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ENVIRONMENTAL STUDIES (726 journals)                  1 2 3 4 5 6 7 8 | Last

Acta Ecologica Sinica     Open Access   (Followers: 10)
Acta Limnologica Brasiliensia     Open Access   (Followers: 1)
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: 13)
Advances in Ecological Research     Full-text available via subscription   (Followers: 25)
Advances in Environmental Protection     Open Access  
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 22)
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: 6)
AGE     Hybrid Journal   (Followers: 5)
Age and Ageing     Hybrid Journal   (Followers: 37)
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: 31)
American Journal of Environmental Engineering     Open Access   (Followers: 8)
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: 48)
Annals of Environmental Science     Open Access   (Followers: 9)
Annals of GIS     Hybrid Journal   (Followers: 17)
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: 43)
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: 23)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 11)
Applied and Environmental Soil Science     Open Access   (Followers: 12)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 11)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 12)
Aquatic Ecology     Hybrid Journal   (Followers: 16)
Aquatic Toxicology     Hybrid Journal   (Followers: 17)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription   (Followers: 1)
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 5)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 9)
Archives of Environmental Protection     Open Access   (Followers: 5)
Archives of Toxicology     Hybrid Journal   (Followers: 11)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 1)
Asian Journal of Earth Sciences     Open Access   (Followers: 18)
Asian Journal of Rural Development     Open Access   (Followers: 10)
ATBU Journal of Environmental Technology     Open Access   (Followers: 1)
Atmospheric and Climate Sciences     Open Access   (Followers: 17)
Atmospheric Environment     Hybrid Journal   (Followers: 29)
Austral Ecology     Hybrid Journal   (Followers: 8)
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: 8)
Basic and Applied Ecology     Hybrid Journal   (Followers: 14)
Behavioral Ecology     Hybrid Journal   (Followers: 44)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 35)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 24)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 2)
Bioremediation Journal     Hybrid Journal   (Followers: 4)
BioRisk     Open Access   (Followers: 2)
BMC Ecology     Open Access   (Followers: 17)
Boston College Environmental Affairs Law Review     Open Access   (Followers: 5)
Bothalia : African Biodiversity & Conservation     Open Access   (Followers: 1)
Built Environment     Full-text available via subscription   (Followers: 5)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 10)
Bulletin of the American Meteorological Society     Open Access   (Followers: 14)
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: 13)
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: 7)
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: 15)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 2)
Chemosphere     Hybrid Journal   (Followers: 10)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 40)
Civil and Environmental Research     Open Access   (Followers: 13)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 17)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 8)
Climate Change Economics     Hybrid Journal   (Followers: 17)
Climate Policy     Hybrid Journal   (Followers: 23)
Coastal Engineering Journal     Hybrid Journal   (Followers: 2)
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     Open Access   (Followers: 24)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (Followers: 10)
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: 11)
Creativity and Innovation Management     Hybrid Journal   (Followers: 219)

        1 2 3 4 5 6 7 8 | Last

Journal Cover   Basic & Clinical Pharmacology & Toxicology
  [SJR: 0.739]   [H-I: 62]   [10 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  [1611 journals]
  • Issue Information
    • Pages: i - ii
      PubDate: 2015-03-13T03:39:23.004161-05:
      DOI: 10.1111/bcpt.12393
  • Expression of CYP3A4 and CYP3A7 in Human Foetal Tissues and its
           Correlation to Nuclear Receptors
    • Authors: Stina Betts; Linda Björkhem‐Bergman, Anders Rane, Lena Ekström
      Abstract: Previous reports have suggested that the nuclear receptors vitamin D receptor (VDR), peroxisome proliferator‐activated receptor α (PPARα), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are involved in the regulation of the drug metabolizing enzyme cytochrome P450 (CYP) 3A4 expression in adults. The aim of this study was to investigate the gene expression of CYP3A4 and the foetal CYP3A7 in human foetal tissues and their relation to gene expression and genetic variations in the nuclear receptors VDR, PPARα, PXR and CAR. We determined the relative expression of CYP3A4 and CYP3A7 and these nuclear receptors in foetal livers, intestines and adrenals, using quantitative PCR. In addition, the expression of these enzymes was also analysed in adult liver. There was a high interindividual variability in CYP3A4 and CYP3A7; 49‐fold and 326‐ fold, respectively. Both CYP3A4 and CYP3A7 had the highest expression in the liver. There were significant correlations (p
      PubDate: 2015-03-09T21:42:26.520347-05:
      DOI: 10.1111/bcpt.12392
  • Post‐Injection Delirium/Sedation Syndrome after Olanzapine
           Long‐Acting Intramuscular Injection – Who is at Risk'
    • Authors: Łukasik‐Głębocka Magdalena; Sommerfeld Karina, Teżyk Artur, Panieński Paweł, Żaba Czesław, Zielińska‐Psuja Barbara
      Abstract: The post‐injection olanzapine delirium/sedation syndrome (PDSS) was observed in a 60‐year‐old Caucasian, schizophrenic, non‐smoker and underweight (Body Mass Index BMI 18.2 kg/m2) female after the fourth intramuscular injection of 405 mg olanzapine pamoate. Clinical symptoms of PDSS were similar to those of acute oral olanzapine intoxication. The patient received supportive treatment and recovered fully. High olanzapine concentrations in serum, with maximum level of 698 ng/mL, were confirmed by liquid chromatography with tandem mass spectrometry (LC‐MS/MS). The authors wonder whether a low BMI and advanced age may predispose patients to PDSS occurrence. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-09T21:42:11.430817-05:
      DOI: 10.1111/bcpt.12394
  • Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics
           and First‐in‐Human Dose Selection for CNTO 5825, an
           Anti‐Interleukin‐13 Monoclonal Antibody
    • Authors: Ivo P. Nnane; Zhenhua Xu, Honghui Zhou, Hugh M. Davis
