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  Subjects -> ENVIRONMENTAL STUDIES (Total: 766 journals)
    - ENVIRONMENTAL STUDIES (703 journals)
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ENVIRONMENTAL STUDIES (703 journals)                  1 2 3 4 5 6 7 8 | Last

Acta Ecologica Sinica     Open Access   (Followers: 10)
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: 6)
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: 5)
AGE     Hybrid Journal   (Followers: 4)
Age and Ageing     Hybrid Journal   (Followers: 24)
Agricultura Tecnica     Open Access   (Followers: 6)
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: 14)
American Naturalist     Full-text available via subscription   (Followers: 37)
Annals of Environmental Science     Open Access   (Followers: 9)
Annals of GIS     Hybrid Journal   (Followers: 15)
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: 37)
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: 5)
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: 28)
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: 18)
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: 13)
Business, Peace and Sustainable Development     Full-text available via subscription  
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: 19)
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: 3)
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: 21)
Civil and Environmental Research     Open Access   (Followers: 11)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 15)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 8)
Climate Change Economics     Hybrid Journal   (Followers: 16)
Climate Policy     Hybrid Journal   (Followers: 19)
Coastal Engineering Journal     Hybrid Journal   (Followers: 1)
Columbia Journal of Environmental Law     Free   (Followers: 8)
Computational Ecology and Software     Open Access   (Followers: 5)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 2)
Conservation and Society     Open Access   (Followers: 6)
Conservation Letters     Hybrid Journal   (Followers: 19)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (Followers: 9)
Construction Innovation: Information, Process, Management     Hybrid Journal   (Followers: 13)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 2)
Continental Journal of Renewable Energy     Open Access   (Followers: 9)
Continental Journal of Sustainable Development     Open Access   (Followers: 9)
Creativity and Innovation Management     Hybrid Journal   (Followers: 154)
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
   Journal TOC RSS feeds Export to Zotero [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  [1603 journals]   [SJR: 0.588]   [H-I: 56]
  • 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
  • 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
  • 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
  • Population Pharmacokinetic Meta‐Analysis of Vortioxetine in Healthy
    • Abstract: The objective was to describe the pharmacokinetics of vortioxetine and evaluate the effect of intrinsic and extrinsic factors in the healthy population. Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75 mg (single dose) and 2.5–60 mg (multiple QD doses). The pharmacokinetics of vortioxetine was best characterised by a two‐compartment model with first‐order absorption, lag‐time and linear elimination, with interindividual error terms for absorption rate constant, oral clearance and central volume of distribution. The population mean was 32.7 L/hr for oral clearance and 1.97∙103 L for the central volume of distribution. The average elimination half‐life was 65.8 hr. CYP2D6 inferred metabolic status (ultra, extensive, intermediate or poor metabolisers) and age on oral clearance and height on central volume of distribution were identified as statistically significant covariate–parameter relationships. For CYP2D6 poor metabolisers, CL/F was approximately 50% to that seen in CYP2D6 extensive metabolisers. The impact of height on V2/F and age on CL/F was low and not considered to be clinically relevant. The final model was found to be reliable, stable and predictive. A reliable, stable and predictive pharmacokinetic model was developed to characterise pharmacokinetics of vortioxetine in the healthy population.
  • Evidence for Involvement of Spinal RANTES in the Antinociceptive Effects
    • 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 this study, we aimed to explore the potential role of spinal regulated activation of 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.
  • Acute Effects of Dipyrone on Renal Function in Patients with Cirrhosis: A
           Randomized Controlled Trial
    • Abstract: Use of Non‐steroidal Anti‐Inflammatory Drugs in cirrhosis has been associated with impairment of renal function based on its ability to inhibit the renal production of prostaglandins. Renal effects of dipyrone in cirrhotic patients have not been evaluated. We aimed to assess the renal effect of therapeutic doses of dipyrone used for short periods of time in patients with cirrhosis. Twenty‐nine patients with cirrhosis were included in an observer‐blind clinical trial. Patients were randomized to receive three times a day oral acetaminophen (500 mg; N=15) or dipyrone (575 mg; N=14) for 72 hr. Serum and urine samples were obtained at baseline, 48 and 72 hr and cystatin C, creatinine, aldosterone, 6‐keto‐Prostaglandin‐F1 alpha and prostaglandin E2 were measured. Cystatin C and creatinine levels remained comparable in patients treated with acetaminophen and dipyrone. Urine and serum prostaglandins concentrations were significantly decreased at 72 hr in patients treated with dipyrone regardless of the status of ascites. One patient with ascites treated with dipyrone required a paracentesis and developed renal insufficiency. We conclude that dipyrone and acetaminophen did not reduce renal function when used for short periods of time (up to 72 hr) in patients with cirrhosis. However, considering that dipyrone lowered renal vasodilator prostaglandins synthesis, acetaminophen appears as the safest choice with respect to kidney function in cirrhosis. This article is protected by copyright. All rights reserved.
  • Pre‐clinical and Clinical Safety Studies of CMX‐2043: A
           Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury
    • Abstract: CMX‐2043 is an α‐lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre‐clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX‐2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14‐day repeat intravenous doses and in dogs (single intravenous dose) with a 2‐week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo‐controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre‐clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX‐2043 in a human efficacy trial.
  • Nifedipine versus Terbutaline, Tocolytic Effectiveness and Maternal and
           Neonatal Adverse Effects: a Randomized, Controlled Pilot Trial
    • Abstract: Although previous evidence suggests advantages of nifedipine over terbutaline as tocolytic agents, in some jurisdictions, terbutaline is approved for use and nifedipine is not. In women in preterm labour, we compared the impact of terbutaline versus nifedipine on inhibition of uterine contractions, preterm birth, neonatal sepsis, intracranial haemorrhage or necrotizing enterocolitis, death or admission to a neonatal intensive care unit and maternal adverse reactions. We randomized 32 women to nifedipine and 34 to terbutaline. We found no difference between groups in tocolysis or preterm birth. No serious maternal adverse effects or serious neonatal adverse outcomes occurred in either group. Less serious maternal adverse effects less common with terbutaline included flushing (2.94% versus 43.7%) and headache (5.9% versus 31.2%). The administration of terbutaline increased tremor (76.4% versus 0%), nausea (58.8% versus 9.4%) and dizziness (29.4% versus 6.25%). The total number of side effects, and the proportion of women experiencing one or more side effects, proved greater with terbutaline. In this study, terbutaline and nifedipine performed similarly in their tocolytic effects. Each drug has specific side effects, though overall, nifedipine was associated with fewer adverse effects. This article is protected by copyright. All rights reserved.
  • Reperfusion Therapy with Low‐Dose Insulin or Insulin‐Like
           Growth Factor 2; Myocardial Function and Infarct Size in a Porcine Model
           of Ischaemia and Reperfusion
    • Abstract: In an open‐chest porcine model, we examined whether myocardial pharmacological conditioning at the time of reperfusion with low‐dose insulin or insulin‐like growth factor 2 (IGF2), not affecting serum glucose levels, could reduce infarct size and improve functional recovery. Two groups of anaesthetized pigs with either 60 or 40 min. of left anterior descending artery occlusion (total n = 42) were randomized to receive either 0.9% saline, insulin or IGF2 infusion for 15 min., starting 5 min. before a 180‐min. reperfusion period. Repeated fluorescent microsphere injections were used to confirm ischaemia and reperfusion. Area at risk and infarct size was determined with Evans blue and triphenyltetrazolium chloride staining. Local myocardial function was evaluated with multi‐layer radial tissue Doppler strain and speckle‐tracking strain from epicardial echocardiography. Western blotting and TUNEL staining were performed to explore apoptosis. Infarct size did not differ between treatment groups and was 56.7 ± 6.8%, 49.7 ± 9.6%, 56.2 ± 8.0% of area at risk for control, insulin and IGF2 group, respectively, in the 60‐min. occlusion series. Corresponding values were 45.6 ± 6.0%, 48.4 ± 7.2% and 34.1 ± 5.8% after 40‐min. occlusion. Global and local cardiac function did not differ between treatment groups. No differences related to treatment could be found in myocardial tissue cleaved caspase‐3 content or the degree of TUNEL staining. Reperfusion therapy with low‐dose insulin or with IGF2 neither reduced infarct size nor improved function in reperfused myocardium in this in vivo porcine model.
