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  Subjects -> ENVIRONMENTAL STUDIES (Total: 779 journals)
    - ENVIRONMENTAL STUDIES (715 journals)
    - POLLUTION (21 journals)
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ENVIRONMENTAL STUDIES (715 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: 8)
Acta Regionalia et Environmentalica     Open Access  
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 12)
Advances in Ecological Research     Full-text available via subscription   (Followers: 26)
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: 2)
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: 33)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 11)
Ambiência     Open Access  
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Applied Sciences     Open Access   (Followers: 29)
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: 15)
American Naturalist     Full-text available via subscription   (Followers: 43)
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: 40)
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: 20)
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: 10)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 11)
Aquatic Ecology     Hybrid Journal   (Followers: 16)
Aquatic Toxicology     Hybrid Journal   (Followers: 18)
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   (Followers: 1)
Atmospheric and Climate Sciences     Open Access   (Followers: 14)
Atmospheric Environment     Hybrid Journal   (Followers: 30)
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: 8)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 6)
Basic and Applied Ecology     Hybrid Journal   (Followers: 13)
Behavioral Ecology     Hybrid Journal   (Followers: 38)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 30)
Biodegradation     Hybrid Journal   (Followers: 2)
Biodiversity     Hybrid Journal   (Followers: 21)
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: 16)
Boston College Environmental Affairs Law Review     Open Access   (Followers: 5)
Bothalia : African Biodiversity & Conservation     Open Access  
Built Environment     Full-text available via subscription   (Followers: 5)
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   (Followers: 1)
Canadian Journal of Earth Sciences     Full-text available via subscription   (Followers: 6)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 13)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 12)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 20)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 12)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
CCLR - Carbon and Climate Law Review     Full-text available via subscription   (Followers: 4)
Cell Biology and Toxicology     Hybrid Journal   (Followers: 8)
Chain Reaction     Full-text available via subscription  
Change and Adaptation in Socio-Ecological Systems     Open Access  
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: 37)
Civil and Environmental Research     Open Access   (Followers: 12)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 16)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 8)
Climate Change Economics     Hybrid Journal   (Followers: 17)
Climate Policy     Hybrid Journal   (Followers: 19)
Coastal Engineering Journal     Hybrid Journal   (Followers: 1)
Columbia Journal of Environmental Law     Free   (Followers: 9)
Computational Ecology and Software     Open Access   (Followers: 5)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 2)
Conservation and Society     Open Access   (Followers: 9)
Conservation Letters     Hybrid Journal   (Followers: 20)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (Followers: 9)
Construction Innovation: Information, Process, Management     Hybrid Journal   (Followers: 14)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 2)
Continental Journal of Renewable Energy     Open Access   (Followers: 10)
Continental Journal of Sustainable Development     Open Access   (Followers: 9)
Creativity and Innovation Management     Hybrid Journal   (Followers: 183)

        1 2 3 4 5 6 7 8 | Last

Journal Cover Basic & Clinical Pharmacology & Toxicology
   [8 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 1742-7835 - ISSN (Online) 1742-7843
     Published by John Wiley and Sons Homepage  [1604 journals]   [SJR: 0.588]   [H-I: 56]
  • A nationwide register‐based survey of baclofen toxicity
    • Authors: Louise Bendix Kiel; Lotte Christine Groth Hoegberg, Tejs Jansen, John Asger Petersen, Kim Peder Dalhoff
      Abstract: To study the use and misuse (poisonings) of baclofen in the time period of 2007‐2012 and to evaluate the severity and clinical symptoms of poisonings including ingested baclofen. The National Patient Register (NPR) was searched for admissions due to baclofen poisonings from 2007 to 2012. The search was conducted with ICD‐10 codes for poisoning, self‐harm and suicide, and coupled with the baclofen ATC code. All enquiries about baclofen to the Danish Poison Information Centre (DPIC) in the same period were evaluated. Demographic and clinical data were extracted, and the poisonings were classified according to the Poison Severity Score. The number of baclofen poisonings did not increase from 2007 to 2012. Thirty‐eight admissions with baclofen poisoning were registered at the NPR, however, only one third of the reviewed DPIC cases were registered at the NPR with the correct coding. In the group of severely poisoned patients (PSS 3), 3 patients had only ingested baclofen (mean 2,000 mg; SD 500 mg) and 8 patients had ingested baclofen together with alcohol or psychotropic drugs (mean 900 mg; SD 641 mg). All patients presented with deep coma and respiratory depression. Additionally, seizures and cardiovascular events (mild hypo‐ or hypertension and bradycardia) occurred. There is a substantial degree of underreporting of baclofen poisonings in Denmark. Symptoms of baclofen poisoning progress very fast, and toxicity was observed even with doses as low as 150 mg. We therefore recommend that observation and treatment of these patients should be carried out in an intermediate or intensive care unit. The most important treatment is the maintenance of a protected airway and respiration. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-22T01:42:09.996219-05:
      DOI: 10.1111/bcpt.12344
  • Intravenous Administration of Apomorphine Does NOT Induce Long QT
           Syndrome: Experimental Evidence from In Vivo Canine Models
    • Authors: Yudai Watanabe; Yuji Nakamura, Xin Cao, Hiroshi Ohara, Yukiko Yamazaki, Norie Murayama, Yosuke Sugiyama, Hiroko Izumi‐Nakaseko, Kentaro Ando, Hiroshi Yamazaki, Atsushi Sugiyama
      Abstract: Apomorphine is a non‐selective dopamine D1/D2 receptor agonist, which has been used for patients with Parkinson's disease and reported to induce QT interval prolongation and cardiac arrest. In order to clarify their causal link, we assessed the cardiovascular and pharmacokinetic profile of apomorphine with the halothane‐anaesthetized canine model (n=4), whereas proarrhythmic potential of apomorphine was analysed with the chronic atrioventricular block canine model (n=4). In the halothane‐anaesthetized model, 0.01 mg/kg, i.v. of apomorphine hydrochloride over 10 min., providing about 10 times of its therapeutic concentration, increased the heart rate and ventricular contraction; 0.1 mg/kg over 10 min., providing about 100 times of the therapeutic, prolonged the ventricular effective refractory period; and 1 mg/kg over 10 min., providing about 1,000 times of the therapeutic, decreased the ventricular contraction, mean blood pressure and cardiac output together with the intraventricular conduction delay and prolongation of the effective refractory period, whereas the left ventricular end‐diastolic pressure, atrioventricular nodal conduction or ventricular repolarization were hardly affected. Meanwhile, in the atrioventricular block model, 1 mg/kg, i.v. of apomorphine hydrochloride over 10 min. neither prolonged the QT interval nor induced torsade de pointes. These results suggest that apomorphine may possess a wide margin of cardiovascular safety contrary to our expectations. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-22T01:40:18.299905-05:
      DOI: 10.1111/bcpt.12343
  • Pharmacogenomic Biomarker Information in FDA‐approved Paediatric
           Drug Labels
    • Authors: Therasa Kim; Nayoung Han, Minji Sohn, Jung Mi Oh, Eui‐Kyung Lee, Eunhee Ji, In‐Wha Kim
      Abstract: Gene maturation differs between paediatric and adult populations and the extrapolation of adult pharmacogenomic information to paediatrics is not always appropriate. We sought to determine the extent of paediatric pharmacogenomic trial translation into US FDA‐approved labels and to evaluate needs for biomarker studies. Using FDA's Table of Genomic Biomarkers and Drugs @ FDA website, 38 pharmacogenomic biomarkers in 56 drug labels were identified with possible application in paediatrics. Of these 56 drugs, biomarker comparison against “Very Important Pharmacogenes (VIPs)” defined in PharmGKB's database revealed a total of eight VIPs labelled among 41 drugs. 139 product reviews posted on the FDA website under the Best Pharmaceuticals for Children Act (BPCA) and Paediatric Research Equity Act (PREA) between October 2007 and July 2014 were examined. Review screening identified 43 drugs with “pharmacogenomic” content of which only three were true genotyping study reviews for proton pump inhibitors, all evaluating CYP2C19 polymorphisms. Pantoprazole was the sole drug labelled with pharmacogenomic information obtained specifically from paediatric trials. was searched to further evaluate the current availability of pharmacogenomic studies in the paediatric population. Of the 33,132 trials registered on, 137 were labelled as paediatric pharmacogenetic and pharmacogenomic studies. Pharmacogenomic studies directly conducted in paediatric patients are lacking and thus pharmacogenomic biomarker information based on adult studies is commonly presented in FDA‐approved labels for use in paediatric patients. Considering differences in gene expression and physiological maturation between paediatric and adult populations, studies investigating pharmacogenomic effects specifically in paediatric patients should be conducted whenever significant biomarkers are available. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-21T23:59:39.209727-05:
      DOI: 10.1111/bcpt.12341
  • Enhanced Eryptosis following Juglone Exposure
    • Authors: Salvatrice Calabrò; Kousi Alzoubi, Rosi Bissinger, Kashif Jilani, Caterina Faggio, Florian Lang
      Abstract: Juglone, a quinone isolated from Juglans mandshurica Maxim, has previously been shown to be effective against malignancy. The effect is at least partially due to stimulation of suicidal death or apoptosis of tumour cells. On the other hand, juglone has been shown to counteract apoptosis, e.g. of neurons. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and breakdown of phosphatidylserine asymmetry of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored whether juglone stimulates eryptosis. To this end, erythrocyte volume was estimated from forward scatter, phosphatidylserine exposure at the erythrocyte surface from FITC annexin V binding, ceramide abundance from binding of fluorescent antibodies in flow cytometry, and cytosolic ATP with a luciferin–luciferase‐based assay. As a result, a 24‐hr exposure of human erythrocytes to juglone (5 μM) significantly decreased erythrocyte forward scatter. Juglone (1‐5 μM) significantly increased the percentage of annexin V binding cells. Juglone (5 μM) significantly increased ceramide abundance at the erythrocyte surface and decreased erythrocyte ATP concentration. The effect of juglone (10 μM) on annexin V binding was slightly but significantly blunted by removal of extracellular Ca2+ and by addition of protein kinase C (PKC) inhibitor staurosporine (1 μM). In conclusion, juglone stimulates suicidal erythrocyte death or eryptosis at least in part by up‐regulation of ceramide abundance, energy depletion and activation of PKC. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-21T23:48:15.635649-05:
      DOI: 10.1111/bcpt.12340
  • Specific Role of α2A‐ and α2B‐, but not
           α2C‐, Adrenoceptor Subtypes in the Inhibition of the
           Vasopressor Sympathetic Outflow in Diabetic Pithed Rats
    • Authors: Alain H. Altamirano‐Espinoza; Guadalupe Manrique‐Maldonado, Bruno A. Marichal‐Cancino, Carlos M. Villalón
      Abstract: Several lines of evidence have shown an association of diabetes with a catecholamines’ aberrant homeostasis involving a drastic change in the expression of adrenoceptors. This homeostatic alteration includes, amongst other things, atypical actions of α2‐adrenoceptor agonists within central and peripheral α2‐adrenoceptors (e.g. profound anti‐nociceptive effects in diabetic subjects). Hence, this study investigated the pharmacological profile of the α2‐adrenoceptor subtypes that inhibit the vasopressor sympathetic outflow in streptozotocin‐pretreated (diabetic) pithed rats. For this purpose, B–HT 933 (up to 30 μg/kg.min) was used as a selective α2–adrenoceptor agonist and rauwolscine as a non‐selective α2A/2B/2C–adrenoceptor antagonist; in addition, BRL 44408, imiloxan and JP–1302 were used as subtype‐selective α2A‐, α2B‐ and α2C–adrenoceptor antagonists, respectively (all given i.v.). I.v. continuous infusions of B–HT 933 inhibited the vasopressor responses induced by electrical sympathetic stimulation without affecting those by i.v. bolus injections of noradrenaline in both normoglycemic and diabetic rats. Interestingly, the ED50 for B‐HT 933 in diabetic rats (25 μg/kg.min) was almost 1–log unit greater than that in normoglycemic rats (3 μg/kg.min). Moreover, the sympatho‐inhibition induced by 10 μg/kg.min B–HT 933 in diabetic rats was: (i) abolished by 300 μg/kg rauwolscine or 100 and 300 μg/kg BRL 44408; (ii) partially blocked by 1000 μg/kg imiloxan; and (iii) unchanged by 1000 μg/kg JP–1302. Our findings, taken together, suggest that B‐HT 933 has a less potent inhibitory effect on the sympathetic vasopressor responses in diabetic (compared to normoglycemic) rats, and that can probably be ascribed to a down‐regulation of α2C–adrenoceptors. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-19T01:11:47.186795-05:
      DOI: 10.1111/bcpt.12354
  • Inclusion of Placebos and Blinding for Ascending Dose
           First‐in‐Human Studies and Other Underpowered Phase 1 Studies
           Has Not Been Justified and On Balance Is Not Useful
    • Authors: Dolly A. Parasrampuria; Leslie Z. Benet
      Abstract: Today, the majority of phase 1 dose‐escalation first‐in‐human studies are designed as blinded, placebo‐controlled protocols. First‐in‐human phase 1 studies are a critical component of the drug development process, but in our opinion the additions of blinding and placebo control to these study protocols are a matter of faith without scientific support to show that the increased complexity, time, burdensome nature and expense of such additions, plus the increase in human subjects studied, are justified and useful in the drug development process. Here, we document the prevalence of such studies, review and respond to the rationalizations for such protocols and propose that the addition of blinding and placebo‐control to first‐in‐human and many other underpowered phase 1 studies is unnecessary since these additions provide little documented benefit to the drug development process. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-19T00:55:56.689885-05:
      DOI: 10.1111/bcpt.12352
  • Is the Measurement of Serum Formate Concentration Useful in the
           Diagnostics of Acute Methanol Poisoning' A Prospective Study of 38
    • Authors: Sergey Zakharov; Ivana Kurcova, Tomas Navratil, Tomas Salek, Martin Komarc, Daniela Pelclova
      Abstract: To study the role of serum formate (S‐formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 – median age 51 (interquartile range (IQR) 37–62) years with confirmed methanol poisoning. S‐formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S‐formate. Asymptomatic patients had median S‐formate of 1.9 (IQR 1.5–2.4) mmol/L. The median S‐formate was 15.2 (IQR 13.9–17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1–18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8–18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p>0.05). Patients with long‐term visual sequelae of poisoning had median S‐formate of 16.1 (IQR 14.3–19.9) mmol/L; with CNS sequelae patients had 15.9 (IQR 14.2–19.5) mmol/L. In lethal cases, the median S‐formate was 15.2 (IQR 13.8–15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S‐formate ≥17.5 mmol/L, S‐lactate ≥7.0 mmol/L, and/or pH
      PubDate: 2014-11-18T04:24:37.200209-05:
      DOI: 10.1111/bcpt.12338
  • Comparison of Systemic Toxicity between Botulinum Toxin Subtypes A1 and A2
           in Mice and Rats
    • Authors: Yasushi Torii; Yoshitaka Goto, Shinji Nakahira, Shunji Kozaki, Ryuji Kaji, Akihiro Ginnaga
      Abstract: The adverse events caused by botulinum toxin type A (subtype A1) product, thought to be aftereffects of toxin diffusion following high‐dose administration, have become serious issues. A preparation showing less diffusion in the body than existing drugs has been sought. We have attempted to produce neurotoxin derived from subtype A2 (A2NTX) with an amino acid sequence different from that of neurotoxin derived from subtype A1 (A1NTX). In this study, to investigate whether A2NTX has the potential to resolve these issues, we compared the safety of A2NTX, a progenitor toxin derived from subtype A1 (A1 progenitor toxin), and A1NTX employing the intramuscular lethal dose 50% (im LD50) in mice and rats and the compound muscle action potential (CMAP) in rats. Mouse im LD50 values for A1 progenitor toxin and A2NTX were 93 and 166 U/kg, and the rat im LD50 values were 117 and 153 U/kg, respectively. In the rat CMAP test, the dose on the contralateral side, which caused a 50% reduction in the CMAP amplitude, i.e., CMAP‐TD50, was calculated as 19.0, 16.6 and 28.7 U/kg for A1 progenitor toxin, A1NTX and A2NTX, respectively. The results indicate that A2NTX is safer than A1 progenitor toxin and A1NTX. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-14T01:11:17.437859-05:
      DOI: 10.1111/bcpt.12351
  • Serum 25‐Hydroxyvitamin D And Parathyroid Hormone Levels In
           Non‐Lactating Women With Postpartum Thyroiditis: The Effect Of
           L‐Thyroxine Treatment
    • Authors: Robert Krysiak; Beata Kowalska, Bogusław Okopien
