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    - ENVIRONMENTAL STUDIES (746 journals)
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ENVIRONMENTAL STUDIES (746 journals)                  1 2 3 4 5 6 7 8 | Last

Acta Ecologica Sinica     Open Access   (Followers: 11)
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: 16)
Advances in Ecological Research     Full-text available via subscription   (Followers: 28)
Advances in Environmental Chemistry     Open Access  
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 17)
Advances in Life Science and Technology     Open Access   (Followers: 7)
Aeolian Research     Hybrid Journal   (Followers: 3)
African Journal of Environmental Science and Technology     Open Access   (Followers: 4)
African Journal of Sustainable Development     Full-text available via subscription   (Followers: 7)
AGE     Hybrid Journal   (Followers: 4)
Age and Ageing     Hybrid Journal   (Followers: 50)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 12)
AIMS Environmental Science     Open Access  
Ambiência     Open Access  
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Applied Sciences     Open Access   (Followers: 32)
American Journal of Environmental Engineering     Open Access   (Followers: 10)
American Journal of Environmental Protection     Open Access   (Followers: 7)
American Journal of Environmental Sciences     Open Access   (Followers: 13)
American Journal of Microbiology     Open Access   (Followers: 15)
American Naturalist     Full-text available via subscription   (Followers: 50)
Annals of GIS     Hybrid Journal   (Followers: 19)
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: 24)
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: 16)
Aquatic Toxicology     Hybrid Journal   (Followers: 15)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 4)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 9)
Archives of Environmental Protection     Open Access   (Followers: 5)
Archives of Toxicology     Hybrid Journal   (Followers: 11)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 4)
Asian Journal of Earth Sciences     Open Access   (Followers: 22)
Asian Journal of Rural Development     Open Access   (Followers: 11)
Atas de Saúde Ambiental - ASA     Open Access  
ATBU Journal of Environmental Technology     Open Access   (Followers: 2)
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: 5)
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: 49)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 37)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 26)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 3)
Bioremediation Journal     Hybrid Journal   (Followers: 4)
BioRisk     Open Access   (Followers: 3)
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: 13)
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   (Followers: 1)
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: 53)
Civil and Environmental Engineering     Open Access   (Followers: 3)
Civil And Environmental Engineering Reports     Open Access   (Followers: 2)
Civil and Environmental Research     Open Access   (Followers: 17)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 17)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 6)
Cleanroom Technology     Full-text available via subscription  
Climate Change Economics     Hybrid Journal   (Followers: 17)
Climate Policy     Hybrid Journal   (Followers: 22)
Coastal Engineering Journal     Hybrid Journal   (Followers: 2)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 10)
Computational Ecology and Software     Open Access   (Followers: 6)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 3)
Conservation and Society     Open Access   (Followers: 10)
Conservation Letters     Open Access   (Followers: 25)
Conservation Physiology     Open Access  
Conservation Science     Open Access   (Followers: 14)

        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  [1597 journals]
  • Response to: Adverse Events Associated with Flumazenil Treatment for the
           Management of Suspected Benzodiazepine Intoxication ‐ A Systematic
           Review with Meta‐Analyses of Randomized Trials
    • PubDate: 2015-11-03T01:20:52.120292-05:
      DOI: 10.1111/bcpt.12498
  • The Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety
           and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator
    • Abstract: Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent for auto‒immune disorders. The impact of hepatic or renal impairment on the pharmacokinetics, safety and tolerability of ponesimod and its inactive metabolites, ACT‒204426 and ACT‒338375, was evaluated. Two separate single‒centre, open‒label studies with 32 (hepatic study) and 24 (renal study) male and female subjects were conducted. Hepatic impairment was based on the Child–Pugh classification and renal impairment was determined by creatinine clearance using the Cockcroft–Gault equation. Subjects with severe hepatic or renal impairment were to be matched (sex and body mass index) with healthy subjects. All subjects received a single dose of 10 mg ponesimod. For ponesimod, the ratio of geometric means of AUC0‒∞ for subjects with severe hepatic impairment versus healthy subjects was 3.07 (90% CI: 2.19, 4.32). For severely renally impaired subjects versus healthy subjects, this ratio was 1.14 (0.82, 1.58). Cmax and tmax values of ponesimod were comparable across all groups in both studies. Exposure to metabolites was increased in subjects with moderate or severe hepatic impairment as compared to healthy subjects. During the course of these studies, there were no clinically relevant abnormalities related to vital signs, 12‒lead electrocardiograms and clinical laboratory values. Sixteen adverse events (AEs) were reported, 12 of them of mild intensity. No AEs were considered to be treatment‒related. Overall, ponesimod was well tolerated. In subjects with renal function impairment, dose adjustment is not warranted, whereas the dose should be reduced in subjects with moderate and severe hepatic impairment. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-03T00:28:32.122303-05:
      DOI: 10.1111/bcpt.12516
  • Cell‐Penetrating Peptides as Carriers for Oral Delivery of
    • Abstract: Oral delivery of biopharmaceuticals, e.g. peptides and proteins, constitute a great challenge in drug delivery due to their low chemical stability and poor permeation across the intestinal mucosa; to a large extent limiting the mode of administration to injections, which is not favouring patient compliance. Nevertheless, cell‐penetrating peptides (CPPs) have shown promising potential as carriers to overcome the epithelium, and this MiniReview highlights recent knowledge gained within the field of CPP‐mediated transepithelial delivery of therapeutic peptides and proteins from the intestine. Two approaches may be pursued: Co‐administration of the carrier and therapeutic peptide in the form of complexes obtained by simple bulk‐mixing, or administration of covalent conjugates demanding more advanced production methodologies. These formulation approaches have their pros and cons, and which is to be preferred depends on the physicochemical properties of both the specific CPP and the specific cargo. In addition to the physical epithelial barrier, a metabolic barrier must be overcome in order to obtain CPP‐mediated delivery of a cargo drug from the intestine, and a number of strategies have been employed to delay enzymatic degradation of the CPP. The mechanisms by which CPPs translocate across membranes is not fully understood, but possibly involve endocytosis as well as direct translocation, and the CPP‐mediated transepithelial delivery of cargo drugs thus likely involves similar mechanisms for the initial membrane interaction and translocation. However, the mechanisms responsible for transcytosis of the cargo drug, if taken up by an endocytic mechanism, or direct translocation across the epithelium are so far not known. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-03T00:18:52.714483-05:
      DOI: 10.1111/bcpt.12515
  • Pharmacokinetics of the Experimental Non‐Nucleosidic DNA Methyl
           Transferase Inhibitor N‐Phthalyl‐L‐Tryptophan
           (RG 108) in Rats
    • Abstract: DNA methyl transferase (DNMT) inhibitors can re‐establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non‐nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non‐specific DNMT inhibitor N‐phthalyl‐L‐tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr post injection and RG 108 in plasma was measured by high‐performance liquid chromatography coupled to mass spectrometry. Trough levels and AUC were significantly higher with multiple dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (tmax, mean±SD) was 37.5±15 min, terminal plasma half‐life was approximately 3.7 hr (60% CI: 2.1 – 15.6 h), maximal plasma concentration (Cmax) 61.3±7.6 μM and area under the curve was 200±54 μmol*h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple dose administration regimens. Maximal tissue levels (Cmax in μmol/kg) were 6.9±6.7, 1.6±0.4 and 3.4±1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 μM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-02T23:52:44.74041-05:0
      DOI: 10.1111/bcpt.12514
  • A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of
           Vortioxetine in Patients with Major Depressive Disorder
    • Authors: Himanshu Naik; Serena Chan, Majid Vakilynejad, Grace Chen, Henrik Loft, Atul R. Mahableshwarkar, Johan Areberg
      Abstract: Vortioxetine is approved for treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure–response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and 2 generalised anxiety disorder studies of vortioxetine (3160 patients), and efficacy data (Montgomery‐Åsberg Depression Rating Scale [MADRS]) from 7 MDD studies (2537 patients), were used for development of PK and PK/Efficacy models. One‐ and two‐compartment models were evaluated as structural PK models, and linear and non‐linear (Emax) models were used to describe the relationship between average vortioxetine concentration at steady state (Cav) and change in MADRS score from baseline (ΔMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterised by a two‐compartment model with first‐order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/h and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F but the effect of each of these covariates was not considered clinically relevant, as they lead to ±26% change in area under the curve (AUC) or Cmax of vortioxetine. An Emax model best described the relationship between ΔMADRS and Cav. Half maximal effective concentration (EC50) and Emax estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterised the vortioxetine exposure–response relationship. This article is protected by copyright. All rights reserved.
