85

Predavanjapopozivu

InvitedLectures

86

SADRŽAJ–CONTENTS

PP1- HOMOLOGYMODELINGOFHUMANHISTONEDEACETYLASE10ANDDESIGNOFPOTENTIALSELECTIVEINHIBITORS

- Abdullahi Ibrahim Uba, Kemal Yelekçi 103

PP2INHIBITORIEPIGENETSKIHENZIMAIZPRIRODNIHIZVORA

INHIBITORSOFEPIGENETICENZYMESFROMNATURALSOURCES

- Slavica Erić 104

PP3FIZIČKO‐HEMIJSKAIADMEKARAKTERIZACIJAANALOGAESTARAETILENDIAMIN‐N,N’‐DI‐2‐(3‐CIKLOHEKSIL)PROPANSKEKISELINESAPOTENCIJALNIMCITOTOKSIČNIMDEJSTVOM

PHYSICOCHEMICALANDADMECHARACTERIZATIONOFESTERSOFETHYLENEDIAMINE‐N,N’‐DI‐2‐(3‐CYCLOHEXYL)PROPIONICACIDANALOGSWITHPOTENTIALCYTOTOXICACTIVITY

- Biljana Tubić, Bojan Marković, Sandra Vladimirov, Vladimir Dobričić, Jelena Poljarević, Aleksandar Savić, Tibor Sabo 106

PP4SINTEZAIBIOLOŠKAAKTIVNOSTPROPIOFENONSKIHDERIVATA

SYNTHESISANDBIOLOGICALACTIVITYOFPROPIONOPHENONEDERIVATIVES

- Branka Ivković, Nemanja Turković, Bojan Marković, Zorica Vujić 108

PP5IZOKUMARINSKIDERIVATI‐SINTEZAIANTIFUNGALNAAKTIVNOST

ISOCOUMARINDERIVATIVES‐SYNTHESISANDANTIFUNGALACTIVITY

- Milena Simić 110

87

PP6PRIMENAPAMPATEHNIKEIQSPRANALIZEUPROCENIGASTROINTESTINALNEAPSORPCIJEIDIZAJNIRANJUNOVIHBIOLOŠKIAKTIVNIHJEDINJENJAAPPLICATIONOFPAMPATECHNIQUEANDQSPRANALYSISINTHEEVALUATIONOFGASTROINTESTINALABSORPTIONANDDESIGNOFNEWBIOLOGICALLYACTIVECOMPOUNDS

- Vladimir Dobričić, Jelena Savić, Biljana Tubić, Katarina Nikolić, Jasmina Brborić, Bojan Marković, Olivera Čudina 112

PP7INVITROISPITIVANJEINHIBITORNOGPOTENCIJALASINTETISANIHβ‐HIDROKSI‐β‐ARILALKANSKIHKISELINAKORIŠĆENJEMKOMERCIJALNOGCOXKITAINVITROASSESSMENTOFTHEINHIBITORYPOTENTIALOFSYNTHESIZEDβ‐HYDROXY‐β‐ARYLALKANOICACIDSUSINGCOMMERCIALCOXKIT

- Jelena Savić, Jelena Kotur-Stevuljević, Sanda Dilber, Sote Vladimirov, Jasmina Brborić 114

PP8EUROPEANASSOCIATIONOFHOSPITALPHARMACY(EAHP)COMPETENCYFRAMEWORKFORHOSPITALPHARMACY- Petr Horak 116

PP9SAVREMENIPRISTUPOPTIMIZACIJIANTIBIOTSKETERAPIJENAOSNOVUIZMERENIHKONCENTRACIJAAMODERNAPPROACHTOOPTIMIZINGANTIBIOTICTHERAPYBASEDONMEASUREDCONCENTRATIONS

- Katarina Vučićević 117

PP10INTERVENCIJEKLINIČKOGFARMACEUTANAODELJENJUHEPATOLOGIJE

CLINICALPHARMACIST'SINTERVENTIONSONAHEPATOLOGYWARD- Milica Ćulafić 119

88

PP11ZDRAVSTVENAANALIZAVRSTEIISHODAGREŠKE‐HEALTHCAREFAILUREMODEANDEFFECTANALYSIS(HFMEA)PRIMENJENANAPROCESSUPSTITUCIJEANTIBIOTSKETERAPIJETOKOMNESTAŠICELEKOVA

HEALTHCAREFAILUREMODEANDEFFECTANALYSIS(HFMEA)APPLIEDTOANTIBIOTICSUBSTITUTIONINMEDICINESHORTAGES

- Nenad Miljković, Karyofyllis Tsiakitzis, Cristina Garcia Yubero, Branislava Miljković 121

PP12MIKROBIOTACREVA,ZNAČAJZAETIOPATOGENEZUITERAPIJUAUTOIMUNSKIHBOLESTI

THEROLEOFGUTMICROBIOTAINETIOPATHOGENESISANDTHERAPYOFAUTOIMMUNEDISEASES

- Đorđe Miljković 123

PP13REGULATORNETĆELIJE‐NOVIPRISTUPULEČENJUAUTOIMUNSKIHBOLESTI

TREGULATORYCELLS‐NEWAPPROACHINTHETREATMENTOFAUTOIMMUNITY

- Ivana Stojanović 125

PP14ADRENERGIČKILEKOVI‐KANDIDATIZANOVENEKONVENCIONALNEIMUNOMODULATORNELEKOVE?ADRENERGICDRUGS–CANDIDATESASNOVELNON‐CONVENTIONALIMMUNOMODULATORYDRUGS?

- Gordana Leposavić 127

PP15SAVREMENATERAPIJAMULTIPLESKLEROZE‐ODIMUNOMODULACIJEDOSELEKTIVNEIMUNEREKONSTITUCIJE

CURRENTTHERAPYOFMULTIPLESCLEROSIS‐FROMIMMUNOMODULATIONTOIMMUNERECONSTITUTION

- Dragana Obradović 129

89

PP16SAVREMENIPRISTUPULEČENJUREUMATOIDNOGARTRITISA

ADVANCESINTHETREATMENTOFRHEUMATOIDARTHRITIS

- Mirjana Šefik Bukilica 131

PP17CARDIOPROTECTIONDURINGCANCERCHEMOTHERAPYWITHTHEUSEOFNATURALANTIOXIDANTS:REVIEWOFLITERATUREANDRESULTSOFOWNSTUDIES

- Jolanta Łukowicz, Grażyna Peszyńska-Sularz, Anita Piasek, Stefan Popadiuk, Agata Kot-Wasik, Monika Janicka, Jacek Namieśnik, Włodzimierz Grajek, Agnieszka Bartoszek 133

PP18VITAMINDIRIZIKZANASTANAKMALIGNIHBOLESTI

VITAMINDANDRISKFORCANCERDEVELOPMENT

- Aleksandra Zeljković 135

PP19PRIMENATUMORSKIHMARKERAUKLINIČKOJPRAKSIIPERSONALIZOVANOJMEDICINI

APPLICATIONOFTUMORMARKERSINCLINICALPRACTICEANDPERSONALIZEDMEDICINE

- Svetlana Ignjatović 137

PP20ENERGETSKIBALANSIULOGAADIPOCITOKINAUPATOGENEZIMALIGNIHBOLESTI

ENERGYBALANCEANDADIPOCYTOKINESINCANCERPATHOGENESIS

- Aleksandra Stefanović 139

90

PP21KADMIJUMKAOFAKTORRIZIKAZARAZVOJKARCINOMAPANKREASA:PODACIIZSTUDIJENALJUDIMA,EKSPERIMENTALNIMŽIVOTINJAMAIĆELIJSKIMKULTURAMA

CADMIUMASARISKFACTORFORPANCREATICCANCERDEVELOPMENT:HUMAN,ANIMALANDINVITRODATA

- Aleksandra Buha Đorđević, Vesna Matović, Novica Boričić, Dejan Radenković, Vladimir Đorđević, David Wallace 141

PP22OLIVEBIOACTIVECOMPOUNDS:CHEMISTRYANDBIOLOGY

- Apostolis Angelis, Leandros Skaltsounis 143

PP23HERBACITRALNOGHEMOTIPAPANONSKOGTIMIJANAKAOPOTENCIJALNONOVABILJNALEKOVITASIROVINA

THEHERBOFPANNONIANTHYMECITRALCHEMOTYPEASPOTENTIALLYNEWHERBALRAWMATERIALWITHMEDICINALPROPERTIES

- Zoran Maksimović 144

PP24PROCENAFARMAKOLOŠKEAKTIVNOSTIODABRANIHVRSTAFAMILIJEERICACEAE

PHARMACOLOGICALSCREENINGOFSELECTEDSPECIESFROMERICACEAEFAMILY

- Dragana Pavlović 146

PP25NOVIJEINFORMACIJEOLEKOVITOMPOTENCIJALUVRSTARODAHYPERICUM

UPDATESONTHERAPEUTICPOTENTIALOFHYPERICUMSPECIES

- Nebojša Kladar, Neda Gavarić, Biljana Božin 148

91

PP26EFEKTIMETANOLNIHEKSTRAKATADVEBILJNEVRSTEIZFLORESRBIJENAISHEMIJSKO‐REPERFUZIONUPOVREDUIZOLOVANOGSRCAPACOVA:UTICAJOKSIDACIONOGSTRESA

EFFECTSOFOFMETHANOLEXTRACTSOFTWOPLANTSPECIESFROMTHEFLORAOFSERBIAONISCHEMIC/REPERFUSIONINJURYOFISOLATEDRATHEART:ROLEOFOXIDATIVESTRESS

- Nevena Jeremić, Jovana Bradić, Vladimir Živković, Ivan Srejović, Jovana Jeremić, Tamara Nikolić-Turnić, Vladimir Jakovljević 150

PP27OPTIMIZACIJAEKSTRAKCIJEPLODAARONIJE,ARONIAMELANOCARPA(MICHX.)ELLIOTT,MIKROINKAPSULACIJAEKSTARKTAIISPITIVANJEBIOLOŠKIHAKTIVNOSTIEKSTRAKTA

OPTIMIZATIONOFCHOKEBERRYEXTRACTION,ARONIAMELANOCARPA(MICHX.)ELLIOTT,EXTRACTMICROENCAPSULATIONANDBIOLOGICALACTIVITIES

- Nada Ćujić, Katarina Šavikin, Gordana Zdunić, Branko Bugarski, Nevena Mihailović-Stanojević, Svetlana Ibrić 152

PP28

GENERIČKILEKOVIODPODNOŠENJAZAHTEVADOODOBRENJASAŽETKAKARAKATERISTIKALEKA

GENERICMEDICINALPRODUCTSFROMAPPLICATIONTOFINALSUMMARYOFPRODUCTCHARACTERISTICS

- Branka Brzaković 154

PP29BIOEQUIVALENCEREQUIREMENTSFORLOCALLYACTINGDOSAGEFORMS

- Alfredo Garcia-Arieta 156

92

PP30POTVRDATERAPIJSKEEKVIVALENTNOSTIORALNIHINHALACIONIHLEKOVA‐REGULATORNIASPEKTI

REGULATORYFRAMEWORKFORDEMONSTRATIONOFTHERAPEUTICEQUIVALENCEOFORALLYINHALEDPRODUCTS

- Zorica Pejčić 157

PP31KADA(NI)JEMOGUĆASUPSTITUCIJAGENERIČKIMLEKOM

WHENGENERICSUBSTITUTIONIS(NOT)APPROPRIATE

- Marija Jovanović 159

PP 32 AKUTNATROVANJAILEGALNIMPSIHOAKTIVNIMSUPSTANCAMA‐ISKUSTVANACIONALNOGCENTRAZAKONTROLUTROVANJA

ACUTEPOISONINGWITHILLICITPSYCHOACTIVESUBSTANCES–EXPERIENCEOFTHENATIONALPOISONCONTROLCENTRE

- Jasmina Jović-Stošić, Tomislav Režić, Nataša Perković-Vukčević, Slavica Vučinić, Gordana Brajković, Snežana Đorđević, Mirjana Đukić 161

PP 33 THEANALYSISOFPSYCHOACTIVESUBSTANCES:CHALLENGESRELATEDTOBIOLOGICALSAMPLESANDANALYTICALTOOLS

- Goran Mitulović 163

PP 34 PREGLEDSITUACIJENATRŽIŠTUDROGAUSRBIJIIPREDOZIRANJASUPSTANCAMAZLOUPOTREBELEČENIHUNACIONALNOMCENTRUZAKONTROLUTROVANJAVMA

ANOVERVIEWOFTHEDRUGMARKETANDSUBSTANCESOFABUSEOVERDOSETREATEDINTHENATIONALPOISONCONTROLCENTERMMA

- Slavica Vučinić, Jasmina Jović-Stošić, Dragana Đorđević, Tomislav Režić, Snežana Đorđević, Vesna Kilibarda 164

93

PP35KURIKULARNEIEKSTRAKURIKULARNEAKTIVNOSTIUDOPRINOSURAZUMEVANJUZLOUPOTREBEPSIHOAKTIVNIHSUPSTANCI

CURRICULARANDEXTRA‐CURRICULARACTIVITIESTODEVELOPCOMPREHENSIONONABUSEOFPSYCHOACTIVESUBSTANCES

- Mirjana Đukić 166

PP 36 THEEFFECTSOFNATURALANDSYNTHETICENVIRONMENTALPOLLUTANTSONHUMANHEALTH:SOMECASESTUDIES

- Emanuela Testai 168

PP 37 METIL‐ŽIVAUNAŠEMOKRUŽENJU:KLJUČNEČINJENICEZASIGURNUBUDUĆNOST

METHYLMERCURYINOURENVIRONMENT:KEYFACTSFORASAFEFUTURE

- Danijela Đukić-Ćosić 169

PP 38 DOKAZITOKSIČNOSTIUSPORIVAČAGORENJA‐POLIBROMOVANIDIFENILETRI

EVIDENCEOFFLAMERETARDANTSTOXICITY‐POLYBROMINATEDDIPHENYLETHERS

- Marijana Ćurčić 171

PP 39 OPASNEHEMIKALIJEUPROIZVODIMAŠIROKEPOTROŠNJEIREGULATORNIASPEKTKAOMEHANIZAMKONTROLEUEUIREPUBLICISRBIJI

HAZARDOUSCHEMICALSINARTICLESFOREVERYDAYUSEANDREGULATORYASPECTASACONTROLMECHANISMINEUANDSERBIA

- Jasminka Ranđelović, Jelena Milić, Valentina Mart, Lazarija Šojić 173

94

PP 40 PRIMENA3DŠTAMPEUFARMACIJI‐IZAZOVIIPERSPEKTIVE

3DPRINTINGFORPHARMACEUTICALAPPLICATIONS–CHALLENGESANDPROSPECTS

- Svetlana Ibrić 175

PP 41 SAVREMENIPRISTUPODABIRUFORMULACIJEIEKSCIPIJENASA

MODERNAPPROACHTOFORMULATIONANDEXCIPIENTSSELECTION

- Ružica Kolaković 177

PP 42 ULOGAKLINIČKOGFARMACEUTAURAZVOJUFORMULACIJALEKOVAZASPROVOĐENJEKLINIČKIHISPITIVANJA

CLINICALPHARMACIST’SROLEINCLINICALTRIALSINVESTIGATIONALDRUGDEVELOPMENT

- Marija Tubić - Grozdanis 179

PP 43 INKAPSULACIJAODABRANIHSUPERKRITIČNIHEKSTRAKATALEKOVITOGBILJAULIPOSOMEMETODOMHOMOGENIZACIJEPODVISOKIMPRITISKOM

INCAPACULATIONOFSELECTEDMEDICINALHERB᾿SSUPERCRITICALEXTRACTSINLIPOSOMESUSINGTHEHIGHPRESSUREHOMOGENIZATIONMETHOD

- Ivana Arsić, Vanja Tadić, Milica Stanković, Vesna Savić 181

PP 44 ANTIEPILEPTICIUSVETLUNOVIHINDIKACIJA

ANTIEPILEPTICSINLIGHTOFNEWINDICATIONS

- Radica Stepanović-Petrović 183

95

PP 45 BENZODIAZEPINESAREALLALIKE‐EXCEPTWHENTHEOPPOSITECOMESTRUE

- Margot Ernst 185

PP 46 ALFA1,2,3,4,5,6GABAARECEPTORI:ŠTOVIŠETOBOLJEKAOCILJZANOVELEKOVE?

ALPHA1,2,3,4,5,6GABAARECEPTORS:THEHIGHERTHEBETTERASATARGETFORNOVELMEDICINES?

- Miroslav Savić 186

PP 47 KOMBINACIJEANALGETIKAUSAVREMENOMLEČENJUBOLA

COMBINATIONSOFANALGESICSINTHECONTEMPORARYTREATMENTOFPAIN

- Maja Tomić 188

PP 48 ISEDUCATINGPHARMACISTSTOBECOMPETENTENOUGHFORTHEFUTUREOFTHEPROFESSION?

- Martin Henman 190

PP 49 STRUČNOOSPOSOBLJAVANJEIPROFESIONALNIRAZVOJFARMACEUTA‐AKADEMSKAPERSPEKTIVA

QUALIFICATIONANDPROFESSIONALDEVELOPMENTOFPHARMACIST‐ACADEMICPERSPECTIVE

- Ljiljana Tasić 191

PP 50 STRUČNOOSPOSOBLJAVANJEIPROFESIONALNIRAZVOJFARMACEUTA‐PERSPEKTIVAAPOTEKARSKEPRAKSE

QUALIFICATIONANDPROFESSIONALDEVELOPMENTOFPHARMACIST‐PHARMACYPRACTICEPERSPECTIVE

- Svetlana Stojkov 193

96

PP 51 WHYCLINICALCOMMUNICATIONSKILLSREALLYMATTER?SOMEEXAMPLESOFEFFECTIVETEACHINGANDLEARNINGMETHODS

- Afonso Miguel Cavaco 195

PP 52 VALUEFRAMEWORKSANDDECISIONMAKINGAROUNDTHEGLOBE

- Wija Oortwijn, Rob Baltussen, Maarten Janssen 196

PP 53 VREDNOSTINOVACIJEPRILIKOMDONOŠENJAODLUKAUZDRAVSTVU

THEVALUEOFINNOVATIONINHEALTHCAREDECISIONMAKING

- Tanja Novaković 197

PP 54 ZAŠTOSISTEMATIČNIPREGLEDILITERATURE?

WHYSISTEMATYCREVIEWS?

- Mark Parker 199

PP 55 INHIBITORIKOTRANSPORTERAZANATRIJUMIGLUKOZUTIPA2KODOBOLELIHODDIJABETESMELITUSATIPA2ISRČANEINSUFICIJENCIJE:KLINIČKIPOGLEDNATERAPIJUKOJAMOŽEDASNIZIMORBIDITETIMORTALITET

SODIUMGLUCOSECONTRANSPORTER‐2INHIBITORSINTYPE‐2DIABETESANDHEARTFAILURE:THECLINICALSTANDPOINTONTREATMENTTHATCANREDUCEMORBIDITYANDMORTALITY

- Marija Polovina 201

PP 56 NOVELANTIDIABETICAGENTSANDCARDIOVASCULARRISK

- Manfredi Rizzo 203

97

PP 57 KONTINUIRANISKORZAMETABOLIČKISINDROMUPOPULACIJIDECEIADOLESCENATA

CONTINUOUSMETABOLICSYNDROMESCOREFORUSEINPEDIATRICPOPULATION

- Rade Vuković, Ivan Soldatović, Tatjana Milenković, Katarina Mitrović, Slađana Todorović, Ljiljana Plavšić 204

PP 58 OPSTRUKTIVNAAPNEJAUSNUIKARDIOMETABOLIČKIRIZIK

OBSTRUCTIVESLEEPAPNEAANDCARDIOMETABOLICRISK

- Jelena Vekić 206

PP 59 GENETIČKAISPITIVANJAUMETABOLIČKOMSINDROMU

GENETICTESTINGFORMETABOLICSYNDROME

- Ana Ninić 208

PP 60 SKORDISLIPIDEMIJE,INFLAMACIJEIOKSIDATIVNOGSTRESAUPROCENIKARDIOVASKULARNOGRIZIKA

DYSLIPIDEMIA,INFLAMMATIONANDOXIDATIVESTRESSSCOREINCARDIOVASCULARRISKESTIMATION

- Jelena Kotur-Stevuljević, Nataša Bogavac-Stanojević, Jelena Vekić, Vesna Kalimanovska-Spasojević, Zorana Jelić-Ivanović, Slavica Spasić 210

PP 61 HRONIČNATERAPIJA–OČEKIVANJAIZABRINUTOSTNAŠIHPACIJENATA

CHRONICTHERAPY–EXPECTATIONSANDCONCERNSOFOURPATIENTS

- Branislava Miljković 212

98

PP 62 FARMACEUTIUSRBIJIIDENTIFIKUJUTERAPIJSKEPROBLEMEKODSTARIJIHPACIJENATA‐KOJE,KAKO,KOLIKO?

PHARMACISTSINSERBIAIDENTIFYDRUG‐RELATEDPROBLEMSINELDERLYPATIENTS‐WHICH,HOW,HOWMANY?

- Sandra Vezmar Kovačević 214

PP 63 PRIMENAKONCEPTAFARMACEUTSKEZDRAVSTVENEZAŠTITEKODPACIJENATASAASTMOMIHOBP–MODELPRIMARNEZDRAVSTVENEZAŠTITE

PHARMACEUTICALCAREMODELINTHECOMMUNITYPHARMACYSETTINGS–FOCUSONASTHMAANDCOPDPATIENTS

- Milena Kovačević 216

PP 64 STOPP/STARTKRITERIJUMIZAOPTIMIZACIJUTERAPIJEUGERIJATRIJSKOJPOPULACIJI

STOPP/STARTCRITERIAFOROPTIMIZATIONOFPHARMACOTHERAPYINELDERLY

- Aleksandra Catić-Đorđević, Nikola Stefanović, Radmila Veličković-Radovanović 218

PP 65 REGULATIVAODODACIMAISHRANI

REGULATIONONFOODSUPPLEMENTS

- Ivan Stanković 220

PP 66 KORISTISUPLEMENTACIJEUPROMOCIJIZDRAVLJA

DIETARYSUPPLEMENTINHEALTHPROMOTION

- Brižita Đorđević, Nevena Ivanović, Ivana Baralić 222

99

PP 67 ZDRAVSTVENIRIZICIUPOTREBEDIJETETSKIHSUPLEMENATA

DIETARYSUPPLEMENTS‐HEALTHRISK

- Zorica Bulat 224

PP 68 ANALIZADIJETETSKIHSUPLEMENATAKOJEKORISTESPORTISTIUSRBIJI

ANALYSISOFDIETARYSUPPLEMENTSUSEDBYSERBIANATHLETES

- Nenad Dikić, Marija Anđelković, Milica Vukašinović Vesić, Brižita Đorđević 226

PP 69 APOTHECARYPROFESSIONANDPHARMACEUTICALACTIVITIESINTHEHEALTHCARESERVICEATTHEENDOFTHEFIRSTWORLDWAR

- Adriana Elena Taerel 228

PP 70 JAČANJEPROFESIONALIZMAUAPOTEKARSKOJPRAKSI:ČEMUNASUČEAPOTEKARSKEZAKLETVEODNAJSTARIJIHDOSAVREMENIH

REINFORCINGPROFESSIONALISMINAPOTHECARYPRACTICE:WHATCOULDWELEARNFROMTHEAPOTHECARIES’OATHSFROMTHEPASTTOTHEMOSTCONTEMPORARY

- Dušanka Krajnović 229

PP 71 QUALITYINDICATORSOFPHARMACEUTICALCARESERVICES

- Mitja Kos 231

PP 72 ANALIZAFARMACEUTSKIHUSLUGAUEVROPIISRBIJI–MODALITETIRAZVOJAUSVETLUNOVIHTEHNOLOGIJA

ANALYSISOFPHARMACEUTICALSERVICESPROVIDEDINCOMMUNITYPHARMACIESINEUROPEANDSERBIA‐MODALITIESFORFUTUREDEVELOPMENTINTHELIGHTOFNEWTECHNOLOGIES

- Ivana Tadić 232

100

PP 73 UNAPREĐENJEZDRAVSTVENEZAŠTITETRUDNICAIDOJILJA–ULOGAFARMACEUTAIDOPRINOSFARMACEUTSKIHUSLUGA

PREGNANTANDBREASTFEEDINGWOMENHEALTHCAREIMPROVEMENT‐THEROLEOFPHARMACISTS

- Marina Odalović 234

PP 74 KOLIKOKOŠTAFARMACEUTSKAUSLUGA?

HOWMUCHDOESTHEPHARMACEUTICALSERVICECOST?

- Dragana Lakić 236

PP 75 PATIENTCENTRICDOSAGEFORMDESIGN

- Andreas Zimmer, Sven Stegemann 238

PP76INCREASEDPATIENTSAFETYBYREADY‐TO‐USE/READY‐TO‐ADMINISTERPARENTERALSPREPAREDINHOSPITALPHARMACIES

- Irene Krämer 239

PP 77 FORMULACIJAFARMACEUTSKIHOBLIKALEKOVAZAPRIMENUUPEDIJATRIJSKOJPOPULACIJI‐ASPEKTIPRIHVATLJIVOST/ADHERENCA

FORMULATIONOFPAEDIATRICDOSAGEFORMS‐ACCEPTABILITYISSUES/COMPLIANCE

- Jela Milić, Sandra Cvijić, Ivana Pantelić 240

PP 78 CANCERIMMUNOTHERAPY:WHEREDIDITSPRECISIONCOMEFROMANDWHEREWILLITGO?

- Farzin Farzaneh 242

101

PP79PRECIZNAMEDICINAUONKOLOŠKOJPRAKSI:PROCENAKORISTIIRIZIKA

PRECISIONMEDICINEINONCOLOGYPRACTICE:BENEFIT‐RISKASSESSMENT

- Ivana Božović-Spasojević 243

PP 80 MOLECULARPATHWAYSTHATOPERATEINMLL‐ASSOCIATEDLEUKEMIATOOVERCOMERESISTANCETOANTICANCERDRUGS

- Boban Stanojević 245

PP 81 PRECIZNEANTIKANCERSKETERAPIJE:KAKOFARMACEUTSKATEHNOLOGIJADAJEDOPRINOS?

PRECISEANTI‐CANCERTHERAPIES:HOWDOESPHARMACEUTICALTECHNOLOGYCONTRIBUTETOTHEM?

- Snežana Savić 246

PP 82 SAVREMENIPRISTUPIUKONTROLIKVALITETABIOLOŠKIHLEKOVA

CONTEMPORARYAPPROACHESINBIOLOGICALDRUGSQUALITYCONTROL

- Borut Štrukelj 248

PP 83 MICRO‐PHOTOGRAMMETRYASANOVELTOOLFORCHARACTERISATIONOFDISSOLUTIONBEHAVIOUROFPHARMACEUTICALDOSAGEFORMS

- Alessandra D'Angelo, Mike Reading, Milan Antonijević 250

102

PP 84 KONCEPTUALNIMODELZAUNAPREĐENJESISTEMATSKEKONTROLE

CONCEPTUALMODELFORTHEIMPROVEMENTOFMARKETSURVEILLANCEPROCESS

- Gordana Pejović 251

PP 85 ANALITIKAPOLARNIHSUPSTANCIPRIMENOMMETODETEČNEHROMATOGRAFIJEHIDROFILNIHINTERAKCIJA

HYDROPHILICINTERACTIONLIQUIDCHROMATOGRAPHY(HILIC)ASAVALUABLEALTERNATIVEFORREVERSED–PHASELIQUIDCHROMATOGRAPHY(RP–LC)INTHEANALYSISOFPOLARCOMPOUNDS

- Biljana Jančić Stojanović 253

PP 86 MOGUĆNOSTIPRIMENEEKOLOŠKIPRIHVATLJIVIHHROMATOGRAFSKIHMETODAUKONTROLILEKOVA

PROSPECTSOFECOLOGICALLYACCEPTABLECHROMATOGRAPHICMETHODSINDRUGCONTROL

- Ana Protić, Nevena Maljurić, Biljana Otašević, Mira Zečević 255

103

Arh.farm 2018;68: 103 PP1

HOMOLOGYMODELINGOFHUMANHISTONEDEACETYLASE10AND

DESIGNOFPOTENTIALSELECTIVEINHIBITORS

AbdullahiIbrahimUba,KemalYelekçi

DepartmentofBioinformaticsandGenetics,FacultyofEngineeringandNaturalSciences,KadirHasUniversity,Istanbul(Turkey)

Histonedeacetylases(HDACs)areimplicatedinthepathologyofvariouscancers

and their pharmacological blockade has proven to be promising in reversing themalignantphenotypes.However,lackofcrystalstructuresofsomeofthehumanHDACisoforms (e.g., HDAC10) hinders the desgn of isoform‐selective inhibitor. Here, therecently‐solved X‐ray crystal structure of Danio rerio (zebrafish) HDAC10 (PDB ID;5TD7,releasedate24‐05‐2017)wasretrievedfromtheProteinDataBank(PDB)andusedasatemplatestructuretomodelthe3DstructureofhumanHDAC10.Theoverallqualityofthebestmodel(M0017)wasassessedbycomputingitsz‐scoreameasureofthedeviationofthetotalenergyofthestructurewithrespecttoanenergydistributionderivedfromrandomconformations,andbydockingofknownHDAC10inhibitorstoitscatalyticcavity.Furthermore,toidentifypotentialHDAC10‐selectiveinhibitorsligand‐based virtual screening was carried out against ZINC database. The free modeledstructure of HDAC10, and its complexes with quisinostat and the highest‐rankedcompound, ZINC19749069 were submitted to molecular dynamics simulation.Comparative analysis of root‐ mean‐squared deviation (RMSD), root‐mean‐squaredfluctuation (RMSF), radius of gyration (Rg), and potential energy of these systemsshowed that HDAC10‐ZINC19749069 complex remained the most stable over time.Thus,M0017couldbepotentiallyused forstructure‐based inhibitoragainstHDAC10,andZINC19749069mayprovideascaffoldforfurtheroptimization.

104

Arh.farm 2018;68: 104-105 PP 2INHIBITORIEPIGENETSKIHENZIMAIZPRIRODNIHIZVORA

SlavicaErić

Katedrazafarmaceutskuhemiju,UniverzitetuBeogradu‐Farmaceutski

fakultet(Srbija)

Epigenetske promene utiču na ekspresiju gena na nivou transkripcije putem

gornje i donje regulacije, ili kompletnim utišavanjem gena. Poremećena regulacijaepigenetskih događaja može biti uzrok patoloških promena koje dovode do razvojakardiovaskularnih, neuroloških, metaboličkih i kancerskih oboljenja. Poznavanjespecifičnihepigenetskihpromenakarakterističnihzaovetipovebolesti jeznačajnozarazvojspecifičnihepigenetskihlekova.Sobziromdaprirazvojuovihbolestidolazidoporemećaja enzima koji učestvuju u epigenetskim reakcijama, oni predstavljajupogodantargetzadizajniranjelekova.

Inhibitori dve klaseovih enzimanašli suprimenuukliničkoj praksi: inhibitoriDNKmetiltransferazeihistondeacetilaze.Pokazalosedasudrugeklaseepigenetskihenzima takođe veoma značajne za razvoj bolesti i trenutno se koriste kao targeti uotkrivanjunovihlekova.

Jedan od aspekata u otkriću novih inhibitora epigenetskih enzima uključujeistraživanje aktivnih komponenata iz prirodnih izvora. Ove komponente mogu seprimeniti za dalju karakterizaciju enzima koji modifikuju hromatin. U mnogimslučajevima predstavljaju samo prve agense koji su identifikovani kao inhibitori ilimodulatoriodređenogenzimaidaljeslužekaovodećemolekulezanovekomponentesa osobinama lekova, ili mogu biti lekovi kandidati. S obzirom da mnogi prirodniproizvodi nisu dovoljno istraženi, kao i da mehanizmi dejstva mnogih agenasa nisudovoljno razjašnjeni, prirodni izvoripredstavljaju veliki potencijaluotkrivanjunovihlekovanaepigenetskomnivou.

