecology and Software     Open Access   (Followers: 6)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 1)
Conservation and Society     Open Access   (Followers: 6)
Conservation Letters     Hybrid Journal   (Followers: 18)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (Followers: 8)
Construction Innovation: Information, Process, Management     Hybrid Journal   (Followers: 13)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 2)
Continental Journal of Environmental Design and Management     Open Access   (Followers: 4)
Continental Journal of Renewable Energy     Open Access   (Followers: 8)
Continental Journal of Sustainable Development     Open Access   (Followers: 9)
Creativity and Innovation Management     Hybrid Journal   (Followers: 140)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 7)

        1 2 3 4 5 6 7 8 | Last

Journal Cover Basic & Clinical Pharmacology & Toxicology
   [8 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  [1602 journals]   [SJR: 0.588]   [H-I: 56]
  • Development of Clinical Pharmacology as a Medical Speciality in Europe
           – The Roles of WHO, IUPHAR and EACPT
    • Authors: Folke Sjöqvist
      Abstract: Clinical pharmacology has now existed as a teaching and research discipline for nearly 50 years, but with notable exceptions, it is not yet established in many countries as a medical speciality. This MiniReview describes the attempts of IUPHAR, WHO and EACPT to involve clinical pharmacology in the global efforts to improve the use of medicines towards increased efficacy and safety. The MiniReview emphasizes the situation in Europe. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-21T01:48:14.063358-05:
      DOI: 10.1111/bcpt.12278
  • Loading Dose of Fomepizole is Safe in Children with Presumed Toxic Alcohol
           Exposure ‐ A Case Series
    • Authors: Dimitri Frémont; Marie‐Pierre Berleur, Bruno Mégarbane
      Abstract: Fomepizole, a potent alcohol dehydrogenase inhibitor was shown to be an effective and safe antidote for treating toxic alcohol poisoning in adults [1]. However, evidence for its effectiveness and safety in children remains limited [2]. We reviewed the records of children treated with fomepizole sulfate (Fomepizole AP‐HP®), the only marketed product in France, manufactured and distributed by the state pharmaceutical agency for Paris hospitals (AGEPS). This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-18T06:39:39.664038-05:
      DOI: 10.1111/bcpt.12276
  • Saquinavir‐NO inhibits IL‐6 production in macrophages
    • Authors: Miljana Momčilović; Katia Mangano, Bojan Jevtić, Santa Mammana, Stanislava Stošić‐Grujičić, Ferdinando Nicoletti, Djordje Miljković
      Abstract: Covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a new chemical entity, named Saquinavir‐NO (Saq‐NO) with reduced toxicity and potent immunoregulatory influence on T lymphocytes. In this study, we have compared head to head the effects of Saq‐NO and Saq on mouse and rat peritoneal macrophage cytokine secretion and NO production upon in vitro, ex vivo and in vivo conditions. The results demonstrate that Saq‐NO, but not Saq, potently decreased interleukin (IL)‐10, IL‐6 and nitrite accumulation and increased the levels of IL‐1β and tumour necrosis factor (TNF) in supernatants of mouse and rat macrophage cultures in vitro. Treatment of mice with Saq‐NO, but not Saq, inhibited ex vivo secretion of IL‐6 from macrophages. Consistent with these findings, Saq‐NO also reduced blood levels of IL‐6 in lipopolysaccharide‐treated mice. The observed inhibitory influence of Saq‐NO on IL‐6 generation in macrophages may be involved in the observed anti‐tumour and immunomodulatory effects of the drug. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-18T06:37:01.267126-05:
      DOI: 10.1111/bcpt.12268
  • Arctigenin Promotes Apoptosis in Ovarian Cancer Cells via the
           iNOS/NO/STAT3/Survivin Signalling
    • Authors: Ke Huang; Li‐an Li, Yuan‐guang Meng, Yan‐qin You, Xiao‐yu Fu, Lei Song
      Abstract: Arctigenin is a biologically active lignan extracted from the seeds of Arctium lappa and shows anti‐cancer activity against a variety of human cancers. The aim of this study was to determine the effects of arctigenin on ovarian cancer cell proliferation and survival and associated molecular mechanisms. Human ovarian cancer OVCAR3 and SKOV3 cells were treated with arctigenin, and cell proliferation and apoptosis were assessed. Western blot analysis was used to examine signal transducer and activator of transcription‐3 (STAT3) phosphorylation and survivin and inducible nitric oxide synthase (iNOS) expression. The involvement of STAT3/survivin/iNOS/NO signalling in arctigenin action was checked. Arctigenin treatment resulted in a significant and dose‐dependent inhibition of cell proliferation. Arctigenin‐treated cells showed a 4‐6‐fold increase in the percentage of apoptosis, compared to control cells. Pre‐treatment with Ac‐DEVD‐CHO, a specific inhibitor of caspase‐3, counteracted the induction of apoptosis by arctigenin. Arctigenin treatment significantly inhibited STAT3 phosphorylation and survivin and iNOS expression. Arctigenin‐induced apoptosis was impaired by pre‐transfection with survivin‐expressing plasmid or addition of chemical nitric oxide (NO) donors. Additionally, exogenous NO prevented the suppression of STAT3 phosphorylation and survivin expression by arctigenin. Arctigenin treatment inhibits the proliferation and induces caspase‐3‐dependent apoptosis of ovarian cancer cells. Suppression of iNOS/NO/STAT3/survivin signalling is causally linked to the anti‐cancer activity of arctigenin. Therefore, arctigenin may be applicable to anti‐cancer therapy for ovarian cancer. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-17T22:01:23.437668-05:
      DOI: 10.1111/bcpt.12270
  • Modulation of Imatinib Cytotoxicity by Selenite in HCT116 Colorectal
           Cancer Cells
    • Authors: Amal Kamal Abdel‐Aziz; Samar Saad Eldeen Azab, Samar Samir Youssef, Abeer Mostafa El‐Sayed, Ebtehal El‐Demerdash, Samia Shouman
      Pages: n/a - n/a
      Abstract: Imatinib is a principal therapeutic agent for targeting colorectal tumours. However, mono‐targeting by imatinib does not always achieve complete cancer eradication. Selenite, a well‐known chemopreventive agent, is commonly used in cancer patients. In the current study, we aimed to explore whether selenite can modulate imatinib cytotoxicity in colorectal cancer cells. HCT116 cells were treated with different concentrations of imatinib and/or selenite for 24, 48 and 72 hr. Imatinib‐selenite interaction was analysed using isobologram equation. As indicators of apoptosis, DNA fragmentation, caspase‐3 activity, Bcl‐2 expression were explored. Autophagic machinery was also checked by visualizing acidic vesicular organelles and measuring Beclin‐1 expression. Furthermore, reactive oxygen and nitrogen species were also examined. The present study demonstrated that selenite synergistically augmented imatinib cytotoxicity in HCT116 cells as evidenced by combination and dose reduction indices. Supranutritional dose of selenite when combined with imatinib induced apoptotic machinery by decreasing Bcl‐2 expression, increasing caspase‐3 activity and subsequently fragmenting DNA and blunted cytoprotective autophagy by decreasing Beclin‐1 expression and autophagosomes formation. Moreover, their combination induced cell cycle S phase block, increased total thiol content and reduced nitric oxide levels. In conclusion, selenite synergizes imatinib cytotoxicity through multi‐barrelled molecular targeting, providing a novel therapeutic approach for colorectal cancer. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-13T08:38:22.371008-05:
      DOI: 10.1111/bcpt.12281
  • 8‐O‐Acetyl Shanzhiside Methylester Attenuates Cerebral
           Ischemia/Reperfusion Injury through an Anti‐Inflammatory Mechanism
           in Diabetic Rats
    • Authors: Liang Zhang; Ze‐Chun Kan, Xiu‐Li Zhang, Han Fang, Wang‐Lin Jiang