      PubDate: 2015-11-02T23:52:36.230514-05:
      DOI: 10.1111/bcpt.12513
  • The Inhibitory Effect of Ciprofloxacin on the
           β‐Glucuronidase‐mediated Deconjugation of the Irinotecan
           Metabolite SN‐38‐G
    • Authors: Takaaki Kodawara; Takashi Higashi, Yutaka Negoro, Yukio Kamitani, Toshiaki Igarashi, Kyohei Watanabe, Hitoshi Tsukamoto, Ryoichi Yano, Mikio Masada, Hiromichi Iwasaki, Toshiaki Nakamura
      Abstract: The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. β‐Glucuronidase, an intestinal bacteria‐produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide‐conjugated drugs. In this study, we established an in vitro system to evaluate the β‐glucuronidase‐mediated deconjugation of the irinotecan metabolite SN‐38‐G to its active SN‐38 form and the effect of ciprofloxacin thereon. SN‐38 formation increased in a time‐dependent manner from 5 to 30 min. in the presence of β‐glucuronidase. Ciprofloxacin and phenolphthalein‐β‐d‐glucuronide (PhePG), a typical β‐glucuronidase substrate, significantly decreased SN‐38‐G deconjugation and, hence, SN‐38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN‐38‐G to SN‐38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose‐dependent inhibitory effect on the β‐glucuronidase‐mediated conversion of SN‐38‐G to SN‐38 with a half‐maximal inhibitory concentration (IC50) value of 83.8 μM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non‐competitive manner, respectively. These findings suggest that the reduction in the serum SN‐38 concentration following co‐administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN‐38 through the non‐competitive inhibition of intestinal β‐glucuronidase‐mediated SN‐38‐G deconjugation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-30T22:38:08.083807-05:
      DOI: 10.1111/bcpt.12511
  • What should Junior Doctors Know about the Drugs they frequently
           prescribe? A Delphi Study among Physicians in The Netherlands
    • Authors: David Brinkman; Guus Disselhorst, Bernard Jansen, Jelle Tichelaar, Michiel Agtmael, Theo Vries, Milan Richir
      Abstract: The aim of this study was to identify the information about commonly prescribed drugs that junior doctors should know in order to prescribe rationally in daily practice, defined as Essential Drug Knowledge (EDK). A two‐round Internet Delphi study was carried out involving general practitioners from one practice cluster, and registrars and consultants from two Dutch academic and eight teaching hospitals. A preliminary list of 377 potential EDK items for three commonly prescribed drugs was assessed on a dichotomous scale; an item was considered EDK if at least 80% consensus was reached. The consensus list of EDK items was discussed by the research team to identify similarities between the three drugs, with a view to forming a list of general EDK items applicable to other commonly prescribed drugs. Sixty experts considered 93 of the 377 items (25%) as EDK. These items were then used to form a list of 10 general EDK items. The list of EDK items identified by primary and secondary care doctors could be used in medical curricula and training programmes and for assessing the prescribing competence of future junior doctors. Further research is needed to evaluate the generalizability of this list for other commonly prescribed drugs. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-27T09:43:51.672556-05:
      DOI: 10.1111/bcpt.12508
  • Elderly Patients Require Higher Doses of Sugammadex for Rapid Recovery
           from Deep Neuromuscular Block
    • Abstract: This study compared the doses of sugammadex needed for rapid recovery from deep neuromuscular blockade (NMB) between young and elderly adults. Twenty‐two young (20‐40 years) and 22 elderly (≥70 years) adults were enrolled, and deep NMB of 1‐2 post‐tetanic counts was maintained with rocuronium intraoperatively. Pre‐determined doses of sugammadex were given at the end of surgery starting at 4.0 mg/kg for the first patient of each group. Doses were decreased or increased in following patients by 0.5 mg/kg, depending on the ‘success’ or ‘failure’ of rapid recovery in the preceding patient. ‘Success’ was defined as adequate recovery (train‐of‐four ratio 0.9) within 2 min. after sugammadex administration. The median (range) of ages were 29 (20‐40) and 73 (70‐84) years for the young and elderly adults, respectively. Doses of sugammadex facilitating adequate recovery from deep NMB within 2 min. in each patient population with 50% and 95% probability were defined as ED50 and ED95, respectively. The ED50 estimated by the Dixon's method was significantly higher in the elderly compared to young adults [4.2 ± 0.4 mg/kg versus 3.3 ± 0.3 mg/kg, P < 0.001]. The ED50 (83% CI) estimated by isotonic regression was 4.5 (4.2‐5.0) mg/kg in elderly adults and 3.3 (3.2‐3.4) mg/kg in young adults. The ED95 (95% CI) estimated by isotonic regression was 5.4 (4.9‐5.5) mg/kg and 4.4 (3.9‐4.5) mg/kg in the elderly and young adults, respectively. In conclusion, dose adjustments of sugammadex should be considered when rapid recovery from deep NMB is needed in elderly adults. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-27T09:35:14.032515-05:
      DOI: 10.1111/bcpt.12507
  • Biochemical and histological effects of thiamine pyrophosphate against
           acetaminophen‐induced hepatotoxicity
    • Abstract: The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by paracetamol (APAP). Rats were divided into the following groups: healthy control (HG), APAP (AG, 1500mg/kg, orally), thiamine‐pyrophosphate (TPPG, 100mg/kg, intraperitoneally), APAP+NAC (ANAC, 100mg/kg, intraperitoneally), APAP+TPP (ATPG) and APAP+NAC+TPP (ANTG). Oxidant, antioxidant parameters, liver function tests and histological assessment were performed between groups. Malondialdehyde levels in the AG, HG, TPPG, ANAC, ATPG and ANTG groups were 0.470±0.210, 0.213±0.004, 0.194±0.001, 0.197±0.06, 0.199±0.008 and 0.173±0.010 μmol/g protein, respectively. Total glutathione levels were 7.787±0.395, 14.925±0.932, 13.200±0.984, 13.162±0.486, 13.287±0.787 and 13.500±0.891 μM/g protein, respectively. In the AG group, marked liver damage occurred with the elevation of liver function tests and oxidative stress markers, such as malondialdehyde, myeloperoxidase and nitric oxide (p
      PubDate: 2015-10-23T21:32:06.592372-05:
      DOI: 10.1111/bcpt.12496
  • HMGCR rs17671591 SNP determines Lower Plasma LDL‐C after
           Atorvastatin Therapy in Chilean Individuals
    • Abstract: Lipid‐lowering response to statin therapy shows large interindividual variability. At a genome‐wide significance level, single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR have been implicated in this differential response. However, the influence of these variants is uncertain in the Chilean population. Hence, we aimed to evaluate the contribution of PCSK9 rs7552841 and HMGCR rs17671591 SNPs as genetic determinants of atorvastin response in Chilean hypercholesterolaemic individuals. One hundred and one hypercholesterolaemic patients received atorvastatin 10 mg/day for 4 weeks. Plasma lipid profile (TC, HDL‐C, LDL‐C and TG) was determined before and after statin treatment, and SNPs were identified by allelic discrimination using TaqMan® SNP Genotyping assays. Adjusted univariate and multivariate analyses models were used for statistical analyses and a p‐value
      PubDate: 2015-10-23T21:20:37.963672-05:
      DOI: 10.1111/bcpt.12493
  • The Effect of a Selective Inhibitor of Phosphodiesterase‐9 on
           Oxidative Stress, Inflammation and Cytotoxicity in Neutrophils from
           Patients with Sickle Cell Anaemia
    • Abstract: The aim of the study was to investigate the possible anti‐inflammatory and antioxidant effects of BAY 73‐6691 on neutrophils from SCA patients. This study included 35 patients with a molecular diagnosis of SCA, whose neutrophils were isolated and treated with BAY 73‐6691 at the concentrations 100, 10, 1.0 and 0.1 μg/mL. LDH release and MTT assays were performed to verify cell viability. To evaluate oxidative stress, the following parameters were determined by spectrophotometric assays: NO and malondialdehyde (MDA) levels and activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). As inflammatory markers, myeloperoxidase (MPO) levels were evaluated by colourimetric assay and TNF‐alpha by enzyme immunoassay. The results showed that neutrophils from SCA patients not treated with hydroxyurea (HU) had significantly lower NO levels and catalase and SOD activity, as well as significantly higher MDA, MPO and TNF‐alpha levels when compared with neutrophils from SCA patients treated with HU and neutrophils from control group. Treatment of SCA neutrophils with BAY 73‐6691 resulted in 94%, 200% and 168% increase in NOx levels, SOD and catalase activity, respectively. In addition, there was a reduction of approximately 46% and 45% in TNF‐α and MPO levels, respectively. In SCAHU neutrophils, there was a 30% and 44% increase in NOx levels and SOD activity and a 28% and 37% decrease in TNF‐α and MPO levels. However, these effects were observed at cytotoxic doses only. The results of this study are original and demonstrate that inhibition of phosphodiesterase 9 in neutrophils from SCA patients with BAY 73‐6691 was able to increase the NO bioavailability and attenuate oxidative stress and inflammation in neutrophils from patients not treated with HU. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-23T01:36:44.822255-05:
      DOI: 10.1111/bcpt.12487
  • Effect of Iron and Carbon Monoxide on Fibrinogenase‐like Degradation
           of Plasmatic Coagulation by Venoms of Six Agkistrodon Species
    • Authors: Vance G. Nielsen; Daniel T. Redford, Patrick K. Boyle
