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  Subjects -> ENVIRONMENTAL STUDIES (Total: 755 journals)
    - ENVIRONMENTAL STUDIES (690 journals)
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ENVIRONMENTAL STUDIES (690 journals)                  1 2 3 4 5 6 7 | Last

Acta Ecologica Sinica     Open Access   (9 followers)
Acta Limnologica Brasiliensia     Open Access   (2 followers)
Acta Oecologica     Hybrid Journal   (9 followers)
Acta Regionalia et Environmentalica     Open Access  
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (11 followers)
Advances in Ecological Research     Full-text available via subscription   (24 followers)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (23 followers)
Advances in Life Science and Technology     Open Access   (4 followers)
Aeolian Research     Hybrid Journal   (1 follower)
African Journal of Environmental Science and Technology     Open Access   (2 followers)
African Journal of Sustainable Development     Full-text available via subscription   (2 followers)
AGE     Hybrid Journal   (4 followers)
Age and Ageing     Hybrid Journal   (12 followers)
Agricultura Tecnica     Open Access   (5 followers)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (9 followers)
Ambiência     Open Access  
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (1 follower)
Ambiente & sociedade     Open Access   (2 followers)
American Journal of Applied Sciences     Open Access   (27 followers)
American Journal of Environmental Engineering     Open Access   (6 followers)
American Journal of Environmental Protection     Open Access   (3 followers)
American Journal of Environmental Sciences     Open Access   (13 followers)
American Journal of Microbiology     Open Access   (12 followers)
American Naturalist     Full-text available via subscription   (32 followers)
Annals of Environmental Science     Open Access   (9 followers)
Annals of GIS     Hybrid Journal   (14 followers)
Annals of Warsaw University of Life Sciences - SGGW. Land Reclamation     Open Access   (2 followers)
Annual Review of Ecology, Evolution, and Systematics     Full-text available via subscription   (33 followers)
Annual Review of Environment and Resources     Full-text available via subscription   (14 followers)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (16 followers)
Annual Review of Resource Economics     Full-text available via subscription   (10 followers)
Applied and Environmental Soil Science     Open Access   (12 followers)
Applied Ecology and Environmental Sciences     Open Access   (6 followers)
Applied Environmental Education & Communication     Hybrid Journal   (10 followers)
Aquatic Ecology     Hybrid Journal   (13 followers)
Aquatic Toxicology     Hybrid Journal   (17 followers)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription   (1 follower)
Archives of Environmental and Occupational Health     Hybrid Journal   (5 followers)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (9 followers)
Archives of Environmental Protection     Open Access   (4 followers)
Archives of Toxicology     Hybrid Journal   (10 followers)
Asian Journal of Earth Sciences     Open Access   (16 followers)
Asian Journal of Rural Development     Open Access   (9 followers)
ATBU Journal of Environmental Technology     Open Access  
Atmospheric and Climate Sciences     Open Access   (14 followers)
Atmospheric Environment     Hybrid Journal   (25 followers)
Austral Ecology     Hybrid Journal   (7 followers)
Australasian Journal of Environmental Management     Hybrid Journal   (4 followers)
Australasian Journal of Human Security, The     Full-text available via subscription   (3 followers)
Australian Journal of Environmental Education     Full-text available via subscription   (6 followers)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (5 followers)
Basic and Applied Ecology     Hybrid Journal   (13 followers)
Behavioral Ecology     Hybrid Journal   (31 followers)
Behavioral Ecology and Sociobiology     Hybrid Journal   (26 followers)
Biodegradation     Hybrid Journal   (2 followers)
Biodiversity     Hybrid Journal   (16 followers)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (3 followers)
Bioremediation Journal     Hybrid Journal   (5 followers)
BioRisk     Open Access   (2 followers)
BMC Ecology     Open Access   (16 followers)
Boston College Environmental Affairs Law Review     Open Access   (5 followers)
Built Environment     Full-text available via subscription   (4 followers)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (11 followers)
Bulletin of the American Meteorological Society     Open Access   (12 followers)
Canadian Journal of Earth Sciences     Full-text available via subscription   (7 followers)
Canadian Journal of Remote Sensing     Full-text available via subscription   (12 followers)
Canadian Journal of Soil Science     Full-text available via subscription   (12 followers)
Canadian Water Resources Journal     Hybrid Journal   (17 followers)
Capitalism Nature Socialism     Hybrid Journal   (9 followers)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
CCLR - Carbon and Climate Law Review     Full-text available via subscription   (2 followers)
Cell Biology and Toxicology     Hybrid Journal   (8 followers)
Chain Reaction     Full-text available via subscription  
Chemical Research in Toxicology     Full-text available via subscription   (13 followers)
Chemico-Biological Interactions     Hybrid Journal   (2 followers)
Chemosphere     Hybrid Journal   (10 followers)
Child and Adolescent Mental Health     Hybrid Journal   (13 followers)
Civil and Environmental Research     Open Access   (11 followers)
CLEAN - Soil, Air, Water     Hybrid Journal   (14 followers)
Clean Technologies and Environmental Policy     Hybrid Journal   (8 followers)
Climate Change Economics     Hybrid Journal   (16 followers)
Climate Policy     Hybrid Journal   (18 followers)
Coastal Engineering Journal     Hybrid Journal   (1 follower)
Columbia Journal of Environmental Law     Free   (7 followers)
Computational Ecology and Software     Open Access   (5 followers)
Computational Water, Energy, and Environmental Engineering     Open Access   (1 follower)
Conservation and Society     Open Access   (6 followers)
