TY - JOUR AU - Veszelka, Szilvia AU - Tóth, András AU - Walter, Fruzsina AU - Tóth, Andrea AU - Gróf, Ilona AU - Mészáros, Mária AU - Bocsik, Alexandra AU - Virághné Hellinger, Éva AU - Vastag, M AU - Rákhely, Gábor AU - Deli, Mária Anna TI - Comparison of a rat primary cell-based blood-brain barrier model with epithelial and brain endothelial cell lines: gene expression and drug transport JF - FRONTIERS IN MOLECULAR NEUROSCIENCE J2 - FRONT MOL NEUROSCI VL - 11 ET - 0 PY - 2018 PG - 20 SN - 1662-5099 DO - 10.3389/fnmol.2018.00166 UR - https://m2.mtmt.hu/api/publication/3365532 ID - 3365532 N1 - These authors have contributed equally to this work: Szilvia Veszelka, András Tóth. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Éliás, Olivér AU - Nógrádi, Katalin AU - Domány, György AU - Szakács, Zoltán AU - Kóti, János AU - Szántay, Csaba (Ifj.) AU - Tarcsay, Ákos AU - Keserű, György Miklós AU - Gere, Anikó AU - Kiss, Béla AU - Kurko, Dalma AU - Kolok, Sándor AU - Némethy, Zsolt AU - Kapui, Zoltán AU - Virághné Hellinger, Éva AU - Vastag, Monika AU - Sághy, Katalin AU - Kedves, Rita AU - Gyertyán, István TI - 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 JF - BIOORGANIC & MEDICINAL CHEMISTRY LETTERS J2 - BIOORG MED CHEM LETT VL - 26 PY - 2016 IS - 3 SP - 914 EP - 920 PG - 7 SN - 0960-894X DO - 10.1016/j.bmcl.2015.12.071 UR - https://m2.mtmt.hu/api/publication/3021919 ID - 3021919 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Elias, O AU - Agai-Csongor, E AU - Domany, G AU - Keserű, György Miklós AU - Gere, A AU - Kiss, Béla AU - Virághné Hellinger, Éva AU - Vastag, M AU - Gyertyán, István TI - Design of novel multiple-acting ligands towards SERT and 5-HT2C receptors JF - BIOORGANIC & MEDICINAL CHEMISTRY LETTERS J2 - BIOORG MED CHEM LETT VL - 24 PY - 2014 IS - 9 SP - 2118 EP - 2122 PG - 5 SN - 0960-894X DO - 10.1016/j.bmcl.2014.03.043 UR - https://m2.mtmt.hu/api/publication/2767216 ID - 2767216 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Kiss, Lóránd AU - Virághné Hellinger, Éva AU - Pilbat, Ana Maria AU - Kittel, Ágnes AU - Török, Zsolt AU - Füredi, András AU - Szakács, Gergely AU - Veszelka, Szilvia AU - Sipos, Péter AU - Ózsvári, B AU - Puskás, László AU - Vastag, M AU - Révész, Piroska AU - Deli, Mária Anna TI - Sucrose esters increase drug penetration, but do not inhibit P-glycoprotein in Caco-2 intestinal epithelial cells JF - JOURNAL OF PHARMACEUTICAL SCIENCES J2 - J PHARM SCI VL - 103 PY - 2014 IS - 10 SP - 3107 EP - 3119 PG - 13 SN - 0022-3549 DO - 10.1002/jps.24085 UR - https://m2.mtmt.hu/api/publication/2709800 ID - 2709800 AB - 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- LA - English DB - MTMT ER - TY - THES AU - Virághné Hellinger, Éva TI - Prediction of intestinal absorption and brain penetration of drugs PY - 2013 DO - 10.14753/SE.2013.1815 UR - https://m2.mtmt.hu/api/publication/2705643 ID - 2705643 LA - English DB - MTMT ER - TY - JOUR AU - Veszelka, Szilvia AU - Tóth, Andrea AU - Walter, Fruzsina AU - Datki, Zsolt László AU - Jánosi-Mózes, Emese AU - Fülöp, Lívia AU - Bozsó, Zsolt AU - Virághné Hellinger, Éva AU - Vastag, M AU - Orsolits, Barbara AU - Környei, Zsuzsanna AU - Penke, Botond AU - Deli, Mária Anna TI - Docosahexaenoic acid reduces amyloid β-induced toxicity in cells of the neurovascular unit JF - JOURNAL OF ALZHEIMER'S DISEASE J2 - J ALZHEIMERS DIS VL - 36 PY - 2013 IS - 3 SP - 487 EP - 501 PG - 15 SN - 1387-2877 DO - 10.3233/JAD-120163 UR - https://m2.mtmt.hu/api/publication/2246475 ID - 2246475 LA - English DB - MTMT ER - TY - JOUR AU - Virághné Hellinger, Éva AU - Veszelka, Szilvia AU - Tóth, Andrea AU - Walter, Fruzsina AU - Kittel, Ágnes AU - Bakk, ML AU - Tihanyi, Károly AU - Háda, Viktor AU - Nakagawa, S AU - Thuy, DH AU - Niwa, M AU - Deli, Mária Anna AU - Vastag, M TI - 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 JF - EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS J2 - EUR J PHARM BIOPHARM VL - 82 PY - 2012 IS - 2 SP - 340 EP - 351 PG - 12 SN - 0939-6411 DO - 10.1016/j.ejpb.2012.07.020 UR - https://m2.mtmt.hu/api/publication/2034983 ID - 2034983 N1 - Division of Pharmacology and Drug Safety Research, Gedeon Richter Plc., Gyömri út. 19-21, H-1103 Budapest, Hungary Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Spectroscopic Research, Gedeon Richter Plc., Budapest, Hungary Department of Pharmacology 1, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan BBB Laboratory, PharmaCo-Cell Co. Ltd., Nagasaki, Japan Cited By :108 Export Date: 1 June 2020 CODEN: EJPBE Correspondence Address: Vastag, M.; Division of Pharmacology and Drug Safety Research, Gedeon Richter Plc., Gyömri út. 19-21, H-1103 Budapest, Hungary; email: m.vastag@richter.hu Chemicals/CAS: aldosterone, 52-39-1, 6251-69-0; atenolol, 29122-68-7, 93379-54-5; caffeine, 58-08-2; chlorothiazide, 58-94-6, 7085-44-1; cimetidine, 51481-61-9, 70059-30-2; colchicine, 64-86-8; corticosterone, 50-22-6; dexamethasone, 50-02-2; digoxin, 20830-75-5, 57285-89-9; estradiol, 50-28-2; furosemide, 54-31-9; hydrocortisone, 50-23-7; indometacin, 53-86-1, 74252-25-8, 7681-54-1; ketoconazole, 65277-42-1; lidocaine, 137-58-6, 24847-67-4, 56934-02-2, 73-78-9; loperamide, 34552-83-5, 53179-11-6; metoprolol, 37350-58-6; multidrug resistance protein, 149200-37-3, 208997-77-7; omeprazole, 73590-58-6, 95510-70-6; paracetamol, 103-90-2; phenazone, 60-80-0; phenytoin, 57-41-0, 630-93-3; progesterone, 57-83-0; propranolol, 13013-17-7, 318-98-9, 3506-09-0, 4199-09-1, 525-66-6; quinidine, 56-54-2; ranitidine, 66357-35-5, 66357-59-3; salicylic acid, 63-36-5, 69-72-7; theobromine, 83-67-0; verapamil, 152-11-4, 52-53-9; vinblastine, 865-21-4; P-Glycoprotein LA - English DB - MTMT ER - TY - CHAP AU - Virághné Hellinger, Éva AU - Vastag, M ED - Tihanyi, Károly ED - Vastag, M TI - Intestinal absorption and models of penetration T2 - Solubility, Delivery and ADME Problems of Drugs and Drug-Candidates PB - Bentham Science Publishers Ltd. CY - Washington DC SN - 9781608051205 T3 - Bentham eBooks PY - 2011 SP - 86 EP - 101 PG - 16 DO - 10.2174/978160805120511101010086 UR - https://m2.mtmt.hu/api/publication/2051430 ID - 2051430 LA - English DB - MTMT ER - TY - JOUR AU - Vastag, M AU - Virághné Hellinger, Éva AU - Bakk, ML AU - Tihanyi, Károly TI - Cell-based models of blood-brain barrier penetration. JF - THERAPEUTIC DELIVERY J2 - THER DELIV VL - 2 PY - 2011 IS - 5 SP - 549 EP - 553 PG - 5 SN - 2041-5990 DO - 10.4155/tde.11.35 UR - https://m2.mtmt.hu/api/publication/2051175 ID - 2051175 N1 - Megjegyzés-21877001 Chemicals/CAS: multidrug resistance protein 4, 299244-49-8; multidrug resistance protein 5, 266988-95-8 LA - English DB - MTMT ER - TY - JOUR AU - Tihanyi, Károly AU - Bakk, ML AU - Virághné Hellinger, Éva AU - Vastag, M TI - CYP inhibition-mediated drug-drug interactions JF - CURRENT ENZYME INHIBITION J2 - CURR ENZYM INHIB VL - 6 PY - 2010 IS - 3 SP - 130 EP - 145 PG - 16 SN - 1573-4080 DO - 10.2174/157340810793384106 UR - https://m2.mtmt.hu/api/publication/2051210 ID - 2051210 AB - 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. LA - English DB - MTMT ER -