      Abstract: Annually, thousands suffer poisonous snake bite, often from defibrinogenating species. It has been demonstrated that iron and carbon monoxide change the ultrastructure of plasma thrombi and improve coagulation kinetics. Thus, the present investigation sought to determine if pre‐treatment of plasma with iron and carbon monoxide could attenuate venom‐mediated catalysis of fibrinogen obtained from Agkistrodon species with fibrinogenase activity. Human plasma was pre‐treated with ferric chloride (0‐10 μM) and carbon monoxide releasing molecule‐2 (CORM‐2, 0‐100 μM) prior to exposure to 0.5‐11 μg/ml of six different Agkistrodon species’ venom. The amount of venom used for experimentation needed to decrease coagulation function of one or more kinetic parameters by at least 50% of normal values for (e.g., half the normal speed of clot formation). Coagulation kinetics were determined with thrombelastography. All six snake venoms degraded plasmatic coagulation kinetics to a significant extent, especially prolonging the onset to clot formation and diminishing the speed of clot growth. Pre‐treatment of plasma with iron and carbon monoxide attenuated these venom‐mediated coagulation kinetic changes in a species‐specific manner, with some venom effects markedly abrogated while others were only mildly decreased. Further in vitro investigation of other pit viper venoms that possess fibrinogenolytic activity is indicated to identify species amenable to or resistant to iron and carbon monoxide‐mediated attenuation of venom‐mediated catalysis of fibrinogen. Lastly, future preclinical investigation with animal models (e.g., rabbit ear bleed model) is planned to determine if iron and carbon monoxide can be used therapeutically after envenomation. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-15T01:15:39.393058-05:
      DOI: 10.1111/bcpt.12504
  • Relationships between Endogenous Plasma Biomarkers of Constitutive CYP3A
           Activity with Single Time‐Point Oral Midazolam Microdose Phenotype
           in Healthy Subjects
    • Abstract: Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4β‐hydroxycholesterol (4βHC) and 6β‐hydroxycortisol (6βHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4βHC and 6βHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single time‐point oral midazolam phenotyping strategy. Plasma 4βHC and 6βHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral midazolam microdose (100 μg). Simple linear and multiple linear regression analyses were performed to assess relationships between midazolam oral clearance, biomarkers and subject covariates. Among study subjects, basal midazolam oral clearance, 4βHC and 6βHCL MRs ranged 6.5‐, 10‐ and 13‐fold, respectively. Participant age and alcohol consumption were negatively associated with midazolam oral clearance (P=0.03 and P=0.045, respectively) while weight and female sex were associated with lower plasma 4βHC MR (P=0.0003 and P=0.032, respectively). Neither 4βHC nor 6βHCL MRs were associated with MDZ oral clearance. Plasma 4βHC and 6βHCL MRs do not relate to MDZ single time‐point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-14T22:13:17.657764-05:
      DOI: 10.1111/bcpt.12492
  • No untoward effect of long‐term ketoconazole administration on
           electrocardiographic qt interval in patients with cushing's disease
    • Abstract: Ketoconazole is listed among drugs which prolong QT interval and may increase the risk of torsade de pointes, a severe ventricular arrhythmia. This compound has recently been approved for treatment of Cushing's syndrome, a severe endocrine disorder. These patients harbour several risk factors for prolonged QT interval, e.g., hypokalaemia, left ventricular hypertrophy, but no study has evaluated whether administration of ketoconazole affects QT interval. The aim of the present study was to assess the QT interval in patients with Cushing's disease during long‐term administration of ketoconazole. Electrocardiograms from 15 patients with Cushing's disease (12 women, 3 men, age 37.8±2.66 years) on ketoconazole treatment (100 mg–800 mg qd) for 1 month to 12 years were reviewed retrospectively. QT interval was measured and corrected for heart rate (QTc). Measurements before and during ketoconazole treatment were compared and any abnormal QTc value recorded. Concurrent medical therapies were also documented. On average, QTc was superimposable before and during ketoconazole treatment (393.2±7.17 versus 403.3±6.05 msec in women; 424.3 ±23.54 versus 398.0±14.93 msec in men, N.S.). QTc normalized on ketoconazole in one man with prolonged QTc prior to treatment; no abnormal QTc was observed in any other patient during the entire observation period, even during concurrent treatment with other QT‐prolonging drugs. In conclusion, long‐term ketoconazole administration does not appear to be associated with significant prolongation of QT interval in patients with Cushing's disease. ECG monitoring can follow recommendations for other low‐risk QT‐prolonging drugs with attention to specific risk factors, e.g, hypokalaemia, drug interactions. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-14T21:46:02.907786-05:
      DOI: 10.1111/bcpt.12490
  • Minocycline Attenuates Depressive‐like Behaviour Induced by Rat
           Model of Testicular Torsion: Involvement of Nitric Oxide Pathway
    • Authors: Seyed Soheil Saeedi Saravi; Seyyedeh Elaheh Mousavi, Seyed Sobhan Saeedi Saravi, Ahmad Reza Dehpour
      Abstract: Testicular torsion/detorsion (T/D) can induce depression in pre‐ and post‐pubertal patients. This study was conducted to investigate the psychological impact of testicular torsion and mechanism underlying its depressive‐like behaviour, as well as antidepressant‐like activity of minocycline and possible involvement of nitric oxide (NO)/cGMP pathway in this paradigm in male rats undergoing testicular T/D. Uni‐lateral T/D was performed in 36 male adult Wistar rats, and different doses of minocycline were injected alone or combined with non‐specific NO synthase (NOS) inhibitor, L‐NAME, specific iNOS inhibitor, aminoguanidine (AG), an NO precursor, L‐arginine, and selective PDE5I, sildenafil. After assessment of locomotor activity in open‐field test, immobility times were recorded in the forced swimming test (FST). Moreover, 30 days after testicular T/D, testicular venous testosterone and serum nitrite concentrations were measured. A correlation was observed between either a decrease of plasma testosterone or an increase in serum nitrite concentrations with prolongation in immobility time in the testicular T/D operated rats FST. Minocycline (160 mg/kg) exerted the highest significant antidepressant‐like effect in the operated rats in the FST (P
      PubDate: 2015-10-14T01:58:26.382698-05:
      DOI: 10.1111/bcpt.12489
  • Triggering of Suicidal Erythrocyte Death by the Antibiotic Ionophore
    • Abstract: The K+,H+ ionophore and antibiotic nigericin has been shown to trigger apoptosis and is thus considered for the treatment of malignancy. Cellular mechanisms involved include induction of oxidative stress, which is known to activate erythrocytic Ca2+ permeable unselective cation channels leading to Ca2+ entry, increase of cytosolic Ca2+ activity ([Ca2+]i) and subsequent stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. The present study explored whether and how nigericin induces eryptosis. Phosphatidylserine exposure at the cell surface was estimated from annexin‐V‐binding, cell volume from forward scatter, [Ca2+]i from Fluo3‐fluorescence, pHi from BCECF‐ fluorescence, ceramide abundance utilizing antibodies and reactive oxygen species (ROS) formation from DCFDA‐dependent fluorescence. A 48‐hr exposure of human erythrocytes to nigericin significantly increased the percentage of annexin‐V‐binding cells (0.1‐10 nM), significantly decreased forward scatter (0.1 ‐ 1 nM), significantly decreased cytosolic pH (0.1 ‐ 1 nM) and significantly increased Fluo3‐fluorescence (0.1 ‐ 10 nM). Nigericin (1 nM) slightly, but significantly, increased ROS, but did not significantly modify ceramide abundance. The effect of nigericin on annexin‐V‐binding was significantly blunted, but not abolished by removal of extracellular Ca2+. The nigericin‐induced increase of [Ca2+]i and annexin‐V‐binding was again significantly blunted but not abolished by the Na+/H+ exchanger inhibitor cariporide (10 μM). Nigericin triggers eryptosis, an effect paralleled by ROS formation, in part dependent on stimulation of Ca2+ entry, and involving the cariporide sensitive Na+/H+ exchanger. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-12T13:01:21.264667-05:
      DOI: 10.1111/bcpt.12503
  • Curcumin, Silybin‐Phytosome® and α‐R‐Lipoic
           Acid Mitigate Chronic Hepatitis in Rat by Inhibiting Oxidative Stress and
           Inflammatory Cytokines Production
    • Authors: Shimaa O. Ali; Hebatallah A. Darwish, Nabila A. Ismail
      Abstract: Chronic hepatitis is recognized as a worldwide health problem that gradually progresses towards cirrhosis and hepatocellular carcinoma. Despite the large number of experiments using animal models for allergic hepatitis, it is still difficult to produce a picture of chronic hepatitis. Therefore, the present study was conducted to introduce an animal model approximating to the mechanism of chronicity in human hepatitis. The study also aimed to examine the hepatoprotective effects of curcumin, silybin phytosome® and α‐R‐lipoic acid against thioacetamide (TAA)‐induced chronic hepatitis in rat model. TAA was administered intraperitoneally at a dose of 200 mg/kg 3 times weekly for 4 weeks. At the end of this period, a group of rats was killed to assess the development of chronic hepatitis in comparison to their respective control group. TAA administration was then discontinued and the remaining animals were subsequently allocated into four groups. Group 1 was left untreated whereas groups 2‐4 were allowed to receive daily oral doses of curcumin, silybin phytosome® or α‐R‐lipoic acid, respectively, for 7 weeks. Increases in hepatic levels of malondialdehyde associated with TAA administration were inhibited in groups receiving supplements. Furthermore, glutathione depletion, collagen deposition, macrophage activation, nuclear factor κappa‐B expression as well as tumour necrosis factor‐α and interleukin‐6 levels were significantly decreased in response to supplements administration. Serological analysis of liver function and liver histopathological examination reinforced the results. The above evidence collectively indicates that the antioxidant and anti‐inflammatory activities of curcumin, silybin phytosome® and α‐R‐lipoic acid may confer therapeutic efficacy against chronic hepatitis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-12T12:45:31.813166-05:
      DOI: 10.1111/bcpt.12502
  • The Effect of the Combined Use of Methylergonovine and Oxytocin during
           Caesarean Section in the Prevention of Postpartum Haemorrhage
    • Abstract: We aimed to show the benefit to patients of postpartum hemorrhage prophylaxis treatment and the effectiveness as a uterotonic agent of the combined use of methylergonovine and oxytocin infusion in the prevention of hemorrhage during and after caesarean section, by comparison with a control group which received oxytocin infusion only. Two groups of patients undergoing caesarean section at the same clinic were included in the study. A combination of methylergonovine and oxytocin was administered to the first group during the intraoperative and postoperative periods. The second group did not receive methylergonovine and was administered only with oxytocin infusion in the intraoperative and postoperative periods. Preoperative and postoperative hemogram readings were taken for all patients in each of the groups for comparison. No difference was found between the two groups with regard to mean ages and preoperative hemogram values. The decrease in postoperative hemoglobin values for the group administered with methylergonovine maleate and oxytocin was found to be significantly greater than for the group administered with oxytocin only. Results indicated that prophylactic methylergonovine treatment was clearly successful for the patients and no adverse side effects were found. The routine use of methylergonovine and oxytocin infusion in combination during the intraoperative period of caesarean section reduced the level of postpartum hemorrhage considerably. We believe that this procedure will also reduce the risk of uterine atony, but clearly prospective studies will be necessary in future to confirm this assumption. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-09T06:55:23.461715-05:
      DOI: 10.1111/bcpt.12500
  • Organoarsenic Roxarsone Promotes Angiogenesis In Vivo
    • Authors: Yumei Zhang; Yujing Wang, Qianqian Lu, Wenfang Xin, Weibo Cui, Jiaqiao Zhu
      Abstract: Roxarsone, an organoarsenic feed additive, is widely used worldwide to promote animal growth. It has been found to exhibit a higher angiogenic index than AsIII at lower concentrations and to promote angiogenic phenotype in human endothelial cell in vitro. Little research has focused on the potential angiogenic effect of roxarsone in vitro or in vivo. Here, we investigated the pro‐angiogenic effect of roxarsone in vivo. The effects of 0.1‐10.0 μM roxarsone were tested in the rat endothelial cell Matrigel plug assay, chicken chorioallantoic membrane (CAM) model and MCF‐7 cell xenograft tumour model; 10 ng/mL vascular endothelial growth factor (VEGF) was used as a positive control and PBS as a negative control. Roxarsone significantly increased the volume, weight and hemoglobin content of the Matrigel plugs compared to PBS group (P < 0.05); 1.0 μM roxarsone exerted the most significant effects. H&E staining and CD31 immunochemistry revealed obviously more new vessels or capillary‐like structures in the plugs of the roxarsone and VEGF groups. Roxarsone significantly increased the numbers of primary/secondary vessels and area of vessels in the CAM assay; obviously increased tumour weight and volume in the xenograft model compared to PBS (P < 0.05). Histochemistry indicated local necrosis was observed at the center of the xenograft tumours in the PBS and roxarsone groups, with less necrosis apparent in the VEGF‐treated tumours. The growth of endothelial cells and VEGF level were obviously affected at blockade of VEGF and its receptor Flt‐1/Flk‐1 by SU5416 or its antibody in vitro. This study demonstrates roxarsone promotes angiogenesis in vivo, and a VEGF/VEGFR mechanism may be involved. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-09T02:51:17.802678-05:
      DOI: 10.1111/bcpt.12501
  • Impaired Glucose Tolerance in Healthy Men Treated with St. John's Wort
    • Abstract: The purpose of this study was to examine if the over‐the‐counter herbal medicinal plant St. John's wort affects glucose tolerance in healthy men. To do this, we included 10 healthy men who were examined by a 2‐hr oral glucose tolerance test on three occasions; A: Baseline, B: After 21 days treatment with St. John's wort and C: At least 6 weeks after the last capsule of St. John's wort was ingested. Plasma glucose, serum insulin and C‐peptide levels were measured during an oral glucose tolerance test and used for estimation of area under the concentration‐time curve (AUC) as well as and indices of insulin sensitivity and insulin secretion. We found that treatment with St. John's wort increased total and incremental glucose AUC and 2‐hr plasma glucose levels. Surprisingly, this effect was sustained and even further increased 6 weeks after the last capsule of St. John's wort was taken. No effect on indices of insulin sensitivity was seen, but indices of insulin secretion were reduced even after adjustment for insulin sensitivity. In conclusion, this study indicates that long‐term treatment with St. John's wort may impair glucose tolerance by reducing insulin secretion in young, healthy men. The unregulated use of this over‐the‐counter drug might be a risk factor for impaired glucose tolerance and type 2 diabetes. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-08T20:01:47.264973-05:
      DOI: 10.1111/bcpt.12486
  • Pinosylvin Inhibits TRPA1‐Induced Calcium Influx In Vitro and
           TRPA1‐Mediated Acute Paw Inflammation In Vivo
    • Abstract: Pinosylvin (3,5‐dihydroxy‐trans‐stilbene) is a stilbenoid polyphenol structurally related to resveratrol, and it is found in heartwood, knot and bark of Pinus species. Pinosylvin has been shown to possess anti‐inflammatory and cancer‐chemopreventive properties as well as being an antioxidant preventing oxidative stress [1‐4]. Transient receptor potential ankyrin 1 (TRPA1) is an ion channel expressed in the terminal ends of sensory neurons throughout the body. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-07T00:01:01.154573-05:
      DOI: 10.1111/bcpt.12485
  • Efficiency of a New Mesh‐Type Nebulizer (NE‐SM1 NEPLUS) for
           Intrapulmonary Delivery of Ipratropium Bromide in Surgical Patients
    • Abstract: This study was aimed to evaluate the efficiency of a new mesh‐type nebulizer for the intrapulmonary delivery of ipratropium bromide in surgical patients under mechanical ventilation. A total of 20 patients were randomly allocated to receive 0.5 mg ipratropium bromide using either a control (Pariboy SX, Pari, Co., Starnberg, Germany, n=10) or test (NE‐SM1 NEPLUS, KTMED Co., Seoul, Korea, n=10) nebulizer during general anaesthesia. Ipratropium bromide was nebulised continuously for 20 min. in each group. Plasma concentrations of ipratropium bromide were obtained from blood samples at preset intervals. Non‐compartmental analysis of ipratropium bromide was performed to compare the efficiency of pulmonary drug delivery in both nebulizers. Population pharmacokinetic analysis of ipratropium bromide was performed. Additionally, in in vitro studies, the noise level during the nebulizer operation and the aerosol particle size for each device were measured. The dose‐normalized AUClast was 0.10 min/L for both nebulizers. The pharmacokinetics of nebulised ipratropium bromide can be described best by a one‐compartment model with first‐order absorption. The apparent volume of distribution and metabolic clearance were 1,340 L and 6.78 L/min, respectively. Type of nebulizer was a significant covariate for absorption rate constant. The equivalent sound level and median aerosol particle diameter were 35.0 dB and 4.52 μm for the test nebulizer, and 60.2 dB and 3.85 μm for the control nebulizer, respectively. From the standpoint of the dose‐normalized AUClast, a new vibrating mesh‐type nebulizer shows similar performance in the intrapulmonary delivery of ipratropium bromide to that of a jet‐type nebulizer in surgical patients. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-06T09:34:11.472629-05:
      DOI: 10.1111/bcpt.12499
  • Antitumour Activity of the Microencapsulation of Annona vepretorum
           Essential Oil
    • Abstract: Annona vepretorum Mart. (Annonaceae), popularly known as “bruteira”, has nutritional and medicinal uses. This study investigated the chemical composition and antitumour potential of the essential oil of A. vepretorum leaf alone and complexed with β‐cyclodextrin in a microencapsulation. The essential oil was obtained by hydrodistillation using a Clevenger‐type apparatus and analysed using GC–MS and GC–FID. In vitro cytotoxicity of the essential oil and some of its major constituents in tumour cell lines from different histotypes was evaluated using the alamar blue assay. Furthermore, the in vivo efficacy of essential oil was demonstrated in mice inoculated with B16‐F10 mouse melanoma. The essential oil included bicyclogermacrene (35.71%), spathulenol (18.89%), (E)‐β‐ocimene (12.46%), α‐phellandrene (8.08%), o‐cymene (6.24%), germacrene D (3.27%) and α‐pinene (2.18%) as major constituents. The essential oil and spathulenol exhibited promising cytotoxicity. In vivo tumour growth was inhibited by the treatment with the essential oil (inhibition of 34.46%). Importantly, microencapsulation of the essential oil increased in vivo tumour growth inhibition (inhibition of 62.66%). This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-06T00:33:15.617839-05:
      DOI: 10.1111/bcpt.12488
  • First‐trimester pregnancy exposure to venlafaxine or duloxetine and
           risk of major congenital malformations: a systematic review
    • Authors: Dorte Lassen; Zandra Nymand Ennis, Per Damkier
