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ENVIRONMENTAL STUDIES (737 journals)                  1 2 3 4 5 6 7 8 | Last

Acta Ecologica Sinica     Open Access   (Followers: 10)
Acta Limnologica Brasiliensia     Open Access   (Followers: 1)
Acta Oecologica     Hybrid Journal   (Followers: 7)
Acta Regionalia et Environmentalica     Open Access  
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 13)
Advances in Ecological Research     Full-text available via subscription   (Followers: 25)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 17)
Advances in Life Science and Technology     Open Access   (Followers: 6)
Aeolian Research     Hybrid Journal   (Followers: 3)
African Journal of Environmental Science and Technology     Open Access   (Followers: 3)
African Journal of Sustainable Development     Full-text available via subscription   (Followers: 7)
AGE     Hybrid Journal   (Followers: 4)
Age and Ageing     Hybrid Journal   (Followers: 39)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 12)
Ambiência     Open Access  
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Applied Sciences     Open Access   (Followers: 29)
American Journal of Environmental Engineering     Open Access   (Followers: 8)
American Journal of Environmental Protection     Open Access   (Followers: 5)
American Journal of Environmental Sciences     Open Access   (Followers: 12)
American Journal of Microbiology     Open Access   (Followers: 15)
American Naturalist     Full-text available via subscription   (Followers: 51)
Annals of GIS     Hybrid Journal   (Followers: 18)
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: 46)
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: 23)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 11)
Applied and Environmental Soil Science     Open Access   (Followers: 12)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 15)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 15)
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: 3)
Asian Journal of Earth Sciences     Open Access   (Followers: 20)
Asian Journal of Rural Development     Open Access   (Followers: 11)
ATBU Journal of Environmental Technology     Open Access   (Followers: 1)
Atmospheric and Climate Sciences     Open Access   (Followers: 15)
Atmospheric Environment     Hybrid Journal   (Followers: 27)
Austral Ecology     Hybrid Journal   (Followers: 9)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 4)
Australasian Journal of Human Security, The     Full-text available via subscription   (Followers: 3)
Australian Journal of Environmental Education     Full-text available via subscription   (Followers: 8)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 7)
Basic and Applied Ecology     Hybrid Journal   (Followers: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 48)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 36)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 25)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 2)
Bioremediation Journal     Hybrid Journal   (Followers: 4)
BioRisk     Open Access   (Followers: 2)
BMC Ecology     Open Access   (Followers: 19)
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: 5)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 9)
Bulletin of the American Meteorological Society     Open Access   (Followers: 16)
Business, Peace and Sustainable Development     Full-text available via subscription   (Followers: 2)
Canadian Journal of Earth Sciences     Full-text available via subscription   (Followers: 6)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 13)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 12)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 20)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 13)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
Cell Biology and Toxicology     Hybrid Journal   (Followers: 7)
Chain Reaction     Full-text available via subscription  
Change and Adaptation in Socio-Ecological Systems     Open Access  
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 14)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 2)
Chemosphere     Hybrid Journal   (Followers: 11)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 46)
Civil and Environmental Engineering     Open Access   (Followers: 1)
Civil And Environmental Engineering Reports     Open Access  
Civil and Environmental Research     Open Access   (Followers: 15)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 18)
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: 21)
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: 2)
Conservation and Society     Open Access   (Followers: 10)
Conservation Letters     Open Access   (Followers: 24)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (Followers: 14)
Construction Innovation: Information, Process, Management     Hybrid Journal   (Followers: 15)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 3)
Creativity and Innovation Management     Hybrid Journal   (Followers: 81)

        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]
  • Issue Information
    • PubDate: 2015-08-04T22:24:23.732212-05:
      DOI: 10.1111/bcpt.12448
  • 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
  • Histamine‐2 Receptor Antagonists and Semen Quality
    • Authors: SA Banihani
      Abstract: Histamine‐2 receptor antagonists are a class of drugs used to treat the acid‐related gastrointestinal diseases such as ulcer and gastro‐oesophageal reflux disease. Although such drugs, especially ranitidine and famotidine, are still widely used, their effects on semen quality, and hence on male infertility, is still unclear. This MiniReview systematically addresses and summarizes the effect of histamine‐2 receptor antagonists (cimetidine, ranitidine, nizatidine and famotidine) on semen quality, particularly, on sperm function. Cimetidine appears to have adverse effects on semen quality. While the effects on semen quality of ranitidine and nizatidine are still controversial, famotidine does not appear to change semen quality. Therefore, additional studies will be required to clarify whether histamine H2 receptor‐independent effects of these drugs play a role in semen quality as well as further clinical studies including direct comparison of the histamine H2 receptor antagonists. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-14T10:56:08.718271-05:
      DOI: 10.1111/bcpt.12446
  • Is Minocycline an Anti‐Viral Agent? A Review of Current
    • Authors: Sandhya Nagarakanti; Eliahu Bishburg
      Abstract: Minocycline is a second‐generation semi‐synthetic derivative of tetracycline and has well‐known anti‐bacterial effects. The drug possesses anti‐inflammatory, anti‐oxidant, anti‐apoptotic and immune modulatory effects. The drug is widely used in bacterial infections and non‐infectious conditions such as acne, dermatitis, periodontitis and neurodegenerative conditions. Minocycline was shown to have antiviral activity in vitro and also against different viruses in some animal models. Some studies have been done on human patients infected with Human Immunodeficiency Virus. We review available data regarding minocycline activity as an antiviral agent. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-14T09:33:22.47201-05:0
      DOI: 10.1111/bcpt.12444
  • Off‐Label and Unlicensed Prescribing of Medicines in Paediatric
           Populations: Occurrence and Safety Aspects
    • Authors: Lise Aagaard
      Abstract: Off‐label (OL) and unlicensed (UL) use of medicines in children and adolescents is common as only few medications are licensed for use in the paediatric population. Hence, lack of knowledge about adverse drug reactions (ADRs) from paediatric OL/UL prescribing makes medicine use in children of public interest and concern [1‐2]. This topic was also the starting point for the study by Hart et al This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-14T09:33:21.072193-05:
      DOI: 10.1111/bcpt.12445
  • Serum Metabolomic Profiling of Sulfur Mustard‐Exposed Individuals
           Using 1HNuclear Magnetic Resonance Spectroscopy
    • Authors: Zahra Zamani; Mostafa Ghanei, Yunus Panahi, Mohammad Arjmand, Sedigheh Sadeghi, Fatemeh Mirkhani, Shahram Parvin, Maryam Salehi, Amirhossein Sahebkar, Farideh Vahabi
      Abstract: Sulfur mustard is an alkylating agent that reacts with different cellular components, causing acute and delayed complications that may remain for decades after exposure. The present study aimed to identify differentially expressed metabolites between mustard‐exposed individuals suffering from chronic complications compared with unexposed individuals as the control group. Serum samples were obtained from 15 mustard‐exposed individuals and 15 apparently healthy unexposed individuals. Metabolomic profiling was performed using 1HNMR spectroscopy, and analyses were carried out using Chenomex and MATLAB softwares. Metabolites were identified using Human Metabolic Data Base (HMDB), and the main metabolic pathways were identified using Metaboanalyst software. Chemometric analysis of serum samples identified 11 differentially expressed metabolites between mustard‐exposed and unexposed groups. The main pathways that were influenced by sulfur mustard exposure were related to vitamin B6 (down‐regulation), bile acid (up‐regulation) and tryptophan (down‐regulation) metabolism. Metabolism of vitamin B6, bile acids and tryptophan are the most severely impaired pathways in individuals suffering from chronic mustard‐induced complications. These findings may find implications in the monitoring of exposed patients and identification of new therapeutic approaches. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-14T08:38:39.86358-05:0
      DOI: 10.1111/bcpt.12441
  • Effects of High‐Dose Cisplatin Chemotherapy and Conventional
           Radiotherapy on Urinary Oxidative and Nitrosative Stress Biomarkers in
           Patients with Head and Neck Cancer
    • Abstract: Cisplatin is a chemotherapeutic agent widely used in the treatment of several solid tumours. For patients with advanced head and neck squamous cell carcinoma in whom surgery is contraindicated, treatment with high‐dose cisplatin administered every 21 days for 3 cycles concomitantly with conventional radiotherapy is recommended [1‐3]. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-14T07:58:45.723626-05:
      DOI: 10.1111/bcpt.12443
  • Switching among Equivalents in Chronic Cardiovascular Therapies:
           “Real World” Data from Italy
    • Authors: Elisabetta Poluzzi; Giacomo Veronese, Carlo Piccinni, Emanuel Raschi, Ariola Koci, Paola Pagano, Brian Godman, Giulio Marchesini, Giuseppe Boriani, Fabrizio De Ponti
      Abstract: Since August 2012, Italian general practitioners are required to prescribe the generic name of medicines, except for refill of chronic therapy. We evaluated the extent of switching among equivalents in chronic cardiovascular therapies, the influence of the 2012 regulatory intervention and of patient‐related or drug‐related factors. Prescription of off‐patent antiarrhythmics, oral antidiabetics and ACE‐inhibitors dispensed from August 2011 to August 2013 within the Bologna Local Health Authority (870,000 inhabitants) were collected. The rate of actual switching among equivalents was evaluated monthly. The effect of the regulatory intervention was estimated by interrupted time series analysis. Adjusted odds ratios (aORs) of switching were calculated for: age, gender, number of different equivalents available for each drug, change in dispensing pharmacy between subsequent refills. The average monthly rates of switches were 9.6%, 16.3% and 16.3% for antiarrhythmics, antidiabetics and ACE inhibitors, respectively. Values significantly increased soon after the regulatory intervention for ACE inhibitors (+1.81%, p
      PubDate: 2015-07-07T05:09:33.603393-05:
      DOI: 10.1111/bcpt.12442
  • The Effect of Alpinia zerumbet Essential Oil on Post‐Stroke Muscle