Conservation Letters     Hybrid Journal   (16 followers)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (7 followers)
Construction Innovation: Information, Process, Management     Hybrid Journal   (12 followers)
Contemporary Problems of Ecology     Hybrid Journal   (2 followers)
Continental Journal of Environmental Design and Management     Open Access   (3 followers)
Continental Journal of Renewable Energy     Open Access   (8 followers)
Continental Journal of Sustainable Development     Open Access   (9 followers)
Creativity and Innovation Management     Hybrid Journal   (89 followers)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (7 followers)
Critical Reviews in Toxicology     Hybrid Journal   (11 followers)
Culture, Agriculture, Food and Environment     Hybrid Journal   (7 followers)

        1 2 3 4 5 6 7 | Last

Basic & Clinical Pharmacology & Toxicology    [7 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  [1594 journals]   [SJR: 0.588]   [H-I: 56]
  • The Neuronal Cytoskeleton as a Potential Target in the Developmental
           Neurotoxicity of Organophosphorothionate Insecticides
    • Abstract: Phosphorothionates are toxicologically the most important class of organophosphorus ester (OP) insecticides. Phosphorothionates are metabolically converted in vivo to their oxon analogues. These oxon metabolites can bind and inhibit acetylcholinesterase, thus causing acute cholinergic neurotoxicity. Oxon binding to the same target may also be partly responsible for manifestation of the ‘intermediate syndrome’. More recent evidence suggests that the oxons may be also capable of inducing developmental neurotoxicity. The neuronal cytoskeleton may represent a potential target for the developmental neurotoxicity of the oxons because of its vital importance in many stages of normal neurodevelopment. Data obtained in the last five years and critically reviewed here indicate that the oxon metabolites, at concentrations that can be attained in vivo, exert potent effects on the neuronal cytoskeleton disrupting all three cytoskeletal networks. This disruption is expressed at the level of cytoskeletal protein expression, intracellular distribution, post translational modification, cytoskeletal dynamics and function and may involve effects on both neuronal and glial cells. These effects are not secondary to other changes but may constitute primary effects of the oxons, as these compounds have been shown to be capable of covalently binding to and organophosphorylating multiple sites on tubulin and actin. Analogous studies must be extended to include other neurodevelopmentally important cytoskeletal proteins, such as NFH, NFM and tau, which are known to contain unusually high numbers of phosphorylatable sites and to establish whether organophosphorylation by the oxons takes place at sites where neurodevelopmentally relevant, endogenous, reversible phosphorylation is known to occur. This article is protected by copyright. All rights reserved.
  • EGCG 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 (p0.05). PCR array test results showed that 18 genes were differentially expressed, among which 8 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. 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 multilayer 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. This article is protected by copyright. All rights reserved.
  • Preclinical 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 preclinical 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 g/mL (10 M). It was not mutagenic by Ames assay; did not produce chromosome aberrations in 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 were 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 preclinical studies and absence of adverse events in the Phase 1 trial have supported investigation of CMX‐2043 in a human efficacy trial. This article is protected by copyright. All rights reserved.
  • High‐Content Analysis in Toxicology: Screening Substances for Human
           Toxicity Potential, Elucidating Subcellular Mechanisms and In Vivo Use as
           Translational Safety Biomarkers
    • Abstract: High‐content analysis (HCA) of in vitro biochemical and morphological effects of classic (small molecule) drugs and chemicals is concordant with potential for human toxicity. For hepatotoxicity, concordance is greater for cytotoxic effects assessed by HCA than for conventional cytotoxicity tests and for regulatory animal toxicity studies. Additionally, HCA identifies chronic toxicity potential, and drugs producing idiosyncratic adverse reactions and/or toxic metabolites are also identified by HCA. Mechanistic information on the subcellular basis for the toxicity is frequently identified, including various mitochondrial effects, oxidative stress, calcium dyshomeostasis, phospholipidosis, apoptosis and antiproliferative effects, and a fingerprinting of the sequence and pattern of subcellular events. As these effects are frequently non‐specific and affect many cell types, some toxicities may be detected and monitored by HCA of peripheral blood cells, such as for anticancer and anti‐infective drugs. Critical methodological and interpretive features are identified that are critical to the effectiveness of the HCA cytotoxicity assessment, including the need for multiple days of exposure of cells to drug, use of a human hepatocyte cell line with metabolic competence, assessment of multiple pre‐lethal effects in individual live cells, consideration of hormesis, the need for interpretation of relevance of cytotoxicity concentration compared to efficacy concentration and quality management. Limitations of the HCA include assessment of drugs that act on receptors, transporters or processes not found in hepatocytes. HCA may be used in a) screening lead candidates for potential human toxicity in drug discovery alongside of in vitro assessment of efficacy and pharmacokinetics, b) elucidating mechanisms of toxicity and c) monitoring in vivo toxicity of drugs with known toxicity of known mechanism.
  • 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 four days. All four tested drugs showed a significant place preference compared to 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. This article is protected by copyright. All rights reserved.