U ovom radu prikazani su prirodni proizvodi koji deluju na epigenetskemehanizmeinhibicijomenzimauključenihupatogenezurazličitihbolesti.Mnogiodnjihpredstavljajusamopolaznutačkuurazvojunovih inhibitoraepigenetskihenzimakojisemoguprimenitiuhemoprevencijiihemoterapijirazličitihbolesti.

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INHIBITORSOFEPIGENETICENZYMESFROMNATURALSOURCES

SlavicaErić DepartmentofPharmaceuticalChemistry,UniversityofBelgrade‐Facultyof

Pharmacy(Serbia)Epigenetic changes alter gene expression at the level of transcription by

upregulating, downregulating, or silencing genes completely. Dysregulation ofepigenetic events can be pathological, leading to cardiovascular disease, neurologicaldisorders, metabolic disorders, and cancer development. Knowledge of the specificepigeneticchangesassociatedwiththesetypesofdiseasesfacilitatesthedevelopmentof specific epigenetic drugs. Many of the enzymes that mediate these epigeneticreactions are dysregulated in human diseases, so could be suitable target for drugdesign.

Inhibitorsagainst twoclassesof theseenzymeshavebeenapproved foruse inpatients: DNAmethyltransferase (DNMT) inhibitors and histone deacetylase (HDCA)inhibitors.Otherclassesofepigeneticenzymeshavebeendemonstratedtohavestrongdiseaseassociationandarecurrentlybeingtargetedforuseindrugdiscovery.

Oneoftheaspectindrugdiscoveryofinhibitorsofepigeneticenzymesissearchforactivecompundsfromnaturalsources.Thosecompoundscouldbeimportanttoolsto furthercharacterize thechromatin‐modifyingenzymes. Inmanycases theyare thefirstagentsidentifiedasinhibitorsormodulatorsoftheparticularenzymeandtherebyserve as lead structures for new drug‐like compounds or may be drug candidatesthemselves.Sincemanynaturalsourcesarenotexaminedyet,aswellasthemechanismof action of many of them is not still elucidated, natural sources represent a greatpotentialindiscoveringnewdrugsonepigeneticlevel.

In this review, natural products that target epigenetic mechanisms by theinhibition of enzymes involved in patghogenesis of various diseases are presented.Many of them are just strating point in developing new inhibitors of epigeneticenzymes that might be used for chemoprevention and chemotherapy of variousdiseases.

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FIZIČKO‐HEMIJSKAIADMEKARAKTERIZACIJAANALOGAESTARAETILENDIAMIN‐N,N’‐DI‐2‐(3‐CIKLOHEKSIL)PROPANSKEKISELINE

SAPOTENCIJALNIMCITOTOKSIČNIMDEJSTVOM

BiljanaTubić1,BojanMarković2,SandraVladimirov2,VladimirDobričić2,JelenaPoljarević3,AleksandarSavić3,TiborSabo3

1AgencijazalekoveimedicinskasredstvaBosneiHercegovine(BosnaiHercegovina),2Katedrazafarmaceutskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet,3UniverzitetuBeogradu‐Hemijskifakultet(Srbija)

Estri (S,S)‐1,2‐etandiamin‐N,N'‐di‐2‐(3‐cikloheksil)propanske kiseline (EDCP) i

(S,S)‐1,3‐propandiamin‐N,N'‐di‐2‐(3‐cikloheksil)propanskekiseline (PDCP)dizajniranisu kao ligandi za Pt(IV) komplekse. U in vitro ispitivanjima utvrđena je značajnacitotoksična aktivnost navedenih kompleksa, ali i liganada u nevezanom obliku. Ciljrada je da se za navedene ligande izvrši in vitro i in silico biofarmaceutskakarakterizacija.

Razvijena je i validirana UHPLC‐MS/MSmetoda za ispitivanje derivata EDCP iPDCP. Metoda je primenjena za određivanje koncentracija analita u toku ispitivanjarastvorljivosti, lipofilnosti i permeabilnosti. Primenom računarskog programaMetabolizer izvršeno je predviđanje potencijalnihmetabolita. Predviđanje apsorpcije,distribucije, metabolizma, eliminacije i toksičnosti za sve ispitivane supstance ipotencijalne metabolite izvršeno je primenom programa ADME(T) predictor. Zapredviđanje mehanizma dejstva ispitivanih supstanci i njihove interakcije sa ciljnimmestimaprimenjenjemolekulskidocking.

Kiseline(EDCPiPDCP)sedobrorastvarajuuizrazitokiselojsrediniiuizrazitobaznojsredini,dokjerastvorljivostestaranajvećauizrazitokiselojsredini.Ispitanajelipofilnost 14 derivata određivanjem LogD7,4 koeficijenta primenom shake‐flaskmetode, kao i određivanjem retencionog faktora (logk), retencionog vremena (tR) iindeksa hidrofobnosti (CHI i φ0) primenom UHPLC‐MS/MS metode. Postavljen jematematički model za predviđanje lipofilnosti za novosintetisane derivate ilipotencijalnemetabolite, a primenom leave‐one‐out validacionemetode ocenjena je ipokazana dobra prediktivna moć predloženog matematičkog modela (Q2=0,89).Primenom paralelnog testa za ispitivanje permeabilnosti na veštačkimmembranama(PAMPA)pokazanojedaseestriznačajnozadržavajuumembrani(30,09‐99,89%),doku niskom procentu prolaze kroz membranu (0,07‐22,00%). In silico ispitivanjapokazuju da se antiproliferativno dejstvo ostvaruje putem više mehanizama i da suaktivnekiseline ipotencijalnimetaboliti (laktam‐karboksilat i laktamalkilestar),doksuestriverovatnoprodrugsupstance.InvitroiinsilicoispitivanjapokazujudasuestriEDCPiPDCPprodrugsupstancesapovoljnombioraspoloživošćunaciljnimmestimazacitotoksičnodelovanje.

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PHYSICOCHEMICALANDADMECHARACTERIZATIONOFESTERSOFETHYLENEDIAMINE‐N,N’‐DI‐2‐(3‐CYCLOHEXYL)PROPIONICACID

ANALOGSWITHPOTENTIALCYTOTOXICACTIVITY

BiljanaTubić1,BojanMarković2,SandraVladimirov2,VladimirDobričić2,JelenaPoljarević3,AleksandarSavić3,TiborSabo3

1AgencyformedicinesandmedicaldevicesofBosniaandHerzegovina(BosniaandHerzegovina),2DepartmentofPharmaceuticalChemistry,UniversityofBelgrade‐FacultyofPharmacy,3UniversityofBelgrade‐FacultyofChemistry

(Serbia)Esters of (S,S)‐1,2‐ethanediamine‐N,N'‐di‐2‐(3‐cyclohexyl)propanoic acid

(EDCP) and (S,S)‐1,3‐propanediamine‐N,N'‐di‐2‐(3‐cyclohexyl)propanoic acid (PDCP)havebeendesignedas ligands forPt(IV) complexes.Resultsof invitro investigationsshowedsignificantcytotoxicactivityofcomplexes,aswellasofligandsalone.Theaimof this study was in vitro and in silico biopharmaceutical characterization of theseligands.

Novel UHPLC‐MS/MS method for quantitative analysis of EDCP and PDCPderivativeswasdevelopedandvalidated.Thismethodwasused forquantificationoftestedcompoundsinsolubility,lipophilicityandmembranepermeabilityexperiments.Metabolizer softwarewas used for the prediction of potentialmetabolites. ADME(T)predictorsoftwarewasusedforabsorption,distribution,metabolism,eliminationandtoxicitypredictions.Moleculardockingstudywasusedforinvestigationofinteractionswithreceptorsandforthepredictionofmechanismsofcytotoxicactivity.

Investigated acids (EDCP and PDCP) and their esters have good solubility inwateratlowpHvalues,whileacidshavegoodwatersolubilityathighpHvaluesalso.Lipophilicitywasevaluatedon thebasisofLogD7.4 coefficients,determinedbyshake‐flaskmethod,andonthebasisofUHPLC‐MS/MSchromatographyparameters(logk,tR,CHIandφ0).Basedonobtainedresults,mathematicalmodelforlipophilicitypredictionof newly synthesized derivatives or potential metabolites was developed and itspredictive power was confirmed by the leave‐one‐out method (Q2=0.89). Results ofPAMPAtestshowedthatesterspossesshighmembraneretention(30.09‐99.89%)andlowmembranepermeability (0.07‐22.00%).On thebasisof insilicoresults, it canbeassumed that antiproliferative effects of investigated substances are result of severalmechanisms, acids and potential metabolites (lactam carboxylate and lactam alkylesters)areactive,whereasestersaremostlikelyprodrugs.

Results of in vitro and in silico experiments showed that esters of EDCP andPDCP are prodrug substanceswith favourable bioavailability at the sites of cytotoxicaction.

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SINTEZAIBIOLOŠKAAKTIVNOSTPROPIOFENONSKIHDERIVATA

BrankaIvković1,NemanjaTurković2,BojanMarković1,ZoricaVujić1

1Katedrazafarmaceutskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija),2AgencijazaljekoveimedicinskasredstvaCrneGore(Crna

Gora)Strukturno jednostavna ibiološkiaktivnapropiofenonskastrukturanalazi seu

osnovi velikog broja jedinjenja koja su našla primenu u terapiji kardiovaskularnih,malignih, infektivnihoboljenja.Biološkaaktivnost,alimalaselektivnostčinistrukturuinteresantnomkaonosiocarazličitihgrupakojećeuticatinaselektivnostudelovanju.In silico i in vitro ispitivanja (antimikrobno, antiproliferativno, vozodilatatorno iantiaritmijsko) koja su sprovedena na do sada sintetisanim propiofenonskimderivatima(PD)pokazalasudaprisustvorazličitihgrupanaPDstrukturiutičekakonaaktivnost,takoinaselektivnostudelovanju.AktivnostsintetisanihPDunajvećojmerisezasnivanainterakcijamasaaminokiselinamakojesenalazeuosnovijonskihkanalakaoesencijalnihstrukturazafunkcijusvakećelije,aliivirusnihčestica.SintetisaniPDuosnovisadržeihidroksietilaminskugrupukaofarmakofornugrupuantivirotikaizklaseinhibitoraHIVproteaze. S timuvezi, cilj daljih istraživanja jeda se ispitaantiviralneaktivnostiPD.

Sprovedena in silico studija omogućila je filtraciju potencijalnih antivirotikameđudosada sintetisanimPD,kao i filtracijupolaznihmolekula za sintezunovihPDkojibibiliuključeniudaljainvitroispitivanja.

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SYNTHESISANDBIOLOGICALACTIVITYOFPROPIONOPHENONEDERIVATIVES

BrankaIvković1,NemanjaTurković2,BojanMarković1,ZoricaVujić1

1DepartmentofPharmaceuticalChemistry,UniversityofBelgrade‐FacultyofPharmacy(Serbia),2AgencyforMedicinesandMedicalDevicesofMontenegro

(Montenegro)

Structurallysimpleandbiologicallyactivepropylphenonicstructureis foundin

the basis of a large number of compounds that have found use in the treatment ofcardiovascular, malignant, infectious diseases. Biological activity, but low selectivitymakes the structure interesting as a carrier of different groups that will affectselectivity in effects. In silico and in vitro studies (antimicrobial, antiproliferative,vasodilatatoryandantiarrhythmic)thathavebeenconductedonthesofarsynthesizedPDhaveshownthatthepresenceofdifferentgroupsonthePDstructureaffectsbothactivity and selectivity in action. The activity of synthesized PDs ismostly based oninteractionswith the amino acids found in the basis of ion channels as the essentialstructures for the function of each cell, but also of viral particles. Synthesized PDbasically contains a hydroxyethylamine group as a pharmacophoric group ofantiviroticsfromtheclassofHIVproteaseinhibitors.Inthisregard,thegoaloffurtherresearchistoinvestigateantiviralactivitiesofthePD.

The conducted in silico study enabled the filtration of potential antiviroticsamongthepreviouslysynthesizedPD,aswellasfiltrationofthestartingmoleculesforthesynthesisofnewPDsthatwouldbeincludedinfurtherinvitrostudies.

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IZOKUMARINSKIDERIVATI‐SINTEZAIANTIFUNGALNAAKTIVNOST

MilenaSimić Katedrazaorganskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)Izokumarini predstavljaju zanimljivu klasu sekundarnih metabolita biljaka i

nekihgljiva.Osnovustruktureovihderivatačini1H‐benzo[c]piran‐1‐on.Izokumarinskiderivati,prirodniisintetski,poznatisuporazličitimbiološkimaktivnostima,kaoštosuantibakterijska, antifungalna, citotoksična, antiviralna, insekticidna. Zahvaljujući ovojčinjenici, istraživanja u oblasti prirodnih i sintetskih izokumarina privlače pažnjumedicinskihhemičara.Ciljovog istraživanjabio je razvojnovesintetskemetodologijeza dobijanje izokumarinskih derivata, sinteza i evaluacija njihove antifungalneaktivnosti. Polazeći od 3‐bromizokumarina, primenom paladijumom‐katalizovanihreakcijakuplovanja,dobijenajeserijanovih3‐supstituisanihizokumarinskihderivata.

Ispitivanajeinvitroantifungalnaaktivnostserijenovosintetisanihizokumarina.Naosnovupreliminarnog ispitivanjadisk‐difuzionim testom,derivati koji supokazaliznačajnu zonu inhibicije rasta C. albicans odabrani su za dalja testiranja. Na osnovuodređivanjaMICvrednostiodabranihderivata,najvećiantifungalnipotencijalpokazalisu 3‐heteroaril izokumarini. Najaktivnije jedinjenje je pokazalo in vitro antifungalnuaktivnostjednakuvorikonazolu.

Razvijena je nova sintetska metodologija za dobijanje 3‐supstituisanihizokumarinskih derivata. Ispitivana je antifungalna aktivnost odabranih sintetisanihjedinjenja. Najveću in vitro antifungalnu aktivnost prema C. albicans pokazali su 3‐heteroarilizokumarini.

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ISOCOUMARINDERIVATIVES‐SYNTHESISANDANTIFUNGAL

ACTIVITY

MilenaSimić DepartmentofOrganicChemistry,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)Isocoumarinsrepresentveryinterestingclassofsecondarymetabolitesofplants

andsomefungi.Structureof thesederivativescontains1H‐benzo[c]pyrane‐1‐oncore.Isocoumarin derivatives, either natural or synthetic, are known to have variousbiological activities such as antibacterial, antifungal, cytotoxic, antiviral, insecticide.Because of these facts, investigations in area of natural and synthetic isocoumarinsattractattentionofmedicinalchemists.Theaimofthisstudywasdevelopmentofnewsynthetic methodology for synthesis of new isocoumarins and evaluation of theirantifungal activity. Applying the palladium‐catalysed coupling reaction to 3‐bromoisocoumarin, a series of novel 3‐substututed isocoumarin derivatives wasprepared.

Invitroantifungalactivityofseriesofnovelsynthesisedisocoumarinderivativeswas investigated and evaluated. Based on preliminary testing using a dics‐diffusionassay, a series of compounds for further testing were selected. By determiningMICvalues of selected derivatives, the highest antifungal potential showed 3‐heteroarylisocoumarins. The most potent compound showed antifungal activity equal tovoriconazole.

The novel methodology for synthesis of 3‐substituted isocoumarins wasdeveloped. A series of novel 3‐substituted isocoumarin derivatives was designed,synthesisedandtestedagainstC.albicans.3‐Heteroarylcoumarinsshowedthehighestinvitroantifungalactivity.

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Arh.farm 2018;68:112-113 PP6 PRIMENAPAMPATEHNIKEIQSPRANALIZEUPROCENI

GASTROINTESTINALNEAPSORPCIJEIDIZAJNIRANJUNOVIHBIOLOŠKIAKTIVNIHJEDINJENJA

VladimirDobričić,JelenaSavić,BiljanaTubić,KatarinaNikolić,

JasminaBrborić,BojanMarković,OliveraČudina

Katedrazafarmaceutskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

PAMPA(ParallelArtificialMembranePermeabilityAssay)jebrzaijednostavnain

vitro tehnikazaprocenugastrointestinalneapsorpcije. Zasniva senapasivnojdifuzijiispitivanih supstanci kroz veštačku membranu koja simulira gastrointestinalni trakt.QSPR (Quantitative Structure‐ Permeability Relationship Analysis) povezuje rezultatePAMPAtestasafizičko‐hemijskimosobinamaispitivanihjedinjenja,naosnovučegajemoguć dizajn novih derivata sa poboljšanom apsorpcijom. Cilj rada je procenagastrointestinalne apsorpcije trinaest β‐hidroksi‐β‐arilalkanskih kiselina saantiinflamatornom aktivnošću i četrnaest derivata 1,2‐etandiamina i 1,3‐propandiaminasaantiproliferativnomaktivnošćuprimenomPAMPAtesta,kaoidizajnnovihjedinjenjanaosnovuQSPRanaliza.

Gastrointestinalna apsorpcija je procenjena na hidrofobnim PVDF PAMPApločama, impregniranim 1% rastvorom lecitina jajeta u dodekanu (w/v). MolekulskideskriptoriispitivanihjedinjenjasuizračunatiuprogramuDragonipomoćuplatformeChemDes.QSPRmodelisunapravljeniuprogramimaSimca12+PiSTATISTICA.

Za sva ispitivana jedinjenja određeni su koeficijenti permeabilnosti (Papp)primenom PAMPA testa, a za formiranje QSPR modela izračunati su i negativnilogaritmi ovih koeficijenata (‐logPapp). Izdvojene su β‐hidroksi‐β‐arilalkanske kiseline(1C, 1B i 2C), kao i derivati 1,2‐etandiamina i 1,3‐propandiamina (DM‐EDCP, EDCP iDM‐PDCP) sanajvećompermeabilnošćukrozPAMPAmembranu.Formirani suANN‐,MLR‐, PLS‐ i SVM‐QSPR modeli, pri čemu su najpouzdaniji modeli za predviđanjepermeabilnosti MLR(‐logPapp) (za β‐hidroksi‐β‐arilalkanske kiseline), odnosnoPLS(‐logPapp) (za derivate 1,2‐etandiamina i 1,3‐propandiamina). Na osnovudeskriptorakojiformirajuizdvojenemodelepredloženesustrukturnepromenekojebitrebalo da poboljšaju permeabilnost kroz PAMPA veštačku membranu igastrointestinalnuapsorpciju.

PrimenomPAMPA tehnike procenjena je gastrointestinalna apsorpcija trinaestβ‐hidroksi‐β‐arilalkanskih kiselina, kao i četrnaest derivata 1,2‐etandiamina i 1,3‐propandiamina.IzdvojenisuderivatisanajvećompermeabilnošćuiformiranisuQSPRmodeli. Analizom najpouzdanijih modela, predložene su strukturne promene idizajnirani su novi derivati od kojih se može očekivati bolja gastrointestinalnaapsorpcija.

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APPLICATIONOFPAMPATECHNIQUEANDQSPRANALYSISINTHEEVALUATIONOFGASTROINTESTINALABSORPTIONANDDESIGNOF

NEWBIOLOGICALLYACTIVECOMPOUNDS

VladimirDobričić,JelenaSavić,BiljanaTubić,KatarinaNikolić,JasminaBrborić,BojanMarković,OliveraČudina

DepartmentofPharmaceuticalChemistry,UniversityofBelgrade‐Facultyof

Pharmacy(Serbia)PAMPA(ParallelArtificialMembranePermeabilityAssay)isafastandsimplein

vitro technique used for the evaluation of gastrointestinal absorption. It is based onpassive diffusion of tested substances through artificial membrane which simulatesgastrointestinal tract. QSPR (Quantitative Structure‐Permeability RelationshipAnalysis) relatesPAMPAresults tophysico‐chemicalpropertiesof testedcompounds,whichcanbeusedfordesignofnewderivativeswithimprovedabsorption.Theaimofthis work was evaluation of gastrointestinal absorption of thirteen β‐hydroxy‐β‐arylalkanoic acids with antiinflammatory activity and fourteen derivatives of 1,2‐ethanediamineand1,3‐propanediaminewithantiproliferativeactivityusingPAMPA,aswellasdesignofnovelderivativesonthebasisofQSPRanalyses.

Gastrointestinal absorption was evaluated using hydrophobic PAMPA platesimpregnatedwith1%egglecithinsolutionindodecane(w/v).Moleculardescriptorsoftested compounds were calculated using Dragon software and ChemDes platform.QSPRmodelswerecreatedinSimca12+PandSTATISTICAprograms.

Permeabilitycoefficients(Papp)ofall testedcompoundsweredeterminedusingPAMPA,whereasforQSPRmodellingnegativelogarithmsofthesecoefficients(‐logPapp)werecalculated.β‐hydroxy‐β‐arylalkanoicacids(1C,1Band2C),aswellasderivativesof 1,2‐ethanediamine and 1,3‐propanediamine (DM‐EDCP, EDCP and DM‐PDCP)withthe highest PAMPA permeability were underlined. ANN‐, MLR‐, PLS‐ and SVM‐QSPRmodels were created, and themost reliable for permeability prediction were MLR(‐logPapp) (β‐hydroxy‐β‐arylalkanoic acids) and PLS(‐logPapp) (derivatives of 1,2‐ethanediamineand1,3‐propanediamine).Onthebasisofdescriptorsthatformselectedmodels, structural modifications that should improve PAMPA permeability andgastrointestinalabsorptionwereproposed.

Gastrointestinal absorption of thirteen β‐hydroxy‐β‐arylalkanoic acids andfourteen derivatives of 1,2‐ethanediamine and 1,3‐propanediamine was evaluatedusing PAMPA technique. Derivatives with the highest permeability were underlinedand QSPR models were created. After the analysis of the most reliable models,structural modifications were proposed and new derivatives with better expectedgastrointestinalabsorptionweredesigned.

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Arh.farm 2018;68: 114-115 PP7

INVITROISPITIVANJEINHIBITORNOGPOTENCIJALASINTETISANIH

β‐HIDROKSI‐β‐ARILALKANSKIHKISELINAKORIŠĆENJEMKOMERCIJALNOGCOXKITA

JelenaSavić1,JelenaKotur‐Stevuljević2,SandaDilber3,

SoteVladimirov1,JasminaBrborić1

1Katedrazafarmaceutskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐

Farmaceutskifakultet,3Katedrazaorganskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Mehanizam delovanja nesteroidnih antiinflamatornih lekova (NSAIL) je

inhibicija enzima ciklooksigenaze (COX) koji postoji u dve izoforme: COX‐1 i COX‐2.Selektivni COX‐2 inhibitori ne izazivaju neželjene gastrointestinalne efekte kojipredstavljaju glavni ograničavajući faktor za primenu NSAIL. Cilj rada je da sekomercijalnimCOXkitom,koji sadržiovčiju izoformuCOX‐1 ihumanu rekombinatnuizoformu COX‐2, in vitro odrede IC50 vrednosti prema svakoj izoformi i proceneantiinflamatorni potencijal i selektivnost sintetisanih β‐hidroksi‐β‐arilalkanskihkiselina.

Sedam odabranih β‐hidroksi‐β‐arilalkanskih kiselina je rastvoreno udimetilsulfoksidu,takodasedobijukoncentracije:0,01µM;0,1µM;1µM;10µM,50µMi100µM.Ostalireagensisupripremljenipremauputstvuproizvođača.Testsesastojaoiz ciklooksigenazne reakcije, u kojoj je ispitivano jedinjenje inkubirano saodgovarajućom COX izoformom, i ELISA testa, kojim je kvantifikovan proizvodprethodneCOXreakcije.

DobijeneIC50vrednosti,kojesenalazeuopsegu21‐327µmolzaCOX‐1i5,2‐62,8µmolzaCOX‐2izoformu,pokazujudatestiranajedinjenjaimajuumereniafinitetzaobeizoforme. Izračunati indeks selektivnosti (odnos IC20(COX‐1)/IC50(COX‐2)) je u opsegu1,7‐62,7. Najveći indeks selektivnosti i najnižu IC50(COX‐2)vrednost ima jedinjenje koje jederivatβ‐hidroksi‐β,β‐difenilpropionskekiselinesapolarnomnitrogrupomnajednomodbenzenovihprstenova. Jedinjenjesanepolarnomtrifluorometilgrupomna jednomodbenzenovihprstenova imanajvišu IC50(COX‐2) i nizak indeks selektivnosti (3,7).Dvekiseline bez supstituenata na benzenovomprstenu imaju najniži indeks selektivnosti(1,7). In vitro testiranjem sedam odabranih β‐hidroksi‐β‐arilalkanskih kiselina nakomercijalnom COX kitu određene su IC50(COX‐1) i IC50(COX‐2)vrednosti, kao i indeksiselektivnosti. Zaključeno je da je jedinjenje sa polarnomnitro grupomna jednomodbenzenovih prestenova najselektivniji COX‐2 inhibitor, a da polarna nitro grupadoprinosijačiniinhibicijeCOX‐2.

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INVITROASSESSMENTOFTHEINHIBITORYPOTENTIALOFSYNTHESIZEDβ‐HYDROXY‐β‐ARYLALKANOICACIDSUSING

COMMERCIALCOXKIT

JelenaSavić1,JelenaKotur‐Stevuljević2,SandaDilber3,SoteVladimirov1,JasminaBrborić1

1DepartmentofPharmaceuticalChemistry,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofMedicalBiochemistry,UniversityofBelgrade‐

FacultyofPharmacy,3DepartmentofOrganicChemistry,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Mechanism of action of nonsteroidal anti‐inflammatory drugs (NSAIDs) is

inhibition of enzyme cyclooxygenase (COX)which exists in two isoforms: COX‐1 andCOX‐2.SelectiveCOX‐2 inhibitorsdonot causegastrointestinal sideeffectswhicharelimitingfactorforNSAIDsadministration.TheaimofthisworkistoinvitrodetermineIC50values towardseach isoform,assesanti‐inflammatorypotentialandselectivityofsynthetized β‐hydroxy‐β‐arylalkanoic acids using commercial COX kitwhich includesovineCOX‐1andhumanrecombinantCOX‐2isoform.

Seven selected β‐hydroxy‐β‐arylalkanoic acids were dissolved in dimethylsulfoxidetoobtainconcentrations:0.01µM;0.1µM;1µM;10µM,50µMand100µM.Therestofthereagentsispreparedaccordingtothemanufacturer`smanual.Thetesthas consisted of cyclooxygenase reaction in which tested compound was incubatedwith corresponding COX isoform and ELISA which quantifies the product of thepreviousreaction.

ObtainedIC50valueswhichareintherange21‐327µmolforCOX‐1and5.2‐62.8µmol for COX‐2 isoform shows that tested compounds exhibit moderate affinity foreachisoform.Calculatedselectivityindex(ratioIC20(COX‐1)/IC50(COX‐2))isintherange1.7‐62.7.Acompoundwhichisaderivativeofβ‐hydroxy‐β,β‐diphenylpropionicacidwithapolar nitro group on one benzene ring showed the highest selectivity index and thelowest IC50(COX‐2) value. A compound with a nonpolar trifluoromethyl group on onebenzeneringhasthehighestIC50(COX‐2)valueandlowselectivityindex(3.7).Twoacidswithoutsubstituentsonbenzeneringhavethelowestselectivityindex(1.7).

IC50(COX‐1)andIC50(COX‐2),aswellasselectivityindicesofsevenselectedβ‐hydroxy‐β‐arylalkanoicacidsweredeterminedusingcommercialCOXkit.Itwasconcludedthatthe compoundwith the polar nitro group on one benzene ring is themost selectiveCOX‐2 inhibitor and that polar nitro group contributes to the strength of COX‐2inhibition.

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Arh.farm 2018;68: 116 PP8EUROPEANASSOCIATIONOFHOSPITALPHARMACY(EAHP)COMPETENCYFRAMEWORKFORHOSPITALPHARMACY

PetrHorak

EuropeanAssociationofHospitalPharmacy

TheEuropeanAssociationofHospitalPharmacists (EAHP),and its35member

country platforms are creating a Common Training Framework (CTF) for hospitalpharmacy education in Europe with a focus on competency‐based approaches totraining,staffdevelopmentandassessmentwhichareincreasinglyviewedasacentralstrategyforimprovingtheeffectivenessofthosewhoprovidecare.

ThroughtheCTFproject,EAHPworkedonsecuringvoluntaryagreementacrosscountriesabouttheknowledge,skillsandattitudes/behavioursthatunderpinadvancedpractice in the hospital sector. This draft frameworkwas reviewed through aDelphiConsultationinwhichadiversegroupofstakeholdersparticipated.Furthermore,EAHPconducted the labour mobility survey aiming at exploring the attitudes andperspectivesofhospitalpharmacistsonlabourmobilitywithinEurope.

The final competency framework has 24 competencies, 87 knowledge itemsidentifiedand136behaviourcompetencies.Clusterswithindividualoutcomesdefinedare: patient care and clinical pharmacy skills competencies;medicines and their userelated competencies; management competencies and professional competencies.Moreover,theresultsofthelaboursurveymakeitclearthathospitalpharmacistsareinterestedinpursuingtheirfreemovementrights,while85%ofthesurveyparticipantswould support the creation of a CTF for the hospital pharmacy specialisation. Thiswould loosen perceived barriers to labour mobility in Europe and make thecomparabilityofcompetencies,knowledgeandskillspossibleacrossthecontinent.

CTFwouldsetaneducationalbenchmarkforallEuropeancountriestostrivefor.Developmentoftheprofession,facilitationofexchangeofexpertise,standardisationinthequalityofeducationandincreaseofmobilityopportunitiesarebenefitstobegainedbycreatinganewtoolforautomaticcross‐borderrecognitionofthehospitalpharmacyspecialisation.

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SAVREMENIPRISTUPOPTIMIZACIJIANTIBIOTSKETERAPIJENA

OSNOVUIZMERENIHKONCENTRACIJA

KatarinaVučićević

Katedrazafarmakokinetikuikliničkufarmaciju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

U fokusu terapijskog praćenja lekova (Therapeutic Drug Monitoring, TDM) su

oduvek bili lekovi varijabilne farmakokinetike, uskog terapijskog raspona, za koje jedokazana iutvrđenaveza izmeđukoncentracije lekauplazmi i farmakološkogefekta.Od svog uvođenja do danasTDM je ostao jedan od glavnih alata u kliničkoj praksi uprocesu individualizacije režima doziranja antibiotika kod različitih populacijapacijenata(npr.kritičnooboleli,pedijatrijski,gerijatrijski).Razvojfarmakometrijekaonaučnedisciplinei intenzivninapredakuoblastibioanalitičkihmetoda,danasojačavapoziciju TDM‐a i pruža mu dodatne mogućnosti u optimizaciji antibiotske terapije.Stoga,ovajradimazaciljdapredstavisavremenipristupTDM‐a.

Populacioni farmakokinetičko‐farmakodinamički modeli proširenimatematičkim modelima koji opisuju razvoj rezistencije, stepen adherence i ishodelečenja sunajsloženiji alatikoji sedanaskoristeuprocesu individualizacije. Jedanodpristupa je da se na osnovu demografskih, farmakogenetičkih i kliničkih podatakapristupi optimizaciji režimadoziranja antibiotika, dok se dodatnou okviruTDM‐a saciljemindividualizacijedoziranjauzimauobzirizmerena/ekoncentracija/eantibiotikaubiološkommaterijalu.

Kakobimodeli razvijeninavelikojgrupipacijenatabiliupotrebljiviukliničkojpraksiilikakobiseunapredilipostojećikorišćenjemizmerenihkoncentracijalekakodpacijenata neophodno je da budu jednostavni za korišćenje u svakodnevnom radu.Stoga su oni inkorporirani u kompjuterske programe koji ne zahtevaju poznavanjesložene farmakometrijske metodologije. Kliničkim farmaceutima su danas naraspolaganju mnogobrojne aplikacije za mobilne telefone, kompjuterski programi iliinter‐/intra‐net platforme. Unosom osnovnih podataka o pacijentu i izborom ostalihključnihpodatakamogurelativnobrzo,jednostavnoipouzdanodobitiključnesmerniceza optimalni izbor doze i dužine terapije antibioticima. Savremeni koncept TDM‐aantibiotika baziran na integrisanim populacionim modelima leka, uzročnika iorganizma pacijenta u kome se procesi odvijaju, povećava verovatnoću postizanjaželjenogishodaterapijekodpacijenta.

