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  Subjects -> ENVIRONMENTAL STUDIES (Total: 811 journals)
    - ENVIRONMENTAL STUDIES (738 journals)
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ENVIRONMENTAL STUDIES (738 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 Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 18)
Advances in Life Science and Technology     Open Access   (Followers: 6)
Aeolian Research     Hybrid Journal   (Followers: 3)
African Journal of Environmental Science and Technology     Open Access   (Followers: 3)
African Journal of Sustainable Development     Full-text available via subscription   (Followers: 7)
AGE     Hybrid Journal   (Followers: 4)
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: 30)
American Journal of Environmental Engineering     Open Access   (Followers: 8)
American Journal of Environmental Protection     Open Access   (Followers: 5)
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: 50)
Annals of Environmental Science     Open Access   (Followers: 9)
Annals of GIS     Hybrid Journal   (Followers: 18)
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: 13)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 13)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
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: 20)
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: 16)
Atmospheric Environment     Hybrid Journal   (Followers: 28)
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: 4)
Australian Journal of Environmental Education     Full-text available via subscription   (Followers: 8)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 7)
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: 25)
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: 4)
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: 2)
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: 14)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
CCLR - Carbon and Climate Law Review     Full-text available via subscription   (Followers: 5)
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: 14)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 2)
Chemosphere     Hybrid Journal   (Followers: 11)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 41)
Civil and Environmental Engineering     Open Access  
Civil And Environmental Engineering Reports     Open Access  
Civil and Environmental Research     Open Access   (Followers: 13)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 17)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 7)
Cleanroom Technology     Full-text available via subscription  
Climate Change Economics     Hybrid Journal   (Followers: 16)
Climate Policy     Hybrid Journal   (Followers: 22)
Coastal Engineering Journal     Hybrid Journal   (Followers: 2)
Columbia Journal of Environmental Law     Free   (Followers: 8)
Computational Ecology and Software     Open Access   (Followers: 5)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 2)
Conservation and Society     Open Access   (Followers: 10)
Conservation Letters     Open Access   (Followers: 24)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (Followers: 14)
Construction Innovation: Information, Process, Management     Hybrid Journal   (Followers: 15)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 2)

        1 2 3 4 5 6 7 8 | Last

Journal Cover   Basic & Clinical Pharmacology & Toxicology
  [SJR: 0.739]   [H-I: 62]   [7 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7835 - ISSN (Online) 1742-7843
   Published by John Wiley and Sons Homepage  [1607 journals]
  • L‐arginine Attenuates Cardiac Dysfunction, but further
           Down‐Regulates Alpha Myosin Heavy Chain Expression in
           Isoproterenol‐Induced Cardiomyopathy
    • Authors: Eva Kralova; Gabriel Doka, Lenka Pivackova, Jasna Srankova, Kristina Kuracinova, Pavol Janega, Pavel Babal, Jan Klimas, Peter Krenek
      Abstract: In view of previously reported increased capacity for NO production, we hypothesized that L‐arginine (ARG), the nitric oxide synthase (NOS) substrate, supplementation would improve cardiac function in isoproterenol (ISO)‐induced heart failure. Male Wistar rats were treated with ISO for 8 days (5 mg/kg/d, i.p.) or vehicle. ARG was given to control (ARG) and ISO‐treated (ISO+ARG) rats in water (0.4 g/kg/d). ISO administration was associated with 40% mortality, ventricular hypertrophy, decreased heart rate, left ventricular dysfunction, fibrosis, ECG signs of ischaemia. RT‐PCR showed increased mRNA levels of cardiac hypertrophy marker ANP, but not BNP, decreased expression of myosin heavy chain isoform MYH6, unaltered expression of pathological MYH7. ISO increased the protein levels of eNOS, but at the same time it markedly up‐regulated mRNA and protein levels of gp91phox, a catalytical subunit of superoxide‐producing NADPH oxidase. Fibrosis was markedly increased by ISO. ARG treatment moderately ameliorated left ventricular dysfunction, but was without effect on cardiac hypertrophy and fibrosis. Combination of ISO+ARG led to a decrease in cav‐1 expression, a further increase in MYH7 expression and a down‐regulation of MYH6 that inversely correlated with gp91phox mRNA levels. Although ARG, at least partially, improved ISO‐impaired basal left ventricular systolic function, it failed to reduce cardiac hypertrophy, fibrosis, oxidative stress and mortality. The protection of contractile performance might be related to increased capacity for NO production and the up‐regulation of MYH7 which may compensate for the marked down‐regulation of the major MYH6 isoform. This article is protected by copyright. All rights reserved.