  • 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 of cytosolic Ca2+‐activity ([Ca2+]i). The present study explored whether salinomycin stimulates eryptosis. Phosphatidylserine‐exposing erythrocytes were identified by measurement of annexin‐V binding, cell volume was estimated from forward scatter, hemolysis determined from hemoglobin 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 of Fluo3‐fluorescence, DCFDA fluorescence and annexin‐V binding, as well as a significant decrease of forward scatter (at 5‐10 nM, but not at 50 and 100 nM). The annexin‐V binding following 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+. This article is protected by copyright. All rights reserved.
  • 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 male 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 mmol/L). 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 multifactorial, and the clinical situation may be further complicated, when ingestion of ethanol and toxic agents are involved. Here, we reported a patient in which 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. This article is protected by copyright. All rights reserved.
  • Professor Folke Sjöqvist is the 2013 BCPT Nordic Prize Winner in
           Basic & Clinical Pharmacology & Toxicology
    • Abstract: Professor Folke Sjöqvist who recently turned 80, is still very active and has accomplished remarkable results in many areas of Clinical Pharmacology. He began his thesis work under the pharmacologist‐toxicologist pioneer Professor Bo Holmstedt and with Professor Börje Uvnäs chairing the institution at the Karolinska Institute in Stockholm. The thesis concerned basic experimental pharmacology and ganglionic autonomic transmission. He then had a long postdoc in the USA where his scientific interest was profoundly reoriented towards clinical pharmacology. The most important influence was in the laboratory of the legendary Bernard B. Brodie at the National Institutes of Health (NIH). Professor Sjöqvist became engaged in the new fields of drug metabolism exploring the roles of species and interindividual differences and innovative methods for specific chemical drug analysis. He also studied clinical trial methodology with Professor Louis Lasagna at Johns Hopkins in Baltimore. This article is protected by copyright. All rights reserved.
  • Workshop of Scandinavian Society for Cell Toxicology (SSCT) 25‐27
           September 2013 in Denmark
    • Abstract: The workshop “Frontiers in Cell Toxicity Testing” consisted of 5 sessions and a poster exhibition. Together, there were 28 oral presentations and 12 poster presentations. The number of participants was 71, from 9 countries and with many young scientists. With this workshop, SSCT celebrated its 30‐year anniversary. This article is protected by copyright. All rights reserved.
  • Corrigendum
  • Late Adverse Events after Enhanced and Unenhanced MRI and CT: A
           Prospective Study
    • Abstract: Prospective evaluation of frequency of late and very late adverse events in patients undergoing enhanced or unenhanced magnetic resonance imaging (MRI) or computed tomography (CT). The imaging procedure was performed according to the protocols of the department. All patients were contacted 3 days after their imaging procedure for the occurrence of late adverse events (LAEs) and a month later for the occurrence of very late adverse events (VLAEs) using a structured questionnaire. A total of 1042 (71%) among 1473 patients completed both the 3‐day and 1‐month questionnaire. The incidence of LAEs was significantly higher in the enhanced MRI (38%) and CT (27%) groups than unenhanced MRI (20%) and CT (16%) groups. The frequency of nausea, dizziness, abdominal pain and diarrhoea was significantly higher in the enhanced MRI group than in the MRI control group, while taste sensation was reported more frequent in the enhanced CT group than in the CT control group. The incidence of VLAEs was significantly higher in the enhanced CT (21%) than unenhanced CT group (13%). The same LAEs and VLAEs were reported in all four groups. LAEs and VLAEs were reported more often in patients with allergy in both the enhanced and unenhanced groups. The incidence of LAEs and VLAEs was higher in the enhanced groups than in the unenhanced groups. The most reported adverse events in the enhanced groups were also reported in the unenhanced groups. Patients with allergy reported LAE and VLAE more often. This suggests that adverse events may not always be caused by the contrast media.
  • Effect of Nitazoxanide on Erythrocytes
    • Abstract: Nitazoxanide, a drug effective against a variety of pathogens, triggers apoptosis and is thus considered to be employed against malignancy. Similar to nucleated cells, erythrocytes may undergo an apoptosis‐like suicidal cell death or eryptosis. Hallmarks of eryptosis include cell shrinkage and phospholipid scrambling of the cell membrane with translocation of phosphatidylserine to the erythrocyte surface. Stimulators of eryptosis include increase in cytosolic Ca2+‐activity ([Ca2+]i). The Ca2+‐sensitivity of eryptosis is increased by ceramide. This study explored whether nitazoxanide triggers eryptosis. [Ca2+]i was estimated from Fluo3‐fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin‐V‐binding, ceramide abundance utilizing fluorescent antibodies and haemolysis from haemoglobin release. A 48‐hr exposure to nitazoxanide (1–50 μg/ml) did not significantly modify [Ca2+]i but significantly increased ceramide formation, decreased forward scatter (≥10 μg/ml), increased the percentage of annexin‐V‐binding erythrocytes (≥10 μg/ml) and, at higher concentrations (≥20 μg/ml), stimulated haemolysis. The stimulation of annexin‐V‐binding was significantly blunted in the absence of calcium. Nitazoxanide thus stimulates eryptosis, an effect in part due to ceramide formation.
