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    - ENVIRONMENTAL STUDIES (758 journals)
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ENVIRONMENTAL STUDIES (758 journals)                  1 2 3 4 5 6 7 8 | Last

Acta Ecologica Sinica     Open Access   (Followers: 12)
Acta Limnologica Brasiliensia     Open Access   (Followers: 2)
Acta Oecologica     Hybrid Journal   (Followers: 7)
Acta Regionalia et Environmentalica     Open Access   (Followers: 1)
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 17)
Advances in Ecological Research     Full-text available via subscription   (Followers: 35)
Advances in Environmental Chemistry     Open Access   (Followers: 1)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 16)
Advances in Life Science and Technology     Open Access   (Followers: 8)
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: 6)
AGE     Hybrid Journal   (Followers: 4)
Age and Ageing     Hybrid Journal   (Followers: 55)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 12)
Amazon's Research and Environmental Law     Open Access  
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: 33)
American Journal of Environmental Engineering     Open Access   (Followers: 10)
American Journal of Environmental Protection     Open Access   (Followers: 7)
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: 57)
Annals of GIS     Hybrid Journal   (Followers: 17)
Annals of Warsaw University of Life Sciences - SGGW. Land Reclamation     Open Access   (Followers: 1)
Annual Review of Ecology, Evolution, and Systematics     Full-text available via subscription   (Followers: 50)
Annual Review of Environment and Resources     Full-text available via subscription   (Followers: 15)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 25)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 10)
Applied and Environmental Soil Science     Open Access   (Followers: 12)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 16)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 24)
Aquatic Toxicology     Hybrid Journal   (Followers: 15)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 4)
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: 4)
Asian Journal of Earth Sciences     Open Access   (Followers: 21)
Asian Journal of Rural Development     Open Access   (Followers: 11)
Asian Review of Environmental and Earth Sciences     Open Access  
Atas de Saúde Ambiental - ASA     Open Access  
ATBU Journal of Environmental Technology     Open Access   (Followers: 3)
Atmospheric and Climate Sciences     Open Access   (Followers: 15)
Atmospheric Environment     Hybrid Journal   (Followers: 29)
Austral Ecology     Hybrid Journal   (Followers: 11)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 6)
Australasian Journal of Human Security, The     Full-text available via subscription   (Followers: 3)
Australian Journal of Environmental Education     Full-text available via subscription   (Followers: 9)
Avicenna Journal of Environmental Health Engineering     Open Access  
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 7)
Basic and Applied Ecology     Hybrid Journal   (Followers: 16)
Behavioral Ecology     Hybrid Journal   (Followers: 49)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 37)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 25)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 5)
Bioremediation Journal     Hybrid Journal   (Followers: 4)
BioRisk     Open Access   (Followers: 3)
BMC Ecology     Open Access   (Followers: 21)
Boston College Environmental Affairs Law Review     Open Access   (Followers: 6)
Bothalia : African Biodiversity & Conservation     Open Access   (Followers: 1)
Built Environment     Full-text available via subscription   (Followers: 6)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 9)
Bulletin of the American Meteorological Society     Open Access   (Followers: 17)
Business, Peace and Sustainable Development     Full-text available via subscription   (Followers: 2)
Cadernos do Desenvolvimento Fluminense     Open Access  
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: 13)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 18)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 13)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
Cell Biology and Toxicology     Hybrid Journal   (Followers: 8)
Chain Reaction     Full-text available via subscription  
Challenges in Sustainability     Open Access  
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 14)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 11)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 58)
Civil and Environmental Engineering     Open Access   (Followers: 3)
Civil And Environmental Engineering Reports     Open Access   (Followers: 2)
Civil and Environmental Research     Open Access   (Followers: 16)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 17)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 6)
Cleanroom Technology     Full-text available via subscription  
Climate Change Economics     Hybrid Journal   (Followers: 16)
Climate Policy     Hybrid Journal   (Followers: 29)
Coastal Engineering Journal     Hybrid Journal   (Followers: 2)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 10)
Computational Ecology and Software     Open Access   (Followers: 6)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 3)

        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  [1598 journals]
  • Neuroprotective Effect of Ginsenoside Rd on Spinal Cord Injury Rats
    • Authors: Lin Cong; Wenting Chen
      Abstract: In the present study, the neuroprotective effects of ginsenoside Rd (GS Rd) were evaluated in a rat model of spinal cord injury (SCI). Rats in SCI groups received a T8 laminectomy and a spinal contusion injury. GS Rd 12.5, 25 and 50 mg/kg were administered intraperitoneally one hour before the surgery and once daily for 14 days. Dexamethasone 1 mg/kg was administered as a positive control. Locomotor function was evaluated using the BBB score system. H&E and Nissl staining were performed to observe the histological changes of the spinal cord. Levels of MDA and GSH and activity of SOD were assessed to reflect the oxidative stress state. The production of TNF‐α, IL‐1β and IL‐1were assessed using ELISA kits to examine the inflammatory responses in the spinal cord. TUNEL staining was used to detect the cell apoptosis in the spinal cord. Western blot analysis was used to examine the expression of apoptotic‐associated proteins and MAPK proteins. The results demonstrated that GS Rd 25 and 50 mg/kg significantly improved the locomotor function of rats after SCI, reduced tissue injury and increased neuron survival in the spinal cord. Mechanically, GS Rd decreased MDA level, increased GSH level and SOD activity, reduced the production of pro‐inflammatory cytokines and prevented cell apoptosis. The effects were equivalent to that of dexamethasone. In addition, GS Rd effectively inhibited the activation of MAPK signalling pathway induced by SCI, which might be involved in the protective effects of GS Rd against SCI. In conclusion, GS Rd attenuates SCI‐induced secondary injury through reversing the redox state imbalance, inhibiting the inflammatory response and apoptosis in the spinal cord tissue. This article is protected by copyright. All rights reserved.
      PubDate: 2016-02-02T07:36:08.626541-05:
      DOI: 10.1111/bcpt.12562
  • Scaffold‐free Tissue Formation under Real and Simulated Microgravity
    • Authors: Ganna Aleshcheva; Johann Bauer, Ruth Hemmersbach, Lasse Slumstrup, Markus Wehland, Manfred Infanger, Daniela Grimm
      Abstract: Scaffold‐free tissue formation in microgravity is a new method in regenerative medicine and an important topic in Space Medicine. In this MiniReview, we focus on recent findings in the field of tissue engineering that were observed by exposing cells to real microgravity in Space or to devices simulating to at least some extent microgravity conditions on Earth (ground‐based facilities). Under both conditions – real as well as simulated microgravity – a part of the cultured cells of various populations detaches from the bottom of a culture flask. The cells form three‐dimensional (3D) aggregates resembling the organs from which the cells have been derived. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-30T09:06:04.480386-05:
      DOI: 10.1111/bcpt.12561
  • Vascular reactivity profile of novel KCa3.1‐selective
           positive‐gating modulators in the coronary vascular bed
    • Abstract: Opening of intermediate‐conductance calcium‐activated potassium channels (KCa3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KCa3.1 selective positive‐gating modulators, SKA‐111 and SKA‐121, to 1) evoke porcine endothelial cell KCa3.1 membrane hyperpolarization, 2) induce endothelium‐dependent and, particularly, endothelium‐derived hyperpolarization (EDH)‐type relaxation in porcine coronary arteries (PCA), and 3) influence coronary artery tone in isolated rat hearts. In whole‐cell patch‐clamp experiments on endothelial cells of PCA (PCAEC), KCa‐currents evoked by bradykinin (BK) were potentiated ≈7‐fold by either SKA‐111 or SKA‐121 (both at 1 μM), and were blocked by a KCa3.1 blocker, TRAM‐34. In membrane potential measurements, SKA‐111 and SKA‐121 augmented bradykinin‐induced hyperpolarization. Isometric tension measurements in large and small‐caliber PCA showed that SKA‐111 and SKA‐121 potentiated endothelium‐dependent relaxation with intact NO‐synthesis and EDH‐type relaxation to BK by ≈2‐fold. Potentiation of the BK response was prevented by KCa3.1 inhibition. In Langendorff‐perfused rat hearts, SKA‐111 potentiated coronary vasodilation elicited by BK. In conclusion, our data show that positive‐gating modulation of KCa3.1 channels improves BK‐induced membrane hyperpolarization and endothelium‐dependent relaxation in small and large PCA as well as in the coronary circulation of rats. Positive‐gating modulators of KCa3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-28T09:11:17.721818-05:
      DOI: 10.1111/bcpt.12560
  • Acute methanol poisoning: Prevalence and predisposing factors of
           haemorrhagic and non‐haemorrhagic brain lesions
    • Authors: Sergey Zakharov; Katerina Kotikova, Manuela Vaneckova, Zdenek Seidl, Olga Nurieva, Tomas Navratil, Blazena Caganova, Daniela Pelclova
      Abstract: The purpose was to study the prevalence and predisposing factors of brain lesions in survivors of acute methanol poisoning. Clinical data on 106 patients with methanol poisoning were collected during the Czech mass poisoning outbreak. Of 83 survivors, in 46 (55%) patients follow‐up examinations including magnetic resonance imaging of brain (MR) were performed 3–8 and 24–28 months after discharge from the hospital. Of 46 patients with a median age of 49 (interquartile range, IQR 35–57) years, 24 (52%) patients had a total of 40 abnormal brain findings with haemorrhagic lesions detected in 15 (33%) and non‐haemorrhagic lesions found in 9 (19%) patients. The patients with haemorrhagic brain lesions were more acidemic (lower arterial blood pH, higher base deficit) and had higher glycaemia and lactacidaemia on admission than those without haemorrhages (all p
      PubDate: 2016-01-25T06:30:40.823548-05:
      DOI: 10.1111/bcpt.12559
  • Utility of Pilot Studies for Predicting Ratios and Intra‐subject
           Variability in High Variability Drugs
    • Abstract: Pilot studies can be used to identify adequate test formulations for pivotal bioequivalence trials. The objective of this study was to evaluate the usefulness of pilot studies in predicting ratios and the intra‐subject coefficient of variation (CVw) for pivotal studies of high‐variability drugs. Seven cross‐over and replicate bioequivalence trials were selected. A hundred simulations of pilot studies were performed for different sample sizes and designs. The pharmacokinetic data of the selected formulations were analysed using WinNonLin based on an analysis of variance (ANOVA). The CVw was estimated using the formula recommended by the European Medicines Agency based on the mean square of the ANOVA. We calculated the predictivity index ± 10% and ± 20% of the real value. The predictivity index of ± 20% in the 2 x 2 design with 12 subjects was 100% for AUC0‐t ratio, 87% for Cmax ratio, 50% for the CVw of AUC0‐t and 52% for the CVw of Cmax. The results of the 4 x 4 design with 8 subjects were similar to those of the 2 x 2 design with 12 subjects. These results were worse for the predictivity index of ± 10% in both designs. Pilot studies do not seem useful for predicting sample size. However, they were very good for predicting the AUC0‐t ratio and good for predicting the Cmax ratio. The most adequate design for pilot studies seems to be the 2 x 2 design with at least 12 volunteers. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-25T06:30:28.605781-05:
      DOI: 10.1111/bcpt.12558
  • Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic
           Metabolizing Enzymes and Transporters in Rat Liver and Kidneys
    • Authors: Hesham M. Korashy; Mushtaq A. Ansari, Zaid H. Maayah, Faisal Imam, Mohd Raish, Ibraheem M. Attaf, Naif O. Alharbi, Badr Moraished
      Abstract: Sunitinib (SUN) is a multi‐targeted tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal and renal cancers. To date, very little is known about the effects of SUN on the expression of hepatic and renal xenobiotic metabolizing enzymes (XME) and transporters. The present study was designed to investigate the capacity of chronic SUN treatment to modulate the mRNA and protein expression levels of phase I cytochrome P450 (CYP), phase II and Phase III transporters in rat liver and kidneys. For this purpose, SUN (25, 50 and 100 mg/kg) was injected IP into Wistar albino rats for 30 days; thereafter, the mRNA and protein expression levels of several XME and transporters were determined by RT‐PCR and Western blot analysis, respectively. Real‐time PCR analysis showed that SUN significantly induced the hepatic and renal CYP1A1, 1A2, 1B1, 2E1 and 4F4, whereas inhibited CYP2C11 and 4A2. Furthermore, SUN specifically induced renal but not hepatic CYP2J3 and 3A2, while it induced only hepatic CYP4A1. With regard to Phase II, SUN induced hepatic GSTA1 and UGT1A and renal NQO1 and UGT1A mRNA levels, whereas it inhibited renal GST1A expression. On the other hand, both renal and hepatic P‐gp, MRP2, and BCRP transporters were significantly induced by SUN at the mRNA and protein expression levels. Importantly, these differential effects were associated with changes in oxidative stress genes and lipid peroxidation levels. In conclusion, SUN can serve as XME and transporters modulator, which potentially may counteract the efficacy of the treatment, adverse reactions and drug interactions in SUN treatment. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-21T09:37:38.800595-05:
      DOI: 10.1111/bcpt.12555
  • Cardiovascular Alterations during the Interictal Period in Awake and
           Pithed Amygdala‐Kindled Tats
    • Abstract: Epileptic seizures are often accompanied by increased sympathetic cardiovascular activity (even interictally), but it remains unknown whether this increased activity is of central and/or peripheral origin. Hence, this study investigated the cardiovascular alterations produced by amygdala kindling in awake and pithed Wistar rats. Blood pressure (BP) and heart rate (HR) were initially recorded by tail cuff plethysmography in awake control, sham‐operated and amygdala kindled rats before and 24 hr after the kindling process. The after‐discharge threshold (ADT) was measured under different conditions to correlate brain excitability with BP and HR in kindled rats. 24 hr after the last kindling seizure: (i) HR, systolic and diastolic BP were increased; and (ii) only higher HR values correlated with lower ADT values. 48 hr after the last kindled seizure, all rats were pithed and prepared for analysing the tachycardic, vasopressor and vasodepressor responses by: (i) stimulation of the sympathetic or sensory vasodepressor CGRPergic outflows (stimulus‐response curves; S–R curves); and (ii) intravenous injections of noradrenaline or α–CGRP (dose‐response curves; D‐R curves). Interestingly: (i) the tachycardic S‐R and D‐R curves were attenuated, whilst the CGRPergic S‐R and D‐R curves were potentiated in kindled rats; and (ii) the vasopressor noradrenergic S‐R and D‐R curves were not significantly different in all groups. Therefore, the kindling process may be associated with overstimulation in the central sympathetic and sensory outflows interictally, producing: (i) peripheral attenuation of cardiac sympathetic outflow and β‐adrenoceptor activity; and (ii) peripheral potentiation of vasodepressor sensory CGRPergic outflow and CGRP receptor activity. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-21T09:35:16.183192-05:
      DOI: 10.1111/bcpt.12556
  • N‐acetylcysteine in Acute Organophosphorus Pesticides Poisoning: A
           Randomized, Clinical Trial