  • Rare Alleles within the CYP2E1 (MEOS System) could be associated with
           better short‐term Health Outcome after Acute Methanol Poisoning
    • Abstract: Genetic polymorphisms influence the metabolism of ethanol and methanol, but the potential effects of genetic predisposition on the clinical course, outcome and short‐term health sequelae of acute methanol poisoning are unknown. To evaluate the role of the MEOS system in methanol poisoning, we analysed the effect of three polymorphisms (RsaI – rs2031920; PstI – rs3813867; insertion/deletion I/D) within the CYP2E1 enzyme (MEOS system) in 50 adult survivors of methanol poisoning and compared their genotype frequencies with 460 controls. The minor allele frequencies of all three polymorphisms were below 5% in both groups. We did not detect significant differences in the genotype frequencies between survivors of methanol poisoning and controls (P = 0.34 for the RsaI variant; P = 0.59 for the PstI variant and P = 0.21 for the I/D polymorphism). The carriers of at least one minor allele in the CYP2E1 gene had less severe clinical symptoms and better short‐term outcomes after acute poisoning. Variants within the CYP2E1 gene are likely not significant genetic determinants of acute methanol poisoning (if survivors are analysed), but they may influence the severity of methanol poisoning and its visual/CNS outcomes. This article is protected by copyright. All rights reserved.
  • Influence of UGT2B7, OPRM1 and ABCB1 Gene Polymorphisms on Postoperative
           Morphine Consumption
    • Abstract: Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in both effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine‐induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsies as morphine is also a very commonly abused drug. Blood samples were collected from 40 patients following abdominal hysterectomy, 24 hr after initiation of analgesia through a patient‐controlled analgesia (PCA) pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsies found positive for morphine in routine forensic analysis. Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. The dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood. Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients. We conclude that gene polymorphisms contribute significantly to the variation in morphine concentrations observed in individual patients.
  • Adverse Drug Reactions Causing Hospital Admissions in Childhood: A
           Prospective, Observational, Single‐Centre Study
    • 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 9 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 and Aronson causality assessment method. During the study period, 2903 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 the differences in the numbers of ADR‐diagnosed patient 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 ADR‐diagnosed patient 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.
  • Novel Points of Attack for Targeted Cancer Therapy
    • Abstract: New molecular insight reveals novel points of attack for targeted cancer therapy. The recent advances in cancer genomics and novel insight into the complex biology of cancer make the promise of personalized, targeted cancer medicine closer than ever. The massive parallel sequencing endeavors performed by The Cancer Genome Atlas, the International Cancer Genome Consortium and by numerous individual investigators have provided a comprehensive genomic characterization of a wide range of cancers. The joint efforts enabled by the improved sequencing technology have demonstrated that individual cancers comprise mutational repertoires with only a few frequently recurrent driver genes. Thus, the identification of new drug targets and novel drugs have accelerated, and renewed the hopes of personalized cancer therapy achieving clinical reality for a wider range of cancers. Together with cost‐effective sequencing technology to perform comprehensive mutational profiling of each individual cancer, this provides the basis for a personalized cancer medicine revolution within the next few years. The aim of this MiniReview is to provide an overview of the history and evolution of targeted cancer therapy, exemplified by molecularly targeted drugs successfully implemented in the clinic. Furthermore, we aim to highlight novel molecular targets for therapeutic intervention, as well as the main present challenges comprising inter‐ and intratumour heterogeneity and cellular plasticity in addition to the importance of the tumour micro‐environment. Many cancer patients already receive some form of tailored therapy, and recent evidence suggests that novel and highly innovative, targeted approaches are on their way into the clinic. This article is protected by copyright. All rights reserved.
  • Attitude Of Physicians And Pharmacists Towards International
           Nonproprietary Name Prescribing In Belgium
    • Abstract: International Non‐proprietary Name (INN) prescribing is the use of the name of the active ingredient(s) instead of the brand name for prescribing. In Belgium, INN prescribing began in 2005 and a major policy change occurred in 2012. The aim was to explore the opinions of Dutch‐speaking general practitioners (GPs) and pharmacists. An electronic questionnaire with 39 5‐point Likert scale statements and one open question was administered in 2013. Multivariate analysis was performed with multiple linear regression on a sum score for benefit statements and for drawback statements. Answers to the open question were qualitatively analysed. We received 745 valid responses with a representable sample for both subgroups. Participants perceived the motives to introduce INN prescribing as purely economic (to reduce pharmaceutical expenditures for the government and the patient). Participants accepted the concept of INN prescribing, but 88% stressed the importance of guaranteed treatment continuity, especially in older, chronic patients, to prevent patient confusion, medication non‐adherence and erroneous drug use. In conclusion, the current way INN prescribing is applied in Belgium leads to many concerns among primary health professionals about patient confusion and medication adherence. Slightly adapting the current concept of INN prescribing to these concerns can turn INN prescribing into one of the major policies in Belgium to reduce pharmaceutical expenditures and to stimulate rational drug prescribing. This article is protected by copyright. All rights reserved.
  • Riccardin D, a Macrocyclic Bisbibenzy, Inhibits Human Breast Cancer Growth
           through the Suppression of Telomerase Activity
    • 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 labelling (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 ataxia telangiectasia‐mutated (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.
  • Do Serotonin Reuptake Inhibitors worsen Outcome of Patients referred to
           the Emergency Department for Deliberate Multidrug Exposure'
    • Abstract: Incidence of poisonings with serotonin reuptake inhibitors (SRIs) is growing. SRI toxicity is considered low but its actual impact in multidrug poisonings remains unclear. Our objective was to evaluate the consequences of SRI exposure in patients referred to the emergency department (ED) for deliberate multidrug exposure. Patients admitted for multidrug exposure involving at least one SRI were matched with patients who did not ingest any SRI, according to age, gender, type of drug and ingested doses. Features of serotonin syndrome according to Sternbach's criteria and Hunter's serotonin toxicity criteria were evaluated from records. In 4 years, 148 SRI‐exposed patients were included and compared to 296 matched controls. The SRIs mainly involved were escitalopram (22%), venlafaxine (20%), fluoxetine (19%), citalopram (15%) and paroxetine (11%). Serotonin syndrome was diagnosed in one patient, but actually occurred in five SRI‐exposed patients based on the retrospective evaluation of records. Twenty patients (14%) exhibited one or more serotonin syndrome criteria. At least 2/11 of Sternbach's criteria and 2/9 of Hunter serotonin toxicity criteria were missing in each chart. Using a conditional logistic regression analysis, seizures (p=0.04) and serotonin syndrome (p=0.01 based on Sternbach's criteria and p=0.004 based on Hunter serotonin toxicity criteria) more frequently occurred in SRI‐exposed patients. Requirement for mechanical ventilation was significantly increased (p=0.03), although admission to the intensive care unit was not. In multidrug‐poisoned patients admitted to the ED, exposure to SRIs significantly increases the risk of seizures and requirement for mechanically ventilation. Diagnosis of serotonin syndrome remains insufficient justifying improved training. This article is protected by copyright. All rights reserved.
  • Compliance with Recommendations on Outpatient Antibiotic Prescribing for
           Respiratory Tract Infections: The Case of Spain
    • Abstract: Inappropriate antibiotic use in primary care, such as in Respiratory Tract Infections (RTIs), is an important cause of bacterial resistance. This study aimed at describing the current pattern of outpatient antibiotic use in acute RTIs in Spain and evaluating adherence to national recommendations. A retrospective observational study was performed including all the episodes of RTIs registered during a 1‐year period in a north‐eastern Spanish region. Data related to patient demography, diagnoses and antibiotic prescriptions were collected from the electronic medical history database in the region, and adherence to recommendations for antibiotic prescribing was assessed. One third of patients with a RTI were prescribed an antibiotic, with young adults (aged 15‐64 years) being the most treated. High prescribing rates were observed in patients with acute otitis, sinusitis and acute tonsillitis (about 70%), whereas low rates were found in acute bronchitis (50%) and non‐specific upper RTIs (24%) episodes. A high prescription of broad‐spectrum agents and antibiotics not recommended as first choice was observed. In accordance with Spanish guidelines, there exists a potential over‐prescribing of antibiotics for all the diagnoses studied, especially in the adult population. Moreover, the choice of antibiotics is frequently based on agents with a high risk of increasing antimicrobial resistance. Multifaceted strategies should be implemented in order to improve the quality of antibiotic prescribing in primary care. This article is protected by copyright. All rights reserved.