    • Abstract: The essential oil of Alpinia zerumbet (EOAz) presents myorelaxant and antispasmodic actions on cardiac and smooth muscles. The aim of this study was to investigate the effect of EOAz on the skeletal muscle contraction in post stroke spasticity. Fifteen adults with unilateral hemiparesis and spasticity resulting from stroke were submitted to surface electromyography readings of the gastrocnemius muscle, before and after 10 daily applications (dermal 0.05 ml per muscle belly) of EOAz. The healthy contralateral muscles without applying the oil were used as controls. The analysis showed that, in both lateral and medial gastrocnemius, the values of all studied variables (root mean square, maximum amplitude and median power frequency) were significantly decreased in pathological legs during muscle contraction (Wilcoxon test, p < 0.05). Moreover, spastic muscles presented different results before and after dermal application of EOAz: The mean values of root mean square and median power frequency were significantly increased in lateral and medial gastrocnemius, and also the maximum amplitude increased in medial gastrocnemius (Mann‐Whitney test, p < 0.05). The results suggest that EOAz acts in the skeletal spastic muscle contraction by promoting relaxation and improvement of the muscular performance. Thus, the EOAz can be useful for the clinical management of secondary effects in patients with cerebral vascular disease. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-01T04:47:44.081426-05:
      DOI: 10.1111/bcpt.12439
  • Potentiation of Glibenclamide Hypoglycaemia in Mice by MK‐467, a
           Peripherally Acting Alpha2‐Adrenoceptor Antagonist
    • Abstract: Pharmacological antagonism and genetic depletion of pancreatic α2A‐adrenoceptors increase insulin secretion in mice, and enhance the insulinotropic action of glibenclamide, a representative of the sulphonylurea class of insulin secretagogues used in the therapy of type 2 diabetes. Antagonism of α2‐adrenoceptors in the central nervous system (CNS) causes tachycardia and hypertension, making generalized α2‐adrenoceptor blockade unfavourable for clinical use despite its potential to decrease blood glucose levels. The purpose of this study was to test the acute effects of the peripherally acting α2‐adrenoceptor antagonist MK‐467 alone and in combination with glibenclamide in non‐diabetic C57BL/6N mice. Cardiovascular safety was assessed in freely moving mice with radiotelemetry. Dose‐dependent decreases in blood glucose and increases in plasma insulin concentrations were seen with the combination of MK‐467 and glibenclamide; the combinations were much more potent than glibenclamide or MK‐467 alone. Furthermore, MK‐467 had no effect on mean arterial pressure or heart rate in freely moving mice, and did not prevent the centrally mediated hypotensive effect of the α2‐adrenoceptor agonist medetomidine. Thus, peripheral blockade of α2‐adrenoceptors does not evoke the same cardiovascular adverse effects as antagonism of CNS α2‐adrenoceptors. The current results indicate that the combined use of small doses of a peripherally acting α2‐adrenoceptor antagonist with a sulphonylurea drug could provide a novel option for the treatment of type 2 diabetes, especially in patients with increased tonic α2‐adrenoceptor‐mediated inhibition of insulin secretion. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-01T04:46:40.871901-05:
      DOI: 10.1111/bcpt.12440
  • Morphine Analgesia Modification in Normotensive and Hypertensive Female
           Rats after Repeated Fluoxetine Administration
    • Abstract: The purpose of this investigation was to determine through the use of fluoxetine the effect of administering a serotonin reuptake inhibitor over several days on the antinociceptive action of μ‐morphine type opioid receptor agonist. Investigations were performed on rats of both sexes, both the WKY normotensive strains as well as on the SHR genetically conditioned hypertensive strains. Results showed that the efficacy of morphine analgesia is higher in the SHR strain compared to normotensive rats (WKY). Surprisingly, repeated administration of fluoxetine reduced morphine analgesia, with the weakening of opioid antinociceptive action comparable to the duration of serotonin reuptake inhibitor administration. It was also concluded that the antinociceptive action of morphine in female rats and the alteration of its efficacy as a result of fluoxetine premedication for several days depend on oestrus cycle phase. The highest sensitivity of female rats to morphine was reported in the diestrus and oestrus phases; much lower values were reported for the metestrus phase. This article is protected by copyright. All rights reserved.
      PubDate: 2015-07-01T04:37:36.196487-05:
      DOI: 10.1111/bcpt.12438
  • Developing a Competency‐based Curriculum in Basic and Clinical
           Pharmacology ‐ A Delphi Study among Physicians
    • Abstract: A new curriculum is planned for the medical school at Lund University, Sweden. Pharmacology, in a broad sense, has been identified as a subject that needs to be strengthened based on needs in the health care system. The aim was to identify the competencies in basic and clinical pharmacology that a newly qualified physician needs. Using a modified three‐round Delphi technique, 31 physicians were invited to list necessary competencies (round 1). After content analysis, these panel members classified the list by importance on two occasions (rounds 2 and 3) using a 4‐point scale (4 = necessary, 3 = desirable, 2 = useful, 1 = not necessary). Competencies with the highest ranks based on necessity were retained. Thirty physicians accepted the invitation and 25 (83%) of them completed all three rounds. Round 1 resulted in 258 suggestions, which were subsequently reduced to 95 competencies. Of these 95 competencies, 40 were considered necessary by at least 75% of the panel members. The degree of consensus increased between round 2 and round 3. Using a modified Delphi technique we identified 40 competencies that could be transferred to learning outcomes for a new curriculum in basic and clinical pharmacology at medical school. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-29T04:41:50.539212-05:
      DOI: 10.1111/bcpt.12436
  • Anticholinergic Accumulation: A Slumbering Interaction between Drugs and
           Food Supplements
    • Abstract: Many compounds display anticholinergic effects which might give rise to cognitive impairment and even delirium. These side effects are caused by their ability to bind to muscarinic receptors in our brain. Especially with combination of compounds, these serious effects are seen. This phenomenon, known as anticholinergic accumulation, is especially seen in the elderly. A classification of drugs for anticholinergic side effects has been made based on clinical observations, the ACB score. Here, we aimed to substantiate this classification by comparing the affinity of numerous drugs for the muscarinic receptors to the ACB score. Additionally, a number of supplements were screened. The affinity of the compounds was determined by their ability to displace the radioligand [3H]pirenzepine of the muscarinic receptor induced by these compounds. Our results show that the affinity of a compound for the muscarinic receptors correlated with its ACB score. Also food supplements appeared to bind to these muscarinic receptors. Moreover, several drug‐drug, supplement‐supplement and supplement‐drug combinations had an affinity that is higher than the affinity of single compounds. This explains the phenomenon of anticholinergic accumulation. In conclusion, care should be taken to drug‐drug and supplement‐drug combinations with respect to anticholinergic accumulation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-29T04:36:16.596653-05:
      DOI: 10.1111/bcpt.12437
  • Drug‐related Inadvertent Deaths in a University Hospital – A
           Declining Trend'
    • Abstract: We studied the incidence of fatal adverse drug reactions (ADR) in a tertiary hospital in order to find out which drugs were involved. The secondary objective was to compare the data from the same hospital published 12 years earlier. All 1708 death cases in the Helsinki University Central Hospital during the year 2012 were retrospectively evaluated. All suspected drug‐related deaths, excluding suicides, were scrutinized by an expert panel using the WHO ADR probability classification. Of all cases, 52 (3.0%) were classified as certainly or probably drug‐related and 24 (1.4%) as possibly drug‐related. Together, these corresponded to 0.02% of all hospital admissions. The most commonly involved drugs in certain or probable cases were cytostatics (18 cases, 1.1% of all cases) and antithrombotics (17, 1.0%). Twelve years earlier, these caused 27 (1.8%) and 22 (1.5%) cases, respectively. Non‐steroidal anti‐inflammatory drugs (NSAIDs) and glucocorticoids caused less (2 and 0 cases) fatal ADRs than earlier (12 and 4 cases, p=0.048 and p=0.005, respectively). Most of the ADRs leading to death were present already in admission and affected seriously ill or elderly patients. Hospital‐born fatal ADRs occurred in 0.003% of patients. In conclusion, cytostatics and antithrombotics are still the leading causes of fatal ADRs, but NSAIDs and glucocorticoids seem to cause fatal ADRs less often than previously. The incidence of fatal ADRs in 2012 was 3.0% of all deaths, suggesting a decline compared to the 2000 value (5.0%). Improved awareness, prevention and treatment of ADRs and safer medicines may explain these declining trends. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-26T03:54:32.929284-05:
      DOI: 10.1111/bcpt.12435
  • Hyperhomocysteinemia: Impact on Neurodegenerative Diseases
    • Authors: Meenakshi Sharma; Manisha Tiwari, Rakesh Kumar Tiwari
      Abstract: Neurodegenerative diseases are the central nervous system diseases with various aetiology and symptoms. Dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and autism are some examples of neurodegenerative diseases. Hyperhomocysteinemia (Hhcy) is considered to be an independent risk factor for numerous pathological conditions under neurodegenerative diseases. Along with genetic factors that are the prime cause of homocysteine (Hcy) imbalance, the nutritional and hormonal factors are also contributing to high Hcy level in the body. Numerous clinical and epidemiological data confirm the direct correlation of Hcy level in the body and generation of different types of central nervous system disorders, cardiovascular diseases, cancer and others. Till now, it is difficult to say whether homocysteine is the cause of the disease, or it is one of the impacts of the diseases. However, Hhcy is a surrogate marker of vitamin B deficiency and is a neurotoxic agent. This MiniReview will give an overview of how far research has gone into understanding the homocysteine imbalance with prognostic, causative and preventive measure in treating neurodegenerative diseases. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-19T21:36:08.483906-05:
      DOI: 10.1111/bcpt.12424
  • Adverse Events Associated with Flumazenil Treatment for the Management of
           Suspected Benzodiazepine Intoxication – A Systematic Review with
           Meta‐Analyses of Randomised Trials
    • Abstract: Flumazenil is used for reversal of benzodiazepine overdose. Serious adverse events (SAEs) including seizures and cardiac arrhythmias have been reported in patients treated with flumazenil, and the clinical advantage of flumazenil treatment has been questioned. The objective was to assess the risk of (S)AEs associated with use of flumazenil in patients with impaired consciousness due to known or suspected benzodiazepine overdose. Studies included in the meta‐analyses were identified by literature search in Medline, Cochrane Library and Embase using combinations of the words flumazenil, benzodiazepines, anti‐anxiety agents, poisoning, toxicity and overdose. Randomised clinical trials (RCTs) in verified or suspected benzodiazepine overdose patients comparing treatment with flumazenil versus placebo were included. Pre‐defined outcome measures were AEs, SAEs and mortality. Thirteen trials with a total of 994 randomised (990 evaluable) patients were included. AEs were significantly more common in the flumazenil group (138/498) compared with the placebo group (47/492) (risk ratio: 2.85; 95% confidence interval: 2.11‐3.84; p