      Abstract: CNTO 5825 is a human anti‐interleukin‐13 (IL‐13) monoclonal antibody (mAb) that inhibits binding of human IL‐13 to IL‐13Rα1 and IL‐13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non‐clinical PK data in order to select the right and safe doses for first‐in‐human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 mL/day/kg in rats, and from 5.78 to 7.19 mL/day/kg in cynomolgus monkeys. The volume of distribution at steady‐state (Vss) in rats was large (151.52 to 155.64 mL/kg) compared to cynomolgus monkey (49.77 to 61.10 mL/kg). The terminal half‐life (T1/2) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1–10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within 2‐fold of observed CL and Vss in human beings; The predicted CL and Vss in human beings (70 kg) based on time‐invariant method with combined PK data from rats and monkeys were 4.84 ± 1.13 mL/day/kg and 68.93 ± 35.55 mL/kg, respectively. The selected doses for the FIH study based on time‐invariant method and NOAEL in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-05T21:23:47.768877-05:
      DOI: 10.1111/bcpt.12391
  • Milrinone for the Treatment of Acute Heart Failure After Acute Myocardial
           Infarction: A Systematic Review and Meta‐analysis
    • Authors: Xiuying Tang; Peng Liu, Runjun Li, Quanmin Jing, Junhao Lv, Li Liu, Yingfeng Liu
      Abstract: Despite advancements in modern medicine, the treatment of acute heart failure (AHF) after acute myocardial infarction (AMI) remains challenging. Milrinone is effective in the treatment of chronic congestive heart failure, but its safety and efficacy in patients with AHF after AMI have not been systematically evaluated. This meta‐analysis was performed to assess the safety and efficacy of milrinone in patients with AHF after AMI. We used a pre‐designed protocol to search electronic databases for randomized trials assessing milrinone for the treatment of AHF after AMI. Data were abstracted from relevant studies. Heterogeneity was assessed qualitatively using a Q test and quantified using the I2 statistic. Pooled risk estimates with 95% confidence intervals (CIs) were obtained using fixed effects models unless substantial heterogeneity was observed (I2≥ 50% and heterogeneity P≤0.1). Four randomized trials met the inclusion criteria. However, there were no significant differences in deaths, blood pressure, premature ventricular contractions, gastrointestinal reactions, or ventricular tachycardia or fibrillation(all P>0.05) between control group and milrinone treatment group. Pooled estimates showed that milrinone significantly increased the left ventricular ejection fraction (MD 5.69; 95% CI4.27 to 7.10; P < 0.00001) and cardiac output (MD 0.35, 95%CI: 0.13 to 0.56; P =0.002, I2 =24%). While studies to date are few and limited by small sample sizes and poor quality, they suggest that treatment with milrinone may be safe and effective for patients with AHF after AMI. However, this meta‐analysis did not show that milrinone could improve prognosis or the survival rate. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-05T21:22:33.023094-05:
      DOI: 10.1111/bcpt.12385
  • Ascorbic Acid may Exacerbate Aspirin‐Induced Increase in Intestinal
    • Authors: Ivana R. Sequeira; Marlena C. Kruger, Roger D. Hurst, Roger G. Lentle
      Abstract: Ascorbic acid in combination with aspirin has been used in order to prevent aspirin‐induced oxidative GI damage. We aimed to determine whether ascorbic acid reduces or prevents aspirin‐induced changes in intestinal permeability over a 6‐hr period using saccharidic probes mannitol and lactulose. The effects of administration of 600 mg aspirin alone, 500 mg ascorbic acid alone and simultaneous dosage of both agents were compared in a cross‐over study in twenty‐eight healthy female volunteers. These effects were also compared with that of a placebo. The ability of ascorbic acid to mitigate the effects of aspirin when administered either half an hour before or after dosage with aspirin was also assessed in nineteen healthy female volunteers. The excretion of lactulose over the 6‐hr period after dosage was augmented, after consumption of either aspirin or ascorbic acid compared with that after consumption of placebo. Dosage with ascorbic acid alone augmented the excretion of lactulose more than did aspirin alone. Simultaneous dosage with both agents augmented the excretion of lactulose in an additive manner. The timing of dosage with ascorbic acid in relation to that with aspirin had no significant effect on the excretion of the two sugars. These findings indicate that ascorbic acid does not prevent aspirin‐induced increase in gut permeability rather that both agents augment it to a similar extent. The additive effect on simultaneous dosage with both agents in augmenting the absorption of lactulose suggests that each influences paracellular permeability by different pathways. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-04T04:12:58.161482-05:
      DOI: 10.1111/bcpt.12388
  • Effect and Placental Transfer of Dexmedetomidine during Caesarean Section
           under General Anaesthesia
    • Authors: Min Yu; Chuanbao Han, Xiuhong Jiang, Xia Wu, Li Yu, Zhengnian Ding
      Abstract: Many drugs can pass through the placenta and cause adverse effects on the foetus. Thus, during caesarean section for puerperas who have contraindications for intravertebral anaesthesia, the use of proper drugs that have sedative, analgesic effects on the puerperas without adverse effects on the foetus is important. In this study, we investigated the effect and placental transfer of dexmedetomidine during caesarean section under general anaesthesia. Thirty‐eight puerperas were randomly divided to receive dexmedetomidine or saline before anaesthesia induction and during the operation. The dexmedetomidine‐treated parturients had lower mean arterial pressure and heart rate at the delivery and at the end of the operation. The dexmedetomidine‐treated parturients also needed 5.5% less propofol and 8.4% less fentanyl than the saline‐treated ones. Between the dexmedetomidine‐treated and saline‐treated parturients, there was no difference of the maternal artery, umbilical vein, umbilical artery blood gas analysis results, and the Apgar scores at 1 and 5 min. after delivery. The placental transfer rate of dexmedetomidine was 0.76. We concluded that dexmedetomidine was effective in maintaining the hemodynamic stability in the parturients during caesarean section under general anaesthesia without adverse neonatal effects. Dexmedetomidine can pass through the placenta with a placental transfer rate of 0.76. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-04T04:09:10.362027-05:
      DOI: 10.1111/bcpt.12389
  • Third‐generation beta‐adrenoceptor antagonists in the
           treatment of hypertension and heart failure
    • Authors: Filip Yang Fisker; Daniela Grimm, Markus Wehland
      Abstract: Hypertensive treatment with beta‐adrenoceptor antagonists (BAA) has been successfully applied for four decades. These drugs have a beneficial effect on the health of the patients both by decreasing number of deaths and improving morbidity. Nevertheless, the BAAs differ in pharmacological properties. They have different lipophilicity, different adrenoceptor‐selectivity and/or varying additional abilities in cardiac tissue and periphery vasculature hereby exceeding their known receptor‐blocking effects. Nebivolol shows nitric oxide‐mediated vasodilating properties that improve arterial rigidity. Carvedilol has anti‐oxidative and anti‐proliferative effects, which exert a beneficial effect on patients with chronic congestive heart failure (CHF). These findings suggest that the true potential of the third‐generation BAAs and their value in the treatment of CHF, hypertension and following cardiovascular events has yet to be acknowledged. This MiniReview provides an overview of the third‐generation BAAs and their effects on the vasculature of hypertensive patients and patients with CHF. Additionally, BBAs that potentially can be used in different patient groups are discussed. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-03T01:43:10.484563-05:
      DOI: 10.1111/bcpt.12396
  • Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity
           is the Principal Driver
    • Authors: Barent DuBois; Samantha Louey, George D. Giraud, Ganesh Cherala, Sonnet S. Jonker
      Abstract: Understanding theophylline pharmacokinetics in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal pharmacokinetics difficult. Six ewes carrying singleton foetuses received theophylline (60mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36 hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non‐compartmental pharmacokinetic parameters were: half‐life 7.37±1.22 hr; volume of distribution 44.62±11.45L; area under the curve 14.82±2.71hr∙μg∙mL−1; clearance 4.15±0.70L∙hr−1. Rapid theophylline distribution across the placenta was observed. Maternal non‐compartmental pharmacokinetics parameters were: half‐life 6.54±2.44 hr; volume of distribution 32.48±9.99L; area under the curve 16.28±4.53hr∙μg∙mL−1; clearance 3.69±1.47L∙hr−1. Foetal and ewe serum concentration‐time profiles were fit together into a 3‐compartment population pharmacokinetic model, parameters were: central volume 1.38±0.11L; 2nd peripheral compartment volume 3.11±0.29L; 3rd peripheral compartment volume 60.14±6.02L; elimination clearance 9.89±0.90L/hr; distribution clearance between central and 2nd compartment 30.87±2.31L/hr; distribution clearance between 2nd and 3rd compartments 13.89±1.11L/hr. Cytochrome‐P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7±4.4 versus 42.0±3.6%‐bound). Free concentrations were lower in the foetus than the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-27T05:25:09.466785-05:
      DOI: 10.1111/bcpt.12395
  • Successful Use of Hydroxocobalamin and Sodium Thiosulfate in Acute Cyanide
           Poisoning: A Case Report with Follow‐up
    • Authors: Sergey Zakharov; Manuela Vaneckova, Zdenek Seidl, Pavel Diblik, Pavel Kuthan, Pavel Urban, Tomas Navratil, Daniela Pelclova
      Abstract: Hydroxocobalamin is an effective first‐line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination with sodium thiosulfate. A 58‐year‐old male committed a suicide attempt by ingesting of 1200‐1500 mg of potassium cyanide; he was unconscious for 1‐1.5 min. after ingestion with the episode of generalized seizures. On admission to the ICU, the patient was acidotic (pH 7.28; HCO3 14.0 mmol/L, base excess ‐12.7 mmol/L, saturation O2 0.999) with high serum lactate (12.5 mmol/L). Hydroxocobalamin was administered 1.5 hr after ingestion in two subsequent intravenous infusions at a total dose of 7.5 g. The infusion was followed by continuous intravenous administration of 1 ml/h/kg of 10% sodium thiosulfate at a total dose of 12 g. No complications and adverse reactions were registered. Serum lactate decreased on 0.6 mmol/L the same day, and arterial blood gases became normal (pH 7.49; HCO3 27.2 mmol/L, base excess 2.2 mmol/L, saturation O2 0.994). The follow‐up examination 5 months later revealed no damage of basal ganglia and cerebellum on magnetic resonance imaging. The neurological examination revealed no pathological findings. On the ocular coherence tomography, the retinal nerve fibers layer was normal. In visual evoked potentials, there was a normal evoked complex on the left eye and minor decrease of amplitude on the right eye. Combination of hydroxocobalamin and sodium thiosulfate can have a positive effect on the survival without long‐term neurological and visual sequelae in the cases of massive cyanide poisonings due to the possibility of a potentiation or synergism of hydroxocobalamin effects by sodium thiosulfate. This synergism can be explained by the different time points of action of two antidotes: the initial and immediate effect of hydroxocobalamin, followed by the delayed, but more persistent effect of sodium thiosulfate. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-25T20:51:05.724713-05:
      DOI: 10.1111/bcpt.12387
  • Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of
           Cancer‐Induced Bone Pain
    • Authors: Li‐Hua Hang; Hong Luo, Shu‐Na Li, Wei‐Wei Shu, Zheng Chen, Yuan‐Feng Chen, Ju‐Fang Yuan, Lei‐Lei Shi, Dong‐Hua Shao
      Abstract: Cancer‐induced bone pain (CIBP) is seriously disruptive to the quality of life in cancer patients, and present therapies are limited. The Bv8/prokineticin 2, a new family of chemokines, has been demonstrated to be involved in inflammatory and neuropathic pain. However, whether it is involved in CIBP remains unclear. The present study was designed to examine whether spinal Bv8 was involved in the development of CIBP in rats. A rat CIBP model was constructed by injecting Walker 256 carcinoma cells into the medullary cavity of rat tibia. Tibia inoculation with Walker 256 tumour cells resulted in the development of mechanical hyperalgesia. Compared with sham rats, spinal Bv8 mRNA and protein levels were markedly and time‐dependently increased in CIBP rats. Intrathecal administration of Bv8 neutralizing antibody (5 ng) could markedly attenuate pain behaviour as well as up‐regulation of spinal TNF‐α expression at day 18 after inoculation. Intrathecal pre‐treatment with synthetic Bv8 (50 pg) almost completely abolished these effects. These data suggested that spinal Bv8/prokineticin 2 participated in the development of CIBP. Targeting of spinal Bv8 might be a promising strategy for the management of cancer‐induced bone pain. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-25T20:41:11.938598-05:
      DOI: 10.1111/bcpt.12386
  • Regulation of Inflammatory Cytokine Production by MKP‐5 in
    • Authors: Tuija Hömmö; Marko Pesu, Eeva Moilanen, Riku Korhonen
      Abstract: Mitogen‐activated protein kinases (MAPKs) include p38 MAPKs, Jun N‐terminal kinases (JNKs) and extracellular‐regulated kinases (ERKs), and they regulate many cell processes, such as cell division, differentiation and release of inflammatory mediators. MAPK activity is controlled by mitogen‐activated protein kinase phosphatases (MKPs), a phosphatase family with eleven members. MKP‐1 is the most studied member of MKP family, and it is one of the anti‐inflammatory factors induced by glucocorticoids. Less is known about the other MAPK phosphatases although they hold a promise as anti‐inflammatory drug targets. In the present study, we investigated the effect of MKP‐5 on MAPK phosphorylation and cytokine production in J774 mouse macrophages. We used MKP‐5 siRNA and an MKP‐5 inhibitor (AS077234‐4) to modulate MKP‐5 function. We found that MKP‐5 controlled p38 MAPK phosphorylation, but not that of JNK or ERK. In addition, the production of IL‐6 and TNF was suppressed by MKP‐5 in macrophages. Our results introduce a novel concept that compounds able to enhance MKP‐5 expression and/or activity hold anti‐inflammatory potential, because MKP‐5 down‐regulates the release of inflammatory mediators by controlling p38 MAPK activity. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-25T20:26:33.5262-05:00
      DOI: 10.1111/bcpt.12380
  • Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and
           Transdermal Administration to the Ewe
    • Authors: Emma M. Heikkinen; Hanna‐Marja Voipio, Sakari Laaksonen, Linnea Haapala, Juha Räsänen, Ganesh Acharya, Tiina Erkinaro, Mervi Haapsamo, Heidi Hautajärvi, Hannu Kokki, Merja Kokki, Aki T. Heikkinen
      Abstract: Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non‐pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5 to 2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118–127 gestational days were used. In the first protocol, one week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/h were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intraoperative 2.5 μg/kg/h infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day, and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra‐ and postoperative fentanyl concentrations were similar and slightly lower than the a priori predictions and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days but the absorption rate was slower than the nominal dose rate and showed a high inter‐individual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-20T03:54:20.756024-05:
      DOI: 10.1111/bcpt.12382
  • A Gelatinases‐targeting scFv‐based Fusion Protein shows
           Enhanced Anti‐Tumour Activity with Endostar against Hepatoma
    • Authors: Ruijuan Gao; Liang Li, Boyang Shang, Chunyan Zhao, Weijin Sheng, Diandong Li
      Abstract: Gelatinases play important roles in tumour invasion and metastasis and are thus considered a promising target for cancer therapy. In this study, a new single‐chain variable fragment (scFv)‐based fusion protein Fv‐LDP, composed of the anti‐gelatinases scFv and lidamycin apoprotein (LDP), was prepared, and its combination with angiogenesis inhibitor Endostar was then investigated. The fusion protein Fv‐LDP specifically bound to various tumour cells, and its binding capability to human pulmonary giant cell carcinoma (PG) cells was higher than that of recombinant LDP. Fv‐LDP inhibited the expression and secretion of gelatinases and could be internalized into tumour cells via endocytosis. Fv‐LDP also suppressed the growth of human hepatoma cells and murine hepatoma 22 transplanted in Kunming mice in various degrees. In addition, Endostar could enhance the synergistic or additive inhibition of Fv‐LDP on the growth, migration or invasion of human hepatoma cells shown by a colony formation assay and a transwell‐based migration or invasion assay, respectively. In vivo, Fv‐LDP/Endostar combination showed a significantly synergistic effect on the growth of a human hepatoma xenograft, with an inhibition rate of 80.8% compared with the Fv‐LDP (44.1%) or Endostar (8.9%)‐treated group. The above‐mentioned results indicate that the fusion protein Fv‐LDP is effective against transplantable hepatoma in mice and human hepatoma xenografts in athymic mice. Moreover, Endostar can potentiate the inhibition effect of Fv‐LDP on the growth of human hepatoma cells and xenografts. These data will provide a new combined strategy for improving the therapeutic efficacy of treatments for hepatoma or other gelatinases‐overexpressing tumours. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-20T03:41:51.947524-05:
      DOI: 10.1111/bcpt.12379
  • Treatment with Carnitine Enhances Bone Fracture Healing under Osteoporotic
           and/or Inflammatory Conditions
    • Authors: Ali Aydin; Zekai Halici, Abdulmecit Albayrak, Beyzagul Polat, Emre Karakus, Omer Selim Yildirim, Yasin Bayir, Elif Cadirci, Arif Kursad Ayan, Ahmet Murat Aksakal
      Abstract: The aim of this study was to examine the effects of carnitine on bone healing in ovariectomy (OVX) and inflammation (INF)‐induced osteoporotic rats. The rats were randomly divided into nine groups (n=8): sham‐operated (Group 1: SHAM), sham+magnesium silicate (Mg‐silicate) (Group 2: SHAM+INF); ovariectomy (Group 3: OVX); ovariectomy+femoral fracture (Group 4: OVX+FRC); ovariectomy+femoral fracture+Mg‐silicate (Group 5:OVX+FRC+INF); ovariectomy+femoral fracture+carnitine 50 mg/kg (Group 6: OVX+FRC+CAR50); ovariectomy+femoral fracture+carnitine 100 mg/kg (Group 7: OVX+FRC+CAR100); ovariectomy+femoral fracture+Mg‐silicate+carnitine 50 mg/kg (Group 8: OVX+FRC+INF+CAR50); ovariectomy+femoral fracture+Mg‐silicate+carnitine 100 mg/kg (Group 9: OVX+FRC+INF+CAR100). Eight weeks after OVX, which allowed for osteoporosis to develop, INF was induced with subcutaneous Mg‐silicate. On day 80, all of the rats in Groups 4‐9 underwent fracture operation on the right femur. Bone mineral density (BMD) showed statistically significant improvements in the treatment groups. The serum markers of bone turnover (osteocalcin and osteopontin) and pro‐inflammatory cytokines (tumour necrosis factor α, interleukin 1β and interleukin 6) were decreased in the treatment group. The X‐ray images showed significantly increased callus formation and fracture healing in the groups treated with carnitine. The present results show that in a rat model with osteoporosis induced by ovariectomy and Mg‐silicate, treatment with carnitine improves the healing of femur fractures. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-19T02:11:32.162166-05:
      DOI: 10.1111/bcpt.12384
  • Epigallocatechin‐3‐Gallate Attenuates Oxidative Stress and
           Inflammation in Obstructive Nephropathy via NF‐κB and
           Nrf2/HO‐1 Signalling Pathway Regulation
    • Authors: Yanqiu Wang; Bowen Wang, Feng Du, Xuesong Su, Guangping Sun, Guangyu Zhou, Xiaohui Bian, Na Liu
      Abstract: Oxidative stress and inflammation contribute importantly to the pathogenesis of chronic kidney disease (CKD). Epigallocatechin‐3‐gallate (EGCG), which is the most abundant and most active catechin polyphenol extracted from green tea, has been proved to have many bioactivities. In this study, the renoprotective effect of EGCG was evaluated in a widely used kidney disease model, the unilateral ureteral obstruction (UUO) mice model. After 14 days of EGCG administration, mean arterial blood pressure, body weight and obstructed kidney weight were measured. Levels of blood urea nitrogen (BUN) and creatinine (CR) and activities of glutamic‐pyruvic transaminase (GPT) and lactate dehydrogenase (LDH) in serum were estimated as indicators of renal function. Periodic acid‐Schiff (PAS) staining was performed to observe the pathological changes of the obstructed kidney. Antioxidant enzymes and pro‐inflammatory cytokine production were estimated to reflect the oxidative stress and inflammatory state in the obstructed kidney. Finally, the main proteins in the NF‐κB and Nrf2 signalling pathway and DNA binding activity of NF‐κB and Nrf2 were measured to investigate the effect of EGCG on these two pathways. The results demonstrated that EGCG could restore UUO‐induced kidney weight loss and renal dysfunction. In addition, UUO‐induced oxidative stress and inflammatory responses in the obstructed kidney were also prevented by EGCG. Furthermore, EGCG could induce both NF‐κB and Nrf2 nuclear translocation in the UUO kidney and promote heme oxygenase‐1 (HO‐1) production. These results indicated that the renoprotective effect of EGCG might be through its NF‐κB and Nrf2 signalling pathway regulations. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-19T02:04:55.996578-05:
      DOI: 10.1111/bcpt.12383