IstraživanjejerealizovanouokviruprojektaON‐175023 finansiranog od strane

Ministarstvaprosvete,naukeitehnološkograzvojaRepublikeSrbije.

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AMODERNAPPROACHTOOPTIMIZINGANTIBIOTICTHERAPYBASEDONMEASUREDCONCENTRATIONS

KatarinaVučićević

DepartmentofPharmacokineticsandClinicalPharmacy,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Drugswithhighlyvariablepharmacokinetics,narrowtherapeuticindex,withthe

established relationship between plasma drug concentration and pharmacologicaleffect have alwaysbeen in the focusof therapeuticdrugmonitoring (TDM). Since itsintroductiontodate,TDMremainedoneofthemaintoolsintheclinicalpracticeintheprocess of individualizing antibiotic dosing regimens in different patient populations(e.g. critically ill, pediatric and geriatric). Development of pharmacometrics as ascientificdisciplineandintensiveadvancementinthefieldofbioanalyticalmethodsarestrengthening TDM's position and provide additional opportunities in optimizingantibiotictherapy.Therefore,thispaperaimstopresentamodernTDMapproach.

Integratedpopulationpharmacokinetic‐pharmacodynamicmodelsexpandedbymathematical models describing the bacterial development of resistance, patient’sadherence over the treatment course and the treatment outcomes are the mostcomplextoolsusedintheprocessofdoseindividualizationtoday.Thebasicapproachutilizes demographic, pharmacogenetic and clinical patient’s data, while TDM‐basedindividualization additionally takes into account measured antibiotic level in thebiologicalmatrix.

The use of big data models developed on a large group of patients and theircontinuous improvement through measured drug concentration inputs ought to bestraightforward in everyday clinical practice. Therefore, they are incorporated intocomputer softwares that do not require knowledge of a complex pharmacometricmethodology.Nowadays,variousapplications formobilephones, computerprogramsor inter/intranet platforms are accessible to clinical pharmacists. Entering basicpatient’s informationandotherrelevantdata,guidelines foroptimalantibioticdosingcouldbequicklyavailableandreliable.

Themodern concept of antibiotics’ TDM is based onpopulationmodels of thedrug, integrated with models of the bacterial resistance and the patient's organism,aiming to increase the probability of achieving the desired therapy outcome in anindividualpatient.

Thisworkwas conducted as a part of the project ON‐175023) funded by the

Ministryof Education, Science and TechnologicalDevelopment,Belgrade,RepublicofSerbia.

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Arh.farm 2018;68: 119-120 PP10

INTERVENCIJEKLINIČKOGFARMACEUTANAODELJENJU

HEPATOLOGIJE

MilicaĆulafić

Katedrazafarmakokinetikuikliničkufarmaciju,UniverzitetuBeogradu‐FarmaceutskifakultetiTransplantacionahepatologija,Klinikaza

gastroenterologijuihepatologiju,KliničkicentarSrbije,Beograd(Srbija)Na odeljenju hepatologije zbrinjavaju se pacijenti sa različitim bolestima jetre,

pacijenti koji se pripremaju za transplantaciju jetre, te vrši kontinuirano praćenjepacijenata nakon transplantacije. Pristup rešavanju problema vezanih za lekove kodpacijenata sa bolestima jetre zahteva znanja o farmakokinetici i farmakodinamicilekova koje je potrebno interpretirati u odnosu na individualne karakteristikepacijenta. Cilj studije je prikazati pregled aktivnosti farmaceuta u posmatranomperiodu kod pacijenata sa oslabljenom funkcijom jetre te kod transplantiranihpacijenata.PraćenesuaktivnostifarmaceutatokomboravkanaodeljenjuhepatologijeKlinikezagastroenterologijuihepatologiju,KliničkogcentraSrbije(2xnedeljno),kaoikonsultacije koje su usledile nakon toga. Procenjen je i stepen prihvaćenostipredloženih intervencija od strane nadležnih lekara uperiodu od juna 2017. do juna2018.godine.

Zabeleženoje519intervencijauvezisalekovimaodčegajefarmaceut inicirao71,9% intervencija. Preostale intervencije koje je imao farmaceut sprovedene su naosnovu upita lekara (22,5%), pacijenta (3,1%), medicinske sestre (2,5%). Najčešćeintervencije su se ticale neželjenih reakcija na lek (24,0%), sledi izborleka/korekcijadoze (18,3%), interakcije (16,5%), savetovanje pacijenata o lekovima posletransplantacije(16,0%),konverzijasaIVnaoralnuprimenu(11,7%),edukacijačlanovazdravstvenogtimao(novim)lekovima(9,9%).Intervencijesubileprihvaćeneu91,6%slučajeva.Sprovedenjeznačajanbrojintervencijaodkojihjevećinainiciranaodstranefarmaceuta. Uključivanje farmaceuta je dovelo do optimizacije farmakoterapije što jereflektovanoprihvatanjemodstranehepatološkog tima.Farmaceutposedujeznanja iveštine kojemogu unaprediti brigu o hepatološkim pacijentima, te poboljšati ishodelečenja.

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CLINICALPHARMACIST'SINTERVENTIONSONAHEPATOLOGYWARD

MilicaĆulafić

DepartmentofPharmacokineticsandClinicalPharmacy,Universityof

Belgrade‐FacultyofPharmacyandHepatologyandLiverTransplantUnit,ClinicforGastroenterologyandHepatology,ClinicalCenterofSerbia,Belgrade

(Serbia)Hepatology unit is involved in the treatment of patients with different liver

disordersbutalsoprovidescareforpatientswhoarepreparingfora livertransplant,andconductscontinuousmonitoringofpost liver transplant recipients. Interventionsto identify and resolve drug‐related problems in patientswith liver diseases requireknowledgeofpharmacokineticandpharmacodynamicmedicationcharacteristics thatneedtobeinterpretedinrelationtotheindividualpatientneeds.Thisstudyaimedtopresent an overview of the activities of pharmacist directed to patientswith hepaticimpairment and liver transplant recipients during the study period. PharmacistactivitiesontheHepatologywardatClinicforGastroenterologyandHepatology(2daysper week), as well as consultations that followed subsequently, were observed. Thedegree of acceptance for the proposed interventions by competent doctorswas alsorecordedduringthestudyperiodfromJune2017toJune2018.

Wedocumented519interventionsinregardstodrug‐relatedproblemsofwhichthemajoritywaspharmacist‐initiated (71.9%).Other interventions conductedby thepharmacistwerearesultofqueriesbyphysicians(22.5%),patients(3.1%)andnurses(2.5%). Themost common interventionswere related to the adverse drug reactions(23.0%), followed by choice of the drug/correction of the dose (19.3%), theinteractions(16.5%),patientcounselingforpostlivertransplantmedications(16.0%),conversion from IV tooral administration (11.7 %), education of members of thehealthcare teamfor the (new)drugs(9.9%).Physicians'acceptancerateofpharmacyinterventionswas91.6%.Significantnumberofinterventions(majorityinitiatedbythepharmacist)wasrecorded.The inclusionofpharmacisthas led to theoptimisationofpharmacotherapy as reflected by the significant intervention acceptance rate ofhepatology/transplantteam.Thepharmacistshavetheknowledgeandskillsthatmayenhancethecareofpatientswithliverdiseasesandimprovetreatmentoutcomes.

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ZDRAVSTVENAANALIZAVRSTEIISHODAGREŠKE‐HEALTHCAREFAILUREMODEANDEFFECTANALYSIS(HFMEA)PRIMENJENANA

PROCESSUPSTITUCIJEANTIBIOTSKETERAPIJETOKOMNESTAŠICELEKOVA

NenadMiljković1,KaryofyllisTsiakitzis2,CristinaGarciaYubero3,

BranislavaMiljković4

1Institutzaortopedsko‐hirurškebolesti„Banjica”,Beograd,2NosokomeioThessalonikisGeorgiosPapanikolaou(Grčka),3ElHospitalUniversitarioInfantaSofíaSaludMadrid(Španija),4Katedrazafarmakokinetikuikliničkufarmaciju,

UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)Zdravstvena analiza vrste i ishoda greške‐Healthcare FailureMode and Effect

Analysis (HFMEA) predstavlja prospektivnu analizu rizika, koja se sprovodi radismanjenja rizika po zdravlje pacijenta, u toku pružanja zdravstvene zaštite. Cilj ovogistraživanja je komparativna procena primene HFMEA u određivanju i prioritizacijirizikakodzameneantibiotsketerapijetokomnestašicelekova.

HFMEA metoda je sprovedena u Institutu za ortopedsko‐hirurške bolesti„Banjica”(bolnicaA),NosokomeioThessalonikisGeorgiosPapanikolaou(bolnicaB)iElHospitalUniversitarioInfantaSofíaSaludMadrid(bolnicaC)uperioduodfebruaradojuna 2018. Nakon identifikacije i kvantifikacije rizika na osnovu njihove ozbiljnosti iverovatnoćenastanka,sprovedenajeikomparativnahazardanalizagrešaka,injihovihuzroka.

HFMEAmetodomjeustanovljeno13tipovagrešakaubolniciB,12ubolniciAi10ubolniciC.UbolnicamaAiBidentifikovanoje12uzrokagrešaka,dokje9određenou bolnici C. Greške vezane za supstituciju antibiotika sa najvišim hazard brojem ubolnicama A, B i C su: nesprovođenje pregleda novonastalih interakcija lekova;nesprovođenje procene potrebe za dodatnim monitoringom pacijenta; neadekvatniprenosinformacijeosupstitucionojterapiji;neodgovarajućaprocenastanjapacijentainepostojanje liste alternativnih antibiotika kada nestašica nastupi. Uzroci grešakazajednički za sve bolnice su nedostatak vremena, neadekvatna komunikacija međuzdravstvenim radnicima i neadekvatna podrška u vidu informacionih tehnologija.Predložene mere kontrole rizika su efikasnija raspodela vremena zaposlenih, pisaniprotokoli za supstituciju antibiotika i validacija procesa zamene leka od stranezdravstvenihradnikakojiučestvujuudonošenjuodlukeoantibiotskojterapijiiprimeniantimikrobneterapije.

Rezultati HFMEA metode, ukazuju na neophodnost potpunog pristupazdravstvenih radnika informacijama o alternatitvnim terapijskim opcijama, efikasnijekomunikacije među zdravstvenim radnicima i detaljnijeg uvida u zdravstvenudokumentacijupacijenta,tepotrebezadodatnimmonitoringom,kaoosnovnihmerazakontrolurizikakojisejavljajuprilikomzameneterapijetokomnestašicelekova.

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HEALTHCAREFAILUREMODEANDEFFECTANALYSIS(HFMEA)APPLIEDTOANTIBIOTICSUBSTITUTIONINMEDICINESHORTAGES

NenadMiljković1,KaryofyllisTsiakitzis2,CristinaGarciaYubero3,

BranislavaMiljković4

1TheInstituteofOrthopaedicSurgeryBanjica,2TheGeorgePapanikolauHospitalThessaloniki,3TheInfantaSofiaHospitalMadrid,4DepartmentofPharmacokineticsandClinicalPharmacy,UniversityofBelgrade‐Facultyof

Pharmacy(Serbia)Healthcare Failure Mode and Effect Analysis (HFMEA) is a prospective risk

assessment applied in healthcare settings to reduce patient riskwhile still providinghealth services. Therein, this study compares HFMEA as a risk assessment andprioritisationtoolwithinantibioticsubstitutioninmedicineshortages.

TheHFMEAwas carried out at the InstituteofOrthopaedic SurgeryBanjica inBelgrade (Hospital A), the George PapanikolauHospital in Thessaloniki (Hospital B),andtheInfantaSofiaHospitalinMadrid(HospitalC)fromFebruarytoJune,2018.Uponidentifying risks and quantifying them as based on their severity and probability,including their proposed control measures, a comparative‐failure mode and causehazard‐scoreanalysiswasconducted.

13 failuremodes inHospitalB,12 inA,and10 inCweredetected.12 failure‐modecauseswereidentifiedinHospitalsAandB,and9inC.Theselinkedtoantibioticsubstitutionwhichscoredhighestamonghazardsinallhospitalswerefoundtobethefollowing: non‐verification of new drug interactions; lack of additional patientmonitoring;inadequatelycommunicatingthesubstitution’s specificstostaff;notfullyreviewing the patient’s condition; and no available list of alternative antibiotics formedicineshortage.Thefailuremodecausesforallhospitalswereanalysedas: lackoftime, insufficient communication among healthcare professionals regarding thesubstitution;andinsufficientITsupport.Theriskcontrolmeasuressuggestedinclude:moreefficient timemanagement;writtenprotocol forantibiotic substitution;and thesubstitution’s validation by healthcare professionals involved in the decisionmakingprocessandmedicineadministration.

The HFMEA results demonstrate that full access to information on treatmentalternatives, more efficient inter‐staff communication, a valid assessment of patientrecords,andtheneedforadditionalpatientmonitoringallrepresentmainrisk‐controlmeasures.Toimproveoutcomes,thesemustbecarriedoutinsubstitutingamedicinewhilethereisashortage.

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MIKROBIOTACREVA,ZNAČAJZAETIOPATOGENEZUITERAPIJU

AUTOIMUNSKIHBOLESTI

ĐorđeMiljkovićОdeljenjezaimunologiju,Institutzabiološkaistraživanja„SinišaStanković”,

UniverzitetuBeogradu(Srbija)

Mikrobiota creva ostvaruje intenzivnu interakciju sa organizmom čoveka i

umnogome utiče na funkciju osnovnih homeostatskih organskih sistema čoveka,uključujući i imunski sistem. Smatra se da je evolucija adaptivnog imunskog sistemauslovljena uspostavljanjem komensalih i simbiotskih odnosa kičmenjaka samikroorganizmimacreva.Znasedamikroorganizmicrevanarazličitenačinedelujunaimunskećelije,kakousamomgastrointestinalnomtraktu,takoinasistemskomnivou.Svejevišepodatakakojiukazujudabimikrobiotacrevamogladaimapresudnuuloguu otpočinjanju i propagaciji, ali i sprečavanju i regulaciji neadekvatnih imunskihodgovora, kakvi se dešavaju u autoimunskim bolestima. U ovom izlaganju će bitipredstavljeni ključni nalazi koji podržavaju hipotezu o značaju mikrobiote creva zaetiopatogenezu autoimunskih bolesti, kao i oni koji ukazuju da bi modulacijamikrobiotecrevamoglabitiadekvatanpristuputerapijiautoimunskihbolesti.Takođe,biće predstavljena i istraživanja Odeljenja za imunologiju Instituta za biološkaistraživanja„SinišaStanković”kojasetičuulogemikrobiotecrevaupatogenezimultiplesklerozeidijabetesamelitusatipI.

124

THEROLEOFGUTMICROBIOTAINETIOPATHOGENESISANDTHERAPYOFAUTOIMMUNEDISEASES

ĐorđeMiljković

DepartmentofImmunology,InstituteforBiologicalResearch„Sinisa

Stankovic”,UniversityofBelgrade(Serbia) Gutmicrobiotainteractsintensivelywithhumanbody,havingenormousimpactonthehomeostatic systems, including immune system. The very origin of the adaptiveimmune system is closely related to the incorporation of commensal and symbioticmicroorganismsintothegut.Gutmicroorganismsinfluenceimmunecellsinhumansinvariousways,bothwithinthegut‐associatedlymphoidtissueandatthesystemiclevel.Anincreasingbodyofevidencesuggeststhatgutmicrobiotahasthedecisiveroleintheinitiation and thepropagation, aswell as in thepreventionand the regulationof theinappropriate immune response that is the major feature of autoimmune disorderpathogenesis.Thekeydatasupportingahypothesis thatgutmicrobiota is thecrucialelementintheetiopathogenesisofautoimmunedisorderswillbepresented.Moreover,results of the Department of Immunology, Institute for biological Research „SinisaStankovic”,relatedtotheroleofgutmicrobiotainmultiplesclerosisanddiabetestype1willbeshown.

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REGULATORNETĆELIJE–NOVIPRISTUPULEČENJU

AUTOIMUNSKIHBOLESTI

IvanaStojanović

Оdeljenjezaimunologiju,Institutzabiološkaistraživanja„SinišaStanković”,UniverzitetuBeogradu(Srbija)

Medicinskiproizvodizanaprednuterapiju(odengl.Advancedtherapymedicinal

products ‐ ATMP) se baziraju na genima, tkivima i ćelijama koje se koriste u terapijioboljenja i povreda kod ljudi. Iako su neke od ATMP ušle u kliničku praksu,imunoterapija autoimunskih bolesti regulatornim T ćelijama (Тreg) još je u fazi Ikliničkih studija. Uobičajeno se koriste Treg iz krvi obolele osobe (iako postojimogućnost disfunkcije Treg), i poliklonske Treg, tj. one koje prepoznaju različiteantigene (naspram antigen‐specifičnih koje su specifičnije). Da bi se prevazišaopotencijalni problemdisfunkcije Treg i obezbedila njihova specifičnost delovanja, ciljnašestudijebiojedanapravimoinsulin‐specifičneTreg(zalečenjetip1dijabetesa)odefektorskihinsulin‐specifičnihTlimfocitaprimenomrazličitihinvitropostupaka.Prvaprepreka na tom putu bio je mali broj insulin‐specifičnih efektorskih Treg u NODmiševimakojispontanorazvijajudijabetes.OvećelijesmoumnožilikultivacijomCD4+Тćelija na dendritskim ćelijama u prisustvu insulin peptida B9:23. Od inicijalnih 0,1%dobilismo5,4±2,1%insulin‐specifičnihćelijanakon24sata,kojesudaljesortiraneuzpomoćinsulin‐specifičnihMHCtetrameraklaseIIiizloženestimulatorimaiIL‐2iTGF‐β.Bilo je neophodno samo 48 sati da efektorske ćelije konvertuju u Treg fenotip(CD4+CD25highFoxP3+GITR+CD127‐). Ove ćelije su proizvodile TGF‐β i suprimiraleproliferaciju efektorskih ćelija in vitro. Takođe, eksprimirale su hemokinski receptorCXCR3 kojimože da upravlja njihovumigraciju u pankreas. Ovi rezultati ukazuju namogućnost in vitro konverzije efektorskih ćelija u regulatorne sa specifičnosšću nazadati antigen, ali njihova efikasnost u terapiji tip 1 dijabetesa tek treba da budeispitana.

Finansirano od strane Porodične fondacije Jakoka (Boston, SAD) i delom sa

projekta 173013Ministrastva prosvete, nauke i tehnološkog razvoja Republike Srbije.ObeleženitetramerisupoklonNIHTetramerCoreFacility.

126

TREGULATORYCELLS‐NEWAPPROACHINTHETREATMENTOF

AUTOIMMUNITY

IvanaStojanovićDepartmentofImmunology,InstituteforBiologicalResearch„Sinisa

Stankovic”,UniversityofBelgrade(Serbia)Advancedtherapymedicinalproducts(ATMPs)aremedicinesthatarebasedon

genes, tissues or cells. Although several ATMPs entered clinical practice,immunotherapy of autoimmune diseaseswith CD4+CD25highFoxP3+ regulatory T cells(Tregs) is still at the stage of phase I clinical trials. Usually, Tregs used for humantherapyare isolatedfromindividual’sblood(concernaboutthe functionofTreg)andtheyarepolyclonali.e.theyrecognizeanumberofdifferentantigens(antigen‐specificTregsaremorespecific).So,toovercometheproblemofpossibleTregmalfunctionandtoprovideantigen‐specificityofTregs,weaimedtogenerateinsulin‐specificTregs(forthetreatmentoftype1diabetes)frominsulin‐specificTeffectorcellsusingvariousinvitromanipulations.Duetolowoccurrenceofinsulin‐specificCD4+TcellsinNODmicethatdeveloptype1diabetesspontaneously(0.1%),CD4+Tcellswereco‐culturedwithautologousmaturedendriticcells(DC)inthepresenceofinsulinB9:23.Theproportionofactivatedinsulin‐specificCD4+CD69+Tcellsincreasedupto5.4±2.1%after24handthew were then sorted using fluorescent insulin‐loaded MHC class II tetramers andculturedwithTCRstimulators,recombinantIL‐2andTGF‐β.Ittookonly48hforcellstofullyconverttoCD4+CD25highFoxP3+GITR+CD127‐Tregsphenotype.Theseconvertedcells produced TGF‐β and suppressed proliferation of T effectors in vitro. Also, theyexpressedCXCR3thatcandirectcellmigrationtowardthepancreas.TheirproliferationwasstimulatedonlyinthecaseofexposuretoimmatureDC.Theseresultsconfirmthatit isfeasibletogenerateantigen‐specificTregsfromantigen‐specificeffectorcells,buttheeffectivenessofthesecellsinvivoremainstobedetermined.

FundedbytheIacoccaFamilyFoundation(Boston,USA)andpartlybytheMinistry

of Science, Education and Technological Development, Republic of Serbia (173013).FluorescentMHCclassIItetramerswereadonationfromNIHTetramerCoreFacility.

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ADRENERGIČKILEKOVI–KANDIDATIZANOVENEKONVENCIONALNEIMUNOMODULATORNELEKOVE?

GordanaLeposavić

Katedrazafiziologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Brojninalazipokazujudasukateholamini,krajnjimedijatorisimpato‐adrenalne

osovine, uključeni umodulaciju urođenog i stečenog imunskog odgovora. Osim toga,pokazano je da imunske ćelije mogu da sintetišu noradrenalin (tzv. „adrenergičkećelije”)kojidelujeautokrino/parakrino.Ovosvojstvoimunskihćelijajeposebnovažnoonda kada je izmenjeno (smanjeno) neurokrino delovanje kateholamina (npr. uhroničnom stresu, inflamaciji). Pokazano je da skoro svi tipovi imunskih ćelijaeksprimiraju β‐adrenergičke receptore i da kateholamini deluju imunomodulatornouglavnom posredstvom ovog tipa adrenergičkih receptora. Međutim, sve je višepodataka da su i α‐adrenergički receptori uključeni u imunomodulaciju. Našaistraživanja pokazuju da α‐adrenergičke receptore ispoljavaju antigen prezentujućećelije,uključujućidendritskećelije(kojeimajuključnuuloguuiniciranjuiusmeravanjustečenogimunskogodgovora)iCD4+CD25+FoxP3+regulatorneT‐ćelije,kojesuvažneza održavanje imunske homeostaze i prevenciju razvoja autoimunskih bolesti. Brojninalaziukazujudasesintezakateholaminamenjaumononuklearnimćelijamaperifernekrvi tokom razvoja autoimunskih bolesti, kao što su reumatoidni artritis i multiplaskleroza.Takođejepokazanodasesadržajnoradrenalinaunervnimvlaknimainjegovasinteza u imunskim ćelijama u sekundarnim limfoidnim organima i ciljnom organumenja tokom razvoja eksperimentalno indukovanih autoimunskih bolesti, kao što sukolagenom‐indukovani artritis (model reumatoidnog artritisa) i eksperimentalniautoimunski encefalomijelitis (model multiple skleroze). Osim toga, farmakološkemanipulacije delovanjem kateholamina tokom razvoja eksperimentalno indukovanihautoimunskih bolesti ukazuju da kateholamini učestvuju u njihovoj patogenezi. Našaskorašnjaispitivanjasuukazalanacelularneimolekularnemehanizmekojibimoglidaobjasneulogukateholaminausklopukompleksne imunopatogenzeeksperimentalnogautoimunskog encefalomijelitisa. Imajući u vidu da su adrenergički lekovi jeftini idobrogbezbednosnogprofila,sagledavanjenjhovogimunomodulatornogpotencijalabimoglo da bude važno za proširenje njihovih terapijskih indikacija na adjuvantnuterapijunesamomultipleskleroze,većidrugihautoimunskihbolesti.

RadjefinansiraloMPNTRRepublikeSrbije,projekat175050.

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ADRENERGICDRUGS–CANDIDATESASNOVELNON‐CONVENTIONALIMMUNOMODULATORYDRUGS?

GordanaLeposavić

DepartmentofPhysiology,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)There is a pile of evidence that catecholamines, the end‐point mediators of

sympathoadrenalaxis,modulateinnateandadaptiveimmuneresponses.Immunecellsalso synthesize noradrenaline, which then acts in autocrine/paracrine manner.Noradrenalinesynthesisinimmunecells(„adrenergic”cells)isshowntobeparticularlyimportantunderconditionaffectingcatecholamineneurocrineaction(e.g.understress,during inflammation). Catecholamine effects on immune cells are mediated mainlythrough β‐adrenoceptors, which are expressed on almost all types of innate andadaptiveimmunitycells.However,emergingdataindicatearoleforα‐adrenoceptorsinimmunomodulation. Our finding showed that α‐adrenoceptors on antigen presentingcells, includingdendriticcells,whicharecrucial ininitiationanddirectionofadaptiveimmune response, but also on CD4+CD25+FoxP3+ regulatory T cells, which areimportant in maintaining immune homeostasis and preventing development ofautoimmune diseases. An accumulating body of evidence indicate that synthesis ofcatecholaminesinperipheralbloodmononuclearcellschangesduringdevelopmentofautoimmune diseases, such asmultiple sclerosis and rheumatoid arthritis. There arealsodata indicating thatnoradrenaline release fromsympatheticnerve fibres and itssynthesis in immune cells in secondary lymphoid organs and target tissues changeduringdevelopmentofexperimentallyinducedautoimmunediseases,suchascollagen‐induced arthritis (rheumatoid arthritis model) and experimental autoimmuneencephalomyelitis (multiple sclerosis model). Additionally, pharmacologicalmanipulations with catecholamine action during development of experimentallyinduced autoimmune diseases strongly suggested that they are involved in theirpathogenesis.Ourrecentstudiespointedouttomechanismsunderlyingadrenoceptor‐mediated immunomodulation during development of experimental autoimmuneencephalomyelitis. Considering the fact that adrenergic drugs are cheap and have agoodsafetyprofile,understanding their role indevelopmentofautoimmunediseasescould be important for extending their therapeutic indications to include adjuvanttherapyofautoimmunediseases.

Thisworkwassupportedbyresearchgrant175050,MinistryofScience,Education

andTechnologicalDevelopment,RepublicofSerbia.

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SAVREMENATERAPIJAMULTIPLESKLEROZE‐OD

IMUNOMODULACIJEDOSELEKTIVNEIMUNEREKONSTITUCIJE

DraganaObradovićKlinikazaneurologiju,Vojnomedicinskaakademija,Beograd(Srbija)Multiplaskleroza(MS)jeimunološkiposredovanooboljenjecentralnognervnog

Sistema koje u u osnovi karakteriše inflamacija, demijelinizcija i progresivan gubitakaksona. Najčešće se javlja u dobi između 20. i 40. godine života i ukoliko se ne lečidovodi do teškog invaliditeta. Postoji globalni porast prevalence oboljevanja od MS,naročitouženskojpopulaciji,oboljevajučaktriputačešće.FaktoririzikazanastanakMS su pušenje, nizak nivo vitamin D3, gojaznost u dečijem dobu, infekcija EBV iprisustvo HLA DRB15 gena. Poslednjih dvadeset godina napravljen je ogromannapredak u lečenju MS i trenutno je na raspolaganju čak 18 različitih lekova.Istovremeno,dokazanojedaranaterapija,nasamompočetkubolesti,bitnomenjatokbolesti i značajnoodlažepojavuonesposobljenosti.Postoje imunomodulatorni lekovi:interferoni beta, glatiramer, dimetil fumarat i imunosupresivni lekovi – fingolimod,teriflunomid,kladribin,natalizumab,alemtuzumab,okrelizumabimitiksantronkojisedanas koriste u lečenju ove bolesti. Pojedini lekovi zahtevaju stalnu, kontinuiranuprimenu da bi se njihov pozitivan efekat održao, dok druga grupa lekova izazivakratkotrajnuimunosupresijusanaknadnomrekonstitucijomimunogsistemaiodrživimkilničkim efektom (kladribin i alemtuzumab, limfoablacija i autologa transplantacijamatičnih ćelija). Efekti terapije se odnose na redukciju broja relapsa,usporavanje/zaustavljanje razvoja onesposobljenosti, redukciju broja novihdemijelinizacionih lezija, zaustavljanje atrofije mozga i čak poboljšanje neurološkogstatusa. Osnovno pravilo u lečenju je da se lek bira prema karaktristikama samogpacijenta i prema karakteristikama njegove bolesti – aktivnosti i težine, tako dagovorimo o pravoj personalizovanoj terapiji. Vrlo je značajan monitoring tokomterapijepojedinimlekovima,obziromnamogućeneželjeneefekte.Potrebnesugodišnjeneurološke i MRI kontrole i u slučaju neefikasnosti leka, neophodna je promenaterapije, odnosno prelazak na efikasniji lek. Rani početak i adekvatan izbor leka suključnizadobrukontrolubolestiidobarkvalitetživotaobolelihodMS.

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CURRENTTHERAPYOFMULTIPLESCLEROSIS–FROMIMMUNOMODULATIONTOIMMUNERECONSTITUTION

DraganaObradović

DepartmentofNeurology,MilitaryMedicalAcademy,Belgrade(Serbia)Multiple sclerosis (MS) is immune mediated disease of the central nervous

system, characterized by inflammation, demyelination and progressive axonal loss.Peek incidence ofMS is between 20 and 40 year of life. There is global trend inMSprevalence increase, especially in female population,women being three timesmoreaffected.MSriskfactorsaresmoking,vitaminD3deficiency,EBVinfectionandobesityandHLADRB15presence.EnormousprogressinMStreatmentwasmadeinthelast20years, and 18 drugs are available at the moment. Early treatment, just after thediagnosisofMS,hasbeenproventomodifyMScourseandpostponedisability.Thereare two groups of drugs, immunomodulatory ones, such as: interferons beta,glatiramer, dimethyl fumarate and immunosuppressive ones, such as: fingolimod,teriflunomid,cladribin,natalizumab,alemtuzumab,ocerlizumabandmitoxantron.Theyhavedifferentmodeofactionanddifferentmodeofapplication.Someofthemneedtobe used continuously in order to maintain efficacy, while others cause short timeimmunosuppression, subsequent immune reconstitution and longer lasting clinicalbenefit.GoalsofMStreatmentsarerelapsereduction,slowingofdisability,reductionofnew demyelinated lesions and brain atrophy on MRI and even improvement ofneurologicalstatus.Today’sguidelinesrecommendselectionoftreatmentaccordingtopatientscharacteristicsandcharacteristics’ofthedisease(activityandseverity),whichmeanspersonalizedtreatment.Consideringpossibleadverseevents,regularfollow‐upis mandatory, specifically for some drugs (fingolimod, alemtuzumab, natalizumab).Yearly clinical and MRI follow‐up is strongly recommended and in case of lack oftreatment response, switching to more active therapy is obligatory. Early start andadequatechoiceofMSdrugarecrucialfordiseasecontrolandsatisfactoryqualityoflifeofMSpatients.

