@article{MTMT:3365532, title = {Comparison of a rat primary cell-based blood-brain barrier model with epithelial and brain endothelial cell lines: gene expression and drug transport}, url = {https://m2.mtmt.hu/api/publication/3365532}, author = {Veszelka, Szilvia and Tóth, András and Walter, Fruzsina and Tóth, Andrea and Gróf, Ilona and Mészáros, Mária and Bocsik, Alexandra and Virághné Hellinger, Éva and Vastag, M and Rákhely, Gábor and Deli, Mária Anna}, doi = {10.3389/fnmol.2018.00166}, journal-iso = {FRONT MOL NEUROSCI}, journal = {FRONTIERS IN MOLECULAR NEUROSCIENCE}, volume = {11}, unique-id = {3365532}, issn = {1662-5099}, abstract = {Cell culture-based blood-brain barrier (BBB) models are useful tools for screening of CNS drug candidates. Cell sources for BBB models include primary brain endothelial cells or immortalized brain endothelial cell lines. Despite their well-known differences, epithelial cell lines are also used as surrogate models for testing neuropharmaceuticals. The aim of the present study was to compare the expression of selected BBB related genes including tight junction proteins, solute carriers (SLC), ABC transporters, metabolic enzymes and to describe the paracellular properties of nine different culture models. To establish a primary BBB model rat brain capillary endothelial cells were co-cultured with rat pericytes and astrocytes (EPA). As other BBB and surrogate models four brain endothelial cells lines, rat GP8 and RBE4 cells, and human hCMEC/D3 cells with or without lithium treatment (D3 and D3L), and four epithelial cell lines, native human intestinal Caco-2 and high P-glycoprotein expressing vinblastine-selected VB-Caco-2 cells, native MDCK and MDR1 transfected MDCK canine kidney cells were used. To test transporter functionality, the permeability of 12 molecules, glucopyranose, valproate, baclofen, gabapentin, probenecid, salicylate, rosuvastatin, pravastatin, atorvastatin, tacrine, donepezil, was also measured in the EPA and epithelial models. Among the junctional protein genes, the expression level of occludin was high in all models except the GP8 and RBE4 cells, and each model expressed a unique claudin pattern. Major BBB efflux (P-glycoprotein or ABCB1) and influx transporters (GLUT-1, LAT-1) were present in all models at mRNA levels. The transcript of BCRP (ABCG2) was not expressed in MDCK, GP8 and RBE4 cells. The absence of gene expression of important BBB efflux and influx transporters BCRP, MRP6,-9, MCT6,-8, PHT2, OATPs in one or both types of epithelial models suggests that Caco-2 or MDCK models are not suitable to test drug candidates which are substrates of these transporters. Brain endothelial cell lines GP8, RBE4, D3 and D3L did not form a restrictive paracellular barrier necessary for screening small molecular weight pharmacons. Therefore, among the tested culture models, the primary cell-based EPA model is suitable for the functional analysis of the BBB. © 2018 Veszelka, Tóth, Walter, Tóth, Gróf, Mészáros, Bocsik, Hellinger, Vastag, Rákhely and Deli.}, keywords = {immunohistochemistry; ARTICLE; human; high performance liquid chromatography; multidrug resistance protein 1; controlled study; nonhuman; animal tissue; animal model; animal experiment; animal cell; valproic acid; gabapentin; Mass spectrometry; Gene Expression; Gene Expression; Blood-Brain Barrier; quality control; human cell; drug metabolism; protein expression; messenger rna; drug transport; unindexed drug; probenecid; ATORVASTATIN; salicylic acid; Cytochrome P450; blood brain barrier; drug penetration; real time polymerase chain reaction; Electric resistance; ABC transporter; rosuvastatin; pravastatin; ASTROCYTE; claudin 