      Abstract: Inflammatory activation plays a vital role in the pathophysiologic mechanisms of stroke and diabetes mellitus (DM), exerts the deleterious effects on the progression of the brain and leads to vascular damage in diabetic stroke. The objectives of this study were to investigate the effects of 8‐O‐acetyl shanzhiside methylester (ND01) on tumour necrosis factor‐α (TNF‐α) stimulated SH‐SY5Y cell line in vitro and the experimental ischaemic diabetic stroke model in vivo. For TNF‐α stimulated SH‐SY5Y cells, pre‐incubated with ND01, then analyze protein expression. For in vivo experiment, the diabetic rats were subjected to middle cerebral artery occlusion (MCAO) for 30 min. followed by reperfusion for 23 hr. Treatment of SH‐SY5Y cells with ND01 blocked TNF‐α‐induced nuclear transcription factor κB (NF‐κB) activation, and decreased high‐mobility group box1 (HMGB1) expression. ND01 40 mg/kg demonstrated significant neuroprotective effect even after delayed administration at 4 hr after I/R. ND01 40 mg/kg attenuated the histopathological damage, decreased brain swelling, inhibited NF‐κB activation and reduced HMGB1 expression in ischaemic brain tissue. These data show that ND01 protects diabetic brain against I/R injury with a favourable therapeutic time‐window by alleviating diabetic cerebral I/R injury and attenuating blood‐brain barrier (BBB) breakdown, and its protective effects may involve HMGB1 and NF‐κB signalling pathway. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-10T05:01:00.083775-05:
      DOI: 10.1111/bcpt.12266
  • Inosine Strongly Enhances Human C32 Melanoma Cells Proliferation through
           PLC‐PKC‐MEK1/2‐ERK1/2 and PI3K Pathways
    • Authors: Ana Sofia Soares; Vera Marisa Costa, Carmen Diniz, Paula Fresco
      Abstract: Malignant melanoma is the most deadly type of skin cancer. The lack of effective pharmacological approaches could be related to the incomplete understanding of the pathophysiological mechanisms involved in cell melanoma proliferation. Adenosine has growth‐promoting and growth‐inhibitory effects on tumour cells. We aimed to investigate effects of adenosine and its metabolic product, inosine, on human C32 melanoma cells and the signalling pathways involved. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) reduction and bromodeoxyuridine (BrdU) proliferation assays were used to evaluate adenosine, adenosine deaminase and inosine effects, in the absence or presence of AR, A3AR and P2Y1R antagonists; and PLC, PKC, MEK1/2 and PI3K inhibitors. ERK1/2 levels were determined using an ELISA kit. Adenosine and inosine levels were quantified using an enzyme‐coupled assay. Adenosine caused cell proliferation through AR activation. Adenosine deaminase increased inosine levels (nanomolar concentrations) on the extracellular space, in a time‐dependent manner, inducing proliferation through A3AR activation. Micromolar concentrations of inosine enhanced proliferation through A3AR activation, causing an increase in ERK1/2 levels, and P2Y1R activation via ENT‐dependent mechanisms. We propose the simultaneous activation of PLC‐PKC‐MEK1/2‐ERK1/2 and PI3K pathways as the main mechanism responsible for the proliferative effect elicited by inosine and its significant role in melanoma cancer progression. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-06T10:30:48.910118-05:
      DOI: 10.1111/bcpt.12280
  • The Evaluation of Prophylactic Efficacy of Newly Developed Reversible
           Inhibitors of Acetylcholinesterase in Soman‐Poisoned Mice – A
           Comparison with commonly used Pyridostigmine
    • Authors: Jiri Kassa; Jan Korabecny, Vendula Sepsova, Martina Tumova
      Abstract: The ability of four newly developed reversible inhibitors of acetylcholinesterase (PC‐37, PC‐48, JaKo 39, JaKo 40) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman‐poisoned mice was evaluated and compared. No reversible inhibitor of acetylcholinesterase studied was able to decrease the LD50 value of soman in mice. Thus, the pharmacological pre‐treatment with pyridostigmine or newly synthesized inhibitors of acetylcholinesterase was not able to significantly protect mice against soman‐induced lethal acute toxicity. In addition, neither pyridostigmine nor new reversible inhibitors of acetylcholinesterase was able to increase the efficacy of antidotal treatment (the oxime HI‐6 in combination with atropine) of soman‐poisoned mice. These findings demonstrate that pharmacological pre‐treatment of soman‐poisoned mice with tested reversible inhibitors of acetylcholinesterase is not promising. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-06T03:37:27.413623-05:
      DOI: 10.1111/bcpt.12269
  • Riccardin D, a Macrocyclic Bisbibenzy, Inhibits Human Breast Cancer Growth
           through the Suppression of Telomerase Activity
    • Authors: Cui‐Cui Sun; Hui‐Min Xu, Yi Yuan, Zu‐Hua Gao, Hong‐Xiang Lou, Xian‐Jun Qu
      Abstract: Riccardin D, a liverwort‐derived naturally occurring macrocyclic bisbibenzyl, has been found to exert anticancer effects in multiple cancer cell types. In this study, we investigated the effect and mechanism of Riccardin D on human breast cancer. Experiments were performed on human breast cancer MCF‐7 and MDA‐MB‐231 cells. The antitumour effects of Riccardin D were assessed by the 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT) assay and human breast cancer xenografts mice model. TRAPeze® XL Telomerase Detection assay was used for the detection of telomerase activity. γ‐H2AX foci formation was tested for the induction of DNA damage response. Cell cycle distribution was analysed by flow cytometry and cell apoptosis was determined by Annexin V‐FITC/PI staining, terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) assay and western blotting. Riccardin D effectively inhibited the growth of MCF‐7 and MDA‐MB‐231 cells in vitro. And Riccardin D also effectively delayed the growth of MCF‐7 and MDA‐MB‐231‐luc‐D3H2LN xenografts without significant loss of body weight. Further analysis suggested that Riccardin D's effects may arise from its suppression of telomerase activity, which led to telomere dysfunction. Telomerase inhibition and telomere dysfunction could activate the canonical ATM kinase‐mediated DNA damage response, as shown by elevated expression of γ‐H2AX, p‐ATM and p‐Chk2. This is finally followed by the induction of cell cycle arrest and apoptosis, as shown by the increase of TUNEL stained cells, caspase activation, PARP cleavage and the increase of bax/bcl‐2 ratio. Moreover, Riccardin D induced p53‐proficient MCF‐7 cells to arrest in G1 phase and p53‐deficient MDA‐MB‐231 cells to arrest in G2/M phase. Overall, these results demonstrate that Riccardin D may inhibit human breast cancer growth through suppression of telomerase activity. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-06T02:46:22.042794-05:
      DOI: 10.1111/bcpt.12267
  • Stimulation of Erythrocyte Cell Membrane Scrambling by Nystatin
    • Authors: Abaid Malik; Rosi Bissinger, Kashif Jilani, Florian Lang
      Abstract: The antifungal ionophore nystatin dissipates the Na+ and K+ gradients across the cell membrane leading to cellular gain of Na+ and cellular loss of K+. The increase of cellular Na+ concentration may result in Ca2+ accumulation in exchange for Na+. Increase of cytosolic Ca2+ activity ([Ca2+]i) and loss of cellular K+ fosters apoptosis‐like suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine‐exposure at the erythrocyte surface. The present study explored whether nystatin stimulates eryptosis. Cell volume was estimated from forward scatter, phosphatidylserine‐exposure from annexin V binding and [Ca2+]i from Fluo3‐fluorescence in flow cytometry. A 48‐hr exposure to nystatin (15 μg/ml) was followed by a significant increase of [Ca2+]i, a significant increase of annexin V binding and a significant decrease of forward scatter. The annexin V binding following nystatin treatment was significantly blunted in the nominal absence of extracellular Ca2+. Partial replacement of extracellular Na+ with extracellular K+ blunted the nystatin‐induced erythrocyte shrinkage but increased [Ca2+]i and annexin V binding. Nystatin triggers cell membrane scrambling, an effect at least partially due to entry of extracellular Ca2+. This article is protected by copyright. All rights reserved.