    • Abstract: Organophosphorus poisoning is a major global health problem with hundreds of thousands of deaths each year. Research interest in N‐acetylcysteine has grown among increasing evidence of the role of oxidative stress in organophosphorus poisoning. We aimed to assess the safety and efficacy of N‐acetylcysteine as an adjuvant treatment in patients with acute organophosphorus poisoning. This was a randomized, controlled, parallel‐group trial on 30 patients suffering from acute organophosphorus poisoning, who were admitted to the Poison Control Center of Tanta University Emergency Hospital, Tanta, Egypt, between April and September, 2014. Interventions included oral N‐acetylcysteine (600 mg three times daily for three days) as an added treatment to the conventional measures versus only the conventional treatment. Outcome measures included mortality, total dose of atropine administered, duration of hospitalization and the need for ICU admission and/or mechanical ventilation. A total of 46 patients were screened and 30 were randomized. No significant difference was found between both groups regarding demographic characteristics and the nature or severity of baseline clinical manifestations. No major adverse effects to N‐acetylcysteine therapy were reported. Malondialdehyde significantly decreased and reduced glutathione significantly increased only in the NAC‐treated patients. The patients on NAC therapy required less atropine doses than those who received only the conventional treatment; however, the length of hospital stay showed no significant difference between both groups. The study concluded that the use of N‐acetylcysteine as an added treatment was apparently safe, and it reduced atropine requirements in patients with acute organophosphorus pesticide poisoning. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-20T06:25:41.365988-05:
      DOI: 10.1111/bcpt.12554
  • Modelling of the Effect of End‐Tidal Carbon Dioxide on Cerebral
           Oxygen Saturation in Beach Chair Position under General Anaesthesia
    • Abstract: Patients undergoing shoulder surgery in the beach chair position (BCP) under general anaesthesia may be at risk of cerebral desaturation. Increasing end‐tidal carbon dioxide (EtCO2) is the most convenient and powerful method for the management of cerebral desaturation. The purpose of this study was to investigate the quantitative relationship between EtCO2 and cerebral oxygen saturation (rSO2) and to identify the associated influencing factors. Fifty‐one patients undergoing arthroscopic shoulder surgery in the BCP under general anaesthesia completed this study. Desflurane and remifentanil were used, and EtCO2 was steadily increased and then decreased by adjusting the ventilator settings every 3 min. so that time lag of rSO2 response to EtCO2 changes could be delineated. Near‐infrared spectroscopy was used to monitor rSO2 response. An indirect response model was used to examine the relationship between EtCO2 and rSO2. To determine the relevant covariates, a stepwise approach was used. There was a linear relationship between rSO2 and EtCO2 with a slight delay in the peak of rSO2 relative to EtCO2. Increase in end‐tidal desflurane concentration led to a slower response of rSO2 to the changes of EtCO2 (P = 0.0002). The presence of diabetes mellitus reduced the reactivity of rSO2 to EtCO2 changes (P
      PubDate: 2016-01-20T03:26:10.750227-05:
      DOI: 10.1111/bcpt.12549
  • Ritonavir‐Induced Suicidal Death of Human Erythrocytes
    • Abstract: The antiviral drug ritonavir has been shown to trigger suicidal death or apoptosis of tumour cells and has thus been considered for the treatment of malignancy. In analogy to apopotosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored whether and how ritonavir induces eryptosis. To this end, flow cytometry was employed to estimate cell volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin‐V‐binding, [Ca2+]i from Fluo3‐fluorescence, abundance of reactive oxygen species (ROS) from 2’,7’‐dichlorodihydrofluorescein diacetate (DCFDA) fluorescence and ceramide abundance utilizing specific antibodies. As a result, a 48‐hr exposure of human erythrocytes to ritonavir significantly increased the percentage of annexin‐V‐binding cells (≥ 5 μg/ml), significantly decreased forward scatter (≥ 5 μg/ml), significantly increased Fluo3‐fluorescence (20 μg/ml), slightly, but significantly increased DCFDA fluorescence (20 μg/ml) and slightly, but significantly increased ceramide abundance (20 μg/ml). The effect of ritonavir on annexin‐V‐binding was significantly blunted but not fully abolished by removal of extracellular Ca2+. In conclusion, ritonavir triggers erythrocyte shrinkage and phosphatidylserine translocation at the erythrocyte cell membrane, an effect in part due to stimulation of Ca2+ entry, oxidative stress and ceramide. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-20T02:56:33.59138-05:0
      DOI: 10.1111/bcpt.12547
  • Changes in biliary levels of arginine and its methylated derivatives after
           hepatic ischaemia/reperfusion
    • Authors: Andrea Ferrigno; Laura Giuseppina Di Pasqua, Clarissa Berardo, Vittoria Rizzo, Plinio Richelmi, Mariapia Vairetti
      Abstract: Arginine (Arg) can be methylated to form symmetrical dimethylarginine (SDMA) and asymmetrical dimethylarginine (ADMA), the latter an endogenous inhibitor of nitric oxide synthase (NOS). SDMA is excreted in the urine, while ADMA is mainly subjected to degradation in the liver. Arg competes with ADMA and SDMA for cellular transport across cationic amino‐acid transporters (CATs). We evaluated the changes in serum, tissue and biliary levels of Arg, citrulline (Cit), ADMA and SDMA and the modifications in CATs after ischaemia‐reperfusion (I/R). Male Wistar rats were subjected to 30‐min. partial‐hepatic ischaemia or sham‐operated. After 60‐min. reperfusion, the concentrations of ADMA, SDMA, Arg and Cit in serum, tissue and bile were measured. Serum levels of AST, ALT and Alkaline Phosphatase (AP) levels were determined. mRNA of cationic transporter 2A (CAT‐2A) and 2B (CAT‐2B) were also quantified. An increase in ADMA and a decrease in SDMA were observed in bile at the end of reperfusion. On the contrary, lower tissue ADMA levels and higher SDMA levels were quantified. No serum changes in ADMA and SDMA were found. A decrease in Arg and an increase of Cit were detected in serum, bile and tissue after I/R. A marked increase in AST, ALT and AP levels in serum confirmed I/R injury. A decrease in mRNA transporter CAT‐2A but not in CAT‐2B was detected. This study supported a biliary CAT‐2B–dependent transport of ADMA and demonstrated, for the first time, that the liver is also responsible for the biliary excretion of SDMA into the bile. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-20T02:51:28.394595-05:
      DOI: 10.1111/bcpt.12540
  • Reduced Mechanical Stretch Induces Enhanced Endothelin B
           Receptor‐mediated Contractility via Activation of Focal Adhesion
           Kinase and Extra Cellular‐regulated Kinase 1/2 in Cerebral Arteries
           from Rat
    • Authors: Marianne N. P. Rasmussen; Stine Spray, Gry F. Skovsted, Karin Warfvinge, Majid Sheykhzade, Lars Edvinsson
      Abstract: Cerebral ischaemia results in enhanced endothelin B (ETB) receptor‐mediated contraction and receptor protein expression in the affected cerebrovascular smooth muscle cells (SMC). Organ culture of cerebral arteries is a method to induce similar alterations in ETB receptor expression. We hypothesize that rapid and sustained reduction in wall tension/stretch is a possible trigger mechanism for this vascular remodelling. Isolated rat middle cerebral artery (MCA) segments were incubated in a wire‐myograph with or without mechanical stretch, prior to assessment of their contractile response to the selective ETB receptor agonist sarafotoxin 6c. The involvement of extracellular regulated kinase (ERK) 1/2 and focal adhesion kinase (FAK) were studied by their specific inhibitors U0126 and PF‐228, respectively. Compared to their stretched counterparts, un‐stretched MCA segments showed a significantly increased ETB receptor‐mediated contractile response following 12 hr of incubation, which was attenuated by either U0126 or PF‐228. The functionally increased ETB‐mediated contractility could be attributed to two different mechanisms: 1) a difference in ETB receptor localization from primarily endothelial expression to SMC expression and 2) an increased calcium sensitivity of the SMCs due to an increased expression of the calcium channel transient receptor potential canonical 1. Collectively, our results present a possible mechanism linking lack of vessel wall stretch/tension to changes in ETB receptor‐mediated contractility via triggering of an early mechanosensitive signalling pathway involving ERK1/2 and FAK signalling. A mechanism likely to be an initiating factor for the increased ETB receptor‐mediated contractility found after cerebral ischaemia. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-19T01:34:30.983787-05:
      DOI: 10.1111/bcpt.12553
  • Efficacy and Safety of FospropofolFD Compared to Propofol When Given
           During the Induction of General Anaesthesia: A Phase II, Multicenter,
           Randomized, Parallel‐Group, Active‐Controlled,
           Double‐Blind, Double‐Dummy Study
    • Authors: Rong Liu; Chaozhi Luo, Jin Liu, Wensheng Zhang, Yan Li, Jing Xu
      Abstract: The present phase II study aimed to compare the efficacy and safety of fospropofol disodium for injection (FospropofolFD) and propofol when given during the induction of general anaesthesia in patients scheduled for elective surgery. FospropofolFD is a water‐soluble prodrug of propofol. Approved by the Ethical Committee, 240 participants aged 18–65 years were equally randomly allocated to receive an intravenous bolus of FospropofolFD 20 mg/kg or propofol 2 mg/kg without any anaesthetic pre‐treatment. The primary efficacy end‐point was the sedation success rate within 5 min. after administering investigational drugs (the sedation success is defined as obtaining Modified Observer's Assessment of Alertness/Sedation scale score of 1). All the participants completed the induction and intubation within 25 min. after administration. The sedation success rates within 5 min. after administration of FospropofolFD 20 mg/kg and propofol 2 mg/kg were 94.50% versus 100% in the intention‐to‐treat population and 95.10% versus 100% in the per‐protocol population, respectively. The non‐inferiority test obtained a P value less than 0.025, and the lower limits of the one‐sided 97.5% confidence interval were more than –0.09. This meant that FospropofolFD 20 mg/kg was considered non‐inferior to propofol 2 mg/kg for the primary efficacy end‐point. Compared with propofol 2 mg/kg, FospropofolFD 20 mg/kg had a slower sedation efficacy. No serious adverse events were observed in the two groups. The sedation success rate within 5 min. after administration of FospropofolFD 20 mg/kg was non‐inferior to propofol 2 mg/kg, and FospropofolFD 20 mg/kg can be used for the induction of general anaesthesia safely. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-19T01:29:22.572482-05:
      DOI: 10.1111/bcpt.12552
  • Impact of Olmesartan Medoxomil on Amiodarone‐ Induced Pulmonary
           Toxicity in Rats: Focus on Transforming Growth
    • Abstract: Amiodarone (AD) is one of the most frequently prescribed antiarrhythmic agents worldwide but its effectiveness is limited due to the development of pulmonary toxicity. Several lines of evidence have suggested that AT1 receptor antagonists can attenuate pulmonary fibrosis in different animal models. This study was performed to evaluate the effect of olmesartan medoxomil (OM) on lung injury induced in rats by AD which was assessed biochemically (hydroxyproline content, MDA level and SOD activity), histologically (Ashcroft criteria and Masson's trichrome stain) and immunohistochemically (TGF‐β1 expression in lung tissue). The expression levels of TGF‐β1 and type I collagen mRNA were also determined by quantitative real‐time polymerase chain reaction. Forty‐eight adult male rats were randomized into six equal groups; control group, OM control groups, AD group received 40 mg/kg/day, p.o. for four weeks to induce pulmonary injury in rats and OM‐treated groups received 0.6 and 6 mg/kg/day, p.o. concomitantly with AD for the same period. The results indicated that OM significantly decreased collagen deposition and hydroxyproline content, ameliorated pathological score and decreased the elevation in type I collagen and TGF‐ß1 mRNA expression in lung tissue. Furthermore, it attenuated the AD‐induced increase in the MDA level and increased SOD activity in lung tissue. It can be concluded that OM exerts a protective effect against AD‐induced lung damage in rats which is attributed to modulation of profibrogenic cytokine (TGF‐β1) and antioxidant effect. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-18T21:22:58.791657-05:
      DOI: 10.1111/bcpt.12551
  • Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic
           Inflammatory Pain in Mice
    • Abstract: Chemokines are chemotactic cytokines whose involvement in nociceptive processing is being increasingly recognised. Based on the previous description of the involvement of CC chemokine receptor type 1 (CCR1) in pathological pain, we have assessed the participation of CCR1 and its endogenous ligands CCL3 and CCL5 in hyperalgesia and allodynia in mice following acute inflammation with carrageenan and chronic inflammation with complete Freund's adjuvant (CFA). The subcutaneous administration of the CCR1 antagonist J113863 (3‐30 mg/kg; 30 min. before) dose‐dependently inhibited carrageenan‐ and CFA‐evoked thermal hyperalgesia and mechanical allodynia produced by CFA but not by carrageenan. The maximal dose of J113863 did not modify the increase in paw thickness induced by carrageenan or CFA. An almost ten‐fold augmentation of CCL3 levels was detected by ELISA assays in following both carrageenan and CFA paws but not in spinal cords of inflamed mice, whereas CCL5 concentrations remained unaltered. Accordingly, a marked increase of CCL3 mRNA expression was observed in inflamed paws, with CCL3 protein detected in neutrophils and macrophages by immunohistochemical experiments. The intraplantar administration of an anti‐CCL3 antibody (0.3‐3 μg) blocked thermal hyperalgesia in carrageenan‐ and CFA‐inflamed mice as well as CFA‐evoked mechanical allodynia. Our data suggest that the increased concentrations of CCL3 present in inflamed tissues can be involved in acute and chronic inflammatory hyperalgesia as well as in chronic mechanical allodynia, and that these hypernociceptive symptoms can be counteracted by its neutralization with an antibody or by the blockade of CCR1 receptors. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:40:37.416653-05:
      DOI: 10.1111/bcpt.12543
  • Antidepressant or Antipsychotic Overdose in the Intensive Care Unit
           ‐ Identification of Patients at Risk
    • Abstract: It is often advised that patients who have ingested an overdose of antidepressants (AD) or antipsychotics (AP) are monitored with continuous ECG for minimum of 12‐24 hr. These patients are often observed in an ICU. Our aim was to identify the number of patients with AD and/or AP overdose without adverse signs at hospital admission that turned out to need intensive care treatment. The effect of the antidepressants overdose risk assessment (ADORA) system was evaluated in patients with antidepressant as well as antipsychotic overdose. Our hypothesis was that patients with low ADORA do not need intensive care treatment. This retrospective study was conducted in adult patients admitted to the ICU at Odense University Hospital after an overdose with AP and/or AD between 1 January 2009 and 1 September 2014. Patients with predefined adverse signs in the emergency department were excluded due to obvious need of intensive care. Of the 157 patients included, 12 patients (8%) developed events during the ICU stay. Only 3 patients received intubation, vasoactive drugs and/or dialysis. None developed ventricular dysrhythmias. There were no fatalities. All the patients with low‐risk assessment by ADORA within the first 6 hr did not develop events within the first 24 hr after hospital admission. The vast majority of patients with AD and/or AP overdose and no adverse signs at admission did not require intensive care treatment. Low ADORA risk assessment identified patients with antidepressant as well as antipsychotic overdose who would not require initial intensive care treatment. This is the first time the ADORA system has been evaluated in patients with antidepressant as well as antipsychotic overdose. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:26:57.747019-05:
      DOI: 10.1111/bcpt.12541
  • Role of Aspirin and Dexamethasone against Experimentally Induced
           Depression in Rats
    • Authors: Shailendra Bhatt; Priyanka Shukla, Jibril Raval, Sunita Goswami