      PubDate: 2015-06-19T06:41:07.63603-05:0
      DOI: 10.1111/bcpt.12434
  • Effect of Truncating AUC at 12, 24 and 48 Hours when Evaluating the
           Bioequivalence of Drugs with a Long Half‐Life
    • Abstract: Bioequivalence studies of drugs with a long half‐life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC0‐t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within‐individual coefficient of variation (CVw) and on the ratio of the formulations was also analysed. Twenty‐eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time points. The degree of agreement of AUC0‐72 in relation to AUC0‐48 and AUC0‐24, according to the Landis and Koch classification, was “almost perfect”. Statistically significant differences were observed when the CVw of AUC truncated at 72, 48 and 24 hr was compared with the CVw of AUC0‐12. There were no statistically significant differences in the AUC ratio at any time point. Compared to AUC0‐72, Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CVw was worse for AUC0‐12 than AUC0‐24 or AUC0‐48. These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalent. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-18T05:48:12.315968-05:
      DOI: 10.1111/bcpt.12432
  • Toxic Epidermal Necrolysis after Exposure to Dithiocarbamate Fungicide
    • Authors: Sergey Zakharov; Jan Csomor, Petr Urbanek, Daniela Pelclova
      Abstract: Toxic epidermal necrolysis (TEN) is a life‐threatening mucocutaneous disease with high mortality. Dithiocarbamates are organosulfur compounds widely used in agriculture, industry and households. We report a case of TEN after exposure to mancozeb in fungicide. A 48‐year‐old 75 kg b.w. male was admitted with fever and generalized skin/mucous lesions after application of fungicide in a homegarden. The patient had necrotic desquamation of gastrointestinal/respiratory tract mucosa, ocular lesion, and skin epidermolysis of 90% of body surface. The laboratory findings included inflammatory parameters elevation, hyperglycemia, increased urea, creatinine, liver enzymes, hypoalbuminemia and electrolyte disturbances. The treatment included supportive care, management of fluid/electrolyte requirements, analgesics and enteral nutrition. Skin lesions were treated with occlusive non‐adhesive biological wound dressings. Due to the proof of Acinetobacter, Escherichia coli and Escherichia faecalis from skin swabs, a combination of meropenem with amikacin was administered. During the next two weeks, complete re‐epithelialization of skin lesions occurred, mucosal lesions healed and the laboratory parameters returned to normal. The patient was discharged on day 42. Toxic epidermal necrolysis is a rare condition that is generally caused by medications. Nevertheless, high attention should be paid to the cases of occupational or household exposure to dithiocarbamate fungicides widely used in agriculture and homegardens because of their ability to cause TEN after skin and inhalation exposure. Greater emphasis on the hazardous properties of these products is necessary to ensure non‐professional users are aware of the necessity of protective clothing during mixing, loading, application and early re‐entry into treated fields. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-13T07:02:12.331207-05:
      DOI: 10.1111/bcpt.12430
  • Headache and Nausea after Treatment with High‐Dose Subcutaneous
           versus Intravenous Immunoglobulin
    • Authors: L.H. Markvardsen; I. Christiansen, H. Andersen, J. Jakobsen
      Abstract: Treatment with intravenous immunoglobulin (IVIG) leads to transient side effects such as headache and nausea during and after the infusion. We hypothesized that subcutaneous administration of smaller doses of immunoglobulin (SCIG) given more frequently leads to less severe headache and nausea and could be an alternative in patients experiencing side effects. Fifty‐nine patients diagnosed with neurological disorders (chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) or post‐polio syndrome) were treated with IVIG, and 27 CIDP or MMN patients with SCIG. For two consecutive weeks daily, registration of the severity of headache and nausea was registered on a Visual Analog Scale (VAS) from 0 to 100 mm. In the SCIG group, headache reached a peak value of 1 (0‐13) mm at day 6 versus 11 (0‐96) mm in the IVIG group at day 4 (P
      PubDate: 2015-06-12T03:23:40.531851-05:
      DOI: 10.1111/bcpt.12428
  • Resveratrol Enhances Etoposide‐Induced Cytotoxicity through
           Down‐Regulating ERK1/2 and AKT‐Mediated X‐ray Repair
           Cross‐Complement Group 1 (XRCC1) Protein Expression in Human
           Non‐Small‐Cell Lung Cancer Cells
    • Abstract: Etoposide (VP‐16), a topoisomerase II inhibitor, is an effective anti‐cancer drug used for the treatment of non‐small cell lung cancer (NSCLC). Resveratrol is a naturally occurring polyphenolic compound that has been proved to have anti‐cancer activity. XRCC1 is an important scaffold protein involved in base excision repair that is regulated by ERK1/2 and AKT signals, and plays an important role in the development of lung cancer. However, the role of ERK1/2 and AKT‐mediated XRCC1 expression in etoposide treatment alone or combined with resveratrol‐induced cytotoxicity in NSCLC cells has not been identified. In this study, etoposide treatment increased XRCC1 mRNA and protein expression through AKT and ERK1/2 activation in two NSCLC cells, H1703 and H1975. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of ERK1/2 and AKT resulted in enhancing cytotoxicity and cell growth inhibition induced by etoposide. Resveratrol inhibited the expression of XRCC1 and enhanced the etoposide‐induced cell death and anti‐proliferation effect in NSCLC cells. Furthermore, transfection with constitutive active MKK1 or AKT vectors could rescue the XRCC1 protein level and also the cell survival suppressed by co‐treatment with etoposide and resveratrol. These findings suggested that down‐regulation of XRCC1 expression by resveratrol can enhance the chemosensitivity of etoposide in NSCLC cells. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-04T07:47:15.096079-05:
      DOI: 10.1111/bcpt.12425
  • Towards Development of a Dermal Pain Model: In Vitro Activation of Rat and
           Human TRPA1 and Safe Dermal Injection of o‐Chlorobenzylidene
           Malononitrile (CS) to Rat
    • Abstract: During clinical development of analgesics, it is important to have access to pharmacologically specific human pain models. o‐Chlorobenzylidene malononitrile (CS) is a selective and potent agonist of the transient receptor potential ankyrin repeat 1 (TRPA1), which is a transducer molecule in nociceptors sensing reactive chemical species. While CS has been subject to extensive toxicological investigations in animals and human beings, its effects on intradermal or subcutaneous injection has not previously been reported. We have investigated the potential of CS to be used as an agonist on TRPA1 in human experimental pain studies. A calcium influx assay was used to confirm the capacity of CS to activate TRPA1 with >100,000‐fold selectivity over the transient receptor potential vanilloid receptor 1 (TRPV1). CS dose‐dependently (EC50 0.9 μM) released calcitonin gene‐related peptide (CGRP) in rat dorsal root ganglion (DRG) cultures, supporting involvement in pain signalling. In a local tolerance study, injection of a single intradermal dose of 20 mM CS to rats resulted in superficial, circular crusts at the injection sites after approximately 4 days. The histopathology evaluation revealed a mild, acute inflammatory reaction in the epidermis and dermis at the intradermal CS injection site one day after administration. After 14 days, the epidermal epithelium was fully restored. The symptoms were not considered to be adverse and it is suggested that doses up to 20 μL of 20 mM CS can be safely administered to human beings. In conclusion, our data support development of a CS human dermal pain model. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-04T07:46:59.215347-05:
      DOI: 10.1111/bcpt.12427
  • Treatment of Community‐Acquired Pneumonia in Adults: Analysis of the
           National Dispensing Database
    • Authors: Maria Matuz; Julia Bognar, Edit Hajdu, Peter Doro, Andrea Bor, Reka Viola, Gyongyver Soos, Ria Benko
      Abstract: Crude national ambulatory antibiotic dispensing data (2007‐2011) of adult patients (aged between 20 and below 65 years) with CAP were obtained and expressed as DDD per 1000 inhabitants and per day (DID). European quality indicators of antibiotic prescribing were calculated and adherence rate to the national CAP guideline was assessed. Antibiotic use for CAP in adults ranged between 0.27 and 0.30 DID in various years. The most frequently used antibacterials were levofloxacin, co‐amoxiclav and clarithromycin. Antibiotic use in CAP was compliant with the European recommendations in 6.4% in 2007, which decreased to 4.9% by 2011, in contrast to the optimal compliant range of 80‐100%. The consumption of fluoroquinolones mounted up to ~40% in both genders, which exceeded the recommended range (0‐5%) substantially. National guideline also favoured the use of macrolides in the empiric therapy of CAP in otherwise healthy adults, hence guideline‐concordant antibiotic use ranged between 24.0%‐32.3%. Agents that were contra‐indicated in the empiric therapy of CAP were also used in 6.5‐9.0% in various years. These data reflect some worrisome figures and trends in the outpatient antibiotic treatment of adults with CAP. Clarified and updated national guidelines focusing on outpatients and incentives/regulations to increase guideline concordance are warranted. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-04T07:46:21.092533-05:
      DOI: 10.1111/bcpt.12426
  • The Effect of Oral Morphine on Pain‐Related Brain Activation –
           An Experimental Functional Magnetic Resonance Imaging Study
    • Abstract: Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 males and 7 females, 24.9±2.6 years) in a randomised, double‐blind, placebo‐controlled, cross‐over study. Painful stimulations were applied to the right forearm using a Contact Heat Evoked Potential Stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n=16, p
      PubDate: 2015-05-29T11:03:21.477592-05:
      DOI: 10.1111/bcpt.12415
  • Stimulation of Suicidal Erythrocyte Death by Naphthazarin
    • Authors: Omar Aljanadi; Kousi Alzoubi, Rosi Bissinger, Florian Lang
      Abstract: The 1,4‐naphthoquinone derivative Naphthazarin may trigger apoptosis and is thus considered for the treatment of malignancy. On the other hand, Naphthazarin decreases neurotoxicity. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with translocation of phosphatidylserine to the erythrocyte surface. Signalling leading to triggering of eryptosis include increase of cytosolic Ca2+‐activity ([Ca2+]i), ceramide and oxidative stress. The present study explored whether Naphthazarin impacts on eryptosis and, if so, to unravel underlying mechanisms. To this end, erythrocyte volume was estimated from forward scatter, phosphatidylserine abundance at the erythrocyte surface from FITC‐annexin‐V‐binding, [Ca2+]i from Fluo3 fluorescence, reactive oxidant species (ROS) from 2′,7′‐dichlorodihydrofluorescein diacetate (DCFDA) fluorescence and ceramide abundance at the erythrocyte surface from binding of fluorescent antibodies in flow cytometry. As a result, a 24‐hr exposure of human erythrocytes to Naphthazarin (10 μM) significantly decreased erythrocyte forward scatter, significantly increased the percentage of annexin‐V‐binding cells, significantly increased ceramide abundance at the erythrocyte surface and significantly increased ROS. The effect of Naphthazarin on annexin‐V‐binding was not significantly blunted by removal of extracellular Ca2+. In conclusion, Naphthazarin stimulates eryptosis, an effect at least in part due to oxidative stress and enhanced ceramide abundance at the erythrocyte surface. This article is protected by copyright. All rights reserved.