  • The Evaluation of Prophylactic Efficacy of Newly Developed Reversible
           Inhibitors of Acetylcholinesterase in Soman‐Poisoned Mice – A
           Comparison with Commonly Used Pyridostigmine
    • 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.
  • Diphenyl Ditelluride‐Induced Cell Cycle Arrest And Apoptosis: A
           Relation With Topoisomerase I Inhibition
    • Abstract: The diphenyl ditelluride (DPDT) is a prototype for the development of new biologically active molecules. In previous studies, DPDT showed an elevated cytotoxicity in Chinese hamster fibroblast (V79) cells but the mechanisms for reduction of cell viability still remain unknown. DPDT showed mutagenic properties by induction of frameshift mutations in bacterium Salmonella typhimurium and yeast Saccharomyces cerevisiae. This organotelluride also induced DNA strand breaks in V79 cells. In this work, we investigated the mechanism of DPDT cytotoxicity by evaluating the effects of this compound on cell cycle progression, apoptosis induction and topoisomerase I inhibition. Significant decrease of V79 cell viability following DPDT treatment was revealed by MTT assay. Morphological analysis showed induction of apoptosis and necrosis by DPDT in V79 cells. An increase of caspase 3/7 activity confirmed apoptosis induction. The cell cycle analysis showed an increase in the percentage of V79 cells in S‐phase and sub‐G1 phase. The yeast strain deficient in topoisomerase 1 (Top1p) showed higher tolerance to DPDT compared with the isogenic wild‐type strain, suggesting that the interaction with this enzyme could be involved in DPDT toxicity. The sensitivity to DPDT found in top3∆ strain indicates that yeast topoisomerase 3 (Top3p) could participate in the repair of DNA lesions induced by the DPDT. We also demonstrated that DPDT inhibits human DNA topoisomerase I (Topo I) activity by DNA relaxation assay. Therefore, our results suggest that the DPDT‐induced cell cycle arrest and reduction in cell viability could be attributed to interaction with topoisomerase I enzyme. This article is protected by copyright. All rights reserved.
  • Galla Chinensis Attenuates Cigarette Smoke‐associated Lung Injury by
           Inhibiting Recruitment of Inflammatory Cells into the Lung
    • Abstract: Inflammation is a common feature in the pathogenesis of cigarette smoke (CS)‐associated diseases. In this study, we investigated the effects of Galla Chinensis (GC) extract on pulmonary inflammatory responses in a CS‐exposed mouse model. In vitro studies showed that GC extract reduced MCP‐1 production in a dose‐dependent manner. In addition, the recruitment of inflammatory cells into the lung was significantly inhibited in the bronchoalveolar lavage fluid (BALF) of the GC‐treated mice after three weeks of daily CS exposure. GC treatment down‐regulated TNF‐α, IL‐6 and MCP‐1 mRNA expression levels in lung tissue. Finally, GC‐treated mice showed less emphysematous change of alveolar compared to mice only exposed to CS. Our results show that GC extract reduces lung inflammation and emphysematous change by inhibiting the infiltration of inflammatory cells to the lung. These data indicate that GC extract is a therapeutic candidate for CS‐induced lung injury. This article is protected by copyright. All rights reserved.
  • Stimulation of Suicidal Erythrocyte Death by Sulforaphane
    • Abstract: Sulforaphane, an isothiocyanate from cruciferous vegetable, counteracts malignancy. The effect is at least in part due to stimulation of suicidal death or apoptosis of tumour cells. Mechanisms invoked in sulforaphane‐induced apoptosis include mitochondrial depolarization and altered gene expression. Even though lacking mitochondria and nuclei, erythrocytes may, similar to apoptosis of nucleated cells, enter eryptosis, a suicidal cell death characterized by cell shrinkage and phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+‐activity ([Ca2+]i). The present study explored whether sulforaphane stimulates eryptosis. Cell volume was estimated from forward scatter, phosphatidylserine exposure at the cell surface from annexin V binding and [Ca2+]i from Fluo3‐fluorescence. A 48‐hr treatment of human erythrocytes with sulforaphane (50‐100 μM) significantly decreased forward scatter, significantly increased the percentage of annexin V binding cells and significantly increased [Ca2+]i. The effect of sulforaphane (100 μM) on annexin V binding was significantly blunted but not abrogated by removal of extracellular Ca2+, sulforaphane (100 μM) significantly increased ceramide formation. This article is protected by copyright. All rights reserved.
  • Epigallocatechin Gallate Promotes the Development of Mouse 2‐Cell
           Embryos In Vitro by Regulating Mitochondrial Activity and Expression of
           Genes Related to p53 Signalling Pathway
    • Abstract: Preliminary studies have found that the epigallocatechin gallate (EGCG) at proper concentration could promote development of pre‐implantation mouse embryos in vitro. However, the underlying mechanisms have not been well understood. In this study, we collected 1‐cell embryos from Kunming (KM) mice, cultured them in M16 medium or M16 medium supplemented with 10 μg/mL EGCG and investigated the effects of EGCG on mitochondrial activity and reactive oxygen species (ROS) level of 2‐cell embryos. Furthermore, we explored expression differences of genes related to p53 signalling pathway in 2‐cell embryos using a PCR array. The results showed that ROS level and mitochondrial membrane potential were significantly lower in embryos cultured in the EGCG group than in the M16 group (p  0.05). PCR array test results showed that 18 genes were differentially expressed, among which eight genes involving cell growth, cell cycle regulation and mRNA transcription were up‐regulated and 10 genes involving apoptosis, cell cycle arrest and DNA repair were down‐regulated in the EGCG groups. It is concluded that EGCG could promote the development of 1‐cell embryos in vitro possibly due to its ability to scavenge ROS and regulate mitochondrial activity. In addition, EGCG could influence expression of genes related to p53 signalling pathway in 2‐cell embryos and promote cell cycle progression.
  • Mephedrone, Methylone and 3,4‐Methylenedioxypyrovalerone (MDPV)
           Induce Conditioned Place Preference in Mice
    • Abstract: During the last decade, there has been a worldwide increase in popularity and abuse of synthetic cathinones. Common ingredients of the so‐called bath salts include mephedrone, methylone and 3,4‐methylenedioxypyrovalerone (MDPV). Relatively little information about the pharmacology and addiction potential of these drugs is available. We used the conditioned place preference (CPP) paradigm to explore the reinforcing effects of three different synthetic cathinones. The primary aim of this study was to investigate whether mephedrone, methylone and MDPV induce CPP in mice. The secondary aims were to investigate a possible dose–response CPP and whether the synthetic cathinones induce higher CPP than amphetamine at equal dose. C57BL/6 mice were conditioned to mephedrone, methylone, MDPV and amphetamine at doses of 0.5, 2, 5, 10 or 20 mg/kg (i.p.). During the conditioning, the mice received two training sessions per day for 4 days. All four tested drugs showed a significant place preference compared with controls. Mice conditioned with MDPV (5 and 10 mg/kg) displayed a greater preference score compared to mice conditioned with amphetamine (5 and 10 mg/kg). Our findings show that mephedrone, methylone and MDPV produce CPP equal or higher than amphetamine strongly suggesting addictive properties. Given the public health concern of abuse, future pharmacological studies are necessary to fully understand the effects of these drugs.