  • Response to “Reduced Prescribing of Benzodiazepines in Denmark and
    • Authors: Sophie Isabel Eriksen; Lars Bjerrum
      Abstract: In 2005, according to the Nordic Medico‐Statistical Committee (NOMESKO), inhabitants in Norway and Denmark had a comparably high consumption of benzodiazepine drugs and benzodiazepine receptor agonists (Z drugs). The Letter to the Editor states that the number of users per 1,000 inhabitants of long‐acting and short‐acting benzodiazepines and Z drugs has been studied in the total Norwegian population between 2005 and 2013. It shows that the number of users of long‐acting benzodiazepines has decreased between 2005 and 2013 (from 45/1000 inhabitants to 30/1000 inhabitants), but no similar reduction has been observed for the short‐acting benzodiazepines (mainly hypnotics). This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-18T23:56:05.929901-05:
      DOI: 10.1111/bcpt.12378
  • Reduced prescribing of Benzodiazepines in Denmark and Norway
    • Authors: Christian Berg; Svetlana Skurtveit, Solveig Sakshaug, Vidar Hjellvik, Marte Handal
      Abstract: The article “Reducing Prescriptions of Long‐Acting Benzodiazepine Drugs in Denmark: A Descriptive Analysis of Nationwide Prescriptions during a 10‐Year Period” (1) showed considerably decreasing use of benzodiazepines and benzodiazepine‐like Z drugs in Denmark in the period of 2003–2013. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-17T01:36:20.660321-05:
      DOI: 10.1111/bcpt.12377
  • Association between Cardiovascular Drugs and Chronic Kidney Disease in
           Non‐Institutionalized elderly patients
    • Authors: Laurent Becquemont; Bernard Bauduceau, Linda Benattar‐Zibi, Gilles Berrut, Philippe Bertin, Sophie Bucher, Emmanuelle Corruble, Nicolas Danchin, Abdallah al‐Salameh, Geneviève Derumeaux, Jean Doucet, Bruno Falissard, Francoise Forette, Olivier Hanon, Florence Pasquier, Michel Pinget, Rissane Ourabah, Celine Piedvache
      Abstract: Background Concern about the renal safety of commonly used cardiovascular drugs with demonstrated clinical benefit appears to be an obstacle to their use in the elderly. Objectives To describe the relationship between cardiovascular drugs and chronic kidney disease (CKD) in elderly individuals in the real‐life setting. Design ancillary study of the prospective non‐interventional S.AGE (aged individuals) cohort. Setting General physicians were free to prescribe any drug their patients needed. Participants non‐institutionalized patients aged 65 years and older treated by their primary physician for either chronic pain or atrial fibrillation or type 2 diabetes mellitus. Measurements estimated glomerular filtration rate (eGFR) derived from the CKD‐EPI formula was determined at inclusion and every year during two years of follow‐up. Results The present study comprised 2505 patients aged 77.8 ± 6.2 years. At inclusion, the factors associated with CKD (eGFR < 60 ml.min−1.1.73m−2) in multivariate analysis, were age, female gender, hypertension, heart failure, history of atherothrombotic disease and renin angiotensin system blockers, loop diuretics and calcium channel inhibitors. Introduction of each of these three drug classes during the follow‐up period led to only a small decrease in the eGFR: ‐3.8 ± 12.7 (p
      PubDate: 2015-02-03T03:11:09.482522-05:
      DOI: 10.1111/bcpt.12376
  • Statin‐induced Myopathy and Ubiquinone Levels in Serum –
           Results from a Prospective, Observational Study
    • Authors: Ilona Skilving; Jure Acimovic, Anders Rane, Marie‐Louise Ovesjö, Linda Björkhem‐Bergman
      Abstract: It has been suggested that an impaired ubiquinone (Q10) synthesis may be responsible for muscular side effects caused by statins. The primary aim of the present study was to investigate whether low Q10 levels in serum could be used as a marker to predict the risk of developing statin‐induced myopathy. The secondary aim was to compare the change in Q10 levels during statin treatment and differences between men and women. Serum samples from a prospective, observational study in statin‐treated patients that were thoroughly followed regarding muscular symptoms were used. In this cohort, 16 developed myopathy and 126 had no muscular symptoms related to statin treatment. Q10 levels were measured with a novel LC‐MS method at baseline and after 2 months of statin treatment. Q10 levels showed no correlation with the risk of developing statin‐induced myopathy. Individuals with low levels, Q10 < 200 ng/ml, at baseline had no increased risk of developing myopathy. In consistence with earlier reports, we showed that Q10 levels were reduced by 30% during statin treatment. There was no significant difference in the reduction between patients with or without myopathy. Women had approximately 30% lower Q10 levels compared to men both before and after treatment. In this study, there was no association between Q10 levels at baseline and statin‐induced muscular side effects during a 2‐month follow‐up period, and our results indicate that Q10 levels in serum is not a useful marker to predict statin‐induced myopathy. This article is protected by copyright. All rights reserved.
      PubDate: 2015-01-02T02:32:15.654892-05:
      DOI: 10.1111/bcpt.12375
  • Inhibition of DMBA‐induced Oral Squamous Cell Carcinomas Growth by
           Brazilian Red Propolis in Rodent Model
    • Authors: Danielle R. Ribeiro; Ângela Valéria F. Alves, Esaú P. dos Santos, Francine F. Padilha, Margarete Z. Gomes, Alessandra S. Rabelo, Juliana C. Cardoso, Adna Prado Massarioli, Severino Matias Alencar, Ricardo Luiz C. Albuquerque‐Júnior
      Abstract: We investigated the effect of oral administration of hydroalcoholic extract of Brazilian red propolis (HERP) on DMBA‐induced oral squamous cell carcinomas (OSCC) in rodents. The chemical components of the HERP were assessed by Ultra‐Fast Liquid Chromatography (UFLC). Carcinogenesis was topically induced in the lower lip of 25 rats using 9,10‐dimethyl‐1,2‐benzanthracene (DMBA); the tumour was treated with saline (TUM1) and Tween 80 (TUM2) as well as HERP at 10, 50 and 100 mg/kg (HERP10, HERP50, and HERP100, respectively) for 20 weeks. Topical application of saline and oral administration of 100 mg/kg HERP was used in five rats as a control group (CTR). After 26 weeks, the histological malignancy grading and immunohistochemical expression of Ki‐67 and p16INK4A were assessed in the tumours/tissue samples. The compounds identified were propyl gallate, daidzein, catechin, epicatechin, formononetin and biochanin A. Formononetin, daidzein and biochanin A showed concentration of 23.29 mg/g, 0.38 mg/g and 0.67 mg/g of HERP, respectively. HERP at doses of 50 and 100 mg/kg inhibited 40% of OSCC growth and promoted a three‐week delay in development of clinically detectable tumours. Epithelial dysplasia was observed in all samples with no clinical tumour, except in CTR. No significant difference in the immunoexpression of Ki‐67 and p16INK4A was observed between HERP‐treated and saline/Tween 80‐treated groups (p > 0.05). Our results suggest that HERP exerts chemopreventive activity on the progression of DMBA‐induced epithelial dysplasia to OSCC in an experimental model of labial carcinogenesis; however, this effect is not associated with Ki‐67 and p16INK4A immunoexpression. This article is protected by copyright. All rights reserved.