      Abstract: Vitamin D deficiency seems to be implicated in the onset and progression of some autoimmune disorders. No previous study has investigated vitamin D homeostasis in postpartum thyroiditis. We compared 25‐hydroxyvitamin D and parathyroid hormone (PTH) levels between four groups of non‐lactating women who gave birth within 12 months before the beginning of the study: hypothyroid women with postpartum thyroiditis (group A; n=14), euthyroid females with postpartum thyroiditis (group B; n=14), women with non‐autoimmune hypothyroidism (group C; n=16) and healthy euthyroid females without thyroid autoimmunity (group D; n=15). In the second part of the study, groups A and C were treated for 6 months with L‐thyroxine. Serum levels of 25‐hydroxyvitamin D were lower while PTH higher in patients with postpartum thyroiditis than in patients without thyroid autoimmunity. They were also lower (25‐hydroxyvitamin D) or higher (PTH) in group A than in group B, as well as in group C in comparison with group D. L‐thyroxine treatment increased 25‐hydroxyvitamin D and reduced PTH levels only in hypothyroid women with postpartum thyroiditis. Baseline levels of 25‐hydroxyvitamin D correlated with thyroid antibody titers, thyroid function and circulating PTH levels, while the effect of L‐thyroxine on serum levels of this vitamin correlated with the changes in thyroid antibody titers and PTH levels. The results of our study suggest the association of vitamin D status with postpartum thyroiditis and L‐thyroxine treatment of this disorder. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-14T01:03:30.752363-05:
      DOI: 10.1111/bcpt.12349
  • Stimulation of Suicidal Erythrocyte Death by Ellipticine
    • Authors: Salvatrice Calabrò; Kousi Alzoubi, Rosi Bissinger, Caterina Faggio, Florian Lang
      Abstract: Ellipticine is a potent antineoplastic alkaloid effective in part by triggering apoptosis. Mechanisms involved in ellipticine‐induced apoptosis include mitochondrial depolarization and DNA damage. Erythrocytes lack mitochondria and nuclei but may nevertheless enter suidical death or eryptosis, which is characterized by cell shrinkage and phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), ceramide formation and oxidative stress. The present study tested whether ellipticine stimulates eryptosis. Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca2+]i from Fluo3‐fluorescence, ceramide abundance from binding of specific antibodies and reactive oxygen species from 2′,7′‐dichlorodihydrofluorescein diacetate fluorescence. A 24‐hr exposure of human erythrocytes to ellipticine (5 μg/ml) significantly increased the percentage of annexin V binding cells, ceramide abundance and oxidative stress. Ellipticine did not significantly modify [Ca2+]i and the stimulation of annexin V binding by ellipticine (5 μg/ml) did not require presence of extracellular Ca2+. Ellipticine (5 μg/ml) did not significantly modify forward scatter. Ionomycin (1 μM, 1 hr) decreased forward scatter, an effect slightly but significantly blunted by ellipticine (5 μg/ml). Ellipticine stimulates phosphatidylserine translocation in the erythrocyte cell membrane, an effect at least partially due to stimulation of oxidative stress and ceramide formation. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-14T01:03:20.699177-05:
      DOI: 10.1111/bcpt.12350
  • Up‐Regulation of miR‐21 and miR‐23a Contributes to
           As2O3‐induced hERG Channel Deficiency
    • Authors: Xin Zhao; Yuan‐Qi Shi, Cai‐Chuan Yan, Panfeng Feng, Xue Wang, Rui Zhang, Xiao Zhang, Bao‐Xin Li
      Abstract: Arsenic trioxide (As2O3) is used to treat acute promyelocytic leukaemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the hERG current via disturbing its trafficking to cellular membrane. Consistent with these findings, in this study we reported that As2O3 inhibited hERG channel at both protein and mRNA levels, damage hERG current but did not affect channel kinetics. Further, we demonstrated that As2O3 up‐regulated miR‐21 and miR‐23a expression in hERG‐HEK293 cells and neonatal cardiomyocytes. In addition, knockdown of miR‐21 by its specific antisense molecules AMO‐21 was able to rescue Sp1 and hERG inhibition caused by As2O3. Consistently, phosphorylation of NF‐κB, the upstream regulatory factor of miR‐21, was significantly up‐regulated by As2O3. This finding revealed that regulation of the NF‐κB‐miR‐21‐Sp1 signalling pathway is a novel mechanism for As2O3‐induced hERG inhibition. Meanwhile, the expression of HSP90 and hERG was rescued by transfection with AMO‐23a. And the hERG channel inhibition induced by As2O3 was rescued after being transfected with AMO‐23a, which may be a molecular mechanism for the role of As2O3 in hERG trafficking deficiency. In brief, our study revealed that miR‐21 and miR‐23a are involved in As2O3‐induced hERG deficiency at transcriptional and transportational levels. This discovery may provide a novel mechanism of As2O3‐induced hERG channel deficiency and these miRNAs may serve as potential therapeutic targets for the handling of As2O3 cardiotoxicity. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-14T01:02:57.8192-05:00
      DOI: 10.1111/bcpt.12348
  • Reducing Prescriptions of Long‐acting Benzodiazepine Drugs in
           Denmark:A Descriptive Analysis of Nationwide Prescriptions during a
           10‐Year Period
    • Authors: Sophie Isabel Eriksen; Lars Bjerrum
      Abstract: Prolonged consumption of benzodiazepine drugs (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone; altogether Z drugs) is related to potential physiological and psychological dependence along with other adverse effects. This study aimed to analyse the prescribing of long‐acting BZD (half‐life >10 hr), compared to short‐acting BZD in Denmark during a 10‐year period. Descriptive analysis of total sales data from the Danish Register of Medicinal Product Statistics, to individuals in the primary healthcare sector, of all BZD and Z‐drugs in the period of 2003‐2013. Prescription data derive from all community and hospital pharmacies in Denmark. The prescribing of long‐acting BZD was reduced from 25.8 DDD/1000 inhabitants/day in 2003 to 8.8 DDD/1000 inhabitants/day in 2013; a relative reduction of 66%. The prescribing of short‐acting BZD was reduced from 26.1 DDD/1000 inhabitants/day in 2003 to 16.4 DDD/1000 inhabitants/day in 2013; a relative reduction of 37%. Prescription data in this study did not include information about indications for initiating treatments. In addition, due to compliance problems, some of the prescribed drugs may not have been consumed according to the prescription. The observed reduction in BZD use was correlated to the introduction of new national guidelines on prescription of addictive drugs, but this study was not designed to detect a causal relationship. The prescribing of long‐acting BZD decreased considerably more than the prescribing of short‐acting BZD in the 10‐year period. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-10T06:53:07.561161-05:
      DOI: 10.1111/bcpt.12347
  • The Role of Rac1 on Carbachol‐induced Contractile Activity in
           Detrusor Smooth Muscle from Streptozotocin‐induced Diabetic Rats
    • Authors: Atiye Sinem Evcim; Serap Cilaker Micili, Meral Karaman, Guven Erbil, Ensari Guneli, Sedef Gidener, Mukaddes Gumustekin
      Abstract: This study was designed to determine the role of the small GTPase Rac1 on carbachol‐induced contractile activity in detrusor smooth muscle by using small inhibitor NSC23766 in diabetic rats. Rac1 expression in bladder tissue was also evaluated. In the Streptozotocin (STZ)‐induced diabetic rat model, three study groups were composed of control, diabetic and insulin‐treated diabetic subjects. The detrusor muscle strips were suspended in organ baths at the end of 8‐12 weeks after STZ injection. Carbachol (CCh) (10‐9‐10‐4 M) concentration‐response curves were obtained both in the absence and in the presence of Rac1 inhibitor NSC 23766 (0.1, 1 and 10 μM). Diabetes‐related histopathological changes and Rac1 expressions were assessed by hematoxylin and eosin staining and immunohistochemical staining, respectively. CCh caused dose‐dependent contractile responses in all study groups. Rac1 inhibitor NSC 23766 inhibited CCh‐induced contractile responses in all groups, but this inhibition seen in both diabetes groups was greater than in the control group. Histological examination revealed an increased bladder wall thickness both in the diabetes and in the insulin‐treated diabetes groups compared to the control group. In immunohistochemical staining, expression of Rac1 was observed to be increased in all layers of bladder in both diabetic groups compared to the control group. In the diabetic bladders, increased expression of Rac1 and considerable inhibition of CCh‐induced responses in the presence of NSC 23766 compared to those of the control group may indicate a specific role of Rac1 in diabetes‐related bladder dysfunction, especially associated with cholinergic mediated detrusor overactivity. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-08T02:41:23.079393-05:
      DOI: 10.1111/bcpt.12346
  • Annotations & Reflections
    • Authors: Ragnhild Eek Brandlistuen; Eivind Ystrom, Irena Nulman, Gideon Koren, Hedvig Nordeng
      Abstract: In a letter to the editor of Basic & Clinical Pharmacology & Toxicology, Per Damkier et al.1 criticise recent studies linking paracetamol exposure in pregnancy with adverse neurodevelopmental outcomes. They state that the recent findings on associations between prolonged prenatal paracetamol exposure and adverse child developmental outcomes rely primarily on questionnaire‐based outcomes such as the Ages and Stages Questionnaire (ASQ)2 which they claim to be invalid and uninterpretable. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-08T02:32:05.864261-05:
      DOI: 10.1111/bcpt.12339
  • Metalloproteinase Inhibition Protects against Reductions in Circulating
           Adrenomedullin during Lead‐induced Acute Hypertension
    • Authors: Regina A. Nascimento; Gabryella Mendes, Jose S. Possomato‐Vieira, Victor Hugo Gonçalves‐Rizzi, Hélio Kushima, Flavia K. Delella, Carlos A. Dias‐Junior
      Abstract: Intoxication with Pb (lead) results in increased blood pressure by mechanisms involving matrix metalloproteinases (MMPs). Recent findings have revealed that MMP type two (MMP‐2) seems to cleave vasoactive peptides. This study examined whether MMP‐2 and MMP‐9 levels/activity increase after acute intoxication with low lead concentrations and if these changes were associated with increases in blood pressure and circulating endothelin‐1 or with reductions in circulating adrenomedullin and calcitonin gene‐related peptide (CGRP). Here, we expand previous findings and examine whether doxycycline (a MMPs inhibitor) affects these alterations. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-08T01:52:20.866808-05:
      DOI: 10.1111/bcpt.12337
  • Effect of Ponesimod, a selective S1P1 Receptor Modulator, on the QT
           Interval in Healthy Subjects
    • Authors: Matthias Hoch; Borje Darpo, Patrick Brossard, Meijian Zhou, Randall Stolz, Jasper Dingemanse
      Abstract: Ponesimod is an orally active selective sphingosine‐1‐phosphate receptor 1 modulator under investigation for the treatment of multiple sclerosis. This was a single‐centre, double‐blind, randomised, placebo‐ and positive‐controlled, parallel‐group study investigating the effects of ponesimod on the QTc interval in healthy subjects. A nested cross‐over comparison between moxifloxacin and placebo was included in the combined moxifloxacin/placebo treatment group. Subjects in group A received multiple doses of 10 to 100 mg ponesimod according to an uptitration regimen on days 2 to 23 and moxifloxacin‐matching placebo on days 1 and 24. Subjects in group B received ponesimod‐matching placebo on days 2 to 23, and were randomised to receive either a single dose of 400 mg moxifloxacin or matching placebo on days 1 and 24. The primary endpoint was the baseline‐adjusted, placebo‐corrected effect on the individually‐corrected QT interval (QTcI) on days 12 (after 5 days of 40 mg ponesimod) and 23 (after 5 days of 100 mg ponesimod). Ponesimod caused a mild QTcI prolongation with a largest effect of 6.9 ms (90% two‐sided confidence interval (CI): 2.5 to 11.3) and 9.1 ms (90% CI: 4.1 to 14.0) for doses of 40 mg and 100 mg, respectively. A concentration‐effect analysis confirmed the QTcI‐prolonging effect of ponesimod with a shallow slope of 0.0053 ms per ng/mL. Using the concentration‐effect analysis, the QTc prolongation caused by 20 mg ponesimod, the current highest therapeutic dose was predicted to be below the level of clinical concern (i.e., an upper bound of the two‐sided 90% CI of ≥ 10 ms). This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-08T01:46:01.705966-05:
      DOI: 10.1111/bcpt.12336
  • The Effect of Induction of CYP3A4 by St John's Wort on Ambrisentan Plasma
           Pharmacokinetics in Volunteers of known CYP2C19 Genotype
    • Authors: Christoph Markert; Ida Maria Kastner, Regina Hellwig, Peter Kalafut, Yvonne Schweizer, Michael Marcus Hoffmann, Jürgen Burhenne, Johanna Weiss, Gerd Mikus, Walter Emil Haefeli
      Abstract: To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, 4 poor and 6 ultrarapid metabolisers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady‐state, ambrisentan exposure was similar in extensive and ultrarapid metabolisers but 43% larger in poor metabolisers (p
      PubDate: 2014-11-08T01:43:39.527803-05:
      DOI: 10.1111/bcpt.12332
  • Anti‐Inflammatory Effect of Rosmarinic Acid and an Extract of
           Rosmarinus officinalis in Rat Models of Local and Systemic Inflammation
    • Authors: Joao Rocha; Maria Eduardo‐Figueira, Andreia Barateiro, Adelaide Fernandes, Dora Brites, Rosario Bronze, Catarina MM Duarte, Ana Teresa Serra, Rui Pinto, Marisa Freitas, Eduarda Fernandes, Beatriz Silva‐Lima, Helder Mota‐Filipe, Bruno Sepodes
      Abstract: Rosmarinic acid is a polyphenolic compound and main constituent of Rosmarinus officinalis and has been shown to possess antioxidant and anti‐inflammatory properties. We aimed to evaluate the anti‐inflammatory properties of rosmarinic acid and of an extract of R. officinalis in local inflammation (carrageenan‐induced paw oedema model in the rat), and further evaluate the protective effect of rosmarinic acid in rat models of systemic inflammation: liver ischaemia‐reperfusion (I/R) and thermal injury models. In the local inflammation model, rosmarinic acid was administered at 10, 25 and 50 mg/kg (p.o.), and the extract was administered at 10 and 25 mg/kg (equivalent doses to rosmarinic acid groups) to male Wistar rats. Administration of rosmarinic acid and extract at the dose of 25 mg/kg reduced paw oedema at 6 hr by over 60%, exhibiting a dose‐response effect, suggesting that rosmarinic was the main contributor to the anti‐inflammatory effect. In the liver I/R model, rosmarinic acid was administered at 25 mg/kg (i.v.) 30 min. prior to induction of ischaemia and led to the significant reduction of the serum concentration of transaminases (AST and ALT) and LDH. In the thermal injury model, rosmarinic acid was administered at 25 mg/kg (i.v.) 5 min. prior to induction of injury and significantly reduced multiorgan dysfunction markers (liver, kidney, lung) by modulating NF‐κB and mettaloproteinase‐9. For the first time, the anti‐inflammatory potential of rosmarinic acid has been identified, since it causes a substantial reduction in inflammation, and we speculate that it might be useful in the pharmacological modulation of injuries associated to inflammation. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-06T04:40:38.144938-05:
      DOI: 10.1111/bcpt.12335
  • Improved Anti‐Emetic Efficacy of 5‐HT3 Receptor Antagonists in
           Cancer Patients with Genetic Polymorphisms of ABCB1 (MDR1) Drug
    • Authors: Teuta Zoto; Saadettin Kilickap, Umit Yasar, Ismail Celik, Atilla Bozkurt, Melih Onder Babaoglu
      Abstract: CINV remains a major adverse effect decreasing quality of life in cancer patients. Genetic variations among patients may be responsible for part of the lack of efficacy of antiemetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect antiemetic treatment with 5‐HT3 receptor antagonists. Patients (n=239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Antiemetic responses were recorded daily. The primary endpoint of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR‐RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT,p=0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p=0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p=0.021). Subjects carrying homozygous variant alleles together (TT‐TT‐TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT‐TT‐TT versus 47.1% in other genotypes, p=0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p=0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination were associated with about 50% higher antiemetic response to 5‐HT3 receptor antagonists in the acute phase of chemotherapy in cancer patients receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the antiemetic efficacy of 5‐HT3 antagonists. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-06T04:16:04.793029-05:
      DOI: 10.1111/bcpt.12334
  • Mucus as a Barrier to Drug Delivery ‐ Understanding and Mimicking
           the Barrier Properties
    • Authors: Marie Boegh; Hanne Mørck Nielsen
      Abstract: Viscoelastic mucus lines all mucosal surfaces of the body and forms a potential barrier to mucosal drug delivery. Mucus is mainly composed of water and mucins; high‐molecular weight glycoproteins forming an entangled network. Consequently, mucus forms a steric barrier and due to its negative charge and hydrophobic domains, the overall hydrophilic mucus also presents an interactive barrier limiting the free diffusion of components within and through the mucus. Furthermore, mucus is a dynamic barrier due to its continuous secretion and shedding from the mucosal surfaces. Mucus is thus a highly complex gel barrier to drug delivery. Current knowledge of mucus characteristics and barrier properties, as achieved by state‐of‐the‐art methodologies, is the topic of this MiniReview emphasizing the gastrointestinal mucus and an overall focus on oral drug delivery. Cell culture‐based in vitro models are well‐established as essential tools in drug research and development, but traditionally, mucus‐containing models have only rarely been applied. However, a number of mucus‐containing in vitro models have recently been described in the literature and their properties and applications will be reviewed and discussed. Finally, studies of peptide and protein drug diffusion in and through mucus and studies of mucus‐penetrating nanoparticles are included to illustrate the mucus as a potentially important barrier to obtain sufficient bioavailability of orally administered drugs, and thus an important parameter to address in the development of future oral drug delivery systems. This article is protected by copyright. All rights reserved.