      PubDate: 2015-04-10T09:52:30.813183-05:
      DOI: 10.1111/bcpt.12405
  • Effect of the Acidic Dental Resin Monomer 10‐methacryloyloxydecyl
           Dihydrogen Phosphate on Odontoblastic Differentiation of Human Dental Pulp
    • Authors: Eun‐Cheol Kim; Haejin Park, Sang‐Im Lee, Sun‐Young Kim
      Abstract: Although 10‐methacryloyloxydecyl dihydrogen phosphate (10‐MDP) is frequently used as an acidic resin monomer in dental adhesives, its effect on dental pulp cells (DPCs) has been rarely reported. The purpose of this study was to examine the effects of 10‐MDP on the inflammatory response and odontoblastic differentiation of DPCs at minimally toxic concentrations. We found that 10‐MDP caused the release of inflammatory cytokines including NO, PGE2, iNOS, COX‐2, TNF‐α, IL‐1β, IL‐6 and IL‐8 in a concentration‐dependent manner. In addition, 10‐MDP reduced alkaline phosphatase activity, mineralization nodule formation and mRNA expression of odontoblastic differentiation markers such as dentin sialophosphoprotein, dentin matrix protein‐1, osterix and Runx2 in a concentration‐dependent manner with low toxicity. In addition, 10‐MDP induced activation of nuclear factor‐E2‐related factor 2 (Nrf2) and its target gene, heme oxygenase‐1 (HO‐1). We evaluated whether the effect of 10‐MDP was related to induction of HO‐1, and found that treatment with a selective inhibitor of HO‐1 reversed production of 10‐MDP‐mediated pro‐inflammatory cytokines and inhibition of differentiation markers. Pre‐treatment with either a GSH synthesis inhibitor or antioxidants blocked 10‐MDP‐induced mitogen‐activated protein kinases (MAPKs), Nrf2 and NF‐κB pathways. Taken together, the results of this study showed that minimally toxic concentrations of 10‐MDP promoted an inflammatory response and suppresses odontoblastic differentiation of DPCs by activating Nrf2‐mediated HO‐1 induction through MAPK and NF‐κB signalling. This article is protected by copyright. All rights reserved.
      PubDate: 2015-04-03T04:17:14.90936-05:0
      DOI: 10.1111/bcpt.12404
  • Intrabronchial Microdialysis: Effects of Probe Localisation on Tissue
           Trauma and Drug Penetration into the Pulmonary Epithelial Lining Fluid
    • Authors: LAH Rottbøll; K Skovgaard, K Barington, HE Jensen, C Friis
      Abstract: Recent intrabronchial microdialysis data indicate that the respiratory epithelium is highly permeable to drugs. Of concern is whether intrabronchial microdialysis disrupts the integrity of the respiratory epithelium and thereby alters drug penetration into the pulmonary epithelial lining fluid (PELF). The objective of this study was to investigate the effect of intrabronchial microdialysis on the integrity of the bronchial epithelium. Microdialysis sampling in PELF in proximal (n=4) and distal bronchi (n=4) was performed after intravenous inulin and florfenicol administration in anaesthetized pigs. Inulin was used as a marker molecule of permeability of the epithelium, and florfenicol was used as test drug. Bronchial tissue was examined by histopathology (distal and proximal bronchi) and gene expression analysis (RT‐qPCR, proximal bronchi) at the termination of the experiment (6.5 hr). The microdialysis probe caused overt tissue trauma in distal bronchi, whereas no histopathological lesions were observed in proximal bronchi. A moderate up‐regulation of the pro‐inflammatory cytokines IL1B, IL6 and acute phase reactant serum amyloid A was seen in proximal bronchi surrounding the microdialysis probes suggesting initiation of an inflammatory response. The observed up‐regulation is considered to have limited impact on drug penetration during short‐term studies. Inulin penetrated the respiratory epithelium in both proximal and distal bronchi without any correlation to histopathological lesions. Likewise, florfenicol penetration into PELF was unaffected by bronchial histopathology. However, this independency of pathology on drug penetration may not be valid for other antibiotics. We conclude that short‐term microdialysis drug quantification can be performed in proximal bronchi without disruption of tissue integrity. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-30T09:55:27.077372-05:
      DOI: 10.1111/bcpt.12403
  • Antidiabetic Agents and Endothelial Dysfunction – Beyond Glucose
    • Authors: Linnéa Eriksson; Thomas Nyström