      Abstract: Major depressive disorder is common among women in childbearing age, and medical treatment is subject to substantial discussions and controversies. For Selective Serotonin Reuptake Inhibitors, SSRIs, a vast amount of data is available. For the newer antidepressant group of serotonin and noradrenaline reuptake inhibitors, SNRIs, significantly less data are available. Following the PRISMA guideline for systematic reviews, we performed a systematic search on the risk of major congenital malformations after first‐trimester in utero exposure to venlafaxine or duloxetine. We identified 8 cohort studies reporting on the outcome upon in utero exposure to venlafaxine or duloxetine during the first trimester. The cumulated data for venlafaxine were 3186 exposed infants and 107 major malformations, resulting in a relative risk estimate and 95% confidence interval of 1.12 (0.92‐1.35). The corresponding data for duloxetine were 668 infants and 16 major malformations, resulting in a relative risk estimate and 95% confidence interval of 0.80 (0.46‐1.29). First‐trimester in utero exposure to venlafaxine is not associated with an increased risk of major congenital malformations. The amount of data for duloxetine is significantly smaller but does not suggest a clinically important increased risk. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-05T05:59:31.627986-05:
      DOI: 10.1111/bcpt.12497
  • Response of authors to Ganju and Dias’ comments on ‘Inclusion
           of Placebos and Blinding for Ascending Dose First‐in‐Human
           Studies and Other Underpowered Phase 1 Studies Has Not Been Justified and
           on Balance is Not Useful’ by D. A. Parasrampuria and L. Z. Benet
    • Authors: Dolly A. Parasrampuria; Leslie Z. Benet
      PubDate: 2015-10-04T21:36:08.581753-05:
      DOI: 10.1111/bcpt.12483
  • Clinical weighting of drug‐drug interactions in hospitalized elderly
    • Abstract: Adverse drug reactions impact on patient health, effectiveness of pharmacological therapy and increased health care costs. The current investigation intended to detect the most critical drug‐drug interactions in hospitalized elderly patients, weighting clinical risk. We conducted a cross‐sectional study between January and April 2014; all patients 70 years or older, hospitalized for >24 hr and prescribed at least one medication were included in the study. Drug‐drug interactions were estimated by combining Stockley's, Hansten and Tatro drug interactions. Drug‐drug interactions were weighted using a risk‐analysis method based on failure modes, effects and criticality analysis. We calculated a criticality index for each drug involved in the drug‐drug interactions based on the severity of the interaction mechanism, the frequency the drug was involved in drug‐drug interactions and the risk of drug‐drug interactions in patients with impaired renal function. The average number of drugs consumed in the hospital was 6 ± 2.69, involving 160 active ingredients. The most frequent were: Furosemide, followed by Enalapril. Of drug‐drug interactions, 2% were classified as contra‐indicated, 14% advised against and 83% advised caution during the hospital stay. Thirty‐four drug‐drug interactions were assessed of which 23 were drug‐drug interactions‐pharmacodynamics, 12 were drug‐drug interactions‐pharmacokinetic (1 was both). The clinical risk calculated for each drug‐drug interaction included heparins+non‐steroidal anti‐inflammatory drugs (NSAIDs) or Digoxin+Calcium Gluconate, cases which are drug‐drug interactions‐pharmacodynamic with agonist effect and clinical risk of bleeding, one of the most common clinical risks in the hospital. An index of clinical risk for drug‐drug interactions can be calculated based on severity by the interaction mechanism, the frequency that the drug is involved in drug‐drug interactions and the risk of drug‐drug interactions in an elderly patient with impaired renal function. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-03T03:46:52.028091-05:
      DOI: 10.1111/bcpt.12495
  • Low vitamin D Levels and Genetic Polymorphism in the Vitamin D Receptor
           are Associated with Increased Risk of Statin‐Induced Myopathy
    • Abstract: The main aim of this study was to test the hypothesis whether 25‐hydroxyvitamin D (25OHD) levels < 50 nmol/L at baseline could predict statin‐induced myopathy during the course of treatment. In addition, we analysed the association between a genetic polymorphism in the vitamin D receptor (VDR) and the risk of statin‐induced myopathy. We used serum samples from a prospective, observational study in statin‐treated patients in Sweden who were thoroughly followed with interviews and questionnaires regarding muscular symptoms (n=127). In this cohort, 16 developed muscular symptoms and 111 had no muscular symptoms associated with statin treatment during the first year of follow‐up. Patients with 25OHD levels 50 nmol/ L; (RR 4.2; 95% CI 1.7‐10.2; p
      PubDate: 2015-10-01T01:06:26.235467-05:
      DOI: 10.1111/bcpt.12482
  • Sodium Nitrite Prevents both Reductions in Circulating Nitric Oxide and
           Hypertension in 7‐Day Lead‐Treated Rats
    • Abstract: Hypotensive effects of oral sodium nitrite have been reported as alternative sources of nitric oxide (NO) formation in animals and human beings. Reductions of NO bioavailability were observed in lead‐induced hypertension. However, no previous study has examined whether a single daily dose of sodium nitrite prevents the reductions in the NO bioavailability in lead‐induced hypertension. Then, we expanded previous reports and evaluated the effects of sodium nitrite in 7‐day lead‐treated rats. Wistar rats were divided into four experimental groups: Pb+sodium nitrite group received intraperitoneally (i.p.) 1st dose 8μg/100g of lead acetate and a subsequent dose of 0.1μg/100g, and daily treatment with sodium nitrite (45mg/kg/day) or water (Pb group) by gavage for seven days; Sodium nitrite group received i.p. 1st dose 8μg/100g of sodium acetate and a subsequent dose of 0.1μg/100g, and daily treatment with sodium nitrite (45mg/kg/day) or water (Saline group) by gavage for seven days. Similar and higher whole‐blood lead levels (11.5±1.2 and 13.2±0.7μg/dL) were found in lead‐exposed rats treated with either water or sodium nitrite (Pb or Pb+sodium nitrite, respectively; both P 
      PubDate: 2015-10-01T00:14:28.103824-05:
      DOI: 10.1111/bcpt.12480
  • Successful Treatment of Aluminium Phosphide Poisoning by Extracorporeal
           Membrane Oxygenation (ECMO)
    • Abstract: Aluminium phosphide (ALP) is one of the most commonly used pesticides worldwide with high mortality rates. Cellular damage and cardio‐respiratory failure are the most common causes of mortality and morbidity after poisoning. It is supposed that giving enough time to the patient to survive, the most critical hours post‐exposure may help the cardiovascular system to recover itself and save the patient's life. During a training workshop for medical extracorporeal membrane oxygenation (ECMO), a 28‐year‐old ALP‐poisoned male was referred to us. Fifty minutes after admission, he developed hypotension and bradycardia and was transferred to ICU. On the second venous blood gas, he had severe metabolic acidosis. After starting the patient on the routine treatment of ALP poisoning, he was a candidate for veno‐arterial (VA) ECMO. After three days, lactate level decreased and his general condition improved. On day four, the patient was completely separated from the ECMO machine with acceptable echocardiography and ejection fraction of 40%. One day later, he was extubated, sent to the ward and subsequently discharged in good condition. We suggest this method of treatment for severe ALP poisoning as well as any other poisoning that causes cell toxicity and abrupt cardiovascular or respiratory failure. This article is protected by copyright. All rights reserved.
      PubDate: 2015-10-01T00:08:45.297118-05:
      DOI: 10.1111/bcpt.12481
  • Adverse Drug Reactions for Medicines Newly Approved in Japan from 1999 to
           2013: Hypertension and Hypotension
    • Authors: Takashi Nagayama; Minoru Nishida, Masanori Hizue, Yamato Ogino, Masato Fujiyoshi
      Abstract: In this survey, the correlation between adverse drug reactions (ADRs) in human and animal toxicities was investigated for 393 medicines which were approved in Japan from September 1999 to March 2013. ADRs were collected from each Japanese package insert. Comparable animal toxicities with ADRs were collected by thorough investigation of common technical documents. The results of this survey show that hypertension and/or hypotension were mainly observed in medicines affecting the central nervous system. Hypertension was also observed in antipyretics, analgesics, anti‐inflammatory agents, vasoconstrictors and agents using antibody. Concordance between human ADRs and animal toxicities was analysed. True positive rate for hypertension and hypotension are 0.29 and 0.52, respectively. Positive likelihood ratio and inverse negative likelihood ratio are 1.98 and 1.21, respectively, in hypertension and 1.67 and 1.44, respectively, in hypotension. Concordance between human ADR and animal toxicities is not so high in hypertension and hypotension. Identified mechanisms as on‐target for hypertension and hypotension are 29.8% and 30.5%, respectively. More than half of the causative factors of hypertension and hypotension were unable to be elucidated. Our results show that the intake of medicines is often linked to blood pressure variations that are not predicted in animal toxicity studies. Improvement of drug development processes may be necessary to provide safer medicines because current animal toxicity studies are insufficient to predict all ADRs in human beings. This article is protected by copyright. All rights reserved.
      PubDate: 2015-09-26T02:51:02.195036-05:
      DOI: 10.1111/bcpt.12494
  • Response to Aravindan Vairaiah's Letter to the Editor regarding our
           article ‘Adverse Events Associated with Flumazenil Treatment for the
           Management of Suspected Benzodiazepine Intoxication – A Systematic
           Review with Meta‐Analyses of Randomised Trials’
    • PubDate: 2015-09-22T01:45:01.248391-05:
      DOI: 10.1111/bcpt.12472
  • Response to ‘Inclusion of Placebos and Blinding for Ascending Dose
           First‐in‐Human Studies and Other Underpowered Phase 1 studies
           has not been Justified and on Balance is Not Useful’ by D.A.