  • A Nationwide Study of Attention‐Deficit/Hyperactivity Disorder Drug
           Use among Adults in Iceland 2003–2012
    • Abstract: In this study, we leveraged on complete nationwide prescription data for the total adult population in Iceland (N = 227,000) to examine how attention‐deficit/hyperactivity disorder (ADHD) drugs have been used over the past decade. In particular, we aimed to describe the prevalence, incidence and duration of use of stimulants and atomoxetine, among adults (≥19 years) in Iceland, with regard to sex, age, type of drug and specialty of the prescribing physician. Our results indicate that the 1‐year period prevalence of ADHD drug use rose, from 2.9 to 12.2 per 1000 adults between 2003 and 2012, with the most pronounced increases among young adults (19–24 years). The annual incidence increased 3 times, similarly among men and women. Extended‐release methylphenidate formulations were the most commonly used ADHD drugs. Specialists in psychiatry initiated treatment in 79% of new adult ADHD drug users. The proportion of users still receiving treatment after 1 year varied from 43.0% (19–24 years), 57.2% (25–49 years) to 47.5% (50+ years). After 3 years, the corresponding proportions still on treatment were 12.4%, 24.5% and 24.3%, and after 5 years 7.9%, 15.9% and 16.8%. These results of increasing ADHD drug use and short treatment durations call for further investigation of the quality of treatment regimens for adults with ADHD and better follow‐up of patients treated with ADHD drugs.
  • Puerarin Attenuates Carbon Tetrachloride‐Induced Liver Oxidative
           Stress and Hyperlipidaemia in Mouse by JNK/c‐Jun/CYP7A1 Pathway
    • Abstract: Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. The aim of this study was to investigate the effects of puerarin on hepatic oxidative stress and hyperlipidaemia in mice exposed to carbon tetrachloride (CCl4). Male ICR mice were injected with CCl4 with or without puerarin co‐administration (200 and 400 mg/kg intragastrically once‐daily) for 8 weeks. Our data showed that puerarin significantly prevented CCl4‐induced hepatotoxicity, indicated by both diagnostic indicators of the liver damage (serum aminotransferase levels) and histopathological analysis. Puerarin decreased the thiobarbituric acid reactive substances (TBARS) and the protein carbonyl content (PCO) in the liver of CCl4‐treated mice. Puerarin also restored the levels of reduced glutathione (GSH) and total antioxidant capacity (TAC) in the liver. Furthermore, the increase in serum cholesterol, triglycerides and low‐density lipoproteins (LDL) induced by CCl4 was effectively suppressed by puerarin. The high‐density lipoprotein (HDL) level in the CCl4 treatment mice was also increased by puerarin. Western blot analysis showed that puerarin remarkably inhibited hyperlipidaemia by regulating the expression of phosphorylated Jun N‐terminal kinases (JNK), phosphorylated c‐Jun protein and cholesterol 7a‐hydroxylase (CYP7A1) in the liver of CCl4‐treated mice. Altogether, these results suggest that puerarin could protect the CCl4‐induced liver injury and hyperlipidaemia by reducing reactive oxygen species S production, renewing the total antioxidant capacity and influencing expression of hepatic lipid biosynthesis and metabolism genes.
  • Triggering of Erythrocyte Cell Membrane Scrambling by Salinomycin
    • Abstract: Salinomycin, a polyether ionophore antibiotic effective against a variety of pathogens, has been shown to trigger apoptosis of cancer cells and cancer stem cells. The substance is thus considered for the treatment of malignancy. Salinomycin compromises tumour cell survival at least in part by interference with mitochondrial function. Erythrocytes lack mitochondria but may undergo apoptosis‐like suicidal cell death or eryptosis, which is characterized by scrambling of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Signalling involved in the triggering of eryptosis includes activation of oxidant‐sensitive Ca2+ permeable cation channels with subsequent increase in cytosolic Ca2+ activity ([Ca2+]i). This study explored whether salinomycin stimulates eryptosis. Phosphatidylserine‐exposing erythrocytes were identified by measurement of annexin‐V binding, cell volume was estimated from forward scatter, haemolysis determined from haemoglobin release, [Ca2+]i quantified utilizing Fluo3‐fluorescence and oxidative stress from 2′,7′ dichlorodihydrofluorescein diacetate (DCFDA) fluorescence in flow cytometry. A 48‐hr exposure to salinomycin (5‐100 nM) was followed by a significant increase in Fluo3‐fluorescence, DCFDA fluorescence and annexin‐V binding, as well as a significant decrease in forward scatter (at 5–10 nM, but not at 50 and 100 nM). The annexin‐V binding after salinomycin treatment was significantly blunted but not abrogated in the nominal absence of extracellular Ca2+ or in the presence of antioxidant n‐acetyl cysteine (1 mM). Salinomycin triggers cell membrane scrambling, an effect at least partially due to oxidative stress and entry of extracellular Ca2+.
  • Educational and Organizational Interventions to Improve the Usefulness of
           Clinical Pharmacological Advice for Personalized Drug Dosing Based on
           Therapeutic Drug Monitoring
    • Abstract: This study was aimed at increasing the clinical usefulness of clinical pharmacological advice (CPA) for personalized drug dosing based on therapeutic drug monitoring (TDM). Educational and organizational interventions focused on improving the knowledge of clinical pharmacology among hospital healthcare workers and reducing the incidence of errors throughout the process were planned. After a pre‐interventional period of risk assessment, different list forms of the types of error occurring in the various phases of the process (Phase 1, request for CPA and blood sampling for TDM; Phase 2, sample delivery to and check in at the CPU; Phase 3, TDM execution and CPA production) were created. In the interventional period, the errors were collected daily and educational programmes were carried out. The pre‐intervention error rate was 19.5%, and resulted significantly higher for the requests coming from the medical wards compared with those from the surgical wards or the ICUs (26.0% versus 10.5% versus 13.7%, p 
  • Severe Lactic Acidosis in a Diabetic Patient after Ethanol Abuse and Floor
           Cleaner Intake
    • Abstract: An intoxication with drugs, ethanol or cleaning solvents may cause a complex clinical scenario if multiple agents have been ingested simultaneously. The situation can become even more complex in patients with (multiple) co‐morbidities. A 59‐year‐old man with type 2 diabetes mellitus (without treatment two weeks before the intoxication) intentionally ingested a substantial amount of ethanol along with ~750 mL of laminate floor cleaner containing citric acid. The patient was admitted with severe metabolic acidosis (both ketoacidosis and lactic acidosis, with serum lactate levels of 22 mM). He was treated with sodium bicarbonate, insulin and thiamine after which he recovered within two days. Diabetic ketoacidosis and lactic acidosis aggravated due to ethanol intoxication, thiamine deficiency and citrate. The high lactate levels were explained by excessive lactate formation caused by the combination of untreated diabetes mellitus, thiamine deficiency and ethanol abuse. Metabolic acidosis in diabetes is multi‐factorial, and the clinical situation may be further complicated, when ingestion of ethanol and toxic agents are involved. Here, we reported a patient in whom diabetic ketoacidosis was accompanied by severe lactic acidosis as a result of citric acid and mainly ethanol ingestion and a possible thiamine deficiency. In the presence of lactic acidosis in diabetic ketoacidosis, physicians need to consider thiamine deficiency and ingestion of ethanol or other toxins.
  • Characterization of a Lamotrigine‐Resistant Kindled Model of
           Epilepsy in Mice: Evaluation of Drug Resistance Mechanisms
    • Abstract: The aims of this study were to characterize a lamotrigine‐resistant kindled model of epilepsy in mice, to study the anticonvulsant effect of carbamazepine (CBZ) and valproic acid (VPA), and to probe into the mechanism for resistance. Swiss albino mice were kindled by a subconvulsive dose of pentylenetetrazole (PTZ, 30 mg/kg, i.p., every other day for 6 weeks). The mice were pre‐treated (30 min.) either with a low dose of LTG (5 mg/kg, i.p.) or with vehicle, and the seizures were scored. The acute treatment with LTG (15 mg/kg, i.p.) on the last day blocked seizure in the vehicle‐treated group, but the LTG pre‐treated group showed resistance. This resistance was extended to CBZ, but not to VPA. The resistant model was successfully replicated in mice with less kindling development time (6 weeks versus 9 weeks 5 days in rats). A highly significant decrease in the level of histamine (p 
  • Studies of the Safety, Pharmacokinetics and Immunogenicity of Repeated
           Doses of Intravenous Staphylococcal Protein A in Cynomolgus Monkeys
    • Abstract: Three Good Laboratory Practice safety studies were performed with intravenous injections of highly purified staphylococcal protein A (SPA) in cynomolgus monkeys, in support of a clinical development programme utilizing this protein as an immunomodulator. These studies established a no‐observable‐adverse‐effect level (NOAEL) for up to 12 weekly doses of SPA, as well as toxicokinetic profiles for SPA, evaluation of antiproduct antibodies and biomarkers to better characterize the pharmacodynamic response to SPA. Biomarkers included neopterin, C‐reactive protein (CRP), troponin I and the change in the blood absolute lymphocyte count (ALC) 24 hr after SPA dosing. The transient decrease in ALC noted at 24 hr after dosing was similar to that seen in human Phase 1 trials. The majority of active‐treated monkeys developed antibodies against SPA. Cmax was not affected by development of antidrug antibodies (ADAs), and after the first dose was 87 (SD 19) ng/mL, 330 (SD 84) ng/mL and 1191 (SD 208) ng/mL for 5, 25 and 100 μg/kg doses, respectively. The development of ADAs increased plasma clearance of SPA. By the sixth weekly dose, the AUC was decreased by 76%, 54% and 66% for the 5, 25 and 100 μg/kg dose groups, respectively. These results indicate that SPA can be administered intravenously to non‐human primates without observable toxicity at weekly doses of up to 100 μg/kg.