      PubDate: 2014-10-27T22:58:28.020405-05:
      DOI: 10.1111/bcpt.12342
  • Reversal of Human MDR Leukaemic Cells by Stemofoline Derivatives via
           Inhibition of P‐Glycoprotein Function
    • Authors: Sonthaya Umsumarng; Pornsiri Pitchakarn, Kwankamol Sastraruji, Suppachai Yodkeeree, Alison T. Ung, Stephen G. Pyne, Pornngarm Limtrakul
      Abstract: Our previous study reported multidrug resistance (MDR) reversing properties of synthetic stemofoline derivatives (STFD), OH‐A1, NH‐B6 and NH‐D6 on P‐glycoprotein (P‐gp) over‐expressing leukemic cells (K562/Adr), however, the mechanism was unclear. In this study, we further investigated whether the STFD reverse MDR through either the inhibition of P‐gp function or expression in K562/Adr cells, or both. The P‐gp functional studies showed that the STFD increased the accumulation of calcein‐AM, rhodamine123 and [14C]‐doxorubicin in K562/Adr cells while the effects have not been seen in their parental sensitive cancer cell line (K562). Further, the STFD did not alter the P‐gp expression as determined by Western blotting. This study concludes that the STFD reverse MDR via inhibition of P‐gp function. The efficacy of the STFD to inhibit P‐gp function followed the order: NH‐B6 > OH‐A1 > NH‐D6. These compounds could be introduced as candidate molecules for treating cancers exhibiting P‐gp‐mediated MDR. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-29T07:12:16.293794-05:
      DOI: 10.1111/bcpt.12331
  • Effects of Cucurbitacin E, a Tetracyclic Triterpene Compound from
           Cucurbitaceae, on the Pharmacokinetics and Pharmacodynamics of Warfarin in
    • Authors: Tonggui Ding; Yuanjin Zhang, Ang Chen, Yu Tang, Mingyao Liu, Xin Wang
      Abstract: This study firstly investigated the effects of cucurbitacin E (CuE), a tetracyclic triterpene compound from Cucurbitaceae, on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin, a model CYP2C probe substrate, in the rat. In PK studies, the concentration of warfarin in blood samples was determined by HPLC‐DAD, and the PK parameters were analysed by using non‐compartmental methods. In PD studies, the prothrombin time (PT) in blood plasma at each sample point was measured via thromboplastin reagents. CuE treatment (50, 100, and 200 μg/kg, i.p.) decreased warfarin clearance (28‐32%), increased the area under the curve (AUC0–∞; 55‐62%) and prolonged plasma half‐life (t1/2; 58‐72%). At the same time, the anticoagulation effect of warfarin (PTmax) was also significantly increased in the presence of CuE. These data demonstrated that CuE affected the PK and PD of warfarin and these effects may be due to the inhibition of CYP2C activity by CuE. Hence, careful monitoring should be done during concomitant use of herbal products containing CuE with drugs that are metabolized by CYP2C enzymes. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-24T02:43:20.219292-05:
      DOI: 10.1111/bcpt.12329
  • Altered Frequency Distribution in the Electroencephalogram is Correlated
           to the Analgesic Effect of Remifentanil
    • Authors: Carina Graversen; Lasse P. Malver, Geana P. Kurita, Camilla Staahl, Lona L. Christrup, Per Sjøgren, Asbjørn M. Drewes
      Abstract: Opioids alter resting state brain oscillations by multiple and complex factors, which are still to be elucidated. To increase our knowledge, multi‐channel electroencephalography (EEG) was subjected to multivariate pattern analysis (MVPA), to identify the most descriptive frequency bands and scalp locations altered by remifentanil in healthy volunteers. Sixty‐two channels of resting EEG followed by independent measures of pain scores to heat and bone pain were recorded in 21 healthy males before and during remifentanil infusion in a placebo‐controlled, double‐blind cross‐over study. EEG frequency distributions were extracted by a continuous wavelet transform and normalized into delta, theta, alpha, beta and gamma bands. Alterations relative to pre‐treatment responses were calculated for all channels and used as input to the MVPA. Compared to placebo, remifentanil increased the delta band and decreased the theta and alpha band oscillations as a mean over all channels (all P≤0.007). The most discriminative channels in these frequency bands were: F1 in delta (83.33%, P=0.0023) and theta bands (95.24%, P
      PubDate: 2014-09-24T02:42:37.83771-05:0
      DOI: 10.1111/bcpt.12330
  • Pregnancy and paracetamol: Methodological considerations on the study of
           associations between in utero exposure to drugs and childhood
    • Authors: Per Damkier; Anton Pottegård, René Christensen, Jesper Hallas
      Pages: n/a - n/a
      Abstract: We have observed an increasing interest in the study of childhood neurodevelopment following in utero exposure to drugs (1‐7). We appreciate the efforts to address an important, difficult and poorly studied subject, but we believe there are some major methodological pitfalls to avoid. With specific reference to recent papers, we wish to discuss some general and specific, methodological issues that we believe complicate the interpretation of such data. Of special interest in this perspective is the publication by Brandlistuen et al. (1) that has stirred some controversy and attracted significant public attention (8‐9). This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-16T01:09:13.634487-05:
      DOI: 10.1111/bcpt.12322
  • Presystemic Elimination of Tilidine: Localisation and Consequences for the
           Formation of the Active Metabolite Nortilidine
    • Authors: Christine Eichbaum; Kristin Mathes, Jurgen Burhenne, Christoph Markert, Antje Blank, Gerd Mikus
      Pages: n/a - n/a
      Abstract: The therapeutic activity of tilidine, an opioid analgesic, is mainly related to its active metabolite nortilidine. Nortilidine formation mainly occurs during the high intestinal first‐pass metabolism of tilidine by N‐demethylation. Elimination of the active nortilidine to the inactive bisnortilidine is also mediated by N‐demethylation and is supposed to take place in the liver, probably at a smaller rate. The aim of this study was the investigation of the pre‐systemic elimination of tilidine using grapefruit juice as an intestinal CYP3A4 inhibitor and efavirenz as a CYP3A4 activator. A randomised, open, placebo‐controlled, cross‐over study was conducted in 12 healthy volunteers using 100 mg tilidine solution p.o., regular strength grapefruit juice 250 mL (3 times at 12‐hr intervals) and efavirenz 400 mg (12 hr before tilidine administration). Tilidine, nortilidine and bisnortilidine in plasma and urine was quantified by a validated LC/MS/MS analysis. Grapefruit juice did not change any pharmacokinetic parameter of tilidine and its metabolites which suggests that intestinal CYP3A4 does not contribute to the first‐pass metabolism of tilidine. No effect of efavirenz on the pharmacokinetics of the active nortilidine was observed except a significant reduction of the terminal elimination half‐life by 15%. Overal elimination (renal and metabolic clearances) was unaffected by every treatment. CYP3A4 does not seem to play a major role in tilidine first‐pass and overall metabolism. Other unknown metabolites and their enzymes responsible for their formation have to be investigated since they account for the majority of renally excreted metabolites. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-15T11:03:27.319343-05:
      DOI: 10.1111/bcpt.12328
  • A Comparison of the Reactivating and Therapeutic Efficacy of Two Newly
           Developed Oximes (K727, K733) with Oxime K203 and Trimedoxime in
           Tabun‐Poisoned Rats and Mice
    • Authors: Jiri Kassa; Vendula Sepsova, Martina Tumova, Anna Horova, Kamil Musilek
      Pages: n/a - n/a
      Abstract: The reactivating and therapeutic efficacy of three original bispyridinium oximes +(K727, K733, K203) and one currently available oxime (trimedoxime) was evaluated in tabun‐poisoned rats and mice. The oxime‐induced reactivation of tabun‐inhibited acetylcholinesterase was measured in diaphragm and brain of tabun‐poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727, K733) does not achieve the level of the reactivation of tabun‐inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun‐inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun‐inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5‐fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-15T11:03:14.61661-05:0
      DOI: 10.1111/bcpt.12327
  • Spatio‐temporal expression of peroxisome
           proliferator‐activated receptor α during human prenatal
    • Authors: Katerina Cizkova; Aneta Rajdova, Jiri Ehrmann
      Pages: n/a - n/a
      Abstract: Peroxisome proliferator‐activated receptor α (PPARα) is a ligand‐dependent transcription factor which is activated by various endogenous as well as exogenous compounds. It is involved in the regulation of a variety of biological processes, such as nutrient metabolism, energy homeostasis, immunological response and xenobiotic metabolism. Little is known about its expression during human prenatal development. We examined the spatio‐temporal expression pattern of PPARα in human embryonic/foetal intestines, liver and kidney from the 5th to 20th week of prenatal life by indirect two‐step immunohistochemistry. PPARα expression can already be detected in the early stages of prenatal development; as early as the 7th week of intrauterine development (IUD) in the intestines, 5th week of IUD in the liver and 6th week of IUD in the kidney. We found age‐dependent changes in the PPARα expression pattern in the intestines and kidney. These events occur approximately at the commencement of function of these organs. In the intestines, we detected an obvious change of the PPARα expression pattern along the crypt‐villous axis in the 11th week of IUD. In the kidney, the most apparent change was increased expression of PPARα in glomeruli in the 12th week of IUD. Moreover, in the liver, we detected a strong positivity in part of the developing blood elements. Information about the spatio‐temporal expression pattern of PPARα could be the first step in evaluating the potential harmful impact of a wide range of environmental or pharmaceutical compounds which serve as PPARα ligands on the developing human organism. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-15T11:03:07.623638-05:
      DOI: 10.1111/bcpt.12326
  • Renoprotective Effects of Gamma‐Aminobutyric Acid (GABA) on
           Cisplatin‐induced Acute Renal Injury in Rats
    • Authors: Badreldin H. Ali; Suhail Al–Salam, Mohammed Al Za'abi, Khalid A. Al Balushi, Ahmed S. AlMahruqi, Somyia Beegam, Intisar Al‐Lawatia, Mostafa I. Waly, Abderrahim Nemmar
      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.