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SAVREMENIPRISTUPULEČENJUREUMATOIDNOGARTRITISA

MirjanaŠefikBukilicaInstitutzareumatologiju,UniverzitetuBeogradu‐Medicinskifakultet(Srbija)

Reumatoidni artritis (RA) je hronično, destruktivno, zapaljensko oboljenjeperifernihzglobova.DokrajaXXvekaterapijaRAseoslanjalanaupotrebulekovakojisu razvijeni empirijskim pristupom bez detaljnog razumevanja molekularnihmehanizama koji su od značaja za patogenezu bolesti. Međutim, poslednjih decenijasvedocismoeksplozijenašegrazumevanjazapaljenskogprocesaimolekularnihputevakojisuuključeniuRA.Tojedovelodonovogpristupaurazvojulekovakojijeomogućioprimenu ciljane terapije uperene direktno na molekule za koje se smatra da suuključeni u proces zapaljenja. Primena tehnologije za proizvodnju monoklonskihantitela u terapijske svrhe bila je glavni preduslov za razvoj biološke terapije. Prvibiološki lekovikojisuuvedeniuterapijuRAbilisu inhibitori faktoranekrozetumoraglavnog citokina uključenog u zapaljenski proces (TNF‐inhibitori). Terapijski uspehTNF‐inhibitora otvorio je vrata i za primenubioloških lekovauperenihprotiv drugihproinflamatornihcitokinakaoštosu IL‐6 i IL‐1.Terapijabiološkim lekovimaunela jerevoluciju u tretman RA, posebno kod bolesnika koji nisu imali dobar odgovor nakonvencionalne sintetske lekove koji menjaju tok bolesti, kao što je metotreksat.Tokom poslednjih nekoliko godina, pojavio se potpuno novi pravac razvoja anti‐zapaljenskihlekova.BrojnestudijesupokazaledajeJAK/STATsignalniputuključenupatogenezu i progresiju RA. Mnogi citokini koriste ovaj put za prenošenje signala uciljnu ćeliju.Jaki inhibitori su nas uveli u eru „malih molekula” koji imaju sličnuefikasnostkaobiološkilekovi.

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ADVANCESINTHETREATMENTOFRHEUMATOIDARTHRITIS

MirjanaŠefikBukilica

InstituteofRheumatology,UniversityofBelgrade‐FacultyofMedicine(Serbia)Rheumatoidarthritis(RA)isachronic,destructive,inflammatorydiseaseofthe

peripheraljoints.Untillateinthe20thcentury,thetherapyofRAreliedontheuseofdrugs that had been developed through empirical approaches without detailedunderstandingofthemolecularmechanismsinvolved.However,thelastdecadeshavewitnessed an explosion of our understanding of the inflammatory process and themolecularpathways involved inRA.This led toanewapproachofdrugdevelopmentwhereby targeted therapiesaredevelopedbydirectly targetingmolecules thought tobe involved in the inflammatory process. A major approach for the development oftargetedtherapeuticshasbeentheapplicationofmonoclonalantibodytechnologiesfortherapeuticpurposes.ThefirsttargetedtherapeuticsinRAwereantibodiesandrelatedmolecules interferingwith the functionof tumornecrosis factor‐α (TNF‐αorTNF), amajor cytokine involved in inflammatory process. The initial advance with anti‐TNFbiologic therapeutics opened up new avenues for targeting other proinflammatorytargets by biologic agents(IL‐6 and IL‐1). The treatment with biological drugs hasrevolutionized the therapeutic approach of RA, particularly in patients resistant tostandard treatment with conventional disease‐modifying antirheumatic drugs such asmethotrexate.During the last fewyears,anentirelydifferentdirection fordevelopingnovel anti‐inflammatory agents has emerged. Numerous studies have implicated theJanuskinase/signaltransducersandactivatorsoftranscription(JAK/STAT)pathwayinthepathogenesisandprogressionofRA.ManycytokinesinvolvedinthepathogenesisofRAuseJAKsandSTATstotransduceintracellularsignals.JAKinhibitorsintroducedusintheeraof'smallmolecules',whichhavesimilarefficacytothebiologictherapies.

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CARDIOPROTECTIONDURINGCANCERCHEMOTHERAPYWITHTHEUSEOFNATURALANTIOXIDANTS:REVIEWOFLITERATUREAND

RESULTSOFOWNSTUDIES

JolantaŁukowicz1,GrażynaPeszyńska‐Sularz1,AnitaPiasek2,StefanPopadiuk1,AgataKot‐Wasik2,MonikaJanicka2,

JacekNamieśnik2,WłodzimierzGrajek3,AgnieszkaBartoszek1

1ChemicalFaculty,GdanskUniversityofTechnology,2MedicalUniversityofGdansk,3UniversityofNaturalSciences,Poznan(Poland)

Cardiotoxicity is a frequent side effect occurring during cancer chemotherapy,often responsible for long term heart failure in surviving cancer patients. Theabnormalities range from small changes in blood pressure and arrhythmias tocardiomyopathy.Thistypeoftoxicityhasbeenmostwidelyinvestigatedinthecaseofanthracyclines, doxorubicin (DOX) inparticular, the effective anticancerdrugswhoseclinical use is limited by cumulative dose‐dependent injury to cardiac tissue, oftenjeopardizingpatients’lifedespitesuccessfulcancereradication.ThoughbestdescribedforDOX, cardiotoxicityas a side effecthasbeenobservedduring chemotherapywithmajority of antineoplastic agents displaying different mechanisms of action:mitoxantrone (cardiomyopathy), fluorouracil (myocardial infraction),cyclophosphamide and vinca alkaloids (cardiac necrosis), trastuzumab (cardiacdisfunction),imatinibmesylate(congestiveheartfailure).

Thecardiotoxicityofanthracyclines,atleastinpart,isattributedtotheirabilityto redox cyclewithmolecular oxygen leading to the formation of superoxide radicalthat initiates cascade of reactive oxygen and nitrogen species. It has therefore beensuggested that some phytochemicals with high antioxidant potential, whenadministeredtogetherwithDOX(andperhapsotherantitumoragents),coulddecreasethe toxic side effects of chemotherapy and reduce the risk of heart failure.Cardioprotective properties have been shown for preparations obtained from suchfoods as grapes, garlic, tomato, spinach, as well as for melatonin (a hormonesynthesized by the pineal gland, but also present in many edible plants), chalcones(precursorsofallknownflavonoids),someherbaldietarysupplementsandvitaminsA,C, and E. However, in the majority of these studies natural antioxidants wereadministeredi.v., thus inawaytypical forpharmacologicalapproach. Incontrast,ourstudiesweredesignedsoas torepresent trulynutritionalapproach inwhichanimalsundergoing chemotherapywere fed thediet enriched in a particular food item– redbeetroot (Beta vulgaris) juice (RBJ). In these experiments, we checked whether thedietary interventionwithRBJmight have any impact on therapeutic efficacy ofDOX.Forthispurpose,leukaemiaL1210bearingmiceweretreatedwithDOXandfedRBJad

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libitum (instead of water) for 7 or 14 days. DOX was very effective in prolongingsurvival time of leukaemia bearingmice (ILS about 400%).However, only in groupsreceiving DOX in combination with RBJ total cures were observed. These were notsporadiceventsbutconcernedabout50%ofanimals.

In accompanying experiments, healthy or leukaemia L1210bearingmicewerefedRBJadlibituminsteadofwaterfor7daysandthenweretreatedwithDOXappliedindifferent schemes.Controlmice receivedwater todrink.Fromcontroland treatedmice,bloodsandheartswerecollectedandanalysedforvariousmarkersofoxidativeinsult. In mice fed with RBJ prior to DOX treatment, the damage of DNA incardiomyocytes and the content of isoprostanes in blood were decreased indicatingmarkedprotectionofferedbytheemployeddietaryintervention.AsRBJonitsownhadno antitumor effect, one can speculate that the improved outcome of chemotherapyresulted from reduced cardiotoxicity. Our research suggests then that appropriatelydesigneddietaryinterventionmayofferveryconsiderablebenefitstocancerpatients.

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VITAMINDIRIZIKZANASTANAKMALIGNIHBOLESTI

AleksandraZeljković

Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐Farmaceutski

fakultet(Srbija)Savremeno razumevanje značaja koji vitamin D ima u humanom organizmu

prevazilazi njegovu dobro poznatu ulogu regulatorametabolizma kalcijuma i fosfata.Prva istraživanja započela su pre više od 80 godina sa postavljanjem hipoteze kojapovezuje nisku izloženost sunčevom zračenju sa povećanom incidencom različitihtipova kancera. S obziromda koncentracija vitaminaD direktno zavisi od izloženostiUVB zracima, predložena je potencijalna protektivna uloga ovog vitamina ukancerogenezi.

BiološkiefektiaktivnogoblikavitaminaD‐kalcitriolaostvarujusevezivanjemzaodgovarajuće receptore u jedru ciljnih ćelija i prevashodno se odnose na regulacijuhomeostazekalcijumaifosfata.Međutim,danasseznadaosimklasičnogmetaboličkogputa postoji i alternativni mehanizam u kojem ključnu ulogu ima hidroksilacija napoložajima C‐20 i C‐22, pod uticajem enzima CYP11A1. Utvrđeno je da 20‐hidroksimetaboliti imaju jednak, ili čak i veći kapacitet delovanja u odnosu na kalcitriol.Istraživanja su pokazala da vitamin D ostvaruje protektivne efekte u svim fazamarazvoja tumora: od inicijacije do pojave metastaza. Predloženi mehanizmi uključujuuticaj na proliferaciju, diferencijaciju, apoptozu, autofagiju i epitelno‐mezenhimnutranziciju ćelija. Osim toga, smatra se da vitamin D učestvuje u modulacijimikrookruženja tumora, delujući na angiogenezu, redoks status, inflamaciju i imuniodgovor.Međutim,mnogapitanjasujošuvekotvorena.OnasepresvegatičuadekvatneprocenestatusavitaminaDuorganizmu,kaoimogućnostiterapijskeprimenerazličitihmetabolita.

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VITAMINDANDRISKFORCANCERDEVELOPMENT

AleksandraZeljković

DepartmentofMedicalBiochemistry,UniversityofBelgrade‐Facultyof

Pharmacy(Serbia)ContemporaryunderstandingoftheroleofvitaminDinthehumanbodylargely

exceeds a traditional perception of this vitamin as a regulator of calcium andphosphate. Eighty years ago, preliminary researches pointed toward the associationbetween low exposure to sunlight and increased incidence of differentmalignancies.GiventhattheconcentrationofvitaminDdirectlydependsonexposuretoUVBlights,thepotentialprotectiveroleofthisvitaminintumorigenesisisproposed.

Biological effects of the active metabolite ‐ calcitriol are achieved throughbinding to the corresponding receptors in the nuclei of the target cells and arepredominantly related to the regulation of calcium and phosphate homeostasis.However,itisrevealedthatthereisanalternativemetabolicpathwaycharacterizedbythe CYP11A1 – driven hydroxylation of vitamin D at C‐20 and C‐22. It has beendemonstrated that20‐hydroxymetaboliteshave thesame,orevenhighercapacityofaction, compared to calcitriol. Vitamin D exhibits beneficial effects at all stages ofcancerogenesis: from the initiation to the onset of metastases. The proposedmechanismsincludemodulationofproliferation,differentiation,apoptosis,autophagy,andepithelial‐mesenchymalcelltransitions.Inaddition,itisconsideredthatvitaminDprovokes changes of tumor microenvironment, by modifying angiogenesis, redoxstatus, inflammationand immuneresponse.However,numerous issuesarestillopen.Inparticular,adequateassessmentsofvitaminDstatus,aswellaspossibilities for itstherapeuticusearestillunderdebate.

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PRIMENATUMORSKIHMARKERAUKLINIČKOJPRAKSII

PERSONALIZOVANOJMEDICINI

SvetlanaIgnjatović

Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐FarmaceutskifakultetiCentarzamedicinskubiohemiju,KliničkicentarSrbije(Srbija)Cirkulisuci tumorskimarkeri (TM)ukrvi idrugimtelesnimtecnostimaklinicki

se koriste vec vise od 50 godina sa izvesnim uspehom i predstavljaju osnovni deomenadžmenta pacijentima sa kancerom, a takođe su uključeni u veći broj kliničkihvodiča. TM se lako mere u uzorcima seruma/plazme i drugim telesnim tečnostima,rezultati su brzo dostupni, a pripadajući troškovi su relativno mali. Iako TM nisudijagnostički za kancer, postoji mnogo TM koji su prilično specifični za određenekancere ‐ na primer, AFP i hCG kod tumora germinativnih celija, kalcitonin umedularnom kanceru tiroidne žlezde, PSA kod kancera prostate i imunoglobulini ulimfomuimultiplommijelomu.KorišćenjeTMumenadžmentupacijenatasasolidnimtumorima ima nekoliko utvrđenih indikacija za upotrebu kod kancera germinativnihcelija, prostate, jajnika i pankreasa, kao i kolorektalnog, hepatocelularnog ineuroendokrinogkancera.TMsukorisnialatiudiferencijalnojdijagnozi,određivanjufaze/prognozi, praćenju tretmana, pracenju nadzora i rekurencije pacijenata sakancerom.NedavnaistrazivanjapokazalasupoboljsanjedijagnostickihperformansiTMukolikosekoristikombinacijaviseTMkaopanelzaprocenu(npr.kombinovanipanelod sest serumskih TM za karcinom pluca), serijsko merenje ili procena TM uodređenom vremenskom periodu. Napredak u molekularnoj i celijskoj biologiji uprotekloj deceniji doveli su do uvođenja novih dijagnostickih alata u onkologiji kojamere celijsku DNK, cirkulisuce tumorske celije, egzozome, mikroRNK, vancelijskevezikuleilirazjašnjavajumolekularnedogađajekanceranapojedinačnompacijentu,štodovodi do promene paradigme u načinu na koji se razvijaju antikancer terapije ipacijentisebirajuzaspecifičneciljaneterapije.Optimalanmenadzmentpacijentimasakancerom u buducnosti ce integrisati nove i uspostavljene alate, ukljucujuci i„tradicionalne"TMkaotestprvelinijekakobisenaodgovarajucinacinpokrenulodaljaobradaiinvazivnijadijagnostika.

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APPLICATIONOFTUMORMARKERSINCLINICALPRACTICEANDPERSONALIZEDMEDICINE

SvetlanaIgnjatović

DepartmentofMedicalBiochemistry,UniversityofBelgrade‐FacultyofPharmacyandCenterforMedicalBiochemistry,ClinicalCentreofSerbia

(Serbia)Circulatingtumormarkers(TMs)inbloodandotherbodyfluidshavebeenused

clinicallyforover50yearswithsomesuccessandhavebecomeanestablishedpartofmanagementofcancerpatientsandarealsoincludedinanumberofclinicalguidelines.TMsareeasilymeasured inserum/plasmasamplesandotherbodyfluids, theresultsarerapidlyavailable,andtheassociatedcostsarerelativelylow.AlthoughTMsarenotdiagnosticforcancer,therearemanyTMsthatarequitespecificforcertaincancers‐‐forexample,AFPandhCGingermcelltumors,calcitonininmedullarythyroidcancer,PSAinprostaticcancer,andimmunoglobulinsinlymphomaandmultiplemyeloma.Theuseof TMs in the management of patients with solid tumors has several establishedindications for use in germ cell, prostate, ovarian and pancreatic cancers, colorectal,hepatocellular, and neuroendocrine cancers. TMs are useful tools in differentialdiagnosis, staging/prognosis, treatment monitoring, surveillance and recurrencemonitoring of cancer patients. Recent research has shown improvement diagnosticperformance of TMs using a combination ofmultiple TMs as a panel for assessment(e.g.,combinedpanelofsixserumTMsforlungcancer),serialmeasurementorassesstheTMtrendoverdefinedperiodof time.Advances inmolecularandcellularbiologyoverthepastdecadehaveledtotheintroductionofnoveldiagnostictoolsinoncologywhich measure cell‐free DNA, circulating tumor cells, exosomes, microRNAs,extracellular vesicles or elucidate themolecular events of tumors on a single patientlevel, leading to a paradigm shift in how antitumor therapies are developed andpatientsareselectedforspecifictargetedtherapies.Theoptimalmanagementofcancerpatientsinfuturewillintegratenovelandestablishedtools,including„traditional”TMsas a first‐line test to appropriately trigger further workup and more invasivediagnostics.

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ENERGETSKIBALANSIULOGAADIPOCITOKINAUPATOGENEZI

MALIGNIHBOLESTI

AleksandraStefanović

Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Prevalenca malignih bolesti poslednjih decenija je u stalnom porastu. U našoj

zemlji maligne bolesti su odgovorne za oko 20% ukupne smrtnosti i nalaze se nadrugommestu, izabolestisrcaikrvnihsudova.Etiologijamalignihbolesti jesloženaitemeljise,kakonagenetskimčiniocima,takoinaživotnimnavikamapojedinaca.Jedanodfaktorarizikakojisepovezujesarazvojem,kaoilošomprognozommalignihbolestijeste gojaznost. Gojaznost poprima karakteristike masovne metaboličke bolesti saozbiljnimposledicamanaopštezdravstvenostanjepopulacije.Rezultativelikogbrojastudija su nedvosmisleno doveli u vezu gojaznost sa umerenim rizikom za razvojkolorektalnog karcinoma, karcinoma endometrijuma, bubrega, pankreasa ipostmenopauzalnog karcinoma dojke. Hipertrofija adipoznog tkiva u gojaznostikarakteriše se hroničnom inflamacijom niskog stepena. Adipociti i makrofageadipoznog tkiva sekretuju peptide, adipocitokine, od kojih su se posebnoproinflamatorni adipocitokini [faktor nekroze tumora α (TNF –α), leptin, rezistin,interleukin 6 (IL‐6), inhibitor aktivatora plazminogena tip 1 (PAI‐1)] pokazaliznačajnim molekularnim medijatorima složenih patofizioloških puteva kako razvoja,tako i progresije malignih bolesti. Kod razvoja i progresije tumora dojke, bubrega,jajnika, kao i kod kolorektalnog karcinoma poseban značaj ima činjenica da se ovitumorirazvijajuokruženimasnimtkivom.Tokommolekularnihinterakcijaadipocitasamalignim ćelijama dolazi do promena samih adipocita koji tako izmenjeni sekretujuadipocitokine koji stimulišu adheziju,migraciju i invazijumalignih ćelija. Takođe, oviizmenjeni adipociti lipolizom oslobađaju slobodnemasne kiseline kojemaligne ćelijekoriste kao značajan izvor energije čime se podstiče progresija i nekontrolisani rasttumora.Razumevanje složenihmehanizamakojimadipozno tkivoutičenanastanak irazvoj malignih bolesti može dovesti do razvoja potencijalnih novih terapijskihpristupamalignimbolestima.

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ENERGYBALANCEANDADIPOCYTOKINESINCANCERPATHOGENESIS

AleksandraStefanović

DepartmentofMedicalBiochemistry,UniversityofBelgrade‐Facultyof

Pharmacy(Serbia)Over the recentdecade, thecancerprevalence ratehasbeen increasing. Inour

country, cancers are responsible for about 20% of total mortality, right behindcardiovascular disease. Etiology of malignant changes in tissue is complex and it isbasedongenetic,aswellasenvironmentalfactors.Obesityisoneoftheimportantriskfactors connected with the development and bad prognosis for some cancers.According to the results of the great number of studies, obesity is associated withincreasedriskofdevelopingcolorectal,endometrial,renalandpostmenopausalbreastcancer. Actually, hypertrophy of adipose tissue in obesity is followed by low gradeinflammation processes. Proinflammatory adipocytokines [tumor necrosis factor α(TNF‐α), leptin, rezisitin, interleukin6 (IL‐6),plasminogenactivatorinhibitor1 (PAI ‐1)] secreted by adipocytes and macrophages are significant molecular mediators ofcomplex pathophysiological pathways involved in cancer initiation and progression.During the initiation and progression of some tumor types (breast, renal, ovarian,colon) it is important tonotice that tumorgrow in specific vicinityof adipose tissue.Interactions between cancer cells and adipose tissue lead to specific adipocyteschanges. They become cancer‐associated adipocytes which are important sources ofspecificadipocytokineswhichstimulatetheadhesion,migrationandinvasionofcancercells.Also,cancer‐associatedadipocytesensurefattyacidsbylipolysis,andthesefattyacidsbecomeimportantenergysourcefortumorprogressionanduncontrolledgrowth.Understanding the complex mechanisms of interaction between adipose tissue andcancer cells is the possible course of the development of potential new therapeuticapproachesfortreatmentofmalignantdiseases.

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Arh.farm 2018;68: 141-142 PP21 KADMIJUMKAOFAKTORRIZIKAZARAZVOJKARCINOMA

PANKREASA:PODACIIZSTUDIJENALJUDIMA,EKSPERIMENTALNIMŽIVOTINJAMAIĆELIJSKIMKULTURAMA

AleksandraBuhaĐorđević1,VesnaMatović1,NovicaBoričić2,DejanRadenković3,VladimirĐorđević3,DavidWallace4

1Katedrazatoksikologiju„AkademikDaniloSoldatović”,Univerzitetu

Beogradu‐Farmaceutskifakultet,2Institutzapatologiju,UniverzitetuBeogradu‐Medicinskifakultet,3Prvahirurškakilnika,KliničkicentarSrbije,Beograd(Srbija),4Katedrazafarmakologijuitoksikologiju,OklahomaStateUniversity

CenterforHealthSciencesTulsa,Oklahoma(SAD)Iako intenzivnoproučavana, etiologija karcinomapankreasa i dalje predstavlja

nepoznanicu. Neki od utvrđenih faktora rizika ovog oboljenja (poput godina starosti,pušenja)povezani su sapovećanimnivoimakadmijuma (Cd)uorganizmu.Kakoovajtoksičnimetal danas predstavlja jednog od najprisutnijih zagađivača životne i radnesredine,svejevišestudijakojeispitujunjegovuuloguunastankukarcinomapankreasa.Cilj ovog rada bio je da istraži potencijalnu ulogu Cd u nastanku ovog oboljenja i tosprovođenjemopservacionehumane,eksperimentalneiinvitrostudije.

Prospektivnastudija slučajaobuhvatila je31pacijenta sahistološkibaziranomdijagnozom karcinoma pankreasa podvrgnutih radikalnoj hirurškoj intervenciji(slučajevi) i 29 slučajnih smrtnih ishoda ili subjekata čije smrti nisu bile posledicekarcinoma(kontrole).

EksperimentalnastudijaobuhvatilajedvetretiranegrupeWistarpacova(15i30mg/kg t.m.) i netretiranu kontrolnu grupu, žrtvovane 24 sata nakon jednokratnogoralnog izlaganja. Nivoi Cd u mineralizovanim pankreasnim tkivima određeni suatomskom apsorpcionom spektrofotometrijom sa grafitnom kivetom. In vitro studijavršenajenahTERT‐HPNEpankreasnimćelijamaizloženimrazličitimkoncentracijamaCd, koje odgovaraju nivoima Cd izmerenim u ljudskom karcinomskom pankreasnomtkivu,iispitivanajeaktivnostenzimakaspazeinivooksidativnogstresa.

Sadržaj Cd u tkivu karcinoma značajno se razlikovao od sadržaja u zdravimkontrolama. Neočekivano visoke koncentracije Cd (1,27‐18,64 μg/g) izmerene su ukarcinomskom tkivu u poređenju sa kontrolnim (0,27‐2,50 μg/g). Odnosi šansi zarazvojkarcinomapankreasabilisu2.79(95%IP0.91‐8.50)i3.44(95%IP1.19‐9.95)utrećem i četvrtom kvartilu distribucije Cd. Eksperimentalna studija potvrdila je tkivopankreasa kao mesto deponovanja Cd u organizmu. In vitro studija ukazala je naznačajnosmanjenjeaktivnostikaspaza3/7pri izlaganjunajvišimkoncentracijamaCd,tepovećanjeoksidativnog stresakoje jebilo izraženijepri višimkoncentracijamaCd.Ovo istraživanjedajetri linijedokazakojiupućujunaCdkaofaktorrizikaunastankukarcinomapankreasa.

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CADMIUMASARISKFACTORFORPANCREATICCANCERDEVELOPMENT:HUMAN,ANIMALANDINVITRODATA

AleksandraBuhaĐorđević1,VesnaMatović1,NovicaBoričić2,DejanRadenković3,VladimirĐorđević3,DavidWallace4

1DepartmentofToxicology„AkademikDaniloSoldatović”,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofPathology,Universityof

Belgrade‐SchoolofMedicine,3FirstSurgicalClinic,ClinicalCenterofSerbia,Belgrade(Serbia),4DepartmentofPharmacology&Toxicology,OklahomaState

UniversityCenterforHealthSciencesTulsa,Oklahoma(USA)Although profoundly studied, etiology of pancreatic cancer (PC) is still rather

scarce.Someofestablishedrisk factorsofPCareconnectedtoan increasedcadmium(Cd)bodyburden(age,smoking,etc).Thistoxicmetalisnowadaysregardedasoneofthemost abundant occupational and environmental pollutants. Hence, an increasingnumberofstudiesareinvestigatingitsroleinPCandthedataissomewhatconflicting.The aim of this study was to investigate Cd possible role in PC development byconductinghumanobservational,experimentalandinvitrostudies.

The case‐control prospective study included 31 patients with a histologicallybased diagnosis of PC subjected to radical surgical intervention as cases and 29accidentalfatalitiesorsubjectswhodiedofanonmalignantillnessascontrols.Animalstudy included two treated groups of Wistar rats (15 and 30 mg Cd/kg b.w) anduntreated control group, sacrificed 24 hours after single oral exposure. Cadmiumcontent in digested pancreatic tissues was assessed by GFAAS. In in vitro studypancreas hTERT‐HPNE cells were exposed to different Cd concentrationscorrespondingto levelsmeasured inhumancancerouspancreatic tissueandoxidativestressandcaspaseactivityweredetermined.

Cd content in cancer tissue significantly differed from the content in healthycontrols. Unexpectedly high Cd concentrations (1.27‐18.64μg/g) were found incancerous tissue in comparison to controls (0.27‐2.50μg/g). Odds ratio levels for PCdevelopmentwere2.79(95%CL0.91‐8.50)and3.44(95%CL1.19‐9.95) inthethirdand fourth quartiles of Cd distribution, respectively. Animal study confirmed Cddeposition in pancreatic tissue. Exposure of hTERT‐HPNE cells to highest Cdconcentrationresulted insignificantreduction incaspase3/7activitywhileobservedincrease in oxidative stress was concentration dependent. This study presents threedifferent lines of evidence pointing towards Cd as an agent responsible for thedevelopmentofPC.

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OLIVEBIOACTIVECOMPOUNDS:CHEMISTRYANDPHARMACOLOGY

ApostolisAngelis,LeandrosA.Skaltsounis

DepartmentofPharmacognosy&NaturalProductsChemistry,Facultyof

Pharmacy,UniversityofAthens(Greece)The olive tree, closely connected to the Mediterranean region has provided a

wealthofgoods.Researchontheolivehasstartedearlybutithasproveninexhaustiblerevealingmainlyavastarrayofnutritionalandhealthproperties.Apartfromoliveoiland table olives, the by‐products coming from olive processing industry have beenprovenattractivematerialsforresearch.Theaimofthiscommunicationistopresentaholistic research strategy towards the multifaceted exploitation of the olive treeincluding activities such as extraction, fractionation, isolation, analysis of olive treeproductsaswellasinvestigationofprocessesrelatedtooliveindustryandvalorizationofby‐products.Themainproductsoftheolivetree,oliveoilandtableolivesaswellasby‐products such as leaves, paste,millwastes and table olivewastewater have beenused as sources for the recovery of valuable secondary metabolites. This has beenperformedwith conventional techniques and also by adsorptive resin technology. Inadditionstandardizedenrichedfractionshavebeenpreparedwithvarioustechniques,suchasMPLC,HPLC,andCCC.Isolationofpromisingleadcompoundswithemphasistoolivepolyphenololeuropein(leaves),hydroxytyrosol&tyrosol(oliveoil,by‐products),oleacein & oleocanthal (olive oil) and lactones (by‐products), has been achieved.Additionally advanced analytical techniques and methodologies (UPLC/HPLC‐DAD,HPLC‐DAD‐HR/MSn,andHPTLC)havebeendevelopedandappliedforthequalitativeand quantitative determination of secondarymetabolites in all the abovementionedmaterials.The labscaleprocesseshavebeenalsoadapted topilotscale systems.Thebiological profile and the therapeutic potential of olive extracts and compounds isexplored and supported by several in vitro and in vivo studies while their possibleapplicationasnutraceuticals,dietarysupplementsandcosmeticsisalsoinvestigated.

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HERBACITRALNOGHEMOTIPAPANONSKOGTIMIJANAKAO

POTENCIJALNONOVABILJNALEKOVITASIROVINA

ZoranMaksimović

Katedrazafarmakognoziju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Panonski timijan (Thymus pannonicus All. Lamiaceae) je rasprostranjen u srednjoj i

istočnoj Evropi na sušnim livadama i kamenjarima. U Srbiji raste pretežno u Vojvodini.Literaturni podaci ukazuju na značajne razlike u sastavu etarskog ulja samoniklog panonskogtimijana. Potvrđeno je postojanje hemotipova; npr. timolnog i citralnog. Stabilna populacijacitralnoghemotipalociranajeuSrbijisamonaVršačkimplaninama.Herbaovoghemotipase,ujužnomBanatu,koristizapripremanječajnognapitkaspecifičnogiprijatnogmirisakojipodsećana limun,ali iprotivnekihrespiratornihidigestivnihoboljenja.Ovojebio iosnovzadetaljnijeispitivanjeovebiljnevrstesapodručjaVršačkihplanina.

Hromatografskom analizom (GC FID/MS; HPLC), ispitivana je polimorfnost samoniklihpopulacija citralnog hemotipa panonskog timijana i procenjivan uticaj ekoloških faktora nanjihove morfološke, anatomske i hemijske karakteristike. Testirana je antimikrobna,antioksidantna,antitumorskaihepatoprotekivnaaktivnost.Izvedenisuoglediplanskoggajenjaiodabrane linije sa poželjnim osobinama. Utvrđeni su parametri kvaliteta herbe panonskogtimijana,kaonovebiljnesirovine.

Rezultati ukazuju da se panonski timijan sa Vršačkih planina može smatrati dobrimizvorombiljnesirovinebogatecitralom.Najvažnijisastojcipolarnihekstrakataherbesamoniklogpanonskogtimijanabilesufenolskekiseline(rozmarinska,salvianolna)iflavonoidi(glukuronidiluteolina i apigenina). Vodeni ekstrakt je ispoljio umereni antioksidantni efekat in vivo, uzznačajno smanjenje intenziteta lipidne peroksidacije i održavanje fizioloških koncentracijaglutationa. Prema ćelijama Erlihovog ascitnog tumora kod miša, vodeni ekstrakt je delovaocitotoksično, ispoljivši prooksidantni efekat kojim je indukovana apoptoza. Uočena je značajnaantimikrobnaaktivnostprematestiranimmikroorganizmima,anaročitopremaCandidaalbicans.Etarsko ulje i metanolni ekstrakt ispoljili su izuzetnu inhibitornu aktivnost prema kliničkimizolatima Helicobacter pylori rezistentnim na metronidazol i klaritromicin. Oplemenjivanjem,dobijenajesortaželjenihtehnološkihsvojstavakojadajevećiprinosbiljnemase,većiistabilnijisadržajetarskoguljauodnosunasamoniklubiljku.

CitralnihemotippanonskogtimijanasepokazaokaoizdašanbiološkiizvordrogeThymipannonici herba. Zahvaljujući visokom sadržaju polifenolnih jedinjenja i etarskog ulja bogatogcitralom, kao i ispoljenoj antioksidantnoj, antimikrobnoj i antitumorskoj aktivnosti, onapredstavlja potencijalno novu biljnu lekovitu sirovinu, koja bi se mogla primenjivati usavremenojfitoterapiji.

Istraživanje je podržaloMinistarstvo prosvete, nauke i tehnološkog razvoja (Projekat TR

31089ION173021).

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THEHERBOFPANNONIANTHYMECITRALCHEMOTYPEASPOTENTIALLYNEWHERBALRAWMATERIALWITHMEDICINAL

PROPERTIES

ZoranMaksimović DepartmentofPharmacognosy,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)

Panonianthyme(ThymuspannonicusAll.Lamiaceae)isdistributedincentralandeastern

Europe,overdrymeadows,grasslandsandrocks.InSerbia,itcanbefoundmostlyinVojvodinaprovince.Referencedatarevealshighvariability inthecompositionofwild‐growingpannonianthyme. A number of chemotypes (e.g. thymol and citral) were confirmed. In Serbia, a stablepopulationof citral chemotypehasbeen foundatMt.Vršačkeplanineonly. In southernBanat,driedherbofthischemotypeisusedtomaketastyandrefreshingherbalteaswithpeculiarandpleasant lemon‐like scent; also, against some respiratory and gastrointestinal disorders. Thisprovided the ground for further and detailed investigations on this plant species from Mt.Vršačkeplanine.