           Parasrampuria and L.Z. Benet
    • Authors: Jitendra Ganju; Clapton Dias
      PubDate: 2015-09-14T00:53:49.993727-05:
      DOI: 10.1111/bcpt.12474
  • Methodological Perspectives from ‘Milrinone for the Treatment of
           Acute Heart Failure After Acute Myocardial Infarction: A Systematic Review
           and Meta‐analysis’
    • PubDate: 2015-09-11T05:15:51.0086-05:00
      DOI: 10.1111/bcpt.12458
  • Response to ‘In Response to “Intravenous Lipid Emulsion Given
           to Volunteers does not Affect Symptoms of Lidocaine Brain
    • Authors: Juho A. Heinonen; Erik Litonius, Per H. Rosenberg
      PubDate: 2015-09-11T05:14:26.977932-05:
      DOI: 10.1111/bcpt.12471
  • Gabapentin, an Analgesic used against Cancer‐Associated Neuropathic
           Pain: Effects on Prostate Cancer Progression in an In Vivo Rat Model
    • Authors: Ilknur Bugan; Zeynep Karagoz, Seyhan Altun, Mustafa B A Djamgoz
      Abstract: A major problem associated with clinical management of cancer is controlling the accompanying pain, and various analgesics are in common use for this purpose. Recent evidence suggests that some of the targets of analgesics, such as ion channels and receptors, may also be involved in the cancer process, thereby raising the possibility that such use of some analgesics may impact upon cancer itself. The main aim of the present study was to determine whether gabapentin, a common adjuvant analgesic in current use against cancer‐associated neuropathic pain, would affect tumour development and progression in vivo. The Dunning rat model of prostate cancer was used. Strongly metastatic Mat‐LyLu cells were implanted subcutaneously into syngeneic Copenhagen rats which were then treated every other day with 4.6‐16.8 μg/kg gabapentin by gavage. Primary tumourigenesis was monitored daily. Lung metastases were counted and measured after killing the rats 21 days later. Gabapentin had no effect on primary tumourigenesis but produced dose‐dependent effects on lung metastasis. Whilst 4.6 μg/kg had no effect, 9.1 μg/kg gabapentin decreased the number of lung metastases significantly by 64%. In contrast, 16.8 μg/kg gabapentin promoted metastasis significantly by 112% and showed a strong tendency to shorten mean survival time. It is concluded that gabapentin prescribed to cancer patients against pain could impact upon the cancer process itself. This article is protected by copyright. All rights reserved.
      PubDate: 2015-09-03T09:44:23.197047-05:
      DOI: 10.1111/bcpt.12484
  • Long‐term Pharmacotherapy of Adults with Attention‐Deficit
           Hyperactivity Disorder (ADHD): A Literature Review and Clinical Study
    • Authors: Mats Fredriksen; Dawn E. Peleikis
      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.
      PubDate: 2015-08-27T05:08:57.106872-05:
      DOI: 10.1111/bcpt.12477
  • Effects of 22 Novel CYP2D6 Variants Found in the Chinese Population on the
           Bufuralol and Dextromethorphan Metabolisms in vitro
    • Abstract: Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that metabolizes a large number of therapeutic drugs. To date, more than 100 CYP2D6 allelic variants have been reported. Among these variants, we recently identified 22 novel variants in the Chinese population. The aim of this study was to functionally characterize the enzymatic activity of these variants in vitro. A baculovirus‐mediated expression system was used to express wild‐type CYP2D6.1 and other variants (CYP2D6.2, CYP2D6.10 and 22 novel CYP2D6 variants) at high levels. Then, the insect microsomes containing expressed CYP2D6 proteins were incubated with bufuralol or dextromethorphan at 37°C for 20 or 25 min., respectively. After termination, the metabolites were extracted and used for the detection with high‐performance liquid chromatography. Among the 24 CYP2D6 variants tested, two variants (CYP2D6.92 and CYP2D6.96) were found to be catalytically inactive. The remaining 22 variants exhibited significantly decreased intrinsic clearance values for bufuralol 1’‐hydroxylation and 20 variants showed significantly lower intrinsic clearance values for dextromethorphan O‐demethylation than those of the wild‐type CYP2D6.1. Our in vitro results suggest that most of the variants exhibit significantly reduced catalytic activities compared with the wild‐type, and these data provide valuable information for personalized medicine in Chinese and other Asian populations. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-27T05:08:16.905814-05:
      DOI: 10.1111/bcpt.12478
  • 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.
      PubDate: 2015-08-27T05:07:02.818466-05:
      DOI: 10.1111/bcpt.12479
  • 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.
      PubDate: 2015-08-24T11:16:17.968995-05:
      DOI: 10.1111/bcpt.12475
  • Risk Factors for Mortality and Endotracheal Intubation after Methadone
    • Abstract: This was a retrospective chart review to evaluate various risk factors associated with in‐hospital mortality and intubation risk in acute methadone overdose. All patients admitted to an academic hospital in Tehran, Iran, during a 10‐year period (2000‐2009) constituted the study sample. Exclusion criteria were significant co‐morbidities and age under 18 years. Primary outcomes were in‐hospital mortality and being intubated during admission. A total of 802 patients were enrolled in the study. There were 15 (1.8%) deaths due to methadone overdose or its complications. The number of yearly admissions was 15 patients in 2000, 16 in 2001, 16 in 2002, 18 in 2003, 23 in 2004, 38 in 2005, 59 in 2006, 110 in 2007, 206 in 2008, and 301 in 2009. Based on logistic regression analysis, the most important independent variable predicting mortality was length of admission in toxicology ward [OR (95% CI): 1.6 (1.1‐2.3)]. For prediction of intubation, independent variables were Glasgow Coma Scale (GCS) score of 5‐9 [OR (95% CI):356.5 (9.8‐12907.4)] in the Emergency Department (ED), miosis in the ED [356.9 (1.4‐87872.5)], and respiratory rate in the ED [1.5 (1.1‐2.1)]. Linear regression model for length of hospitalization showed patient age as the most important variable for prediction of this outcome. Despite a relatively low mortality rate, the increasing number of methadone‐poisoned patients requires special attention to this common intoxication. Careful disposition of patients from ED to ordinary wards or Intensive Care Units and also from higher to lower levels of care should be considered in methadone overdose. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-24T11:12:43.87314-05:0
      DOI: 10.1111/bcpt.12476
  • 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.
      PubDate: 2015-08-24T06:07:34.299349-05:
      DOI: 10.1111/bcpt.12473
  • Diabetic Ketoacidosis in a Patient with Type 2 Diabetes after Initiation
           of Sodium‐Glucose Co‐Transporter 2 Inhibitor Treatment
    • Abstract: Sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) were recently introduced for the treatment of type 2 diabetes (T2D). SGLT2i lower plasma glucose by inhibiting the renal reuptake of glucose leading to glucosuria. Generally, these drugs are considered safe to use. However, recently, SGLT2i have been suggested to predispose to ketoacidosis. Here, we present a case of diabetic ketoacidosis (DKA) developed in an obese, poorly controlled male patient with T2D treated with the SGLT‐2i dapagliflozin. He was admitted with DKA five days after initiation of treatment with the SGLT2i dapagliflozin. On admission, the primary symptoms were nausea and dizziness, and he was hypertensive (170/103) and tachycard (119 bpm), had mild hyperglycaemia (15.3 mmol/l), severe ketonuria and severe metabolic acidosis (pH 7.08). He responded well to infusions of insulin, glucose and saline and was discharged after 72 hr with insulin as the only glucose‐lowering therapy. After one month, dapagliflozin was reintroduced as add‐on to insulin with no recurrent signs of ketoacidosis. During acute illness or other conditions with increased insulin demands in diabetes, SGLT2i may predispose to the formation of ketone bodies and ensuing acidosis. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-20T07:23:58.068388-05:
      DOI: 10.1111/bcpt.12457
  • Concurrent Use of Low‐Dose Aspirin and Omega‐3 Fatty Acids and
           Risk of Upper Gastrointestinal Complications: A Cohort Study with Nested
           Case‐Control Analysis
    • Authors: G. Roberto; M. Simonetti, C. Cricelli, I. Cricelli, S.E. Giustini, D. Parretti, F. Lapi
      Abstract: The risk of upper gastrointestinal complications (UGIC) due to low‐dose aspirin (LDA) can be further increased by the concurrent exposure to other antithrombotic agents. Little is known on the combined therapy with LDA and medications containing omega‐3 fatty acids (OM3), which also exert antiplatelet activity. The aim of this study was to investigate the risk of UGIC in patients exposed to LDA‐OM3 combination. The Italian Health Search IMS Longitudinal Patients Database was used to perform a population‐based cohort study. Patients aged ≥18 years with cardio or cerebrovascular ischaemic disease recorded between 2002 and 2012 (cohort entry) were selected. All UGIC cases (index date) observed up to December 2013 were identified. According to a nested case‐control analysis, up to 10 controls were matched to each case on age, sex and calendar period. The risk of UGIC was investigated among current (up to 30 days preceding index date), recent (31–60 days) and past users (61–365 days) of the LDA‐OM3 combination. Exposure assessment was lagged by 30 days to minimize reverse causation. Additionally, a duration–response analysis was performed. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Non‐users of the LDA‐OM3 combination were the reference category. Current (OR=0.66; 95%CI: 0.44–1.00), recent (OR=0.83; 95%CI: 0.52–1.33) and past users (OR=0.81; 95%CI: 0.57–1.15) did not statistically significantly increase the risk of UGIC. No duration–response relationship was found. Our results suggest that LDA‐OM3 combination therapy does not affect the UGIC risk in patients with cardio or cerebrovascular ischaemic diseases. Given the novelty of these findings, further studies are needed. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-17T10:18:56.203315-05:
      DOI: 10.1111/bcpt.12454
  • Erythrocyte Shrinkage and Cell Membrane Scrambling after Exposure to the
           Ionophore Nonactin
    • Authors: Thomas Peter; Rosi Bissinger, Florian Lang
      Abstract: The ionophore antibiotic nonactin permeabilizes cell membranes to NH4+ and K+. Treatment of erythrocytes with nonactin is expected to trigger cellular K+ loss with subsequent cell shrinkage, which in turn is known to trigger suicidal death of a wide variety of cells including erythrocytes. The present study explored whether nonactin exposure induces eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and translocation of cell membrane phosphatidylserine to the erythrocyte surface. Signalling of eryptosis include increase of cytosolic Ca2+‐activity ([Ca2+]i) and stimulation of protein kinase C as well as p38 mitogen activated protein kinase. Phosphatidylserine abundance at the cell surface was estimated from annexin‐V‐binding, cell volume from forward scatter and [Ca2+]i from Fluo3‐fluorescence. A 48‐hr treatment of human erythrocytes with nonactin significantly decreased forward scatter (≥ 10 ng/ml) and significantly increased the percentage of annexin‐V‐binding cells (≥10 ng/ml), effects paralleled by increase of [Ca2+]i (≥ 50 ng/ml) and virtually abrogated by increase of extracellular K+ concentration to 120 mM at the expense of Na+. The up‐regulation of annexin‐V‐binding after nonactin treatment was significantly blunted but not abolished by removal of extracellular Ca2+ and by addition of either PKC inhibitor staurosporine (0.4 μM) or p38 kinase inhibitor SB203580 (2 μM). In conclusion, exposure of erythrocytes to the K+ ionophore nonactin induces erythrocyte shrinkage and subsequent erythrocyte membrane scrambling, effects involving cellular K+ loss, Ca2+ entry and activation of staurosporine as well as SB203580 sensitive kinases. This article is protected by copyright. All rights reserved.
