bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinção social e comportamento não civilizado em espaços comerciais abertos ao público
Authors: Sautkina Elena , Rouquette Michel-Louis , Amador Sarah , Castano Christophe , Casal Aimée
Published: March 2016

O presente artigo propõe uma reflexão teórica que se baseia no estudo exploratório conduzido em três empresas francesas: SNCF (Sociedade Nacional de Caminhos-de-Ferro), La Poste (empresa pública, fornecedora de serviços postais e bancários) e Galeries Lafayette (grandes armazéns). O objectivo deste artigo é mostrar que o fenómeno de comportamento não civilizado pode ser visto numa perspectiva psicossocial como uma consequência de ruptura de ligações sociais entre grupos (empregados, clientes). Neste sentido, propõe-se uma definição de comportamento não civilizado, em termos de interacções entre grupos sociais. Finalmente, mostra-se como as características de diferenciação de espaços de cada empresa estão ligadas com a manifestação de comportamentos não civilizados.DOI: http://dx.doi.org/10.17575/rpsicol.v21i2.371
A (ir)racionalidade na decisão de selecção de pessoal
Authors: Proença Teresa
Published: March 2016

Este artigo apresenta uma reflexão conceptual sobre o processo de selecção de pessoal, centrando-se nos elementos irracionais que lhe estão subjacentes. Argumenta-se que o tradicional modelo normativo-preditivo de selecção de pessoal, assente numa racionalidade positivista visitando a decisão óptima, traduzido pela escolha da “pessoa certa para o lugar certo”, não é suficiente para compreender o modo como este processo decorre. Os desafios a este modelo relacionam-se com a crescente complexidade das características de trabalho, bem como com as lógicas cognitivas mobilizadas, que tornam a decisão mais incerta e complexa. Propõe-se um modelo baseado numa racionalidade de acção e fazendo uso de lógica implícitas ou intuitivas, como alternativa à compreensão do processo de selecção de pessoal.DOI: http://dx.doi.org/10.17575/rpsicol.v21i2.372
Observações criticas sobre as regras dadas pelo Snr Jeronymo Soares Barboza por Francisco Solano Constâncio
Authors: Coelho Sonia , Fontes Susana
Published: March 2016

Resumo: Em inícios do século XIX foi publicada, postumamente, a Grammatica Philosophica da Lingua Portugueza (1822) da autoria de Jerónimo Soares Barbosa, que conheceu, ao longo deste século, sete edições (1822, 1830, 1862, 1866, 1871, 1875, 1881). Dada a importância desta obra, impressa sob a chancela da Academia Real das Ciências, vários foram os autores que a ela se referiram, seja para a adotar como modelo, seja para a criticar. Francisco Solano Constâncio, autor da Grammatica analytica da lingua portugueza, é um desses exemplos. Ao longo desta gramática, referencia frequentemente esta obra de Soares Barbosa, apresentando, inclusive, na parte quinta, dedicada ao estudo da ortografia, um conjunto de considerações críticas acerca da doutrina ortográfica barboseana. No presente artigo, pretende-se analisar estas Observações criticas sobre as regras dadas pelo Snr Jeronymo Soares Barboza, dando a conhecer a opinião de Francisco Solano Constâncio acerca de algumas propostas ortográficas postuladas por Jerónimo Soares Barbosa.Palavras-chave: Grammatica Philosophica da Lingua Portugueza; Jerónimo Soares Barboza; Grammatica analytica da lingua portugueza; Francisco Solano Constâncio; ortografia.Abstract: In the early 19th century, the Grammatica philosophica da Lingua Portugueza written by Jerónimo Soares Barbosa was published posthumously, in 1822. It had throughout this century seven editions (1822, 1830, 1862, 1866, 1871, 1875, 1881). Given the importance of this work, printed under the auspices of the Royal Academy of Sciences, several authors referred to it whether to adopt it as a model or to criticize it. Francisco Solano Constâncio, the author of the Grammatica analytica da lingua portugueza, is one of these examples. Throughout his grammar, he often refers to this work of Soares Barbosa, and in its fifth part, dedicated to the study of orthography, he presents a set of critical considerations about the Soares Barboza’s orthographic doctrine. In this paper, it is our purpose to analyze these Observações criticas sobre as regras dadas pelo Snr Jeronymo Soares Barboza (Critical remarks about the [grammar] rules published by Jeronymo Soares Barbosa), in order to present Francisco Solano Constâncio’s views on some orthographic proposals postulated by the author Jeronymo Soares Barbosa.Keywords: Grammatica Philosophica da Lingua Portugueza; Jerónimo Soares Barbosa; Grammatica Analytica da Lingua Portugueza; Francisco Solano Constâncio; Orthography.
Wim Klinkert, Samuël Kruizinga, Paul Moeyes, Nederland Neutraal. De Eerste Wereldoorlog 1914-1918
Authors: Van der Jagt Hans
Published: March 2016