      Abstract: A large number of current studies indicate that inflammatory mediators may contribute to depression in experimental models as well as in human beings. Nevertheless, the subject, whether anti‐inflammatory treatments can prevent depression still remains controversial. In the present study, a chronic mild stress (CMS) model of male Sprague–Dawley rats was used to investigate the role of anti‐inflammatory drugs in the treatment of depression. All the animals in different groups, except the normal control group, were exposed to CMS procedure for 28 days and concurrently treated with aspirin (10 mg/kg, p.o.) dexamethasone (1mg/kg p.o.) and amitriptyline (10 mg/kg p.o., reference standard), respectively. Amitriptyline was also used in combination with aspirin and dexamethasone to inspect any synergistic effects. Tests performed towards the end of the study included Sucrose preference test, behavioural tests like forced swim test, elevated plus maze, light dark box, locomotor activity, and biochemical estimations like serum cortisol and brain neurotransmitters. Disease control group (CMS‐treated) produced significant depressive behaviour in rats. The animals treated with aspirin showed increased sucrose preference, decreased immobility time in forced swim test, decreased serum cortisol and increased brain serotonin levels signifying antidepressant action. In contrast, there was aggravation of depressive behaviour in rats treated with dexamethasone. Together, these findings suggest that aspirin can serve as a potential antidepressant both individually and as adjunctive agent in the treatment of depression. Inhibition of the inflammatory mediators during stress procedures or any other potential physiological and biochemical mechanisms may be involved in its antidepressant effect. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:16:26.965025-05:
      DOI: 10.1111/bcpt.12539
  • Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats
    • Authors: Mohamed A. Morsy; Gehan H. Heeba
      Abstract: Treatment with cisplatin is associated with dose‐limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β1‐adrenoceptor antagonist, exhibits vasodilatory and anti‐oxidative properties. The present study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as evidenced by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor‐alpha, caspase‐3, angiotensin II, and endothelin‐1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre‐treatment with Nω‐nitro‐L‐arginine methyl ester, the non‐specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin‐induced nephrotoxicity that is most likely through its antioxidant, anti‐inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin‐1 levels. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T23:02:10.143578-05:
      DOI: 10.1111/bcpt.12538
  • Effect of Statin Treatment on Plasma 4β‐Hydroxycholesterol
    • Abstract: The endogenous oxysterol 4β‐hydroxycholesterol may be used as a marker for the drug‐metabolizing enzymes cytochrome P450 3A (CYP3A). The primary aim of this study was to investigate the effect of statin treatment on plasma 4β‐hydroxycholesterol concentrations. Plasma samples from a previously performed clinical study where gallstone patients had been treated with placebo (n=6), 20 mg fluvastatin (n=9) or 80 mg atorvastatin (n=9) daily for 4 weeks were analysed. Hepatic CYP3A mRNA levels had previously been shown to be unchanged in all three treatment groups. Plasma 4β‐hydroxycholesterol did not change significantly (p=0.92) in the placebo group, but treatment with low‐dose fluvastatin or high‐dose atorvastatin resulted in reductions in plasma concentration of 10.7% (p
      PubDate: 2016-01-14T22:49:43.49538-05:0
      DOI: 10.1111/bcpt.12537
  • Effect of omeprazole and dextromethorphan on the urinary metabolic ratio
           of flurbiprofen
    • Abstract: Interindividual differences in drug response ‐ especially due to drug metabolism ‐ are among the most important reasons for severe adverse drug reactions (ADR) in patients. About 80% of drugs causing clinically relevant ADR are metabolized by polymorphic enzymes [1]. The most important human enzymes for oxidative drug metabolism belong to the cytochrome P450 (CYP) monooxygenase superfamily. Several CYP possess high levels of genetic polymorphism and can be induced or inhibited, thereby causing pronounced differences in interindividual enzyme activity and drug response. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:43:09.279088-05:
      DOI: 10.1111/bcpt.12536
  • Modelling of the Sedative Effects of Propofol in Patients undergoing
           Spinal Anaesthesia: A Pharmacodynamic Analysis
    • Authors: Go Un Roh; Youngsoon Kim, Sang Hee Ha, Kyu Hee Jeong, Sumin Choi, Dong Woo Han
      Abstract: Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect‐site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect‐site target‐controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3‐4] and deep sedation (OAA/S scores of 1‐2) were developed using Nonlinear Mixed Effects Modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce50 values for adequate and deep sedation were 0.94 and 1.52 μg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (P=0.0003). The simulated Ce50 values for adequate sedation in 20‐year‐old patients with a T12 sensory level and in 80‐year‐old patients with a T4 level were 1.63 and 0.53 μg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:30:48.794887-05:
      DOI: 10.1111/bcpt.12535
  • MicroRNAs in Bladder Outlet Obstruction: Relationship to Growth and Matrix
    • Abstract: The discovery of microRNAs (miRNAs), which are ~22 nucleotide RNAs that inhibit protein synthesis in a sequence‐specific manner and are present in a range of species, has born hope of new therapeutic strategies. miRNAs play important roles in development “Development” of what''and disease, but they remain poorly studied in uropathologies beyond cancer. Here, we discuss biological functions of miRNAs in the lower urogenital tract. A special focus is on miRNAs that change in bladder outlet obstruction (BOO). This is a condition that affects nearly one third of all men over 60 years and that involves growth and fibrosis of the urinary bladder. Animal models of BOO, such as that in rat, have been developed and they feature a massive 6‐fold bladder growth over 6 weeks. Using microarrays, we have charted the miRNAs that change during the time‐course of this process and identified several with important modulatory roles. We discuss known and predicted functions of miR‐1, miR‐29, miR‐30, miR‐132/212, miR‐204 and miR‐221, all of which change in BOO. The majority of the miRNA‐mediated influences in BOO are expected to favour growth. We also outline evidence that miR‐29 represents a key effector molecule in a generic response to mechanical distension that is designed to counteract exaggerated organ deformation via effects on matrix deposition and stiffness. We conclude that miRNAs play important roles in bladder remodelling and growth and that they may be targeted pharmacologically to combat diseases of the lower urinary tract. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:12:24.671191-05:
      DOI: 10.1111/bcpt.12534
  • Sulfated Polysaccharide Isolated from the Seaweed Gracilaria caudata
           Exerts an Antidiarrhoeal Effect in Rodents
    • Abstract: Diarrhoea is a significant health problem for children in developing countries that causes more than 1 million deaths annually. The present study aimed to evaluate the antidiarrhoeal effect of sulfated polysaccharide (PLS) from the alga Gracilaria caudata in rodents. For the evaluation, acute diarrhoea was induced in Wistar rats (150–200 g) by administration of castor oil (10 mg/kg). Then, different parameters, including enteropooling and gastrointestinal transit and its pharmacological modulation by opioid and cholinergic pathways were assessed using activated charcoal in Swiss Mice (25–30 g). Secretory diarrhoea was examined using cholera toxin (1 mg/loop)‐treated, isolated intestinal loops from Swiss mice (25–30 g), which were also used to examine fluid secretion, loss of chloride ions into the intestinal lumen, and absorption. In addition, a GM1‐dependent ELISA was used to evaluate the interaction between PLS, cholera toxin and the GM1 receptor. Pre‐treatment with PLS (10, 30, and 90 mg/kg) reduced foecal mass, diarrhoeal faeces and enteropooling. However, 90 mg/kg more effectively reduced these symptoms; therefore, it was used as the standard dose in subsequent experiments. Gastrointestinal transit was also reduced by PLS treatment via a cholinergic mechanism. Regarding the diarrhoea caused by cholera toxin, PLS reduced all study parameters, and the ELISA showed that PLS can interact with both the GM1 receptor and cholera toxin. These results show that PLS from G. caudata effectively improved the parameters observed in acute and secretory diarrhoea, which affects millions of people, and may lead to the development of a new alternative therapy for this disease. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T22:10:04.477163-05:
      DOI: 10.1111/bcpt.12531
  • Structural Studies of Nicotinic Acetylcholine Receptors: Using
           Acetylcholine Binding Protein as a Structural Surrogate
    • Authors: Azadeh Shahsavar; Michael Gajhede, Jette S. Kastrup, Thomas Balle
      Abstract: Nicotinic acetylcholine receptors (nAChRs) are members of the pentameric ligand‐gated ion channel superfamily that play important roles in control of neurotransmitter release in the central and peripheral nervous system. These receptors are important therapeutic targets for development of drugs against a number of mental health disorders and for marketed smoking cessation aids. Unfortunately, drug discovery has been hampered by difficulties in obtaining sufficiently selective compounds. Together with functional complexity of the receptors, this has made it difficult to obtain drugs with sufficiently high‐target to off‐target affinity ratios. The recent and on‐going progress in structural studies holds promise to help understand structure‐function relationships of nAChR drugs at the atomic level. This will undoubtedly lead to design of more efficient drugs with fewer side effects. As a high‐resolution structure of a nAChR is yet to be determined, structural studies are to a large extent based on acetylcholine binding proteins (AChBPs) that despite low overall sequence identity display high degree of conservation of overall structure and amino acids at the ligand‐binding site. Further, AChBPs reproduce relative binding affinities of ligands at nAChRs. Over the past decade, AChBPs have been used extensively as models for nAChRs and have aided the understanding of drug receptor interactions at nAChRs significantly. This article is protected by copyright. All rights reserved.
      PubDate: 2016-01-14T05:49:29.058086-05:
      DOI: 10.1111/bcpt.12528
  • Issue Information
    • First page: 97
      PubDate: 2016-01-14T23:45:58.817-05:00
      DOI: 10.1111/bcpt.12460
  • Omeprazole and Semen Quality
    • Authors: Saleem A. Banihani
      Abstract: A number of studies have linked omeprazole, a commonly used acid reducer under the brand name Prilosec, with semen quality. This MiniReview systematically addresses and summarizes the effect of omeprazole on semen quality, and male infertility. We searched the MEDLINE electronic database for English‐language articles by using the key words ‘omeprazole’ versus ‘sperm’ and “testosterone” and the references from selected articles were reviewed, if relevant. In summary, omeprazole does not appear to change semen quality. This may be because, at least in part, it does not alter the basal levels of pituitary‐gonadal hormones; in addition, it counteracts the damaging effect of reactive oxygen species. However, further research is still required to confirm this effect. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T04:36:15.468743-05:
      DOI: 10.1111/bcpt.12529
  • Variability of Voriconazole Trough Levels in Haematological Patients:
           Influence of Co‐Medications with CYP Inhibitors and/or with CYP
           Inhibitors plus CYP Inducers
    • Authors: Piergiorgio Cojutti; Anna Candoni, Fabio Forghieri, Miriam Isola, Maria Elena Zannier, Sara Bigliardi, Mario Luppi, Renato Fanin, Federico Pea
      Abstract: Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of co‐medications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough levels (Cmin). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed‐effect regression analyses were performed to identify independent predictors of normalized Cmin. Among the 83 included patients, 35 had co‐medication with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin (n=199) was 2.4 mg/L with a wide range of distribution (< 0.2‐13.5 mg/L). Median (IQR) normalized voriconazole Cmin was significantly higher in presence of CYP inhibitors (4.20 mg/L, 3.23–5.51 mg/L) than either in absence of interacting co‐treatments (2.55 mg/L, 1.54–3.47 mg/L) or in presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19–3.09 mg/L). Presence of CYP inhibitors resulted highly significantly associated with Cmin > 5.5 mg/L (OR: 23.22, 95% CI: 3.01–179.09, P=0.003). No significant association emerged when CYP inhibitors were co‐administered with CYP inducers (OR: 3.53, 95% CI: 0.36–34.95, P=0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are co‐treated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T04:29:15.011925-05:
      DOI: 10.1111/bcpt.12530
  • Acetaminophen for Chronic Pain: A Systematic Review on Efficacy
    • Abstract: Acetaminophen (paracetamol) is the most commonly used analgesic worldwide and recommended as first‐line treatment in all pain conditions by WHO. We performed a systematic literature review to evaluate the efficacy of acetaminophen when used for chronic pain conditions. Applying three broad search strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1,551 hits were obtained. Following cross‐reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than two weeks with placebo were included. The review was conducted according to PRISMA guidelines. All studies were conducted in patients with hip‐ or knee osteoarthritis and six out of seven studies had observation periods of less than three months. All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little evidence to support the efficacy of acetaminophen treatment in patients with chronic pain conditions. Assessment of continuous efficacy in the many patients using acetaminophen worldwide is recommended. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:57:40.490251-05:
      DOI: 10.1111/bcpt.12527
  • Cardiovascular Drugs and Metformin Drug Dosage According to Renal Function
           in Non‐Institutionalized Elderly Patients
    • Abstract: Background Adaptation of drug dosage to kidney function is a common problem in general practice. Aim To describe adaptation of cardiovascular drugs and metformin according to renal function and its association with mortality with regard to metformin in a cohort of elderly patients. Design and Setting Ancillary study to the S.AGES cohort made up of patients over 65 years old managed by their general practitioner under real‐life conditions and followed up prospectively for 3 years. Methods The medications studied were digoxin, spironolactone and metformin. Adaptation of their daily dose according to renal function (eGFR according to CKD/EPI) was compared to that recommended in the summaries of product characteristics (SPCs) or international scientific societies (ISS). Results 900 patients were included, including 588 on metformin. At baseline, dose adjustment according to renal function was 100% and 87.6% (95%CI:82.6‐92.6) for patients on digoxin and spironolactone, respectively. For metformin, only 71.3% (95%CI:67.6‐74.9) or 78.1% (95%CI:74.7‐81.4) of patients had their dosage adapted at inclusion according to their renal function depending on whether the SPCs or ISS recommendations were considered. During the 3 year follow‐up period, 42/588 patients died (none from lactic acidosis). At inclusion, a metformin dosage not adapted for renal function according to ISS was not associated with an increase in all cause mortality (OR 1.7; 95%CI 0.6‐5.0, p=0.32). Conclusion Approximately one quarter of elderly patients treated with metformin do not have their dosage adapted for renal function according to ISS although there is no increase in mortality after follow‐up for 3 years. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:46:44.809687-05:
      DOI: 10.1111/bcpt.12526
  • Glucagon‐like Peptide‐1 Formulation – the Present and
           Future Development in Diabetes Treatment
    • Authors: Chooi Yeng Lee
      Abstract: Type 2 diabetes mellitus is a chronic metabolic disorder that has become the fourth leading cause of death in the developed countries. The disorder is characterised by pancreatic β‐cells dysfunction, which causes hyperglycaemia leading to several other complications. Treatment by far, which focuses on insulin administration and glycaemic control, has not been satisfactory. Glucagon‐like peptide‐1 (GLP1) is an endogenous peptide that stimulates post‐prandial insulin secretion. Despite being able to mimic the effect of insulin, GLP1 has not been the target drug in diabetes treatment due to the peptide's metabolic instability. Following a decade‐long effort to improve the pharmacokinetics of GLP1, a number of GLP1 analogues are currently available on the market. The current MiniReview does not discuss these drugs but presents strategies that were undertaken to address the weaknesses of the native GLP1, particularly drug delivery techniques used in developing GLP1 nanoparticles and modified GLP1 molecule. The article highlights how each of the selected preparations have improved the efficacy of GLP1, and more importantly, through an overview of these studies, it will provide an insight into strategies that may be adopted in the future in the development of a more effective oral GLP1 formulation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:27:40.242695-05:
      DOI: 10.1111/bcpt.12524
  • Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse
           Intrauterine Environment and Modulated by a Post‐Weaning
           High‐Fat Diet
    • Authors: Barent N. DuBois; Jacob Pearson, Tahir Mahmood, Kent Thornburg, Ganesh Cherala
      Abstract: Adult individuals born with intrauterine growth restriction (IUGR) have physiological maladaptations that significantly increase risk of chronic disease. We hypothesized that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low protein diet (9% protein) to produce IUGR offspring. Offspring were weaned onto either laboratory chow (11% fat) or high‐fat diet (45% fat). Adult offspring (5 months old) were dosed with furosemide (10 mg/kg i.p.) and serum and urine collected. The overall exposure profile in IUGR males was significantly reduced due to a ~35% increase in both clearance and volume of distribution. Females appeared resistant to the IUGR phenotype. The effects of the high‐fat diet trended in the opposite direction to that of IUGR, with increased drug exposure due to decreases in both clearance (31% males, 46% females) and volume of distribution (24% males, 44% females), with a 10% longer half‐life in both genders. The alterations in furosemide pharmacokinetics and pharmacodynamics were explained by changes in the expression of renal organic anion transporters‐1 and ‐3, and sodium‐potassium‐chloride cotransporter‐2. In summary, this study suggests that IUGR and diet interact to produce sub‐populations with similar body weights but dissimilar pharmacokinetic profiles; this underlines the limitation of one‐size‐fits‐all dosing which does not account for physiological differences in body composition resulting from IUGR and diet. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:25:09.926587-05:
      DOI: 10.1111/bcpt.12523
  • Effect of the combination of ezetimibe and simvastatin on gluconeogenesis
           and oxygen consumption in the rat liver
    • Abstract: The aim of this work was to investigate the effects of chronic treatment with the combination ezetimibe/simvastatin on gluconeogenesis in rat liver. Rats were treated daily with the combination ezetimibe/simvastatin (10/40 mg/Kg) by oral gavage. To measure gluconeogenesis and the associated pathways, isolated perfused rat liver was used. In addition, subcellular fractions, such as microsomes and mitochondria, were used for complementary measures of enzymatic activities. Treatment with the combination simvastatin/ezetimibe resulted in a decrease of gluconeogenesis from pyruvate (‐62%). Basal oxygen consumption of the treated animals was higher (+22%) than the control rats, but the resulting oxygen consumption that occurred after pyruvate infusion was 43% lower in animals treated with the combination simvastatin/ezetimibe. Oxygen consumption in the livers from treated animals was completely inhibited by cyanide (electron transport chain inhibitor), but not by proadifen (cytochrome P450 inhibitor). Chronic treatment with ezetimibe/simvastatin decreased the activity of the key enzymes glucose‐6‐phosphatase and fructose‐1,6‐bisphosphatase by 59% and 45%, respectively, which is probably the major reason for the decreased gluconeogenesis seen in ezetimibe/simvastatin‐treated rats. It is also possible that part of the effect of this combination on gluconeogenesis and on the oxygen consumption is related to the impairment of mitochondrial energy transduction. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T03:10:11.399441-05:
      DOI: 10.1111/bcpt.12522
  • Evidence of Different Propofol Pharmacokinetics under Short and Prolonged
           Infusion Times in Rabbits
    • Abstract: Propofol is an anaesthetic widely used both in human beings and animals. However, the characterization of propofol pharmacokinetics (PK) is not well understood when long‐term infusions are used. The main objective of this study was to explore the pharmacokinetic behaviour of propofol in a rabbit model during short and prolonged propofol infusions and to develop an internally validated PK model, for propofol dose individualization in the rabbit for future use. Population 1 (P1) was constituted by seven New Zealand rabbits and was used to characterize the pharmacokinetic profile of propofol at short infusions. Animals were anaesthetized with a bolus of 20−1, followed by an infusion rate of 50−1.h−1 of propofol at 1%, which was then maintained for 30 min. A second rabbit population (P2, n=7) was sedated according to reflexes responses and Index of Consciousness values, for 20 consecutive hours using propofol 2% aiming at characterizing propofol behaviour at long‐term infusions. Clinical data and blood samples were collected at specific time‐points in both populations. Propofol plasma concentrations were determined by GC/IT‐MS1. The NONMEM VII software was used to evaluate the relationships between dose and plasma concentrations. A linear two‐compartment model with different central compartment volume and plasma clearance (separately modelled in the two populations) was the one that best described propofol concentrations. The time course of propofol plasma concentrations was well characterized by the PK model developed, which simultaneously accounts for propofol short‐ and long‐term infusions and can be used to optimize future PK studies in rabbits. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T02:02:39.298437-05:
      DOI: 10.1111/bcpt.12521
  • The role of CYP2C8 and CYP2C9 Genotypes in Losartan‐Dependent
           Inhibition of Paclitaxel Metabolism in Human Liver Microsomes
    • Authors: Yuji Mukai; Asuna Senda, Takaki Toda, Erik Eliasson, Anders Rane, Nobuo Inotsume
      Abstract: The aim of the present study was to further investigate a previously identified metabolic interaction between losartan and paclitaxel, which is one of the marker substrates of CYP2C8, by using human liver microsomes (HLMs) from donors with different CYP2C8 and CYP2C9 genotypes. Although CYP2C8 and CYP2C9 exhibit genetic linkage, previous studies have yet to determine if losartan or its active metabolite, EXP‐3174, which is specifically generated by CYP2C9, is responsible for CYP2C8 inhibition. Concentrations of 6α‐hydroxypaclitaxel and EXP‐3174 were measured by HPLC after incubations with paclitaxel, losartan or EXP‐3174 in HLMs from seven donors with different CYP2C8 and CYP2C9 genotypes. The half maximal inhibitory concentration (IC50) values were not fully dependent on CYP2C8 genotypes. Although the degree of inhibition was small, losartan significantly inhibited production of 6α‐hydroxypaclitaxel at a concentration of 1 μmol/L in only HL20 with the CYP2C8*3/*3 genotype. HLMs with either CYP2C9*2/*2 or CYP2C9*1/*3 exhibited a lower losartan intrinsic clearance (Vmax/Km) than other HLMs including those with CYP2C9*1/*1 and CYP2C9*1/*2. Significant inhibition of 6α‐hydroxypaclitaxel formation by EXP‐3174 could only be found at levels that were 50‐fold higher (100 μmol/L) than the maximum concentration generated in the inhibition study using losartan. These results suggest that the metabolic interaction between losartan and paclitaxel is dependent on losartan itself rather than its metabolite, and that the CYP2C8 inhibition by losartan is not affected by the CYP2C9 genotype. Further study is needed to define the effect of CYP2C8 genotypes on losartan‐paclitaxel interaction. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-28T01:15:36.392136-05:
      DOI: 10.1111/bcpt.12520
  • Sydnone 1: A Mesoionic Compound with Anti‐tumoural and Hematological
           Effects In Vivo
    • Abstract: The present study evaluated the anti‐tumour activity of the mesoionic compound sydnone 1 (Syd‐1) against Walker‐256 carcinosarcoma. Tumour cells were subcutaneously inoculated in the hind limb in male Wistar rats. The animals were orally treated for 12 days with Syd‐1 (75 mg•kg−1) or vehicle. At the end of treatment, considerable decreases in tumour volume and tumour weight were observed in treated animals. Samples of these tumours presented increases in apoptotic bodies and pro‐apoptotic protein expression (Bax and p53), while the expression of the anti‐apoptotic protein Bcl‐2 was reduced. A decrease in reduced glutathione levels and an increase in glutathione peroxidase activity were observed in tumour after Syd‐1 treatment. However, significant splenomegaly was evident in animals that received Syd‐1, most likely attributable to the induction of hemolysis. The present study demonstrated the anti‐tumour activity of Syd‐1 against Walker‐256 carcinosarcoma. Its mechanism of action is linked to the activation of apoptotic pathways that lead to tumour cell death. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-26T08:31:45.161482-05:
      DOI: 10.1111/bcpt.12545
  • Mechanisms Involved in Thromboxane A2‐induced Vasoconstriction of
           Rat Intracavernous Small Penile Arteries
    • Abstract: Diabetes is associated with erectile dysfunction and with hypercontractility in erectile tissue and this is in part ascribed to increased formation of thromboxane. Rho kinase (ROCK) is a key regulator of calcium sensitization and contraction in vascular smooth muscle. This study investigated the role of calcium and ROCK in contraction evoked by activation of the thromboxane receptors. Rat intracavernous penile arteries were mounted for isometric tension and intracellular calcium ([Ca2+]i) recording and corpus cavernosum for measurements of MYPT1 phosphorylation. In penile arteries, U46619 by activation of thromboxane receptors concentration‐dependently increased calcium and contraction. U46619‐induced calcium influx was blocked by nifedipine, a blocker of L‐type calcium channels, and by 2‐aminoethoxydiphenyl borate, a blocker of transient receptor potential (TRP) channels. Inhibitors of ROCK, Y27632 and glycyl‐H1152P, concentration‐dependently reduced U46619‐induced contraction, but only Y27632 reduced [Ca2+]i‐levels in the penile arteries activated with either high extracellular potassium or U46619. MYPT‐Thr850 phosphorylation in corpus cavernous strips was increased in response to U46619 through activation of TP receptors and was found to be a direct result of phosphorylation by ROCK. Y27632 induced less relaxation in mesenteric arteries, H1152P induced equipotent relaxations, and a protein kinase C inhibitor, Ro‐318220, failed to relax intracavernous penile arteries, but induced full relaxation in rat mesenteric arteries. Our findings suggest that U46619 contraction depends on Ca2+ influx through L‐type and TRP channels, and ROCK‐dependent mechanisms in penile arteries. Inhibition of the ROCK pathway is a potential approach for the treatment of erectile dysfunction associated with hypertension and diabetes. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-26T08:31:32.570507-05:
      DOI: 10.1111/bcpt.12544
  • Systematic Review and Meta‐Analysis: Macrolides and
           Amoxicillin/Clavulanate‐induced Acute Liver Injury
    • Abstract: Antibacterials are frequently associated with idiosyncratic drug‐induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta‐analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials. gov, Livertox and Toxline (1980‐2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non‐user comparator. We summarised the evidence with a random‐effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case‐control, one cohort and one case‐population studies) and 9 (case‐population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 (95% Confidence Interval [CI] 1.81‐4.47), p
      PubDate: 2015-12-26T08:31:20.834261-05:
      DOI: 10.1111/bcpt.12550
  • Varenicline and Nicotine Patch Therapies in Young Adults Motivated to Quit
           Smoking: A Randomised, Placebo‐controlled, Prospective Study
    • Authors: Anna Tuisku; Merita Salmela, Pentti Nieminen, Tuula Toljamo
      Abstract: This study compares the nicotine patch to placebo in young adult light smokers, and the nicotine patch to varenicline in heavy smokers. Volunteer daily smokers were recruited into a randomised, placebo‐controlled study via community media, colleges and the army (aged 18 to 26 years). Those subjects with light tobacco dependence were randomised to 1) placebo patch (n=86) and 2) nicotine patch 10 mg/16 hr for 8 weeks (n=94), and those with stronger dependence to 3) nicotine patch 15 mg/16 hr for 8 weeks (n=51) and 4) varenicline for 12 weeks (n=60). The primary outcome variable was self‐reported smoking abstinence at week 12. Secondary outcome variables were self‐reported smoking abstinence at weeks 4 and 26, and self‐reported abstinence verified by saliva cotinine level at week 12. The prevalence of self‐reported smoking abstinence did not differ statistically significantly in light smokers during the follow‐up (week 4: 19.8% for placebo patch and 26.6% for nicotine patch 10 mg/16 hr; week 12: 17.4% versus 23.4%; week 26: 15.1% versus 20.2%), but the groups of heavy smokers differed significantly for 12 weeks (week 4: 19.6% for nicotine patch 15 mg/16 hr and 73.3% for varenicline, p
      PubDate: 2015-12-26T08:21:31.600831-05:
      DOI: 10.1111/bcpt.12548
  • Physiology and Pharmacology of Ejaculation
    • Abstract: Ejaculation is the final stage of coitus in mammalian male and is mandatory for natural procreation. Two synchronized phases, emission and expulsion, form the ejaculatory response and involve specific organs and anatomical structures. The peripheral events leading to ejaculation are commanded by autonomic (sympathetic and parasympathetic) and somatic divisions of the nervous system. The autonomic and somatic motor efferents originate in spinal nuclei located in thoracolumbar and lumbosacral segments. Coordinated activation of autonomic and somatic spinal nuclei is orchestrated by a group of lumbar spinal interneurons defined as the spinal generator of ejaculation. The generator of ejaculation together with the autonomic and somatic spinal nuclei constitute a spinal network that is under the strong influence of stimulating or inhibiting genital sensory and supraspinal inputs. A brain circuitry dedicated to ejaculation has been delineated that is part of a more global network controlling other aspects of the sexual response. This circuitry includes discrete neuronal populations distributed in all divisions of the brain. The corollary to the expanded CNS network is the variety of neurotransmitter systems participating to the ejaculatory process. Among them, serotonin neurotransmission plays a key role and its targeting led to the development of the first registered pharmacological treatment of premature ejaculation in human beings. Critical gaps remain in the understanding of neurophysiopharmacology of ejaculation and management of ejaculatory disorders in human beings needs improvement. Because the ejaculatory response in laboratory animals and in human beings share many similarities, the use of animal models will certainly provide further advances in the field. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-26T08:21:10.176586-05:
      DOI: 10.1111/bcpt.12546
  • New 1,4‐Dihydropyridines Down‐regulate Nitric Oxide in Animals
           with Streptozotocin‐induced Diabetes Mellitus and Protect DNA
           against Peroxynitrite Action
    • Abstract: Diabetes mellitus (DM) and its complications cause numerous health and social problems throughout the world. Pathogenic actions of nitric oxide (NO) are responsible to a large extent for development of complications of DM. Search for compounds regulating NO production in DM patients is thus important for the development of pharmacological drugs. Dihydropyridines (1,4‐DHPs) are prospective compounds from this point of view. The goals of the present work were to study the in vivo effects of new DHPs on NO and reactive nitrogen and oxygen species production in a streptozotocin (STZ) ‐induced model of DM in rats and to study their ability to protect DNA against nocive action of peroxynitrite. STZ‐induced diabetes caused an increase of NO production in the liver, kidneys, blood and muscles, but by a decrease of NO in adipose tissue of STZ‐treated animals. Cerebrocrast treatment was followed by normalization of NO production in the liver, kidneys and blood. Two other DHPs, etaftorone and fenoftorone, were effective in decreasing NO production in kidneys, blood and muscles of diabetic animals. Furthermore, inhibitors of nitric oxide synthase (NOS) and an inhibitor of xanthine oxidoreductase (XOR) decreased NO production in kidneys of diabetic animals. Treatment with etaftorone decreased expression of inducible NOS and XOR in kidneys whereas it increased the expression of endothelial NOS. In vitro, the studied DHPs did not significantly inhibit the activities of NOS and XOR but affected the reactivity of peroxynitrite with DNA. These new DHPs thus appear of strong interest for treatment of DM complications. This article is protected by copyright. All rights reserved.