      PubDate: 2015-05-25T08:35:23.504227-05:
      DOI: 10.1111/bcpt.12420
  • Effects of NO‐Hybridization on the Immunomodulatory Properties of
           the HIV Protease Inhibitors Lopinavir and Ritonavir
    • Abstract: HIV protease inhibitors (PIs) are antiretroviral agents, which have been found to also affect several cellular processes, such as inflammation and cell progression. In studies on non‐steroidal, anti‐inflammatory drugs, the addition of a nitric oxide (NO) moiety has been shown to both reduce their toxicity and enhance their pharmacological efficacy. Along this line of research, several derivatives of PIs have been synthesized by covalent attachment of NO moiety to the parental molecules. Previous work has indicated that NO‐hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir‐NO that while retaining the antiretroviral effect, acquires anti‐tumoural and immunomodulatory properties along with reduced toxicity in vitro and in vivo. These data prompted us to evaluate the effects of NO‐hybridization on two other PIs, Lopinavir and Ritonavir. The two NO‐derivatives were compared head to head with their parental compounds on human primary peripheral blood mononuclear cells as well as on human primary macrophages. Lopinavir‐NO and Lopinavir were also screened in an in vivo model of autoimmune hepatitis. Our results prove that Lopinavir‐NO exerts markedly superior effects as compared to the parental compound both in vitro and in vivo. On the contrary, Ritonavir‐NO effects overlapped those of Ritonavir. These data demonstrate that NO‐hybridization of Lopinavir generates a derivative with significantly stronger immunomodulatory effects that are apparently related to an action of the compound on T cell secretory capacity. Lopinavir‐NO deserves additional studies for its possible use in T‐cell mediated autoimmune diseases including, but not limited to autoimmune hepatitis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-05-25T03:24:23.242931-05:
      DOI: 10.1111/bcpt.12414
  • Nonchemotherapy‐induced agranulocytosis detected by a prospective
           pharmacovigilance program in a tertiary hospital
    • Abstract: We conducted a prospective evaluation of nonchemotherapy‐induced agranulocytosis (NIA) in a tertiary hospital in Spain. Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital, we detected agranulocytosis cases over a period of 42 consecutive months. This report estimates incidence, drug causality, clinical features, outcomes of NIA cases, and assesses laboratory differences with respect to non‐NIA. We detected 1,349 cases of agranulocytosis in 538 adult patients; of these, 43 cases in 40 patients were caused by non‐chemotherapy drugs. The incidence rate for 10,000 patients during the study period was 2.75 (Poisson Confidence Interval (CI)‐95%: 0.62–7.22). The mean (SD) age was 48 (21) years. All cases were categorized as serious, because they required hospitalization (28 cases) or prolongation of hospitalization (15 cases). The outcome was recovery without sequela (39 cases), recovery with sequela (1 case of toe amputation) or death (3 cases, 7%). The most frequent cause of NIA was antimicrobial drugs (19 cases). The highest incidence rate per 10,000 Defined Daily Doses was for cefepime (83.85; Poisson‐CI 95%: 67‐102.89). Automatic linear modelling (n=75, R2=77.9%) showed a significant inverse association with platelets, alkaline phosphatase, C reactive protein, fibrinogen, lactate dehydrogenase and direct to mean corpuscular hemoglobin, and hematocrit. A generalized linear model retained platelets, total serum proteins, creatinine and hemoglobin. The findings suggest an immune‐mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure. There might be additional contributing factors, such nutritional deficiencies or chronic diseases, to develop NIA after exposure to a potentially causative drug. This article is protected by copyright. All rights reserved.
      PubDate: 2015-05-23T09:11:44.936982-05:
      DOI: 10.1111/bcpt.12418
  • Age‐related Differences in CYP3A Abundance and Activity in the Liver
           of the Göttingen Minipig
    • Authors: Els Van Peer; Lies De Bock, Koen Boussery, Jan Van Bocxlaer, Christophe Casteleyn, Chris Van Ginneken, Steven Van Cruchten
      Abstract: In view of paediatric drug development, regulatory authorities often request safety studies in juvenile animals, including minipigs. Unfortunately, knowledge on the ontogeny of the biotransformation processes in animal models remains scarce and impedes a correct interpretation of the toxicity findings. CYP3A4 is one of the most important drug‐metabolizing enzymes in human beings and shows important similarities with CYP3A in the minipig. Therefore, the aim of this study was to assess the abundance and activity of CYP3A in liver microsomes from foetal, juvenile (Day 1, 3, 7 and 28) and adult male and female Göttingen minipigs. CYP3A abundance was studied by an indirect enzyme‐linked immunosorbent assay (ELISA), whereas CYP3A activity was assessed by a biotransformation assay with Luciferin‐IPA. CYP3A abundance could not be detected until day 3. From day 7 onwards, a gradual increase in expression was noted, leading to the highest abundance in adult animals. CYP3A activity was not detectable in foetuses and 1‐day‐old animals. The CYP3A activity was detectable, but below the LLOQ in day 3 animals and increased gradually with age to reach the highest level in adults. The CYP3cide and ketoconazole inhibition, and testosterone and midazolam reduction of Luciferin‐IPA metabolism in minipig liver microsomes substantiate that Luciferin‐IPA is metabolized by CYP3A in minipigs. A positive correlation was found between CYP3A abundance and biotransformation of Luciferin‐IPA (Pearson r = 0.863; p < 0.0001). In conclusion, both abundance and activity of CYP3A increased gradually in juvenile minipigs, but remained below the levels observed in adult animals. This article is protected by copyright. All rights reserved.