      Abstract: Diabetes is rapidly increasing worldwide, and the number of patients suffering from diabetes is projected to rise by 50 % over the next 25 years, then affecting almost 600 million adults. Type 2 diabetes comprises 90‐95% of all people with diabetes, and they constitute a patient group that carries a high burden of cardiovascular disease. The relationship between hyperglycaemia and macrovascular complications is still uncertain, at least in terms of the possibility of reducing cardiovascular events solely by improving glycaemic control. This MiniReview has thus focused on the effect of common antidiabetic agents, with emphasis on glucagon like peptide‐1, on the endothelial cells of the vasculature. Patients with type 2 diabetes suffer a 2‐4 times higher risk of myocardial infarction and stroke than healthy persons. In addition to this, diabetic patients have an increased atherosclerotic burden. Endothelial dysfunction is thought to be an early and important predictor of atherosclerosis and cardiovascular disease, and in people with type 2 diabetes endothelial dysfunction is a common finding. It is therefore of importance to consider whether drugs used within the clinical management of T2DM exert direct and positive effects on the vasculature independent of their glucose‐lowering ability. This might serve to limit the adverse consequences of the macrovascular complications of T2DM, as dysfunction of endothelial cells is believed to contribute to a premature development of atherosclerosis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-30T09:49:56.822216-05:
      DOI: 10.1111/bcpt.12402
  • Levothyroxine Poisoning – Symptoms and Clinical Outcome
    • Authors: Birgitte Nygaard; Eva Aggerholm Saedder, Kim Dalhoff, Mette Wikkelsoe, Gesche Jürgens
      Abstract: Levothyroxine, T4 (LT) poisoning is rarely associated with a severe outcome. However, cases with significant complications have been reported. The aim of the present study was to identify factors associated with symptoms of poisoning including late onset symptoms. All enquiries to the Danish Poison Information Centre (DPIC) concerning LT poisoning between March 2007 and September 2012 were reviewed and the following parameters were recorded: age, dose, time from ingestion, multiple drug intake and symptoms. In order to evaluate the frequency of late onset symptoms, a subgroup of patients without initial symptoms were contacted. A total of 181 patients were registered (112 children). Ingested LT dose ranged from 10 to 9000 mcg (median 275 mcg). A total of 29/181 (16%) patients were symptomatic at the time of enquiry, and there was no difference in ingested LT dose between asymptomatic and symptomatic patients; neither in children nor in adults (age 16‐92 years) (p
      PubDate: 2015-03-28T08:52:35.394348-05:
      DOI: 10.1111/bcpt.12401
  • The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents
           Cardiac Remodelling and Matrix Metalloproteinase‐2
           Up‐Regulation in Renovascular Hypertension
    • Authors: Stefany B.A. Cau; Danielle A. Guimaraes, Elen Rizzi, Carla S. Ceron, Raquel F. Gerlach, Jose E. Tanus‐Santos
      Abstract: Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF‐кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up‐regulation. We hypothesized that treatment with PDTC could prevent 2‐kidney, 1‐clip (2K1C) hypertension‐induced left ventricular remodelling. Sham‐operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg.Kg‐‐1) by gavage for eight weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with hematoxylin/eosin sections and fibrosis was quantified in picrosirius red‐stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography and cardiac MMP‐2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C Vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricle and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP‐2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP‐2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMPs expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-28T08:39:05.069635-05:
      DOI: 10.1111/bcpt.12400
  • The Effect of a Polyvalent Antivenom on the Serum Venom Antigen Levels of
           Naja sputatrix (Javan Spitting Cobra) Venom in Experimentally Envenomed
    • Authors: Michelle Khai Khun Yap; Nget Hong Tan, Si Mui Sim, Shin Yee Fung, Choo Hock Tan