      PubDate: 2014-06-03T04:10:28.514081-05:
      DOI: 10.1111/bcpt.12279
  • Adjuvant Anticholinesterase Therapy for the Management of
           Epilepsy‐inducedMemory Deficit:A Critical Preclinical Study
    • Authors: Awanish Mishra; Rajesh Kumar Goel
      Abstract: Epilepsy is one of the major neurological disorders still awaiting safer drugs with improved antiepileptic effect and lesser side effects. Apart from epilepsy itself, AEDs also have been shown to induce cognitive impairment in patients with epilepsy. There are limited data for the treatment of this menace. As cholinergic approach has widely been practiced for the restoration of memory in various neurodegenerative disorders, hence this study was envisaged to evaluate add on effect of acetylcholinesterase inhibitor (tacrine) with phenytoin in pentylenetetrazole‐kindling induced learning and memory deficit in mice. In this study, mice were kindled using subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.; at interval of 48±2 hr) andsuccessfully kindled animals were divided into different groups and treated with vehicle, phenytoinand phenytoinin combination with tacrine (0.3 mg/kg), atropine (1 mg/kg) and tacrine + atropine. Effect of different interventions on learning and memory was evaluated using elevated plus maze and passive shock avoidance on days 5, 10, 15 and 20. Phenytoin‐treated kindled animals were associated with learning and memory deficit, while tacrinesupplementation improved memory deficit with increased seizure severity score. Atropine treatment significantly reversed the protective effect of tacrine. Neurochemical findingsalso support the behavioural finding of the study. Our results suggest the use of anticholinesterases, with better seizuretolerance, for the management of cognitive impairment of epilepsy, as adjunct therapy. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-30T00:08:22.880888-05:
      DOI: 10.1111/bcpt.12275
  • Pharmacogenetics, Plasma Concentrations, Clinical Signs and EEG during
           Propofol Treatment
    • Authors: Muhammad Suleman Khan; Eva‐Lena Zetterlund, Henrik Gréen, Anna Oscarsson, Anna‐Lena Zackrisson, Eva Svanborg, Maj‐Lis Lindholm, Harald Persson, Christina Eintrei
      Abstract: A variety of techniques have been developed to monitor the depth of anaesthesia. Propofol's pharmacokinetics and response vary greatly, which might be explained by genetic polymorphisms. We investigated the impact of genetic variations on dosage, anaesthetic depth, and recovery after total intravenous anaesthesia with propofol. A total of 101 patients were enrolled in the study. The plasma concentration of propofol during anaesthesia was measured using high‐performance liquid chromatography. EEG was monitored during the surgical procedure as a measure of anaesthetic depth. Pyrosequencing was used to determine genetic polymorphisms in CYP2B6, CYP2C9, the UGTIA9‐promotor and the GABRE gene. The correlation between genotype and to plasma concentration at the time of loss of consciousness (LOC), the total induction dose, the time to anaesthesia, eye opening and clearance were investigated. EEG monitoring showed that the majority of the patients had not reached a sufficient level of anaesthetic depth (sub‐delta) at the time of loss of consciousness despite a high induction dose of propofol. Patients with UGT1A9‐331C/T had a higher propofol clearance than those without (p=0.03) and required a higher induction dose (p=0.03). The patients with UGT1A9 ‐1818T/C required a longer time to LOC (p=0.03). The patients with CYP2C9*2 had a higher concentration of propofol at the time of LOC (p=0.02). The polymorphisms in the metabolizing enzymes and the receptor could not explain the large variation seen in the pharmacokinetics of propofol and the clinical response seen. At LOC, the patients showed a large difference in EEG pattern. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-28T11:40:31.061649-05:
      DOI: 10.1111/bcpt.12277
  • Geraniol Blocks Calcium And Potassium Channels In The Mammalian
           Myocardium: Useful Effects To Treat Arrhythmias
    • Authors: José Evaldo Rodrigues Menezes‐Filho; Antônio Nei Santana Gondim, Jader Santos Cruz, Américo Azevedo Souza, José Nilson Andrade dos Santos, Eduardo Antônio Conde‐Garcia, Damião Pergentino Sousa, Michel Santana Santos, Evaleide Diniz Oliveira, Carla Maria Lins Vasconcelos
      Abstract: Geraniol is a monoterpene present in several essential oils and it is known to have a plethora of pharmacological activities. In this study, we explored the contractile and electrophysiological properties of geraniol and its antiarrhythmic effects in the heart. The geraniol effects on atrial contractility, L‐type Ca2+ current, K+ currents, action potential (AP) parameters, ECG profile and on the arrhythmia induced by ouabain were evaluated. In the atrium, geraniol reduced the contractile force (~98%, EC = 1,510 ± 160 μM) and diminished the positive inotropism of CaCl2 and BAY K8644. In cardiomyocytes, the ICa,L was reduced by 50.7% (n = 5) after perfusion with 300 μM geraniol. Moreover, geraniol prolonged the AP duration (APD) measured at 50% (n = 5) after repolarization, without changing the resting potential. The increased APD could be attributed to the blockade of the transient outward K+ current (Ito) (59.7%, n = 4), the non‐inactivation K+ current (Iss) (39.2%, n = 4), and the inward rectifier K+ current (IK1) (33.7%, n = 4). In isolated hearts, geraniol increased PRi and QTi without affecting the QRS complex (n = 6), and it reduced both the left ventricular pressure (83%) and heart rate (16.5%). Geraniol delayed the time to onset of ouabain‐induced arrhythmias by 128%, preventing 30% of the increase in resting tension (n = 6). Geraniol exerts its negative inotropic and chronotropic responses in the heart by decreasing both L‐type Ca2+ and voltage‐gated K+ currents, ultimately acting against ouabain‐induced arrhythmias. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-26T23:47:14.898932-05:
      DOI: 10.1111/bcpt.12274
  • Adverse Drug Reactions Causing Hospital Admissions in Childhood: A
           Prospective, Observational, Single‐Centre Study
    • Authors: Petra Langerová; Jiří Vrtal, Karel Urbánek
      Abstract: Adverse drug reactions (ADRs) are common problems in both paediatric and adult medicine. The aim of this study was to prospectively identify the ADRs causing hospital admission of children and identification of the risk factors and involved drugs. The study was performed at the University Hospital in Olomouc, Czech Republic. All patients aged 19 years or under admitted to hospital were included in the study, and all admissions for ADRs were prospectively screened for a period of nine months. Suspected ADRs were subsequently evaluated in detail and causality assessment was undertaken to determine whether each suspected reaction was possible, probable or definite. The assessment of ADR causality was performed using the Naranjo algorithm, the Liverpool ADR Causality Assessment Tool and the Edwards & Aronson causality assessment method. During the study period, 2,903 admissions were identified; of these, there were 143 admissions of patients with an oncological disease. Sixty‐four admissions (2.2%) were caused by an ADR. Anticancer chemotherapy accounted for 35% of the cases, followed by antibiotics (18%), immunosuppressants and vaccines (9% each). The use of different scoring systems does not lead to differences in the numbers of ADRs diagnosed but may result in differences in the determination of the level of certainty. ADRs cause a substantial proportion of children's hospital admissions. The majority of the ADRs diagnosed affected the hematopoietic and gastrointestinal systems; the drugs most frequently involved were cytotoxic agents and antibiotics. The most important risk factors identified were female sex and oncological disease. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-26T04:58:07.26363-05:0