      PubDate: 2015-05-18T21:08:03.313531-05:
      DOI: 10.1111/bcpt.12410
  • Endothelin‐1 and Endothelin‐3 Regulate Endothelin Receptor
           Expression in Rat Coronary Arteries
    • Authors: Gry Freja Skovsted; Semsi Kilic, Lars Edvinsson
      Abstract: In ischaemic hearts, endothelin (ET) levels are increased, and vasoconstrictor responses to ET‐1 are greatly enhanced. We previously reported that ETB receptors are up‐regulated in the smooth muscle layer of coronary arteries after myocardial ischaemia‐reperfusion and that the MEK‐ERK‐1/2 signalling pathway is involved in ETB receptor up‐regulation. Whether ETs are directly involved in receptor regulation has not been determined. We hypothesised that ET‐1 and ET‐3 alter the expression/activity of ET receptors in coronary vascular smooth muscle cells. Vasoconstrictor responses were studied in endothelium‐denuded coronary artery segments from rats that were subjected to experimental ischaemia‐reperfusion or in organ‐cultured segments. Post‐ischaemic and cultured coronary arteries exhibited similar increased sensitivity to ET‐3. ETA receptor‐mediated vasoconstriction was dominant in fresh and non‐ischaemic arteries. Organ culture significantly up‐regulated ETB receptors and down‐regulated ETA receptor expression. Co‐incubation with ET‐1 (1 nM) or ET‐3 (100 nM) induced further down‐regulation of the ETA receptor mRNA, while the function and protein level of ETA remained unchanged. ET‐3 (100 nM) further up‐regulated ETB receptor mRNA and proteins but abolished ETB receptor‐mediated vasoconstriction, suggesting a desensitisation of ETB receptors that was not observed with ET‐3 (1 nM). In conclusion, ET‐1, which is the most prevalent isoform in the cardiovascular system, induces down‐regulation of ETA receptor expression without changing ETA or ETB receptor function or protein levels. Intermediate concentrations of ET‐3 had an effect that was similar to that of ET‐1, such that high concentrations of ET‐3 (100 nM) up‐regulated the ETB receptor at the gene and protein levels but switched off the function of the ETB receptors via desensitisation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-05-18T20:53:14.693575-05:
      DOI: 10.1111/bcpt.12407
  • Dabigatran concentration: variability and potential bleeding prediction in
           “real–life” patients with atrial fibrillation
    • Abstract: Routine laboratory monitoring is currently not recommended in patients receiving dabigatran despite its considerable variation in plasma concentration. However, in certain clinical situations, measurements of the dabigatran effect may be desirable. We aimed to assess the variability of dabigatran trough and peak concentration and explore the potential relationship between dabigatran concentration and adverse events. We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (D150) or 110 mg (D110) twice daily. They contributed 170 trough and peak blood samples that were collected 2–4 and 6–8 weeks after dabigatran initiation. Plasma dabigatran concentration was measured by LC‐MS/MS and indirectly, by selected coagulation tests. D110 patients were older (74±7 versus 68±6 years), had lower creatinine clearance (68±21 versus 92±24 mL/min) and higher CHA2DS2‐VASc score (3.1±1.3 versus 2.3±0.9) compared to D150 patients (all p
      PubDate: 2015-05-15T09:02:57.146188-05:
      DOI: 10.1111/bcpt.12417
  • Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of
           Tissue Plasminogen Activator in a Rat Stroke Model
    • Abstract: Delayed treatment of stroke with recombinant tissue plasminogen activator (r‐tPA) induces over‐expression of matrix metalloproteinase 9 (MMP‐9) which leads to breakdown of the blood‐brain barrier (BBB) and causes more injuries to the brain parenchyma. In the current study, the effect of Ascorbic Acid (AA), an anti‐oxidant agent, on the delayed administration of r‐tPA in a rat model of permanent middle cerebral artery occlusion (MCAO) was investigated. Forty male rats were randomly divided into 4 groups: untreated control rats (ischaemic animals), AA‐treated (500 mg/kg; 5 hr after stroke), r‐tPA‐treated (5 hr after stroke 1mg/kg) and the combination of AA+r‐tPA rats. MCAO was induced by occluding the right middle cerebral artery. Infarct size, blood‐brain barrier, brain oedema and the levels of MMP‐9 were measured at the end of study. Neurological deficits were evaluated at 24 and 48 hr after stroke. Compared to the control or r‐tPA‐treated animals, AA alone (P
      PubDate: 2015-05-09T01:02:22.099652-05:
      DOI: 10.1111/bcpt.12413
  • The Fentanyl Patch Boil‐Up – A Novel Method of Opioid Abuse
    • Authors: Cameron K. M. W. Schauer; James A. D. Shand, Thomas M. Reynolds
      Abstract: Fentanyl is a potent opioid analgesic used in the treatment of pain. Transdermal fentanyl patches are now widely utilised as an acceptable and efficacious method of medication delivery. Unfortunately, the potential for their abuse is well recognised. Previous case reports have documented deaths after intravenous (IV) misuse of fentanyl which had been extracted from Duragesic (liquid reservoir type) patches. We present a case of IV fentanyl abuse after extraction from a Mylan (matrix type) patch. This method of abuse has not previously been described in the literature. This article is protected by copyright. All rights reserved.
      PubDate: 2015-05-09T01:01:53.826247-05:
      DOI: 10.1111/bcpt.12412
  • Pediatric Off‐Label Use of Melatonin – A Register Linkage
           Study between the Norwegian Prescription Database and Patient Register
    • Authors: Ingeborg Hartz; Marte Handal, Aage Tverdal, Svetlana Skurtveit
      Abstract: The aims were, for the entire Norwegian population aged 4–17 years, to study prevalence of melatonin use during 2004–2012, recurrent use in incident users and psychiatric and neurological morbidity in recurrent users. Data on dispensed melatonin were retrieved from the Norwegian Prescription Database and linked to diagnostic data from the Norwegian Patient Register. Outcome measures were: 1‐year prevalence of use, proportion of recurrent use (use over three consecutive 365‐day periods among incident users in 2009) and annual number of milligrams and number of prescriptions dispensed in recurrent users. The prevalence of registered ICD‐10 diagnoses during the period of 2008‐2012 was given for the recurrent users. Prevalence of melatonin use increased annually in both genders during 2004–2012 (boys: 3.4–11.0 per 1000; girls: 1.5–7.7 per 1000). 29% of boys and 23% of girls were recurrent melatonin user, and the prevalence was highest among the youngest (aged 4–8 years; boys: 47%, girls: 42%). In the third year, the median annual amount of melatonin dispensed was 1080 (IQR 586‐1800) milligrams in boys and 900 (IQR 402‐1620) milligrams in girls. Among recurrent users, 91% had a diagnosis of either psychiatric (84%) or neurological (32%) disorder. Off‐label recurrent use of melatonin seems to have acquired a role mainly in treating secondary sleep problems in children and adolescent with psychiatric and neurological disorders. Once melatonin has been started, a large proportion of patients continue for at least 3 years, in doses corresponding to daily use in the majority. This article is protected by copyright. All rights reserved.
      PubDate: 2015-05-09T00:55:36.690999-05:
      DOI: 10.1111/bcpt.12411
  • L‐arginine Attenuates Cardiac Dysfunction, but further
           Down‐Regulates Alpha Myosin Heavy Chain Expression in
           Isoproterenol‐Induced Cardiomyopathy
    • Authors: Eva Kralova; Gabriel Doka, Lenka Pivackova, Jasna Srankova, Kristina Kuracinova, Pavol Janega, Pavel Babal, Jan Klimas, Peter Krenek
      Abstract: In view of previously reported increased capacity for NO production, we hypothesized that L‐arginine (ARG), the nitric oxide synthase (NOS) substrate, supplementation would improve cardiac function in isoproterenol (ISO)‐induced heart failure. Male Wistar rats were treated with ISO for 8 days (5 mg/kg/d, i.p.) or vehicle. ARG was given to control (ARG) and ISO‐treated (ISO+ARG) rats in water (0.4 g/kg/d). ISO administration was associated with 40% mortality, ventricular hypertrophy, decreased heart rate, left ventricular dysfunction, fibrosis, ECG signs of ischaemia. RT‐PCR showed increased mRNA levels of cardiac hypertrophy marker ANP, but not BNP, decreased expression of myosin heavy chain isoform MYH6, unaltered expression of pathological MYH7. ISO increased the protein levels of eNOS, but at the same time it markedly up‐regulated mRNA and protein levels of gp91phox, a catalytical subunit of superoxide‐producing NADPH oxidase. Fibrosis was markedly increased by ISO. ARG treatment moderately ameliorated left ventricular dysfunction, but was without effect on cardiac hypertrophy and fibrosis. Combination of ISO+ARG led to a decrease in cav‐1 expression, a further increase in MYH7 expression and a down‐regulation of MYH6 that inversely correlated with gp91phox mRNA levels. Although ARG, at least partially, improved ISO‐impaired basal left ventricular systolic function, it failed to reduce cardiac hypertrophy, fibrosis, oxidative stress and mortality. The protection of contractile performance might be related to increased capacity for NO production and the up‐regulation of MYH7 which may compensate for the marked down‐regulation of the major MYH6 isoform. This article is protected by copyright. All rights reserved.
      PubDate: 2015-04-10T09:52:30.813183-05:
      DOI: 10.1111/bcpt.12405
  • Effect of the Acidic Dental Resin Monomer 10‐methacryloyloxydecyl
           Dihydrogen Phosphate on Odontoblastic Differentiation of Human Dental Pulp
    • Abstract: Although 10‐methacryloyloxydecyl dihydrogen phosphate (10‐MDP) is frequently used as an acidic resin monomer in dental adhesives, its effect on dental pulp cells (DPCs) has been rarely reported. The purpose of this study was to examine the effects of 10‐MDP on the inflammatory response and odontoblastic differentiation of DPCs at minimally toxic concentrations. We found that 10‐MDP caused the release of inflammatory cytokines including NO, PGE2, iNOS, COX‐2, TNF‐α, IL‐1β, IL‐6 and IL‐8 in a concentration‐dependent manner. In addition, 10‐MDP reduced alkaline phosphatase activity, mineralization nodule formation and mRNA expression of odontoblastic differentiation markers such as dentin sialophosphoprotein, dentin matrix protein‐1, osterix and Runx2 in a concentration‐dependent manner with low toxicity. In addition, 10‐MDP induced activation of nuclear factor‐E2‐related factor 2 (Nrf2) and its target gene, heme oxygenase‐1 (HO‐1). We evaluated whether the effect of 10‐MDP was related to induction of HO‐1, and found that treatment with a selective inhibitor of HO‐1 reversed production of 10‐MDP‐mediated pro‐inflammatory cytokines and inhibition of differentiation markers. Pre‐treatment with either a GSH synthesis inhibitor or antioxidants blocked 10‐MDP‐induced mitogen‐activated protein kinases (MAPKs), Nrf2 and NF‐κB pathways. Taken together, the results of this study showed that minimally toxic concentrations of 10‐MDP promoted an inflammatory response and suppresses odontoblastic differentiation of DPCs by activating Nrf2‐mediated HO‐1 induction through MAPK and NF‐κB signalling. This article is protected by copyright. All rights reserved.