      PubDate: 2014-09-13T02:34:21.657658-05:
      DOI: 10.1111/bcpt.12291
  • Early Discontinuation of ADHD Drug Treatment: A Danish Nationwide Drug
           Utilization Study
    • Authors: Anton Pottegård; Bine Kjøller Bjerregaard, Lisbeth Sandal Kortegaard, Helga Zoëga
      Pages: n/a - n/a
      Abstract: Knowledge of patterns of treatment discontinuation in ADHD drug treatment is of importance, both for clinical practice and the study of long‐term treatment outcomes. The purpose of this study was to describe early discontinuation of ADHD drug treatment. Using the Danish National Prescription Registry, all first‐time users of the ADHD drugs methylphenidate and atomoxetine were identified between 2000 and 2012. Early discontinuation was defined as failing to fill a second prescription for any ADHD drug within six months. Analyses were conducted stratified by calendar year, drug formulation, patient sex, age and region of residence. 59,116 first‐time users of methylphenidate and atomoxetine with at least six months of eligible follow‐up were identified. Overall, 12.6% (n=7,441) failed to fill a second prescription within six months. This proportion changed over time, dropping from 20.8% in 2000 to 12.5% in 2012. The proportion of early discontinuation was considerably lower among children than among adults. Proportions were comparable when stratifying by index drug. Proportions of early discontinuation were similar between regions of Denmark, except in the capital region, where it remained at around 20% among 18‐49‐year‐olds throughout the study period (22.6% in 2012). We found that the proportion of early discontinuation among ADHD drug users in Denmark dropped markedly during the past decade for both sexes, all age groups and all regions, except for adults in the capital region. Overall, early discontinuation was somewhat lower than expected, considering rates of side effects or non‐response to ADHD drug treatment. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-12T09:17:12.47068-05:0
      DOI: 10.1111/bcpt.12325
  • Group I Metabotropic Glutamate Receptors: A Potential Target for
           Regulation of Proliferation and Differentiation of an Immortalized Human
           Neural Stem Cell Line
    • Authors: Julie Ladeby Erichsen; Morten Blaabjerg, Helle Bogetofte, Alberto Martinez Serrano, Morten Meyer
      Pages: n/a - n/a
      Abstract: Human neural stem cells (NSCs) from the developing embryo or the subventricular zone of the adult brain can potentially elicit brain repair after injury or disease, either via endogenous cell proliferation or by cell transplantation. Profound knowledge of the diverse signals affecting these cells is, however, needed to realise their therapeutic potential. Glutamate and group I metabotropic glutamate receptors (mGluRs) affect proliferation and survival of rodent NSCs both during embryonic and postnatal development. To investigate the role of group I mGluRs (mGluR1 and mGluR5) on human NSCs, we differentiated an immortalized, forebrain‐derived stem cell line in the presence or absence of glutamate and with addition of either the group I mGluR agonist DHPG or the selective antagonists; MPEP (mGluR5) and LY367385 (mGluR1). Characterization of differentiated cells revealed that both mGluR1 and mGluR5 were present on the cells. Addition of glutamate to the growth medium significantly increased cell proliferation and reduced cell death, resulting in increased cell numbers. In the presence of glutamate, selective activation of group I mGluRs reduced gliogenesis, whereas selective inhibition of group I mGluRs reduced neurogenesis. Our results substantiate the importance of glutamate signalling in regulation of human NSCs and may as such be applied to promote proliferation and neuronal differentiation. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-12T09:17:03.704976-05:
      DOI: 10.1111/bcpt.12324
  • Elimination of Ascorbic Acid following High‐Dose Infusion in
           Prostate Cancer Patients: A Pharmacokinetic Evaluation
    • Authors: Torben K. Nielsen; Martin Højgaard, Jon T. Andersen, Henrik E. Poulsen, Jens Lykkesfeldt, Kári J. Mikines
      Pages: n/a - n/a
      Abstract: Treatment with high‐dose intravenous (IV) ascorbic acid (AA) is used in complementary and alternative medicine for various conditions including cancer. Cytotoxicity to cancer cell lines has been observed with millimolar concentrations of AA. Little is known about the pharmacokinetics of high dose IV AA. The purpose of the present study was to assess the basic kinetic variables in human beings over a relevant AA dosing interval for proper design of future clinical trials. Ten patients with metastatic prostate cancer were treated for four weeks with fixed AA doses of 5, 30 and 60 g. AA was measured consecutively in plasma and indicated first‐order elimination kinetics throughout the dosing range with supra‐physiological concentrations. The target dose of 60g AA IV produced a peak plasma AA concentration of 20.3 mM. Elimination half‐life was 1.87 hr (mean, SD ± 0.40), volume of distribution 0.19 L/kg (SD ±0.05) and clearance rate 6.02 L/hr (100mL/min). No differences in pharmacokinetic parameters were observed between weeks/doses. A relatively fast first‐order elimination with half‐life of about 2 hr makes it impossible to maintain AA concentrations in the potential cytotoxic range after infusion stop in prostate cancer patients with normal kidney function. We propose a regimen with a bolus loading followed by a maintenance infusion based on the calculated clearance. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-12T09:16:55.920327-05:
      DOI: 10.1111/bcpt.12323
  • Different Effects Of Cabergoline And Bromocriptine On Metabolic And
           Cardiovascular Risk Factors In Patients With Elevated Prolactin Levels
    • Authors: Robert Krysiak; Bogusław Okopien
      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.
      PubDate: 2014-09-11T22:27:40.360912-05:
      DOI: 10.1111/bcpt.12307
  • ASC, a Bioactive Steroidal Saponin from Ophitopogin japonicas, Inhibits
           Angiogenesis through Interruption of Src Tyrosine Kinase‐dependent
           Matrix Metalloproteinase Pathway
    • Authors: Ke‐Wu Zeng; Fang‐Jiao Song, Ning Li, Xin Dong, Yong Jiang, Peng‐Fei Tu
      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.
      PubDate: 2014-09-11T22:27:29.477214-05:
      DOI: 10.1111/bcpt.12305
  • Intravenous Lipid Emulsion given to Volunteers does not affect Symptoms of
           Lidocaine Brain Toxicity
    • Authors: Juho A. Heinonen; Erik Litonius, Tapani Salmi, Juhani Haasio, Pekka Tarkkila, Janne T. Backman, Per H. Rosenberg
      Pages: n/a - n/a
      Abstract: Intravenous lipid emulsion has been suggested as treatment for local anaesthetic toxicity but the exact mechanism of action is still uncertain. Controlled studies on the effect of lipid emulsion on toxic doses of local anaesthetics have not been performed in man. In randomized, subject‐blinded and two‐phase cross‐over fashion, eight healthy volunteers were given a 1.5‐ml/kg bolus of 20% Intralipid® (200 mg/ml) or Ringer's acetate solution intravenously, followed by a rapid injection of lidocaine 1.0 mg/kg. Then, the same solution as in the bolus was infused at a rate of 0.25 ml/kg/min. for 30 min. Electroencephalography (EEG) was recorded and five minutes after lidocaine injection, the volunteers were asked to report subjective symptoms. Total and un‐entrapped lidocaine plasma concentrations were measured from venous blood samples. EEG band power changes (delta, alpha and beta) following the lidocaine bolus were similar during lipid and during Ringer infusion. There were no differences between infusions in the subjective symptoms of central nervous system toxicity. Lidocaine was only minimally entrapped in the plasma by lipid emulsion, but the mean un‐entrapped lidocaine area under concentration‐time curve from 0 to 30 min. was clearly smaller during lipid than Ringer infusion (16.4 versus 21.3 mg × min/l, p = 0.044). Intravenous lipid emulsion did not influence subjective toxicity symptoms, nor affect the EEG changes caused by lidocaine. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-10T05:33:08.725704-05:
      DOI: 10.1111/bcpt.12321
  • The Targeting of IDO‐Mediated Immune Escape in Cancer
    • Authors: Trine Zeeberg Iversen; Mads Hald Andersen, Inge Marie Svane
      Pages: n/a - n/a
      Abstract: The era of immunotherapies was unleashed in 2010 with the Food and Drug Administration (FDA) approval of the first therapeutic vaccine Sipuleucel‐T as a standard treatment for metastatic prostate cancer. Next, the first immune‐activating anti‐cytotoxic lymphocyte antigen‐4 (CTLA‐4) antibody Ipilimumab exhibiting “immune check‐point blockade” was approved by FDA and European Medical Agency (EMA) for treatment of patients with metastatic melanoma. New generations of immune checkpoint blockading antibodies targeting programmed cell death 1 (PD‐1) and its ligand (PD‐L1) are now under intense investigation in metastatic melanoma (MM) and non small‐cell lung cancer (NSCLC), and impressive clinical results are anticipated. Despite these successes, only a fraction of patients become clinical responders to therapy. Thus, to improve the selection of patients likely to respond, scrutinizing different immune parameters during treatment is essential. In the summary of this PhD thesis, we investigated changes in immune parameters and their possible correlation with clinical efficacy in MM patients during treatments with the standard chemo‐ and immunotherapies, Temozolomide (TMZ) and Interferon α2b/Interleukin2 (IFNα/IL2) immunotherapy. The overall aim was to assess changes in frequency and absolute counts of different immune cell subsets before and after treatment and correlate to clinical benefit. Furthermore, the thesis covers a finalized, clinical phase 1 study in NSCLC patients testing a peptide vaccination with a HLA‐A2 restricted epitope derived from indoleamine 2,3 dioxygenase (IDO). The overall aim in this trial was to evaluate safety and tolerability of IDO as an anticancer vaccine target in NSCLC patients and to assess if immunity correlated to clinical response. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-10T05:32:58.484889-05:
      DOI: 10.1111/bcpt.12320
  • Cardioprotective and Cardiotoxic Effects of Quercetin and Two of Its In
           Vivo Metabolites on Differentiated H9c2 Cardiomyocytes
    • Authors: James Daubney; Philip L. Bonner, Alan J. Hargreaves, John M. Dickenson
      Abstract: Whilst mitotic rat embryonic cardiomyoblast‐derived H9c2 cells have been widely used as a model system to study the protective mechanisms associated with flavonoids, they are not fully differentiated cardiac cells. Hence, the aim of this study was to investigate the cardioprotective and cardiotoxic actions of quercetin and two of its major in vivo metabolites, quercetin 3‐glucuronide and 3’‐O‐methyl quercetin, using differentiated H9c2 cells. The differentiated cardiomyocyte‐like phenotype was confirmed by monitoring expression of cardiac troponin 1 following 7 days of culture in reduced serum medium containing 10 nM all‐trans retinoic acid. Quercetin‐induced cardiotoxicity was assessed by monitoring MTT reduction, LDH release, caspase 3 activity and reactive oxygen species production following prolonged flavonoid exposure (72 hr). Cardiotoxicity was observed with quercetin and 3’‐O‐methyl quercetin but not quercetin 3‐glucuronide. Cardioprotection was assessed by pre‐treating differentiated H9c2 cells with quercetin or its metabolites for 24 hr prior to 2‐hr exposure to 600 μM H2O2, after which oxidative stress‐induced cell damage was assessed by measuring MTT reduction and LDH release. Cardioprotection was observed with quercetin and 3’‐O‐methyl quercetin but not with quercetin 3‐glucuronide. Quercetin attenuated H2O2‐induced activation of ERK1/2, PKB, p38 MAPK and JNK but inhibitors of these kinases did not modulate quercetin‐induced protection or H2O2‐induced cell death. In summary, quercetin triggers cardioprotection against oxidative stress–induced cell death and cardiotoxicity following prolonged exposure. Further studies are required to investigate the complex interplay between the numerous signalling pathways that are modulated by quercetin and which may contribute to the cardioprotective and cardiotoxic effects of this important flavonoid. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-09T08:15:50.765782-05:
      DOI: 10.1111/bcpt.12319
  • Does Bosentan Protect Diabetic Brain Alterations in Rats' The Role of
           Endothelin‐1 in the Diabetic Brain
    • Authors: Recep Demir; Elif Cadirci, Erol Akpinar, Yasemin Cayir, Hasan Tarik Atmaca, Harun Un, Celalettin Semih Kunak, Muhammed Yayla, Zafer Bayraktutan, Ilknur Demir
      Abstract: Diabetes mellitus (DM) is a major problem all over the world, affecting more people in recent years. Individuals with diabetes are more prone to disease than non‐diabetics, especially vascular complications. The aim of this study was to examine the roles of the endothelin (ET) 1 in brain damage formed in a streptozocin (STZ)‐induced diabetes model, and the effect of bosentan, which is the non‐specific ET1 receptor blocker in the prevention of the diabetes‐induced brain damage. To examine the effects of bosentan (50mg/kg and 100mg/kg) in this study, the rats were given the drug for 3 months. The rats were divided into four groups: The sham group (n=10), the diabetic control group (n=10), the group of diabetic rats given bosentan 50mg/kg (n=10) and the group of diabetic rats given bosentan 100mg/kg (n=10). Diabetes was induced in the rats by STZ (60 mg/kg i.p.). On day 91, all rats were killed. Brain tissues of the rats were measured by molecular, biochemical and histopathological methods. Antioxidant levels in the therapy groups were observed as quite near to the values in the healthy group. In this study, while the brain eNOS levels in the diabetic groups decreased, the ET1 and iNOS levels were found to be increased. However, in the diabetes group, hippocampus and cerebellum, pericellular oedema and a number of neuronal cyto‐retraction were increased in neuropiles, whereas these results were decreased in the therapy group. Based on all of these results, ET1 will not be ignored in diabetes‐induced cerebral complications. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-08T07:22:31.869739-05:
      DOI: 10.1111/bcpt.12318
  • Efficacy and Safety of PPC‐5650 on Experimental Rectal Pain in
           Patients with Irritable Bowel Syndrome
    • Authors: Lecia Møller Nielsen; Anne Estrup Olesen, Trine Andresen, Magnus Simrén, Hans Törnblom, Asbjørn Mohr Drewes
      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.
      PubDate: 2014-09-08T04:30:14.743476-05:
      DOI: 10.1111/bcpt.12294
  • Methadone is a Non‐Competitive Antagonist at the α4β2 and
           α3* Nicotinic Acetylcholine Receptors and an Agonist at the α7
           Nicotinic Acetylcholine Receptor
    • Authors: Reeta Talka; Outi Salminen, Raimo K. Tuominen
      Abstract: Nicotine‐methadone interactions have been studied in human beings and in various experimental settings regarding addiction, reward and pain. Most methadone‐maintenance treatment patients are smokers, and methadone administration has been shown to increase cigarette smoking. Previous in vitro studies have shown that methadone is a non‐competitive antagonist at rat α3β4 nicotinic acetylcholine receptors (nAChR) and an agonist at human α7 nAChRs. In this study, we used cell lines expressing human α4β2, α7 and α3* nAChRs to compare the interactions of methadone at the various human nAChRs under the same experimental conditions. A [3H]epibatidine displacement assay was used to determine whether methadone binds to the nicotinic receptors, and 86Rb+ efflux and changes in intracellular calcium [Ca2+]i were used to assess changes in the functional activity of the receptors. Methadone displaced [3H]epibatidine from nicotinic agonist binding sites in SH‐EP1‐hα7 and SH‐SY5Y cells but not in SH‐EP1‐hα4β2 cells. The Ki values for methadone were 6.3 μM in SH‐EP1‐hα7 cells and 19.4 μM and 1008 μM in SH‐SY5Y cells. Methadone increased [Ca2+]i in all cell lines in a concentration‐dependent manner, and in SH‐EP1‐hα7 cells, the effect was more pronounced than the effect of nicotine treatment. In SH‐EP1‐hα4β2 cells, the effect of methadone was negligible compared to that of nicotine. Methadone pre‐treatment abolished the nicotine‐induced response in [Ca2+]i in all cell lines expressing nAChRs. In SH‐EP1‐hα4β2 and SH‐SY5Y cells, methadone had no effect on the 86Rb+ efflux, but it antagonised the nicotine‐induced 86Rb+ ion efflux in a non‐competitive manner. These results suggest that methadone is an agonist at human α7 nAChRs and a non‐competitive antagonist at human α4β2 and α3* nAChRs. The present study adds further support to the previous findings that opioids interact with nAChRs, which may underlie their frequent co‐administration in human beings and might be of interest to the field of drug discovery. This article is protected by copyright. All rights reserved.
      PubDate: 2014-09-04T08:35:01.326042-05:
      DOI: 10.1111/bcpt.12317
  • Compliance with Recommendations on Outpatient Antibiotic Prescribing for
           Respiratory Tract Infections: The Case of Spain
    • Authors: Sara Malo; Lars Bjerrum, Cristina Feja, María‐Jesús Lallana, Javier Moliner, María‐José Rabanaque
      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.
      PubDate: 2014-08-28T10:34:09.799132-05:
      DOI: 10.1111/bcpt.12316
  • Diphenyl Ditelluride‐Induced Cell Cycle Arrest And Apoptosis: A
           Relation With Topoisomerase I Inhibition
    • Authors: Patrícia Mendes Jorge; Iuri Marques Oliveira, Eduardo Cremonese Filippi Chiela, Cassiana Macagnan Viau, Jenifer Saffi, Fabiana Horn, Renato Moreira Rosa, Temenouga Nikolova Guecheva, João Antonio Pêgas Henriques
      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.
      PubDate: 2014-08-28T10:33:58.86122-05:0
      DOI: 10.1111/bcpt.12315
  • Exogenous Metallothionein Potentiates the Insulin Response at Normal
           Glucose Concentrations in INS‐1E Beta Cells without disturbing
           Intracellular ZnT8 Expression
    • Authors: Sanne B. Nygaard; Ninna S. Lund, Agnete Larsen, Nanna Pedersen, Jørgen Rungby, Kamille Smidt
      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.
      PubDate: 2014-08-28T00:13:50.059722-05:
      DOI: 10.1111/bcpt.12287
  • Attitude Of Physicians And Pharmacists Towards International
           Nonproprietary Name Prescribing In Belgium
    • Authors: Elien Van Bever; Monique Elseviers, Marijke Plovie, Lieselot Vandeputte, Luc Van Bortel, Robert Vander Stichele
      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.
      PubDate: 2014-08-24T21:22:30.359017-05:
      DOI: 10.1111/bcpt.12314
  • Novel Points of Attack for Targeted Cancer Therapy
    • Authors: Gro Vatne Røsland; Agnete Svendsen Tenfjord Engelsen
      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.
      PubDate: 2014-08-22T09:34:04.548343-05:
      DOI: 10.1111/bcpt.12313
  • Acute Effects of Dipyrone on Renal Function in Patients with Cirrhosis: A
           Randomized Controlled Trial
    • Authors: P Zapater; L Llanos, C Barquero, P Bellot, S Pascual, F Carnicer, JM Palazón, P Gimenez, A Esteban, L Llorca, R Francés, JF Horga, J Such
      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.