  • Exposure to Bisphenol A Affects Lipid Metabolism in Drosophila
    • Abstract: Exposure to bisphenol A (BPA) in rodents was shown to induce obesity, yet the mechanism by which BPA might induce obesity is still unclear. We employed the genetically tractable model organism, Drosophila melanogaster, to test the effects of raising them on food containing various concentrations of BPA. Of note, raising males on food containing BPA were susceptible to starvation, possibly by inhibiting their ability to perform lipolysis during starvation, leading to significantly increased lipid content after 24 hr of fasting. Furthermore, feeding males with BPA significantly inhibited the expression of insulin‐like peptides. From these results, we conclude that BPA may inhibit lipid recruitment during starvation in Drosophila.
  • Drug Dosing in Patients with Renal Insufficiency in a Hospital Setting
           using Electronic Prescribing and Automated Reporting of Estimated
           Glomerular Filtration Rate
    • Abstract: In patients with impaired renal function, drug dose adjustment is often required. Non‐adherence to clinical prescribing recommendations may result in severe adverse events. In previous studies, the prevalence rate of non‐adherence to recommended dosing has been reported to be 19–67%. Using the clinical support system Renbase® as reference, we investigated the use and dosing of drugs in patients with impaired renal function in a university hospital setting using electronic prescription and automatic reporting of estimated glomerular filtration rate (eGFR). In all, 232 patients with an eGFR in the range of 10–49 ml/min./1.73 m2 were included. We identified 436 episodes with administration of renal risk drugs (prescribed to 183 patients): 410 drugs required dose adjustment according to the eGFR and 26 should be avoided. In total, the use or dosing of 66 (15%) of the 436 renal risk drugs was not in agreement with recommendations in Renbase®. This reflects less disagreement with expert guidelines than reported previously, indicating a possible beneficial effect of electronic prescribing and reporting of eGFR. However, we also found that disagreement to some extent reflected inappropriate drug use. We conclude that despite implementation of electronic prescribing and automated reporting of eGFR, patients with renal insufficiency may still be exposed to inappropriate drug use, with potential increased risk of adverse effects. Initiatives to reduce medication errors such as the use of electronic decision support systems should be explored.
  • Population Pharmacokinetic–Pharmacogenetic Model of Tacrolimus in
           the Early Period after Kidney Transplantation
    • Abstract: As tacrolimus has a rather narrow therapeutic range and high individual variability in its pharmacokinetics, it is important to determine the cause of the variation in tacrolimus pharmacokinetics. The purpose of this study was to establish a population pharmacokinetic–pharmacogenetic model of tacrolimus and identify covariates that affect pharmacokinetic parameters to prevent fluctuations in the tacrolimus trough concentration during the early period after transplantation. Data from 1501 trough concentrations and 417 densely collected concentrations were compiled from 122 patients who were on post‐operative days 10–20 and analysed with a nonlinear mixed‐effect model. The first‐order conditional estimation (FOCE) with interaction method was used to fit the model using the NONMEM program. Clinical/laboratory data were also collected for the same period, and CYP3A5 and ABCB1 genotypes were analysed for use in modelling from all included patients. An empirical Bayesian approach was used to estimate individual pharmacokinetic profiles. A one‐compartment model with first absorption and elimination and lag time best described the data. The estimated population mean of clearance (CL/F), volume of distribution (V/F) and absorption rate (Ka) were 21.9 L/hr, 205 L, and 3.43/hr, respectively, and the lag time was fixed at 0.25 hr. Clearance increased with days after transplantation and decreased with CYP3A5*3/*3 about 18.4% compared with CYP3A5*1 carriers (p 
  • Ontogeny of CYP3A and P‐Glycoprotein in the Liver and the Small
           Intestine of the Göttingen Minipig: An Immunohistochemical Evaluation
    • Abstract: Despite the increasing use of the minipig as a non‐rodent species in general and juvenile toxicity studies, knowledge on their biotransformation processes and their ontogeny is scarce. Such data are prerequisite for the correct interpretation of non‐clinical studies in this species. Therefore, the aim of our investigation was to immunohistochemically document the presence of the drug transporter P‐glycoprotein (Pgp) and the metabolizing cytochrome P450 (CYP) 3A subfamily in the livers (n = 115) and the small intestines (n = 74) of foetal, neonatal, juvenile and adult Göttingen minipigs. Pgp was expressed in the liver in all age groups, whereas its presence in the jejunum was detected from 86 days of gestation onwards. Low expression of CYP3A was detected in the jejunums and livers from foetal and neonatal piglets. During postnatal development, the immunoreactivity for CYP3A increased in both organs. A centrilobular pattern, with a more intense staining for CYP3A of the hepatocytes surrounding the central vein, was noticed in the postnatal livers. In conclusion, the presented data suggest that the intestinal and hepatic ontogeny of P‐glycoprotein and CYP3A in minipigs corresponds to that in man, in which a similar spatio‐temporal expression has been reported.