      PubDate: 2015-04-03T04:17:14.90936-05:0
      DOI: 10.1111/bcpt.12404
  • Intrabronchial Microdialysis: Effects of Probe Localisation on Tissue
           Trauma and Drug Penetration into the Pulmonary Epithelial Lining Fluid
    • Abstract: Recent intrabronchial microdialysis data indicate that the respiratory epithelium is highly permeable to drugs. Of concern is whether intrabronchial microdialysis disrupts the integrity of the respiratory epithelium and thereby alters drug penetration into the pulmonary epithelial lining fluid (PELF). The objective of this study was to investigate the effect of intrabronchial microdialysis on the integrity of the bronchial epithelium. Microdialysis sampling in PELF in proximal (n=4) and distal bronchi (n=4) was performed after intravenous inulin and florfenicol administration in anaesthetized pigs. Inulin was used as a marker molecule of permeability of the epithelium, and florfenicol was used as test drug. Bronchial tissue was examined by histopathology (distal and proximal bronchi) and gene expression analysis (RT‐qPCR, proximal bronchi) at the termination of the experiment (6.5 hr). The microdialysis probe caused overt tissue trauma in distal bronchi, whereas no histopathological lesions were observed in proximal bronchi. A moderate up‐regulation of the pro‐inflammatory cytokines IL1B, IL6 and acute phase reactant serum amyloid A was seen in proximal bronchi surrounding the microdialysis probes suggesting initiation of an inflammatory response. The observed up‐regulation is considered to have limited impact on drug penetration during short‐term studies. Inulin penetrated the respiratory epithelium in both proximal and distal bronchi without any correlation to histopathological lesions. Likewise, florfenicol penetration into PELF was unaffected by bronchial histopathology. However, this independency of pathology on drug penetration may not be valid for other antibiotics. We conclude that short‐term microdialysis drug quantification can be performed in proximal bronchi without disruption of tissue integrity. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-30T09:55:27.077372-05:
      DOI: 10.1111/bcpt.12403
  • Levothyroxine Poisoning – Symptoms and Clinical Outcome
    • Abstract: Levothyroxine, T4 (LT) poisoning is rarely associated with a severe outcome. However, cases with significant complications have been reported. The aim of the present study was to identify factors associated with symptoms of poisoning including late onset symptoms. All enquiries to the Danish Poison Information Centre (DPIC) concerning LT poisoning between March 2007 and September 2012 were reviewed and the following parameters were recorded: age, dose, time from ingestion, multiple drug intake and symptoms. In order to evaluate the frequency of late onset symptoms, a subgroup of patients without initial symptoms were contacted. A total of 181 patients were registered (112 children). Ingested LT dose ranged from 10 to 9000 mcg (median 275 mcg). A total of 29/181 (16%) patients were symptomatic at the time of enquiry, and there was no difference in ingested LT dose between asymptomatic and symptomatic patients; neither in children nor in adults (age 16‐92 years) (p
      PubDate: 2015-03-28T08:52:35.394348-05:
      DOI: 10.1111/bcpt.12401
  • The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents
           Cardiac Remodelling and Matrix Metalloproteinase‐2
           Up‐Regulation in Renovascular Hypertension
    • Abstract: Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF‐кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up‐regulation. We hypothesized that treatment with PDTC could prevent 2‐kidney, 1‐clip (2K1C) hypertension‐induced left ventricular remodelling. Sham‐operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg.Kg‐‐1) by gavage for eight weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with hematoxylin/eosin sections and fibrosis was quantified in picrosirius red‐stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography and cardiac MMP‐2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C Vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricle and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP‐2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP‐2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMPs expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-28T08:39:05.069635-05:
      DOI: 10.1111/bcpt.12400
  • The Effect of a Polyvalent Antivenom on the Serum Venom Antigen Levels of
           Naja sputatrix (Javan Spitting Cobra) Venom in Experimentally Envenomed
    • Authors: Michelle Khai Khun Yap; Nget Hong Tan, Si Mui Sim, Shin Yee Fung, Choo Hock Tan
      Abstract: The treatment protocol of antivenom in snake envenomation remains largely empirical, partly due to the insufficient knowledge of the pharmacokinetics of snake venoms and the effects of antivenoms on the blood venom levels in victims. In the present study, we investigated the effect of a polyvalent antivenom on the serum venom antigen levels of Naja sputatrix (Javan spitting cobra) venom in experimentally envenomed rabbits. Intravenous infusion of 4 ml of Neuro Polyvalent Snake Antivenom (NPAV, F(ab’)2) at 1‐hr post‐envenomation caused a sharp decline of the serum venom antigen levels, followed by transient resurgence an hour later. The venom antigen resurgence was unlikely to be due to the mismatch of pharmacokinetics between the F(ab’)2 and venom antigens, as the terminal half‐life and volume of distribution of the F(ab’)2 in serum were comparable to that of venom antigens (p>0.05). Infusion of an additional 2 ml of NPAV was able to prevent resurgence of the serum venom antigen level, resulting in a substantial decrease (67.1%) of the total amount of circulating venom antigens over time course of envenomation. Our results showed that the neutralisation potency of NPAV determined by neutralisation assay in mice may not be an adequate indicator of its capability to modulate venom kinetics in relation to its in vivo efficacy to neutralise venom toxicity. The findings also support the recommendation of giving high initial dose of NPAV in cobra envenomation, with repeated doses as clinically indicated in the presence of rebound antigenemia and symptom recurrence. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-27T05:30:34.850476-05:
      DOI: 10.1111/bcpt.12398
  • Expression of CYP3A4 and CYP3A7 in Human Foetal Tissues and its
           Correlation to Nuclear Receptors
    • Abstract: Previous reports have suggested that the nuclear receptors vitamin D receptor (VDR), peroxisome proliferator‐activated receptor α (PPARα), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are involved in the regulation of the drug metabolizing enzyme cytochrome P450 (CYP) 3A4 expression in adults. The aim of this study was to investigate the gene expression of CYP3A4 and the foetal CYP3A7 in human foetal tissues and their relation to gene expression and genetic variations in the nuclear receptors VDR, PPARα, PXR and CAR. We determined the relative expression of CYP3A4 and CYP3A7 and these nuclear receptors in foetal livers, intestines and adrenals, using quantitative PCR. In addition, the expression of these enzymes was also analysed in adult liver. There was a high interindividual variability in CYP3A4 and CYP3A7; 49‐fold and 326‐ fold, respectively. Both CYP3A4 and CYP3A7 had the highest expression in the liver. There were significant correlations (p
      PubDate: 2015-03-09T21:42:26.520347-05:
      DOI: 10.1111/bcpt.12392
  • Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics
           and First‐in‐Human Dose Selection for CNTO 5825, an
           Anti‐Interleukin‐13 Monoclonal Antibody
    • Authors: Ivo P. Nnane; Zhenhua Xu, Honghui Zhou, Hugh M. Davis
      Abstract: CNTO 5825 is a human anti‐interleukin‐13 (IL‐13) monoclonal antibody (mAb) that inhibits binding of human IL‐13 to IL‐13Rα1 and IL‐13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non‐clinical PK data in order to select the right and safe doses for first‐in‐human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 mL/day/kg in rats, and from 5.78 to 7.19 mL/day/kg in cynomolgus monkeys. The volume of distribution at steady‐state (Vss) in rats was large (151.52 to 155.64 mL/kg) compared to cynomolgus monkey (49.77 to 61.10 mL/kg). The terminal half‐life (T1/2) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1–10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within 2‐fold of observed CL and Vss in human beings; The predicted CL and Vss in human beings (70 kg) based on time‐invariant method with combined PK data from rats and monkeys were 4.84 ± 1.13 mL/day/kg and 68.93 ± 35.55 mL/kg, respectively. The selected doses for the FIH study based on time‐invariant method and NOAEL in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-05T21:23:47.768877-05:
      DOI: 10.1111/bcpt.12391
  • Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity
           is the Principal Driver
    • Authors: Barent DuBois; Samantha Louey, George D. Giraud, Ganesh Cherala, Sonnet S. Jonker
      Abstract: Understanding theophylline pharmacokinetics in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal pharmacokinetics difficult. Six ewes carrying singleton foetuses received theophylline (60mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36 hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non‐compartmental pharmacokinetic parameters were: half‐life 7.37±1.22 hr; volume of distribution 44.62±11.45L; area under the curve 14.82±2.71hr∙μg∙mL−1; clearance 4.15±0.70L∙hr−1. Rapid theophylline distribution across the placenta was observed. Maternal non‐compartmental pharmacokinetics parameters were: half‐life 6.54±2.44 hr; volume of distribution 32.48±9.99L; area under the curve 16.28±4.53hr∙μg∙mL−1; clearance 3.69±1.47L∙hr−1. Foetal and ewe serum concentration‐time profiles were fit together into a 3‐compartment population pharmacokinetic model, parameters were: central volume 1.38±0.11L; 2nd peripheral compartment volume 3.11±0.29L; 3rd peripheral compartment volume 60.14±6.02L; elimination clearance 9.89±0.90L/hr; distribution clearance between central and 2nd compartment 30.87±2.31L/hr; distribution clearance between 2nd and 3rd compartments 13.89±1.11L/hr. Cytochrome‐P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7±4.4 versus 42.0±3.6%‐bound). Free concentrations were lower in the foetus than the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-27T05:25:09.466785-05:
      DOI: 10.1111/bcpt.12395
  • Professor Olavi Pelkonen is the 2014 BCPT Nordic Prize Winner in Basic
           & Clinical Pharmacology & Toxicology
    • First page: 145
      Abstract: Professor Olavi Pelkonen, MD, PhD, has dedicated his working life for the development of pharmacology and toxicology. His main position was the Professor of pharmacology as well as the Head of the department at the University of Oulu, Finland in 1986–2009. He was a post‐doctoral fellow at the National Institutes of Health, Bethesda, Maryland in 1976–1977 and was appointed as a Visiting Professor in United Kingdom (1994 1 mo), Spain (1995 1 mo) and Australia (1997 1 mo). After retirement from his full‐time position, he has acted as a scientific expert and advisor in several scientific and advisory committees, and has contributed in several scientific papers. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-16T05:26:09.575328-05:
      DOI: 10.1111/bcpt.12431
  • Drug Metabolism ‐ From In Vitro to In Vivo, from Simple to Complex
           Reflections of the BCPT Nordic Prize 2014 Awardee
    • Authors: Olavi Pelkonen
      First page: 147
      Abstract: Drug metabolism is the crucial part of pharmaco‐ and toxicokinetics and consequently is associated with both desirable and adverse effects of most xenobiotics, compounds foreign to the body. This MiniReview follows some advances of the field over the last 50 years or so through the experiences and work of one scientist. Thus, this MiniReview represents a rather personal view of research in one research field. Drug metabolism is affected and controlled by a huge number of factors and conditions such as individual development, species differences, drug‐drug interactions and various environmental, host and genetic factors working via a variable set of regulatory mechanisms. All these different factors create wide individual, population and species variability with obvious repercussions to clinical drug therapy and chemical risk assessment. This MiniReview also provides glimpses to methodological developments over recent decades and ends up presenting a few promising approaches and techniques such as various omics and high content and high throughput techniques feeding huge amounts of data to computational integration and modelling, which constitute the basis for systems or network pharmacology and toxicology. This article is protected by copyright. All rights reserved.