  • Incorporation of Flurbiprofen in a 4‐Drug Cytochrome P450
           Phenotyping Cocktail
  • Can Physical Exercise or Food Deprivation Cause Release of
           Fat‐Stored Cannabinoids'
    • Abstract: The aim of this study was to evaluate whether physical exercise or food deprivation may increase cannabinoid levels in serum or urine in abstinent chronic cannabis users. The study took place in a drug detoxification ward parallel to study participants receiving treatment. Six chronic, daily cannabis users (one female, five males, average age 30.0 years; BMI 20.8) were exposed to a 45‐min. moderate‐intensity workout and a 24‐hr period of food deprivation. Serum samples were drawn prior to and after interventions and analysed for ∆9‐tetrahydrocannabinol (THC) and 11‐nor‐9‐carboxy‐∆9‐tetrahydrocannabinol (THCCOOH) by liquid chromatography–tandem mass spectrometry (LCMSMS), and all voided urine was tested for THCCOOH by LCMSMS and normalized to the creatinine levels, yielding ng/mg ratios. There were no major differences in the measured cannabinoid levels in serum or urine before and after physical exercise or food deprivation. We conclude that exercise and/or food deprivation are unlikely to cause sufficient cannabinoid concentration changes to hamper correct interpretations in drug testing programmes.
  • Peripheral Antinociception and Anti‐Inflammatory Effects of
           Sulphated Polysaccharides from the Alga Caulerpa mexicana
    • Abstract: Sulphated polysaccharides from marine algae are widely used in biotechnological and pharmaceutical areas. In this study, we evaluated the effects of sulphated polysaccharides from the green marine alga Caulerpa mexicana (Cm‐SPs) in nociceptive and inflammatory models in rodents. Cm‐SPs (10 or 20 mg/kg), administered i.v. in Swiss mice, significantly reduced nociceptive responses, as measured by the number of writhes in response to acetic acid. Cm‐SPs (10 or 20 mg/kg) also reduced second‐phase responses in the formalin test, but did not exhibit a significant antinociceptive effect in the hot plate test, suggesting that its antinociceptive action occurs through a peripheral mechanism. Cm‐SPs (5, 10 or 20 mg/kg), administered s.c. in wistar rats 1 hr before carrageenan, dextran, histamine or serotonin, were tested in paw oedema models. Cm‐SPs (10 or 20 mg/kg) reduced carrageenan‐induced paw oedema and myeloperoxidase activity in the paw. In addition, Cm‐SPs (20 mg/kg) inhibited dextran‐ or histamine‐induced paw oedema, but not serotonin‐induced oedema, suggesting that histamine is the major target of Cm‐SPs anti‐oedematogenic activity. Finally, Cm‐SPs (20 mg/kg) administered in mice did not show significant signs of toxicity. In conclusion, Cm‐SPs appear to be promising natural modulatory agents for pain and inflammatory conditions.
  • Anticonvulsant Effects of N‐Arachidonoyl‐Serotonin, a Dual
           Fatty Acid Amide Hydrolase Enzyme and Transient Receptor Potential
           Vanilloid Type‐1 (TRPV1) Channel Blocker, on Experimental Seizures:
           The Roles of Cannabinoid CB1 Receptors and TRPV1 Channels
    • Abstract: Selective blockade of anandamide hydrolysis, through the inhibition of the FAAH enzyme, has anticonvulsant effects, which are mediated by CB1 receptors. Anandamide, however, also activates TRPV1 channels, generally with an opposite outcome on neuronal modulation. Thus, we suggested that the dual FAAH and TRPV1 blockade with N‐arachidonoyl‐serotonin (AA‐5‐HT) would be efficacious in inhibiting pentylenetetrazole (PTZ)‐induced seizures in mice. We also investigated the contribution of CB1 activation and TRPV1 blockade to the overt effect of AA‐5‐HT. In the first experiment, injection of AA‐5‐HT (0.3–3.0 mg/kg) delayed the onset and reduced the duration of PTZ (60 mg)‐induced seizures in mice. These effects were reversed by pre‐treatment with the CB1 antagonist, AM251 (1.0–3.0 mg/kg). Finally, we observed that administration of the selective TRPV1 antagonist, SB366791 (0.1–1 mg/kg), did not entirely mimic AA‐5‐HT effects. In conclusion, AA‐5‐HT alleviates seizures in mice, an effect inhibited by CB1 antagonism, but not completely mimicked by TRPV1 blockage, indicating that the overall effect of AA‐5‐HT seems to depend mainly on CB1 receptors. This may represent a new strategy for the development of drugs against seizures, epilepsies and related syndromes.
  • Plasma Levels of 25‐Hydroxyvitamin D3 and In Vivo Markers of
           Cytochrome P450 3A Activity in Swedes and Koreans: Effects of a Genetic
           Polymorphism and Oral Contraceptives
    • Abstract: In vitro studies have shown that vitamin D may induce several cytochrome P450 (CYP) enzymes in general and CYP3A4 in particular. The primary aim of this study was to investigate the relationship between plasma levels of 25‐hydroxyvitamin D3 and suggested in vivo markers of CYP3A activity in healthy volunteers from Sweden and Korea. Plasma concentrations of 25‐hydroxyvitamin D3 were analysed in samples from three previously performed studies, and the correlation between these levels and suggested in vivo markers of CYP3A activity was investigated by means of nonparametric correlation. In addition, we studied the modulating effects of three vitamin D receptor promoter polymorphisms on the association between 25‐hydroxyvitamin D3 and CYP3A enzyme activity in Swedish subjects. The plasma levels of 25‐hydroxyvitamin D3 were not significantly associated with CYP3A phenotypes in any of the three studies, but after accounting for the vitamin D receptor polymorphism rs4516035, there was a significant positive association between 25‐hydroxyvitamin D3 and CYP3A activity (p = 0.004). Swedes (n = 65) had significantly higher 25‐hydroxyvitamin D3 levels than Koreans (n = 67), 75 nM compared with 31 nM (p 
  • Inhibition of Polyamine Formation Antagonizes Vascular Smooth Muscle Cell
           Proliferation and Preserves the Contractile Phenotype
    • Abstract: The polyamines putrescine, spermidine and spermine play essential roles in cell proliferation and migration, two processes involved in the development of vascular disease. Thus, intervention with polyamine formation may represent a way to inhibit unwanted vascular smooth muscle cell (VSMC) proliferation. The aim of the present study was to assess the importance of polyamines for VSMC proliferation and vascular contractility. The rate‐limiting step in polyamine biosynthesis is catalysed by ornithine decarboxylase (ODC). Treatment with α‐difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, reduced DNA synthesis in primary rat VSMCs in a concentration‐dependent manner with an IC50 value of 100 μM. Moreover, DFMO reduced VSMC migration assessed in a scratch assay. The DFMO‐induced attenuation of VSMC proliferation was associated with lowered cellular amount of polyamines. The antiproliferative effect of DFMO was specific because supplementation with polyamines reversed the effect of DFMO on proliferation and normalized cellular polyamine levels. Isometric force recordings in cultured rat tail artery rings showed that DFMO counteracts the decrease in contractility caused by culture with foetal bovine serum as growth stimulant. We conclude that inhibition of polyamine synthesis by DFMO may limit the first wave of cell proliferation and migration, which occurs in the acute phase after vascular injury. Besides its antiproliferative effect, DFMO may prevent loss of the smooth muscle contractile phenotype in vascular injury.