Wim Klinkert, Samuël Kruizinga, Paul Moeyes, Nederland Neutraal. De Eerste Wereldoorlog 1914-1918 (Amsterdam: Boom, 2014, 534 pp., isbn 978 94 6105 351 0).
Paulus Bijl, Emerging Memory: Photographs of Colonial Atrocity in Dutch Cultural Remembrance
Authors: Coté Joost
Published: March 2016

Paulus Bijl, Emerging Memory: Photographs of Colonial Atrocity in Dutch Cultural Remembrance (PhD 2010; Amsterdam: Amsterdam University Press, 2015, 258 pp., ISBN 978 90 8964 590 6, e-ISBN 9789048522019).
Picking up the Pieces: Catholic Material Culture and Iconoclasm in the Low Countries
Authors: De Boer David
Published: March 2016

In 1566 the Catholic majority in the Low Countries witnessed the large-scale destruction of their religious habitat during the Beeldenstorm. Afterwards, Catholics treated the objects that had fallen to (or survived) iconoclasm in different ways. This article analyses how Netherlandish Catholics interacted with and renegotiated their material religious culture after its violent dislocation. I will argue that church objects had multiple layers of meaning and were tied to individuals, groups and local communities in various ways. Moreover, iconoclasm could fundamentally change the meaning that was ascribed to these objects. By evaluating the diverse qualities of the objects that had come under attack, Catholics simultaneously found strategies to condemn the Beeldenstorm in secular terms. This article is part of the special issue 'Beeldenstorm'. In 1566 moest de katholieke meerderheid in de Nederlanden toezien hoe een groot deel van haar religieuze habitat werd vernietigd tijdens de Beeldenstorm. Katholieken behandelden de objecten die wel (of juist niet) aan iconoclasme ten prooi waren gevallen op verschillende manieren. Dit artikel analyseert hoe Nederlandse katholieken opnieuw duiding gaven aan hun religieuze materiële cultuur na haar gewelddadige ontwrichting. De rol van kerkobjecten in de vroegmoderne samenleving was complex en ambigu, omdat ze op verschillende manieren verbonden waren met individuen, groepen en lokale gemeenschappen. Iconoclasme kon er bovendien voor zorgen dat de betekenis van een kerkobject fundamenteel veranderde. Door de verschillende kwaliteiten van de aangevallen kerkobjecten nader te beschouwen vonden katholieken strategieën om de Beeldenstorm ook op seculiere gronden te veroordelen. Dit artikel maakt deel uit van het themanummer 'Beeldenstorm'.
Effects of fertilization on some quantitative and qualitative characteristics of winter wheat in Great Cumania
Authors: Czimbalmos Ágnes , Jóvér János , Zsembeli József
Published: March 2016

Due to the drastically increasing food prices during the last few years in Europe and also in Hungary, good and medium quality winter wheat varieties produced at low costs with high yield potential came to the front. Although food overproduction is characteristic to one part, while shortage of food to the other part of the world, the newest tendencies show an increasing role of the production and consumption of high quality food that can be produced only from high quality raw materials. When a new variety is certified, the qualitative parameters are more and more important beyond the quantitative ones. Several programmes were started to breed and produce winter wheat varieties with excellent qualitative parameters including the determination of the adequate, variety- and habitat specific agro- techniques and plant nutrition. In Karcag Research Institute plant breeding and long-term fertilization experiments have been carried out separately from one another for several decades. In the vegetation period of 2012/2013 a new series of experiments was started that includes the determination of the fertilizer doses optimal for our high quality winter wheat varieties with high yield potential. The determination of the adequate and optimal fertilizer doses are essential not only from economic point of view and lower environmental loads, but also for the most effective utilization of the genetic potential of our winter wheat varieties without the degradation of the qualitative parameters. After the assessment of the data we established that extreme high doses of fertilizers are needed for the spectacular improvement of the parameters we examined. As the financial possibilities of farmers are limited, the fertilizer cost is a determining factor: they have to consider if the yield or the quality of a given variety can be increased at an affordable fertilizer input. Our goal is to determine the often empiric hence not so accurate fertilizer doses more precisely providing the producers a proper production technology and plant nutrition recipe adequate to the varieties bred by us. Due to the complexity of this topic high number of further examinations is required.
Effect of soil tillage and digestate application on some soil properties
Authors: Badalíková Barbora , Bartlová Jaroslava
Published: March 2016

The effect of different methods of tillage on basic physical and chemical properties of soil was tested in a pilot field experiment. The digestate was applied simultaneously and it was tested if this type of dressing did not influence soil in a negative manner. Results obtained in the Variant 2 (i.e. with the minimum tillage) indicated that, as compared with the conventional ploughing, (Variant 1) values of reduced bulk density were increased and those of soil porosity decreased. However, better values of soil humidity were recorded in Variant 2. In Variant 2, a certain trend to increasing values of Corg/Nt ratio was observed while in Variant 1 values of soil reaction were decreased. It was concluded that these changes could induce soil degradation processes.
Food and Therapeutic Product Interactions – A Therapeutic Perspective
Authors: MacDonald Laura , Foster Brian C. , Akhtar Humayoun
Published: March 2016