      Abstract: The treatment protocol of antivenom in snake envenomation remains largely empirical, partly due to the insufficient knowledge of the pharmacokinetics of snake venoms and the effects of antivenoms on the blood venom levels in victims. In the present study, we investigated the effect of a polyvalent antivenom on the serum venom antigen levels of Naja sputatrix (Javan spitting cobra) venom in experimentally envenomed rabbits. Intravenous infusion of 4 ml of Neuro Polyvalent Snake Antivenom (NPAV, F(ab’)2) at 1‐hr post‐envenomation caused a sharp decline of the serum venom antigen levels, followed by transient resurgence an hour later. The venom antigen resurgence was unlikely to be due to the mismatch of pharmacokinetics between the F(ab’)2 and venom antigens, as the terminal half‐life and volume of distribution of the F(ab’)2 in serum were comparable to that of venom antigens (p>0.05). Infusion of an additional 2 ml of NPAV was able to prevent resurgence of the serum venom antigen level, resulting in a substantial decrease (67.1%) of the total amount of circulating venom antigens over time course of envenomation. Our results showed that the neutralisation potency of NPAV determined by neutralisation assay in mice may not be an adequate indicator of its capability to modulate venom kinetics in relation to its in vivo efficacy to neutralise venom toxicity. The findings also support the recommendation of giving high initial dose of NPAV in cobra envenomation, with repeated doses as clinically indicated in the presence of rebound antigenemia and symptom recurrence. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-27T05:30:34.850476-05:
      DOI: 10.1111/bcpt.12398
  • 4,4’‐DMAR: Chemistry, Pharmacology and Toxicology of a New
           Synthetic Stimulant of Abuse
    • Authors: Maurizio Coppola; Rafaella Mondola
      Abstract: In recent years, the spread of new psychoactive substances has dramatically increased in term of availability of both number of compounds and chemical families. In November 2012, 4,4’‐Dimethylaminorex (4,4’‐DMAR), a novel synthetic stimulant, was first detected in the Netherlands. Between June 2013 and June 2014, thirty‐one deaths associated with the consumption of this new drug have been registered across Europe. In this MiniReview, we have summarized the chemical, pharmacological and toxicological information about this new legal high. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-27T05:30:26.606129-05:
      DOI: 10.1111/bcpt.12399
  • 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
  • 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
      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
      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
  • 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
      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
  • 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
  • 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
  • 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
  • Dabigatran concentration: variability and potential bleeding prediction in
           “real–life” patients with atrial fibrillation
    • Abstract: Routine laboratory monitoring is currently not recommended in patients receiving dabigatran despite its considerable variation in plasma concentration. However, in certain clinical situations, measurements of the dabigatran effect may be desirable. We aimed to assess the variability of dabigatran trough and peak concentration and explore the potential relationship between dabigatran concentration and adverse events. We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (D150) or 110 mg (D110) twice daily. They contributed 170 trough and peak blood samples that were collected 2–4 and 6–8 weeks after dabigatran initiation. Plasma dabigatran concentration was measured by LC‐MS/MS and indirectly, by selected coagulation tests. D110 patients were older (74±7 versus 68±6 years), had lower creatinine clearance (68±21 versus 92±24 mL/min) and higher CHA2DS2‐VASc score (3.1±1.3 versus 2.3±0.9) compared to D150 patients (all p
  • Adverse Events during Immunotherapy against Grass Pollen‐Induced
           Allergic Rhinitis – Differences between Subcutaneous and Sublingual
    • Abstract: Allergic rhinitis triggered by grass pollen is a common disease, affecting millions of people worldwide. Treatment consists of symptom‐alleviating drugs, such as topical corticosteroids or antihistamines. Another option is potentially curative immunotherapy, currently available as sublingual and subcutaneous treatment. We investigated the potential differences in the prevalence and severity of adverse events related to subcutaneous and sublingual immunotherapy against grass pollen‐induced allergic rhinitis. A thorough literature search was performed using PubMed and EMBASE. The findings were compared with the available summaries of product characteristics and with commercial pharmacology databases (Micromedex). The majority