      PubDate: 2015-01-02T02:16:07.107675-05:
      DOI: 10.1111/bcpt.12374
  • Corrigendum
    • Pages: 384 - 384
      PubDate: 2015-03-13T03:39:19.174103-05:
      DOI: 10.1111/bcpt.12390
  • Adiponectin ‐11377C/G and +276G/T Polymorphisms affect Adiponectin
           Levels but do not Modify Responsiveness to Therapy in Resistant
    • Authors: Ana Paula C. Faria; Rodrigo Modolo, Andréa R Sabbatini, Natália R Barbaro, Nathália B Corrêa, Veridiana Brunelli, José E. Tanus‐Santos, Vanessa Fontana, Heitor Moreno
      Pages: n/a - n/a
      Abstract: Resistant hypertension (RHTN) is a multifactorial and polygenic disease, frequently associated with obesity. Low plasma adiponectin levels, a hormone produced by the adipose tissue, were associated with RHTN. Single‐nucleotide polymorphisms (SNPs) ‐11377C/G (rs266729) and +276G/T (rs1501299) in ADIPOQ (adiponectin gene) were associated with hypertension. This study evaluated the association between two SNPs (‐11377C/G and +276G/T) and adiponectin levels in RHTN. This study comprised 109 RHTN patients genotyped for both polymorphisms. A cross‐sectional study was designed to compare features of CC homozygous versus G‐allele carriers for ‐11377C/G and GG homozygous versus T‐allele carriers for +276G/T. Office and ambulatory BP measurements were similar among genotypes subgroups in both SNPs as well as the markers of target organ damage (arterial stiffness, left ventricular mass index and microalbuminuria). Adiponectin concentrations were significantly higher in CC compared to G‐carrier for ‐11377C/G (CC=7.0 (4.0‐10.2) versus G allele=5.5 (2.5‐7.9), p=0.04) and lower in GG compared to T‐carrier for +276G/T (GG=5.3 (2.3‐7.7) versus T allele=7.1 (3.6‐10.5), p=0.04). Adjusting for systolic ambulatory BP, body mass index, age, gender, race and presence of type 2 diabetes, multiple linear regression analyses revealed that the minor alleles G (beta coefficient= ‐0.14, SE=0.07, p=0.03) and T (beta coefficient=0.12, SE=0.06, p=0.04) were independent predictors of adiponectin. The ‐1377C/G and +276G/T SNPs in ADIPOQ were associated with adiponectin levels in RHTN individuals. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-29T00:41:22.452762-05:
      DOI: 10.1111/bcpt.12368
  • Co‐prescribing of Potentially Interacting Drugs during Warfarin
           Therapy – A Population‐based Register Study
    • Authors: Maria Rikala; Milka Hauta‐aho, Arja Helin‐Salmivaara, Riitta Lassila, Maarit Jaana Korhonen, Risto Huupponen
      Pages: n/a - n/a
      Abstract: We analysed the occurrence of co‐prescribing of potentially interacting drugs during warfarin therapy in the community‐dwelling population of Finland. We identified drugs having interaction potential with warfarin using the Swedish Finnish INteraction X‐referencing drug‐drug interaction database (SFINX) and obtained data on drug purchases from the nationwide Prescription Register. We defined warfarin users as persons purchasing warfarin in 2010 (n=148,536) and followed them from their first prescription in 2010 until the end of the calendar year. Co‐prescribing was defined as at least one‐day overlap between warfarin and interacting drug episodes. In addition, we identified persons who initiated warfarin therapy between 1 January 2007 and 30 September 2010 (n=110,299) and followed these incident users for a 3‐month period since warfarin initiation. Overall, 74.4% of warfarin users were co‐prescribed interacting drugs. Co‐prescribing covered 46.4% of the total person‐years of warfarin exposure. Interacting drugs that should be avoided with warfarin were co‐prescribed for 13.4% of warfarin users. The majority of the co‐prescriptions were for drugs that are not contraindicated during warfarin therapy but require special consideration. Among incident users, 57.1% purchased potentially interacting drugs during the 3‐month period following initiation, while 9.0% purchased interacting drugs that should be avoided with warfarin. To conclude, the occurrence of co‐prescribing of potentially interacting drugs was high during warfarin therapy. Our findings highlight the importance of close monitoring of warfarin therapy and the need for further studies on the clinical consequences of co‐prescribing of interacting drugs with warfarin. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-23T09:41:24.034882-05:
      DOI: 10.1111/bcpt.12373
  • Pregnancy Exposure to Olanzapine, Quetiapine, Risperidone, Aripiprazole
           and Risk of Congenital Malformations. A Systematic Review
    • Authors: Zandra Nymand Ennis; Per Damkier
      Pages: n/a - n/a
      Abstract: To review available data on first‐trimester exposure to olanzapine, quetiapine, risperidone and aripiprazole and risk of congenital malformations.We performed a systematic literature search in accordance with PRISMA guidelines identifying studies containing original data on first‐trimester exposure and pregnancy outcome with respect to congenital malformations. Cumulated data for olanzapine were 1090 first‐trimester‐exposed pregnancies with 38 malformations resulting in a malformation rate of 3.5%. The corresponding numbers for quetiapine, risperidone and aripiprazole were 443/16 (3.6%), 432/22 (5.1%) and 100/5 (5.0%), respectively. Relative risk estimates and 95% confidence intervals were 1.0 (0.7‐1.4) (olanzapine), 1.0(0.6‐1.7)(quetiapine), 1.5 (0.9‐2.2) (risperidone) and 1.4 (0.5‐3.1) (aripiprazole). First‐trimester exposure to olanzapine is not associated with an increased risk of congenital malformation. Data for quetiapine and risperidone do not suggest a substantially increased risk, while the risk estimate for aripiprazole remains imprecise owing to a low amount of data. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-23T09:41:16.976767-05:
      DOI: 10.1111/bcpt.12372
  • The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements
           in Kidney Transplant Recipients: A Meta‐Analysis
    • Authors: Jun Lee; Rongrong Wang, Yuan Yang, Xiaoyang Lu, Xingguo Zhang, Linrun Wang, Yan Lou
      Pages: n/a - n/a
      Abstract: Cyclosporine A (CsA) is a substrate of the multidrug efflux pump P‐glycoprotein (P‐gp) encoded by ABCB1. Among the various single nucleotide polymorphisms (SNPs) of ABCB1, C3435T has been extensively investigated to determine the relationship with the pharmacokinetics of CsA. However, the results are controversial. This meta‐analysis was designed to evaluate the influence of C3435T SNP on the dose‐adjusted trough (C0/D) and peak (Cmax/D) concentrations of CsA. Based on a literature search of four authoritative databases, 13 studies since 2001 concerning 1293 kidney transplant recipients were included. The results indicated a significant difference of C0/D and Cmax/D between 3435CC and 3435TT genotype carriers (Weighted mean difference (WMD) of C0/D: 4.18 (ng ml−1)/(mg kg−1), 95% CIs: 1.00–7.37, P=0.01; WMD of Cmax/D: 20.85 (ng ml−1)/(mg kg−1), 95% CIs: 2.25–39.46, P=0.03). Subgroup analysis by ethnicity demonstrated that C0/D was lower in Asian CC versus TT genotype carriers (WMD=10.32 (ng ml−1)/(mg kg−1), 95% CIs: 4.78–15.85, P=0.0003) but did not vary by genotype for Caucasian recipients. Moreover, significant variation of C0/D was found at 1 week and 1‐3 months after transplantation between CC and TT genotype carriers. Therefore, this meta‐analysis showed a correlation between ABCB1 C3435T polymorphism and the dose‐adjusted concentration of CsA. Patients with 3435CC genotype will require a higher dose of CsA to achieve target therapeutic concentrations when compared with 3435TT carriers after kidney transplantation, especially in the Asian population and especially during the early and middle time periods after transplantation. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-23T09:36:40.774274-05:
      DOI: 10.1111/bcpt.12371
  • In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic
           Variants in the Chinese Population
    • Authors: Da‐Peng Dai; Pei‐Wu Geng, Shuang‐Hu Wang, Jie Cai, Li‐Ming Hu, Guo‐Xin Hu, Jian‐Ping Cai
      Abstract: Cytochrome P450 2D6 (CYP2D6) is one of the most widely investigated CYPs in related to genetic polymorphisms and is responsible for one quarter of the currently used clinical drugs. We previously detected 22 novel, non‐synonymous, mutated sites in the Chinese population, but nothing is known about the functional effects of these mutations in terms of specific CYP2D6 substrates. In this study, wild‐type CYP2D6, two common allelic variants and 22 newly reported CYP2D6 isoforms were transiently expressed in 293FT cells, and the enzymatic activities of these variants were systematically assessed using dextromethorphan and bufuralol as the probing substrates. Consequently, 19 and 21 allelic variants were found to exhibit significantly decreased enzymatic activities for dextromethorphan and bufuralol, respectively. Of 22 novel CYP2D6 variants, six allelic isoforms (CYP2D6.89, CYP2D6.92, CYP2D6.93, CYP2D6.96, E215K and R440C) exhibited absent or extremely reduced metabolic activities compared with those observed for the wild‐type enzyme. Our in vitro functional data can be useful for CYP2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP2D6 variants in China. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-03T02:51:27.283871-05:
      DOI: 10.1111/bcpt.12363
  • Dietary Flavonoids Added To Pharmacological Antihypertensive Therapy Are
           Effective In Improving Blood Pressure
    • Authors: Marina María Jesús Romero‐Prado; Jesús Aarón Curiel‐Beltrán, María Viviana Miramontes‐Espino, Ernesto Germán Cardona‐Muñoz, Angeles Rios‐Arellano, Lol‐Be Balam‐Salazar
      Abstract: Epidemiological studies have suggested that the daily intake of flavonoids is associated with a decreased risk of developing cardiovascular disease. Our purpose was to evaluate the effect of the addition of dietary flavonoids (DF) to antihypertensive treatment (AHT), based on telmisartan (Tms) or captopril (Cpr), on blood pressure (BP), body mass index (BMI), waist:hip ratio (WHR), leptin, lipid profile and inflammation in hypertensive young patients An open‐label, randomized, controlled trial was performed among 79 patients aged 20‐55 years with grade I or grade II systemic arterial hypertension. The subjects were assigned to one of four groups for AHT plus DF during 6 months: Cpr (n=14), Cpr + DF (n=19), Tms (n=25) and Tms + DF (n=21). DF consisted of dark chocolate, dehydrated red apple and green tea in an infusion to obtain a daily dose of 425.8 ± 13.9 mg epicatechin equivalents. The BP and anthropometric parameters were measured every two weeks. Lipid profile, leptin and hsCRP were determined by standard methods.The combination AHT‐DF produced an additional and significant reduction of (a) SBP/DBP of ‐5/‐4 mmHg; being ‐7/‐5 for Cpr+DF; and ‐4/‐3 for Tms+DF¸(b) triglyceride levels (‐30.6%) versus AHT alone (‐9.6%); (c) Leptin: Cpr+DF versus Tms+DF (P < 0.005). Finally, CRP plasma levels were reduced significantly in all groups independently of the applied treatment We conclude that the addition of flavonoids to pharmacological antihypertensive therapy show additional benefits on blood pressure, lipid profile, leptin, obesity and inflammation. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-01T09:57:01.256122-05:
      DOI: 10.1111/bcpt.12360
  • Drug−drug Interaction between Losartan and Paclitaxel in Human Liver
           Microsomes with Different CYP2C8 Genotypes
    • Authors: Yuji Mukai; Asuna Senda, Takaki Toda, Toru Hayakawa, Erik Eliasson, Anders Rane, Nobuo Inotsume
      Abstract: The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs), and to determine the impact of the CYP2C8*3 polymorphism. HLMs that contained the CYP2C8*1 homozygote (HL60) or CYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in the HL60 (p
      PubDate: 2014-11-25T06:51:51.83517-05:0
      DOI: 10.1111/bcpt.12355
  • Paraesthesia after Local Anaesthetics: An Analysis of Reports to the FDA
           Adverse Event Reporting System
    • Authors: Carlo Piccinni; Davide B. Gissi, Andrea Gabusi, Lucio Montebugnoli, Elisabetta Poluzzi
      Abstract: This study was aimed to evaluate the possible alert signals of paraesthesia by local anaesthetics, focusing on those used in dentistry. A case/non‐case study of spontaneous adverse events recorded in FAERS (FDA Adverse Event Reporting System) between 2004 and 2011 was performed. Cases were represented by the reports of reactions grouped under the term “Paraesthesias and dysaesthesias” involving local anaesthetics (ATC:N01B*); non‐cases were all other reports of the same drugs. Reporting odds ratios (ROR) with the relevant 95% confidence intervals (95CI) were calculated. Alert signal was considered when: number of cases >3 and lower limit of ROR 95CI >1. To estimate the specificity of signals for dentistry, the analysis was restricted to the specific term “Paraesthesia Oral” and to reports concerning dental practice. Overall, 528 reports of “Paraesthesias and dysaesthesias” were retrieved, corresponding to 573 drug reaction pairs (247 lidocaine, 99 bupivacaine, 85 articaine, 30 prilocaine, 112 others). The signal was significant only for articaine (ROR=18.38; 95CI=13.95‐24.21) and prilocaine (2.66; 1.82‐3.90). The analysis of the specific term “Oral Paraesthesia” retrieved 82 reports corresponding to 90 drug reaction pairs (37 articaine, 19 lidocaine, 14 prilocaine, 7 bupivacaine, 13 others) and confirmed the signal for articaine (58.77; 37.82‐91.31) and prilocaine (8.73; 4.89‐15.57). The analysis of reports concerning dental procedures retrieved a signal for articaine, both for any procedures (8.84; 2.79‐27.97) and for non‐surgical ones (15.79; 1.87‐133.46). In conclusion, amongst local anaesthetics, only articaine and prilocaine generated a signal of paraesthesia, especially when used in dentistry. This article is protected by copyright. All rights reserved.