      DOI: 10.1111/bcpt.12264
  • Anti‐metastatic Effects of Licochalcone B on Human Bladder
           CarcinomaT24 by Inhibition of MMP‐9 and NF‐кB Activity
    • Authors: Hong Zhao; Xuan Yuan, Jiangtao Jiang, Penglong Wang, Xiling Sun, Dong Wang, Qiusheng Zheng
      Abstract: This study investigated the mechanisms by which licochalcone B (LCB) inhibits the adhesion,invasion and metastasis of human malignant bladder cancer T24 cells. Cell viability was evaluated using a sulforhodamine B (SRB) assay. Cell migration and invasion ability was conducted using wound‐healing assay and matrigel transwell invasion assay. The activities of matrix metalloproteinases (MMP)‐2 and MMP‐9 were measured by gelatin zymography protease assays. The expression in protein level of NF‐κBP65 and AP‐1 was determined using the ELISA method; the protein levels of MMP‐9, NF‐κBP65, IκBα and P‐IκBα were detected by Western blot. The expression in mRNA level of MMP‐9 was assessed using quantitative real‐time polymerase chain reaction (PCR) and reverse transcription‐PCR. The results indicated that LCB attenuated T24 cell migration, adhesion and invasion in a concentration‐dependent manner. LCB treatment down‐regulated the mRNA expression, protein expression and activity of matrix metalloproteinases (MMP)‐9 but had no effect on MMP‐2. In addition, LCB treatment decreased the protein level of NF‐кBP65 and nuclear translocation of NF‐кB. These findings suggested that LCB attenuated bladder cancer T24 cells migration, adhesion and invasion accompanied with down‐regulation protein expression of MMP‐9 and the nuclear translocation of NF‐кB, Our results provide support that LCB may be a potent adjuvant therapeutic agent in the prevention and therapy of bladder cancer. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-26T01:45:19.979319-05:
      DOI: 10.1111/bcpt.12273
  • Effects of Colistin on the Sensory Nerve Conduction Velocity and
           F‐wave in Mice
    • Authors: Chongshan Dai; Shusheng Tang, Jichang Li, Jiping Wang, Xilong Xiao
      Abstract: The aim of this study was to examine the changes of sensory nerve conduction velocity (SNCV) and F‐wave for colistin‐induced peripheral neurotoxicity using a mouse model. Mice were administered with colistin 5, 7.5 and 15 mg/kg/d via a 3‐min. intravenous infusion. The sensory nerve conduction velocity (SNCV) and F‐wave were measured using the bipolar recording electrodes. The SNCV and F‐wave latency changed in a dose‐ and time‐dependent manner. The significant increase of F‐wave latency and significant decrease of SNCV appeared on day 3 (p < 0.05 and 0.01, respectively) in the 15 mg/kg/d group, and they were markedly changed on day 7 in the 7.5 mg/kg/d (p < 0.01 and 0.05, respectively) and 15 mg/kg/d groups (both p < 0.01). In addition, F‐wave latency also significantly increased on day 7 in the 5 mg/kg/d group (p < 0.05) without any clinical signs. These results indicate that SNCV and F‐wave latency were more sensitive in colistin‐induced neurotoxicity in mice, which highlights the early monitoring tool of polymyxins neurotoxicity in the clinic. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-26T01:45:18.839703-05:
      DOI: 10.1111/bcpt.12272
  • [3H]‐L685,458 Binding Sites are abundant in Multiple Peripheral
           Organs in Rats: Implications for Safety Assessment of Putative
           γ‐secretase Targeting Drugs
    • Authors: Zhi‐Ying Yang; Jian‐Ming Li, Ling Xiao, Lin Mou, Yan Cai, He Huang, Xue‐Gang Luo, Xiao‐Xin Yan
      Abstract: γ‐Secretase is a multimeric enzyme complex that carries out proteolytic processing to a variety of cellular proteins. It is currently explored as a therapeutic target for Alzheimer's disease (AD) and cancer. Mechanism‐based toxicity needs to be thoroughly evaluated for γ‐secretase inhibitory and/or modulatory drugs. The present study comparatively assessed putative γ‐secretase catalytic sites in rat peripheral tissues relative to brain, and explored an effort of its pharmacological inhibition on hair regeneration. Using [3H]‐labeled L685,458, a potent γ‐secretase inhibitor, as probe, we found more abundant presence of γ‐secretase binding sites in the liver, gastrointestinal tract, hair follicle, pituitary gland, ovary and testis, as compared to the brain. Local application of L658,458 delayed vibrissal regrowth following whisker removal. These results suggest that γ‐secretase may execute important biological functions in many peripheral systems, as in the brain. The development of γ‐secretase inhibitors/modulators for AD and cancer therapy should include close monitoring of toxicological panels for hepatic, gastrointestinal, endocrinal and reproductive functions. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-26T01:45:17.906861-05:
      DOI: 10.1111/bcpt.12271
  • Chemotherapy‐Induced Polyneuropathy: Major Agents and Assessment by
    • Authors: Ahmed H. Zedan; Ole J. Vilholm
      Abstract: Chemotherapy‐induced polyneuropathy (CIPN) is a common, but underestimated, clinical challenge. Incidence varies depending on many factors that are equally as important as the type of chemotherapeutic agent itself. Moreover, the assessment of CIPN is still uncertain, as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients’ reports and examiners’ interpretations. Therefore, the aim of this MiniReview is to introduce the most common chemotherapies that cause neuropathy, and in addition to this, highlight the most significant differences between the neuropathic pain scales, which are most commonly used for assessing CIPN. Polyneuropathy induced by chemotherapies is often described as ‘Chemotherapy‐induced polyneuropathy’(CIPN). CIPN is frequently recorded in patients treated with platinum drugs, Antitubulins, Thalidomide and Bortezomib, representing one of the most severe and potentially dose‐limiting non‐haematological toxic side effects. CIPN commonly occurs in 30 ‐ 40% of patients, but its incidence can vary from 0 ‐ 70% [1].In a significant proportion of patients, CIPN severity can progress months after the discontinuation of treatment, a phenomenon known as ‘coasting’ [2]. This MiniReview will discuss the main features of the CIPN regarding clinical presentation with an overview of the most commonly used scales in the assessment of the CIPN. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-24T02:00:44.865425-05:
      DOI: 10.1111/bcpt.12262
  • Evidence for Involvement of Spinal RANTES in the Antinociceptive Effects
    • Authors: Li‐Hua Hang; Shu‐Na Li, Dong‐Hua Shao, Zheng Chen, Yuan‐Feng Chen, Wei‐Wei Shu
      Abstract: It has been shown that triptolide has beneficial effects in the treatment of neuropathic pain but its effects on bone cancer pain (BCP) remain unclear. In the present study, we aimed to explore the potential role of spinal regulated on activation normal T cell expressed and secreted (RANTES) in the antinociceptive effects of triptolide on BCP. A BCP model was induced by injecting Walker 256 mammary gland carcinoma cells into the intramedullary space of rat tibia. Intrathecal administration of triptolide (0.5, 1, 2 μg) could dose‐dependently alleviate mechanical hyperalgesia and spontaneous pain. In addition, there were also concomitant decreases in RANTES mRNA and protein expression levels in spinal dorsal horn. These results suggest that the antinociceptive effects of triptolide are related with inhibition of spinal RANTES expression in BCP rats. The findings of this study may provide a promising drug for the treatment of BCP. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-24T02:00:18.986428-05:
      DOI: 10.1111/bcpt.12265
  • Drug‐Induced Peripheral Neuropathy
    • Authors: Ole J. Vilholm; Alex A. Christensen, Ahmed H. Zedan, Mustapha Itani
      Abstract: Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term ‘drug‐induced peripheral neuropathy’ (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated with DIPN. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-19T23:38:20.601385-05:
      DOI: 10.1111/bcpt.12261
  • The Neuronal Cytoskeleton as a Potential Target in the Developmental
           Neurotoxicity of Organophosphorothionate Insecticides
    • Authors: John Flaskos
      Abstract: Phosphorothionates are toxicologically the most important class of organophosphorus ester (OP) insecticides. Phosphorothionates are metabolically converted in vivo to their oxon analogues. These oxon metabolites can bind and inhibit acetylcholinesterase, thus causing acute cholinergic neurotoxicity. Oxon binding to the same target may also be partly responsible for manifestation of the ‘intermediate syndrome’. More recent evidence suggests that the oxons may be also capable of inducing developmental neurotoxicity. The neuronal cytoskeleton may represent a potential target for the developmental neurotoxicity of the oxons because of its vital importance in many stages of normal neurodevelopment. Data obtained in the last five years and critically reviewed here indicate that the oxon metabolites, at concentrations that can be attained in vivo, exert potent effects on the neuronal cytoskeleton disrupting all three cytoskeletal networks. This disruption is expressed at the level of cytoskeletal protein expression, intracellular distribution, post translational modification, cytoskeletal dynamics and function and may involve effects on both neuronal and glial cells. These effects are not secondary to other changes but may constitute primary effects of the oxons, as these compounds have been shown to be capable of covalently binding to and organophosphorylating multiple sites on tubulin and actin. Analogous studies must be extended to include other neurodevelopmentally important cytoskeletal proteins, such as NFH, NFM and tau, which are known to contain unusually high numbers of phosphorylatable sites and to establish whether organophosphorylation by the oxons takes place at sites where neurodevelopmentally relevant, endogenous, reversible phosphorylation is known to occur. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-16T04:07:36.775188-05:
      DOI: 10.1111/bcpt.12204
  • Professor Folke Sjöqvist is the 2013 BCPT Nordic Prize Winner in
           Basic & Clinical Pharmacology & Toxicology
    • Authors: Kim Brøsen
      Abstract: Professor Folke Sjöqvist who recently turned 80, is still very active and has accomplished remarkable results in many areas of Clinical Pharmacology. He began his thesis work under the pharmacologist‐toxicologist pioneer Professor Bo Holmstedt and with Professor Börje Uvnäs chairing the institution at the Karolinska Institute in Stockholm. The thesis concerned basic experimental pharmacology and ganglionic autonomic transmission. He then had a long postdoc in the USA where his scientific interest was profoundly reoriented towards clinical pharmacology. The most important influence was in the laboratory of the legendary Bernard B. Brodie at the National Institutes of Health (NIH). Professor Sjöqvist became engaged in the new fields of drug metabolism exploring the roles of species and interindividual differences and innovative methods for specific chemical drug analysis. He also studied clinical trial methodology with Professor Louis Lasagna at Johns Hopkins in Baltimore. This article is protected by copyright. All rights reserved.
      PubDate: 2014-05-05T01:14:28.97447-05:0
      DOI: 10.1111/bcpt.12247
  • At the Centennial of Michaelis and Menten, Competing
           Michaelis–Menten Steps Explain Effect of GLP‐1 on
           Blood–Brain Transfer and Metabolism of Glucose
    • Abstract: Glucagon‐like peptide‐1 (GLP‐1) is a potent insulinotropic incretin hormone with both pancreatic and extrapancreatic effects. Studies of GLP‐1 reveal significant effects in regions of brain tissue that regulate appetite and satiety. GLP‐1 mimetics are used for the treatment of type 2 diabetes mellitus. GLP‐1 interacts with peripheral functions in which the autonomic nervous system plays an important role, and emerging pre‐clinical findings indicate a potential neuroprotective role of the peptide, for example in models of stroke and in neurodegenerative disorders. A century ago, Leonor Michaelis and Maud Menten described the steady‐state enzyme kinetics that still apply to the multiple receptors, transporters and enzymes that define the biochemical reactions of the brain, including the glucose‐dependent impact of GLP‐1 on blood–brain glucose transfer and metabolism. This MiniReview examines the potential of GLP‐1 as a molecule of interest for the understanding of brain energy metabolism and with reference to the impact on brain metabolism related to appetite and satiety regulation, stroke and neurodegenerative disorders. These effects can be understood only by reference to the original formulation of the Michaelis–Menten equation as applied to a chain of kinetically controlled steps. Indeed, the effects of GLP‐1 receptor activation on blood–brain glucose transfer and brain metabolism of glucose depend on the glucose concentration and relative affinities of the steps both in vitro and in vivo, as in the pancreas.
  • The Impact of NSAID Treatment on Cardiovascular Risk – Insight from
           Danish Observational Data
    • Abstract: This MiniReview describes the present evidence for the relationship between cardiovascular risk and use of non‐steroidal anti‐inflammatory drugs (NSAIDs) with special focus using Danish register‐based data. NSAIDs are among the most widely used drugs worldwide and mainly used for management of pain and inflammatory conditions. Through the past decade, much attention has been given to the cardiovascular safety of these drugs, and several studies have shown increased risk of adverse cardiovascular effects associated with NSAID use. Current guidelines discourage any use of NSAIDs in patients with cardiovascular disease, yet over a period of 8–10 years, 35–44% of patients with myocardial infarction or heart failure were exposed to NSAIDs in Denmark. Furthermore, NSAID use was associated with an increased risk of death or myocardial infarction by up to 5 times that of non‐users. There was also a clear indication for a dose‐related response in risk associated with NSAID therapy, supporting a causal association. Notably, the cardiovascular risk associated with NSAID treatment was prevalent at start of treatment, suggesting no safe treatment window for NSAIDs in patients with cardiovascular disease. Thus, evidence from observational studies is accumulating, suggesting that NSAIDs are a major public health concern due to the widespread use of these drugs. Although it seems unlikely that we can completely avoid use of NSAIDs, even among high‐risk patients, these results highlight the importance of balancing the benefit versus the risk of treatment before initiating NSAID treatment.