Bychromatographicanalysis(GCFID/MS;HPLC),polymorphismwithinwildpopulationsof this species was studied, as well as dominant ecological factors that influenced theirmorphologic, anatomic and chemical properties. Antimicrobial, antioxidant, antitumour andhepatoprotective activity were also tested. Planned cultivation was attempted and lines withdesirable traitswerechosen.Parametersofquality forpannonian thymeherbasanewherbalrawmaterialweredefined.

TheresultsindicatethatpannonianthymefromMt.Vršačkeplaninecouldbeconsideredasaplenifulsourceofherbalrawmaterialrichincitral.Principalconstituentsofpolarextractsofwild growing pannonian thyme were phenolic acids (rosmarinic, salvianolic) and flavonoids(luteolinandapigeninglucuronides).Aqueousextractexpressedmoderateantioxidanteffect invivo, along with a significant decrease of lipid peroxidation intensity and preservation ofphysiological levels of glutathione.AgainstEhrlich ascites tumor cells inmice, aqueous extractexpressed significant cytotoxic activity, through prooxidant effect that induced apoptosis.Significant antimicrobial activity against tested microorganisms was observed; in particular,againstCandida albicans.Essentialoil andmethanolic extract expressed remarkable inhibitoryactivity against clinical strains of Helicobacter pylori resistant to metronidazol andclaritromycine. Finally, a variety with desired technological characteristics was bred, yieldingsuperior biomass quantity, as well as higher and more stabile essential oil contents incomparisontowild‐growingplants.

PannonianthymecitralchemotypeappearedtobeaplentifulbiologicalsourceofherbalsubstanceThymipannoniciherba.Owingtohighcontentsofpolyphenolsandessentialoilrichincitral,aswellastoexpressedantioxidant,antimicrobialandantitumoractivity,itisapotentiallynewherbalrawmaterialthatcouldbeusedincontemporaryphytotherapy.

The study was supported by the Ministry of Education, Science and Technological

Development(ProjectsON173021andON173021).

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PROCENAFARMAKOLOŠKEAKTIVNOSTIODABRANIHVRSTA

FAMILIJEERICACEAE

DraganaPavlovićKatedrazafarmaciju,UniverzitetuNišu‐Medicinskifakultet(Srbija)Pored vrste Arctostaphylos uva‐ursi, najpoznatijeg predstavnika familije

Ericaceae,idrugevrsteovefamilijesepominjuutradicionalnojmedicini.CiljstudijejeprocenaipoređenjefarmakološkeaktivnostipetvrstafamilijeEricaceaesaBalkanskogpoluostrva:ArbutusunedoL.,Bruckenthaliaspiculifolia,Callunavulgaris,EricaarboreaiEricacarnea.

Farmakološko ispitivanje suvih etanolnih ekstrakata je uključilo procenuantioksidativne, antimikrobne, antiiritantne, spazmolitičke i antiinflamatorneaktivnosti.Sviuzorcisuispoljiliodličnuantioksidativnuaktivnostu4komplementarnatestsistema.NajvećusposobnostuklanjanjaslobodnihradikalairedukcijejonagvožđasupokazaliekstraktiA.unedo(verovatnousledprisustvaarbutinakojinijedetektovanu ostalim uzorcima), dok je ekstrakt herbe vrste B. spiculifolia bio najjači inhibitorlipidne peroksidacije. Antimikrobna aktivnost ispitivana na 10 bakterijskih sojeva jebilaveomaslaba.Hidrogeloviformulisanisapo2%jednogodispitivanihekstrakatasuispoljili pozitivne efekte na kožu dobrovoljaca. Svi uzorci su značajno snižavali nivoiritacijeivraćalipHinivohidriranostikoženavrednostipreiritacije.EkstraktvrsteA.unedo pokazuje značajnu spazmolitičku aktivnost, posredovanu inhibicijomkalcijumovihkanala,pričemujeekstrakt listovasakupljenihuGrčkoj ispoljiosnažnijiefekat od listova sakupljenih u Crnoj Gori. Ekstrakt vrste B. spiculifolia (0.001–0.3mg/ml)opuštaspontaneiindukovanekontrakcijeizolovanogileumaidistalnogkolona,dok inhibicija kontraktilnosti fundusa, duodenuma, jejunuma i proksimalnog kolonanijestatističkiznačajna.EfektiekstraktavrsteB. spiculifolia (50,100 i200mg/kgperos) u karageninom‐indukovanom edemu šapice pacova su značajni, dozno‐zavisni iuporedivi sa efektima indometacina (4mg/kgper os). Etilacetatna frakcija i etanolniekstrakt herbe su ispoljile najsnažnije antioksidativno i antiinflamatorno dejstvo odtestiranihetanolnihekstrakatarazličitihorganavrsteB.spiculifolia(koren,list,herbaicvet) i frakcija metanolnog ekstrakta njene herbe. Rezultati izvedenih istraživanjaukazali su da je B. spiculifolia ispoljila odlične efekte u sprovedenim farmakološkimtestovima.

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PHARMACOLOGICALSCREENINGOFSELECTEDSPECIESFROMERICACEAEFAMILY

DraganaPavlović

DepartmentofPharmacy,UniversityofNiš‐FacultyofMedicine(Serbia)Beside Arctostaphylos uva‐ursi, the famous member of the Ericaceae family,

other species of this family are alsomentioned in traditionalmedicine. The presentstudyestimatesandcomparespharmacologicalactivityoffiveEricaceaespeciesnativetoBalkanPeninsula: Arbutus unedo, Bruckenthaliaspiculifolia, Calluna vulgaris, EricaarboreaandEricacarnea.

Pharmacological screaning of dry ethanol extracts inculded the studies ofantioxidant, antimicrobial, antiiritant, spasmolytical andantiinflamatory activity. Allsamplesexertedexcellentantioxidanteffectsinfourcomplamentarytestsystems.Thehighestscavengingactivityandferi‐ionreductionwereobtainedwithA.unedoextracts(probably due to the presence of arbutin, which is absent in other samples). B.spiculifolia herb extract was the most potent inhibitor of lipid peroxidation.Antimicrobial activity against 10 tested strains of bacteria was generallyweak.Hydrogels, each containing 2 % of one investigated extract, showed positiveeffectsonthehumanskin.Allsamplessignificantlydecreasedtheskin irritation levelandreversedthepHoftheskindisturbedbypre‐irritationalongsidewithitshydration.A. unedo extracts showed significant spasmolytic activity (mediated through calciumchannel inhibition) in isolated rat ileum,with stronger effects of extract from leavescollected in Greece. B. spiculifolia extract (concentration range 0.001–0.3 mg/ml)decreasedspontaneousandinducedcontractionsofileumanddistalcolonwhiletherewere no statistically significant inhibition of contractions of fundus, duodenum,jejunumandproximalcolon.B.spiculifoliaextract(50,100and200mg/kg/dayperos)showedsignificantanddose–dependentactivitycomparabletothatofindomethacin(4mg/kgperos)incarrageenan‐inducedratpawoedemamodel.Ehylacetatfractionandethanolextractofherbdemonstratedthestrongestantioxidantandanti‐inflammatoryactivities among tested ethanol extracts of different B. spiculifolia organs (root, leaf,herb and flower) and fractions of methanol extract of its herb. The results of theperformed studies indicated that B. spiculifolia exhibited very good effects in theconductedpharmacologicaltests.

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NOVIJEINFORMACIJEOLEKOVITOMPOTENCIJALUVRSTARODA

HYPERICUM

NebojšaKladar,NedaGavarić,BiljanaBožin

Katedrazafarmaciju,UniverzitetuNovomSadu‐Medicinskifakultet(Srbija)Rod Hypericum obuhvata više od 500 vrsta klasifikovanih u 36 filogenetskih

sekcija. Tokom istorije, ali i u današnje vreme kantarion (Hypericum perforatum,Hypericaceae) je najčešće proučavan predstavnik roda. Međutim, u poslednje tridecenijezabeležen jeporast istraživačkog interesovanja izaostalepredstavnikerodaHypericum.UzimajućiuobziraktivneprincipeH.perforatumkojiuključujujedinjenjaizklasanaftodiantrona,floroglucinola,fenola,flavonoida,biflavonoidaiksantona,možesezaključitidapredstavnicifilogenteskimlađihsekcijarodapokazujuznačajanstepensličnosti u pogledu kvalitativnog hemijskog profila, dok je sadržaj određenihkomponenti izuzetnopodložanvarijacijama.Međutim,poreduočenihsličnosti izmeđurazličitih vrsta u pogledu hemijskog sastava, ne smeju se zanemariti nove izolovanekomponente iz različitih predstavnika sa obećavajućim biološkim potencijalom.Generalno, veliki broj vrsta roda Hypericum je okarakterisan visokim sadržajemfenolnih i flavonoidnih jedinjenja, što u značajnoj meri objašnjava snažanantioksidantni potencijal, uglavnom pokazan u in vitro istraživanjima. Takođe,nadaleko poznat antidepresivni efekat kantariona je prema poslednjim hipotezamaposledica sinergističkog delovanja nekoliko klasa jedinjenja i nije isključivo odlikaH.perforatum. Trenutna istraživanja ukazuju na snažan potencijal predstavnika rodaHypericumda inhibišu biološki aktivne enzime što bimoglo biti od koristi u terapijiodređenih patoloških stanja kao što su Alchajmerova i Parkinsonov bolest, odnosnodijabetestip2.Takođe,uzimajućiuobzirporastincidencekanceranasvetskomnivou,značajni su rezultati zabeleženi za ekstrakte predstavnika roda Hypericum, ali iizolovana jedinjenja. Naime, istraživanja ukazuju na njihovo antiproliferativnodelovanje i mogućnost inhibicije procesa angiogeneze kada su primenjeni u oblikumonoterapijeiliko‐terapijesakonvencionalnimantikancerskimlekovima.

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UPDATESONTHERAPEUTICPOTENTIALOFSPECIESFROMGENUSHYPERICUM

NebojšaKladar,NedaGavarić,BiljanaBožin

DepartmentofPharmacy,UniversityofNoviSad‐FacultyofMedicine(Serbia)

The genus Hypericum includes more than 500 species classified into 36

phylogeneticsections.Duringhistory,aswellasnowadays,StJohn’swort(Hypericumperforatum,Hypericaceae)isthemoststudiedspeciesofthegenus.However,inthelastthreedecades an increasing trendof researches concerningotherHypericumspeciescan be noticed. Regarding the identified active principles of H. perforatum, whichinclude compounds belonging to classes of naphtodianthrones, phloroglucinols,phenolics, flavonoids, biflavonoids and xantones, it can be noticed that speciesbelonging to phylogenetically younger sectionsmostly share the qualitative chemicalprofileofH.perforatum,whilethequantitiesofthespecificcompoundsaresubjectiveto significant variations. However, beside the observed interspecies chemicalsimilarities,newvaluablecompoundswithbiologicalactivities isolatedfromdifferentrepresentativesmustnotbeneglected.Generally,alargenumberofHypericumspecieshasbeen suggestedasa rich sourceofphenolic and flavonoidcompoundswhich canexplain strong antioxidant potential, mostly recorded in vitro. Also, the well‐knownantidepressantactivityofSt.John’swortisbylatesthypothesesaresultofsynergisticactionofseveralclassesofcompoundsandisnotexclusivelyrelatedtoH.perforatum.Current studies suggest strong potential of Hypericum species to inhibit biologicallyimportant enzymes, which has the power to be utilized in treatment of certainpathologicalconditionssuchareAlzheimer’sandParkinson’sdiseaseanddiabetestype2.Furthermore,consideringtheworldwidegrowingincidenceofcancer,thepromisingeffects of Hypericum‐based extracts, as well as isolated compounds, have beenrecorded. Specifically, data suggest their antiproliferative and anti‐angiogenesisactivitieswhen applied asmonotherapy, or co‐therapywith conventional anticancerdrugs.

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EFEKTIMETANOLNIHEKSTRAKATADVEBILJNEVRSTEIZFLORESRBIJENAISHEMIJSKO‐REPERFUZIONUPOVREDUIZOLOVANOG

SRCAPACOVA:UTICAJOKSIDACIONOGSTRESA

NevenaJeremić1,JovanaBradić1,VladimirŽivković2,IvanSrejović2,JovanaJeremić1,TamaraNikolić‐Turnić1,VladimirJakovljević2

1Odsekzafarmaciju,UniverzitetuKragujevcu‐FakultetMedicinskihnauka,2Katedrazafiziologiju,UniverzitetuKragujevcu‐FakultetMedicinskihnauka

(Srbija)Poredširoketradicionalneprimeneivanjskogcveća(GaliumverumL.‐G.verum)

i sremuša (Allium ursinum L.‐ A. ursinum) u terapiji brojnih bolesti i stanja njihoviefektina funkciju srca i redoksstatus jošuveknisuupotpunosti razjašnjeni.CiljnašestudijebiodaispitaefektemetanolnihekstrakataG.verumiA.ursinumnaishemijsko‐reperfuzionaoštećenjanaizolovanomsrcupacova.

30muškihWistaralbinopacovasunasumičnopodeljeniutrigrupe:kontrolnuigrupeG.verumiA.ursinum,kojesuobuhvatileživotinjetretiranesa500mg/kgtelesnemasemetanolnogekstraktaG.verum iA.ursinumperos tokomperiodaod4nedelje,redom. Nakon završenog tretmana srca životinja iz svih grupa su bila izolovana iretrogradno perfundovana prema Langendorff tehnici pri konstantnom perfuzionompritiskuod70cmH2O.Nakonperiodastabilizacijesrcasubilapodvrgnuta ishemijiutrajanju od 20minuta, koja je praćena reperfuzijom u trajanju od 30 minuta.Registrovani suparametri srčane funkcije uključujućimaksimalnu iminimalnu stopurazvoja pritiska, sistolni i dijastolni pritisak u levoj komori i srčanu frekvencu.Koronarni protok je meren floumetrijski. Nivoi superoksid anjon radikala, vodonikperoksida,nitritaiindekslipidneperoksidacije(merenkaothiobarbituricacidreactivesubstances‐ TBARS) određivani su spektrofotometrijski u koronarnom venskomefluentu.NaširezultatisupokazalidajetretmanmetanolnimekstraktimaG.verumiA.ursinumtokom4nedeljeočuvaokontraktilnusnagusrca,sistolnuidijastolnufunkcijuiumanjioprodukcijuprooksidanasa.

Obećavajući potencijal G. verum i A.ursinum u ovoj studiji na modelufarmakološkog prekondicioniranja može biti polazna osnova za buduća istraživanjakoja bi u potpunosti otkrila njihove efekte na funkciju srca i redoks ravnotežu narazličitimmodelimaishemijsko‐reperfuzionogoštećenja.

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EFFECTSOFOFMETHANOLEXTRACTSOFTWOPLANTSPECIESFROMTHEFLORAOFSERBIAONISCHEMIC/REPERFUSIONINJURY

OFISOLATEDRATHEART:ROLEOFOXIDATIVESTRESS

NevenaJeremić1,JovanaBradić1,VladimirŽivković2,IvanSrejović2,JovanaJeremić1,TamaraNikolić‐Turnić1,VladimirJakovljević2

1DepartmentofPharmacy,UniversityofKragujevac‐FacultyofMedicalSciences,2DepartmentofPhysiology,UniversityofKragujevac‐Facultyof

MedicalSciences(Serbia)Beside thewidespread traditional use ofGaliumverum (G. verum) andAllium

ursinum (A. ursinum) in the treatment of numerous diseases and conditions, theireffectsonheart functionandredoxstatushasstillnotbeenfullyclarified.TheaimofourstudywastoexaminetheeffectsofmethanolextractofG.verumandA.ursinumonischemia‐reperfusioninjuryinisolatedratheart.

ThirtymaleWistaralbinoratswererandomlydividedintothreegroups:controlandG.verumandA.ursinumgroups,whichincludedanimalstreatedwith500mg/kgbodyweightof themethanol extractofG. verumandA.ursinumperos for4weeks,respectively.AttheendofthetreatmentheartsfromanimalsinallgroupswereexcisedandretrogradelyperfusedaccordingtotheLangendorfftechniqueatconstantperfusionpreassureof70cmH2O.Afterstabilizationperiodheartsweresubjectedto20minutesischemia followed by 30 minutes reperfusion. The parameters of cardiac functionincluding the maximum and minimum rate of pressure development, systolic anddyastolic left ventricular pressure and heartratewere registered. Coronary flowwasmeasured flowmetrically. Levels of superoxide anion radical, hydrogen peroxide,nitrites and index of lipid peroxidation (measured as thiobarbituric acid reactivesubstances‐TBARS) were determined spectrophotometrically in coronary venouseffluent.OurresultsdemonstratedthattreatmentwithmethanolextractsofG.verumand A. ursinum preserved cardiac contractility, systolic and diastolic function anddiminishedproductionofpro‐oxidants.PromisingpotentialofG.verumandA.ursinuminthepresentstudy inamodelofpharmacologicalpreconditioningmaybeastartingpoint for futureresearches,whichwould fullyreveal theireffectsoncardiac functionandredoxstatusinvariousmodelsofI/Rinjury.

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Arh.farm 2018;68:152-153 PP27 OPTIMIZACIJAEKSTRAKCIJEPLODAARONIJE,ARONIA

MELANOCARPA(MICHX.)ELLIOTT,MIKROINKAPSULACIJAEKSTARKTAIISPITIVANJEBIOLOŠKIHAKTIVNOSTIEKSTRAKTA

NadaĆujić1,KatarinaŠavikin1,GordanaZdunić1,BrankoBugarski2,

NevenaMihailović‐Stanojević3,SvetlanaIbrić4 1Odsekzafarmaceutskaistraživanjairazvoj,Institutzaproučavanjelekovitogbilja„DrJosifPančić”,2Odsekzahemijskiinženjering,UniverzitetuBeogradu‐Tehnološko‐metalurškifakultet,3Odesekzakardiovaskularnufiziologiju,UniverzitetuBeogradu–Institutzamedicinskaistraživanja,4Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu–

Farmaceutskifakultet(Srbija)

Aronija je jedan od najbogatijih izvora polifenolnih jedinjenja (antocijani,proantocijanidini,fenolnekiseline,flavanoli).Upravoovipolifenolipredstavljajubogatipotencijal prirodnih antioksidanasa i njihova primenamože imati povoljne efekte nasmanjenje rizika od nastanka kardiovaskularnih, malignih i različitih degenerativnihbolesti. Primena ekstrakata bogatih polifenolima ima i niz ograničenja, a pre sveganestabilnost.Ciljradajebilaoptimizacijaekstrakcijepolifenolaizsuvogplodaaronije,mikroinkapsulacijaekstraktauciljupoboljšanjastabilnostiibioraspoloživosti,kaoiinvivo ispitivanje antihipertenzivnog delovanja ekstrakta na modelu esencijalnehipertenzije.

Eksperimentalni rad sadrži tri faze. 1) Optimizacija ekstrakcije i primenaeksperimentalnogdizajnazadobijanjeekstraktasanajvećomkoličinompolifenola.2)Ekstrakt sa najvećom količinom polifenola je mikroinkapsuliran, elektrostatičkomekstruzijom i sušenjem raspršivanjem. Mikročestice su fizičkohemijski ibiofarmaceutski okarakterisane: efikasnost inkapsulacije, ispitivanje brzineoslobađanjapolifenola,FTIR,SEM,veličinačestica(optičkimikroskopiMastersizer).3)Ispitivanje antihipertenzivnog delovanja ekstrakta. Kod eksperimentalnih grupaodređivani su sistemski i regionalni hemodinamski parametri, stepen lipidneperoksidacije (TBARS u plazmi i eritrocitima) i aktivnosti enzima antioksidativnezaštite.

Ekstrakt sa najvećom količinom aktivnih principa, dobijen je maceracijom sa50% etanolom, 1:20 odnosom droga‐rastvarač, 0.75 mm stepenom usitnjenosti, utrajanju od 60 minuta. HPLC analiza je potvrdila da se pod istim ekstrakcionimuslovimapostizenajveciprinospolifenola.Obetehnikezamikroinkapsulacijuekstraktasu pogodne za proizvodnju malih i uniformih mikročestica, sa produženimoslobađanjem polifenola, kao efikasni sistemi za isporuku i očuvanje stabilnosti.Četvoronedeljnom primenom ekstrakta kod SHR pacova, značajno je redukovansistolniipulsnipritisak,kojisupovezanisapovećanomdiurezom.RedukovanjeTBARSuplazmiieritrocitima,kaoilipidnaperoksidacija,usledsmanjenogoksidativnogstresakodživotinjakojesuprimaleekstrakt.

Ekstraktaronije,samaksimalnomkoličinomaktivnihprincipasemožekoristitikao blag antihipertenziv u početnim fazama bolesti ili kao dopuna konvencionalnojantihipertenzivnojterapiji.Mikroinkapsulacionemetodesusepokazalekaoefikasneuočuvanjustabilnostiekstrahovanihjedinjenja.

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OPTIMIZATIONOFCHOKEBERRYEXTRACTION,ARONIAMELANOCARPA(MICHX.)ELLIOTT,EXTRACT

MICROENCAPSULATIONANDBIOLOGICALACTIVITIES

NadaĆujić1,KatarinaŠavikin1,GordanaZdunić1,BrankoBugarski2,NevenaMihailović‐Stanojević3,SvetlanaIbrić4

1DepartmentforPharmaceuticalResearchandDevelopment,InstituteforMedicinalPlantResearch„Dr.JosifPančić”;2DepartmentofChemical

Engineering,UniversityofBelgrade‐FacultyofTechnologyandMetallurgy;3DepartmentforCardiovascularPhysiology,UniversityofBelgrade‐Institute

forMedicalResearch,4DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Chokeberry is one of the richest sources of polyphenolic compounds

(anthocyanins, proanthocyanidins, phenolic acids, flavanols). These polyphenolsrepresent the rich potential of natural antioxidants and their application can havebeneficial effects on reducing the risk of developing cardiovascular, malignant andvariousdegenerativediseases.Theuseofextractsrichinpolyphenolshasanumberofconstraints, and above all, instability. The aim of the paper was to optimize theextraction of polyphenol from dry chokeberry, microencapsulation of the extract inorder to improve stability and bioavailability, as well as in vivo testing theantihypertensiveactivityoftheextractonthemodelofessentialhypertension.

The experimental work consists of three phases. 1) Optimization of theextraction and application of experimental design to produce the extract with thehighest amount of polyphenols. 2) Extractwith the highest polyphenols contentwasencapsulated, by the electrostatic extrusion and spray drying. Microparticles werephysicochemical and biopharmaceutical characterized: encapsulation efficiency,releaserateofencapsulatedpolyphenols,FTIR,SEM,particlesizes(opticalmicroscopeandMastersizer).3)Antihypertensiveeffectexaminationoftheextract.Inexperimentalgroups were determined the systemic and regional hemodynamic parameters, lipidperoxidationbyTBARSmethodinplasmaanderythrocytesandantioxidativeenzymesactivities.

Extract with the greatest amount of active principles was obtained bymacerationusing50%ethanol,1:20solid‐solventratio,0.75mmparticlesize,during60minutes.HPLCanalysisconfirmedthatwiththesame,selectedextractionconditionswas achieved the highest yield of polyphenols. Both microencapsulation techniquesweresuitabletechniqueforsmallanduniformparticlesproduction,asefficientsystemsfor the prolonged polyphenols delivery and increased stability. A four week extractadministrationinSHRratssignificantlyreducedsystolicandpulsepressure,associatedwith increased diuresis. Plasma and erythrocytes TBARSwere decreased, as well aslipidperoxidationasaconsequenceofdecreasedoxidativestressintheextracttreatedexperimentalgroup.Chokeberryextract,withamaximumamountofactiveprinciples,couldbeused as amild antihypertensive agent in the early stages of disease or as asupplement to conventional antihypertensive therapy. Microencapsulation methodshavebeenproventobeeffectiveinpreservingthestabilityoftheextractedcompounds.

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GENERIČKILEKOVIODPODNOŠENJAZAHTEVADOODOBRENJA

SAŽETKAKARAKATERISTIKALEKA

BrankaBrzaković

AgencijazalekoveimedicinskasredstvaSrbije(Srbija)Generički lekovi se često razmatraju u okviru strategija za smanjenje troškova

zdravstvenezaštite.Razvojgeneričkoglekaimazaciljdobijanjelekaekvivalentnogvećregistrovanomlekukojisenazivareferentnilek.Aktivnasupstancajeista,koristiseuistojdoziza lečenje istebolesti, farmaceutskioblik je isti,doksepomoćnesupstance,ime, izgled i pakovanje mogu razlikovati. Generički lekovi se proizvode prema istimstandardima kvaliteta kao i drugi lekovi i poštovanje smernica Dobre proizvođačkeprakse(GMP)jeneophodno.

Posle podnošenje zahteva za dobijanje dozvole za stavljanje leka u promet,regulatorno telo kao što je u našoj zemlji Agencija za lekove i medicinska sredstvaSrbije, spovodi stručnu procenu kvaliteta, efikasnosti i bezbednosti leka. Proizvođačgeneričkoglekauobavezijedadostavipotpunudokumentacijuokvalitetuovogleka.Uvećinislučajevaneophodnojepriložitiipodatkeostudijibiološkeekvivalentnosti,čijirezultati trebadapokažudagenerički lekpostiže istenivoeaktivne supstanceu telukaoreferentni lek,doksesprovođenje toksikoloških, farmakoloških ikliničkihstudijapo pravilu ne zahteva za generički lek. Informacije o generičkom leku sadržane uSažetkukarakteristikaleka,Uputstvuzalekinacrtupakovanjasuistekaozareferentnilek, sa izuzetkom indikacija ili farmaceutskog oblika, koji su još uvek pokrivenipatentnom zaštitom. Posle registracije, regulatorno telo će nastaviti da pratibezbednostodobrenoggeneričkogleka.

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GENERICMEDICINALPRODUCTSFROMAPPLICATIONTOFINALSUMMARYOFPRODUCTCHARACTERISTICS

BrankaBrzaković

MedicinesandMedicalDevicesAgencyofSerbia(Serbia)

Generic medicinal products are often regarded as one of strategies to reduce

healthcare expenses. They are developed to be equivalent to a medicine that hasalready been authorised (the referencemedicine) having the same active substance,usedatthesamedosestotreatthesamediseases,andthesamepharmaceuticalform.Excipients, name, appearance and packaging can be different. Genericmedicines aremanufacturedaccordingtothesamequalitystandardsasallothermedicinesandgoodmanufacturingpractices(GMP)arerequired.

After application for marketing authorisation, a regulatory authority such asMedicinesandMedicalDevicesAgencyofSerbia,willconductascientificevaluationofthemedicine’sefficacy, safetyandquality.Aproducerofagenericmedicineneeds toprovidecompleteinformationonthequalityofthemedicine.Inmostcasesdatafromabioequivalencestudyarerequiredtodemonstratethatthegenericmedicineproducesthe same levels of the active substance in the body as the referencemedicine. For agenericmedicinalproductitisnotnecessarytoprovidetheresultsoftoxicologicalandpharmacologicaltestsortheresultsofclinicaltrials.Thesameinformationwillappearin theproduct information(thesummaryofproductcharacteristics, the labellingandthepackageleaflet)ofthegenericmedicinalproduct,asintheproductinformationofthereferencemedicine,except for indicationsordosageformsstillcoveredbypatentlaw. After authorization, the regulatory authorities continue tomonitor the safety ofgenericmedicines.

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BIOEQUIVALENCEREQUIREMENTSFORLOCALLYACTINGDOSAGE

FORMS

AlfredoGarcíaArieta

AgenciaEspañoladeMedicamentosyProductosSanitarios(España)/SpanishAgencyofMedicinesandMedicalDevice(Spain)

Therequirementstodemonstrateequivalencebetweenlocallyactingmedicinal

products has evolve in the European Union since the overarching guideline „Clinicalrequirements for locally applied, locally acting products containing knownconstituents”publishedin1995andthenewguidelinesfor:

Orally inhaled products („Requirements for clinical documentation for orallyinhaledproducts(OIP)includingthe96requirementsfordemonstrationoftherapeuticequivalence between two inhaled products for use in the treatment of Asthma andChronicObstructivePulmonaryDisease(COPD)”),whichispresentlyunderrevision.

Gastrointestinal products („Guideline on equivalence studies for thedemonstration of therapeutic equivalence for locally acting products in thegastrointestinaltract”),whichistobeapprovedfinallyin2018.

Cutaneousproducts(„Guidelineonqualityandequivalenceoftopicalproducts”),whichisexpectedtobereleasedforconsultationin2018.

Thepresentationsummarisestherequirementsofthesethreenewguidelinesonlocallyactingproducts,whosebasicprinciplescanbeusedforsimilarproductswithoutanspecificguidelinelikelocallyactingnasalproducts.

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POTVRDATERAPIJSKEEKVIVALENTNOSTIORALNIHINHALACIONIHLEKOVA‐REGULATORNIASPEKTI

ZoricaPejčić

AgencijazalekoveimedicinskasredstvaSrbije(Srbija)

Za potvrdu terapijske ekvivalentnosti oralnih inhalacionih lekova koji deluju

lokalno u plućima, u EU se primenjuje stupnjeviti pristup u skladu sa smernicomCPMP/EWP/4151/00 Rev1. Prvi korak uključuje in vitro ispitivanja leka, drugifarmakokinetička (FK), a treći farmakodinamska (FD) ili klinička ispitivanja. In vitroispitivanjavršeseuzpomoćuređajakojiinvitrosimuliraponašanjeinhaliranoglekaurespiratornomtraktu(npr.Andersenovogkaskadnogimpaktora).Ukolikosuispunjenisvidefinisaniuslovinavedeniusmernici,terapijskaekvivalentnostdvainhalacionalekamožesepotvrditivećuovomprvomkoraku,aakonisuispunjeni,pristupaseinvivoFKispitivanjima.

ZapotvrduekvivalentneefikasnostiuFKstudijamapotrebno jepokazatidasugenerički i referentni lek ekvivalentni u pogledu plućne depozicije, odnosno količinelekadospeloguplućairasporedačesticalekaunutarpluća.UovesvrhesprovodeseFKstudije u kojima je resorpcija aktivne susptance iz gastrointestinalnog trakta (GIT)blokirana p.o. primenom aktivnog uglja, te se prati samo resorpcija leka iz pluća. Zapotvrdu ekvivalentne bezbednosti generičkog i referentnog leka potrebno jemeriti iporediti ukupnu sistemsku izloženost leku, odnosno ukupnu količinu lekaresorbovanogizGITipluća,zaštatrebasprovestiFKstudijubezp.o.primeneaktivnoguglja. Ukoliko se u FK studijama dobiju zadovoljavajući rezultati, terapijskaekvivalentnostmožesesmatratipotvrđenom.

Ukoliko terapijska ekvivalentost nije pokazana FK studijama neophodno jesprovesti FD ili kliničke studije u kojima se generički inhalacioni lek poredi sareferentnim na osnovu odgovarajućih parametara praćenja efikasnosti i bezbednosti.NajvećibrojgeneričkihinhalacionihlekovauEUdobijadozvolunaosnovuFKstudija.UtokujerevizijasmerniceCPMP/EWP/4151/00Rev1,odkojeseočekujedadodatnoprecizira i pojasni pojedine detalje u pogledu ispitivanja terapijske ekvivalentnostiinhalacionihlekova.

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REGULATORYFRAMEWORKFORDEMONSTRATIONOF

THERAPEUTICEQUIVALENCEOFORALLYINHALEDPRODUCTS

ZoricaPejčić

MedicinesandMedicalDevicesAgencyofSerbia(Serbia)

Whenconcludingtherapeuticequivalencefororallyinhaledproductswhichare

locallyactinginlungs,astep‐wiseapproachisappliedintheEUaccordingtoguidelineCPMP/EWP/4151/00 Rev1. In vitro approach is recommended as the first step, thesecondsteparepharmacokinetic(PK)studiesandthethirdsteparepharmacodynamic(PD)orclinicalstudies.Invitroinvestigationsareconductedusinganapparatusthatinvitro simulates behaviour of the inhaleddrug in the respiratory tract (e.g., Andersencascadeimpactor).Ifallconditionsrecommendedintheguidelinearemet,therapeuticequivalencecanbeshowninthisfirststep,andiftheyarenotmet,PKstudiesshouldbeconducted.