      PubDate: 2015-08-17T10:18:20.117007-05:
      DOI: 10.1111/bcpt.12455
  • LCZ696 (Valsartan/Sacubitril) ‐ A Possible New Treatment for
           Hypertension and Heart Failure
    • Authors: Mathilde Borring Andersen; Ulf Simonsen, Markus Wehland, Jessica Pietsch, Daniela Grimm
      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.
      PubDate: 2015-08-17T10:16:40.331219-05:
      DOI: 10.1111/bcpt.12453
  • 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
      PubDate: 2015-08-14T05:57:02.932286-05:
      DOI: 10.1111/bcpt.12452
  • In Response to ‘Intravenous Lipid Emulsion Given to Volunteers Does
           Not Affect Symptoms of Lidocaine Brain Toxicity’
    • Authors: Janeva Kircher; Brandy Stauffer, Benjamin D. Kessler, Mark Su
      PubDate: 2015-08-13T01:22:12.961624-05:
      DOI: 10.1111/bcpt.12450
  • This meta‐analysis does not reflect current practice and
           overestimates SAEs
    • Authors: Aravindan Veiraiah
      PubDate: 2015-08-10T19:39:53.712228-05:
      DOI: 10.1111/bcpt.12451
  • 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
  • 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
  • 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
  • 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
  • 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
  • MicroRNAs in Bladder Outlet Obstruction: Relationship to Growth and Matrix
    • Abstract: The discovery of microRNAs (miRNAs), which are ~22 nucleotide RNAs that inhibit protein synthesis in a sequence‐specific manner and are present in a range of species, has born hope of new therapeutic strategies. miRNAs play important roles in development “Development” of what''and disease, but they remain poorly studied in uropathologies beyond cancer. Here, we discuss biological functions of miRNAs in the lower urogenital tract. A special focus is on miRNAs that change in bladder outlet obstruction (BOO). This is a condition that affects nearly one third of all men over 60 years and that involves growth and fibrosis of the urinary bladder. Animal models of BOO, such as that in rat, have been developed and they feature a massive 6‐fold bladder growth over 6 weeks. Using microarrays, we have charted the miRNAs that change during the time‐course of this process and identified several with important modulatory roles. We discuss known and predicted functions of miR‐1, miR‐29, miR‐30, miR‐132/212, miR‐204 and miR‐221, all of which change in BOO. The majority of the miRNA‐mediated influences in BOO are expected to favour growth. We also outline evidence that miR‐29 represents a key effector molecule in a generic response to mechanical distension that is designed to counteract exaggerated organ deformation via effects on matrix deposition and stiffness. We conclude that miRNAs play important roles in bladder remodelling and growth and that they may be targeted pharmacologically to combat diseases of the lower urinary tract. This article is protected by copyright. All rights reserved.
  • Modelling of the Sedative Effects of Propofol in Patients undergoing
           Spinal Anaesthesia: A Pharmacodynamic Analysis
    • Abstract: Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect‐site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect‐site target‐controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3‐4] and deep sedation (OAA/S scores of 1‐2) were developed using Nonlinear Mixed Effects Modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce50 values for adequate and deep sedation were 0.94 and 1.52 μg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (P=0.0003). The simulated Ce50 values for adequate sedation in 20‐year‐old patients with a T12 sensory level and in 80‐year‐old patients with a T4 level were 1.63 and 0.53 μg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation. This article is protected by copyright. All rights reserved.
  • Omeprazole and Semen Quality
    • Abstract: A number of studies have linked omeprazole, a commonly used acid reducer under the brand name Prilosec, with semen quality. This MiniReview systematically addresses and summarizes the effect of omeprazole on semen quality, and male infertility. We searched the MEDLINE electronic database for English‐language articles by using the key words ‘omeprazole’ versus ‘sperm’ and “testosterone” and the references from selected articles were reviewed, if relevant. In summary, omeprazole does not appear to change semen quality. This may be because, at least in part, it does not alter the basal levels of pituitary‐gonadal hormones; in addition, it counteracts the damaging effect of reactive oxygen species. However, further research is still required to confirm this effect. This article is protected by copyright. All rights reserved.
  • Variability of Voriconazole Trough Levels in Haematological Patients:
           Influence of Co‐Medications with CYP Inhibitors and/or with CYP
           Inhibitors plus CYP Inducers
    • Abstract: Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of co‐medications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough levels (Cmin). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed‐effect regression analyses were performed to identify independent predictors of normalized Cmin. Among the 83 included patients, 35 had co‐medication with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin (n=199) was 2.4 mg/L with a wide range of distribution (< 0.2‐13.5 mg/L). Median (IQR) normalized voriconazole Cmin was significantly higher in presence of CYP inhibitors (4.20 mg/L, 3.23–5.51 mg/L) than either in absence of interacting co‐treatments (2.55 mg/L, 1.54–3.47 mg/L) or in presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19–3.09 mg/L). Presence of CYP inhibitors resulted highly significantly associated with Cmin > 5.5 mg/L (OR: 23.22, 95% CI: 3.01–179.09, P=0.003). No significant association emerged when CYP inhibitors were co‐administered with CYP inducers (OR: 3.53, 95% CI: 0.36–34.95, P=0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are co‐treated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously. This article is protected by copyright. All rights reserved.
  • Cardiovascular Drugs and Metformin Drug Dosage According to Renal Function
           in Non‐Institutionalized Elderly Patients
    • Abstract: Background Adaptation of drug dosage to kidney function is a common problem in general practice. Aim To describe adaptation of cardiovascular drugs and metformin according to renal function and its association with mortality with regard to metformin in a cohort of elderly patients. Design and Setting Ancillary study to the S.AGES cohort made up of patients over 65 years old managed by their general practitioner under real‐life conditions and followed up prospectively for 3 years. Methods The medications studied were digoxin, spironolactone and metformin. Adaptation of their daily dose according to renal function (eGFR according to CKD/EPI) was compared to that recommended in the summaries of product characteristics (SPCs) or international scientific societies (ISS). Results 900 patients were included, including 588 on metformin. At baseline, dose adjustment according to renal function was 100% and 87.6% (95%CI:82.6‐92.6) for patients on digoxin and spironolactone, respectively. For metformin, only 71.3% (95%CI:67.6‐74.9) or 78.1% (95%CI:74.7‐81.4) of patients had their dosage adapted at inclusion according to their renal function depending on whether the SPCs or ISS recommendations were considered. During the 3 year follow‐up period, 42/588 patients died (none from lactic acidosis). At inclusion, a metformin dosage not adapted for renal function according to ISS was not associated with an increase in all cause mortality (OR 1.7; 95%CI 0.6‐5.0, p=0.32). Conclusion Approximately one quarter of elderly patients treated with metformin do not have their dosage adapted for renal function according to ISS although there is no increase in mortality after follow‐up for 3 years. This article is protected by copyright. All rights reserved.
  • Acetaminophen for Chronic Pain: A Systematic Review on Efficacy
    • Abstract: Acetaminophen (paracetamol) is the most commonly used analgesic worldwide and recommended as first‐line treatment in all pain conditions by WHO. We performed a systematic literature review to evaluate the efficacy of acetaminophen when used for chronic pain conditions. Applying three broad search strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1,551 hits were obtained. Following cross‐reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than two weeks with placebo were included. The review was conducted according to PRISMA guidelines. All studies were conducted in patients with hip‐ or knee osteoarthritis and six out of seven studies had observation periods of less than three months. All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little evidence to support the efficacy of acetaminophen treatment in patients with chronic pain conditions. Assessment of continuous efficacy in the many patients using acetaminophen worldwide is recommended. This article is protected by copyright. All rights reserved.
  • Structural Studies of Nicotinic Acetylcholine Receptors: Using
           Acetylcholine Binding Protein as a Structural Surrogate
    • Abstract: Nicotinic acetylcholine receptors (nAChRs) are members of the pentameric ligand‐gated ion channel superfamily that play important roles in control of neurotransmitter release in the central and peripheral nervous system. These receptors are important therapeutic targets for development of drugs against a number of mental health disorders and for marketed smoking cessation aids. Unfortunately, drug discovery has been hampered by difficulties in obtaining sufficiently selective compounds. Together with functional complexity of the receptors, this has made it difficult to obtain drugs with sufficiently high‐target to off‐target affinity ratios. The recent and on‐going progress in structural studies holds promise to help understand structure‐function relationships of nAChR drugs at the atomic level. This will undoubtedly lead to design of more efficient drugs with fewer side effects. As a high‐resolution structure of a nAChR is yet to be determined, structural studies are to a large extent based on acetylcholine binding proteins (AChBPs) that despite low overall sequence identity display high degree of conservation of overall structure and amino acids at the ligand‐binding site. Further, AChBPs reproduce relative binding affinities of ligands at nAChRs. Over the past decade, AChBPs have been used extensively as models for nAChRs and have aided the understanding of drug receptor interactions at nAChRs significantly. This article is protected by copyright. All rights reserved.