      PubDate: 2014-11-25T05:20:15.385884-05:
      DOI: 10.1111/bcpt.12357
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Lipid Signalling Dynamics at the β‐cell Plasma Membrane
    • Authors: Anne Wuttke
      First page: 281
      Abstract: Pancreatic β‐cells are clustered in islets of Langerhans and secrete insulin in response to increased concentrations of circulating glucose. Insulin in turn acts on liver, muscle and fat tissue to store energy and normalize the blood glucose level. Inappropriate insulin release may lead to impaired glucose tolerance and diabetes. In addition to glucose, other nutrients, neural and hormonal stimuli control insulin secretion. Many of these signals are perceived at the plasma membrane, which is also the site where insulin granules undergo exocytosis. Therefore, it is not surprising that membrane lipids play an important role in the regulation of insulin secretion. β‐cells release insulin in a pulsatile fashion. Signalling lipids integrate the nutrient and neurohormonal inputs to fine‐tune, shape and coordinate the pulsatility. An important group of signalling lipids are phosphoinositides and their downstream messengers. This MiniReview will discuss new insights into lipid signalling dynamics in β‐cells obtained from live‐cell imaging experiments with fluorescent translocation biosensors. The plasma membrane concentration of several phosphoinositides and of their downstream messengers changes rapidly upon nutrient or neurohormonal stimulation. Glucose induces the most complex spatio‐temporal patterns, typically involving oscillations of messenger concentrations, which sometimes are locally restricted. The tightly controlled levels of lipid messengers can mediate specific binding of downstream effectors to the plasma membrane, contributing to the appropriate regulation of insulin secretion. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-22T01:36:10.564281-05:
      DOI: 10.1111/bcpt.12369
  • Diagnosis and Pharmacotherapy of Stable Chronic Obstructive Pulmonary
           Disease: The Finnish Guidelines Guidelines of the Finnish Medical Society
           Duodecim and the Finnish Respiratory Society
    • Authors: Hannu Kankaanranta; Terttu Harju, Maritta Kilpeläinen, Witold Mazur, Juho T. Lehto, Milla Katajisto, Timo Peisa, Tuula Meinander, Lauri Lehtimäki
      First page: 291
      Abstract: The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for Chronic Obstructive Pulmonary Disease (COPD). The Finnish COPD guideline was revised in order to acknowledge the progress in diagnosis and management of COPD. This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD. It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other health care workers. The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations. The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient. The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma‐COPD overlap syndrome (ACOS). These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions. For the low exacerbation risk phenotype, pharmacotherapy with short‐acting β2‐agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol – ipratropium) is recommended in patients with less symptoms. If short‐acting bronchodilators are not enough to control symptoms, a long‐acting β2‐agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long‐acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended. For the high exacerbation risk phenotype, pharmacotherapy with a long‐acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long‐acting β2‐agonist (budesonide ‐ formoterol, beclomethasone dipropionate ‐ formoterol, fluticasone propionate ‐salmeterol or fluticasone furoate – vilanterol) is recommended as a first choice. Other treatment options for this phenotype include combination of long‐acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium – indacaterol or umeclidinium – vilanterol) or a triple combination of an inhaled glucocorticoid, a long‐acting β2‐agonist and a long‐acting anticholinergic. If the patient has severe to very severe COPD (FEV1 < 50% predicted), chronic bronchitis and frequent exacerbations despite long‐acting bronchodilators, the pharmacotherapy may include also roflumilast. ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD. Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and COPD. Thus, evidence‐based recommendation of treatment cannot be given. The treatment should cover both diseases. Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long‐acting bronchodilator (β2‐agonist or anticholinergic or both). This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-17T01:08:36.078401-05:
      DOI: 10.1111/bcpt.12366
  • Use of Inhaled and Oral Corticosteroids in Pregnancy and the Risk of
           Malformations or Miscarriage
    • Authors: Anne‐Mette Bay Bjørn; Vera Ehrenstein, Ellen Aagaard Nohr, Mette Nørgaard
      First page: 308
      Abstract: Corticosteroids are potent anti‐inflammatory and immunosuppressive drugs, which sometimes must be given to pregnant women. Corticosteroids have been suspected to be teratogenic for many years; however, there is conflicting evidence regarding the association. Based on a literature review of three databases, this MiniReview provides an overview of inhaled and oral corticosteroid use in pregnancy with specific emphasis on the association between use of corticosteroids during pregnancy and risk of miscarriage and congenital malformations in offspring. Use of corticosteroids among pregnant women ranged from 0.2% to 10% and increased nearly two‐fold in recent years. Taken together, the evidence suggests that use of corticosteroids in early pregnancy is not associated with an increased risk of congenital malformations overall or oral clefts in offspring; at the same time, published estimates are inconsistent. Use of inhaled corticosteroids was associated with a slightly increased the risk of miscarriage, whereas use of oral corticosteroids was not; however, confounding by indication could not be ruled out. This article is protected by copyright. All rights reserved.
      PubDate: 2014-12-17T01:08:08.575611-05:
      DOI: 10.1111/bcpt.12367
  • 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
      First page: 321
      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
      First page: 337
      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
  • 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
      First page: 354
      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
  • 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
      First page: 372
      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
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