of available safety data originates from registered products of standardized allergens. A surprisingly large percentage of drugs, especially those used in the United States, have no systematically collected safety data. No sufficiently powered randomized trials comparing sublingual and subcutaneous immunotherapy were available, but general safety assessments indicate that sublingual tablet treatment is safer than subcutaneous treatment. Not all commonly used immunotherapy drugs are officially registered and not all have systematically collected safety data. This is especially true for older drugs used in the United Stages. In contrast, newer drugs that have undergone extensive clinical testing have better documentation, but unified collection of safety data is still lacking. Considering the evidence available, most drugs elicit similar side effects from the same organ systems, and symptoms from the sublingual drug classes are probably less severe. However, a head‐to‐head comparison of safety and efficacy is lacking. This article is protected by copyright. All rights reserved.
  • Issue Information
  • The Effect of Oral Morphine on Pain‐Related Brain Activation –
           An Experimental Functional Magnetic Resonance Imaging Study
    • Abstract: Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 males and 7 females, 24.9±2.6 years) in a randomised, double‐blind, placebo‐controlled, cross‐over study. Painful stimulations were applied to the right forearm using a Contact Heat Evoked Potential Stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n=16, p
  • Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of
           Tissue Plasminogen Activator in a Rat Stroke Model
    • Abstract: Delayed treatment of stroke with recombinant tissue plasminogen activator (r‐tPA) induces over‐expression of matrix metalloproteinase 9 (MMP‐9) which leads to breakdown of the blood‐brain barrier (BBB) and causes more injuries to the brain parenchyma. In the current study, the effect of Ascorbic Acid (AA), an anti‐oxidant agent, on the delayed administration of r‐tPA in a rat model of permanent middle cerebral artery occlusion (MCAO) was investigated. Forty male rats were randomly divided into 4 groups: untreated control rats (ischaemic animals), AA‐treated (500 mg/kg; 5 hr after stroke), r‐tPA‐treated (5 hr after stroke 1mg/kg) and the combination of AA+r‐tPA rats. MCAO was induced by occluding the right middle cerebral artery. Infarct size, blood‐brain barrier, brain oedema and the levels of MMP‐9 were measured at the end of study. Neurological deficits were evaluated at 24 and 48 hr after stroke. Compared to the control or r‐tPA‐treated animals, AA alone (P
  • Effects of NO‐Hybridization on the Immunomodulatory Properties of
           the HIV Protease Inhibitors Lopinavir and Ritonavir
    • Abstract: HIV protease inhibitors (PIs) are antiretroviral agents, which have been found to also affect several cellular processes, such as inflammation and cell progression. In studies on non‐steroidal, anti‐inflammatory drugs, the addition of a nitric oxide (NO) moiety has been shown to both reduce their toxicity and enhance their pharmacological efficacy. Along this line of research, several derivatives of PIs have been synthesized by covalent attachment of NO moiety to the parental molecules. Previous work has indicated that NO‐hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir‐NO that while retaining the antiretroviral effect, acquires anti‐tumoural and immunomodulatory properties along with reduced toxicity in vitro and in vivo. These data prompted us to evaluate the effects of NO‐hybridization on two other PIs, Lopinavir and Ritonavir. The two NO‐derivatives were compared head to head with their parental compounds on human primary peripheral blood mononuclear cells as well as on human primary macrophages. Lopinavir‐NO and Lopinavir were also screened in an in vivo model of autoimmune hepatitis. Our results prove that Lopinavir‐NO exerts markedly superior effects as compared to the parental compound both in vitro and in vivo. On the contrary, Ritonavir‐NO effects overlapped those of Ritonavir. These data demonstrate that NO‐hybridization of Lopinavir generates a derivative with significantly stronger immunomodulatory effects that are apparently related to an action of the compound on T cell secretory capacity. Lopinavir‐NO deserves additional studies for its possible use in T‐cell mediated autoimmune diseases including, but not limited to autoimmune hepatitis. This article is protected by copyright. All rights reserved.