  • The Inhibitory Effect of Intravesical Fisetin against Bladder Cancer by
           Induction of p53 and Down‐Regulation of NF‐kappa B Pathways in
           a Rat Bladder Carcinogenesis Model
    • Abstract: Intravesical chemotherapy after transurethral resection has been widely used as an adjuvant therapy to prevent recurrence and progression of superficial bladder cancer. Due to the insufficiency of the current chemotherapeutics, there is an urgent need to search for more novel, effective and safe intravesical agents. Previously, we have proved the in vitro apoptotic effects of fisetin, a dietary flavonoid, on bladder carcinoma cells. In the present study, we have further explored its intravesical efficacy and investigated the underlying mechanisms of its inhibitory effect of bladder cancer through an autochthonous rat model of bladder cancer induced by intravesical N‐methyl‐N‐nitrosourea (MNU). We found that fisetin‐induced apoptosis in bladder cancer is mediated via modulation of two related pathways: up‐regulation of p53 and down‐regulation of NF‐κB pathway activity, causing changes in the ratio of pro‐ and antiapoptotic proteins. Meanwhile, administration of fisetin significantly reduced the incidence of MNU‐induced bladder tumours by suppressing NF‐κB activation and modulating the expression of NF‐κB target genes that regulate cell proliferation and cell apoptosis. Our study suggests that the activation of p53 and inhibition of the NF‐κB pathway may play important roles in the fisetin‐induced apoptosis in bladder cancer. Furthermore, intravesical fisetin effectively inhibited, without any toxicity, the carcinogenesis of bladder cancer in MNU‐initiated rats. These findings identify the in vivo chemopreventive efficacy of fisetin and suggest that fisetin could be used as a novel, effective and safe intravesical agent for bladder cancer.
  • Neurogenic Contraction Induced by the Antiarrhythmic Compound, AVE 0118,
           in Rat Small Mesenteric Arteries
    • Abstract: The purpose of this study was to investigate the vasoactivity of two inhibitors of potassium ion (K+) channels, a potential antiarrhythmic compound, AVE 0118, and 4‐aminopyridine (4‐AP). Basal and stimulated tones of rat small mesenteric arteries as well as the possible involvement of KV1.5 ion channel in the mechanism of vascular effect induced by the compounds were analysed. The standard organ bath technique for vascular tone and immunohistochemistry for the localization of ion channels in the arterial tissue were performed. Third‐ or fourth‐order branch of arterial segments was mounted in myographs for recording the isometric tension. AVE 0118 (10−5 M) and 4‐AP (10−5 M) modulated neither the basal tone nor the contraction induced by noradrenaline but increased the contraction evoked by electrical field stimulation, sensitive to the block of alpha‐1 adrenergic receptors. KV1.5 ion channel‐specific immunostaining demonstrated the presence of immunoreactive nerves, and Schwann‐cell‐specific (S100) immunostaining confirmed the presence of myelin sheath in rat small mesenteric arteries. The study supports an indirect, sympathetic effect of AVE 0118 similar to that of 4‐AP, which is mediated, at least in part, by blocking neuronal KV1.5 type potassium ion channels in the medio‐adventitial layer of rat small mesenteric artery.
  • Semi‐Mechanistic Modelling and Simulation of Inhibition of Platelet
           Aggregation by Antiplatelet Agents
    • Abstract: Antiplatelet agents are a class of pharmaceuticals that decrease platelet aggregation and thus inhibit thrombus formation. We examined the relationships between plasma concentrations of antiplatelet agents (triflusal, clopidogrel and cilostazol) and the platelet aggregation inhibitory effect after dosing. We used triflusal, cilostazol and clopidogrel for the development of a semi‐mechanistic PK/PD model. The drugs chosen are used widely and reflect various mechanisms of antiplatelet agents. Time courses of plasma concentrations of the antiplatelet agents and their platelet aggregation effects were analysed using ADPAT V. Pharmacokinetic profiles were fitted to an extended parent–metabolite pharmacokinetic model, based on a two‐compartment model, and the pharmacodynamic effects of the agents were fitted to a platelet aggregation effect model that consisted of the following parameters: Ks, the active‐form platelet synthesis rate constant; K, the apparent reaction rate constant of the agent and active‐form platelets; Kel‐PRP, the apparent rate constant of platelets; and ε, an intrinsic activity parameter. This semi‐mechanistic PK/PD model described well the relationship between plasma concentrations of antiplatelet agents and platelet aggregation effects. In addition, the estimated parameters were suitable for the explanation of the agents and also have a good correlation with platelet characteristics, such as platelet half‐life and platelet aggregation baseline effects. Specifically, we discovered the strong correlations between estimated K parameter and in vitro drug activity. We conclude that this semi‐mechanistic PK/PD model explained drug PK/PD characteristics well and will be useful for accurate predictions of antiplatelet effect in the clinical situations.
  • Effects of Seijo‐bofu‐to, a Traditional Japanese Herbal
           Medicine Containing Furanocoumarin Derivatives, on the
           Drug‐Metabolizing Enzyme Activities in Healthy Male Volunteers
    • Abstract: Seijo‐bofu‐to, a traditional medicine used to treat acne in Asian countries, contains twelve herbal components, including Angelica dahurica root, a source of furanocoumarin derivatives. In this study, we investigated potential herb–drug interactions of seijo‐bofu‐to in healthy male volunteers. Thirty‐two young, healthy, non‐smoking males were assessed for the baseline activity of cytochrome P450 (CYP) 1A2, CYP3A, CYP2D6, N‐acetyltransferase 2 and xanthine oxidase according to the urinary metabolic indices of 8‐hr urine samples collected after the administration of a 150‐mg dose of caffeine and a 30‐mg dose of dextromethorphan, and the ratio of urinary excretion of 6β‐hydroxycortisol to cortisol. Thereafter, the volunteers received 3.75 g of seijo‐bofu‐to twice daily for 7 days and underwent the same tests on post‐dose day 7. The geometric mean ratio of the CYP1A2 activity on day 7 to that observed at baseline was 0.66 (95% CI, 0.55–0.79, p = 0.001). The geometric mean phenotypic indices for CYP3A, CYP2D6, N‐acetyltransferase 2 and xanthine oxidase on day 7 did not differ from the baseline values. The findings of the present study suggest that seijo‐bofu‐to may inhibit the activity of CYP1A2, whereas it is unlikely to participate in herb–drug interactions involving medications predominantly metabolized by CYP3A, CYP2D6, N‐acetyltransferase 2 or xanthine oxidase.
  • Pharmacodynamic Modelling of Placebo and Buprenorphine Effects on
           Event‐Related Potentials in Experimental Pain
    • Abstract: The purpose of the study was to investigate placebo and buprenorphine effects on event‐related potentials (ERPs) in experimental pain and the potential benefit of population pharmacodynamic modelling in data analysis. Nineteen healthy volunteers received transdermal placebo and buprenorphine in a cross‐over study. Drug plasma concentrations and ERPs after electrical stimulation at the median nerve with intensity adjusted to pain detection threshold were recorded until 144 hrs after administration. Placebo and concentration‐effect models were fitted to data using non‐linear mixed‐effects modelling implemented in NONMEM (V7.2.0.). Pharmacodynamic models were developed to adequately describe both placebo and buprenorphine ERP data. Models predicted significant placebo effects, but did not predict significant effects related to buprenorphine concentration. Models revealed that ERPs varied both between subjects and between study occasions. ERPs were found to be reproducible within subjects and occasions as population variance was found to be eight times higher than the unexplained variances. Between‐subject variance accounted for more than 75% of the population variance. In conclusion, pharmacodynamic modelling was successfully implemented to allow for placebo and variability correction in ERP of experimental pain. Improved outcome of ERP studies can be expected if variation between subjects and study occasions can be identified and described.