  • Inhibition of UVB‐induced Skin Damage by Exopolymers from
           Aureobasidium pullulans SM–2001 in Hairless Mice
    • Abstract: Because antioxidants from natural sources may be an effective approach to the treatment and prevention of UV radiation‐induced skin damage, the effects of purified exopolymers from Aureobasidium pullulans SM‐2001 (“E‐AP‐SM2001”) were evaluated in UVB‐induced hairless mice. E‐AP‐SM2001 consists of 1.7% β‐1,3/1,6‐glucan, fibrous polysaccharides and other organic materials, such as amino acids, and mono‐ and di–unsaturated fatty acids (linoleic and linolenic acids), and shows anti‐osteoporotic and immunomodulatory effects, through anti‐oxidant and anti‐inflammatory mechanisms. Hairless mice were treated topically with vehicle, E‐AP‐SM2001 stock and two‐ and four‐fold diluted solutions once per day for 15 weeks against UVB irradiation (three times per week at 0.18 J/cm2). The following parameters were evaluated in skin samples: myeloperoxidase (MPO) activity, cytokine levels (interleukin (IL)‐1β and IL‐10), endogenous antioxidant content (glutathione, GSH), malondialdehyde (MDA) levels, superoxide anion production; matrix metalloproteases (MMP‐1, ‐9 and ‐13), GSH reductase and Nox2 (gp91phox) mRNA levels, and immunoreactivity for nitrotyrosine (NT), 4‐hydroxynonenal (HNE), caspase‐3, and cleaved poly(ADP‐ribose) polymerase (PARP). Photoageing was induced by UVB irradiation through ROS‐mediated inflammation, which was related to the depletion of endogenous antioxidants, activation of MMPs and keratinocyte apoptosis. Topical treatment with all three doses of E‐AP‐SM2001 and 5 nM myricetin attenuated the UV‐induced depletion of GSH, activation of MMPs, production of IL‐1β, the decrease in IL‐10 and keratinocyte apoptosis. In the present study, E‐AP‐SM2001 showed potent inhibitory effects against UVB‐induced skin photoageing. Thus, E‐AP‐SM2001 may be useful as a functional ingredient in cosmetics, especially as a protective agent against UVB‐induced skin photoageing. This article is protected by copyright. All rights reserved.
  • R1: Effects of Anti‐Hypertensive and Triglyceride Lowering Agents on
           Hepatic Copper Concentrations in Rats with Fatty Liver Disease
    • Abstract: Copper deficiency had been suggested to link between fructose‐enriched diet (FED) and the development of non‐alcoholic fatty liver disease (NFALD). In this study, we characterized changes in hepatic copper concentrations and hepatic oxidative milieu, in rats with the metabolic syndrome and NAFLD as a result of FED with pharmacological manipulations to reduce blood pressure or plasma triglycerides. Changes in plasma and hepatic copper concentrations were correlated with changes observed in the immunohistochemical hepatic expression of copper–zinc–superoxide dismutase (CuZnSOD; SOD1), metallothionein (MT) and nitrotyrosine (NITT). FED administration was associated with a 2.2‐fold reduction in hepatic copper concentrations, a decrease in the hepatic SOD1 expression, disappearance of the hepatic MT expression and increase in the hepatic NITT expression. Bezafibrate administration restored the hepatic copper concentrations and the hepatic SOD1 expression to levels that were observed in the control rats. A significant positive correlation between hepatic copper concentrations and the values of hepatic SOD1 expression of each animal included in this study was found. Administration of either captopril or bezafibrate increased hepatic MT expression, however, to levels that were lower than those observed in the control group. Administration of either amlodipine, or captopril or bezafibrate to the FED rats, had no effect on hepatic NITT expression. NAFLD development in FED rats is associated with a decrease in hepatic copper concentrations that is associated with a decrease in the hepatic SOD1 expression. Bezafibrate administration increases hepatic copper concentrations and restores the hepatic SOD1 expression. This article is protected by copyright. All rights reserved.
  • Oseltamivir Blocks Human Neuronal Nicotinic Acetylcholine
           Receptor‐mediated Currents
    • Abstract: The effects of oseltamivir, a neuraminidase inhibitor, were tested on the function of neuronal nicotinic acetylcholine receptors (nAChRs) in a neuroblastoma cell line IMR32 derived from human peripheral neurons, and on recombinant human α3β4 nAChRs expressed in HEK cells. IMR32 cells predominately express α3β4 nAChRs. Nicotine (nic, 30 μM)‐evoked currents recorded at −90 mV in IMR32 cells using the whole‐cell patch clamp technique were reversibly blocked by oseltamivir in a concentration‐dependent manner. In contrast, an active metabolite of oseltamivir, oseltamivir carboxylate (OC) at 30 μM had little effect on the nic‐evoked currents. Oseltamivir also blocked nic‐evoked currents derived from HEK cells with recombinant α3β4 nAChRs. This blockade was voltage‐dependent with 10, 30 and 100 μM oseltamivir inhibiting ~50% at −100, −60 and −40 mV, respectively. Non‐inactivating currents in IMR32 cells and in HEK cells with α3β4 nAChRs, which were evoked by an endogenous nicotinic agonist, ACh (5 μM), were reversibly blocked by oseltamivir. These data demonstrate that oseltamivir blocks nAChRs, presumably via binding to a site in the channel pore. This article is protected by copyright. All rights reserved.
  • Chlorpyrifos and Cypermethrin Induce Apoptosis in Human Neuroblastoma Cell
           Line SH‐SY5Y
    • Abstract: Our previous in vivo studies showed that chlorpyrifos (CPF) and cypermethrin (CM) in a mixture dermally administered, strongly inhibited cholinesterase activity in plasma and the brain and were very toxic to the rat central nervous system. In this work, the mechanisms of neurotoxicity have not been elucidated. We used human undifferentiated SH‐SY5Y cells to study mechanisms of pesticide‐induced neuronal cell death. It was found that chlorpyrifos (CPF) and its mixture with cypermethrin (CPF+CM) induced cell death of SH‐SY5Y cells in a dose‐ and time‐dependent manner, as shown by MTT assays. Pesticide‐induced SH‐SY5Y cell death was characterized by concentration‐dependent down‐regulation of Bcl‐2 and Bcl‐xL as well as an increase in the caspase 3 activation. Pan‐caspase inhibitor Q‐VD‐OPh produced a slight but significant reversal effect of pesticide‐induced toxicity indicating that the major caspase pathways are not integral to CPF‐ and CPF+CM‐induced cell death. Furthermore, signal transduction inhibitors PD98059, SL‐327, SB202190, SP600125 and mecamylamine failed to attenuate pesticides effect. Atropine exhibited minimal ability to reverse toxicity. Finally, it was shown that inhibition of TNF‐α by pomalidomide attenuated CPF‐/CPF+CM‐induced apoptosis. Overall, our data suggest that FAS/TNF signalling pathways may participate in CPF and CPF+CM toxicity.