      PubDate: 2015-12-12T14:11:36.137923-05:
      DOI: 10.1111/bcpt.12542
  • Response to: Adverse Events Associated with Flumazenil Treatment for the
           Management of Suspected Benzodiazepine Intoxication ‐ A Systematic
           Review with Meta‐Analyses of Randomized Trials
    • PubDate: 2015-11-03T01:20:52.120292-05:
      DOI: 10.1111/bcpt.12498
  • The Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety
           and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator
    • Abstract: Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent for auto‒immune disorders. The impact of hepatic or renal impairment on the pharmacokinetics, safety and tolerability of ponesimod and its inactive metabolites, ACT‒204426 and ACT‒338375, was evaluated. Two separate single‒centre, open‒label studies with 32 (hepatic study) and 24 (renal study) male and female subjects were conducted. Hepatic impairment was based on the Child–Pugh classification and renal impairment was determined by creatinine clearance using the Cockcroft–Gault equation. Subjects with severe hepatic or renal impairment were to be matched (sex and body mass index) with healthy subjects. All subjects received a single dose of 10 mg ponesimod. For ponesimod, the ratio of geometric means of AUC0‒∞ for subjects with severe hepatic impairment versus healthy subjects was 3.07 (90% CI: 2.19, 4.32). For severely renally impaired subjects versus healthy subjects, this ratio was 1.14 (0.82, 1.58). Cmax and tmax values of ponesimod were comparable across all groups in both studies. Exposure to metabolites was increased in subjects with moderate or severe hepatic impairment as compared to healthy subjects. During the course of these studies, there were no clinically relevant abnormalities related to vital signs, 12‒lead electrocardiograms and clinical laboratory values. Sixteen adverse events (AEs) were reported, 12 of them of mild intensity. No AEs were considered to be treatment‒related. Overall, ponesimod was well tolerated. In subjects with renal function impairment, dose adjustment is not warranted, whereas the dose should be reduced in subjects with moderate and severe hepatic impairment. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-03T00:28:32.122303-05:
      DOI: 10.1111/bcpt.12516
  • Pharmacokinetics of the Experimental Non‐Nucleosidic DNA Methyl
           Transferase Inhibitor N‐Phthalyl‐L‐Tryptophan
           (RG 108) in Rats
    • Abstract: DNA methyl transferase (DNMT) inhibitors can re‐establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non‐nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non‐specific DNMT inhibitor N‐phthalyl‐L‐tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr post injection and RG 108 in plasma was measured by high‐performance liquid chromatography coupled to mass spectrometry. Trough levels and AUC were significantly higher with multiple dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (tmax, mean±SD) was 37.5±15 min, terminal plasma half‐life was approximately 3.7 hr (60% CI: 2.1 – 15.6 h), maximal plasma concentration (Cmax) 61.3±7.6 μM and area under the curve was 200±54 μmol*h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple dose administration regimens. Maximal tissue levels (Cmax in μmol/kg) were 6.9±6.7, 1.6±0.4 and 3.4±1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 μM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-02T23:52:44.74041-05:0
      DOI: 10.1111/bcpt.12514
  • A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of
           Vortioxetine in Patients with Major Depressive Disorder
    • Authors: Himanshu Naik; Serena Chan, Majid Vakilynejad, Grace Chen, Henrik Loft, Atul R. Mahableshwarkar, Johan Areberg
      Abstract: Vortioxetine is approved for treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure–response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and 2 generalised anxiety disorder studies of vortioxetine (3160 patients), and efficacy data (Montgomery‐Åsberg Depression Rating Scale [MADRS]) from 7 MDD studies (2537 patients), were used for development of PK and PK/Efficacy models. One‐ and two‐compartment models were evaluated as structural PK models, and linear and non‐linear (Emax) models were used to describe the relationship between average vortioxetine concentration at steady state (Cav) and change in MADRS score from baseline (ΔMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterised by a two‐compartment model with first‐order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/h and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F but the effect of each of these covariates was not considered clinically relevant, as they lead to ±26% change in area under the curve (AUC) or Cmax of vortioxetine. An Emax model best described the relationship between ΔMADRS and Cav. Half maximal effective concentration (EC50) and Emax estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterised the vortioxetine exposure–response relationship. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-02T23:52:36.230514-05:
      DOI: 10.1111/bcpt.12513
  • The Inhibitory Effect of Ciprofloxacin on the
           β‐Glucuronidase‐mediated Deconjugation of the Irinotecan
           Metabolite SN‐38‐G
    • Authors: Takaaki Kodawara; Takashi Higashi, Yutaka Negoro, Yukio Kamitani, Toshiaki Igarashi, Kyohei Watanabe, Hitoshi Tsukamoto, Ryoichi Yano, Mikio Masada, Hiromichi Iwasaki, Toshiaki Nakamura
      Abstract: The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. β‐Glucuronidase, an intestinal bacteria‐produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide‐conjugated drugs. In this study, we established an in vitro system to evaluate the β‐glucuronidase‐mediated deconjugation of the irinotecan metabolite SN‐38‐G to its active SN‐38 form and the effect of ciprofloxacin thereon. SN‐38 formation increased in a time‐dependent manner from 5 to 30 min. in the presence of β‐glucuronidase. Ciprofloxacin and phenolphthalein‐β‐d‐glucuronide (PhePG), a typical β‐glucuronidase substrate, significantly decreased SN‐38‐G deconjugation and, hence, SN‐38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN‐38‐G to SN‐38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose‐dependent inhibitory effect on the β‐glucuronidase‐mediated conversion of SN‐38‐G to SN‐38 with a half‐maximal inhibitory concentration (IC50) value of 83.8 μM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non‐competitive manner, respectively. These findings suggest that the reduction in the serum SN‐38 concentration following co‐administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN‐38 through the non‐competitive inhibition of intestinal β‐glucuronidase‐mediated SN‐38‐G deconjugation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-30T22:38:08.083807-05:
      DOI: 10.1111/bcpt.12511
  • What should Junior Doctors Know about the Drugs they frequently
           prescribe? A Delphi Study among Physicians in The Netherlands
    • Authors: David Brinkman; Guus Disselhorst, Bernard Jansen, Jelle Tichelaar, Michiel Agtmael, Theo Vries, Milan Richir
      Abstract: The aim of this study was to identify the information about commonly prescribed drugs that junior doctors should know in order to prescribe rationally in daily practice, defined as Essential Drug Knowledge (EDK). A two‐round Internet Delphi study was carried out involving general practitioners from one practice cluster, and registrars and consultants from two Dutch academic and eight teaching hospitals. A preliminary list of 377 potential EDK items for three commonly prescribed drugs was assessed on a dichotomous scale; an item was considered EDK if at least 80% consensus was reached. The consensus list of EDK items was discussed by the research team to identify similarities between the three drugs, with a view to forming a list of general EDK items applicable to other commonly prescribed drugs. Sixty experts considered 93 of the 377 items (25%) as EDK. These items were then used to form a list of 10 general EDK items. The list of EDK items identified by primary and secondary care doctors could be used in medical curricula and training programmes and for assessing the prescribing competence of future junior doctors. Further research is needed to evaluate the generalizability of this list for other commonly prescribed drugs. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-27T09:43:51.672556-05:
      DOI: 10.1111/bcpt.12508
  • Elderly Patients Require Higher Doses of Sugammadex for Rapid Recovery
           from Deep Neuromuscular Block
    • Abstract: This study compared the doses of sugammadex needed for rapid recovery from deep neuromuscular blockade (NMB) between young and elderly adults. Twenty‐two young (20‐40 years) and 22 elderly (≥70 years) adults were enrolled, and deep NMB of 1‐2 post‐tetanic counts was maintained with rocuronium intraoperatively. Pre‐determined doses of sugammadex were given at the end of surgery starting at 4.0 mg/kg for the first patient of each group. Doses were decreased or increased in following patients by 0.5 mg/kg, depending on the ‘success’ or ‘failure’ of rapid recovery in the preceding patient. ‘Success’ was defined as adequate recovery (train‐of‐four ratio 0.9) within 2 min. after sugammadex administration. The median (range) of ages were 29 (20‐40) and 73 (70‐84) years for the young and elderly adults, respectively. Doses of sugammadex facilitating adequate recovery from deep NMB within 2 min. in each patient population with 50% and 95% probability were defined as ED50 and ED95, respectively. The ED50 estimated by the Dixon's method was significantly higher in the elderly compared to young adults [4.2 ± 0.4 mg/kg versus 3.3 ± 0.3 mg/kg, P < 0.001]. The ED50 (83% CI) estimated by isotonic regression was 4.5 (4.2‐5.0) mg/kg in elderly adults and 3.3 (3.2‐3.4) mg/kg in young adults. The ED95 (95% CI) estimated by isotonic regression was 5.4 (4.9‐5.5) mg/kg and 4.4 (3.9‐4.5) mg/kg in the elderly and young adults, respectively. In conclusion, dose adjustments of sugammadex should be considered when rapid recovery from deep NMB is needed in elderly adults. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-27T09:35:14.032515-05:
      DOI: 10.1111/bcpt.12507
  • HMGCR rs17671591 SNP determines Lower Plasma LDL‐C after
           Atorvastatin Therapy in Chilean Individuals
    • Abstract: Lipid‐lowering response to statin therapy shows large interindividual variability. At a genome‐wide significance level, single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR have been implicated in this differential response. However, the influence of these variants is uncertain in the Chilean population. Hence, we aimed to evaluate the contribution of PCSK9 rs7552841 and HMGCR rs17671591 SNPs as genetic determinants of atorvastin response in Chilean hypercholesterolaemic individuals. One hundred and one hypercholesterolaemic patients received atorvastatin 10 mg/day for 4 weeks. Plasma lipid profile (TC, HDL‐C, LDL‐C and TG) was determined before and after statin treatment, and SNPs were identified by allelic discrimination using TaqMan® SNP Genotyping assays. Adjusted univariate and multivariate analyses models were used for statistical analyses and a p‐value
      PubDate: 2015-10-23T21:20:37.963672-05:
      DOI: 10.1111/bcpt.12493
  • The Effect of a Selective Inhibitor of Phosphodiesterase‐9 on
           Oxidative Stress, Inflammation and Cytotoxicity in Neutrophils from
           Patients with Sickle Cell Anaemia
    • Abstract: The aim of the study was to investigate the possible anti‐inflammatory and antioxidant effects of BAY 73‐6691 on neutrophils from SCA patients. This study included 35 patients with a molecular diagnosis of SCA, whose neutrophils were isolated and treated with BAY 73‐6691 at the concentrations 100, 10, 1.0 and 0.1 μg/mL. LDH release and MTT assays were performed to verify cell viability. To evaluate oxidative stress, the following parameters were determined by spectrophotometric assays: NO and malondialdehyde (MDA) levels and activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). As inflammatory markers, myeloperoxidase (MPO) levels were evaluated by colourimetric assay and TNF‐alpha by enzyme immunoassay. The results showed that neutrophils from SCA patients not treated with hydroxyurea (HU) had significantly lower NO levels and catalase and SOD activity, as well as significantly higher MDA, MPO and TNF‐alpha levels when compared with neutrophils from SCA patients treated with HU and neutrophils from control group. Treatment of SCA neutrophils with BAY 73‐6691 resulted in 94%, 200% and 168% increase in NOx levels, SOD and catalase activity, respectively. In addition, there was a reduction of approximately 46% and 45% in TNF‐α and MPO levels, respectively. In SCAHU neutrophils, there was a 30% and 44% increase in NOx levels and SOD activity and a 28% and 37% decrease in TNF‐α and MPO levels. However, these effects were observed at cytotoxic doses only. The results of this study are original and demonstrate that inhibition of phosphodiesterase 9 in neutrophils from SCA patients with BAY 73‐6691 was able to increase the NO bioavailability and attenuate oxidative stress and inflammation in neutrophils from patients not treated with HU. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-23T01:36:44.822255-05:
      DOI: 10.1111/bcpt.12487
  • Effect of Iron and Carbon Monoxide on Fibrinogenase‐like Degradation
           of Plasmatic Coagulation by Venoms of Six Agkistrodon Species
    • Authors: Vance G. Nielsen; Daniel T. Redford, Patrick K. Boyle
      Abstract: Annually, thousands suffer poisonous snake bite, often from defibrinogenating species. It has been demonstrated that iron and carbon monoxide change the ultrastructure of plasma thrombi and improve coagulation kinetics. Thus, the present investigation sought to determine if pre‐treatment of plasma with iron and carbon monoxide could attenuate venom‐mediated catalysis of fibrinogen obtained from Agkistrodon species with fibrinogenase activity. Human plasma was pre‐treated with ferric chloride (0‐10 μM) and carbon monoxide releasing molecule‐2 (CORM‐2, 0‐100 μM) prior to exposure to 0.5‐11 μg/ml of six different Agkistrodon species’ venom. The amount of venom used for experimentation needed to decrease coagulation function of one or more kinetic parameters by at least 50% of normal values for (e.g., half the normal speed of clot formation). Coagulation kinetics were determined with thrombelastography. All six snake venoms degraded plasmatic coagulation kinetics to a significant extent, especially prolonging the onset to clot formation and diminishing the speed of clot growth. Pre‐treatment of plasma with iron and carbon monoxide attenuated these venom‐mediated coagulation kinetic changes in a species‐specific manner, with some venom effects markedly abrogated while others were only mildly decreased. Further in vitro investigation of other pit viper venoms that possess fibrinogenolytic activity is indicated to identify species amenable to or resistant to iron and carbon monoxide‐mediated attenuation of venom‐mediated catalysis of fibrinogen. Lastly, future preclinical investigation with animal models (e.g., rabbit ear bleed model) is planned to determine if iron and carbon monoxide can be used therapeutically after envenomation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-15T01:15:39.393058-05:
      DOI: 10.1111/bcpt.12504
  • Relationships between Endogenous Plasma Biomarkers of Constitutive CYP3A
           Activity with Single Time‐Point Oral Midazolam Microdose Phenotype
           in Healthy Subjects
    • Abstract: Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4β‐hydroxycholesterol (4βHC) and 6β‐hydroxycortisol (6βHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4βHC and 6βHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single time‐point oral midazolam phenotyping strategy. Plasma 4βHC and 6βHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral midazolam microdose (100 μg). Simple linear and multiple linear regression analyses were performed to assess relationships between midazolam oral clearance, biomarkers and subject covariates. Among study subjects, basal midazolam oral clearance, 4βHC and 6βHCL MRs ranged 6.5‐, 10‐ and 13‐fold, respectively. Participant age and alcohol consumption were negatively associated with midazolam oral clearance (P=0.03 and P=0.045, respectively) while weight and female sex were associated with lower plasma 4βHC MR (P=0.0003 and P=0.032, respectively). Neither 4βHC nor 6βHCL MRs were associated with MDZ oral clearance. Plasma 4βHC and 6βHCL MRs do not relate to MDZ single time‐point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-14T22:13:17.657764-05:
      DOI: 10.1111/bcpt.12492
  • No untoward effect of long‐term ketoconazole administration on
           electrocardiographic qt interval in patients with cushing's disease
    • Abstract: Ketoconazole is listed among drugs which prolong QT interval and may increase the risk of torsade de pointes, a severe ventricular arrhythmia. This compound has recently been approved for treatment of Cushing's syndrome, a severe endocrine disorder. These patients harbour several risk factors for prolonged QT interval, e.g., hypokalaemia, left ventricular hypertrophy, but no study has evaluated whether administration of ketoconazole affects QT interval. The aim of the present study was to assess the QT interval in patients with Cushing's disease during long‐term administration of ketoconazole. Electrocardiograms from 15 patients with Cushing's disease (12 women, 3 men, age 37.8±2.66 years) on ketoconazole treatment (100 mg–800 mg qd) for 1 month to 12 years were reviewed retrospectively. QT interval was measured and corrected for heart rate (QTc). Measurements before and during ketoconazole treatment were compared and any abnormal QTc value recorded. Concurrent medical therapies were also documented. On average, QTc was superimposable before and during ketoconazole treatment (393.2±7.17 versus 403.3±6.05 msec in women; 424.3 ±23.54 versus 398.0±14.93 msec in men, N.S.). QTc normalized on ketoconazole in one man with prolonged QTc prior to treatment; no abnormal QTc was observed in any other patient during the entire observation period, even during concurrent treatment with other QT‐prolonging drugs. In conclusion, long‐term ketoconazole administration does not appear to be associated with significant prolongation of QT interval in patients with Cushing's disease. ECG monitoring can follow recommendations for other low‐risk QT‐prolonging drugs with attention to specific risk factors, e.g, hypokalaemia, drug interactions. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-14T21:46:02.907786-05:
      DOI: 10.1111/bcpt.12490
  • Minocycline Attenuates Depressive‐like Behaviour Induced by Rat
           Model of Testicular Torsion: Involvement of Nitric Oxide Pathway
    • Authors: Seyed Soheil Saeedi Saravi; Seyyedeh Elaheh Mousavi, Seyed Sobhan Saeedi Saravi, Ahmad Reza Dehpour
      Abstract: Testicular torsion/detorsion (T/D) can induce depression in pre‐ and post‐pubertal patients. This study was conducted to investigate the psychological impact of testicular torsion and mechanism underlying its depressive‐like behaviour, as well as antidepressant‐like activity of minocycline and possible involvement of nitric oxide (NO)/cGMP pathway in this paradigm in male rats undergoing testicular T/D. Uni‐lateral T/D was performed in 36 male adult Wistar rats, and different doses of minocycline were injected alone or combined with non‐specific NO synthase (NOS) inhibitor, L‐NAME, specific iNOS inhibitor, aminoguanidine (AG), an NO precursor, L‐arginine, and selective PDE5I, sildenafil. After assessment of locomotor activity in open‐field test, immobility times were recorded in the forced swimming test (FST). Moreover, 30 days after testicular T/D, testicular venous testosterone and serum nitrite concentrations were measured. A correlation was observed between either a decrease of plasma testosterone or an increase in serum nitrite concentrations with prolongation in immobility time in the testicular T/D operated rats FST. Minocycline (160 mg/kg) exerted the highest significant antidepressant‐like effect in the operated rats in the FST (P
      PubDate: 2015-10-14T01:58:26.382698-05:
      DOI: 10.1111/bcpt.12489
  • Triggering of Suicidal Erythrocyte Death by the Antibiotic Ionophore
    • Abstract: The K+,H+ ionophore and antibiotic nigericin has been shown to trigger apoptosis and is thus considered for the treatment of malignancy. Cellular mechanisms involved include induction of oxidative stress, which is known to activate erythrocytic Ca2+ permeable unselective cation channels leading to Ca2+ entry, increase of cytosolic Ca2+ activity ([Ca2+]i) and subsequent stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. The present study explored whether and how nigericin induces eryptosis. Phosphatidylserine exposure at the cell surface was estimated from annexin‐V‐binding, cell volume from forward scatter, [Ca2+]i from Fluo3‐fluorescence, pHi from BCECF‐ fluorescence, ceramide abundance utilizing antibodies and reactive oxygen species (ROS) formation from DCFDA‐dependent fluorescence. A 48‐hr exposure of human erythrocytes to nigericin significantly increased the percentage of annexin‐V‐binding cells (0.1‐10 nM), significantly decreased forward scatter (0.1 ‐ 1 nM), significantly decreased cytosolic pH (0.1 ‐ 1 nM) and significantly increased Fluo3‐fluorescence (0.1 ‐ 10 nM). Nigericin (1 nM) slightly, but significantly, increased ROS, but did not significantly modify ceramide abundance. The effect of nigericin on annexin‐V‐binding was significantly blunted, but not abolished by removal of extracellular Ca2+. The nigericin‐induced increase of [Ca2+]i and annexin‐V‐binding was again significantly blunted but not abolished by the Na+/H+ exchanger inhibitor cariporide (10 μM). Nigericin triggers eryptosis, an effect paralleled by ROS formation, in part dependent on stimulation of Ca2+ entry, and involving the cariporide sensitive Na+/H+ exchanger. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-12T13:01:21.264667-05:
      DOI: 10.1111/bcpt.12503
  • Curcumin, Silybin‐Phytosome® and α‐R‐Lipoic
           Acid Mitigate Chronic Hepatitis in Rat by Inhibiting Oxidative Stress and
           Inflammatory Cytokines Production
    • Authors: Shimaa O. Ali; Hebatallah A. Darwish, Nabila A. Ismail
      Abstract: Chronic hepatitis is recognized as a worldwide health problem that gradually progresses towards cirrhosis and hepatocellular carcinoma. Despite the large number of experiments using animal models for allergic hepatitis, it is still difficult to produce a picture of chronic hepatitis. Therefore, the present study was conducted to introduce an animal model approximating to the mechanism of chronicity in human hepatitis. The study also aimed to examine the hepatoprotective effects of curcumin, silybin phytosome® and α‐R‐lipoic acid against thioacetamide (TAA)‐induced chronic hepatitis in rat model. TAA was administered intraperitoneally at a dose of 200 mg/kg 3 times weekly for 4 weeks. At the end of this period, a group of rats was killed to assess the development of chronic hepatitis in comparison to their respective control group. TAA administration was then discontinued and the remaining animals were subsequently allocated into four groups. Group 1 was left untreated whereas groups 2‐4 were allowed to receive daily oral doses of curcumin, silybin phytosome® or α‐R‐lipoic acid, respectively, for 7 weeks. Increases in hepatic levels of malondialdehyde associated with TAA administration were inhibited in groups receiving supplements. Furthermore, glutathione depletion, collagen deposition, macrophage activation, nuclear factor κappa‐B expression as well as tumour necrosis factor‐α and interleukin‐6 levels were significantly decreased in response to supplements administration. Serological analysis of liver function and liver histopathological examination reinforced the results. The above evidence collectively indicates that the antioxidant and anti‐inflammatory activities of curcumin, silybin phytosome® and α‐R‐lipoic acid may confer therapeutic efficacy against chronic hepatitis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-12T12:45:31.813166-05:
      DOI: 10.1111/bcpt.12502
  • The Effect of the Combined Use of Methylergonovine and Oxytocin during
           Caesarean Section in the Prevention of Postpartum Haemorrhage
    • Abstract: We aimed to show the benefit to patients of postpartum hemorrhage prophylaxis treatment and the effectiveness as a uterotonic agent of the combined use of methylergonovine and oxytocin infusion in the prevention of hemorrhage during and after caesarean section, by comparison with a control group which received oxytocin infusion only. Two groups of patients undergoing caesarean section at the same clinic were included in the study. A combination of methylergonovine and oxytocin was administered to the first group during the intraoperative and postoperative periods. The second group did not receive methylergonovine and was administered only with oxytocin infusion in the intraoperative and postoperative periods. Preoperative and postoperative hemogram readings were taken for all patients in each of the groups for comparison. No difference was found between the two groups with regard to mean ages and preoperative hemogram values. The decrease in postoperative hemoglobin values for the group administered with methylergonovine maleate and oxytocin was found to be significantly greater than for the group administered with oxytocin only. Results indicated that prophylactic methylergonovine treatment was clearly successful for the patients and no adverse side effects were found. The routine use of methylergonovine and oxytocin infusion in combination during the intraoperative period of caesarean section reduced the level of postpartum hemorrhage considerably. We believe that this procedure will also reduce the risk of uterine atony, but clearly prospective studies will be necessary in future to confirm this assumption. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-09T06:55:23.461715-05:
      DOI: 10.1111/bcpt.12500
  • Organoarsenic Roxarsone Promotes Angiogenesis In Vivo
    • Authors: Yumei Zhang; Yujing Wang, Qianqian Lu, Wenfang Xin, Weibo Cui, Jiaqiao Zhu
      Abstract: Roxarsone, an organoarsenic feed additive, is widely used worldwide to promote animal growth. It has been found to exhibit a higher angiogenic index than AsIII at lower concentrations and to promote angiogenic phenotype in human endothelial cell in vitro. Little research has focused on the potential angiogenic effect of roxarsone in vitro or in vivo. Here, we investigated the pro‐angiogenic effect of roxarsone in vivo. The effects of 0.1‐10.0 μM roxarsone were tested in the rat endothelial cell Matrigel plug assay, chicken chorioallantoic membrane (CAM) model and MCF‐7 cell xenograft tumour model; 10 ng/mL vascular endothelial growth factor (VEGF) was used as a positive control and PBS as a negative control. Roxarsone significantly increased the volume, weight and hemoglobin content of the Matrigel plugs compared to PBS group (P < 0.05); 1.0 μM roxarsone exerted the most significant effects. H&E staining and CD31 immunochemistry revealed obviously more new vessels or capillary‐like structures in the plugs of the roxarsone and VEGF groups. Roxarsone significantly increased the numbers of primary/secondary vessels and area of vessels in the CAM assay; obviously increased tumour weight and volume in the xenograft model compared to PBS (P < 0.05). Histochemistry indicated local necrosis was observed at the center of the xenograft tumours in the PBS and roxarsone groups, with less necrosis apparent in the VEGF‐treated tumours. The growth of endothelial cells and VEGF level were obviously affected at blockade of VEGF and its receptor Flt‐1/Flk‐1 by SU5416 or its antibody in vitro. This study demonstrates roxarsone promotes angiogenesis in vivo, and a VEGF/VEGFR mechanism may be involved. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-09T02:51:17.802678-05:
      DOI: 10.1111/bcpt.12501
  • Impaired Glucose Tolerance in Healthy Men Treated with St. John's Wort
    • Abstract: The purpose of this study was to examine if the over‐the‐counter herbal medicinal plant St. John's wort affects glucose tolerance in healthy men. To do this, we included 10 healthy men who were examined by a 2‐hr oral glucose tolerance test on three occasions; A: Baseline, B: After 21 days treatment with St. John's wort and C: At least 6 weeks after the last capsule of St. John's wort was ingested. Plasma glucose, serum insulin and C‐peptide levels were measured during an oral glucose tolerance test and used for estimation of area under the concentration‐time curve (AUC) as well as and indices of insulin sensitivity and insulin secretion. We found that treatment with St. John's wort increased total and incremental glucose AUC and 2‐hr plasma glucose levels. Surprisingly, this effect was sustained and even further increased 6 weeks after the last capsule of St. John's wort was taken. No effect on indices of insulin sensitivity was seen, but indices of insulin secretion were reduced even after adjustment for insulin sensitivity. In conclusion, this study indicates that long‐term treatment with St. John's wort may impair glucose tolerance by reducing insulin secretion in young, healthy men. The unregulated use of this over‐the‐counter drug might be a risk factor for impaired glucose tolerance and type 2 diabetes. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-08T20:01:47.264973-05:
      DOI: 10.1111/bcpt.12486
  • Pinosylvin Inhibits TRPA1‐Induced Calcium Influx In Vitro and
           TRPA1‐Mediated Acute Paw Inflammation In Vivo
    • Abstract: Pinosylvin (3,5‐dihydroxy‐trans‐stilbene) is a stilbenoid polyphenol structurally related to resveratrol, and it is found in heartwood, knot and bark of Pinus species. Pinosylvin has been shown to possess anti‐inflammatory and cancer‐chemopreventive properties as well as being an antioxidant preventing oxidative stress [1‐4]. Transient receptor potential ankyrin 1 (TRPA1) is an ion channel expressed in the terminal ends of sensory neurons throughout the body. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-07T00:01:01.154573-05:
      DOI: 10.1111/bcpt.12485
  • Efficiency of a New Mesh‐Type Nebulizer (NE‐SM1 NEPLUS) for
           Intrapulmonary Delivery of Ipratropium Bromide in Surgical Patients
    • Abstract: This study was aimed to evaluate the efficiency of a new mesh‐type nebulizer for the intrapulmonary delivery of ipratropium bromide in surgical patients under mechanical ventilation. A total of 20 patients were randomly allocated to receive 0.5 mg ipratropium bromide using either a control (Pariboy SX, Pari, Co., Starnberg, Germany, n=10) or test (NE‐SM1 NEPLUS, KTMED Co., Seoul, Korea, n=10) nebulizer during general anaesthesia. Ipratropium bromide was nebulised continuously for 20 min. in each group. Plasma concentrations of ipratropium bromide were obtained from blood samples at preset intervals. Non‐compartmental analysis of ipratropium bromide was performed to compare the efficiency of pulmonary drug delivery in both nebulizers. Population pharmacokinetic analysis of ipratropium bromide was performed. Additionally, in in vitro studies, the noise level during the nebulizer operation and the aerosol particle size for each device were measured. The dose‐normalized AUClast was 0.10 min/L for both nebulizers. The pharmacokinetics of nebulised ipratropium bromide can be described best by a one‐compartment model with first‐order absorption. The apparent volume of distribution and metabolic clearance were 1,340 L and 6.78 L/min, respectively. Type of nebulizer was a significant covariate for absorption rate constant. The equivalent sound level and median aerosol particle diameter were 35.0 dB and 4.52 μm for the test nebulizer, and 60.2 dB and 3.85 μm for the control nebulizer, respectively. From the standpoint of the dose‐normalized AUClast, a new vibrating mesh‐type nebulizer shows similar performance in the intrapulmonary delivery of ipratropium bromide to that of a jet‐type nebulizer in surgical patients. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-06T09:34:11.472629-05:
      DOI: 10.1111/bcpt.12499
  • Antitumour Activity of the Microencapsulation of Annona vepretorum
           Essential Oil
    • Abstract: Annona vepretorum Mart. (Annonaceae), popularly known as “bruteira”, has nutritional and medicinal uses. This study investigated the chemical composition and antitumour potential of the essential oil of A. vepretorum leaf alone and complexed with β‐cyclodextrin in a microencapsulation. The essential oil was obtained by hydrodistillation using a Clevenger‐type apparatus and analysed using GC–MS and GC–FID. In vitro cytotoxicity of the essential oil and some of its major constituents in tumour cell lines from different histotypes was evaluated using the alamar blue assay. Furthermore, the in vivo efficacy of essential oil was demonstrated in mice inoculated with B16‐F10 mouse melanoma. The essential oil included bicyclogermacrene (35.71%), spathulenol (18.89%), (E)‐β‐ocimene (12.46%), α‐phellandrene (8.08%), o‐cymene (6.24%), germacrene D (3.27%) and α‐pinene (2.18%) as major constituents. The essential oil and spathulenol exhibited promising cytotoxicity. In vivo tumour growth was inhibited by the treatment with the essential oil (inhibition of 34.46%). Importantly, microencapsulation of the essential oil increased in vivo tumour growth inhibition (inhibition of 62.66%). This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-06T00:33:15.617839-05:
      DOI: 10.1111/bcpt.12488
  • Clinical weighting of drug‐drug interactions in hospitalized elderly
    • Abstract: Adverse drug reactions impact on patient health, effectiveness of pharmacological therapy and increased health care costs. The current investigation intended to detect the most critical drug‐drug interactions in hospitalized elderly patients, weighting clinical risk. We conducted a cross‐sectional study between January and April 2014; all patients 70 years or older, hospitalized for >24 hr and prescribed at least one medication were included in the study. Drug‐drug interactions were estimated by combining Stockley's, Hansten and Tatro drug interactions. Drug‐drug interactions were weighted using a risk‐analysis method based on failure modes, effects and criticality analysis. We calculated a criticality index for each drug involved in the drug‐drug interactions based on the severity of the interaction mechanism, the frequency the drug was involved in drug‐drug interactions and the risk of drug‐drug interactions in patients with impaired renal function. The average number of drugs consumed in the hospital was 6 ± 2.69, involving 160 active ingredients. The most frequent were: Furosemide, followed by Enalapril. Of drug‐drug interactions, 2% were classified as contra‐indicated, 14% advised against and 83% advised caution during the hospital stay. Thirty‐four drug‐drug interactions were assessed of which 23 were drug‐drug interactions‐pharmacodynamics, 12 were drug‐drug interactions‐pharmacokinetic (1 was both). The clinical risk calculated for each drug‐drug interaction included heparins+non‐steroidal anti‐inflammatory drugs (NSAIDs) or Digoxin+Calcium Gluconate, cases which are drug‐drug interactions‐pharmacodynamic with agonist effect and clinical risk of bleeding, one of the most common clinical risks in the hospital. An index of clinical risk for drug‐drug interactions can be calculated based on severity by the interaction mechanism, the frequency that the drug is involved in drug‐drug interactions and the risk of drug‐drug interactions in an elderly patient with impaired renal function. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-03T03:46:52.028091-05:
      DOI: 10.1111/bcpt.12495
  • Low vitamin D Levels and Genetic Polymorphism in the Vitamin D Receptor
           are Associated with Increased Risk of Statin‐Induced Myopathy
    • Abstract: The main aim of this study was to test the hypothesis whether 25‐hydroxyvitamin D (25OHD) levels < 50 nmol/L at baseline could predict statin‐induced myopathy during the course of treatment. In addition, we analysed the association between a genetic polymorphism in the vitamin D receptor (VDR) and the risk of statin‐induced myopathy. We used serum samples from a prospective, observational study in statin‐treated patients in Sweden who were thoroughly followed with interviews and questionnaires regarding muscular symptoms (n=127). In this cohort, 16 developed muscular symptoms and 111 had no muscular symptoms associated with statin treatment during the first year of follow‐up. Patients with 25OHD levels 50 nmol/ L; (RR 4.2; 95% CI 1.7‐10.2; p
      PubDate: 2015-10-01T01:06:26.235467-05:
      DOI: 10.1111/bcpt.12482
  • Sodium Nitrite Prevents both Reductions in Circulating Nitric Oxide and
           Hypertension in 7‐Day Lead‐Treated Rats
    • Abstract: Hypotensive effects of oral sodium nitrite have been reported as alternative sources of nitric oxide (NO) formation in animals and human beings. Reductions of NO bioavailability were observed in lead‐induced hypertension. However, no previous study has examined whether a single daily dose of sodium nitrite prevents the reductions in the NO bioavailability in lead‐induced hypertension. Then, we expanded previous reports and evaluated the effects of sodium nitrite in 7‐day lead‐treated rats. Wistar rats were divided into four experimental groups: Pb+sodium nitrite group received intraperitoneally (i.p.) 1st dose 8μg/100g of lead acetate and a subsequent dose of 0.1μg/100g, and daily treatment with sodium nitrite (45mg/kg/day) or water (Pb group) by gavage for seven days; Sodium nitrite group received i.p. 1st dose 8μg/100g of sodium acetate and a subsequent dose of 0.1μg/100g, and daily treatment with sodium nitrite (45mg/kg/day) or water (Saline group) by gavage for seven days. Similar and higher whole‐blood lead levels (11.5±1.2 and 13.2±0.7μg/dL) were found in lead‐exposed rats treated with either water or sodium nitrite (Pb or Pb+sodium nitrite, respectively; both P 
      PubDate: 2015-10-01T00:14:28.103824-05:
      DOI: 10.1111/bcpt.12480
  • Successful Treatment of Aluminium Phosphide Poisoning by Extracorporeal
           Membrane Oxygenation (ECMO)
    • Abstract: Aluminium phosphide (ALP) is one of the most commonly used pesticides worldwide with high mortality rates. Cellular damage and cardio‐respiratory failure are the most common causes of mortality and morbidity after poisoning. It is supposed that giving enough time to the patient to survive, the most critical hours post‐exposure may help the cardiovascular system to recover itself and save the patient's life. During a training workshop for medical extracorporeal membrane oxygenation (ECMO), a 28‐year‐old ALP‐poisoned male was referred to us. Fifty minutes after admission, he developed hypotension and bradycardia and was transferred to ICU. On the second venous blood gas, he had severe metabolic acidosis. After starting the patient on the routine treatment of ALP poisoning, he was a candidate for veno‐arterial (VA) ECMO. After three days, lactate level decreased and his general condition improved. On day four, the patient was completely separated from the ECMO machine with acceptable echocardiography and ejection fraction of 40%. One day later, he was extubated, sent to the ward and subsequently discharged in good condition. We suggest this method of treatment for severe ALP poisoning as well as any other poisoning that causes cell toxicity and abrupt cardiovascular or respiratory failure. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-01T00:08:45.297118-05:
      DOI: 10.1111/bcpt.12481
  • Adverse Drug Reactions for Medicines Newly Approved in Japan from 1999 to
           2013: Hypertension and Hypotension
    • Authors: Takashi Nagayama; Minoru Nishida, Masanori Hizue, Yamato Ogino, Masato Fujiyoshi
      Abstract: In this survey, the correlation between adverse drug reactions (ADRs) in human and animal toxicities was investigated for 393 medicines which were approved in Japan from September 1999 to March 2013. ADRs were collected from each Japanese package insert. Comparable animal toxicities with ADRs were collected by thorough investigation of common technical documents. The results of this survey show that hypertension and/or hypotension were mainly observed in medicines affecting the central nervous system. Hypertension was also observed in antipyretics, analgesics, anti‐inflammatory agents, vasoconstrictors and agents using antibody. Concordance between human ADRs and animal toxicities was analysed. True positive rate for hypertension and hypotension are 0.29 and 0.52, respectively. Positive likelihood ratio and inverse negative likelihood ratio are 1.98 and 1.21, respectively, in hypertension and 1.67 and 1.44, respectively, in hypotension. Concordance between human ADR and animal toxicities is not so high in hypertension and hypotension. Identified mechanisms as on‐target for hypertension and hypotension are 29.8% and 30.5%, respectively. More than half of the causative factors of hypertension and hypotension were unable to be elucidated. Our results show that the intake of medicines is often linked to blood pressure variations that are not predicted in animal toxicity studies. Improvement of drug development processes may be necessary to provide safer medicines because current animal toxicity studies are insufficient to predict all ADRs in human beings. This article is protected by copyright. All rights reserved.
      PubDate: 2015-09-26T02:51:02.195036-05:
      DOI: 10.1111/bcpt.12494
  • Gabapentin, an Analgesic used against Cancer‐Associated Neuropathic
           Pain: Effects on Prostate Cancer Progression in an In Vivo Rat Model
    • Authors: Ilknur Bugan; Zeynep Karagoz, Seyhan Altun, Mustafa B A Djamgoz
      Abstract: A major problem associated with clinical management of cancer is controlling the accompanying pain, and various analgesics are in common use for this purpose. Recent evidence suggests that some of the targets of analgesics, such as ion channels and receptors, may also be involved in the cancer process, thereby raising the possibility that such use of some analgesics may impact upon cancer itself. The main aim of the present study was to determine whether gabapentin, a common adjuvant analgesic in current use against cancer‐associated neuropathic pain, would affect tumour development and progression in vivo. The Dunning rat model of prostate cancer was used. Strongly metastatic Mat‐LyLu cells were implanted subcutaneously into syngeneic Copenhagen rats which were then treated every other day with 4.6‐16.8 μg/kg gabapentin by gavage. Primary tumourigenesis was monitored daily. Lung metastases were counted and measured after killing the rats 21 days later. Gabapentin had no effect on primary tumourigenesis but produced dose‐dependent effects on lung metastasis. Whilst 4.6 μg/kg had no effect, 9.1 μg/kg gabapentin decreased the number of lung metastases significantly by 64%. In contrast, 16.8 μg/kg gabapentin promoted metastasis significantly by 112% and showed a strong tendency to shorten mean survival time. It is concluded that gabapentin prescribed to cancer patients against pain could impact upon the cancer process itself. This article is protected by copyright. All rights reserved.