  • An Outbreak of Pyrimethamine Toxicity in Patients with Ischaemic Heart
           Disease in Pakistan
    • Abstract: We investigated an outbreak of darkening of skin, bleeding from multiple sites, leucopenia and thrombocytopenia in ischaemic heart disease patients. Case patients were defined as patients who had received medicines from the pharmacy of Punjab Institute of Cardiology between 1 December 2011 and 12 January 2012 and who developed any one of the following: darkening of skin, bleeding from any site, thrombocytopenia and leucopenia. Clinical and drug‐related data were abstracted. All 664 case patients had received iso‐sorbide‐mono‐nitrate contaminated with about 50 mg of pyrimethamine, and 151 (23%) died. The median age of 117 patients admitted at Jinnah Hospital Lahore was 57 years (range, 37–100) and 92 (79%) were male. The median time from intake of medicine to presentation was 37 days (range 13–72). Symptoms and signs included bleeding (in 95% of the patients), skin hyperpigmentation (in 61%), diarrhoea (in 53%) and abdominal pain (in 48%). At presentation, the median white cell count was 2.3 × 109/L (range, 0.1 × 109–16.0 × 109), the median hemoglobin concentration was 109 g/L (range 58–169) and the median platelet count was 18 × 109/L (range, 0 × 109–318 × 109). Bone marrow examination revealed trileneage dysplasia and severe megaloblastosis. The predictors of mortality included presentation prior to 15 January 2012, age more than 57 years, hypotension and leukocyte count less than 1.5 × 109/L. None of the patients who died received Calcium folinate because all deaths occurred prior to contaminant identification. We describe an outbreak of pyrimethamine toxicity in ischaemic heart disease patients receiving medicines from a single pharmacy due to accidental contamination of iso‐sorbide mono‐nitrate tablets at industrial level. Late recognition of illness resulted in high mortality.
  • Gene Expression Change in Human Dental Pulp Cells Exposed to a
           Low‐Level Toxic Concentration of Triethylene Glycol Dimethacrylate:
           An RNA‐seq Analysis
    • Abstract: Dental composite resin restoration for defective tooth may lead unpolymerized resin monomers to be leached into dental pulp tissue. The aim of this study was to investigate the early gene expression change over time of human dental pulp cells (HDPCs) treated with a low‐level toxic concentration of Triethylene Glycol Dimethacrylate (TEGDMA), a common dental resin monomer, by adopting the novel high‐throughput transcriptome analysis of RNA‐seq. The low‐level toxic concentration of TEGDMA was determined through MTT assays with serially diluted concentrations. After the HDPCs were exposed to TEGDMA for 6, 12, 24 or 48 hr, the total RNA of the samples was prepared for RNA‐seq. qRT‐PCR for several genes was performed for validation of RNA‐seq results. In the treated group, 1280 genes were differentially expressed compared with the control group. Five patterns of time‐series gene expression profiles were identified through k‐means clustering analysis. Angiogenesis, cell adhesion and migration, extracellular matrix organization, response to extracellular stimulus, inflammatory response and mineralization‐related process were major gene ontology terms in functional annotation clustering. HMOX1, OSGIN1, SMN2, SRXN1 AKR1C1, SPP1 and TOMM40L were highly up‐regulated genes, and WRAP53 and CCL2 were highly down‐regulated genes over time. qRT‐PCR for several genes exhibited a high level of agreement with RNA‐seq. TEGDMA induced the HDPCs to show massive and dynamic gene expression changes over time. The previously suggested toxic mechanism of TEGDMA was not only verified, but new genes whose functions have yet to be determined were also found.
  • The Association between Use of Serotonergic Antidepressants and
           Perioperative Bleeding during Total Hip Arthroplasty – A Cohort
    • Abstract: In vitro studies have shown that selective serotonin reuptake inhibitors inhibit platelet aggregation. It is well documented that SSRIs cause serious gastrointestinal bleeding, but studies on other bleeding manifestations have been equivocal. Our objective was to determine a possible association between use of serotonergic antidepressants (SA) and perioperative bleeding during hip replacements. We conducted a retrospective study between 1 January 2007 and 30 June 2012 among patients that underwent a primary unilateral uncemented total hip arthroplasty (THA). Information was collected on the observed blood loss and the need for blood transfusions among this group. We compared the blood loss between users of SA, users of non‐serotonergic antidepressants (NSA) and non‐users, while adjusting for potential confounders using multivariate linear regression. We indentified 1318 patients that underwent a THA in the study period. The average volume of surgical bleeding was 350 ml. The adjusted incremental blood loss associated with use of SA and NSA was 93, 95% confidence interval (38–147) ml and −50 (−125 to 25) ml compared with non‐use. Only 48 subjects (3.6%) had transfusions. Use of SA was associated with an increased blood loss compared with non‐users. The hypothesis that SA impairs haemostasis is supported by these results.
  • An Analytical Framework for Assessing Drug and Therapeutics Committee
           Structure and Work Processes in Tertiary Brazilian Hospitals
    • Abstract: University teaching hospitals usually provide tertiary care and are subject to early adoption of new technologies, which may compromise healthcare systems when uncritically adopted. Knowledge on the decision‐making process – drug selection by drug selection committees or DTCs – is crucial to improve the quality of care. There are no models for studying the selection of drugs in Brazilian healthcare services. This study aims to discuss DTC structure and the processes regarding adoption of medicines in tertiary university hospitals in Brazil and to propose an analytical structure for providing direction for the future. State of the art content regarding drug selection processes and DTC procedures was reviewed in three databases. Information on the medicine selection process in a Brazilian gold standard teaching hospital was collected through observations and a review of existing procedures. A structured discussion on medicine selection and DTC procedures in tertiary hospitals ensued. This discussion resulted in findings that were organized in three dimensions, composing an analytical framework for the application in tertiary Brazilian hospitals (i) motivations for the adoption of drugs; (ii) necessary structural and organizational aspects for decision‐making; and (iii) criteria and methods employed by the decision‐making process. We believe that the suggested framework is compatible with tertiary Brazilian hospitals, because a gold standard in the country was able to conduct all its procedures in the light of WHO and international recommendations. We hope to contribute in producing knowledge which may hopefully be adopted in tertiary hospitals across Brazil.
  • Pharmacokinetic–Pharmacodynamic Modelling of the Analgesic and
           Antihyperalgesic Effects of Morphine after Intravenous Infusion in Human
    • Abstract: Using a modelling approach, this study aimed to (i) examine whether the pharmacodynamics of the analgesic and antihyperalgesic effects of morphine differ; (ii) investigate the influence of demographic, pain sensitivity and genetic (OPRM1) variables on between‐subject variability of morphine pharmacokinetics and pharmacodynamics in human experimental pain models. The study was a randomized, double‐blind, 5‐arm, cross‐over, placebo‐controlled study. The psychophysical cutaneous pain tests, electrical pain tolerance (EPTo) and secondary hyperalgesia areas (2HA) were studied in 28 healthy individuals (15 males). The subjects were chosen based on a previous trial where 100 subjects rated (VAS) their pain during a heat injury (47°C, 7 min., 12.5 cm2). The 33% lowest‐ and highest pain‐sensitive subjects were offered participation in the present study. A two‐compartment linear model with allometric scaling for weight provided the best description of the plasma concentration–time profile of morphine. Changes in the EPTo and 2HA responses with time during the placebo treatment were best described by a linear model and a quadratic model, respectively. The model discrimination process showed clear evidence for adding between‐occasion variability (BOV) on baseline and the placebo slope for EPTo and 2HA, respectively. The sensitivity covariate was significant on baseline EPTo values and genetics as a covariate on the placebo slope for 2HA. The analgesic and antihyperalgesic effects of morphine were pharmacologically distinct as the models had different effect site equilibration half‐lives and different covariate effects. Morphine had negligible effect on 2HA, but significant effect on EPTo.
  • Structure–Activity Relationship of Terpenes with
           Anti‐Inflammatory Profile – A Systematic Review
    • Abstract: Inflammation is a complex biological response that in spite of having available treatments, their side effects limit their usefulness. Because of this, natural products have been the subject of incessant studies, among which the class of terpenes stands out. They have been the source of study for the development of anti‐inflammatory drugs, once their chemical diversity is well suited to provide skeleton for future anti‐inflammatory drugs. This systematic review reports the studies present in the literature that evaluate the anti‐inflammatory activity of terpenes suffering any change in their structures, assessing whether these changes also brought changes in their effects. The search terms anti‐inflammatory agents, terpenes, and structure–activity relationship were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between January 2002 and August 2013. Twenty‐seven papers were found concerning the structural modification of terpenes with the evaluation of anti‐inflammatory activity. The data reviewed here suggest that modified terpenes are an interesting tool for the development of new anti‐inflammatory drugs.