  • The Fentanyl Patch Boil‐Up – A Novel Method of Opioid Abuse
    • Abstract: Fentanyl is a potent opioid analgesic used in the treatment of pain. Transdermal fentanyl patches are now widely utilised as an acceptable and efficacious method of medication delivery. Unfortunately, the potential for their abuse is well recognised. Previous case reports have documented deaths after intravenous (IV) misuse of fentanyl which had been extracted from Duragesic (liquid reservoir type) patches. We present a case of IV fentanyl abuse after extraction from a Mylan (matrix type) patch. This method of abuse has not previously been described in the literature. This article is protected by copyright. All rights reserved.
  • Age‐related Differences in CYP3A Abundance and Activity in the Liver
           of the Göttingen Minipig
    • Abstract: In view of paediatric drug development, regulatory authorities often request safety studies in juvenile animals, including minipigs. Unfortunately, knowledge on the ontogeny of the biotransformation processes in animal models remains scarce and impedes a correct interpretation of the toxicity findings. CYP3A4 is one of the most important drug‐metabolizing enzymes in human beings and shows important similarities with CYP3A in the minipig. Therefore, the aim of this study was to assess the abundance and activity of CYP3A in liver microsomes from foetal, juvenile (Day 1, 3, 7 and 28) and adult male and female Göttingen minipigs. CYP3A abundance was studied by an indirect enzyme‐linked immunosorbent assay (ELISA), whereas CYP3A activity was assessed by a biotransformation assay with Luciferin‐IPA. CYP3A abundance could not be detected until day 3. From day 7 onwards, a gradual increase in expression was noted, leading to the highest abundance in adult animals. CYP3A activity was not detectable in foetuses and 1‐day‐old animals. The CYP3A activity was detectable, but below the LLOQ in day 3 animals and increased gradually with age to reach the highest level in adults. The CYP3cide and ketoconazole inhibition, and testosterone and midazolam reduction of Luciferin‐IPA metabolism in minipig liver microsomes substantiate that Luciferin‐IPA is metabolized by CYP3A in minipigs. A positive correlation was found between CYP3A abundance and biotransformation of Luciferin‐IPA (Pearson r = 0.863; p < 0.0001). In conclusion, both abundance and activity of CYP3A increased gradually in juvenile minipigs, but remained below the levels observed in adult animals. This article is protected by copyright. All rights reserved.
  • Pediatric Off‐Label Use of Melatonin – A Register Linkage
           Study between the Norwegian Prescription Database and Patient Register
    • Abstract: The aims were, for the entire Norwegian population aged 4–17 years, to study prevalence of melatonin use during 2004–2012, recurrent use in incident users and psychiatric and neurological morbidity in recurrent users. Data on dispensed melatonin were retrieved from the Norwegian Prescription Database and linked to diagnostic data from the Norwegian Patient Register. Outcome measures were: 1‐year prevalence of use, proportion of recurrent use (use over three consecutive 365‐day periods among incident users in 2009) and annual number of milligrams and number of prescriptions dispensed in recurrent users. The prevalence of registered ICD‐10 diagnoses during the period of 2008‐2012 was given for the recurrent users. Prevalence of melatonin use increased annually in both genders during 2004–2012 (boys: 3.4–11.0 per 1000; girls: 1.5–7.7 per 1000). 29% of boys and 23% of girls were recurrent melatonin user, and the prevalence was highest among the youngest (aged 4–8 years; boys: 47%, girls: 42%). In the third year, the median annual amount of melatonin dispensed was 1080 (IQR 586‐1800) milligrams in boys and 900 (IQR 402‐1620) milligrams in girls. Among recurrent users, 91% had a diagnosis of either psychiatric (84%) or neurological (32%) disorder. Off‐label recurrent use of melatonin seems to have acquired a role mainly in treating secondary sleep problems in children and adolescent with psychiatric and neurological disorders. Once melatonin has been started, a large proportion of patients continue for at least 3 years, in doses corresponding to daily use in the majority. This article is protected by copyright. All rights reserved.