  • Improving Amphetamine Therapeutic Selectivity:
           N,N‐dimethyl‐MTA has Dopaminergic Effects and does not Produce
           Aortic Contraction
    • Abstract: Amphetamine derivatives have therapeutic potential in diseases such as attention deficit hyperactivity disorder, narcolepsy and obesity. However, their prolonged use has been associated with cardiovascular toxicity and addiction. In recent years, we have studied the pharmacological effects of amphetamine derivatives such as methylthioamphetamine (MTA) and N,N‐dimethyl‐thioamphetamine, with the aim of improving their therapeutic selectivity. In this work, we show that similarly to MTA, N,N‐dimethyl‐thioamphetamine has effects on the dopamine system, producing a significant increase in extracellular levels of dopamine (as measured by in vivo brain microdialysis) and locomotor activity, which is a behavioural measure of dopaminergic activation. However, unlike MTA, N,N‐dimethyl‐ thioamphetamine does not produce aortic contraction in vitro. Our results show that N,N‐dimethyl‐thioamphetamine is a drug that retains the dopaminergic effects of amphetamine derivatives but exhibits a lower potential for producing cardiovascular side effects.
  • Influence of UGT2B7, OPRM1 and ABCB1 Gene Polymorphisms on Morphine Use
    • 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 and 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. This article is protected by copyright. All rights reserved.
  • 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 to those from the surgical wards or the ICUs (26.0% versus 10.5% versus 13.7%, p
  • Response to “Antibiotic Use and Resistance” Children and
           elderly people in Spain are heavy users of antibiotics
    • Abstract: As mentioned, antibiotic consumption in heavy users, especially in children, is really striking. Certainly, our results revealed an antibiotic use in this age group higher than published in previous studies, and in line with different reports repeatedly presenting the high antibiotic consumption existing in Spain compared with other European countries (1). Determinants involved in antibiotic prescribing are numerous and varied. It is true that therapeutic failures lead to repeated courses of antibiotic treatment. However, it is not probably the only reason. Frequent and high consumption of antibiotics, as observed in heavy users, could also be due to factors related to the GP, patient and parents’ expectations or the influence exerted by the pharmaceutical industry (2). This article is protected by copyright. All rights reserved.
  • A Nationwide Study of ADHD Drug Use among Adults in Iceland
    • 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 1,000 adults between 2003 and 2012, with the most pronounced increases among young adults (19‐24 years). The annual incidence increased 3‐fold, 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 one 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. This article is protected by copyright. All rights reserved.
  • The Impact of NSAID Treatment on Cardiovascular Risk – Insight from
           Danish Observational Data
    • Abstract: The present MiniReview describes the present evidence for the relationship between cardiovascular risk and use of non‐steroidal anti‐inflammatory drugs (NSAIDs) with special focus using Danish register‐based data. NSAIDs are among the most widely used drugs worldwide and mainly used for management of pain and inflammatory conditions. Through the past decade, much attention has been given to the cardiovascular safety of these drugs, and several studies have shown increased risk of adverse cardiovascular effects associated with NSAID use. Current guidelines discourage any use of NSAIDs in patients with cardiovascular disease, yet over a period of 8‐10 years, 35‐44% of patients with myocardial infarction or heart failure were exposed to NSAIDs in Denmark. Furthermore, NSAID use was associated with an increased risk of death or myocardial infarction by up to 5‐fold that of non‐users. There was also a clear indication for a dose‐related response in risk associated with NSAID therapy, supporting a causal association. Notably, the cardiovascular risk associated with NSAID treatment was prevalent at start of treatment suggesting no safe treatment window for NSAIDs in patients with cardiovascular disease. Thus, evidence from observational studies is accumulating suggesting that NSAIDs are a major public health concern due to the widespread use of these drugs. Although it seems unlikely that we can completely avoid use of NSAIDs, even among high‐risk patients, these results highlight the importance of balancing the benefit versus the risk of treatment before initiating NSAID treatment. This article is protected by copyright. All rights reserved.
  • 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 the present 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 eight 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 of 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 ROS production, renewing the total antioxidant capacity and influencing expression of hepatic lipid biosynthesis and metabolism genes. This article is protected by copyright. All rights reserved.
  • Can Physical Exercise or Food Deprivation Cause Release of
           Fat‐Stored Cannabinoids in Humans'
    • Abstract: The aim of this study was to evaluate whether physical exercise or food deprivation may increase cannabionoid 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 y; 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 Δ9‐tetrahydrocannabinol (THC) and 11‐nor‐9‐carboxy‐Δ9‐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. This article is protected by copyright. All rights reserved.
  • Peripheral Antinociception and Anti‐Inflammatory Effects of Sulfated
           Polysaccharides from the Alga Caulerpa Mexicana
    • Abstract: Sulfated polysaccharides from marine algae are widely used in biotechnological and pharmaceutical areas. In this study, we evaluated the effects of sulfated 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, was 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. This article is protected by copyright. All rights reserved.
  • 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 sub‐convulsive dose of pentylenetetrazole (PTZ, 30 mg/kg, i.p., every other day for six weeks). The mice were pre‐treated (30 min.) with either 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
  • In Vitro and Modelling Approaches to Risk Assessment from the U.S.
           Environmental Protection Agency ToxCast Programme
    • Abstract: A significant challenge in toxicology is the “too many chemicals” problem. Humans and environmental species are exposed to tens of thousands of chemicals, only a small percentage of which have been tested thoroughly using standard in vivo test methods. This paper reviews several approaches that are being developed to deal with this problem by the U.S. Environmental Protection Agency, under the umbrella of the ToxCast programme ( The overall approach is broken into seven tasks: (1) identifying biological pathways that, when perturbed, can lead to toxicity; (2) developing high‐throughput in vitro assays to test chemical perturbations of these pathways; (3) identifying the universe of chemicals with likely human or ecological exposure; (4) testing as many of these chemicals as possible in the relevant in vitro assays; (5) developing hazard models that take the results of these tests and identify chemicals as being potential toxicants; (6) generating toxicokinetics data on these chemicals to predict the doses at which these hazard pathways would be activated; and (7) developing exposure models to identify chemicals for which these hazardous dose levels could be achieved. This overall strategy is described and briefly illustrated with recent examples from the ToxCast programme. This article is protected by copyright. All rights reserved.