  • Isopropoxy‐Carvacrol, a Derivative Obtained from Carvacrol, Reduces
           Acute Inflammation and Nociception in Rodents
    • Abstract: Monoterpenes, compounds mainly presented in essential oils, have important pharmacological actions. Isopropoxy‐carvacrol (IPC) is a derivative of the monoterpene carvacrol, and its pharmacological properties have not yet been investigated. The aim of this study was to analyse the acute anti‐inflammatory and antinociceptive properties of IPC. Mice (25–30 g) and rats (150–230 g) were pre‐treated (i.p.) with IPC at the doses of 10, 30 or 100 mg/kg or vehicle (Tween 80, 0.5%), 30 min. before injection of the phlogistic agents. Both the first and the second phases of formalin‐induced nociception were significantly reduced by IPC (100 mg/kg). Injection of carrageenan in mice paw reduced the threshold of stimulus intensity, applied with an analgesymeter, necessary to cause paw withdrawal, which was significantly reduced by 100 mg/kg of IPC. The area under curve (0–4 hr) of rat paw oedema induced by injection of carrageenan was also significantly diminished by the administration of IPC (100 mg/kg). Administration of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) markedly increased mice ear oedema and myeloperidase (MPO) activity. Topical co‐administration of IPC (0.3–3 mg/ear) during the induction did not affect TPA‐induced ear oedema, but significantly decreased MPO activity in the ears, when compared with the vehicle. In in vitro experiments, IPC reduced lipoperoxidation induced by different stimuli, showed nitric oxide scavenger activity and did not interfere with murine macrophage viability in concentrations up to 100 μg/mL. These results demonstrate that IPC exerts acute anti‐inflammatory and antinociceptive activities, suggesting that it may represent an alternative in the development of new future therapeutic strategies.
  • High Antibiotic Consumption: A Characterization of Heavy Users in Spain
    • Abstract: Heavy antibiotic users are those individuals with the highest exposure to antibiotics. They play an important role as contributors to the increasing risk of antimicrobial resistance. We applied different methods to identify and characterize the group of heavy antibiotic users in Spain as well as their exposure to antibiotics. Data on outpatient prescribing of antimicrobials (ATC J01) in 2010 were obtained from a prescription database covering Aragón (northeastern Spain). The antimicrobial consumption at the individual level was analysed both according to the volume of DDD and the number of packages purchased per year. Heavy antibiotic users were identified according to Lorenz curves and characterized by age, gender, and their antimicrobial prescription profile. Lorenz curves demonstrated substantial differences in the individual use of antimicrobials. Heavy antibiotic users (5% of individuals with highest consumption) were responsible for 21% of the total DDD consumed and received ≥6 packages per year. Elderly adults (≥60 years) and small children (0–9 years) were those exposed to the highest volume of antibiotics and with the most frequent exposure, respectively. Heavy users received a high proportion of antibiotics not recommended as first choice in primary health care. In conclusion, heavy antibiotic users consisted mainly of children and old adults. Inappropriate overuse of antibiotics (high quantity, high frequency, and inappropriate antibiotic choice) leads to a substantial risk of the emergence and spread of resistant bacteria, and interventions to reduce overuse of antibiotics should therefore primarily be targeted children and elderly people.
  • ASC, a Bioactive Steroidal Saponin from Ophitopogin japonicas, Inhibits
           Angiogenesis through Interruption of Src Tyrosine Kinase‐dependent
           Matrix Metalloproteinase Pathway
    • Abstract: Since angiogenesis is an important target for anti‐tumour drugs, the agents that inhibit angiogenesis may help reduce the use of chemotherapy by blocking tumour blood supply. In this study, we investigated a potent angiogenesis inhibitor, ASC, a steroidal saponin compound which has been purified from Ophitopogin japonicus (L.f) Ker.‐Gawl. Our observations showed that ASC significantly suppressed human umbilical vein endothelial cell (HUVECs) growth both in vitro and in vivo. This may be resulted from the G2/M cell cycle arrest effects of ASC. Moreover, ASC inhibited HUVECs invasion and tube formation processes, which were associated with endothelial cells remodelling. A mechanism study indicated that ASC down‐regulated the expression of Src tyrosine kinase, further leading to the blockage of Akt‐dependent maturix metalloproteinases (mainly for MMP‐9) signalling pathway, which was functionally associated with angiogenic blood vessels. Finally, ASC significantly inhibited angiogenesis and MMPs/VEGF expression in the subcutaneously injected matrigel in C57/BL mice. These findings suggest that ASC might be a potential drug candidate in anti‐angiogenesis and anti‐cancer therapies. This article is protected by copyright. All rights reserved.
  • Different Effects Of Cabergoline And Bromocriptine On Metabolic And
           Cardiovascular Risk Factors In Patients With Elevated Prolactin Levels
    • Abstract: Hyperprolactinaemia is suggested to be associated with metabolic and hormonal complications. No previous study has compared the effect of different dopamine agonists on plasma lipids, carbohydrate metabolism markers and cardiovascular risk factors in patients with elevated prolactin levels. The study included eight bromocriptine‐resistant women with prolactinoma (group 1) and twelve matched women with hyperprolactinaemia unrelated to prolactinoma (group 2). Group 1 was then treated with cabergoline, while group 2 with bromocriptine. Plasma lipids, glucose homeostasis markers and plasma levels of prolactin, insulin‐like growth factor‐1 (IGF‐1), and cardiovascular risk factors were assessed before and after 6 months of therapy. Both treatments normalized plasma prolactin levels. Cabergoline reduced triglycerides, 2‐hr post‐challenge plasma glucose, the homeostatic model assessment of insulin resistance (HOMA‐IR), and circulating levels of IGF‐1, free fatty acids (FFA), uric acid, high‐sensitivity C‐reactive protein (hsCRP), homocysteine and fibrinogen, as well as increased HDL‐cholesterol and 25‐hydroxyvitamin D. With the exception of a reduction in HOMA‐IR, bromocriptine treatment produced no significant effect on the investigated biomarkers. Cabergoline was superior to bromocriptine in affecting 2‐hr post‐challenge plasma glucose levels, HOMA‐IR, as well as circulating levels of IGF‐1, FFA, uric acid, hsCRP, homocysteine, fibrinogen and 25‐hydroxyvitamin D. Our results may suggest that cabergoline is superior to bromocriptine when it comes to affecting atherogenic dyslipidaemia, insulin sensitivity and circulating levels of cardiovascular risk factors in hyperprolactinaemic patients. These findings seem to support previous observations that cabergoline may be a better treatment for patients with elevated prolactin levels than bromocriptine. This article is protected by copyright. All rights reserved.
  • Simplified Acute Physiology Score II/Acute Physiology and Chronic Health
           Evaluation II and Prediction of the Mortality and Later Development of
           Complications in Poisoned Patients Admitted to Intensive Care Unit
    • Abstract: We aimed to determine the acute physiology and chronic health evaluation (APACHE) II and simplified acute physiology score (SAPS) II in poisoned patients admitted to the poisoning ICU and compare them to see which is a more sensitive and specific system for prognostication of the mortality and complications in these patients. Between February 2013 and July 2013, all patients referring to our centre with any poisoning mandating ICU admission were prospectively included. On ICU arrival, a questionnaire containing the demographic data, parameters of the APACHE II and SAPS II scores, the sum of the scores, complications during the stay and the patients' final outcome (compete recovery versus death) was filled for every single patient. A total of 195 patients were evaluated. Forty‐two patients (21.5%) died. Mean SAPS and APACHE scores were 41 ± 16 and 15 ± 6, respectively. Mean SAPS and APACHE scores were significantly different between the survivors and non‐survivors. Both scores could successfully prognosticate the development of the complications (p = 0.07 and 0.013, respectively). APACHE II was a better score in prediction of both mortality and later complications in the setting of poisoning ICU. APACHE >22 has a good specificity in determining the mortality and development of further complications in poisoned patients admitted to the medical toxicology ICUs. SAPS II score >59 and >43 can predict the risk of mortality and later complications in these patients, as well.
  • 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.
  • 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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