Foods and therapeutic products are both used for well defined purposes. In simple terms food provides energy for sustenance, while therapeutic products are taken for managing ailments (1). However, over the years roles of foods have changed considerably. Now, food no longer is seen as simply the provider of energy, but it is expected to provide physiological benefits for good health and productive lifestyles. Well managed combination of foods and therapeutic products plays important role in the prevention and treatment of many diseases, including a number of chronic diseases such as cancer, diabetes, hypertension, obesity. Most often food is combined with medicine to enhance the benefits of medicine - an additive and/or synergistic effect: food-therapeutic product synergism. At the most basic level, food is a complex mixture of chemicals with many functional groups; hence, they not only confer positive effects, but may also make negative contributions. The later effect is of major concerns among the health practitioners and regulatory officials.
Determination of Bioequivalence for Drugs with Narrow Therapeutic Index: Reduction of the Regulatory Burden
Authors: Endrenyi Laszlo , Tothfalusi Laszlo
Published: March 2016

The US Food and Drug Administration (FDA) has recently suggested that the bioequivalence (BE) for products of drugs with narrow therapeutic indices (NTI) be assessed by the approach of reference-scaled average BE (SABE). Subsequently, in December, 2012, the FDA issued draft guidances for the comparison of products of warfarin sodium and of tacrolimus. The guidances expect that 4-period studies be performed, that the results be evaluated by SABE, and that the analysis include also unscaled average BE as well as the comparison of the estimated within-subject variations (sW) of the test and reference drug products. This communication discusses the new guidances and suggests considerations to reduce the regulatory burden. It is demonstrated that SABE could be applied when the within-subject variation of the reference product is not higher than 21.42%. Beyond this variation, the BE limits would remain 80% to 125%, as usual. No further testing by unscaled average BE is needed. It is also suggested that a comparison of the within-subject variations of the two drug products although interesting for both NTI and other drugs, is not essential for the determination of BE. In addition, when the within-subject variabilities are low then their ratio depends mainly on the non-product dependent factors. Moreover, introduction of an additional test would affect the probabilities involved in the primary comparison of the two means. Therefore, the test of comparing variances is not needed and replicate measurements of the test formulation need not be performed. Alternative considerations and approaches, including the use of partial AUC’s, are suggested for the determination of BE for NTI drugs.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Development and Characterization of Niosomal Formulations of Doxorubicin Aimed at Brain Targeting
Authors: Bragagni Marco , Mennini Natascia , Ghelardini Carla , Mura Paola
Published: March 2016

ABSTRACT - Purpose. The aim of the present work was the development and characterization of a niosomal formulation functionalized with the glucose-derivative N-palmitoylglucosamine (NPG) to obtain a potential brain targeted delivery system for the anticancer agent doxorubicin. Methods. Five different methods have been examined for vesicle preparation. Light scattering and transmission electron microscopy were used for vesicle characterization, in terms of mean size, homogeneity and Zeta potential, and selection of the best composition and preparation conditions for developing NPG-functionalized niosomes. Drug entrapment efficiency was determined after separation of loaded from unloaded drug by size exclusion chromatography or dialysis. Preliminary in vivo studies were performed on rats, injected i.v. with 12 mg/kg of doxorubicin as commercial solution (Ebewe, 2mg/mL) or NPG-niosomal formulation. Drug amounts in the blood and in the major organs of the animals, sacrificed 60 min post injection, were determined by HPLC. Results. The selected formulation consisted in Span:cholesterol:Solulan:NPG (50:40:10:10 mol ratio) vesicles obtained by thin-layer evaporation, leading to homogeneous vesicles of less than 200 nm diameter. This formulation was used for preparation of NPG-niosomes loaded with doxorubicin (mean size 161±4 nm, encapsulation efficacy 57.8±1.8%). No significant changes (P>0.05) in vesicle dimensions, Zeta potential or entrapment efficiency were observed after six months storage at room temperature, indicative of good stability. I.v. administration to rats of the NPG-niosomal formulation allowed for reducing drug accumulation in the heart and keeping it longer in the blood circulation with respect to the commercial formulation. Moreover, a doxorubicin brain concentration of 2.9±0.4 µg/g was achieved after 60 min, while the commercial solution yielded undetectable drug brain concentrations (
Do Regulatory Bioequivalence Requirements Adequately Reflect the Therapeutic Equivalence of Modified-Release Drug Products?
Authors: Endrenyi Laszlo , Tothfalusi Laszlo
Published: March 2016

Purpose. To demonstrate that current regulatory requirements for bioequivalence (BE) do not always reflect therapeutic equivalence. To investigate the potential usefulness of an additional metric, the partial AUC. Methods. Pharmacokinetic information was reviewed and evaluated on the pharmacokinetics of modified-release methylphenidate and nifedipine products. Results. In studies of modified-release products of methylphenidate as well as of nifedipine, traditional regulatory criteria found two formulations to be bioequivalent even though their concentration profiles strongly diverged during the period of absorption. An additional metric, partial AUC, discriminated strongly between the concentrations of the drug products. Conclusions. The current regulatory criteria for the acceptance of BE do not always reflect the therapeutic equivalence of modified-release drug products. With some modified-release products, the application of an additional metric, the partial AUC, yields an improved discriminatory representation.
Innovations in Epilepsy Management – An Overview
Authors: Abraham Suja , Shaju Minumaria
Published: March 2016