In PK studies, equivalent efficacy between generic and reference product isassumedifpulmonarydepositionandpatternofdepositionwithinthelungsisshownto be equivalent. This can be assessed if PK studies are performed in the conditionswhendrugabsorption through thegastrointestinal tract (GIT) isblocked (e.g., byp.oadministration of active charcoal), and the drug absorption occurs only through thelungs.Fordemonstrationofequivalentsafety,totalsystemicdrugexposureshouldbemeasured,i.e.,theportionofthedoseabsorbedboththroughthelungsandGITinthePK study without charcoal blockage. If the results of PK studies are acceptable,therapeuticequivalencecanbeconfirmedinthisstep.

If therapeutic equivalence is not confirmed by PK studies, it is necessary toconductPDorclinical studies inwhichgenericandreferenceproductsarecomparedbased on appropriate efficacy and safety endpoints. Most generic orally inhaledproducts are now being approved in the EU based on PK studies.Currently, theguidelineCPMP/EWP/4151/00Rev1isunderrevisionwiththeaimof itsupdatinginorder to reflect the knowledge gained from regulatory experience in the previousperiod.

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KADA(NI)JEMOGUĆASUPSTITUCIJAGENERIČKIMLEKOM

MarijaJovanović

Katedrazafarmakokinetikuikliničkufarmaciju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Generičkilekovisepojavljujunatržištuposleistekapatentnihpravaoriginalnog

leka.Dokumentacijakojasepodnosizaizdavanjedozvolezastavljanjegeneričkoglekau promet je u manjem obimu u odnosu na originalni lek i, pored dokumentovanogkvaliteta, sadrži podatke o biološkoj ekvivalentnosti u odnosu na referentnilek.Generički lek ima isti kvalitativni i kvantitativni sastav aktivnih supstanci kao ireferentnilek.Takođe,generičkilekimaistifarmaceutskioblikkaoreferentnilek,alisemogurazlikovatiupogleduimena,pomoćnihsupstanci,izgledaipakovanja.

Generičkasupstitucijasezasnivanapretpostavcidajegeneričkilekekvivalentanreferentnomupogleduefikasnosti ibezbednosti. Iakosepolitikavezanazageneričkusupstituciju razlikuje od zemlje do zemlje, često se ohrabruje kao pokušaj smanjenjatroškova zdravstvene zaštite. Međutim, u slučaju određenih lekova ili određenihokolnostimoždajeboljedaseizbegnerizik.Posebnojeproblematičnagrupalekovasauskim terapijskim opsegom kao što su određeni antiepileptici, antikoagulansi,imunosupresivi i drugi, što može rezultovati nepovoljnim kliničkim ishodima. Malevarijacije u koncentraciji leka mogu dovesti do izostanka terapijskog odgovora ilipovećane toksičnosti. Pored toga, i druge aspekte vezane za lek ili pacijenta trebapažljivorazmotriti.Nakraju,kadapostojerazlozizazabrinutost,adekvatnostgeneričkesupstitucijetrebaprocenjivatiindividualno,zaodređenogpacijenta.Svakakojekorisnokonsultovati validne i pouzdane izvore informacija prilikom donošenja odluke ozameni.

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WHENGENERICSUBSTITUTIONIS(NOT)APPROPRIATE

MarijaJovanovićDepartmentofPharmacokineticsandClinicalPharmacy,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Generic drugs appear on the market after the expiry of patent rights of the

original drug. The documentation submitted for marketing authorisation of genericmedicine is reduced compared to the original medicine, and besides documentedquality, contains data on bioequivalence with the reference medicinal product. Ageneric drug has the same qualitative and quantitative composition in activesubstances as the referencemedicinal product. Also, it has the same pharmaceuticalform as the reference drug, but it can be different in terms of the name, inactiveingredients,appearanceandpackaging.

Generic substitution rests on the assumption that the generic medicine isequivalenttothereferenceproductintermsofefficacyandsafety.Althoughpoliciesongenericsubstitutionvaryfromcountrytocountry,itisoftenencouragedasanattempttoreducehealthcarecosts.However, inconjunctionwithcertainmedicinesorcertaincircumstances,itmaybebettertoavoidtherisk.Drugswithnarrowtherapeuticrangessuch as certain antiepileptics, anticoagulants, immunosuppressants and others areparticularlyproblematicandmayresultinadverseclinicaloutcomes.Smallvariationsindrugconcentrationmayresultinlackoftherapeuticresponseorincreasedtoxicity.In addition, other aspects related to themedicinal product or the patient should becarefully considered. Finally, when there are reasons to be concerned, theappropriatenessofgenericsubstitutionshouldbeassessedonanindividualbasis,foraspecific patient. Undoubtedly, valid and trusted sources of information should beconsultedwhenmakingadecisionaboutthesubstitution.

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AKUTNATROVANJAILEGALNIMPSIHOAKTIVNIMSUPSTANCAMA‐ISKUSTVANACIONALNOGCENTRAZAKONTROLUTROVANJA

JasminaJović‐Stošić1,TomislavRežić1,NatašaPerković‐Vukčević1,SlavicaVučinić1,GordanaBrajković1,SnežanaĐorđević1,MirjanaĐukić2

1Nacionalnicentarzakontrolutrovanja,MedicinskifakultetVojnomedicinskeakademije,Univerzitetodbrane,Beograd,2Katedrazatoksikologiju„AkademikDaniloSoldatović”,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Zloupotreba ilegalnih psihoaktivnih supstanci može dovesti do neželjenih

efekata i predoziranja sa ozbiljnim akutnim poremećajima i eventualno smrtnimishodom.Godišnje se uNacionalnom Centru za kontrolu trovanja zbog predoziranjadrogamazbrine300–400pacijenatakojisudoveženikaohitni slučajevi,uglavnomsateritorijeBeogradaiobližnjihgradova.Prikazujemoaktuelneepidemiološkepodatkeiukazujemona osnovne karakteristike ovih trovanja u pogledu dijagnostike, terapije iishoda. Retrospektivno su analizirani slučajevi predoziranja ilegalnim drogama upetogodišnjemperodu(2013‐2017).

Uposmatranomperiodusulečene1683osobe,životnedobiod14do60godina,pri čemu je zastupljenost mlađih od 18 godina iznosila 12,6%. Predoziranja su bilaznačajnočešćakodmuškaraca(uoko75%slučajeva).Najčešćeseradilooheroinu,kod51%bolesnika.Tegobenakonkonzumiranjamarihuanesubilerazlog javljanja lekarukod 18% bolesnika. Derivati amfetamina [3,4‐metilendioksimetamfetamin (MDMA,metamfetaminidr.]subiliuzročnicitrovanjau11%,akokainu7%slučajeva.„Nove”psihoaktivne supstance [sintetski kanabinoidi, γ‐hidroksibuterna kiselina (GHB)] suregistrovanekod4%bolesnika,dokkod9%nijepotvrđenetiološkiagens.Kodvećinepacijenata za potvrdu dijagnoze su korišćene standardne metode, dok su za novepsihoaktivnesupstancerazvijeneLC/MSiliHPLC/PDAmetode.

Velika većina (skoro 90%) pacijenata je zbrinuta u dnevnoj bolnici. Opijatnisindrom uzrokovan heroinom, sa depresijom disanja, hipotenzijom i ARDS‐om je bionajčešći uzrok teških trovanja i produženog hospitalnog lečenja. Letalitet u trovanjuheroinom je iznosio1%.Kodostalih agenasa je zabeležen samo jedan letalni ishodutrovanjuamfetaminimačijesuglavnemanifestacijebilehipertermijaikonvulzije.Kodpredoziranja marihuanom su dominirali tahikardija i psihički simpotomi, a oviporemećajisubiliizraženijinakonzloupotrebesintetskihkanabionoida.

IskustvoNCKTukazujedaheroinidaljepredstavljanajznačajnijiuzrokteškihiletalnih trovanja, dok zloupotreba amfetaminskih psihostimulanasa i drugih novihpsihoaktivnihsupstanci,predstavljasvevećiizazovupogledudijagnostikeiterapije.

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ACUTEPOISONINGWITHILLICITPSYCHOACTIVESUBSTANCES–EXPERIENCEOFTHENATIONALPOISONCONTROLCENTRE

JasminaJović‐Stošić1,TomislavRežić1,NatašaPerković‐Vukčević1,SlavicaVučinić1,GordanaBrajković1,SnežanaĐorđević1,MirjanaĐukić2

1NationalPoisonControlCentre,MilitaryMedicalAcademy,MedicalFaculty,UniversityofDefence,Belgrade,2DepartmentofToxicology„AkademikDanilo

Soldatović”,UniversityofBelgrade‐FacultyofPharmacy(Serbia)Abuse of illicit psychoactive substances may result in adverse effects and

overdoses with serious disorders and sometimes fatal outcomes. National PoisonControl Centre admits per year about 300‐400 emergency cases due to illicit drugsoverdoses, mainly from the territory of Belgrade and nearby cities.We present thecurrentepidemiologicaldataandpointtothebasiccharacteristicsofthesepoisoningsintermsofdiagnostics,therapyandoutcomes.

Duringtheobservedperiod,1683persons,agedfrom14to60weretreated.Theshare of younger than18was12.6%.Overdoseswere significantlymore common inmen (in about 75%of cases). Themost commonly used drugwas heroin, in 51%ofpatients. The symptoms after consuming marijuana were the cause of medical helpasking in 18% of patients. Amphetamine derivatives [3,4‐methylenedioxymethamphetamine (MDMA), methamphetamine, etc.] were toxic in11%, and cocaine in 7% of cases. „New” psychoactive substances [syntheticcannabinoids,γ‐hydroxybutyricacid(GHB)]wereregisteredin4%ofpatients,whilein9%theetiologicalagentwasnotconfirmed.Inthemajorityofcases,standardmethodswere used to confirm the diagnosis, while LC/MS or HPLC/PDA methods weredevelopedfornewpsychoactivesubstances.

Thevastmajority(almost90%)ofpatientsaretreatedinadailyhospital.Opioidsyndromecausedbyheroin,with respiratorydepression,hypotensionandARDSwasthe most common cause of severe poisoning with prolonged hospital treatment.Mortalityinheroinpoisoningwas1%.Amongtheotheragents,onlyonelethaloutcomewas recorded, in case of amphetamine poisoning, manifested by hyperthermia andconvulsions. Adverse effects of marijuana were mainly tachycardia and psychoticsymptoms, and these disorders were more pronounced after abuse of syntheticcannabinoids.

Theexperienceof theNCKT indicates thatheroin remains themost significantcauseofsevereandlethalpoisoning,whiletheabuseofamphetaminepsychostimulantsandothernewpsychoactivesubstancesisanincreasingchallengeintermsofdiagnosisandtherapy.

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THEANALYSISOFPSYCHOACTIVESUBSTANCES:CHALLENGESRELATEDTOBIOLOGICALSAMPLESANDANALYTICALTOOLS

GoranMitulović

MedicalUniversityofVienna,ClinicalInstituteofLaboratoryMedicine(Austria)Blood,urine,hair, andsalivaare themainandmost commonlyusedbiological

materialsfordrugtesting.Othermatricescanalsobeusedbuthavebeenappliedonlyinlimitedamountandnumberofcases.Dependingonclinicalandanalyticalquestiontobeanswered,butalsoonlegalrestraintsandenvironmentalandtechnologicalsettings,thechoiceofmatrixandtheanalyticalapproachforanalysismustbecarefullychosen.For example, blood reflects a recent drug intake and is used to assess users’impairment.Analysisofsalivawillalsoshowarecentdrugintakeandindirectlyshowdrugpresenceinbloodbutit isnopossibletoassesstheconcentrationofthedruginblood. As for urine and hair, these matrices can be applied for detecting the drug(mis)useduringalongerperiodoftime.

Drugdetectionmustnotalwaysbedifficultandmodernanalyticaltechnologiesallow for fast detection of very low amounts of substances in biological matrices.However,beforeanalyzingsuchamatrixonemustconsiderthefollowing:

thetimeframeofdrugs’use, samplingmethods, samplestorage/transport, typeofbiologicalmatrix(blod,urine,saliva,tissueetc.), steps for sample preparation prior to analysis and detection (protein

precipitation,extractionetc.), theuseofsample–court,screeningetc.Furthermore,theanalyticalmethodtobeusedshallberobust,reproducible,and

relatively insensitive towardbiologicalmatrix applied.All these requirementspose achallengeformethoddevelopmentandvalidation,andforlaterqualitycontrol(thinkofblanksandcontrols).

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PREGLEDSITUACIJENATRŽIŠTUDROGAUSRBIJIIPREDOZIRANJASUPSTANCAMAZLOUPOTREBELEČENIHUNACIONALNOMCENTRU

ZAKONTROLUTROVANJAVMA

SlavicaVučinić,JasminaJović‐Stošić,DraganaĐorđević,TomislavRežić,SnežanaĐorđević,VesnaKilibarda

Nacionalnicentarzakontrolutrovanja,Vojnomedicinskaakademija,Medicinski

fakultetUniverzitetodbrane,Beograd(Srbija)EvropskicentarzamonitoringdrogaizavisnostioddrogaiEUROPOLbeležisve

većupojavudrogauslovljenuveomadinamičnimpromenamanatržištudroga,novimtehnikamaproizvodnjeinačinadistribucije.Naosnovubrojnihindikatorasezaključujedajeupotrebakanabisaiilegalnihstimulanasatipakokaina,amfetaminainjemusličnihsupstanci(ATS) inovihpsihoaktivnihsupstanci(NPS)uEvropiuporastu,dok jebrojkorisnikaheroina relativnostabilan.Cilj rada jeanaliziratiučestalost i težinu trovanjarazličitimpsihoaktivnimsupstancama(PAS)lečenihuNacionalnomcentruzakontrolutrovanja(NCKT),VMA,Srbija.

Primenjena je retrospektivna studija pacijenata lečenih u NCKT zbogpredoziranja supstancama zloupotrebe u petogodišnjem periodu. Od ukupnog brojtrovanja,PASsuregistrovaneu162slučaja(4,06%)u2011.,224(5,36%)u2012.,281(6,69%) u 2013., 312 (7,07%) u 2014. i 442 (9,31%) u 2015. godini što je značajanporastbrojatrovanja(p<0.001).Upoređenjusa2011.g.,sledećihgodinabrojpacijenatalečenihzbogpredoziranjaheroinom(67,3%;60,3%;61,9%;54,5%;50,9%)jeznačajnomanji(p<0,001),dokrastebrojpacijenatasapredoziranjemATS.Ipaknijebilorazlikeustepenutežinetrovanjauanaliziranomperiodu.NekiodpotencijalnozabrinjavajućihtrendovanatržištudrogapovezanisusaporastombrojapacijenatakojisezbogefekataATS i NPS leče u NCKT. Ponovni interes za MDMA praćen je odgovarajućimpreventivnim akcijamaNCKT. U Srbiji je ustanovljen zakonski okvir za organizovanuakcijuunutarSistemaranogupozoravanjanaNPSukomesepodaciizNCKTkoristezareagovanje.

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ANOVERVIEWOFTHEDRUGMARKETANDSUBSTANCESOFABUSEOVERDOSETREATEDINTHENATIONALPOISONCONTROLCENTER

MMA

SlavicaVučinić,JasminaJović‐Stošić,DraganaĐorđević,TomislavRežić,SnežanaĐorđević,VesnaKilibarda

NationalPoisonControlCentre,MilitaryMedicalAcademy,Medicalfaculty

UniversityofDefense,Belgrade(Serbia)As the drug phenomenon continues to evolve, highly dynamic changes in the

drug market, production techniques, and methods of distribution are noted by theEuropean Monitoring Centre for Drugs and Drug Addiction and EUROPOL. Multipleindicators suggest that cannabis and illicit stimulant drugs, such as cocaine,amphetaminetypesubstances(ATS),andnewpsychoactivesubstances(NPS)useareon the rise in Europe, while the number of heroin users is relatively stable. Theobjectiveofthecurrentstudywastoanalyzethefrequencyandseverityofpoisoningbydifferentpsychoactivesubstances(PAS)treatedattheNationalPoisonControlCentre(NPCC),MMA,Serbia.Retrospectivestudyofpatients treated for substancesofabuseoverdoseattheNPCCinfive‐yearperiodhasbeenperformed.

Out of all poisonings, PAS were represented with 162 (4.06%) in 2011, 224(5.36%)in2012,281(6.69%)in2013,312(7.07%)in2014and442(9.31%)in2015whichisasignificantincrease(p<0.001).Comparedto2011,inthefollowingyears,thenumberofpatientstreatedforheroinoverdose(67.3%;60.3%;61.9%;54.5%;50.9%)was significantly reduced (p<0.001), while the number of ATS overdose increased.However there was no differences in the severity of poisoning in the analyzed timeperiod.Somepotentiallyworryingchanges inthedrugmarketareassociatedwiththeincrease of patients with ATS and NPS effects, treated at the NPCC. Resurgence ofMDMAwasfollowedbyappropriatepreventiveactionsoftheNPCC.TheframeworkfororganizedactionwithintheEarlyWarningSystemonNPSisestablishedinSerbiaandthedatafromtheNPCCwillbeusedintheresponse.

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KURIKULARNEIEKSTRAKURIKULARNEAKTIVNOSTIUDOPRINOSURAZUMEVANJUZLOUPOTREBEPSIHOAKTIVNIHSUPSTANCI

MirjanaĐukić

Katedrazatoksikologiju„AkademikDaniloSoldatović”,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Izborni predmet (kurs) „Sredstva koja izazivaju zavisnost sa analitikom” je

uveden 2008. u dodiplomske studije na Farmaceutskom fakultetu Univerziteta uBeogradu. Kurikulum je postavljen po ugledu na svetske i evropske (EU) obrazovneprograme na temu zloupotrebe droga (ZD). Kurs evoluira u skladu sa politikom,planovimaiprogramimaprotivZD,odglobalnogdonacionalnognivoa.Ciljkursajedaupoznastudenatefarmacijesasloženošćuovogproblema,samedicinskog,analitičkog,aliisaaspektadruštva.

Nastavne aktivnosti su podeljene između profesora, kliničkog toksikologa,psihijatra, socijalnog radnika policije i samih studenata. Studenti izlažu sopstveneseminarske radove, referišu prikaze slučajeva (situacije iz realnog života), obavljajulaboratorijskiradikoristeplatformuzae‐učenje.

Kurikulum kursa pokriva sledeće oblasti: i) struktura‐doza‐efekat, mehanizmitoksičnosti, toksikokinetika i analitika droga (i u biološkim uzorcima); ii)medikamentoznaterapija(prvapomoć,detoksikacioniprotokoli,kliničkezbrinjavanjezavisnika); iii) tzv. „društveni detoksikacioni protokoli” (program rehabilitacije ireintegracije u12koraka i ostali pojedinačni ili grupnipsihoterapijskiprogrami); iv)nacionalna i EU politika protiv zloupotrebe droga i njihova klasifikacija (izvori:programi i godišnji izveštaji EU članica o zloupotrebi droga, a bazirano naustanovljenimkriterijumimaipokazateljimaodstraneEvropskogcentrazapraćenje izloupotrebu droge); i v) aktuelnosti o novim drogama, debate na temu legalizacijekanabisa,itd.

Za sada, farmaceuti u Srbiji nisu uključeni u kreiranje, razvoj i sprovođenjenacionalnogsistemazaobrazovanje,strategijuipolitikuZD.Uovomdomenuobavljajudvatipausluga:sudsko‐ikliničko‐toksikološkeanalize(ureferentniminstitucijama)ikontrolu zloupotrebe recepata i lekova (pogotovo analgetika i na baziefedrina/amfetamina)uslobodnojprodaji(uapotekama).

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CURRICULARANDEXTRA‐CURRICULARACTIVITIESTODEVELOPCOMPREHENSIONONABUSEOFPSYCHOACTIVESUBSTANCES

MirjanaĐukićDepartmentofToxicology„AkademikDaniloSoldatović”,Universityof

Belgrade‐FacultyofPharmacy(Serbia)

Theundergraduateelectivecourse „Substanceabuse”wasestablished2008,at

the University of Belgrade‐Faculty of Pharmacy. The curriculum was established inaccordancewith global and EuropeanUnion (EU) educational system on drug abuse(DA).Ithasbeenevolvingwithtrendsinanti‐drugpolicies,plansandprograms,fromglobaltonationallevel.

ThegoalofthecourseistoteachstudentsofpharmacyabouttheDAcomplexityfromthemedical,analyticalandsocialprospective.

Teaching activities are shared between professors, clinical toxicologists, policesocial workers, psychiatrists and students themselves. Students present seminarpapers, report on case studies (depict real‐life situations), perform toxicologicalanalysisandusee‐learningplatform.

The course curriculum includes the following topics: i) assessing of structure‐dose‐effect relationship, toxicity mechanisms, toxicokinetics and drug analysis; ii)medical treatmentofSA(firstaid,drugdetoxprotocolsand innovations, clinicalcasestudies, etc.); iii) social programs (12‐ step rehabilitation and reintegration programand socio detox protocols‐individual or group psychotherapy sessions); iv)classifications of SA and National and EU anti‐drug policies (sources: programmingdocuments and EU countries’ annual surveys on SA, grounded on the criteria andindicators established by EuropeanMonitoring Centre for Drugs andDrug Addiction(EMCDDA);andv)actualitiesonnoveldrugs,debatesoncannabislegalization,etc.

Pharmacists in Serbia have not been participating in creating, developing andprovidingthenationaleducatingsystem,strategyandpolicyonDA.Sofar,theymanagetwo types ofDA services: forensic and clinico‐toxicological analysis (within referringinstitutions) and controlling the abuse of prescription and over‐the‐countermedications(emphasison:analgesicsandephedrine/amphetaminecontainingdrugs),inpharmacies.

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THEEFFECTSOFNATURALANDSYNTHETICENVIRONMENTALPOLLUTANTSONHUMANHEALTH:SOMECASESTUDIES

EmanuelaTestaiNationalInstituteforHealthEnvironmentandHealthDept.(Italy)Among environmental pollutants, those known as ‘contaminants of emerging

concern’ have received an increasing attention, especially when chronic exposure isconcerned. This is particularly true forwater bodies contaminants, used as drinkingwatersupplies,consideringthefrequencyofexposureforalargepartofthepopulation.Beside some ‘well known’ chemicals which are routinely monitored, the improvedanalyticalmethodssensitivityhasallowedtodetectchemicalsthathadnotpreviouslybeendetected:amongthemmicrocystins(MCs),producedbycyanobacterianaturallypresent inmanywaterbodies, andper‐ andpolyfluorinatedalkyl substances (PFAS),persistentenvironmentalchemicalsusedinawiderangeofindustrialapplicationsandcommercial products. Dense blooms of cyanobacteria increasingly occurringworldwide, due to eutrophication and climate changes. MCs are among the moststudied cyanotoxins; the group consists ofmore than 100 hepatotoxic variants,withdifferent potency, associated to differences in their kinetic behaviour, acting throughinhibitionofPPA1andPP2A trigginga cascadeof events leading tohepatoxicityandtumorpromotion.Somevariantsshowedinvitroalsoaneurotoxicpotential.AlsointhecaseofPFASkineticsplayacrucialrole,determiningtheirbioaccumulationpotentialbybinding to plasma proteins paralled by a lack of biotransformation and a very slowurinary excretionwith renal resorption. Some epidemiological studies carried out inhighlycontaminatedareasshowedapositiveassociationofPFASwithincreasedtotalcholesteroland lowandhighdensity lipoproteins inblood, suggestingdysfunction inlipidmetabolism.Othereffectsweredescribedbuttheyarestillunderdiscussion.Bothclass of contaminants consist of a group of variants, to which it is possible to besimultaneouslyexposed,butunfortunatelydatagapsinknowledgeabout thetoxicityofdifferentMCvariantsorPFASfamilymemberslimittheapplicationofacumulativeriskassessmentprocedure.

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METIL‐ŽIVAUNAŠEMOKRUŽENJU:KLJUČNEČINJENICEZASIGURNUBUDUĆNOST

DanijelaĐukić‐Ćosić

Katedrazatoksikologiju„AkademikDaniloSoldatović”,UniverzitetuBeogradu

‐Farmaceutskifakultet(Srbija)Povećanoprisustvožive(Hg)uživotnojsredini jeglobalniproblemzbognjene

perzistentnosti,potencijalazabioakumulaciju i toksičnostiza ljude.UživotnusredinuHgdolaziizprirodnihiantropogenihizvoraiprisutnajeutrioblika:elementarnaHg,neorganska jedinjenja Hg i organska jedinjenja Hg. Pomoću bakterija neorganskajedinjenja Hg se transformišu u organski oblik,metil‐živu (MeHg) koja se akumuliranajvišeuribama.IzloženostMeHgputemkontaminiraneribeiproizvodaodnjihmožepredstavljatiopasnostpozdravljeljudi.Metil‐živaimapoznatoštetnodejstvonanervnisistemjerseapsorbujeokošestputalakšeodneorganskihjedinjenjaHgiprolazikrv‐moždanu barijeru. Novija istraživanja pokazuju da čak izlaganje malim količinamaMeHgmožeizazvatiozbiljnezdravstveneproblemeipredstavljatiopasnostzainuterorazvoj irazvojmaledece.StogajeSZOMeHgsvrstalameðuprvihdesethemikalijaodznačaja za javno zdravlje. Unos MeHg putem ribe i proizvoda od ribe se procenjuješiromsvetauosetljivimpopulacijama,poputtrudnicaimaledeceiovakvipreliminarnirezultatipostojeiuSrbiji.KodosetljivihpopulacijaunosMeHgtrebasvestinanajmanjumoguću meru uzimajući u obzir da riba predstavlja neophodnu namirnicu uuravnoteženojishrani.Međunarodneorganizacije(FDAiEPA)dalesupreporukeuvezisa vrstama ribe koje su bezbedne za ishranu kako bi informisale trudnice i roditeljemaledece.

GlobalnasituacijaoprisustvuMeHgu lancu ishrane ipokazaninegativniefektikod ljudi zabrinjavajuće je delovala na vlade zemalja širom sveta koje su se 2013.godine složile o donošenju Minamata konvencije. Konvencija obuhvata niz akcija,uključujući smanjenje emisije Hg u vazduh eliminisanjem upotrebe Hg za dobijanjezlata, eliminisanjem iskopavanja Hg ruda i ograničenjima i zabranama određenihproizvodakojisadržeHg.

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METHYLMERCURYINOURENVIRONMENT:KEYFACTSFORASAFEFUTURE

DanijelaĐukić‐Ćosić

DepartmentofToxicology„AkademikDaniloSoldatović”,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Mercury (Hg) pollution is a global problem due to its persistence in the

environment,potentialtobioaccumulate,andtoxicitytohumans.Intheenvironment,itcomesfromthenaturalandanthropogenicsourcesandexistsinthreeforms:elemental,inorganic, and organic Hg. Once there, Hg can be transformed by bacteria intomethylmercury(MeHg)whichbioaccumulatesmainlyinfish.HumanexposuretoMeHgfrom contaminated fish and fish products can pose a variety of health risks.Methymercuryisaknownneurotoxin.ItisabsorbedintothebodyaboutsixtimesmoreeasilythaninorganicHgandhastheabilitytocrosstheblood‐brainbarrier.Moreover,new investigations indicate thatevenexposure to smallamountsofMeHgmaycauseserious health problems, especially in utero and early in life. Thus, WHO classifiedMeHgasoneofthetoptenchemicalsofmajorpublichealthconcern.

Intake of MeHg through fish and fish products is assessed in sensitivepopulationsworldwide, aswell as in Serbia,where thepreliminary results exist. Thevulnerablepopulationsarepregnantwomen,theirunbornchildrenandchildren.Theirexposure to MeHg should therefore be minimized, while recognizing that fishconstitutesanimportantpartofabalanceddiet.Internationalorganizations(FDAandEPA)haveissuedrecommendationsregardingfishspeciesthatarehealthyandsafetoeatinordertoinformpregnantwomenandparentsofyoungchildren.

The global situation about the presence of MeHg in the food chain anddemonstrated adverse effects on human health have raised the concern of thegovernmentsworldwideandledtotheadoptionoftheMinimataConventionin2013.TheConventioncoversarangeofactions,includingdecreaseinmercuryemissionsintothe air by stopping the use of mercury in gold mining, eliminating the mining ofmercuryandphasingoutcertainmercury‐containingproducts.

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DOKAZITOKSIČNOSTIUSPORIVAČAGORENJA‐POLIBROMOVANIDIFENILETRI

MarijanaĆurčić

Katedrazatoksikologiju„AkademikDaniloSoldatović”,UniverzitetuBeogradu

‐Farmaceutskifakultet(Srbija)Polibromovanidifeniletri(PBDEs)suindustrijskehemikalijekojesukorišćeneu

različitim vrstama proizvoda kao što su računari, mobilni telefoni, bela tehnika,predmeti od plastike i poliuretanske pene, itd. I pored dobrih karakteristika kaousporivačagorenja,utvrđeno jedaovehemikalije izazivajubrojne toksičneefektenazdravljeljudiiživotnusredinu.

PBDEssemogutransportovatinavelikeudaljenostiiperzistentnisuzagađivačiživotnesredinesobziromnadugopoluvremerazgradnje.NajvišekoncentracijePBDEsizmerene su u krvi stanovništva koje živi u blizini deponija opasnog električnog ielektronskog otpada ili zaposlenih na poslovima njihove reciklaže. Epidemiološke ieksperimentalne studije ukazuju da izloženost PBDEs može ispoljiti toksičnost nabrojneorgane i sistemeorgana.Dokazana je toksičnostPBDEsna štitastu žlezdu i tonajčešće u vidu sniženja nivoa hormona T4, T3 i TSH što može dalje rezultirati iporemećajimaurazvojucentralnognervnogsistema.PoredštitasteStudijeukazujuinahepato toksičnosti ovih hemikalija, kao i toksične efekte na imuni system, muškireproduktivnisistemipankreas(nastanakDiabetesmellitus‐a).Međunarodnaagencijaza istraživanje karcinoma (IARC) klasifikuje PBDEs u grupu 3 (ne klasifikuju se kaokarcinogenizaljude),ainvitroispitivanjasvedočeiocito‐igenotoksičnompotencijaluovihhemikalija.MehanizmitoksičnostiPBDEsnisuupotpunostirazjašnjeni,anekiodpredloženih mehanizama su vezivanje za receptore za aromatične ugljovodonike,nastanakoksidativnogstresa,uticajnaaktivnostenzimakaoštosumonooksigenazaitransferaza, itd.Dokazanneprihvatljiv rizikPBDEs za zdravlje ljudi i životnu sredinuiniciraojezabranuiliograničenjenjihoveproizvodnje,stavljanjauprometikorišćenja,aregulatorniosnovzasprovođenjeovihaktivnostijedalaStokholmskakonvencija.

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EVIDENCEOFFLAMERETARDANTSTOXICITY‐POLYBROMINATEDDIPHENYLETHERS

MarijanaĆurčić

DepartmentofToxicology„AkademikDaniloSoldatović”,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Polybrominated diphenyl ethers (PBDEs) are industrial chemicalswhichwere

used in different type of products such as PCs, cell phones, appliances, plastics,polyurethanefoams,etc.Despitegoodcharacteristicsasflameretardants,itwasfoundthatPBDEscausenumeroustoxiceffectsinhumanandenvironment.