  • Antibiotic use and resistance
    • Abstract: I recently read the study of Malo et al., “High Antibiotic Consumption: The Characterisation of Heavy Users in Spain” [1]. The study is very good and shows an interesting way to evaluate the intake of medications, especially antibiotics, using the Lorenz curve.The study indicates that children and the elderly are heavy users of antibiotics (January–December 2010). The Lorenz curve is constructed from the number of antibiotics packages purchased per patient per year. This article is protected by copyright. All rights reserved.
  • At Centennial of Michaelis and Menten, Competing Michaelis‐Menten
           Steps Explain Effect of GLP‐1 on Blood‐Brain Transfer and
           Metabolism of Glucose
    • Abstract: Glucagon‐like peptide‐1 (GLP‐1) is a potent insulinotropic incretin hormone with pancreatic and extrapancreatic effects. Studies reveal significant effects in regions of brain tissue that regulate appetite and satiety. The effects cause that mimetics of GLP‐1 serves as treatment of type 2 diabetes mellitus. GLP‐1 interacts with peripheral functions in which the autonomic nervous system plays an important role, and emerging preclinical findings indicate a potential neuroprotective role of the peptide, e.g., in models of stroke and in neurodegenerative disorders. A century ago, Leonor Michaelis and Maud Menten described the steady‐state enzyme kinetics that still apply to the multiple receptors, transporters and enzymes that define the biochemical reactions of the brain, including the glucose‐dependent impact of GLP‐1 on blood‐brain glucose transfer and metabolism. This MiniReview examines the potential of GLP‐1 as a molecule of interest to the understanding of brain energy metabolism and notes the impact on brain metabolism related to appetite and satiety regulation, stroke and neurodegenerative disorders, among others. These effects can be understood only by reference to the original formulation of the Michaelis‐Menten equation as applied to a chain of kinetically controlled steps. Indeed, the effects of GLP‐1 receptor activation on blood‐brain glucose transfer and brain metabolism of glucose depend on the glucose concentration and relative affinities of the steps both in vitro and in vivo, as in pancreas. The apparent neuroprotective potential of GLP‐1, indirectly acting through changes of cerebral blood flow, glucose metabolism or brain glucose concentration, or all of these, is worthy of close attention. This article is protected by copyright. All rights reserved.
  • Incorporation of Flurbiprofen in a 4‐Drug Cytochrome P450
           Phenotyping Cocktail
    • Abstract: Cytochromes P450 (CYP) constitute the major drug‐metabolizing enzyme system in humans. The activity of these enzymes is subjected to a great inter‐individual variability which can cause interindividual differences in plasma drug concentrations and result in therapeutic failure or side effects. To avoid these problems, it is of great importance to evaluate the in vivo CYP activity (phenotyping). In the beginning of the 1990s, a ‘cocktail’ approach was developed, aiming to simultaneously assess the activity of multiple CYPs by the administration of a cocktail of CYP‐specific probe drugs [1]. Several cocktails using different probe drugs have been developed in the past years [2‐7]. Few of these cocktails use well‐validated probes such as caffeine, omeprazole, dextromethorphan and midazolam for the phenotyping of CYP1A2, CYP2C19, CYP2D6 and CYP3A, respectively [2, 4, 5]. These drugs have no mutual interactions as previously demonstrated [5]. Two of these cocktails also include losartan [4] or warfarin [2] as probes for CYP2C9 activity. These drugs, as well as tolbutamide [8] and phenytoin [9], have been proposed as potentially useful CYP2C9 probes. However, all of the proposed CYP2C9 substrates are associated with limitations which make them less than ideal as probes for this enzyme [10]. Recently, flurbiprofen has been validated as a reliable probe for CYP2C9 phenotyping both in urine [10] and single point plasma samples [11]. Flurbiprofen has also been incorporated in the Pittsburgh cocktail and was shown not to interact with the other probes. [7]. In this study, we aimed to validate the incorporation of flurbiprofen as a CYP2C9 probe to a cocktail composed of caffeine, omeprazole, dextromethorphan and midazolam and verify the effect these drugs have on flurbiprofen metabolic ratio. This article is protected by copyright. All rights reserved.
  • Anticonvulsant Effects of N‐Arachidonoyl‐Serotonin, a Dual
           FAAH Enzyme and TRPV1 Channel Blocker, on Experimental Seizures: The Roles
           of Cannabinoid CB1 Receptors and TRPV1 Channels
    • Abstract: Selective blockade of anandamide hydrolysis, through inhibition of the FAAH enzyme, has anticonvulsant effects, which are mediated by CB1 receptors. Anandamide, however, also activates TRPV1 channels, generally with opposite outcomes on neuronal modulation. Thus, we hypothesized 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 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. This article is protected by copyright. All rights reserved.