In the past twenty years, thirteen new antiepileptic drugs (AEDs) have been introduced, each differing in their efficacy spectrum, mechanism of action, pharmacokinetics, safety and tolerability profiles. These newer AEDs symbolize a welcoming future in the management of epilepsy because they are able to produce a remarkable reduction in seizure frequency in up to 40% to 50% of the patients who had been refractory to old generation drugs. Despite the current availability of these new drugs, only a few patients with truly refractory seizures can be made seizure free. Although the newer agents are not superior to that of the older drugs, some have been shown to be non-inferior in terms of their efficacy. They offer additional advantages like better tolerability, ease of use, reduced interaction profile. Even though in most situations the older generation drugs still represent the best choice, advancing studies show that in many conditions, new generation drugs may be entirely vindicated for initial therapy. This urges a need for the search of novel and more efficacious new antiepileptic drugs in the management of uncontrollable seizures. More direct comparisons of newer versus newer and newer versus older drugs in clinical trials, both for monotherapy and adjunctive therapy must be conducted. More than 20 compounds with promising antiepileptic and neuroprotective properties have been discovered and are under various stages of drug development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Functional Food and Nutraceutical Registration Processes in Japan and China: A Diffusion of Innovation Perspective
Authors: Patel Darshika , Dufour Yvon , Domigan Neil
Published: March 2016

Purpose - This paper looks into the functional food and nutraceutical registration processes in Japan and China. The Japanese have developed the Foods for Specified Health Use (FOSHU) registration process whereas the Chinese have put into place the Health Food (HF) registration process. The aim of this paper is to compare the regulation processes between the two countries in search for answers to three core empirical questions: (1) how have the registration processes developed and changed? (2) What are the similarities and differences between the processes of registration in the two countries investigated? (3) Why are the registration processes similar/different? Method – The study was conducted using secondary sources. The literature surveyed covered academic journals, trade journals, magazine and newspaper articles, market reports, proceedings, books and web pages of relevant regulatory authorities and regulatory consultants. Information from the more recently published sources was used preferentially over older sources. As well as using the most recent sources, information was selected on the basis of which source it was from. Official regulations and SFDA and MHLW websites would contain accurate and up to date information and information from here would be taken as true over other sources of information. Results - The two diagrams of the registration processes respectively in Japan and China clearly show that there are similarities and differences. There are six categories under which these can be found: (1) the scientific evidence required; (2) the application process; (3) the evaluation process; (4) the law and the categories of products; (5) the labels and the types of claims; and finally (6) the cost and the time involved. Conclusions -The data analysis suggests that the process of diffusion of innovation played a role in the development of the regulations. Further it was found that while Japan was at the outset a pioneer innovator in nutraceutical registration processes, there are indications that in more recent years it too imitated other countries.

NOVELTY STATEMENT:

The assortment of regulatory regimes creates much uncertainty for the firms and the lack of familiarity and poor knowledge of the regulatory situation increases the risk of failure. The research presented in this paper provides highly valuable information to any biotech/pharmaceutical/nutraceutical companies developing their market entry strategy in Japan and China. There are few national and international studies of drug registration application processes but even fewer comparative studies of functional food and neutraceutical registration application processes such as this one and none using a diffusion of innovation perspective.
Application of Counter-propagation Artificial Neural Networks in Prediction of Topiramate Concentration in Patients with Epilepsy
Authors: Jovanovic Marija , Sokić Dragoslav , Grabnar Iztok , Vovk Tomaž , Prostran Milica , Erić Slavica , Kuzmanovski Igor , Vučićević Katarina , Miljković Branislava
Published: March 2016

Purpose: The application of artificial neural networks in the pharmaceutical sciences is broad, ranging from drug discovery to clinical pharmacy. In this study, we explored the applicability of counter-propagation artificial neural networks (CPANNs), combined with genetic algorithm (GA) for prediction of topiramate (TPM) serum levels based on identified factors important for its prediction. Methods: The study was performed on 118 TPM measurements obtained from 78 adult epileptic patients. Patients were on stable TPM dosing regimen for at least 7 days; therefore, steady-state was assumed. TPM serum concentration was determined by high performance liquid chromatography with fluorescence detection. The influence of demographic, biochemical parameters and therapy characteristics of the patients on TPM levels were tested. Data analysis was performed by CPANNs. GA was used for optimal CPANN parameters, variable selection and adjustment of relative importance. Results: Data for training included 88 measured TPM concentrations, while remaining were used for validation. Among all factors tested, TPM dose, renal function (eGFR) and carbamazepine dose significantly influenced TPM level and their relative importance were 0.7500, 0.2813, 0.0625, respectively. Relative error and root mean squared relative error (%) and their corresponding 95% confidence intervals for training set were 2.14 [(-2.41) - 6.70] and 21.5 [18.5 - 24.1]; and for test set were -6.21 [(-21.2) - 8.77] and 39.9 [31.7 - 46.7], respectively. Conclusions: Statistical parameters showed acceptable predictive performance. Results indicate the feasibility of CPANNs combined with GA to predict TPM concentrations and to adjust relative importance of identified variability factors in population of adult epileptic patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Effects of One Year Treatment of Sibutramine on Insulin Resistance Parameters in Type 2 Diabetic Patients
Authors: Derosa Giuseppe , Maffioli Pamela , Ferrari Ilaria , Palumbo Ilaria , Randazzo Sabrina , D'Angelo Angela , Cicero Arrigo FG
Published: March 2016