7; claudin 5; claudin 4; claudin 3; claudin 1; coculture; baclofen; MDCK; glucose transporter 1; amino acid transporter; Caco-2; donepezil; brain cell culture; Caco-2 cell line; glucose transporter 5; MONOCARBOXYLATE TRANSPORTER 1; tacrine; claudin 11; claudin 2; HBEC cell line (brain); epithelial cell line; tight junction protein; brain pericyte; transendothelial electrical resistance; Brain endothelial cells; CNS drug permeability; HCMEC/D3; RBE4; claudin 16; glucose transporter 3; solute carrier protein; rat}, year = {2018}, eissn = {1662-5099}, orcid-numbers = {Walter, Fruzsina/0000-0001-8145-2823; Rákhely, Gábor/0000-0003-2557-3641; Deli, Mária Anna/0000-0001-6084-6524} } @article{MTMT:3021919, title = {The influence of 5-HT2A activity on a 5-HT2C specific in vivo assay used for early identification of multiple acting SERT and 5-HT2C receptor ligands}, url = {https://m2.mtmt.hu/api/publication/3021919}, author = {Éliás, Olivér and Nógrádi, Katalin and Domány, György and Szakács, Zoltán and Kóti, János and Szántay, Csaba (Ifj.) and Tarcsay, Ákos and Keserű, György Miklós and Gere, Anikó and Kiss, Béla and Kurko, Dalma and Kolok, Sándor and Némethy, Zsolt and Kapui, Zoltán and Virághné Hellinger, Éva and Vastag, Monika and Sághy, Katalin and Kedves, Rita and Gyertyán, István}, doi = {10.1016/j.bmcl.2015.12.071}, journal-iso = {BIOORG MED CHEM LETT}, journal = {BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, volume = {26}, unique-id = {3021919}, issn = {0960-894X}, abstract = {As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1- phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2- aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.}, year = {2016}, eissn = {1464-3405}, pages = {914-920}, orcid-numbers = {Szántay, Csaba (Ifj.)/0000-0002-1056-1421; Némethy, Zsolt/0000-0002-0909-4416; Gyertyán, István/0000-0002-5727-1974} } @article{MTMT:2767216, title = {Design of novel multiple-acting ligands towards SERT and 5-HT2C receptors}, url = {https://m2.mtmt.hu/api/publication/2767216}, author = {Elias, O and Agai-Csongor, E and Domany, G and Keserű, György Miklós and Gere, A and Kiss, Béla and Virághné Hellinger, Éva and Vastag, M and Gyertyán, István}, doi = {10.1016/j.bmcl.2014.03.043}, journal-iso = {BIOORG MED CHEM LETT}, journal = {BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, volume = {24}, unique-id = {2767216}, issn = {0960-894X}, abstract = {This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure-activity relationship of this series of compounds is presented herein. (C) 2014 Elsevier Ltd. All rights reserved.}, keywords = {Brain; ANTAGONISTS; BIOLOGICAL EVALUATION; DRUG DISCOVERY; 5-HT2C antagonist; SERT inhibitor; Designed multiple ligands}, year = {2014}, eissn = {1464-3405}, pages = {2118-2122}, orcid-numbers = {Gyertyán, István/0000-0002-5727-1974} } @article{MTMT:2709800, title = {Sucrose esters increase drug penetration, but do not inhibit P-glycoprotein in Caco-2 intestinal epithelial cells}, url = {https://m2.mtmt.hu/api/publication/2709800}, author = {Kiss, Lóránd and Virághné Hellinger, Éva and Pilbat, Ana Maria and Kittel, Ágnes and Török, Zsolt and Füredi, András and Szakács, Gergely and Veszelka, Szilvia and Sipos, Péter and Ózsvári, B and Puskás, László and Vastag, M and Révész, Piroska and Deli, Mária Anna}, doi = {10.1002/jps.24085}, journal-iso = {J PHARM SCI}, journal = {JOURNAL OF PHARMACEUTICAL SCIENCES}, volume = {103}, unique-id = {2709800}, issn = {0022-3549}, abstract = {Sucrose fatty acid esters are increasingly used as excipients in pharmaceutical products, but few data are available on their toxicity profile, mode of action, and efficacy on intestinal epithelial