  • Studies of the Safety, Pharmacokinetics and Immunogenicity of Repeated
           Doses of Intravenous Staphylococcal Protein A in Cynomolgus Monkeys
    • Abstract: Three GLP 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 anti‐product antibodies and biomarkers to better characterize the pharmacodynamic response to SPA. Biomarkers included neopterin, C‐reactive protein (CRP), troponin‐1 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 anti‐drug 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. This article is protected by copyright. All rights reserved.
  • 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 catalyzed by ornithine decarboxylase. Treatment with α‐difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, 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 anti‐proliferative effect of DFMO was specific since 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 anti‐proliferative effect, DFMO may prevent loss of the smooth muscle contractile phenotype in vascular injury. This article is protected by copyright. All rights reserved.
  • Modelling of Human Transplacental Transport as Performed in Copenhagen,
    • Abstract: Placenta perfusion models are very effective when studying the placental mechanisms in order to extrapolate to real‐life situations. The models are most often used to investigate the transport of substances between mother and foetus, including the potential metabolism of these. We have studied the relationships between maternal and foetal exposures to various compounds including pollutants such as polychlorinated biphenyls, polybrominated flame retardants, nanoparticles as well as recombinant human antibodies. The compounds have been studied in the human placenta perfusion model and to some extent in vitro with an established human monolayer trophoblast cell culture model. Results from our studies distinguish placental transport of substances by physicochemical properties, adsorption to placental tissue, binding to transport and receptor proteins, and metabolism. We have collected data from different classes of chemicals and nanoparticles for comparisons across chemical structures as well as different test systems. Our test systems are based on human material to bypass the extrapolation from animal data. By combining data from our two test systems, we are able to rank and compare the transport of different classes of substances according to their transport ability. Ultimately, human data including measurements in cord blood contribute to the study of placental transport. This article is protected by copyright. All rights reserved.
  • 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‐kappa B pathway activity, causing changes in the ratio of pro‐ and anti‐apoptotic 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‐kappa B 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. This article is protected by copyright. All rights reserved.
  • 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 non‐parametric 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 nmol/L compared to 31 nmol/L (p
  • 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. 3rd or 4th 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. This article is protected by copyright. All rights reserved.
  • Intravenous Lipid Emulsion Improves Recovery Time and Quality from
           Isoflurane Anaesthesia: A Double‐Blind Clinical Trial
    • Abstract: Recovery time and quality after general anaesthesia is important for patient safety. This study aimed to determine whether intravenous lipid emulsion could improve recovery profiles from isoflurane anaesthesia in adult patients undergoing laparoscopic cholecystectomy. Sixty‐six patients were enrolled. After anaesthesia induction, inspired isoflurane concentration was adjusted to maintain stable vital signs and the suitable conditions for operation. At the end of the operation, the isoflurane was discontinued and either 2 ml/kg 30% lipid emulsions or 0.9% saline solution was administered intravenously. The time to eye opening, extubation and exit from the operation room was recorded, and the quality of recovery from anaesthesia was assessed. Sixty patients completed the study. The median time to eye opening and exit from the operation room was significantly shorter in the lipid emulsion group than in the saline group (15.5 [interquartile range 9.0] versus 20.0 [10.0] min., P = 0.01; 19.5 [8.3] versus 23.6 [6.3] min., P = 0.04, respectively), whereas the median time to extubation did not show any noticeable difference. The quality of recovery was better in the lipid emulsion group than that of the saline solution group with respect to drowsiness visual analogue scale score (P < 0.01), Observer's Assessment of Alertness/Sedation score (P < 0.01), Mini‐Mental State Examination score (P = 0.04), and Modified Aldrete Post Anaesthesia Recovery score (P = 0.03). No serious adverse events were observed during the study period. In conclusion, intravenous lipid emulsion may effectively improve the recovery time and quality from isoflurane anaesthesia for laparoscopic cholecystectomy. This article is protected by copyright. All rights reserved.
  • The 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 seven 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. This article is protected by copyright. All rights reserved.
  • 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. 19 healthy volunteers received transdermal placebo and buprenorphine in a cross‐over study. Drug plasma concentrations and ERPs following electrical stimulation at the median nerve with intensity adjusted to pain detection threshold were recorded until 144 hours 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 8‐fold 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. This article is protected by copyright. All rights reserved.
  • 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, 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 evaluation of the anti‐inflammatory activity. The data reviewed here suggest that modified terpenes are an interesting tool for the development of new anti‐inflammatory drugs. This article is protected by copyright. All rights reserved.
  • Semi‐Mechanistic Modelling and Simulation of Inhibition of Platelet
           Aggregation by Anti‐Platelet Agents
    • Abstract: Anti‐platelet agents are a class of pharmaceuticals that decrease platelet aggregation and thus inhibit thrombus formation. We examined the relationships between plasma concentrations of anti‐platelet agents (triflusal, clopidogrel, 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 anti‐platelet agents. Time courses of plasma concentrations of the anti‐platelet 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 anti‐platelet agents and platelet aggregation effects. In addition, the estimated parameters were suitable for explanation of the agents and also have a good correlation with platelet characteristics, such as platelet half‐life and platelet aggregation baseline effects. Especially, we discovered the strong correlations between estimated K parameter and in vitro drug activity. We conclude that this semi‐mechanistic PK/PD model explained well drug PK/PD characteristics, and will be useful for accurate predictions of anti‐platelet effect in the clinical situations. This article is protected by copyright. All rights reserved.