      PubDate: 2015-06-13T07:01:23.618327-05:
      DOI: 10.1111/bcpt.12429
  • Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and
           Transdermal Administration to the Ewe
    • First page: 156
      Abstract: Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non‐pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5 to 2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118–127 gestational days were used. In the first protocol, one week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/h were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intraoperative 2.5 μg/kg/h infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day, and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra‐ and postoperative fentanyl concentrations were similar and slightly lower than the a priori predictions and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days but the absorption rate was slower than the nominal dose rate and showed a high inter‐individual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-20T03:54:20.756024-05:
      DOI: 10.1111/bcpt.12382
  • Epigallocatechin‐3‐Gallate Attenuates Oxidative Stress and
           Inflammation in Obstructive Nephropathy via NF‐κB and
           Nrf2/HO‐1 Signalling Pathway Regulation
    • Authors: Yanqiu Wang; Bowen Wang, Feng Du, Xuesong Su, Guangping Sun, Guangyu Zhou, Xiaohui Bian, Na Liu
      First page: 164
      Abstract: Oxidative stress and inflammation contribute importantly to the pathogenesis of chronic kidney disease (CKD). Epigallocatechin‐3‐gallate (EGCG), which is the most abundant and most active catechin polyphenol extracted from green tea, has been proved to have many bioactivities. In this study, the renoprotective effect of EGCG was evaluated in a widely used kidney disease model, the unilateral ureteral obstruction (UUO) mice model. After 14 days of EGCG administration, mean arterial blood pressure, body weight and obstructed kidney weight were measured. Levels of blood urea nitrogen (BUN) and creatinine (CR) and activities of glutamic‐pyruvic transaminase (GPT) and lactate dehydrogenase (LDH) in serum were estimated as indicators of renal function. Periodic acid‐Schiff (PAS) staining was performed to observe the pathological changes of the obstructed kidney. Antioxidant enzymes and pro‐inflammatory cytokine production were estimated to reflect the oxidative stress and inflammatory state in the obstructed kidney. Finally, the main proteins in the NF‐κB and Nrf2 signalling pathway and DNA binding activity of NF‐κB and Nrf2 were measured to investigate the effect of EGCG on these two pathways. The results demonstrated that EGCG could restore UUO‐induced kidney weight loss and renal dysfunction. In addition, UUO‐induced oxidative stress and inflammatory responses in the obstructed kidney were also prevented by EGCG. Furthermore, EGCG could induce both NF‐κB and Nrf2 nuclear translocation in the UUO kidney and promote heme oxygenase‐1 (HO‐1) production. These results indicated that the renoprotective effect of EGCG might be through its NF‐κB and Nrf2 signalling pathway regulations. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-19T02:04:55.996578-05:
      DOI: 10.1111/bcpt.12383
  • Treatment with Carnitine Enhances Bone Fracture Healing under Osteoporotic
           and/or Inflammatory Conditions
    • Authors: Ali Aydin; Zekai Halici, Abdulmecit Albayrak, Beyzagul Polat, Emre Karakus, Omer Selim Yildirim, Yasin Bayir, Elif Cadirci, Arif Kursad Ayan, Ahmet Murat Aksakal
      First page: 173
      Abstract: The aim of this study was to examine the effects of carnitine on bone healing in ovariectomy (OVX) and inflammation (INF)‐induced osteoporotic rats. The rats were randomly divided into nine groups (n=8): sham‐operated (Group 1: SHAM), sham+magnesium silicate (Mg‐silicate) (Group 2: SHAM+INF); ovariectomy (Group 3: OVX); ovariectomy+femoral fracture (Group 4: OVX+FRC); ovariectomy+femoral fracture+Mg‐silicate (Group 5:OVX+FRC+INF); ovariectomy+femoral fracture+carnitine 50 mg/kg (Group 6: OVX+FRC+CAR50); ovariectomy+femoral fracture+carnitine 100 mg/kg (Group 7: OVX+FRC+CAR100); ovariectomy+femoral fracture+Mg‐silicate+carnitine 50 mg/kg (Group 8: OVX+FRC+INF+CAR50); ovariectomy+femoral fracture+Mg‐silicate+carnitine 100 mg/kg (Group 9: OVX+FRC+INF+CAR100). Eight weeks after OVX, which allowed for osteoporosis to develop, INF was induced with subcutaneous Mg‐silicate. On day 80, all of the rats in Groups 4‐9 underwent fracture operation on the right femur. Bone mineral density (BMD) showed statistically significant improvements in the treatment groups. The serum markers of bone turnover (osteocalcin and osteopontin) and pro‐inflammatory cytokines (tumour necrosis factor α, interleukin 1β and interleukin 6) were decreased in the treatment group. The X‐ray images showed significantly increased callus formation and fracture healing in the groups treated with carnitine. The present results show that in a rat model with osteoporosis induced by ovariectomy and Mg‐silicate, treatment with carnitine improves the healing of femur fractures. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-19T02:11:32.162166-05:
      DOI: 10.1111/bcpt.12384
  • Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of
           Cancer‐Induced Bone Pain
    • First page: 180
      Abstract: Cancer‐induced bone pain (CIBP) is seriously disruptive to the quality of life in cancer patients, and present therapies are limited. The Bv8/prokineticin 2, a new family of chemokines, has been demonstrated to be involved in inflammatory and neuropathic pain. However, whether it is involved in CIBP remains unclear. The present study was designed to examine whether spinal Bv8 was involved in the development of CIBP in rats. A rat CIBP model was constructed by injecting Walker 256 carcinoma cells into the medullary cavity of rat tibia. Tibia inoculation with Walker 256 tumour cells resulted in the development of mechanical hyperalgesia. Compared with sham rats, spinal Bv8 mRNA and protein levels were markedly and time‐dependently increased in CIBP rats. Intrathecal administration of Bv8 neutralizing antibody (5 ng) could markedly attenuate pain behaviour as well as up‐regulation of spinal TNF‐α expression at day 18 after inoculation. Intrathecal pre‐treatment with synthetic Bv8 (50 pg) almost completely abolished these effects. These data suggested that spinal Bv8/prokineticin 2 participated in the development of CIBP. Targeting of spinal Bv8 might be a promising strategy for the management of cancer‐induced bone pain. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-25T20:41:11.938598-05:
      DOI: 10.1111/bcpt.12386
  • Milrinone for the Treatment of Acute Heart Failure After Acute Myocardial
           Infarction: A Systematic Review and Meta‐analysis
    • Authors: Xiuying Tang; Peng Liu, Runjun Li, Quanmin Jing, Junhao Lv, Li Liu, Yingfeng Liu
      First page: 186
      Abstract: Despite advancements in modern medicine, the treatment of acute heart failure (AHF) after acute myocardial infarction (AMI) remains challenging. Milrinone is effective in the treatment of chronic congestive heart failure, but its safety and efficacy in patients with AHF after AMI have not been systematically evaluated. This meta‐analysis was performed to assess the safety and efficacy of milrinone in patients with AHF after AMI. We used a pre‐designed protocol to search electronic databases for randomized trials assessing milrinone for the treatment of AHF after AMI. Data were abstracted from relevant studies. Heterogeneity was assessed qualitatively using a Q test and quantified using the I2 statistic. Pooled risk estimates with 95% confidence intervals (CIs) were obtained using fixed effects models unless substantial heterogeneity was observed (I2≥ 50% and heterogeneity P≤0.1). Four randomized trials met the inclusion criteria. However, there were no significant differences in deaths, blood pressure, premature ventricular contractions, gastrointestinal reactions, or ventricular tachycardia or fibrillation(all P>0.05) between control group and milrinone treatment group. Pooled estimates showed that milrinone significantly increased the left ventricular ejection fraction (MD 5.69; 95% CI4.27 to 7.10; P < 0.00001) and cardiac output (MD 0.35, 95%CI: 0.13 to 0.56; P =0.002, I2 =24%). While studies to date are few and limited by small sample sizes and poor quality, they suggest that treatment with milrinone may be safe and effective for patients with AHF after AMI. However, this meta‐analysis did not show that milrinone could improve prognosis or the survival rate. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-05T21:22:33.023094-05:
      DOI: 10.1111/bcpt.12385
  • Ascorbic Acid may Exacerbate Aspirin‐Induced Increase in Intestinal
    • Authors: Ivana R. Sequeira; Marlena C. Kruger, Roger D. Hurst, Roger G. Lentle
      First page: 195
      Abstract: Ascorbic acid in combination with aspirin has been used in order to prevent aspirin‐induced oxidative GI damage. We aimed to determine whether ascorbic acid reduces or prevents aspirin‐induced changes in intestinal permeability over a 6‐hr period using saccharidic probes mannitol and lactulose. The effects of administration of 600 mg aspirin alone, 500 mg ascorbic acid alone and simultaneous dosage of both agents were compared in a cross‐over study in twenty‐eight healthy female volunteers. These effects were also compared with that of a placebo. The ability of ascorbic acid to mitigate the effects of aspirin when administered either half an hour before or after dosage with aspirin was also assessed in nineteen healthy female volunteers. The excretion of lactulose over the 6‐hr period after dosage was augmented, after consumption of either aspirin or ascorbic acid compared with that after consumption of placebo. Dosage with ascorbic acid alone augmented the excretion of lactulose more than did aspirin alone. Simultaneous dosage with both agents augmented the excretion of lactulose in an additive manner. The timing of dosage with ascorbic acid in relation to that with aspirin had no significant effect on the excretion of the two sugars. These findings indicate that ascorbic acid does not prevent aspirin‐induced increase in gut permeability rather that both agents augment it to a similar extent. The additive effect on simultaneous dosage with both agents in augmenting the absorption of lactulose suggests that each influences paracellular permeability by different pathways. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-04T04:12:58.161482-05:
      DOI: 10.1111/bcpt.12388
  • Effect and Placental Transfer of Dexmedetomidine during Caesarean Section
           under General Anaesthesia
    • Authors: Min Yu; Chuanbao Han, Xiuhong Jiang, Xia Wu, Li Yu, Zhengnian Ding
      First page: 204
      Abstract: Many drugs can pass through the placenta and cause adverse effects on the foetus. Thus, during caesarean section for puerperas who have contraindications for intravertebral anaesthesia, the use of proper drugs that have sedative, analgesic effects on the puerperas without adverse effects on the foetus is important. In this study, we investigated the effect and placental transfer of dexmedetomidine during caesarean section under general anaesthesia. Thirty‐eight puerperas were randomly divided to receive dexmedetomidine or saline before anaesthesia induction and during the operation. The dexmedetomidine‐treated parturients had lower mean arterial pressure and heart rate at the delivery and at the end of the operation. The dexmedetomidine‐treated parturients also needed 5.5% less propofol and 8.4% less fentanyl than the saline‐treated ones. Between the dexmedetomidine‐treated and saline‐treated parturients, there was no difference of the maternal artery, umbilical vein, umbilical artery blood gas analysis results, and the Apgar scores at 1 and 5 min. after delivery. The placental transfer rate of dexmedetomidine was 0.76. We concluded that dexmedetomidine was effective in maintaining the hemodynamic stability in the parturients during caesarean section under general anaesthesia without adverse neonatal effects. Dexmedetomidine can pass through the placenta with a placental transfer rate of 0.76. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-04T04:09:10.362027-05:
      DOI: 10.1111/bcpt.12389
  • Successful Use of Hydroxocobalamin and Sodium Thiosulfate in Acute Cyanide
           Poisoning: A Case Report with Follow‐up
    • Authors: Sergey Zakharov; Manuela Vaneckova, Zdenek Seidl, Pavel Diblik, Pavel Kuthan, Pavel Urban, Tomas Navratil, Daniela Pelclova
      First page: 209
      Abstract: Hydroxocobalamin is an effective first‐line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination with sodium thiosulfate. A 58‐year‐old male committed a suicide attempt by ingesting of 1200‐1500 mg of potassium cyanide; he was unconscious for 1‐1.5 min. after ingestion with the episode of generalized seizures. On admission to the ICU, the patient was acidotic (pH 7.28; HCO3 14.0 mmol/L, base excess ‐12.7 mmol/L, saturation O2 0.999) with high serum lactate (12.5 mmol/L). Hydroxocobalamin was administered 1.5 hr after ingestion in two subsequent intravenous infusions at a total dose of 7.5 g. The infusion was followed by continuous intravenous administration of 1 ml/h/kg of 10% sodium thiosulfate at a total dose of 12 g. No complications and adverse reactions were registered. Serum lactate decreased on 0.6 mmol/L the same day, and arterial blood gases became normal (pH 7.49; HCO3 27.2 mmol/L, base excess 2.2 mmol/L, saturation O2 0.994). The follow‐up examination 5 months later revealed no damage of basal ganglia and cerebellum on magnetic resonance imaging. The neurological examination revealed no pathological findings. On the ocular coherence tomography, the retinal nerve fibers layer was normal. In visual evoked potentials, there was a normal evoked complex on the left eye and minor decrease of amplitude on the right eye. Combination of hydroxocobalamin and sodium thiosulfate can have a positive effect on the survival without long‐term neurological and visual sequelae in the cases of massive cyanide poisonings due to the possibility of a potentiation or synergism of hydroxocobalamin effects by sodium thiosulfate. This synergism can be explained by the different time points of action of two antidotes: the initial and immediate effect of hydroxocobalamin, followed by the delayed, but more persistent effect of sodium thiosulfate. This article is protected by copyright. All rights reserved.
      PubDate: 2015-02-25T20:51:05.724713-05:
      DOI: 10.1111/bcpt.12387
  • Post‐Injection Delirium/Sedation Syndrome after Olanzapine
           Long‐Acting Intramuscular Injection – Who is at Risk'
    • First page: 213
      Abstract: The post‐injection olanzapine delirium/sedation syndrome (PDSS) was observed in a 60‐year‐old Caucasian, schizophrenic, non‐smoker and underweight (Body Mass Index BMI 18.2 kg/m2) female after the fourth intramuscular injection of 405 mg olanzapine pamoate. Clinical symptoms of PDSS were similar to those of acute oral olanzapine intoxication. The patient received supportive treatment and recovered fully. High olanzapine concentrations in serum, with maximum level of 698 ng/mL, were confirmed by liquid chromatography with tandem mass spectrometry (LC‐MS/MS). The authors wonder whether a low BMI and advanced age may predispose patients to PDSS occurrence. This article is protected by copyright. All rights reserved.
      PubDate: 2015-03-09T21:42:11.430817-05:
      DOI: 10.1111/bcpt.12394
  • Detection of Patients at High Risk of Medication Errors: Development and
           Validation of an Algorithm
    • 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.
  • 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.
  • Pharmacological Evidence that Histamine H3 Receptors Mediate
           Histamine‐Induced Inhibition of the Vagal Bradycardic Outflow in
           Pithed Rats
    • 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.
  • 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.
  • Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and
           Patch Administration in Rats
    • 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.
  • Long‐term Pharmacotherapy of Adults with Attention‐Deficit
           Hyperactivity Disorder (ADHD): A Literature Review and Clinical Study
    • Abstract: This MiniReview reports and discusses the main findings of the author's thesis including a literature study of long‐term pharmacological treatment of adult ADHD, and a clinical study of one‐year medication. Electronic databases were systematically reviewed for original studies on pharmacotherapy of the defined duration, 24 weeks or more. Although few trials were found and with limitations such as excluding co‐morbidities, treatment with stimulants and atomoxetine were reported tolerated and effective compared to non‐treatment. The clinical study of the thesis was conducted on 250 medication‐naïve ADHD patients referred to a specialized outpatient clinic. Co‐morbid psychiatric disorders were diagnosed among 75% of the patients. About 56% had not completed secondary school, and 51% had been unable to work the preceding year. Persisting inattentive symptoms and co‐morbid mental disorders in adulthood were related to long‐term work disability. In the prospective observational study of the thesis, patients were treated with methylphenidate as first‐line drug and atomoxetine or dexamphetamine as second‐line drugs, according to current treatment guidelines. At 12‐month follow‐up, 232 patients completed evaluation and 70% persisted on medication. About 80% of these used methylphenidate. Sustained improvement of symptoms and functioning were related to continued medication. Co‐morbid mental disorders and side‐effects were related to lower effectiveness and adherence, and 12% stopped medication due to side‐effects. Summing up the MiniReview, treatment with stimulants and atomoxetine of adult ADHD has long‐term beneficial effects and is tolerated but more longitudinal studies should be performed. With stated limitations, the findings of the thesis should contribute to a relevant guidance for clinical practice. This article is protected by copyright. All rights reserved.
  • Diabetic Ketoacidosis in a Patient with Type 2 Diabetes after Initiation
           of Sodium‐Glucose Co‐Transporter 2 Inhibitor Treatment
    • 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.
  • LCZ696 (Valsartan/Sacubitril) ‐ A Possible New Treatment for
           Hypertension and Heart Failure
    • Abstract: The aim of this MiniReview was to introduce the newly invented dual‐acting drug valsartan/sacubitril (LCZ696), which combines an angiotensin receptor blocker (valsartan) with sacubitril, a specific inhibitor of the neutral endopeptidase (NEP) that degrades vasoactive peptides, including natriuretic peptides ANP and BNP, but also glucagon, enkephalins and bradykinin, among others. The MiniReview presents the data of four available trials NCT01193101, NCT00549770, NCT00887588 and NCT01035255, and provides the current knowledge about LCZ696 effects in patients with hypertension and heart failure. Presently, patients suffering from hypertension and heart failure are treated with ACE inhibitors or angiotensin receptor antagonists often in combination with other drugs. These current medications lead to a reduction in blood pressure in hypertensive patients and a decreased mortality and morbidity in patients with heart failure with reduced ejection fraction, but not in patients with heart failure with preserved ejection fraction. LCZ696 had been tested in order to utilize the beneficial properties of natriuretic peptides in combination with angiotensin receptor antagonism. It induces even greater blood pressure reductions and decreased mortality and morbidity in patients with heart failure with reduced ejection fraction, while patients with heart failure with preserved ejection fraction show lowered blood pressure and decreased NT‐proBNP levels. Although long‐term studies remain to be performed, these initial data suggest that there is a potential clinical benefit of LCZ696 in the treatment of hypertension and heart failure. This article is protected by copyright. All rights reserved.
  • Erythrocyte Shrinkage and Cell Membrane Scrambling after Exposure to the
           Ionophore Nonactin
    • 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.
  • 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
    • 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.
  • In Response to ‘Intravenous Lipid Emulsion Given to Volunteers Does
           Not Affect Symptoms of Lidocaine Brain Toxicity’
  • Similar Adiponectin Levels in Obese Normotensive and Obese Hypertensive
           Men and No Vasorelaxant Effect of Adiponectin on Human Arteries
    • 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
  • This meta‐analysis does not reflect current practice and
           overestimates SAEs
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