models. Three water-soluble sucrose esters, palmitate (P-1695), myristate (M-1695), laurate (D-1216), and two reference absorption enhancers, Tween 80 and Cremophor RH40, were tested on Caco-2 cells. Caco-2 monolayers formed a good barrier as reflected by high transepithelial resistance and positive immunostaining for junctional proteins claudin-1, ZO-1, and -catenin. Sucrose esters in nontoxic concentrations significantly reduced resistance and impedance, and increased permeability for atenolol, fluorescein, vinblastine, and rhodamine 123 in Caco-2 monolayers. No visible opening of the tight junctions was induced by sucrose esters assessed by immunohistochemistry and electron microscopy, but some alterations were seen in the structure of filamentous actin microfilaments. Sucrose esters fluidized the plasma membrane and enhanced the accumulation of efflux transporter ligands rhodamine 123 and calcein AM in epithelial cells, but did not inhibit the P-glycoprotein (P- gp)-mediated calcein AM accumulation in MES-SA/Dx5 cell line. These data indicate that in addition to their dissolution-increasing properties sucrose esters can enhance drug permeability through both the transcellular and paracellular routes without inhibiting P-}, year = {2014}, eissn = {1520-6017}, pages = {3107-3119}, orcid-numbers = {Füredi, András/0000-0002-7883-9901; Révész, Piroska/0000-0002-5336-6052; Deli, Mária Anna/0000-0001-6084-6524} } @mastersthesis{MTMT:2705643, title = {Prediction of intestinal absorption and brain penetration of drugs}, url = {https://m2.mtmt.hu/api/publication/2705643}, author = {Virághné Hellinger, Éva}, doi = {10.14753/SE.2013.1815}, unique-id = {2705643}, year = {2013} } @article{MTMT:2246475, title = {Docosahexaenoic acid reduces amyloid β-induced toxicity in cells of the neurovascular unit}, url = {https://m2.mtmt.hu/api/publication/2246475}, author = {Veszelka, Szilvia and Tóth, Andrea and Walter, Fruzsina and Datki, Zsolt László and Jánosi-Mózes, Emese and Fülöp, Lívia and Bozsó, Zsolt and Virághné Hellinger, Éva and Vastag, M and Orsolits, Barbara and Környei, Zsuzsanna and Penke, Botond and Deli, Mária Anna}, doi = {10.3233/JAD-120163}, journal-iso = {J ALZHEIMERS DIS}, journal = {JOURNAL OF ALZHEIMER'S DISEASE}, volume = {36}, unique-id = {2246475}, issn = {1387-2877}, year = {2013}, eissn = {1875-8908}, pages = {487-501}, orcid-numbers = {Walter, Fruzsina/0000-0001-8145-2823; Datki, Zsolt László/0000-0002-2537-4741; Jánosi-Mózes, Emese/0000-0003-1532-289X; Fülöp, Lívia/0000-0002-8010-0129; Bozsó, Zsolt/0000-0002-5713-3096; Penke, Botond/0000-0003-0938-0567; Deli, Mária Anna/0000-0001-6084-6524} } @article{MTMT:2034983, title = {Comparison of brain capillary endothelial cell based and epithelial cell based (MDCK-MDR1, Caco-2, and VB-Caco-2) surrogate blood-brain barrier penetration models}, url = {https://m2.mtmt.hu/api/publication/2034983}, author = {Virághné Hellinger, Éva and Veszelka, Szilvia and Tóth, Andrea and Walter, Fruzsina and Kittel, Ágnes and Bakk, ML and Tihanyi, Károly and Háda, Viktor and Nakagawa, S and Thuy, DH and Niwa, M and Deli, Mária Anna and Vastag, M}, doi = {10.1016/j.ejpb.2012.07.020}, journal-iso = {EUR J PHARM BIOPHARM}, journal = {EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS}, volume = {82}, unique-id = {2034983}, issn = {0939-6411}, year = {2012}, eissn = {1873-3441}, pages = {340-351}, orcid-numbers = {Walter, Fruzsina/0000-0001-8145-2823; Deli, Mária Anna/0000-0001-6084-6524} } @inbook{MTMT:2051430, title = {Intestinal absorption and models of penetration}, url = {https://m2.mtmt.hu/api/publication/2051430}, author = {Virághné Hellinger, Éva and Vastag, M}, booktitle = {Solubility, Delivery and ADME Problems of Drugs and Drug-Candidates}, doi = {10.2174/978160805120511101010086}, unique-id = {2051430}, year = {2011}, pages = {86-101} } @article{MTMT:2051175, title = {Cell-based models of blood-brain barrier penetration.