PBDEs could be transported to long distances and they are persistentenvironmentalpollutantshavinginmindtheirlongdegradationhalf‐time.ThehighestPBDEs concentrations weremeasured in blood of citizens living in the proximity ofelectronical and electrical waste landfills or who work in recycling factories.Epidemiological and experimental studies imply that exposure to PBDEs may exerttoxicityonnumerousorgansandorgansystems.Toxicityforthethyroidglandhasbeenprovenand ismost frequentlymanifested asdecreasedT4,T3 andTSH levelswhichresultsincentralnervoussystemdevelopmentaldisorders.Studiesalsogiveevidenceoftheirhepatotoxicity,immunotoxicity,malereproductivetoxicityandtoxiceffectsonpancreas (Diabetesmellitus development). The InternationalAgency forResearchonCancer (IARC) has classified PBDE as aGroup3 carcinogen (not classifiable as to itscarcinogenicitytohumans)andinvitrostudiespointtocyto–andgenotoxicpotentialofthesechemicals.Mechanismsoftoxicityarestillratherunexplained,butsomeofthesuggested mechanisms are bounding to aryl hydrocarbon receptor, oxidative stressinduction, interference with the activity of enzymes such as monooxigenase andtranspherase,etc.Provenunacceptableriskforhumanhealthandenvironmentinitiatedbans and restrictions of their production, placing on the market and use, whileregulatorybasisfortheseactivitieswassetbytheStockholmconvention.

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REPUBLICISRBIJIJasminkaRanđelović,JelenaMilić,ValentinaMart,LazarijaŠojićAlternativazabezbednijehemikalije‐ALHem,Beograd(Srbija)

JedanodvažnihciljevaALHem‐a,kaoorganizacijecivilnogdruštvakojasebavi

bezbednim upravljanjem hemikalijama, jeste praćenje primene zakonske regulativekoja se odnosi na hemikalije i u tom smislu ALHem redovno sprovodi ispitivanjaprisustva opasnih hemikalija u proizvodima za široku potrošnju koji se nalaze natržištu RS. U toku 2017/2018 godine sproveli smo kampanju pod nazivom „Toksičniračun” sa ciljem da skrenemo pažnju javnosti na prisustvo bisfenola A (BPA) utermalnimpapirima,presvegafiskalnimračunimaibankovnimisečcima,sakojimasvisvakodnevnodolazimoukontakt.

BPAseodjanuara2018.godinenalazinaListikandidatasupstancikojeizazivajuzabrinutost(Substancesofveryhighconcern–SVHC)uEU,sobziromdajedokazanodamožeštetnodautičenaplodnost idaometaradendokrinogsistema.Udecembru2016. godine Evropska komisija je donela odluku o zabrani, odnosno ograničenjuupotrebe bisfenola A u termalnom papiru, ukoliko je koncentracija BPA veća od ilijednaka 0,02masenih procenata. Ova odluka počinje da se primenjuje od 2. januara.2020.godine.RepublikaSrbijajeuaprilu2018.godinepreuzelaovuodredbuudomaćezakonodavstvo.PrisustvoBPAjelaboratorijskitestiranouukupno33uzorka,odčega:20 termalnihpapira (fiskalnih računa i drugih termalnihpapira iz javnog i privatnogsektora),kaoipapirneiplastičneambalažezahranu.

Rezultatisupokazalidasusviuzorciuvezenihfiskalnihrolni termalnogpapirapozitivninasadržajBPA,ukoncentracijiod0,63do0,91masenih%.Imajućiuvidudanaevropskomtržištupostojesnabdevači termalnogpapirakojinesadržeovuopasnuhemikaliju,apelujemonainstitucijeudržavnomijavnomsektoru,kaoinakompanijeuprivatnomsektoru,naročitonatrgovačkelancedazameneovajproizvodbezbednijomalternativombezBPAkakobidoprineli očuvanju zdravlja svojih zaposlenih, naročitokasirki,aliisvihgrađanaSrbije.

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HAZARDOUSCHEMICALSINARTICLESFOREVERYDAYUSEANDREGULATORYASPECTASACONTROLMECHANISMINEUAND

SERBIAJasminkaRanđelović,JelenaMilić,ValentinaMart,LazarijaŠojić

SaferChemicalsAlternative‐ALHem,Belgrade(Serbia)OneoftheimportantgoalsofALHem,asacivilsocietyorganizationdealingwith

the safe chemicals management, is to monitor the implementation of chemicalslegislation, and in this aspect ALHem regularly tests the presence of hazardouschemicals in consumer goods placed on the Serbian market. During 2017/2018, weconductedacampaigncalled„ToxicCashReceipts”withthegoalofdrawingattentionof thepublic to thepresence of bisphenolA (BPA) in thermal papers, primarily cashreceiptsandbankingslips,withwhichweareinthecontacteveryday.

Since January2018,BPAhasbeenon theCandidateListof SubstancesofVeryHighConcern(SVHC) in theEU,because itwasproved tobeharmful for fertilityanddisruptiveforendocrinesystem.InDecember2016,theEuropeanCommissionmadeadecisiontoban,i.e.restrictuseofBPAinthermalpaper,ifconcentrationofBPAequalsor exceeds 0.02 mass %. This decision shall be applied as of 2 January 2020. TheRepublic of Serbia has transposed this provision in April this year into the nationallegislation. The presence of BPA was laboratory tested in a total of 33 samples, ofwhich: 20 thermal papers (cash receipts and other thermal paper from public andprivatesectors),aswellasonplasticandpaperfoodpackaging.

The results indicated that all samples of imported cash receipts rolls werepositive on BPA, in the range of 0.63 and 0.91mass%. Taking into account that onEuropean market exists suppliers of BPA free thermal paper, ALHem calls uponinstitutions from state and public sectors, as well as upon companies from privatesector,especiallyupontradechains,toreplacethisproductwithsaferalternative,soasto contribute to health protection of their staff, especially cashiers, but also of allcitizensofSerbia.

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PRIMENA3DŠTAMPEUFARMACIJI‐IZAZOVIIPERSPEKTIVE

SvetlanaIbrić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Tehnologija3Dštampeseintezivnorazvijalauproteklojdeceniji,aprimenaove

tehnologijeumedicinskesvrhepostajeveomaaktuelna.NakonregistracijeSPIRITAM®tableta,koje jeFDAregistrovala2015.godine,akojesuproizvedenetehnologijom3Dstampe,postojipovecan intereszaprimenuaditivneproizvodnjeu farmaciji,posebnokada su u pitanju čvrsti oralni farmaceutski oblici. Uvedena je i nova rec za tabletepripremljenekoriscenjemove tehnike– „printlete”.Glavnipokretači za3Dštampanjelekova su personalizovana terapija za posebne grupe pacijenata (pedijatrijska iligerijatrijska populacija); precizne doze lekova, kao i proizvodnja na zahtevpojedinacnog pacijenta, sa leksibilnoscu doze. Pored toga, moguce je proizvoditi„polypill”‐jedandoziraniobliksadveilivišelekovitesupstanceivišerazličitihkinetikaoslobađanja leka.Magistralna izrada lekova u apoteci se cini odgovarajucimmestomgde bi se mogli pripremati 3D štampani lekovi, kada su propisani za potrebepojedinačnog pacijenta, a sadrže personalizovane doze sa unapred određenimkoličinama leka. Postoji nekoliko 3D tehnologija štampe koje su na raspolaganjuistraživačima: (1) „ink‐jet” štampa u obliku mlaznica; (2) modeliranje fuzionimtaloženjem ‐ ekstruzijamaterijala; (3) stereolitografija – fotopolimerizacija; (4) fuzijapraška ‐ selektivno lasersko sinterovanje; (5) ekstruzija gela/paste. Prednosti 3Dštampeupoređenjusakonvencionalnomproizvodnjomlekovaogledajuseupreciznojkontrolidoziranja, reproduktivnosti, inovativnosti imogućnostimodelovanjakinetikeoslobađanjaleka.

Uprkos napretku, 3D štampanje i dalje ostaje nova tehnologija i zbog toga jesuočenasabrojnimetičkimiregulatornimpitanjima.Postojinizznačajnihpitanjakojamorajubitirazmotrenaubudućnosti,kaoštosuproblemfalsifikovanjalekova,prometneregistrovanihlekova,kaoibrojnaregulatornapitanja.

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3DPRINTINGFORPHARMACEUTICALAPPLICATIONS–

CHALLENGESANDPROSPECTS

SvetlanaIbrić

DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade–FacultyofPharmacy(Serbia)

3Dprintingtechnologyhasbecomeveryatractiveinmedicineinthepastdecade.

WithFDAapprovalof SPIRITAM® tabletsmanufacturedby3Dprinting technology in2015, there is increased interest in the fieldof additivemanufacturing, especially forsolid oral dosage forms. Even the new word for the tablets prepared using thistechnique is addopted – printlets. Main drivers for 3D printing of medicines arepersonalizedtherapyforspecialgroupsofpatients(pediatricorgeriatricpopulation);precisedosemedicationaswellason‐demand,point‐of‐caremanufacturing(withdoseflexibility). Additionaly, using additive manufacturing, it is possible to manufacture„polypill”‐onedosageformwithtwoormoredrugs.Thecompoundingpharmacyseemsto be the appropriate site where 3D printing medications can be prepared whenprescribed/ordered,andpackaged,handled,administeredandchargedinpersonalizeddoseunitscontainingapredeterminedamountofdrug.Thereareseveral3Dprintingtechnologiesthatareavailableforresearchers:(1)powderbedink‐jetheadprinting‐binder jetting; (2) fused deposition modeling – material extrusion; (3)stereolithography– vatphotopolymerisation; (4)powderbed fusion– selective lasersintering; (5) gel/paste extrusion ‐material extrusion. The advantages and obstaclesforeachmethodwillbediscussed.

Considering the advantages of 3Dprinting, i.e. accurate control of droplet sizeanddosage,highreproducibility,complexstandardizeddrugmanufacturingprocesses,andtheabilitytoproducedosageformscharacterizedbyinnovativeanduniquedosageforms,personalizeddrugdosing,andcomplexdrug‐releaseprofiles,undoubtedly, thechallengetoconventionaldrugproduction is imminent.Despiteprogress,3Dprintingstill remains a new technology and therefore suffers from ethical and regulatoryproblems. There are a number of significant concerns related to possibility ofcounterfeit drugs, proliferation of illegal medicines, mislabelling and regulatoryvacuum,thatmustbeaddressed.

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SAVREMENIPRISTUPODABIRUFORMULACIJEIEKSCIPIJENASA

RužicaKolaković

JanssenPharmaceutica,Johnson&Johnson(Belgija)

Većina novih aktivnih supstanci koje ulaze u fazu razvoja poseduju slabu

rastvorljivot i/ilibrzinurastvaranjauvodištodovodidoniskebioraspoloživosti.Dvanajčešća pristupa rešenju ovog problema su formulacija aktivne supstance u oblikumekihželatinskihkapsulaikonverzijakristalnesupstanceuamorfnučvrstudisperziju(tehnikom sušenja raspršivanjem ili ekstruzijom). Veliki broj faktora mora bitirazmotren u toku razvoja mekih kaspula i čvrstih disperzija pri čemu je odabirekscipijenasainjihovekoličineuformulacijijedanodnajvažnijih.

Trenutno dostupne tehnike za selekciju, unapređene od strane mnogobrojnihsvetskih laboratorija, zasnovane su na različitim teorijskim i eksperimentalnimprincipima, ali u svrhu ostvarenja zajedničkog cilja ‐ odabir formulacije koja ćeobezbeditipotrebnubioraspoloživostiistovremenoposedovatifizičkustabilnost.Izboroptimalne formulacije često zahteva veliko finansijsko i vremensko ulaganje, kao iutrošak značajne količine aktivne supstance koja je u ranim fazama razvoja čestonedostupna. U cilju rešenja ovog problema unapređen je automatizovani skriningvisokogoperativnogkapaciteta (High throughput screening ‐HTS)koji se zasnivanaupotrebimale zapremine uzorka. Skrining se koristi u cilju odabira ekscipijenasa zaformulacijumekihkapsulaičvrstihdisperzijaiizvodiseupločamasa96‐bazenčića(96well‐plate).Začvrstedisperzijeskriningsebaziranaizraditankihfilmovakojisadrže25‐75µgaktivnesupstance.Odabirnajboljeformulacijeizvodisenaosnovutestiranjaoslobađanja supstance iz filma, kao i stabilnosti filma (na povišenoj tempraturi ivlažnosti). Istovremeno se mogu testirati 43 formulacije uz utrošak 1 g aktivnesupstance.Zaformulacijumekihkapsularastvorljivostaktivnesupstanceu96različitihekscipijenasa i njihovih kombinacija se testira istovremeno uz korišćenje 300 µlekscipijensa po uzorku. Primenom ove tehnike značajno se redukuju vreme i novacpotrebnizaunapređenjenoveformulacijeuzminimalanutrošakaktivnesupstance.

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MODERNAPPROACHTOFORMULATIONANDEXCIPIENTSSELECTION

RužicaKolaković

JanssenPharmaceutica,Johnson&Johnson(Belgium)

Vast majority of new active pharmaceutical ingredients (APIs) entering

developmentpipelinepossessinsufficientwatersolubilityand/orlowdissolutionrate.Thesecausechallengesinachievingdesiredbioavailability.Twomostfrequentlyusedapproaches to overcome this problem are incorporation of API in a lipid baseddrugdelivery system (LBDDs) (i.e. soft‐gel capsule formulation) and conversion ofcrystallineAPItoitsamorphousformbymeansofspraydryingorhot‐meltextrusion(i.e.amorphoussoliddispersions,ASD).

Variety of formulation parameters can affect the development of ASDs andLBDDs with selection of appropriate excipients and their ratio being one of them.Number of research laboratories have been developing their own screeningmethodologies, either based on experimental data or based on theoreticalfundamentals with one common goal ‐ choosing the right formulation compositionwhichwill ensure both desired bioavailability and physical stability of drug productoverintendedshelf‐life.

Selectingtheoptimalformulationcantakeavastamountoftime,beextremelycostlyand,importantly,requiresignificantamountofAPIwhichisnotreadilyavailableintheearlyphaseofdevelopment.Totacklethis,JanssenPharmaceuticahasdevelopedlow‐volume automated high throughput screening platform for selection of ASD andlipidbasedformulations.Suchascreenisperformedin96well‐plateusingautomatedliquidand soliddispensing.ForASDsa filmcastingmethod isused resulting in filmscontaining25‐75μgofAPI.Producedfilmsareevaluatedfortheirdissolutionratebysmall scale dissolution method and their stability assessed by exposing them tostressingconditions(elevatedtemperatureand/orrelativehumidity). Inthatway,43ASDformulationscanbetestedsimultaneouslywithuseofonly1gofAPI.ForLBDDssolubilityofAPIisperformedin96prototypeformulationssimultaneously.Usingthisapproach significant reduction in development time and cost, improved success rateandminimizedAPIconsumptionareachieved.

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LEKOVAZASPROVOĐENJEKLINIČKIHISPITIVANJA

MarijaTubić‐Grozdanis

Univerzitetskikliničkicentar,JohanGutenbergUniverzitetuMajncu(Nemačka)Timkliničkogfarmaceutasesvakodnevnosuočavasarazličitimizazovimatokom

sprovođenjakliničkihstudijarazličitihfaza.Adekvatnoobučenoosobljeiodgovarajućiresursi kvalifikuju bolničku apoteku za učešće u kliničkim ispitivanjima na različitenačine:odpripremeiizdavanjaleka,popunjavanjapropratnedokumentacije,pasvedopreuzimanja uloge koordinatora studije i glavnog istraživača. Tokom kliničkogispitivanja (sponzorisanog od strane industrije ili pokrenutog od strane istrazivača)klinički farmaceut učestvuje u procesu revizije protokola kliničke studije, izrade,pakovanja i obeležavanja lekakoji se ispituje, kao iudefinisanju strategijeuplacebokontrolisanim studijama. Klinički farmaceut je takođe uključen u sagledavanjemogućnosti nabavke kvalitetnih aktivnih i pomoćnih supstanci, proceni troškovarazvoja formulacije i izrade preparata, proces pribavljanja saglasnosti za izvođenjekliničke studije, kao i u određivanju mogućih rizika primene i problema u izradipreparatazasprovođenjekliničkih ispitivanja.ADKA(Udruženjekliničkih farmaceutaNemačke) je objavila smernice o učestvovanju kliničkih farmaceuta u komercijalnimkliničkim ispitivanjima prema GCP pravilima, koje utvrđuju standarde u pogledurekonstitucije,čuvanjaidistribucijepreparatakojisekoristeukliničkimispitivanjima.Odeljenje za kliničke studije bolničke apoteke Univerzitetskog kliničkog centra uMajncuposedujeGMPdozvoluod2006.godineiučestvujeurazvojuformulacija,izradii distribuciji lekova za klinička ispitivanja u različitim centrima širom sveta.Proizvodnja obuhvata pripremu kapsula, punjenje ili prepakivanje ispitivanih, kao iplacebo preparata. Analitičkemetode i testovi stabilnosti su važna potpora razvoju iizradipreparatakojisekoristeukliničkimstudijama.PostojanjeOdeljenjazakliničkestudijeubolničkojapoteci,kaoimogućnostštoranijeguključenjakliničkogfarmaceutau kliničko istraživanje je presudno za uspešnu saradnju kliničkog centra (pacijenti imedicinsko osoblje), bolničke apoteke i farmaceutske industrije, čime se kliničkoistraživanjeusmeravakabrzojiuspešnojprimenioptimizovaneinovativneterapije.

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CLINICALPHARMACIST’SROLEINCLINICALTRIALSINVESTIGATIONALDRUGDEVELOPMENT

MarijaTubić‐Grozdanis

UniversityMedicalCenter,JohannesGutenbergUniversityMainz(Germany)

Clinical pharmacists team daily faces different challenges in terms of running

multipleclinicalstudiesatmultiplestages.Withadequatetrainedstaffandresources,hospitalpharmacycanbe involved inclinical trialresearch inavarietyofways, fromproviding drug and record keeping for drug accountability to taking on the rolesranging from study coordinator to principal investigator. In clinical trials (industry‐sponsored or investigator‐initiated trials), clinical pharmacist is able to advise onreviewprocessofclinicaltrialprotocols,pharmacymanuals,manufacturing,packagingandlabelingofinvestigationaldrug,aswellasthetechniques,challengesandstrategiesin comparatorblinding.Clinicalpharmacist isalso involved in the issuessuchas: thesource,qualityandcostsof investigationaldrug, the regulatoryapprovalprocess, theidentificationof possible clinical risk and safety aspects of drughandling, dispensingandreconstitution.TheADKA(AssociationofGermanHospitalPharmacists)releasedaguideline on the participation of hospital pharmacies in commercial clinical trials inadherencetoGCP(GoodClinicalPractice).Theguidelineconstitutesqualitystandardsfor pharmacy services in Germany regarding: reconstitution, storage, logistics,documentationanddestruction.Clinical trialUnitof thePharmacyDepartment in theUniversityMedicalCenterinMainz,asaholderofaGMP(GoodManufacturingPractice)manufacturinglicencesince2006,providesformulationassistance,manufacturinganddistribution to national and international clinical sites. Manufacturing comprisesencapsulation, filling or re‐packaging of investigational and placebo products.Formulation development is supported by analytical and stability testing (includingmicrobiologicalassays).TheexistenceofClinicaltrialunitwithinahospitalpharmacyand early as possible involvement of clinical pharmacists in clinical trial research iscrucial for successful partnership between clinical site (patients and health careprofessionals), hospital pharmacy and pharmaceutical industry, support clinical trialresearchintherightdirectionandleadtolesstimeconsumingandcostoptimization.

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INKAPSULACIJAODABRANIHSUPERKRITIČNIHEKSTRAKATALEKOVITOGBILJAULIPOSOMEMETODOMHOMOGENIZACIJEPOD

VISOKIMPRITISKOMIvanaArsić1,VanjaTadić2,MilicaStanković1,VesnaSavić1

1Katedrazafarmaciju,UniverzitetuNišu‐Medicinskifakultet,2Institutza

proučavanjelekovitogbilja„DrJosifPančić”,Beograd(Srbija)

Liposomi su fosfolipidni, biodegradabilni i biokompatibilni vezikularni sistemi

koji se koriste za stabilizaciju, poboljšanje penetracije i permeacije,produženo/kontrolisano oslobađanje, kao i povećanje bioraspoloživosti teškorastvornihlekovitihsupstanci.Zaproizvodnjubiljnihitradicionalnihbiljnihlekovasvečešće se koriste ekstrakti dobijeni procesom superkritične ekstrakcije koja ima nizprednostiuodnosunakonvencionalnemetode:dobijajuseekstraktisaznačajnovećomkoncentracijom aktivnih principa, povećane stabilnosti, bez teških metala i drugihzagađivača(mikroorganizama),bezugrožavanjaintegritetatermolabilnihsupstanci,uzočuvanježivotnesredine(brzouklanjanjeekstragensa‐gasausuperkritičnomstanju)imogućnostvišestrukog frakcionisanjaekstrakta.Ekstrakti suvisoke lipofilnosti,paseradipoboljšanjarastvorljivostiuvodi,resorpcijeibioraspoloživostimoguinkapsuliratiu liposome. Proces se može izvesti korišćenjem prečišćenih frakcija fosfolipida,metodom homogenizacije pod visokim pritiskom. Cilj rada bio je utvrđivanje uticajaprirode ekstrakta i parametara procesa (pritisak i broj ciklusa homogenizacije) naefikasnost inkapsulacije, veličinu (srednji prečnik, RL) i indeks polidisperziteta (IP)liposoma iz prečišćenog fosfolipida Phosal‐a 75SA (Lipoid GmbH, Nemačka) inatkritičnihekstrakata:talusališajbrade,herbetimijana,smiljaimajkinedušice, listamatičnjakaišišaricahmelja.Liposomisuformiraniprimenompritiskaod300,odnosno500 bara, a broj ciklusa homogenizacije iznosio je 7, odnosno 10. Proces je izvedenkorišćenjemhomogenizatorapodvisokimpritiskom(EmulsiFlex‐C3,Avestin,Kanada).Dobijene disperzije liposoma čuvane su u staklenim bočicama, dobro zatvorene, nasobnojtemperaturiuperioduod3mesecaastabilnostjepraćenamerenjemRLiIPudefinisanimtestterminima.RPiIPmerenisunaaparatuZetasizerNanoZS90(MalvernInstruments,VelikaBritanija).Rezultatiukazujunaznačajanuticajvrstesuperkritičnogekstrakta, primenjenog pritiska i broja ciklusa homogenizacije na RL i IP i njihovufizičku stabilnost. Postupkom homogenizacije (10 ciklusa, 500 bar), korišćenjemPhosal‐a 75SA mogu se inkapsulirati ispitivani superkritični ekstrakti u liposomezadovoljavajućih karakteristika (srednji prečnik u rasponu 179‐235 nm, efikasnostinkapsulacije45‐55%)istabilnostiuposmatranomperiodu.

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INCAPACULATIONOFSELECTEDMEDICINALHERB᾿SSUPERCRITICALEXTRACTSINLIPOSOMESUSINGTHEHIGH

PRESSUREHOMOGENIZATIONMETHODIvanaArsić1,VanjaTadić2,MilicaStanković1,VesnaSavić1

1DepartmentofPharmacy,UniversityofNiš‐FacultyofMedicine,2Institutefor

MedicinalPlantResearch„DrJosifPančić”,Belgrade(Serbia)Liposomesarephospholipid,biodegradableandbiocompatiblevesicularsystems

which are used to stabilize, improve penetration and permeation, forprolonged/controlled releaseand increase thebioavailabilityofmedicinal substancesthat are difficult to dissolve. The usage of extracts obtained by the supercriticalextraction process for the production of herbal and traditional herbal remedies isincreasing,duetoanumberofadvantagesofsupercriticalextractionincomparisontoconventional extraction methods: it gives extracts with significantly higherconcentrationofactiveprincipleswithbetterstability,withoutheavymetalsandotherpollutants (microorganisms), without compromising the integrity of thermolabilesubstances,withthepreservationoftheenvironment(rapidremovalofextragent‐gasinsupercriticalstate)andwiththepossibilityofmultiplefractionationoftheextracts.Becausetheextractshaveahighleveloflipophilicity,theycanbeencapsulatedintheliposomes,inordertoimprovesolubilityinwaterandtoenablebetterapsorptionandbioavailability. The process can be carried out using purified phospholipid fractionsandahighpressurehomogenizationmethod.Theaimoftheworkwastodeterminetheinfluence of extract characteristics andprocess parameters (pressure andnumber ofhomogenization cycles) on the efficiency of encapsulation, size (mean diameter, RL)andindexofpolydispersity(IP)ofliposomesfrompurifiedphospholipidsPhosal75SA(LipoidGmbH,Germany)andsupercriticalextracts:thallusofbeardlichen,wildthymeherb,curryplantherb,commonthymeherb, lemonbalm leavesandhops.Liposomeswereformedusingapressureof300and500barandthenumberofhomogenizationcycleswas7and10.Theprocesswascarriedoutusingahighpressurehomogenizer(EmulsiFlex‐C3,Avestin, Canada). The obtained liposomal dispersionswere stored inglass bottles, well closed, at room temperature for a period of 3 months, and thestabilitywastestedbymeasuringRLandIPatdefinedtimeintervals.RLandIPweredetermined using the Zetasizer Nano ZS90 (Malvern Instruments, UK). The resultsshowedthattypeofsupercriticalextract, theappliedpressureandthenumberof thehomogenisationcyclehadaninfluenceontheRL,IPandtheirphysicalstability.Usingthe homogenization procedure (10 cycles, 500 bar), with Phosal 75SA, investigatedsupercriticalextractscanbeencapsulatedinliposomeswithsatisfactorycharacteristics(meandiameterintherangeof179‐235nm,efficiencyofencapsulation45‐55%)andstabilityintheobservedperiod.

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ANTIEPILEPTICIUSVETLUNOVIHINDIKACIJA

RadicaStepanović‐Petrović

Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Uposlednjih 30‐tak godina u upotrebu je ušlo oko 20‐tak novih antiepileptika

(AE). Imajući u vidu da je incidenca epilepsije 0,5‐1%, jasno je da sa ovakvimnapretkomurazvojunovihAEzafarmaceutskuindustrijunemožesamoepilepsijabitiatraktivnakaoindikacija,madajesakliničkogaspektaproblemrezistentnihepilepsijajoš uvek nerešen. S druge strane,mnogi AE imajumultimodalanmehanizam dejstvakojičestouključujemodulacijuGABA‐ergičkeiglutamatergičkeneurotransmisijekaoipromeneuaktivnostivoltažnozavisnihkanalazanatrijumikalcijumiintracelularnihsignalnihputeva.Zbogsvegaovoga,poslednjihdecenijajeindikacijskopoljepojedinihAE postalo bogatije za izvesne neurološke i psihijatrijske bolesti. Konkretno,najznačajnije nove indikacije za AE su neuropatski bol, profilaksa migrene,fibromijalgija,bipolarniporemećajigeneralizovanianksiozniporemećaj.Pregabalinjeupravo zbog proširenja indikacijskog područja (neuropatski bol, dodatna terapija ulečenju fokalnih epileptičkih napada, generalizovani anksiozni poremećaj) postao u2018.godinijedanodlekovakojijeostvarioenormneprihode(blockbuster).

Nisu sviAEefikasniunavedenim indikacijamakojenisuuvezi saepilepsijom.Samo oni AE čiji se mehanizam dejstva dobro uklapa sa patofiziologijom određenihbolesti imaju potencijal da budu efikasni u ne‐epileptičnim indikacijama. Tako sukarbamazepin, valproinska kiselina i lamotrigin odobreni za primenu u bipolarnomporemećaju, dok karbamazepin i gabapentinoidi (gabapentin i pregabalin)predstavljaju osnovne lekove u lečenju različitih neuropatskih bolnih sindroma. Zaprofilaksu migrene se koriste valproati, topiramat i gabapentin, dok se gabapentinkoristijošizaublažavanjesimptomamenopauze.

Posebno se novi AE ispituju preklinički i klinički u nekim ne‐epileptičnimoboljenjima.IdokvelikavećinanovihAEpokazujuefikasnostuprekliničkimimanjimotvorenim kliničkim studijama, u randomizovanim placebo kontrolisanim kliničkimstudijama neki AE pokazuju odsustvo efikasnosti. Zato prednost treba datikontrolisanim kliničkim studijama kako bi njihovi pozitivni rezultati vodili ka čvrstoutemeljenojindikacijiane„off‐label”upotrebi.

OvajradjefinansiranodstraneMinistarstvaprosvete,naukeitehnološkograzvoja

RepublikeSrbije(Projekatbr.175045).

184

ANTIEPILEPTICSINLIGHTOFNEWINDICATIONS

RadicaStepanović‐Petrović

DepartmentofPharmacology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Inthelast30years,20newantiepilepticdrugs(AEDs)havebeenintroducedin

themarket.Bearinginmindthattheincidenceofepilepsyis0.5‐1%,itisclearthatwithsuchprogress indevelopingnewAEDs,epilepsyalonecouldnotbeattractive for thepharmaceutical industry, although the clinical needs of refractory epilepsy remainunmet. On the other hand, most AEDs have multiple mechanisms of action whichincludemodulationofGABA‐ergicandglutamatergicneurotransmission,andalterationofvoltage‐gatedsodiumandcalciumchannelsorintracellularsignalingpathways.Asaresult of all this, in recent decades there has been an expansion of indications ofindividualAEDforcertainneurologicalandpsychiatricdiseases.Inparticular,themostsignificant new indications for AEDs are neuropathic pain, migraine prophylaxis,fibromyalgia, bipolar disorder and generalized anxiety disorder. Because of thewideningof indicationarea (neuropathicpain,adjunctive therapy in the treatmentoffocal seizures, generalized anxietydisorder) pregabalin has becomeoneof thedrugsthatgeneratesenormousrevenues(blockbuster)in2018.

NotallAEDsare effective in treatingnonepileptic conditions.Only thoseAEDswhosemechanismofactionfitswellwiththepathophysiologyofcertaindiseaseshavethe potential to be effective in nonepileptic indications. In that way, carbamazepine,valproic acid and lamotrigine are approved for use in bipolar disorder, andcarbamazepineandgabapentinoids(gabapentinandpregabalin)arecentral drugs inthe treatment of various neuropathic pain syndromes. Valproate, topiramate andgabapentin areused forprophylaxis ofmigraine, andgabapentin is usedalso for thereliefofmenopausalsymptoms.

New AEDs are particularly tested preclinically and clinically in somenonepilepticconditions.ThevastmajorityofnewAEDsshowefficacyinpreclinicalandsmall open‐label clinical studies, but fail to provide strong evidence in randomized,placebo‐controlled clinical trials. Therefore, priority should be given to controlledclinical trialswhosepositiveresultscould leadtoa firmlygroundedindicationratherthanoff‐labeluse.

This work was supported by the Serbian Ministry of Education, Science and

TechnologicalDevelopment(grant175045).

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Arh.farm 2018;68:185 PP45

BENZODIAZEPINESAREALLALIKE‐EXCEPTWHENTHEOPPOSITECOMESTRUE

MargotErnst

MedicalUniversityofVienna‐DepartmentofMolecularNeurosciences

(Austria)Pharmacology textbooks to this date still state that all benzodiazepine based

medicinesactbythesamemechanism,namelytheunselectiveallostericmodulationofGABA‐Areceptorsbyinteractionwithfourhighaffinitybindingsites.Thisviewhasalsoled toefforts fordevelopingagents thatare selective foronlyoneof these four sites,where„Z‐drugs”areconsideredprototypical„alpha‐1‐selective”agents.

Carefulscrutinyoftheliteraturesuggestsamorecomplexpicture,andcliniciansare convinced that the assumption of a „common mechanism” falls short of anyobjectively useful and correct model. Here we approach the issue from twoperspectives,namelythemolecularviewpointwhichrevealsamuchlargernumberofpotentially importantbindingsites thatmayaccount for invivoeffects, and fromtheclinicalperspective.Thecaseofapatientwhodisplaysmassiveparadoxicaleffectstobromazepam, but not to several other benzodiazepines, suggests that the notion of„positiveallostericmodulation”alsoshouldberefinedandrevisited.