Purpose. Comparison of the effects of one year treatment with sibutramine compared to placebo on body weight, glycemic control, lipid profile, and insulin resistance parameters in type 2 diabetic patients. Methods. Two hundred and forty-six patients with uncontrolled type 2 diabetes mellitus in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take sibutramine 10 mg or placebo for one year. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, and high sensitivity-C reactive protein (Hs-CRP). Results. We observed a faster improvement of HbA1c, FPG and PPG with sibutramine compared to the control group; furthermore we recorded a decrease of FPI, TC, LDL-C, body weight, and BMI in the sibutramine group, but not in the control group. A faster decrease of HOMA-IR, resistin, and RBP-4 was recorded with sibutramine compared to the control group. We observed a significant decrease of Hs-CRP in both groups. Conclusions. Sibutramine gave a faster improvement of glycemic control, and of insulin resistance parameters compared to placebo; furthermore sibutramine gave also an improvement of lipid profile, and body weight.
Neurochemical effects of the monoamine oxidase inhibitor phenelzine on brain GABA and alanine: A comparison with vigabatrin
Authors: Todd Kathryn G. , Baker Glen B.
Published: March 2016

PURPOSE. To compare phenelzine (PLZ), an antidepressant drug with anxiolytic properties which inhibits monoamine oxidase (MAO) but also elevates rat brain levels of the amino acids ?-aminobutyric acid (GABA) and alanine (ALA), with vigabatrin (VIG), an anticonvulsant which elevates brain GABA by inhibition of GABA transaminase (GABA-T), with regard to their actions on brain levels of GABA and ALA and on activities of MAO, GABA-T and ALA transaminase (ALA-T). METHODS. Male rats were administered PLZ (10 mg/kg) or VIG (1,000 mg/kg) i.p., and the rats were euthanized 4 hours later and the brains removed for analysis of levels of GABA and ALA (by electron capture gas chromatography after derivatization) and activities of MAO, GABA-T and ALA-T (radiochemical assays). RESULTS. Both PLZ and VIG inhibited GABA-T and elevated GABA levels. Only PLZ inhibited MAO and ALA-T and elevated ALA levels. The effects of PLZ on both amino acids and their transaminases were blocked by pre-treatment with the MAO inhibitor tranylcypromine. This pretreament had no effect on the inhibition of GABA-T or the elevation of brain GABA levels produced by VIG. CONCLUSIONS. At the doses studied, PLZ was as effective as VIG at elevating brain GABA levels, but, unlike VIG, also inhibited MAO and ALA-T (and increased brain ALA levels). Pretreatment of rats with the MAO inhibitor tranylcypromine prevented the increase in brain GABA and ALA levels with PLZ, but did not block the effect of VIG on GABA. These observations with tranylcypromine and PLZ support the hypothesis that an active metabolite of PLZ produced by the actions of MAO on this drug plays a major role in its GABA- and ALA-elevating actions.
Artificial Neural Network Modeling for Drug Dialyzability Prediction
Authors: Daheb Kahina , Lipman Mark L. , Hildgen Patrice , Roy Julie J
Published: March 2016

Purpose. The purpose of this study was to develop an artificial neural network (ANN) model to predict drug removal during dialysis based on drug properties and dialysis conditions. Nine antihypertensive drugs were chosen as model for this study. Methods. Drugs were dissolved in a physiologic buffer and dialysed in vitro in different dialysis conditions (UFRmin/UFRmax, with/without BSA). Samples were taken at regular intervals and frozen at -20ºC until analysis. Extraction methods were developed for drugs that were dialysed with BSA in the buffer.  Drug concentrations were quantified by high performance liquid chromatography (HPLC) or mass spectrometry (LC/MS/MS). Dialysis clearances (CLDs) were calculated using the obtained drug concentrations.  An ANOVA with Scheffe’s pairwise adjustments was performed on the collected data in order to investigate the impact of drug plasma protein binding and ultrafiltration rate (UFR) on CLD. The software Neurosolutions® was used to build ANNs that would be able to predict drug CLD (output). The inputs consisted of dialysis UFR and the herein drug properties: molecular weight (MW), logD and plasma protein binding. Results. Observed CLDs were very high for the majority of the drugs studied. The addition of BSA in the physiologic buffer statistically significantly decreased CLD for carvedilol (p= 0.002) and labetalol (p<0.001), but made no significant difference for atenolol (p= 0.100). In contrast, varying UFR does not significantly affect CLD (p>0.025). Multiple ANNs were built and compared, the best model was a Jordan and Elman network which showed learning stability and good predictive results (MSEtesting = 129). Conclusion. In this study, we have developed an ANN-model which is able to predict drug removal during dialysis. Since experimental determination of all existing drug CLDs is not realistic, ANNs represent a promising tool for the prediction of drug CLD using drug properties and dialysis conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Exposure of LS-180 Cells to Drugs of Diverse Physicochemical and Therapeutic Properties Up-regulates P-glycoprotein Expression and Activity
Authors: Abuznait Alaa H , Patrick Shawn G , Kaddoumi Amal
Published: March 2016