  • Polymorphisms in CYP2D6 have a Greater Effect on Variability of
           Risperidone Pharmacokinetics than Gender
    • Abstract: Within‐subject coefficient of variation (CVw) plays a decisive role in the determination of sample size in bioequivalence clinical trials. Highly variable drugs may require the participation of a large number of subjects. The aim of this study was to investigate whether gender and polymorphisms in CYP2D6 affect the CVw of risperidone. Two single‐dose, two‐period crossover studies of risperidone (n = 70) were reanalysed to calculate CVw for AUCt and Cmax. Subjects were classified into four different CYP2D6 phenotype groups [poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM)]. The effect of gender was evaluated in EM and IM. CVw was lower in PM (13.3% for AUCt and 10.9% for Cmax) and UM (17.4% and 8.7%) than in EM (28.7% and 34.7%) and IM (33.2% and 27.3%). Variability was slightly lower in women (27.9% for AUCt and 25.7% for Cmax) than in men (33.3% and 37.2%, respectively). Genetic polymorphisms affect within‐subject variability more than gender and could considerably affect sample size calculation. Therefore, subjects participating in bioequivalence trials should be genotyped.
  • CYP2D6‐Inhibiting Drugs and the Increased Risk of Fall‐Related
           Injuries Due to Newly Initiated Opioid Treatment – A Swedish,
           Register‐Based Case‐Cross over Study
    • Abstract: It has been shown that newly initiated opioid therapy increases the risk of fall‐related injuries. Yet, it remains to be determined whether drug–drug interactions can affect this negative effect, for instance with drugs inhibiting cytochrome P4502D6 (CYP2D6) that metabolizes codeine and also has a partial effect on tramadol and oxycodone. Our aim was to investigate how CYP2D6‐inhibiting drugs contribute to explaining the risk of fall‐related injuries for newly initiated opioid treatments with codeine, tramadol or oxycodone. Data from a Swedish national case‐cross over study were revisited. This study identified a total of 167,257 fall‐related injuries leading to hospitalization that occurred between 1 May 2006 and 31 December 2009 and linked information about dispensed drugs to them. Use of newly dispensed opioids in the 28 days before fall‐related injury with and without CYP2D6‐inhibiting drugs was compared with an earlier control period. For codeine, there was a two‐times increased risk with concomitant CYP2D6‐inhibiting drug use (OR, 1.76; 95% CI 1.40–2.20) and a three‐times risk increase without (OR, 3.17; 95% CI 2.88–3.50). For tramadol, the risks were doubled when CYP2D6‐inhibiting drugs were used (OR, 2.19; 95% CI 1.84–2.60) and tripled without their use (OR, 3.04; 95% CI 2.82–3.27). The risks were about the same for oxycodone, morphine, fentanyl and buprenorphine irrespective of CYP2D6‐inhibiting drug use. In newly initiated opioid therapies, drug–drug interactions from concomitant use of CYP2D6‐inhibiting drugs are associated with a lower risk of fall‐related injury for codeine and tramadol that undergo metabolism via CYP2D6, but not for other opioids.
  • PI3K Inhibitors LY294002 and IC87114 Reduce Inflammation in
           Carrageenan‐Induced Paw Oedema and Down‐Regulate Inflammatory
           Gene Expression in Activated Macrophages
    • Abstract: PI3K/Akt pathway is a well‐characterized pathway controlling cellular processes such as proliferation, migration and survival and its role in cancer is vastly studied. There is also evidence to suggest the involvement of this pathway in the regulation of inflammatory responses. In the present study, an attempt was made to investigate the role of PI3Ks in acute inflammation in vivo by using pharmacological inhibitors against PI3Ks in the carrageenan‐induced paw oedema model. A non‐selective PI3K inhibitor LY294002 and a PI3Kδ‐selective inhibitor IC87114 were used. Both of these inhibitors reduced inflammatory oedema upon carrageenan challenge in the mouse paw. To explain this result, the effects of the two inhibitors on inflammatory gene expression were investigated in activated macrophages. LY294002 and IC87114 prevented Akt phosphorylation as expected and down‐regulated the expression of inflammatory factors IL‐6, MCP‐1,TNFα and iNOS. These findings suggest that PI3K inhibitors could be used to attenuate inflammatory responses and that the mechanism of action behind this effect is the down‐regulation of inflammatory gene expression. This article is protected by copyright. All rights reserved.
  • Renoprotective Effects of Gamma‐Aminobutyric Acid (GABA) on
           Cisplatin‐induced Acute Renal Injury in Rats
    • Abstract: To investigate the effect of gamma‐aminobutyric acid (GABA) on acute renal injury (ARI), we used here a rat model of acute tubular necrosis induced by the anticancer drug cisplatin (CP). GABA was given orally (100 or 500 mg/kg/day for ten consecutive days), and on the 6th day, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Four days after CP treatment, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous injection of norepinephrine for the assessment of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several functional, biochemical and structural parameters. GABA treatment (at 500 but not 100 mg/kg) significantly mitigated all the measured physiological and biochemical indices. Sections from saline‐ and GABA‐treated rats showed apparently normal proximal tubules. However, kidneys of CP‐treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with GABA (500 mg/kg). The concentration of platinum in the cortical tissues was not significantly altered by GABA treatment. The results suggested that GABA can ameliorate CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies, GABA may be considered a potentially useful nephroprotective agent in CP–induced ARI. This article is protected by copyright. All rights reserved.
  • Matrix Metalloproteinases are Involved in Cardiovascular Diseases
    • Abstract: This MiniReview describes the essential biochemical and molecular aspects of matrix metalloproteinases (MMPs) and briefly discusses how they engage in different diseases, with particular emphasis on cardiovascular diseases. There is compelling scientific evidence that many MMPs, especially MMP‐2, play important roles in the development of cardiovascular diseases; inhibition of these enzymes is beneficial to many cardiovascular conditions, sometimes precluding or postponing end‐organ damage and fatal outcomes. Conducting comprehensive discussions and further studies on how MMPs participate in cardiovascular diseases is important, because inhibition of these enzymes may be an alternative or an adjuvant for current cardiovascular disease therapy.
  • Exogenous Metallothionein Potentiates the Insulin Response at Normal
           Glucose Concentrations in INS‐1E Beta Cells without disturbing
           Intracellular ZnT8 Expression
    • Abstract: As a consequence of the global epidemic of obesity, the incidence of type 2 diabetes (T2D) is increasing worldwide. T2D is characterized by hyperglycaemia, hyper‐insulinaemia and a reduced insulin response in muscular and fatty tissue. Over time, an increased insulin demand leads to cellular fatigue and death of the insulin producing β‐cells. In response, the T2D patients become insulin‐dependent and subjected to the boundaries of life‐long insulin treatment. Preservation of β‐cell insulin secretion and a sufficient β‐cell mass is thus a corner stone in optimal TD2 treatment. This article is protected by copyright. All rights reserved.