  • Sulfated Polysaccharide Isolated from the Seaweed Gracilaria caudata
           Exerts an Antidiarrhoeal Effect in Rodents
    • Abstract: Diarrhoea is a significant health problem for children in developing countries that causes more than 1 million deaths annually. The present study aimed to evaluate the antidiarrhoeal effect of sulfated polysaccharide (PLS) from the alga Gracilaria caudata in rodents. For the evaluation, acute diarrhoea was induced in Wistar rats (150–200 g) by administration of castor oil (10 mg/kg). Then, different parameters, including enteropooling and gastrointestinal transit and its pharmacological modulation by opioid and cholinergic pathways were assessed using activated charcoal in Swiss Mice (25–30 g). Secretory diarrhoea was examined using cholera toxin (1 mg/loop)‐treated, isolated intestinal loops from Swiss mice (25–30 g), which were also used to examine fluid secretion, loss of chloride ions into the intestinal lumen, and absorption. In addition, a GM1‐dependent ELISA was used to evaluate the interaction between PLS, cholera toxin and the GM1 receptor. Pre‐treatment with PLS (10, 30, and 90 mg/kg) reduced foecal mass, diarrhoeal faeces and enteropooling. However, 90 mg/kg more effectively reduced these symptoms; therefore, it was used as the standard dose in subsequent experiments. Gastrointestinal transit was also reduced by PLS treatment via a cholinergic mechanism. Regarding the diarrhoea caused by cholera toxin, PLS reduced all study parameters, and the ELISA showed that PLS can interact with both the GM1 receptor and cholera toxin. These results show that PLS from G. caudata effectively improved the parameters observed in acute and secretory diarrhoea, which affects millions of people, and may lead to the development of a new alternative therapy for this disease. This article is protected by copyright. All rights reserved.
  • Issue Information
  • The role of CYP2C8 and CYP2C9 Genotypes in Losartan‐Dependent
           Inhibition of Paclitaxel Metabolism in Human Liver Microsomes
    • Abstract: The aim of the present study was to further investigate a previously identified metabolic interaction between losartan and paclitaxel, which is one of the marker substrates of CYP2C8, by using human liver microsomes (HLMs) from donors with different CYP2C8 and CYP2C9 genotypes. Although CYP2C8 and CYP2C9 exhibit genetic linkage, previous studies have yet to determine if losartan or its active metabolite, EXP‐3174, which is specifically generated by CYP2C9, is responsible for CYP2C8 inhibition. Concentrations of 6α‐hydroxypaclitaxel and EXP‐3174 were measured by HPLC after incubations with paclitaxel, losartan or EXP‐3174 in HLMs from seven donors with different CYP2C8 and CYP2C9 genotypes. The half maximal inhibitory concentration (IC50) values were not fully dependent on CYP2C8 genotypes. Although the degree of inhibition was small, losartan significantly inhibited production of 6α‐hydroxypaclitaxel at a concentration of 1 μmol/L in only HL20 with the CYP2C8*3/*3 genotype. HLMs with either CYP2C9*2/*2 or CYP2C9*1/*3 exhibited a lower losartan intrinsic clearance (Vmax/Km) than other HLMs including those with CYP2C9*1/*1 and CYP2C9*1/*2. Significant inhibition of 6α‐hydroxypaclitaxel formation by EXP‐3174 could only be found at levels that were 50‐fold higher (100 μmol/L) than the maximum concentration generated in the inhibition study using losartan. These results suggest that the metabolic interaction between losartan and paclitaxel is dependent on losartan itself rather than its metabolite, and that the CYP2C8 inhibition by losartan is not affected by the CYP2C9 genotype. Further study is needed to define the effect of CYP2C8 genotypes on losartan‐paclitaxel interaction. This article is protected by copyright. All rights reserved.
  • Evidence of Different Propofol Pharmacokinetics under Short and Prolonged
           Infusion Times in Rabbits
    • Abstract: Propofol is an anaesthetic widely used both in human beings and animals. However, the characterization of propofol pharmacokinetics (PK) is not well understood when long‐term infusions are used. The main objective of this study was to explore the pharmacokinetic behaviour of propofol in a rabbit model during short and prolonged propofol infusions and to develop an internally validated PK model, for propofol dose individualization in the rabbit for future use. Population 1 (P1) was constituted by seven New Zealand rabbits and was used to characterize the pharmacokinetic profile of propofol at short infusions. Animals were anaesthetized with a bolus of 20−1, followed by an infusion rate of 50−1.h−1 of propofol at 1%, which was then maintained for 30 min. A second rabbit population (P2, n=7) was sedated according to reflexes responses and Index of Consciousness values, for 20 consecutive hours using propofol 2% aiming at characterizing propofol behaviour at long‐term infusions. Clinical data and blood samples were collected at specific time‐points in both populations. Propofol plasma concentrations were determined by GC/IT‐MS1. The NONMEM VII software was used to evaluate the relationships between dose and plasma concentrations. A linear two‐compartment model with different central compartment volume and plasma clearance (separately modelled in the two populations) was the one that best described propofol concentrations. The time course of propofol plasma concentrations was well characterized by the PK model developed, which simultaneously accounts for propofol short‐ and long‐term infusions and can be used to optimize future PK studies in rabbits. This article is protected by copyright. All rights reserved.
  • Effect of the combination of ezetimibe and simvastatin on gluconeogenesis
           and oxygen consumption in the rat liver
    • Abstract: The aim of this work was to investigate the effects of chronic treatment with the combination ezetimibe/simvastatin on gluconeogenesis in rat liver. Rats were treated daily with the combination ezetimibe/simvastatin (10/40 mg/Kg) by oral gavage. To measure gluconeogenesis and the associated pathways, isolated perfused rat liver was used. In addition, subcellular fractions, such as microsomes and mitochondria, were used for complementary measures of enzymatic activities. Treatment with the combination simvastatin/ezetimibe resulted in a decrease of gluconeogenesis from pyruvate (‐62%). Basal oxygen consumption of the treated animals was higher (+22%) than the control rats, but the resulting oxygen consumption that occurred after pyruvate infusion was 43% lower in animals treated with the combination simvastatin/ezetimibe. Oxygen consumption in the livers from treated animals was completely inhibited by cyanide (electron transport chain inhibitor), but not by proadifen (cytochrome P450 inhibitor). Chronic treatment with ezetimibe/simvastatin decreased the activity of the key enzymes glucose‐6‐phosphatase and fructose‐1,6‐bisphosphatase by 59% and 45%, respectively, which is probably the major reason for the decreased gluconeogenesis seen in ezetimibe/simvastatin‐treated rats. It is also possible that part of the effect of this combination on gluconeogenesis and on the oxygen consumption is related to the impairment of mitochondrial energy transduction. This article is protected by copyright. All rights reserved.
  • Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse
           Intrauterine Environment and Modulated by a Post‐Weaning
           High‐Fat Diet
    • Abstract: Adult individuals born with intrauterine growth restriction (IUGR) have physiological maladaptations that significantly increase risk of chronic disease. We hypothesized that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low protein diet (9% protein) to produce IUGR offspring. Offspring were weaned onto either laboratory chow (11% fat) or high‐fat diet (45% fat). Adult offspring (5 months old) were dosed with furosemide (10 mg/kg i.p.) and serum and urine collected. The overall exposure profile in IUGR males was significantly reduced due to a ~35% increase in both clearance and volume of distribution. Females appeared resistant to the IUGR phenotype. The effects of the high‐fat diet trended in the opposite direction to that of IUGR, with increased drug exposure due to decreases in both clearance (31% males, 46% females) and volume of distribution (24% males, 44% females), with a 10% longer half‐life in both genders. The alterations in furosemide pharmacokinetics and pharmacodynamics were explained by changes in the expression of renal organic anion transporters‐1 and ‐3, and sodium‐potassium‐chloride cotransporter‐2. In summary, this study suggests that IUGR and diet interact to produce sub‐populations with similar body weights but dissimilar pharmacokinetic profiles; this underlines the limitation of one‐size‐fits‐all dosing which does not account for physiological differences in body composition resulting from IUGR and diet. This article is protected by copyright. All rights reserved.
  • Glucagon‐like Peptide‐1 Formulation – the Present and
           Future Development in Diabetes Treatment
    • Abstract: Type 2 diabetes mellitus is a chronic metabolic disorder that has become the fourth leading cause of death in the developed countries. The disorder is characterised by pancreatic β‐cells dysfunction, which causes hyperglycaemia leading to several other complications. Treatment by far, which focuses on insulin administration and glycaemic control, has not been satisfactory. Glucagon‐like peptide‐1 (GLP1) is an endogenous peptide that stimulates post‐prandial insulin secretion. Despite being able to mimic the effect of insulin, GLP1 has not been the target drug in diabetes treatment due to the peptide's metabolic instability. Following a decade‐long effort to improve the pharmacokinetics of GLP1, a number of GLP1 analogues are currently available on the market. The current MiniReview does not discuss these drugs but presents strategies that were undertaken to address the weaknesses of the native GLP1, particularly drug delivery techniques used in developing GLP1 nanoparticles and modified GLP1 molecule. The article highlights how each of the selected preparations have improved the efficacy of GLP1, and more importantly, through an overview of these studies, it will provide an insight into strategies that may be adopted in the future in the development of a more effective oral GLP1 formulation. This article is protected by copyright. All rights reserved.
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