      PubDate: 2014-08-22T09:33:59.440102-05:
      DOI: 10.1111/bcpt.12312
  • Do Serotonin Reuptake Inhibitors worsen Outcome of Patients referred to
           the Emergency Department for Deliberate Multidrug Exposure'
    • Authors: Sébastien Beaune; Emmanuel Curis, Enrique Casalino, Philippe Juvin, Bruno Mégarbane
      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.
      PubDate: 2014-08-22T09:33:55.210731-05:
      DOI: 10.1111/bcpt.12311
  • Rare Alleles within the CYP2E1 (MEOS System) could be associated with
           better short‐term Health Outcome after Acute Methanol Poisoning
    • Authors: Jaroslav A. Hubacek; Daniela Pelclova, Zdenek Seidl, Manuela Vaneckova, Jiri Klempir, Evzen Ruzicka, Petr Ridzon, Pavel Urban, Zdenka Fenclova, Vit Petrik, Pavel Diblik, Pavel Kuthan, Michal Miovsky, Barbara Janikova, Vera Adamkova, Sergey Zakharov
      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.
      PubDate: 2014-08-21T10:20:19.862133-05:
      DOI: 10.1111/bcpt.12310
  • Nifedipine versus Terbutaline, Tocolytic Effectiveness and Maternal and
           Neonatal Adverse Effects: a Randomized, Controlled Pilot Trial
    • Authors: Tania Regina Padovani; Gordon Guyatt, Luciane Cruz Lopes
      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.
      PubDate: 2014-08-21T10:19:44.121114-05:
      DOI: 10.1111/bcpt.12306
  • Stimulation of Suicidal Erythrocyte Death by Sulforaphane
    • Authors: Kousi Alzoubi; Salvatrice Calabrò, Caterina Faggio, Florian Lang
      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.
      PubDate: 2014-08-18T09:57:33.781722-05:
      DOI: 10.1111/bcpt.12309
  • Galla Chinensis Attenuates Cigarette Smoke‐associated Lung Injury by
           Inhibiting Recruitment of Inflammatory Cells into the Lung
    • Authors: Hyojung Lee; Seung‐Ryeol Yu, Dahae Lim, Hyejung Lee, Eun‐Young Jin, Young‐Pyo Jang, Jinju Kim
      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.
      PubDate: 2014-08-18T09:57:27.387807-05:
      DOI: 10.1111/bcpt.12308
  • Inhibition of UVB‐induced Skin Damage by Exopolymers from
           Aureobasidium pullulans SM–2001 in Hairless Mice
    • Authors: Kyung Hu Kim; Soo Jin Park, Young Joon Lee, Ji Eun Lee, Chang Hyun Song, Seong Hun Choi, Sae Kwang Ku, Su Jin Kang
      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.
      PubDate: 2014-08-06T07:39:33.983722-05:
      DOI: 10.1111/bcpt.12288
  • Oseltamivir Blocks Human Neuronal Nicotinic Acetylcholine
           Receptor‐mediated Currents
    • Authors: Katsuhiko Muraki; Noriyuki Hatano, Hiroka Suzuki, Yukiko Muraki, Yui Iwajima, Yasuhiro Maeda, Hideki Ono
      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.
      PubDate: 2014-07-31T03:51:54.263241-05:
      DOI: 10.1111/bcpt.12290
  • PI3K Inhibitors LY294002 and IC87114 Reduce Inflammation in
           Carrageenan‐Induced Paw Oedema and Down‐Regulate Inflammatory
           Gene Expression in Activated Macrophages
    • Authors: Heikki Eräsalo; Mirka Laavola, Mari Hämäläinen, Tiina Leppänen, Riina Nieminen, Eeva Moilanen
      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.
      PubDate: 2014-07-31T03:51:52.377572-05:
      DOI: 10.1111/bcpt.12284
  • 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
    • Authors: Jette Möller; Lucie Laflamme, Karin Söderberg Löfdal
      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.
      PubDate: 2014-07-25T02:12:07.262854-05:
      DOI: 10.1111/bcpt.12289
  • Polymorphisms in CYP2D6 have a Greater Effect on Variability of
           Risperidone Pharmacokinetics than Gender
    • Authors: Teresa Cabaleiro; Dolores Ochoa, Manuel Román, Isabel Moreno, Rosario López‐Rodríguez, Jesús Novalbos, Francisco Abad‐Santos
      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.
      PubDate: 2014-07-25T02:10:50.065067-05:
      DOI: 10.1111/bcpt.12286
  • Chlorpyrifos and Cypermethrin Induce Apoptosis in Human Neuroblastoma Cell
           Line SH‐SY5Y
    • Authors: Grzegorz Raszewski; Marta Kinga Lemieszek, Krzysztof Łukawski, Małgorzata Juszczak, Wojciech Rzeski
      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.
      PubDate: 2014-07-25T02:10:47.799165-05:
      DOI: 10.1111/bcpt.12285
  • Phytoestrogen α‐Zearalanol exerts Anti‐Apoptotic Effects
           in Differentiated PC12 Cells via Estrogen Receptor α
    • Authors: YiLong Dong; YanMei Wang, HongJu Yang, XiaoZhou Yang, HaiJing Yu
      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.
      PubDate: 2014-07-22T10:24:51.484223-05:
      DOI: 10.1111/bcpt.12296
  • Quality Indicators as a Tool in Improving the Introduction of New
    • Authors: Stephen M. Campbell; Brian Godman, Eduardo Diogene, Jurij Fürst, Lars L. Gustafsson, Sean MacBride‐Stewart, Rickard E. Malmström, Hanne Pedersen, Gisbert Selke, Vera Vlahović‐ Palčevski, Menno Woerkom, Durhane Wong‐Rieger, Björn Wettermark
      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.
      PubDate: 2014-07-22T10:24:49.813177-05:
      DOI: 10.1111/bcpt.12295
  • 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
  • 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
  • Evidence for Involvement of Spinal RANTES in the Antinociceptive Effects
    • Authors: Li‐Hua Hang; Shu‐Na Li, Dong‐Hua Shao, Zheng Chen, Yuan‐Feng Chen, Wei‐Wei Shu
      First page: 477
      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.
      PubDate: 2014-05-24T02:00:18.986428-05:
      DOI: 10.1111/bcpt.12265
  • 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
      First page: 481
      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
  • Riccardin D, a Macrocyclic Bisbibenzy, Inhibits Human Breast Cancer Growth
           through the Suppression of Telomerase Activity
    • Authors: Cui‐Cui Sun; Hui‐Min Xu, Yi Yuan, Zu‐Hua Gao, Hong‐Xiang Lou, Xian‐Jun Qu
      First page: 488
      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.
      PubDate: 2014-06-06T02:46:22.042794-05:
      DOI: 10.1111/bcpt.12267
  • Saquinavir‐NO inhibits IL‐6 production in macrophages
    • Authors: Miljana Momčilović; Katia Mangano, Bojan Jevtić, Santa Mammana, Stanislava Stošić‐Grujičić, Ferdinando Nicoletti, Djordje Miljković
      First page: 499
      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
      First page: 507
      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
  • Adjuvant Anticholinesterase Therapy for the Management of
           Epilepsy‐inducedMemory Deficit:A Critical Preclinical Study
    • Authors: Awanish Mishra; Rajesh Kumar Goel
      First page: 512
      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
  • [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
      First page: 518
      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
  • 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
      First page: 527
      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
  • 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
      First page: 534
      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
  • R1: Effects of Anti‐Hypertensive and Triglyceride Lowering Agents on
           Hepatic Copper Concentrations in Rats with Fatty Liver Disease
    • Authors: Zvi Ackerman; Galina Skarzinski, Maria Grozovski, Mor Oron‐Herman, Ben‐Ami Sela
      First page: 545
      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.
      PubDate: 2014-08-06T07:39:31.829845-05:
      DOI: 10.1111/bcpt.12283
  • Population Pharmacokinetic Meta‐Analysis of Vortioxetine in Healthy
    • Authors: Johan Areberg; Kamilla B. Petersen, Grace Chen, Himanshu Naik
      First page: 552
      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.
      PubDate: 2014-05-22T05:35:34.499314-05:
      DOI: 10.1111/bcpt.12256
  • Adverse Drug Reactions Causing Hospital Admissions in Childhood: A
           Prospective, Observational, Single‐Centre Study
    • Authors: Petra Langerová; Jiří Vrtal, Karel Urbánek
      First page: 560
      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.
      PubDate: 2014-05-26T04:58:07.26363-05:0
      DOI: 10.1111/bcpt.12264
  • 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
      First page: 565
      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
  • The Evaluation of Prophylactic Efficacy of Newly Developed Reversible
           Inhibitors of Acetylcholinesterase in Soman‐Poisoned Mice – A
           Comparison with Commonly Used Pyridostigmine
    • Authors: Jiri Kassa; Jan Korabecny, Vendula Sepsova, Martina Tumova
      First page: 571
      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.
      PubDate: 2014-06-06T03:37:27.413623-05:
      DOI: 10.1111/bcpt.12269
  • 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
      First page: 577
      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
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