}, url = {https://m2.mtmt.hu/api/publication/2051175}, author = {Vastag, M and Virághné Hellinger, Éva and Bakk, ML and Tihanyi, Károly}, doi = {10.4155/tde.11.35}, journal-iso = {THER DELIV}, journal = {THERAPEUTIC DELIVERY}, volume = {2}, unique-id = {2051175}, issn = {2041-5990}, keywords = {Humans; Models, Biological; Permeability; Brain/metabolism; *Blood-Brain Barrier}, year = {2011}, eissn = {2041-6008}, pages = {549-553} } @article{MTMT:2051210, title = {CYP inhibition-mediated drug-drug interactions}, url = {https://m2.mtmt.hu/api/publication/2051210}, author = {Tihanyi, Károly and Bakk, ML and Virághné Hellinger, Éva and Vastag, M}, doi = {10.2174/157340810793384106}, journal-iso = {CURR ENZYM INHIB}, journal = {CURRENT ENZYME INHIBITION}, volume = {6}, unique-id = {2051210}, issn = {1573-4080}, abstract = {Adverse drug reaction is a frequent cause of drug withdrawals from the market. The drug-drug interaction (DDI) potential of new drug candidates is an increasing safety concern of pharmaceutical companies. DDIs frequently occur between coadministered drugs on a pharmacokinetic ground and sometimes create life-threatening conditions. The unexpected increase of the exposure of a drug is most frequently evoked by the inhibition of metabolic enzymes. While the inhibition of CYPs by new drug candidates is unwanted, one has to recognize that several currently marketed successful drugs with relatively clean record of drug-drug interactions are time-dependent inhibitors of drug metabolic enzymes. Therefore, the correct and high throughput prediction of drug-drug interaction propensity of new chemical entities (NCEs) at an affordable cost is a major interest of pharmaceutical research. False negatives and positives, also the misinterpretation of otherwise flawlessly generated data are equally costly or hazardous. While screening methods for the detection of CYP inhibition are available now, the quantitative estimation of DDI potential and its PK effect leaves an ample room for improvement. This is reflected in the great research activity focused on the establishment of correct in vitro-in vivo correlations. The impressing number of recent publications and methods recommended in this field provide an increasingly solid ground for the selection of lead compounds and development candidates. © 2010 Bentham Science Publishers Ltd.}, keywords = {ARTICLE; human; nonhuman; dose response; in vitro study; diltiazem; enzyme inhibition; drug blood level; drug metabolism; cytochrome P450 2D6; unclassified drug; drug safety; drug efficacy; protein expression; minimum inhibitory concentration; area under the curve; drug bioavailability; fluoxetine; TROGLITAZONE; liver toxicity; Cytochrome P450; drug screening; clarithromycin; erythromycin; paroxetine; midazolam; first pass effect; drug interaction; enzyme kinetics; calcium channel blocking agent; drug research; ritonavir; microsome; adverse drug reaction; Ketoconazole; enzyme synthesis; cytochrome P450 3A4; cytochrome p450 inhibitor; enzyme polymorphism; dextromethorphan; cytochrome P450 1A2; competitive inhibition; enzyme active site; cytochrome P450 2C9; Drug-drug interaction; Quinidine; ethinylestradiol; cytochrome P450 2C19; gestodene; delavirdine; troleandomycin; lopinavir plus ritonavir; lopinavir; Human immunodeficiency virus proteinase inhibitor; cytochrome P450 3A5; a 792611; IVIVE; CYP450}, year = {2010}, eissn = {1875-6662}, pages = {130-145} }