      PubDate: 2015-09-03T09:44:23.197047-05:
      DOI: 10.1111/bcpt.12484
  • Effects of 22 Novel CYP2D6 Variants Found in the Chinese Population on the
           Bufuralol and Dextromethorphan Metabolisms in vitro
    • Abstract: Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that metabolizes a large number of therapeutic drugs. To date, more than 100 CYP2D6 allelic variants have been reported. Among these variants, we recently identified 22 novel variants in the Chinese population. The aim of this study was to functionally characterize the enzymatic activity of these variants in vitro. A baculovirus‐mediated expression system was used to express wild‐type CYP2D6.1 and other variants (CYP2D6.2, CYP2D6.10 and 22 novel CYP2D6 variants) at high levels. Then, the insect microsomes containing expressed CYP2D6 proteins were incubated with bufuralol or dextromethorphan at 37°C for 20 or 25 min., respectively. After termination, the metabolites were extracted and used for the detection with high‐performance liquid chromatography. Among the 24 CYP2D6 variants tested, two variants (CYP2D6.92 and CYP2D6.96) were found to be catalytically inactive. The remaining 22 variants exhibited significantly decreased intrinsic clearance values for bufuralol 1’‐hydroxylation and 20 variants showed significantly lower intrinsic clearance values for dextromethorphan O‐demethylation than those of the wild‐type CYP2D6.1. Our in vitro results suggest that most of the variants exhibit significantly reduced catalytic activities compared with the wild‐type, and these data provide valuable information for personalized medicine in Chinese and other Asian populations. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-27T05:08:16.905814-05:
      DOI: 10.1111/bcpt.12478
  • Risk Factors for Mortality and Endotracheal Intubation after Methadone
    • Abstract: This was a retrospective chart review to evaluate various risk factors associated with in‐hospital mortality and intubation risk in acute methadone overdose. All patients admitted to an academic hospital in Tehran, Iran, during a 10‐year period (2000‐2009) constituted the study sample. Exclusion criteria were significant co‐morbidities and age under 18 years. Primary outcomes were in‐hospital mortality and being intubated during admission. A total of 802 patients were enrolled in the study. There were 15 (1.8%) deaths due to methadone overdose or its complications. The number of yearly admissions was 15 patients in 2000, 16 in 2001, 16 in 2002, 18 in 2003, 23 in 2004, 38 in 2005, 59 in 2006, 110 in 2007, 206 in 2008, and 301 in 2009. Based on logistic regression analysis, the most important independent variable predicting mortality was length of admission in toxicology ward [OR (95% CI): 1.6 (1.1‐2.3)]. For prediction of intubation, independent variables were Glasgow Coma Scale (GCS) score of 5‐9 [OR (95% CI):356.5 (9.8‐12907.4)] in the Emergency Department (ED), miosis in the ED [356.9 (1.4‐87872.5)], and respiratory rate in the ED [1.5 (1.1‐2.1)]. Linear regression model for length of hospitalization showed patient age as the most important variable for prediction of this outcome. Despite a relatively low mortality rate, the increasing number of methadone‐poisoned patients requires special attention to this common intoxication. Careful disposition of patients from ED to ordinary wards or Intensive Care Units and also from higher to lower levels of care should be considered in methadone overdose. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-24T11:12:43.87314-05:0
      DOI: 10.1111/bcpt.12476
  • The Role of Urotensin Receptors in the Paracetamol‐Induced
           Hepatotoxicity Model in Mice: Ameliorative Potential of Urotensin II
    • Abstract: We aimed to evaluate the possible protective effect of a UTR antagonist and to determine the effect of the antagonist on ALT and AST levels in serum, the mRNA expression level of UTR, TNF‐α and IL‐1β and SOD activity, GSH and MDA levels in liver tissues, which are important mediators or markers for the hepatotoxicity animal model in mice. Animals fasted overnight and were divided into seven equal groups (n=12). The first group was the healthy group (administered 0.1% DMSO intraperitoneally). Group 2 received only PARA (administered orally at a dosage of 300 mg/kg). Groups 3 and 4 were treated with only AGO (AC7954, UTR agonist) 15 mg/kg and 30 mg/kg intraperitoneally, respectively. Groups 5 and 6 were treated with only ANTA (SB657510, UTR antagonist) 30 mg/kg and 60 mg/kg intraperitoneally, respectively. Group 7 was treated with AGO 30 mg/kg and ANTA 60 mg/kg intraperitoneally. One hour after the pre‐treatment drugs were administered, groups 3 through 7 were given PARA. After the experimental period, the mice were killed 6 and 24 hr after PARA was administered. Antagonist administration significantly decreased the ALT and AST levels, while agonist administration did not. In addition, SOD activity and GSH levels increased, and the MDA level decreased with the pre‐treatment of two antagonist doses. The increased UTR gene expression through PARA was significantly lower in both doses of the antagonist groups at 24 hr when compared with the agonist and PARA groups. This study showed that UTR antagonists have hepatoprotective and anti‐inflammatory effects on high‐dose PARA‐induced hepatotoxicity in mice. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-14T10:59:14.637477-05:
      DOI: 10.1111/bcpt.12447
  • Bile Acid‐Induced Toxicity in HepaRG Cells Recapitulates the
           Response in Primary Human Hepatocytes
    • Authors: Benjamin L. Woolbright; Mitchell R. McGill, Huimin Yan, Hartmut Jaeschke
      Abstract: Cholestatic liver injury is a pathological component of numerous disease states. Much of the current literature on cholestatic liver injury is derived from in vitro studies using rodent hepatocytes or cell lines transfected with bile acid (BA) uptake transporters. While these studies demonstrate BA‐driven apoptosis, it is debatable if these models reflect the human pathophysiology, as primary human hepatocytes undergo primarily necrosis. HepaRG cells are a bipotential, human hepatoma line that express apical and basolateral bile acid transporters. Thus, we sought to determine if HepaRG cells could replicate the response of primary human hepatocytes to BA exposure in vitro. HepG2 cells, primary murine hepatocytes (PMH) or HepaRG cells were exposed to taurocholic acid (TCA), or glycochenodeoxycholate (GCDC) and lactate dehydrogenase (LDH) release was measured to determine cell death. Cell death occurred dose‐responsively in HepaRG cells when exposed to GCDC; however, HepG2 cells died acutely only at very high concentrations of GCDC. In HepaRG cells, pre‐treatment with the caspase inhibitor z‐VD‐FMK had no effect on cell death, indicating a lack of apoptotic cell death, and while JNK protein was activated by GCDC treatment in HepaRG cells, inhibition of JNK did not protect. Although previous data indicate that TCA stimulates pro‐inflammatory gene induction in PMH, there was no change in gene expression after TCA stimulation in HepaRG cells, which mimicked previous data found in primary human hepatocytes. These data provide evidence for HepaRG cells as a new model for the study of the effect of BA on human hepatocytes. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-14T10:58:29.376364-05:
      DOI: 10.1111/bcpt.12449
  • Cell‐Penetrating Peptides as Carriers for Oral Delivery of
    • First page: 99
      Abstract: Oral delivery of biopharmaceuticals, e.g. peptides and proteins, constitute a great challenge in drug delivery due to their low chemical stability and poor permeation across the intestinal mucosa; to a large extent limiting the mode of administration to injections, which is not favouring patient compliance. Nevertheless, cell‐penetrating peptides (CPPs) have shown promising potential as carriers to overcome the epithelium, and this MiniReview highlights recent knowledge gained within the field of CPP‐mediated transepithelial delivery of therapeutic peptides and proteins from the intestine. Two approaches may be pursued: Co‐administration of the carrier and therapeutic peptide in the form of complexes obtained by simple bulk‐mixing, or administration of covalent conjugates demanding more advanced production methodologies. These formulation approaches have their pros and cons, and which is to be preferred depends on the physicochemical properties of both the specific CPP and the specific cargo. In addition to the physical epithelial barrier, a metabolic barrier must be overcome in order to obtain CPP‐mediated delivery of a cargo drug from the intestine, and a number of strategies have been employed to delay enzymatic degradation of the CPP. The mechanisms by which CPPs translocate across membranes is not fully understood, but possibly involve endocytosis as well as direct translocation, and the CPP‐mediated transepithelial delivery of cargo drugs thus likely involves similar mechanisms for the initial membrane interaction and translocation. However, the mechanisms responsible for transcytosis of the cargo drug, if taken up by an endocytic mechanism, or direct translocation across the epithelium are so far not known. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-03T00:18:52.714483-05:
      DOI: 10.1111/bcpt.12515
  • Erythrocyte Shrinkage and Cell Membrane Scrambling after Exposure to the
           Ionophore Nonactin
    • Authors: Thomas Peter; Rosi Bissinger, Florian Lang
      First page: 107
      Abstract: The ionophore antibiotic nonactin permeabilizes cell membranes to NH4+ and K+. Treatment of erythrocytes with nonactin is expected to trigger cellular K+ loss with subsequent cell shrinkage, which in turn is known to trigger suicidal death of a wide variety of cells including erythrocytes. The present study explored whether nonactin exposure induces eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and translocation of cell membrane phosphatidylserine to the erythrocyte surface. Signalling of eryptosis include increase of cytosolic Ca2+‐activity ([Ca2+]i) and stimulation of protein kinase C as well as p38 mitogen activated protein kinase. Phosphatidylserine abundance at the cell surface was estimated from annexin‐V‐binding, cell volume from forward scatter and [Ca2+]i from Fluo3‐fluorescence. A 48‐hr treatment of human erythrocytes with nonactin significantly decreased forward scatter (≥ 10 ng/ml) and significantly increased the percentage of annexin‐V‐binding cells (≥10 ng/ml), effects paralleled by increase of [Ca2+]i (≥ 50 ng/ml) and virtually abrogated by increase of extracellular K+ concentration to 120 mM at the expense of Na+. The up‐regulation of annexin‐V‐binding after nonactin treatment was significantly blunted but not abolished by removal of extracellular Ca2+ and by addition of either PKC inhibitor staurosporine (0.4 μM) or p38 kinase inhibitor SB203580 (2 μM). In conclusion, exposure of erythrocytes to the K+ ionophore nonactin induces erythrocyte shrinkage and subsequent erythrocyte membrane scrambling, effects involving cellular K+ loss, Ca2+ entry and activation of staurosporine as well as SB203580 sensitive kinases. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-17T10:18:20.117007-05:
      DOI: 10.1111/bcpt.12455
  • Pharmacological Evidence that Histamine H3 Receptors Mediate
           Histamine‐Induced Inhibition of the Vagal Bradycardic Outflow in
           Pithed Rats
    • First page: 113
      Abstract: In vivo stimulation of cardiac vagal neurons induces bradycardia by acetylcholine (ACh) release. Since vagal release of ACh may be modulated by autoreceptors (muscarinic M2) and heteroreceptors (including serotonin 5‐HT1), this study has analysed the pharmacological profile of the receptors involved in histamine‐induced inhibition of the vagal bradycardic outflow in pithed rats. For this purpose, 180 male Wistar rats were pithed, artificially ventilated and pretreated (i.v.) with 1 mg/kg atenolol, followed by i.v. administration of physiological saline (1 ml/kg), histamine (10, 50, 100 and 200 μg/kg) or the selective histamine H1 (2‐pyridylethylamine), H2 (dimaprit), H3 (methimepip) and H4 (VUF 8430) receptor agonists (1, 10, 50 and 100 μg/kg each). Under these conditions, electrical stimulation (3, 6 and 9 Hz; 15±3 V and 1 ms) of the vagus nerve resulted in frequency‐dependent bradycardic responses, which were: (i) unchanged during the infusions of saline, 2‐pyridylethylamine, dimaprit or VUF 8430; and (ii) dose‐dependently inhibited by histamine or methimepip. Moreover, the inhibition of the bradycardia caused by 50 μg/kg of either histamine or methimepip (which failed to inhibit the bradycardic responses to i.v. bolus injections of acetylcholine; 1‐10 μg/kg) was abolished by the H3 receptor antagonist JNJ 10181457 (1 mg/kg, i.v.). In conclusion, our results suggest that histamine‐induced inhibition of the vagal bradycardic outflow in pithed rats is mainly mediated by prejunctional activation of histamine H3 receptors, as previously demonstrated for the vasopressor sympathetic outflow and the vasodepressor sensory CGRPergic (calcitonin gene‐related peptide) outflow. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-24T11:16:17.968995-05:
      DOI: 10.1111/bcpt.12475
  • Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and
           Patch Administration in Rats
    • First page: 122
      Abstract: Memantine is a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple‐ or single‐dose oral and transdermal administration. Venous blood was collected at pre‐set intervals in single‐ and multiple‐dose studies. Non‐compartmental pharmacokinetics were analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg, and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half‐life longer after patch administration, than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single‐ to multiple‐dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each doses. Additionally, the memantine patch formulation displayed a smaller inter‐individual variability and lower accumulation than the oral formulation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-27T05:07:02.818466-05:
      DOI: 10.1111/bcpt.12479
  • Similar Adiponectin Levels in Obese Normotensive and Obese Hypertensive
           Men and No Vasorelaxant Effect of Adiponectin on Human Arteries
    • First page: 128
      Abstract: Obesity is a strong risk factor for hypertension but the mechanism linking obesity to hypertension is not fully elucidated. In obesity, circulating concentrations of adiponectin are decreased and hypoadiponectinaemia has in some but not all studies been associated with increased risk of hypertension. Due to this inconsistency, we decided to study adiponectin from two aspects in a cross‐sectional in vivo study and in an experimental in vitro study. In the cross‐sectional study, 103 men with body mass index (BMI) ≥30.0 kg/m2 were studied; 63 had 24‐hr ambulatory blood pressure (ABP) ≥130/80 mmHg (ObeseHT) and 40 had 24‐hr ABP
      PubDate: 2015-08-14T05:57:02.932286-05:
      DOI: 10.1111/bcpt.12452
  • Concurrent Use of Low‐Dose Aspirin and Omega‐3 Fatty Acids and
           Risk of Upper Gastrointestinal Complications: A Cohort Study with Nested
           Case‐Control Analysis
    • Authors: G. Roberto; M. Simonetti, C. Cricelli, I. Cricelli, S.E. Giustini, D. Parretti, F. Lapi
      First page: 136
      Abstract: The risk of upper gastrointestinal complications (UGIC) due to low‐dose aspirin (LDA) can be further increased by the concurrent exposure to other antithrombotic agents. Little is known on the combined therapy with LDA and medications containing omega‐3 fatty acids (OM3), which also exert antiplatelet activity. The aim of this study was to investigate the risk of UGIC in patients exposed to LDA‐OM3 combination. The Italian Health Search IMS Longitudinal Patients Database was used to perform a population‐based cohort study. Patients aged ≥18 years with cardio or cerebrovascular ischaemic disease recorded between 2002 and 2012 (cohort entry) were selected. All UGIC cases (index date) observed up to December 2013 were identified. According to a nested case‐control analysis, up to 10 controls were matched to each case on age, sex and calendar period. The risk of UGIC was investigated among current (up to 30 days preceding index date), recent (31–60 days) and past users (61–365 days) of the LDA‐OM3 combination. Exposure assessment was lagged by 30 days to minimize reverse causation. Additionally, a duration–response analysis was performed. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Non‐users of the LDA‐OM3 combination were the reference category. Current (OR=0.66; 95%CI: 0.44–1.00), recent (OR=0.83; 95%CI: 0.52–1.33) and past users (OR=0.81; 95%CI: 0.57–1.15) did not statistically significantly increase the risk of UGIC. No duration–response relationship was found. Our results suggest that LDA‐OM3 combination therapy does not affect the UGIC risk in patients with cardio or cerebrovascular ischaemic diseases. Given the novelty of these findings, further studies are needed. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-17T10:18:56.203315-05:
      DOI: 10.1111/bcpt.12454
  • Detection of Patients at High Risk of Medication Errors: Development and
           Validation of an Algorithm
    • First page: 143
      Abstract: Medication errors (MEs) are preventable and can result in patient harm and increased expenses in the health care system in terms of hospitalization, prolonged hospitalizations and even death. We aimed to develop a screening tool to detect acutely admitted patients at low or high risk of MEs comprised by items found by literature search and use of theoretical weighting. Predictive variables used for the development of the risk score were found by literature search. Three retrospective patient populations and one prospective pilot population were used for modelling. The final risk score was evaluated for precision by use of sensitivity, specificity and area under the ROC (Receiver Operating Characteristic) curves. The variables used in the final risk score were reduced renal function, the total number of drugs and the risk of individual drugs to cause harm and drug‐drug interactions. We found a risk score in the prospective population with an area under the ROC curve of 0.76. The final risk score was found to be quite robust as it showed an area under the ROC curve of 0.87 in a recent patient population, 0.74 in a population of internal medicine and 0.66 in an orthopaedic population. We developed a simple and robust score, MERIS, with the ability to detect patients and divide them according to low and high risk of MEs in a general population admitted at acute admissions unit. The accuracy of the risk score was at least as good as other models reported using multiple regression analysis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-24T06:07:34.299349-05:
      DOI: 10.1111/bcpt.12473
  • Diabetic Ketoacidosis in a Patient with Type 2 Diabetes after Initiation
           of Sodium‐Glucose Co‐Transporter 2 Inhibitor Treatment
    • First page: 168
      Abstract: Sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) were recently introduced for the treatment of type 2 diabetes (T2D). SGLT2i lower plasma glucose by inhibiting the renal reuptake of glucose leading to glucosuria. Generally, these drugs are considered safe to use. However, recently, SGLT2i have been suggested to predispose to ketoacidosis. Here, we present a case of diabetic ketoacidosis (DKA) developed in an obese, poorly controlled male patient with T2D treated with the SGLT‐2i dapagliflozin. He was admitted with DKA five days after initiation of treatment with the SGLT2i dapagliflozin. On admission, the primary symptoms were nausea and dizziness, and he was hypertensive (170/103) and tachycard (119 bpm), had mild hyperglycaemia (15.3 mmol/l), severe ketonuria and severe metabolic acidosis (pH 7.08). He responded well to infusions of insulin, glucose and saline and was discharged after 72 hr with insulin as the only glucose‐lowering therapy. After one month, dapagliflozin was reintroduced as add‐on to insulin with no recurrent signs of ketoacidosis. During acute illness or other conditions with increased insulin demands in diabetes, SGLT2i may predispose to the formation of ketone bodies and ensuing acidosis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-20T07:23:58.068388-05:
      DOI: 10.1111/bcpt.12457
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