  • Intravenous Lipid Emulsion Improves Recovery Time and Quality from
           Isoflurane Anaesthesia: A Double‐Blind Clinical Trial
    • Abstract: Recovery time and quality after general anaesthesia is important for patient safety. This study aimed to determine whether intravenous lipid emulsion could improve recovery profiles from isoflurane anaesthesia in adult patients undergoing laparoscopic cholecystectomy. Sixty‐six patients were enrolled. After anaesthesia induction, inspired isoflurane concentration was adjusted to maintain stable vital signs and the suitable conditions for operation. At the end of the operation, the isoflurane was discontinued, and either 2 ml/kg 30% lipid emulsions or 0.9% saline solution was administered intravenously. The time to eye opening, extubation and exit from the operation room was recorded, and the quality of recovery from anaesthesia was assessed. Sixty patients completed the study. The median time to eye opening and exit from the operation room was significantly shorter in the lipid emulsion group than in the saline group [15.5 (interquartile range 9.0) versus 20.0 (10.0) min., p = 0.01; 19.5 (8.3) versus 23.6 (6.3) min., p = 0.04, respectively], whereas the median time to extubation did not show any noticeable difference. The quality of recovery was better in the lipid emulsion group than that of the saline solution group with respect to drowsiness visual analogue scale score (p 
  • Induction of Neurotrophic and Differentiation Factors in Neural Stem Cells
           by Valproic Acid
    • Abstract: Valproic acid (VPA), a short‐chain fatty acid, is used clinically as an anticonvulsant and mood stabilizer. Valproic acid also inhibits histone deacetylase activity, which is associated with histone hyperacetylation and changes in gene expression. In this study, we examined the effects of VPA on the expression of selected neurotrophic and differentiation factors in C17.2 neural stem cells. Reverse transcription‐polymerase chain reaction analysis revealed a significant increase in conserved dopamine neurotrophic factor (CDNF) and glial cell line‐derived neurotrophic factor mRNA expression, after treatment with clinically relevant concentrations of VPA (0.5 or 1.0 mM) for 24 hr. Increases in the protein expression of CDNF and mesencephalic astrocyte‐derived neurotrophic factor were also observed, after similar treatment with VPA. In addition, significant increases in the mRNA levels of the early dopaminergic neuron marker, nuclear receptor‐related protein 1(Nurr1), and the transcriptional regulator, early growth response protein 1 (Egr1), were observed after treatment with VPA for 24 hr. C17.2 neural stem cells exhibited high basal mRNA expression of brain‐derived neurotrophic factor and SRY (sex determining region Y)‐box 2 (Sox2), which was not altered by VPA treatment. Western analysis revealed hyperacetylation of histone H3 proteins in C17.2 cells after VPA treatment for 24 hr or 48 hr, suggesting involvement of an epigenetic mechanism in the observed gene induction by this drug. These findings support a role for VPA in modulating neurotrophic and differentiation factor expression, in keeping with its reported neuroprotective and neurodevelopmental effects.
  • Preventative Effect of Zingiber officinale on Insulin Resistance in a
           High‐Fat High‐Carbohydrate Diet‐Fed Rat Model and its
           Mechanism of Action
    • Abstract: Insulin resistance is a core component of metabolic syndrome and usually precedes the development of type 2 diabetes mellitus. We have examined the preventative effect of an ethanol extract of ginger (Zingiber officinale, Zingiberaceae) on insulin resistance in a high‐fat high‐carbohydrate (HFHC) diet‐fed rat model of metabolic syndrome. The HFHC control rats displayed severe insulin resistance, whilst rats treated with ginger extract (200 mg/kg) during HFHC diet feeding showed a significant improvement of insulin sensitivity using the homeostatic model assessment of insulin resistance (HOMA‐IR) after 10 weeks (p 
  • Quality Indicators as a Tool in Improving the Introduction of New
    • Abstract: Quality indicators are increasingly used as a tool to achieve safe and quality clinical care, cost‐effective therapy, for professional learning, remuneration, accreditation and financial incentives. A substantial number focus on drug therapy but few address the introduction of new medicines even though this is a burning issue. The objective was to describe the issues and challenges in designing and implementing a transparent indicator framework and evaluation protocol for the introduction of new medicines and to provide guidance on how to apply quality indicators in the managed entry of new medicines. Quality indicators need to be developed early to assess whether new medicines are introduced appropriately. A number of key factors need to be addressed when developing, applying and evaluating indicators including dimensions of quality, suggested testing protocols, potential data sources, key implementation factors such as intended and unintended consequences, budget impact and cost‐effectiveness, assuring the involvement of medical professions, patients and the public, and reliable and easy‐to‐use computerised tools for data collection and management. Transparent approaches include the need for any quality indicators developed to handle conflicts of interests to enhance their validity and acceptance. The suggested framework and indicator testing protocol may be useful in assessing the applicability of indicators for new medicines and may be adapted to healthcare settings worldwide. The suggestions build on existing literature to create a field testing methodology that can be used to produce country‐specific quality indicators for new medicines as well as a pan‐international approach to facilitate access to new medicines. This article is protected by copyright. All rights reserved.
  • Phytoestrogen α‐Zearalanol exerts Anti‐Apoptotic Effects
           in Differentiated PC12 Cells via Estrogen Receptor α
    • Abstract: Our previous studies have demonstrated that phytoestrogen α‐zearalanol (α‐ZAL) possesses potential benefits in alleviating cell apoptotic death just like estrogen. However, the underlying mechanism is not fully understood. This study was designed to test the hypothesis that the neuroprotective effect of α‐ZAL is mediated by estrogen receptor (ER) since α‐ZAL owns the benzene ring structure may interact with ER. The present results showed a significant increase in apoptosis in differentiated PC12 cells following a 24‐hr exposure to amyloid β‐peptide fragment 25‐35 (Aβ25‐35), accompanied by decreasing of bcl‐2 expression and increasing bax expression, whereas a pre‐treatment with α‐ZAL ameliorated these changes induced by Aβ25‐35. In addition, the α‐ZAL‐mediated cytoprotection was abrogated by ERα antagonist but not by ERβ antagonist. In summary, these data suggest that α‐ZAL intervenes against Aβ‐induced apoptosis via intersecting bcl‐2‐bax apoptotic pathway in an ERα‐sensitive manner. This article is protected by copyright. All rights reserved.
  • Efficacy and Safety of PPC‐5650 on Experimental Rectal Pain in
           Patients with Irritable Bowel Syndrome
    • Abstract: PPC‐5650 is a new pharmacological agent that can modulate acid‐sensing ion channel activity, leading to a reduction in the pain signal under up‐regulated conditions. The non‐clinical programme for PPC‐5650 supported a role for this novel agent in the treatment of pain in patients with irritable bowel syndrome (IBS). In IBS patients, the aims of the study were: 1) to assess the efficacy of a single bolus of PPC‐5650 locally applied in the rectum using multimodal stimulations of the recto sigmoid and 2) to assess the safety profile of PPC‐5650. The study was a randomized, double‐blind, placebo‐controlled, cross‐over trial in IBS patients, excluding females of child‐bearing potential. The study consisted of a training visit, study visit 1 and 2 and a follow‐up visit. Rectosigmoid electrical, thermal and mechanical stimulations were performed, pain perception was rated on a pain intensity scale and referred pain areas were assessed. All adverse events were registered. Twenty‐five IBS patients were enrolled and completed the study (9 women and 16 men; mean age 50.4±12.7 years). No effects of the study drug were found on any of the rectal stimulations or for referred pain areas (all P>0.05). No significant or clinically relevant treatment‐related differences were seen for the laboratory safety variables or any other reported adverse event. In conclusion, in patients with IBS on rectal sensitivity to multimodal stimulations, PPC‐5650 did not produce efficacy relative to placebo. The overall safety and tolerability of PPC‐5650 was acceptable. This article is protected by copyright. All rights reserved.
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