  • Response to “CYP2E1 Polymorphism and better outcome after methanol
    • Abstract: The median serum formate concentration in the population of 50 survivors of methanol poisoning studied in our paper was 578 mg/L with interquartile range of 256‐748 mg/L. For detailed information regarding the results of formate measurements in the patients poisoned with methanol in 2012, see Zakharov et al., 2015 (1). We agree that the description of the individual cases was not fully exhaustive, so we include a complete description of the cases below. This article is protected by copyright. All rights reserved.
  • CYP2E1 Polymorphism and better outcome after methanol poisoning
    • Abstract: Hubacek et al. published in a recent issue an interesting paper on the possible influence of CYP2E1 polymorphism on the outcome of methanol‐poisoned patients [1]. As mentioned by the authors and by previous papers, the poor prognosis (death or permanent visual or neurological damage) in methanol poisoning is mainly linked to the severity of metabolic acidosis, as a consequence of formate production and to a lesser degree of lactate accumulation for the most severe forms. The metabolism of methanol is mainly under the influence of alcohol dehydrogenase, and partly also of the inducible hepatic microsomal ethanol oxidizing system (MEOS). This article is protected by copyright. All rights reserved.
  • Endothelin‐1 and Endothelin‐3 Regulate Endothelin Receptor
           Expression in Rat Coronary Arteries
    • Abstract: In ischaemic hearts, endothelin (ET) levels are increased, and vasoconstrictor responses to ET‐1 are greatly enhanced. We previously reported that ETB receptors are up‐regulated in the smooth muscle layer of coronary arteries after myocardial ischaemia‐reperfusion and that the MEK‐ERK‐1/2 signalling pathway is involved in ETB receptor up‐regulation. Whether ETs are directly involved in receptor regulation has not been determined. We hypothesised that ET‐1 and ET‐3 alter the expression/activity of ET receptors in coronary vascular smooth muscle cells. Vasoconstrictor responses were studied in endothelium‐denuded coronary artery segments from rats that were subjected to experimental ischaemia‐reperfusion or in organ‐cultured segments. Post‐ischaemic and cultured coronary arteries exhibited similar increased sensitivity to ET‐3. ETA receptor‐mediated vasoconstriction was dominant in fresh and non‐ischaemic arteries. Organ culture significantly up‐regulated ETB receptors and down‐regulated ETA receptor expression. Co‐incubation with ET‐1 (1 nM) or ET‐3 (100 nM) induced further down‐regulation of the ETA receptor mRNA, while the function and protein level of ETA remained unchanged. ET‐3 (100 nM) further up‐regulated ETB receptor mRNA and proteins but abolished ETB receptor‐mediated vasoconstriction, suggesting a desensitisation of ETB receptors that was not observed with ET‐3 (1 nM). In conclusion, ET‐1, which is the most prevalent isoform in the cardiovascular system, induces down‐regulation of ETA receptor expression without changing ETA or ETB receptor function or protein levels. Intermediate concentrations of ET‐3 had an effect that was similar to that of ET‐1, such that high concentrations of ET‐3 (100 nM) up‐regulated the ETB receptor at the gene and protein levels but switched off the function of the ETB receptors via desensitisation. This article is protected by copyright. All rights reserved.
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