Purpose. Drug transporters are increasingly recognized as important determinants of variability in drug disposition and therapeutic response, both in pre-clinical and clinical stages of drug development process. The role P-glycoprotein (P-gp) plays in drug interactions via its inhibition is well established. However, much less knowledge is available about drugs effect on P-gp up-regulation. The objective of this work was to in vitro investigate and rank commonly used drugs according to their potencies to up-regulate P-gp activity utilizing the same experimental conditions. Methods. The in vitro potencies of several drugs of diverse physicochemical and therapeutic properties including rifampicin, dexamethasone, caffeine, verapamil, pentylenetetrazole, hyperforin, and β-estradiol over broad concentration range to up-regulate P-gp expression and activity were examined. For dose-response studies, LS-180 cells were treated with different concentrations of the selected drugs followed by P-gp protein and gene expressions analyses. P-gp functionality was determined by uptake studies with rhodamine 123 as a P-gp substrate, followed by Emax/EC50 evaluation. Results. The results demonstrated a dose-dependent increase in P-gp expression and activity following treatments. At 50 uM concentration (hyperforin, 0.1 uM), examined drugs increased P-gp protein and gene expressions by up to 5.5 and 6.2-fold, respectively, while enhanced P-gp activity by 1.8-4-fold. The rank order of these drugs potencies to up-regulate P-gp activity was as following: hyperforin >>> dexamethasone ~ beta-estradiol > caffeine > rifampicin ~ pentylenetetrazole > verapamil. Conclusions. These drugs have the potential to be involved in drug interactions when administered with other drugs that are P-gp substrates. Further studies are needed to in vivo evaluate these drugs and verify the consequences of such induction on P-gp activity for in vitro-in vivo correlation purposes.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
In Situ Intestinal Perfusion of Irinotecan: Application to P-gp Mediated Drug Interaction and Introduction of an Improved HPLC Assay
Authors: Rabba Abdullah Khalil , Si Luqin , Xue Kewen , Li Ming , Li Gao
Published: March 2016

PURPOSE: To determine experimentally the intestinal permeability of the anticancer prodrug irinotecan, and to quantify the amount of its cytotoxic metabolite SN-38 that is intestinally excreted (exsorped) as a predictor of intestinal toxicity, and to assess the effect of p-glycoprotein (p-gp) inhibitors (verapamil as a model) on the permeability and toxicity of irinotecan. METHODS: Single pass intestinal perfusion of rat’s whole length small intestines is applied to assess the permeability of the parent drug and quantify the intestinally excreted metabolite. The perfusion solution contained 30μg/ml of irinotecan (control group) without or with verapamil (verapamil group). A simple reversed phase HPLC method with UV detection is developed and validated for simultaneous determination of irinotecan and SN-38 using camptothecin as an internal standard. RESULTS: HPLC-UV method found to be simple, specific, accurate, and precise. Effective permeability coefficient of irinotecan found to be 4.9±1.7 10-3 mm/min and was doubled in verapamil group (P=0.007). Average cumulative amount of SN-38 exsorped found to be 29 ng/cm over 2 hours perfusion time which was decreased to 15 ng/cm in verapamil group (P=0.016). CONCLUSIONS: in situ intestinal perfusion method was successfully applied to quantify the permeability of irinotecan and the exsorption of SN-38 in the same experiment, in a manner that robustly reflects real in vivo situation. P-gp inhibition using verapamil found to significantly enhance the intestinal permeability of irinotecan and potentially decrease the intestinal toxicity due to SN-38 exposure.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Validation of Bone Marrow Derived Dendritic Cells as an Appropriate Model to Study Tumor-Mediated Suppression of DC Maturation through STAT3 Hyperactivation
Authors: Alshamsan Aws , Hamdy Samar , Saswati Das Saswati Das , Lavasanifar Afsaneh , Samuel John , El-Kadi Ayman O.S.
Published: March 2016