  • Application of High‐Content Analysis in Clinical Cytology for
           Translational Safety Biomarkers of Drug‐Induced Toxicity for
           Lymphoma Chemotherapy
    • Abstract: Drug cytotoxicity detected by high‐content analysis (HCA) of live, cultured, human hepatocytes concurs with human toxic potential. We assessed HCA effectiveness in vivo using human, lymphoma line (HuT‐78) and blood cells from healthy dogs and lymphomatous dogs treated with anti‐cancer drugs: cytarabine, arsenic trioxide (AT), doxorubicin and mitozanthrone. DNA was stained with Hoechst‐33342, calcium with fluo‐4, mitochondria with TMRM and cell permeability with toto‐3. HuT‐78 and canine blood lymphocytes were treated 24 hr with 10‐fold increasing drug concentrations had concentration‐response relationships to test agents. These showed hormesis (biphasic response) for TMRM and nuclear area. Fluorescence intensity was decreased with AT and mitozanthrone but increased with cytarabine for TMRM, decreased from cell injury or anthracycline interaction for Hoechst‐33342, and decreased with AT and interfered with by doxorubicin for fluo‐4. Nuclear area increased with anthracyclines and AT. Mitochondria, calcium and nuclear area were affected in peripheral blood lymphocytes of lymphomatous dogs receiving chemotherapy: mitochondria were inhibited by acute treatment, but increased 2 weeks after treatment, as were ionized calcium, nuclear area and DNA. We conclude: a) concentration‐response relationships are determinable in vitro for human and canine lymphocytes by HCA, b) cytotoxicity is detectable in vivo during and after anti‐cancer drug treatment using canine blood lymphocytes: mitochondria are most affected, with smaller changes in calcium and nuclei. c) blood cell viability may be a biomarker for anti‐cancer drug toxicity. This article is protected by copyright. All rights reserved.
  • 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. This article is protected by copyright. All rights reserved.
  • Selenium Cytotoxicity in Cancer
    • Abstract: Selenium is an essential trace element with growth modulating properties. Decades of research clearly demonstrate that selenium compounds inhibit the growth of malignant cells in diverse experimental model systems. However, the growth modulating and cytotoxic mechanisms are diverse and far from clear. Lately, a remarkable tumour selective cytotoxicity of selenium compounds has been shown, indicating the potential of selenium in the treatment of cancer. Of particular interest are the redox‐active selenium compounds exhibiting cytotoxic potential to tumour cells. These selenium compounds elicit complex patterns of pharmacodynamics and pharmacokinetics, leading to cell death pathways that differ among compounds. Modern oncology often focuses on targeted ligand‐based therapeutic strategies that are specific to their molecular targets. These drugs are initially efficient but the tumour cells often rapidly develop resistance against these drugs. In contrast, certain redox‐active selenium compounds induce complex cascades of pro‐death signalling at pharmacological concentrations with superior tumour specificity. The target molecules are often the ones that are important for the survival of cancer cells and often implicated in drug resistance. Therefore, the chemotherapeutic applications of selenium offer great possibilities of multi‐target attacks on tumour cells. This MiniReview focuses on the tumour‐specific cytotoxic effects of selenium, with special emphasis on cascades of cellular events induced by the major groups of pharmacologically active selenium compounds. Furthermore, the great pharmacological potential of selenium in the treatment of resistant cancers is discussed. This article is protected by copyright. All rights reserved.
  • Low‐Density Lipoprotein is a Potential Target for Curcumin: Novel
           Mechanistic Insights
    • Abstract: A recent paper published by Um et al. in Basic & Clinical Pharmacology & Toxicology provides interesting data supporting the idea that curcumin supplementation counteracts metabolic abnormalities induced by lipogenic diet [1]. Along with the reduction of hepatic fat accumulation, a particularly interesting finding of the mentioned study was the beneficial impact of curcumin on serum levels of lipids, evidenced by reduction of total cholesterol and triglycerides [1]. Surprisingly, the study did not report changes in serum low‐density lipoprotein cholesterol (LDL‐C) as a leading risk factor for atheroma formation and coronary artery disease. This letter intends to point to some recent findings which provide a strong mechanistic rationale for the effectiveness of curcumin in modulating circulating LDL‐C levels. This article is protected by copyright. All rights reserved.
  • Pharmacokinetic‐Pharmacodynamic Modelling of the Analgesic and
           Anti‐hyperalgesic Effects of Morphine after Intravenous Infusion in
           Human Volunteers
    • Abstract: Using a modelling approach, this study aimed to (i) examine whether the pharmacodynamics of the analgesic and anti‐hyperalgesic 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 subjects (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 anti‐hyperalgesic 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. This article is protected by copyright. All rights reserved.
  • Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other
           Inflammatory Airway Diseases
    • Abstract: Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti‐inflammatory (PDE4) and bifunctional bronchodilator/anti‐inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose‐limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active Roflumilast‐n‐oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non‐selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regards to anti‐inflammatory and bronchodilator effects that have been observed pre‐clinically with dual inhibition of PDE3 and PDE4 compared to inhibition of either isozyme alone. This MiniReview will summarise recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis. This article is protected by copyright. All rights reserved.
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