PURPOSE: Tumors can escape immune eradication by harnessing dendritic cell (DC) maturation. However, DC types used as in vitro models to study tumor-mediated immunosuppression possess fundamental variability that could influence research outcomes. Therefore, we assessed the behavior of two distinct murine DC models upon exposure to tumor-conditioned medium of B16.F10 melanoma (B16-CM). METHODS: Using primary bone-marrow derived dendritic cells (BMDCs) or immortalized DC2.4 cell line, we evaluated the level of signal transducer and activator of transcription 3 (STAT3) phosphorylation by Western blot as a molecular parameter. We also examined the surface expression of co-stimulatory molecules on DCs by flow cytometry as a phenotypic parameter. RESULTS: Our results revealed critical discrepancies between the two models in response to tumor-conditioned medium. While conditioned medium was able to induce STAT3 phosphorylation in BMDCs, it did not significantly induce STAT3 phosphorylation in DC2.4 cell line. Moreover, only in BMDCs, the expression of CD86 and CD40 was remarkably downregulated by B16-CM and was not totally recovered after LPS stimulation. In contrast, DC2.4 cells did not show any signs of harnessed maturation upon exposure to B16-CM. CONCLUSIONS: In order to study the effect of tumor-mediated immunosuppression on DC maturation in vitro via tumor-induction of STAT3 activation, primary BMDCs are more reliable as a model than DC2.4.
Prediction of Oral Absorption of Low-Solubility Drugs by Using Rat Simulated Gastrointestinal Fluids: The Importance of Regional Differences in Membrane Permeability and Solubility
Authors: Tanaka Yusuke , Baba Toshiyuki , Tagawa Koji , Waki Ryoichi , Nagata Shunji
Published: March 2016

Purpose. This study aimed to develop a novel approach for predicting the oral absorption of low-solubility drugs by considering regional differences in solubility and permeability within the gastrointestinal (GI) tract. Methods. Simulated GI fluids were prepared to reflect rat in vivo bile acid and phospholipid concentrations in the upper and lower small intestine. The saturated solubility and permeability of griseofulvin (GF) and albendazole (AZ), a drug with low aqueous solubility, were measured using these simulated fluids, and fraction absorbed (Fa) at time t after oral administration was calculated. Results. The saturated solubility of GF and AZ, a drug with low aqueous solubility, differed considerably between the simulated GI fluids. Large regional differences in drugs concentration were also observed following oral administration in vivo. The predicted Fa values using solubility and permeability data of the simulated GI fluid were found to correspond closely to the in vivo data. Conclusion. These results indicated the importance of evaluating regional differences in drug solubility and permeability in order to predict oral absorption of low-solubility drugs accurately. The new methodology developed in the present study could be useful for new oral drug development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Monoterpenoids Induce Agonist-Specific Desensitization of Transient Receptor Potential Vanilloid-3 (TRPV3) ion Channels
Authors: Sherkheli Muhammad Azhar , Benecke Heike , Doerner Julia Franca , Kletke Olaf , Vogt-Eisele A. K. , Gisselmann Guenter , Hatt Hanns
Published: March 2016

Transient receptor potential vanilloid-3 (TRPV3) is a thermo-sensitive ion channel expressed in skin keratinocytes and in a variety of neural cells. It is activated by warmth as well as monoterpenoids including camphor, menthol, dihydrocarveol and 1,8-cineol. TRPV3 is described as a putative nociceptor and previous studies revealed sensitization of the channel during repeated short-term stimulation with different agonists. In the present investigation TRPV3 was transiently expressed in either Xenopus oocytes or HEK293 cells. Whole-cell voltage-clamp techniques were used to characterize the behavior of TRPV3 when challenged with different agonists. Similarly, a human keratinocyte-derived cell line (HaCaT cells) was used to monitor the behavior of native TRPV3 when challenged with different agonists. We report here that prolonged exposure (5-15 minutes) of monoterpenoids results in agonist-specific desensitization of TRPV3. Long-term exposure to camphor and 1,8-cineol elicits desensitizing currents in TRPV3 expressing oocytes, whereas the non-terpenoid agonist 2-APB induces sustained currents. Agonist-specific desensitization of endogenous TRPV3 was also found in HaCaT cells, which may be taken as a representative for the native system. Terpenoids have a long history of use in therapeutics, pharmaceuticals and cosmetics but knowledge about underpinning molecular mechanisms is incomplete. Our finding on agonist-induced desensitization of TRPV3 by some monoterpenoids displays a novel mechanism through which TRP channels could be functionally modulated. Therefore, we conclude that desensitization of TRPV3 channels might be the molecular basis of action for some of the medicinal properties of camphor and 1,8-cineol.
The Single Dose Poloxamer 407 Model of Hyperlipidemia; Systemic Effects on Lipids Assessed Using Pharmacokinetic Methods, and its Effects on Adipokines
Authors: Chaudhary Hetal R , Brocks Dion R
Published: March 2016

Purpose: The induction of hyperlipidemia using poloxamer 407 (P407) is gaining use for studying the effect of the condition on drug pharmacokinetics. Although a single intraperitoneal dose of P407 causes a rapid onset of hyperlipidemia, the initial lipid concentrations are much higher than seen in humans. The hyperlipidemia is also reversible in nature. Here, pharmacokinetic methods were used to assess the P407 dose response on serum lipids, adipokines and cytokines. Methods: Single 0.5 and 1 g/kg doses of P407 were injected into rats followed by blood collection at various times for up to 12 d. Serum was assayed for lipids, selected adipokines and cytokines. Results: As expected, large increases in lipid levels were seen by 36 h after dosing. Using area under the concentration vs. time curve as a measure of systemic lipid exposure, P407 increased serum baseline corrected serum lipids in a nearly dose proportional fashion. The maximum increase in lipids was observed at ~36 h, with most lipids remaining elevated for up to ~180 h, although for the 1 g/kg dose triglyceride concentrations had still not quite returned to baseline by 12 days postdose. In addition to changes in lipids, P407 significantly increased serum leptin and decreased the serum adiponectin concentrations but did not affect cytokine levels. Conclusion: Depending on study aims, for the use of the model it may be beneficial to perform single-dose assessments at time points later than 36 h when the lipoprotein concentrations will be more similar to those seen in patient with hyperlipidemia.

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The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion
Authors: Ogura Jiro , Terada Yusuke , Tsujimoto Takashi , Koizumi Takahiro , Kuwayama Kaori , Maruyama Hajime , Fujikawa Asuka , Takaya Atsushi , Kobayashi Masaki , Itagaki Shirou , Takahashi Natsuko , Hirano Takeshi , Yamaguchi Hiroaki , Iseki Ken
Published: March 2016

Purpose. Intestinal ischemia-reperfusion (I/R) damages remote organs, including the liver, and promotes multi-organ failure (MOF). However, the molecular mechanisms underlying acute liver injury after intestinal I/R have not been completely elucidated. Farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate metabolizing enzymes and transporters, and coordinately prevent hepatotoxicity reflecting an inability of appropriate excretion of endogenous toxic compounds. In this study, we assessed FXR, PXR and CAR expression levels and their localization levels in nuclei in the liver after intestinal I/R. We also investigated the effect of IL-6 on FXR, PXR and CAR expression levels and their localization levels in nuclei in in vitro experiments. Methods. We used intestinal I/R model rats. Moreover, HepG2 cells were used in in vitro study. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Nuclear receptor localization in nuclei was analyzed by Western blotting using nuclear extracts. Results. FXR and PXR expression levels began to be decreased at 3 h, and FXR, PXR and CAR expression levels were decreased at 6 h after intestinal I/R. The localization levels of FXR, PXR and CAR in nuclei began to be decreased at 3 h, and all of them were decreased at 6 h after intestinal I/R. In HepG2 cells, FXR, PXR and CAR expression levels were decreased by 0.5-1 ng/mL, 0.5-100 ng/mL and 100 ng/mL IL-6 treatment for 24 h, respectively. FXR, PXR and CAR localization levels in nuclei were suppressed by 0.5-10 ng/mL, 10-100 ng/mL and 10-100 ng/mL IL-6 treatment for 24 h, respectively. Conclusions. FXR, PXR and CAR expression levels are decreased in the liver after intestinal I/R. IL-6 is one of main causes the decreases in expressions of these receptors.

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Involvement of Cholesterol Membrane Transporter Niemann-Pick C1-Like 1 in the Intestinal Absorption of Lutein
Authors: Sato Yuki , Suzuki Risa , Kobayashi Masaki , Itagaki Shirou , Hirano Takeshi , Noda Toshihiro , Mizuno Satoshi , Sugawara Mitsuru , Iseki Ken
Published: March 2016

PURPOSE. Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. Since humans cannot synthesize lutein de novo, it must be digested as food. The physiological importance of an orally administered compound depends on its interaction with target tissues. It is therefore important to clarify the absorption mechanism in the intestine. Cholesterol membrane transporters Niemann-Pick C1 Like 1 (NPC1L1) and scavenger receptor class B type 1 (SR-B1) are involved in the intestinal absorption of highly lipophilic compounds including cholesterol. Ezetimibe, a selective inhibitor of intestinal NPC1L1, is the widespread lipid-lowering agent. It is important to investigate the possibility of food-drug interactions in order to prevent undesirable and harmful clinical consequences. The aim of this work was to determine whether NPC1L1, SR-B1 and other transporters are involved in absorption of lutein. METHODS. Caco-2 cells were used for accumulation and permeability study of lutein. Lutein concentration was determined by an HPLC system. The cDNA of transporters was isolated from total RNA of Caco-2 cells, and the expression of these transporters was confirmed by RT-PCR (reverse transcription - polymerase chain reaction). RESULTS. Ezetimibe inhibited up to 40% of lutein accumulation by Caco-2 cell monolayers. Block lipid transport 1 (BLT-1), a selective chemical inhibitor of SR-B1, also inhibited lutein accumulation by Caco-2 cells. On the other hand, ATP-depletion reagents (sodium fluoride and sodium azide or carbonyl cyanide m-chlorophenylhydrazone) did not influence the accumulation or permeation of lutein significantly. CONCLUSIONS. The results show that lutein absorption is, at least in part, mediated by influx transporters NPC1L1 and SR-B1 rather than mediated by efflux transporters such as ABC (ATP-binding cassette) transporters.

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