Thus,wewillprovideanoverviewofallknownbenzodiazepinebindingsitesonthelargefamilyofbenzodiazepine‐sensitiveGABA‐Areceptorsubtypes.Basedonthismolecularmultitudeof sites,wewilldiscuss theneed toclosegaps in theknowledgeabout the interactionsofapprovedmedicationswithso far lessstudiedbindingsites.We will further provide a literature review which clearly indicates that acute andchronicbenzodiazepineeffectsindicatecomplexitywellbeyondany„four‐site‐model”.We finally will discuss the molecular nature of „positive allosteric modulation” andsuggestrefinedviewsontothetermsof„benzodiazepine‐siteagonists,inverseagonistsandantagonists”.

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ALFA1,2,3,4,5,6GABAARECEPTORI:ŠTOVIŠETOBOLJEKAOCILJZANOVELEKOVE?

MiroslavSavić

Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)

Jonotropni GABAA receptori su najzastupljenija populacija receptora u

centralnomnervnomsistemu,kojukarakterišeizuzetnaraznovrsnost.Nesamodačak19podjedinica()možedaučestvujeu formiranjupentamernogagregata, već suone različito eskprimiraneu različitim reginimaneurona (sinaptičkaprema ekstrasinaptičkoj lokalizaciji) i osim toga u različitim strukturama mozga.Pojedinačna karakteristika GABAA receptora koja u najvećoj meri određuje uloguodgovarajuće populacije receptora jeste prisustvo jednog od šest podtipova alfapodjedinice.Doksuprvetripopulacije(alfa1GABAA,alfa2GABAAialfa3GABAApodtip)lokalizovanegotovoupotpunostisinaptički,narednetripopulacije(alfa4GABAA,alfa5GABAAialfa6GABAApodtip)prisutnesupretežno,akoneiisključivo,ekstrasinaptički.Mnogo napora je ulagano da se sintetišu novi ligandi koji bi posedovali selektivnostafiniteta ili funkcionalnu selektivnost za samo jednu populaciju GABAA receptora.Aktuelnostanjeznanjasugerišedafiziološkaaktivacijai/ilifarmakološkapotencijacijaodgovarajućepopulacijeGABAAreceptoramogudadovedudosledećihbihejvioralnihefekata:sedacije,amnezije,antikonvulzivneaktivnostiipodložnostirazvojuzavisnostiprekoalfa1GABAAreceptora;anksiolize,smanjenereaktivnostinastres,miorelaksacijei antihiperalgezije preko alfa2 GABAA receptora; izmenjene aktivnostisenzornomotornih vratnica, miorelaksacije i antihiperalgezije preko alfa3 GABAAreceptora; kognitivnog oštećenja i regulacije unosa alkohola preko alfa4 GABAAreceptora; anksiolize, smanjenog odgovora na stres, izmenjene aktivnostisenzornomotornih vratnica, kognitivnog oštećenja u zadacima niske interferencije ikognitivnogpoboljšanjautestovimavisokeinterferencijeprekoalfa5GABAAreceptora,iizmenjeneaktivnostisenzornomotornihvratnicaianithiperalgezijeprekoalfa6GABAAreceptora. Sveukupni razvoj koncepta selektivne modulacije populacija GABAAreceptora upućuje na veću verovatnoću postizanja terapijskih proboja u sklopuistraživanja sa ligandima koji deluju preko onih receptora čija je distribucijaograničenija i pretežno ekstrasinaptička, što je slučaj sa alfa5 i alfa6 GABAAreceptorima.

187

ALPHA1,2,3,4,5,6GABAARECEPTORS:THEHIGHERTHEBETTERASATARGETFORNOVELMEDICINES?

MiroslavSavić

DepartmentofPharmacology,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)The ionotropicGABAA receptors aremost abundantpopulationof receptors in

thecentralnervoussystem,characterizedbyanexceptionaldiversity.Notonlythatasmany as 19 subunits () can contribute to formation of thepentameric aggregate, but they are differentially expressed in various regions of aneuron(synapticvs.extrasynaptic localization)andalso indifferentstructuresof thebrain.ThesinglecharacteristicofGABAAreceptorsthatmostlygovernstheroleoftherespectivepopulationofreceptorsisthepresenceofoneofsixalphasubunitsubtypes.While the first three populations (alpha1 GABAA, alpha2 GABAA and alpha3 GABAAsubtype) are located nearly completely synaptically, the latter three (alpha4 GABAA,alpha5GABAAandalpha6GABAAsubtype)arepredominantlyifnotexclusivelypresentextrasynaptically. Much effort has been directed towards synthesis of novel ligandswithaffinity‐or functionalselectivitytoonlyonepopulationofGABAAreceptors.Thepresent state of knowledge suggests that physiological activation and/orpharmacological potentiation of the respective population of GABAA receptors mayresultinthefollowingbehavioraleffects:sedation,amnesia,anticonvulsantactivityanddependenceliabilitythroughalpha1GABAAreceptors;anxiolysis,diminishedreactivityto stress, myorelaxation and antihyperalgesia through alpha2 GABAA receptors;changed sensorimotor gating, myorelaxation and antihyperalgesia through alpha3GABAAreceptors;cognitiveimpairmentandregulationofalcoholintakethroughalpha4GABAA receptors; anxiolysis, diminished response to stress, changed sensorimotorgating, cognitive impairment in low interference tasks and cognitive improvement inhigh interference tasks through alpha5 GABAA receptors; and changed sensorimotorgatingandantihyperalgesiathroughalpha6GABAAreceptors.Theoveralldevelopmentof concept of selective modulation of GABAA receptor populations implies that it ismorerealistictoexpecttherapeuticbreakthroughsatthelevelofnovel ligandsactingthrough those receptors which distribution is more limited and predominantlyextrasynaptic,suchisthecasewithalpha5andalpha6GABAAreceptors.

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Arh.farm 2018;68:188-189 PP47KOMBINACIJEANALGETIKAUSAVREMENOMLEČENJUBOLA

MajaTomić

Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Ublažavanjebola je jedanodnajzahvalnijih zadataka farmakoterapije. Primena

kako klasičnih analgetika (opioida, nesteroidnih antiinflamatornih lekova iparacetamola), tako i alternativnih analgetika (prevashodno antiepileptika iantidepresiva), u pojedinačnoj terapiji, često je nedovoljno efikasna i/ili je praćenaneželjenimefektimakojisenemogupodneti.Dugotrajnaprimenaopioidapovezanajeisarazvojemtolerancijeizavisnosti.Sobziromdaposlednjihnekolikodecenijanijebilootkrićanovihklasičnihanalgetikakojebiznačajnounapredilolečenjebola,traganjezanovim,efikasnijimibezbednijimtretmanimapredstavlja jedanodnajznačajnihciljevasavremenefarmakoterapijebola.

Jedan od načina za postizanje ovog cilja jeste multimodalna analgezija, kojapodrazumevakombinovanuprimenuanalgetikaizrazličitihfarmakološkihgrupa,tj.sarazličitim mehanizmima dejstva. Koncept multimodalne analgezije zasniva se napoznavanju mehanizama transmisije i modulacije bola i delovanju na više različitihciljnihmestaznačajnihuovimprocesimai/ilinavišenivoadužbolnogputa(periferija,spinalni,supraspinalninivo),čimesemogupostićisinergizamiliaditivnostudejstvu.Uprekliničkim uslovima, sinergizam se karakteriše značajnom, više nego dvostrukomredukcijom doza lekova primenjenih u dvokomponentnoj kombinaciji, i može semanifestovatikaopostizanjeodređenognivoaanalgezijemnogomanjimdozamalekovaodonihpotrebnihzapostizanjeistognivoaanalgezijeumonoterapiji,ilikaopovećanjeanalgetičke efikasnosti kombinacije u odnosu na monoterapiju. Iako aditivnostpodrazumevamanju redukcijudoza lekovaprimenjenihukombinaciji negou slučajusinergizma, ona i dalje može biti značajna sa aspekta redukovanja dozno‐zavisnihneželjenihefekata.

Postoje brojni dokazi iz kliničkih studija i veliko kliničko iskustvo samultimodalnomanalgezijomulečenjupostoperativnogimalignogbola.Međutim,koddrugihakutnih,aposebnokodhroničnihbolnihstanjane‐maligneetiologije(kaoštosuneuropatskibol,artritis,fibromijalgija),čijejelečenjevelikiizazov,dokazisuoskudniji,aprimenakombinacija analgetika je često empirijska.Potrebna sudaljapreklinička iklinička ispitivanja kako bi se identifikovale najpovoljnije kombinacije analgetika zarazličitabolnastanja.

OvajradjefinansiranodstraneMinistarstvaprosvete,naukeitehnološkograzvoja

RepublikeSrbije(Projekatbr.175045).

189

COMBINATIONSOFANALGESICSINTHECONTEMPORARY

TREATMENTOFPAIN

MajaTomić

DepartmentofPharmacology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Alleviatingpainisoneofthemostrewardingtasksofpharmacotherapy.Theuse

of both classic analgesics (opioids, nonsteroidal antiinflammatory drugs andparacetamol)andalternativeanalgesics(mainlyantiepilepticsorantidepressants),asasingle‐drug treatment, is often not efficient enough and/or is accompanied byintolerableside‐effects.Long‐termadministrationofopioidsisalsoassociatedwiththedevelopmentoftoleranceanddependence.Sincetherewasnodiscoveryofnewclassicanalgesics in the last few decades thatwould significantly improve the treatment ofpain, the search for new, more effective and safer treatments is one of the mostimportantgoalsofmodernpainpharmacotherapy.

One of the ways to achieve this goal is to use multimodal analgesia, whichinvolves the combined administration of analgesics from various pharmacologicalgroups,i.e.withdifferentmechanismsofaction.Theconceptofmultimodalanalgesiaisbased on knowledge of the mechanisms of pain transmission and modulation, andactingondifferenttargetsinvolvedinthisprocessesand/oratseverallevelsalongthepainpathway (periphery, spinal, supraspinal level),which can result in synergismoradditivity. In preclinical conditions, synergism is characterized by significant, morethanadoublereductionofdosesof thedrugsadministered intwo‐drugcombination,andcanbemanifestedasachievingacertainlevelofanalgesiawithmuchlowerdosesof components than those required to achieve the same level of analgesia inmonotherapy,orasanincreaseintheanalgesicefficacyofthecombination,comparedto monotherapy. Although additivity implies less reduction of the doses of drugsadministeredincombinationthan inthecaseofsynergism, itstillmaybemeaningfulfromtheaspectofdose‐dependentsideeffectsreduction.

Thereisampleevidencefromclinicalstudiesandlargeclinicalexperiencewithmultimodalanalgesia inthetreatmentofpostoperativeandmalignantpain.However,for other types of acute and particularly chronic non‐malignant pain states (such asneuropathic pain, arthritis, fibromyalgia), whose treatment is a major challenge,evidenceisscarce,andtheuseofacombinationofanalgesicsisoftenempirical.Furtherpreclinicalandclinicalstudiesareneededtoidentifythemostfavourablecombinationsofanalgesicsfordifferentpainfulconditions.

This work was supported by the Serbian Ministry of Education, Science and

TechnologicalDevelopment(grant175045).

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ISEDUCATINGPHARMACISTSTOBECOMPETENTENOUGHFORTHEFUTUREOFTHEPROFESSION?

MartinHenman

SchoolofPharmacyandPharmaceuticalSciences,TrinityCollege,Universityof

Dublin(Ireland)In response to the changing needs of patients, of health practitioners in

managingmedicines in complex casesandofhealth services inoptimising theuseofmedicines,theprofessionofPharmacyhasrevisedpharmacyeducationtomeettheseneeds.Fromtheexampleofotherhealthprofessions,pharmacistshavesoughttodefinetheiractivitiesintermsofcompetencies.Eachcompetencycanbedescribedindetailbywhatthepharmacistshouldbeabletodo,bybehaviours,andthecompetenciescanbegrouped together as domains or areas containing the related competencies and theirbehaviours.

Co‐ordinated by the International Pharmacy Federation (FIP), in 2012 thePharmacyEducationTaskforce,launched‘AGlobalCompetencyFramework’.Withfourdomains, Pharmaceutical Care, Pharmaceutical Public Health, Organisation andManagementandPersonal/Professional,and17competencies,thedocumentprovidedconcise guidance for, in its ownwords, ‘anoverviewofhowpractice at a foundationlevelcanbetranslatedinto‘what’and‘how’studentsshouldlearn’.

However, competencies and, in particular, the behaviours that are used todescribethem,canbecomealistofelementstobeassessedandonethatislimitedbythe vision used to create the competency framework and the purpose forwhich theframework is used. Yet pharmacy education is about the student becoming aprofessional, it is a process not an itemised list of outcomes, it is about exercisingjudgementunderdifficultcircumstances,whenmorethanoneoptionmayappeartobeappropriate.Iftheprofessionistohaveafutureinpatientcare,itmustconsidertheseaspectsaswell.

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Arh.farm 2018;68:191-192 PP49STRUČNOOSPOSOBLJAVANJEIPROFESIONALNIRAZVOJ

FARMACEUTA‐AKADEMSKAPERSPEKTIVA

LjiljanaTasić

Katedrazasocijanufarmacijuifarmaceutskozakonodavstvo,UniverzitetuBeogradu–Farmaceutskifakultet(Srbija)

Farmaceutskikadrovisuključnizaočuvanjeiunapređenjezdravlja,aposebnoza

bezbednost pacijenata shodno izazovima novih tehnologija. Farmaceuti treba da sukvalifikovani i visoko kompetentni stručnjaci, aktivni učesnici zdravstvene zaštiteorijentisaninapacijenta,spremnizakolaborativnupraksu,profesionalniiličnirazvojikontinuirano unapređenje. Ovo zahteva promene u pristupu obrazovanju kojeakademska zajednica treba da prepozna, prihvati, sprovodi i unapređuje. Stručnoosposobljavanje farmaceuta podrazumeva stepenasti sistem koji obuhvata najmanječetiri godine teorijske i praktične nastave na univerzitetu i najmanje šest meseciprofesionalneprakseuapoteciutokudodiplomskihstudija iliuokvirupripravničkogstaža,presticanjalicencezasamostalanrad.Nakonlicenciranjafarmaceutitrebadaseceloživotnousavršavaju,uokviruformalnogsistemakontinuiraneedukacije(KE),kaoiuneformalnomsistemuedukacije(sopstvenoiskustvenoučenjenaradnommestukojeintegriše profesionalni i lični razvoj). Visokoobrazovne ustanove prate, istražuju iaktivno učestvuju u ovim procesima i susreću se samnogim izazovima počev od: (i)usklađenosti nastavnih sadržaja sa potrebama zdravstvenih ustanova vs. potrebamagrađana(formalno i fizičkoradnomesto farmaceutasemenja;građanisuzahtevniji);(ii) novom organizacijom zdravstvenih sistema i novih usluga (fokus na pacijentu iprimarnoj zdravstvenoj zaštiti); (iii) novom ulogom edukatora/savetnika ufarmakoterapijiiprevencijibolestiipromocijizdravlja;(iv)ulogomagenta/advokataubezbednoj upotrebi lekova i upravljanju lekovima. Iskustva i publikacije o ovoj temirazvijenih zemalja (UK, SAD, Australija) ukazuju da se akademska zajednicamenja irazvijashodnopotrebama,jasnimpolitičkimporukama,tedaregulativaintezivnopratiiuređujeodnoseakademijeiprofesionalnihudruženja,adaMinistarstvozdravljapratitržište farmaceutskih kadrova. Sveukupno ovo značajno utiče naprofesionalni razvojfarmaceuta,te jetimekvalitetuslugaibezbednostpacijenataunapređena.Usrednjeinižerazvijenimzemljamaformalnoobrazovanjeiusavršavanje(KE)jevišezastupljenoodneformalnog,modaliteti profesionalnog razvoja su različiti, prisutan jenedostatakpolitičke volje, nedovoljno istraživanja ovih fenomena, i inertnost/nemotivisanostnastavnika, kao i pojačano interesovanje (pritisak) građana. Rezultati istraživanjasprovedenih u okviru Erasmus+ projekta ReFEEHS u Srbiji, pojedinih pilot studijasprovedenihuSloveniji,HrvatskojiBiH(RepubliciSrpskoj)ćebitiprikazani.

192

QUALIFICATIONANDPROFESSIONALDEVELOPMENTOF

PHARMACIST‐ACADEMICPERSPECTIVE

LjiljanaTasić

DepartmentofSocialPharmacyandPharmaceuticalLegislation,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Pharmacists as health workers are essential for the preservation and

improvementofhealthwithemphasisonthepatientsafetyinlinewiththechallengesof new technologies. Pharmacists should be qualified and highly competentprofessionals,activeparticipantsinhealthcareorientedtowardspatients,preparedforcollaborative practice, professional and personal development and continuousimprovement. This requires changes in the approach to education that the academiccommunity should recognize, accept, implement and promote. Qualification as apharmacistrequiresstep‐by‐stepsystemwhichincludesatleastfouryearsoffull‐timetheoretical and practical training at a university and six‐month traineeship in apharmacy during the undergraduate study program, or as internship beforeprofessional licensure. After licensing pharmacists are expected to conduct lifelonglearning, either through the formal system of continuing education (CE) or in theinformal system of work‐based learning which integrates professional and personaldevelopment.Highereducationinstitutionssupervise,researchandactivelyparticipatein these processes and are facing many challenges starting from: (i) alignment ofcurriculum with the health institutions needs vs. citizens' needs (pharmacist'sworkplace is changing; citizens are more demanding); (ii) a new organization andservicesinhealthcaresystems(focusonpatientandprimaryhealthcare);(iii)thenewroleofpharmacistsaseducators/advisorsinpharmacotherapy,diseasepreventionandhealthpromotion; (iv) theroleofanagent/advocate in thesafeuseofmedicinesanddrug management. Developed countries (UK, USA, Australia) experiences andpublications on this subject indicate that the academic community is changing anddeveloping in accordance with needs, clear political messages, regulation thatintensively monitors and regulates relation: academy‐professional associations andwith Ministry of Health which monitors the pharmaceutical workforce. Thissignificantlyinfluencespharmacists’professionaldevelopmentandqualityservicesandpatientsafetyimprovement.Inthedevelopingcountries,formaleducationandtraining(CE) ismore common than informal, themodalities of professional development aredifferent,thereisalackofpoliticalwill,insufficientresearchofthesephenomena,andteachers’andpreceptors’inertiawithlackofmotivationfollowedbyincreasedcitizens’pressure.TheresultsoftheresearchconductedwithintheErasmus+projectReFEEHSinSerbia,somepilotstudiesconductedinSlovenia,CroatiaandBosniaandHerzegovina(RepublicofSrpska)willbepresented.

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Arh.farm 2018;68:193-194 PP50STRUČNOOSPOSOBLJAVANJEIPROFESIONALNIRAZVOJFARMACEUTA‐PERSPEKTIVAAPOTEKARSKEPRAKSE

SvetlanaStojkov

UniverzitetPrivrednaakademijauNovomSadu‐FarmaceutskifakultetNovi

Sad,ApotekaSubotica(Srbija)PoslednjihdecenijaXXvekafarmaceutskaprofesijaznačajnojepomerilaaspekte

ipolja svogdelovanja, čime je generisanapotrebakanovimedukacionimsadržajima,programima i modelima, uključujući dostignuća informacionih tehnologija (IT). Ciljradajedaseprikažustavoviipreferencijefarmaceutaopodručjimaukojimasmatrajuda treba da da se razvijaju, formatima i modalitetima edukacije, sa akcentom naprimenuIT.

Studijom preseka je za period 2014‐2017. godina izvršeno istraživanje putemon‐line anketedostupnenana sajtuFarmaceutskekomoreSrbije. Kreiran jeupitnikkojije,poredostalog,uključiopreferencijeistavovefarmaceutaoedukacijiuzprimenuLikertoveskaleod1do5(1‐najmanjeineresantno,5‐najvišeinteresantno).Anketajebila anonimna i dobrovoljna. U studiju je uključeno 565 diplomiranihfarmaceuta/magistarafarmacije.

Ispitanicima je bio ponuđen set pitanja u kojima su mogli da izraze svojuzainteresovanost za razvoj u određenim oblastima: 28,4% je odabralo bezbednost idelotvornost dijetetskih suplemenata u politerapiji, 26,2% posebne populacije ibezbednost lekova, 21,8% oblast novih odobrenih lekova, dok je dobra praksafarmakovigilanceinovaEMA(EuropeanMedicalAgency)bilanajzanimljivijaza18,7%ispitanika.Istraživanjepreferencijafarmaceutapremaodređenimformatimaučenja,naskali od 1 do 5, je kod oko 60% ispitanika pokazalo najveći afinitet prema „prikazuslučaja”.Odponuđenihmodalitetaučenja,prvi izbori ispitanicimasuedukacijaputemInterneta(57,7%)idigitalniformatidostupninainternetusamogućnošćuautomatskogpreuzimanja podkastova (49,4%). Telekonferencije, live streams webcastovi i on‐demandwebcastovinisuprviizborzavećinuispitanika(7,4%;17,4%;17,5%,redom).

Kvalitetzdravstvenezaštiteibezbednostpacijenatazahtevastručneilogističkepreduslove, kao i modele učenja koji su usklađeni sa potrebama i mogućnostimapraktičara. Razvoj IT i dostupnost odgovarajućih edukativnih sadržaja, prilagođenihsavremenom trenutku odnosno potrebama pacijenata, prepoznat je od farmaceuta uSrbijikaopoželjanputuprofesionalnomrazvoju.

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QUALIFICATIONANDPROFESSIONALDEVELOPMENTOFPHARMACIST‐PHARMACYPRACTICEPERSPECTIVE

SvetlanaStojkov

UniversityBusinessAcademyinNoviSad‐FacultyofPharmacyNoviSad,

PharmacySubotica(Serbia)In last decades of the XX century the pharmaceutical profession significantly

altereditsaspectsandareaofoperation,wherebyaneedforneweducationalcontent,programmesandmodels,includingadvancementsinITweregenerated.Theobjectiveofthepaperistodemonstratepharmacists’attitudesandpreferencesreferringtotheareaswhichtheyfeelshouldbedeveloped,viaeducationalformatsandmodalities,withemphasisonITapplication.

In theperiodfrom2014to2017,across‐sectionalstudywasconductedviaanonline surveyavailableon thewebsiteof thePharmaceuticalChamberof Serbia.Thesurvey, inter alia, includedpharmacists’ preferences and attitudes on educationwiththeapplicationofaLikertscalefrom1to5(1‐leastinteresting,5‐mostinteresting).Thesurveywas anonymous and voluntary. 565BPharms/MPharmswere included in thestudy.

Thosesurveyedwasofferedasetofquestionswheretheywereabletoexpresstheirinterestinthedevelopmentofcertainareas:28.4%chosesafetyandtheefficacyof nutritional supplements in polypharmacy, 26.2% chose specific populations anddrug safety, 21.8% the area of newly approveddrugs,while goodpharmacovigilancepractices and the new EMA (European Medical Agency) was of greatest interest to18.7% of respondents. Researching pharmacists’ preferences in terms of specificeducational formats, on a scale of 1 to 5, approx. 60% demonstrated the greatestaffinitytowards„casereview”.Oftheavailablemodalitiesoflearning,thefirstchoiceoftherespondentsiseducationviatheInternet(57.7%),anddigitalformatsavailableonthe Internet with the option of downloading podcasts (49.4%). Teleconferences,livestreamwebcastsandondemandwebcastsarenotthefirstchoiceofthemajorityofrespondents(7.4%;17.4%;17.5%,respectively).

The quality of healthcare and patient safety requires expert and technicalpreconditions,aswellasmodelsoflearningthatcomplywiththeneedsandcapabilitiesof practitioners. IT development and the availability of corresponding educationalcontent, adapted to modern times i.e. patient needs, has been recognised bypharmacistsinSerbiaasthedesiredpathinprofessionaldevelopment.

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Arh.farm 2018;68:195 PP51WHYCLINICALCOMMUNICATIONSKILLSREALLYMATTER?SOMEEXAMPLESOFEFFECTIVETEACHINGANDLEARNING

METHODS

AfonsoMiguelCavaco

DepartmentofSocialPharmacy,FacultyofPharmacy,UniversityofLisbon(Portugal)

Pharmacy practice encompasses a number of professional activities, usually

associatedwithmedicinesusagebypatients.Pharmacists’dutiesshouldcomprisetheoptimizationoftheclinicaleffectivenessandsafetyofmedicinestakenbypatients.Tobe able to manage pharmacotherapy and evaluate its success with each patient,pharmacistsneedtocollectandprovideinformation.Theindividualpatientisthemainsourceofinformation,bothobjectiveandsubjective.However,patientsaremorethandata providers or recipients. Human nature is complex, suggesting the use ofappropriateclinicalcommunicationskills.Althoughwidelyrecognizedasakeyelementinhealthcare,theseskillsareusuallylesscoveredinpharmacyeducationandresearch.This presentation aims to address and debate how clinical communication skills areessential to take full advantageof theexistingpharmaceuticalknowledge, translatingscience into caring pharmacy practice. Some examples of teaching and learningresourcesforcommunicationandclinicalinteractionskillswillbepresented,includingoptionsbasedonvirtualreality.

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VALUEFRAMEWORKSANDDECISIONMAKINGAROUNDTHEGLOBE

WijaOortwijn,RobBaltussen,MaartenJanssen

RadboudUniversityMedicalCentre(Netherlands)Health technology assessment (HTA) practices all employ so‐called value

frameworks forpriority setting, i.e.making recommendationsand/or reimbursementdecisionsregardingnewhealthtechnologies.This includesa judgmentontherelativeimportanceofcertainassessmentcriteria,suchasclinicalbenefitandtheincrementalcost‐effectivenessof(new)healthtechnologies.

Some HTA practices focus on the development and use of evidence (e.g.Argentina), while others explicitly combine the use of evidence with proceduralaspects, involving relevantstakeholders (e.g. theNetherlands).Although thepracticalapplicationofavalueframeworkiscontext‐dependent,itisimportanttonotethattheunderlyingdesignhas implications for theway inwhichpriorities are set. Currently,some value frameworks may seriously comprise the legitimacy of reimbursementdecisions.ThisindicatestheneedbutalsopotentialtoimproveHTApractices.

Away forwardareevidence‐informeddeliberativeprocesses(EDPs).EDPs isanewconceptualframeworkbasedontwovalidatedframeworks,multi‐criteriadecisionanalysis and the Accountability for Reasonableness framework. EDPs provides apracticaltoolforHTAagenciesaimingtosetprioritiesregardingwhatisrelevantandmeaningfulfromabroaderhealthsystem’sperspective.ItincludesseveralstepsrelatedtotheHTAprocess(scoping,assessment,appraisal,dissemination).Thesestepsshouldnotbeconsideredasablueprintbutratherasanaspirationalgoal–organizationscantake incremental steps. We will present the steps to undertake EDPs, substantiatedwithrealworldexamplestoenhancelegitimatedecision‐making.

EDPs can facilitate democratic decision‐making in various ways. It supportsorganizations to be more systematic, explicit and transparent, by makingrecommendations/decisions sensitive to a wider range of needs and values, and bypromotingconsistencyacrossdecisions.

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Arh.farm 2018;68:197-198 PP53VREDNOSTINOVACIJEPRILIKOMDONOŠENJAODLUKAU

ZDRAVSTVU

TanjaNovaković

ZEMSolutions,Beograd(Srbija)Pruzaoci zdravstvenezastiteuCentralnoj i IstocnojEvropi (CEE)su suoceni sa

nizomizazovakojisejavljajuusledsvevecegbrojazahtevairastucihocekivanja.Kaoikod mnogih zdravstvenih sistema širom sveta, neophodno je da se poboljša pristupinovativnim tehnologijamau okviru sveograničenijih budžeta.Ograničenodonošenjeodlukaikašnjenjeuprocesuprocenenovihtehnologijamoguimatiznačajanuticajnazdravljepacijenata.

Inovacijemogudovestidopovecanepotrosnjeuzdravstvenojzastitikaorezultatsupstitucije terapija sa nižom cenom novim tehnologijama čija je cena viša, efektimakomplementarnosti, tj. novim i starim proizvodima koji se koriste istovremeno, ipružanjem terapije za bolesti zakojeprethodnonisubile dostupne terapije.Dabi sepostigla finansijska stabilnost, potrebno je odgovoriti na dva ključna izazova. Prvi jeodlučivanjeonivouraspoloživih resursa;drugi,osiguratioptimalnualokaciju resursaunutarograničenihbudžeta.Dabibili relevantni zadonošenjeodlukau regionuCEE,vladeiHTAagencijemorajusebavitiovimključnimizazovima.

NakonnekolikogodinaograničenogodlučivanjauSrbijiizaustavljenihraspravapostavljasepitanjedalijebudžetvažnijiodspašavanjaiunapređenjakvalitetaživotapacijenata?

198

THEVALUEOFINNOVATIONINHEALTHCAREDECISIONMAKING

TanjaNovaković

ZEMSolutions,Belgrade(Serbia)Central and Eastern European (CEE) health care providers are faced with a

numberofchallengesasaresultofincreaseddemandandrisingexpectations.Aswithmany health systems across the world improving access to innovative technologieswithin increasingly constrained budgets is required. Limited decision‐making anddelays in evaluations of new technologies may have a significant health impact onpatients.

Innovations can drive increased spending in health care as a result ofsubstitution of lower priced products with new higher priced technologies,complementarityeffects,i.e.newandoldproductsusedconcurrently,andbyprovidingtreatments for conditions for which previously no treatments were available. Toachievefinancialstability,twokeychallengesneedaddressing.Firstly,decidingonthelevelofavailableresources;secondly,ensuringoptimalresourceallocationwithinfinitebudgets.Tobe relevant todecisionmaking in theCEE region, governmentsandHTAagenciesmustaddressthesekeychallenges.

AfterseveralyearsoflimiteddecisionmakinginSerbiaandstalleddiscussionsatwhatpointisbudgetmoreimportantthansavingandimprovinglives?

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Arh.farm 2018;68:199-200 PP54

ZAŠTOSISTEMATIČNIPREGLEDILITERATURE?

MarkParker

ZEMSolutions,Beograd(Srbija)Randomizovanekontrolisanestudijepredstavljajuzlatnistandardudefinisanju

kliničkih dokaza lečenja. Ove studije su dizajnirane da minimiziraju različite vrstepristrasnostiidrugeproblemekojiprateprocenukliničkogbenefita.Međutim,ovakvestudije suograničenevremenom iprostorom,dosta je skupodase realizuju.Kliničkapraksa, tzv., „real word” je mnogo komplikovaniji od onog predstavljenog u studiji.Trenutna tehnološka dostignuća su dovela do eksplozije dostupnih dokaza koji suprikupljeniizrealnogživota,izbolnicaiopšteprakse,ispecifičnihregistarapacijenatakoji sadržemnoštvopodataka o nizu terapija i primera iz prakse. Iako su ovi podaciznačajnidaseomogućiznanjeopružanjuzdravstvenezaštite,sposobnostobradeovihpodatakajejošuvekupovoju.Ciljovogpredavanjajedasepomoćuinovativnogalatakoji predstavlja analizu „velikih podataka” medicinske naučne literature podoriginalnim nazivomPublicationOcean, pokažu problemi i rešenja izazova koji pratemedicinu zasnovanu na dokazima (engl. Evidence based medicine ‐ EBM). Pristupinformacijama baziranim na dokazima je ključno za donošenje odluka koje koristekoristi (benefite) tehnologije da bi se postigla njena najbolja vrednost za određenozdravstveno stanje i naj taj način da bi se postigao efikasan i kvalitetan zdravstvenisistem.

200

WHYSISTEMATYCREVIEWS?

MarkParker

ZEMSolutions,Belgrade(Serbia)Randomised controlled trials represent the gold standard in defining clinical

evidencefortreatments.Thesetrialsaredesignedtominimisethevariousbiasesandother problems which accompany an assessment of clinical benefit. However, suchtrialsarelimitedintimeandplace,extremelyexpensivetoconductandtherealworldisinfinitelymorecomplicatedthanisrepresentedbythetrials.Recentadvancementsintechnologyhaveresulted inanexplosionofavailableevidencecollected inrealworldsettings, from hospital and general practice, to specific patient registries collecting awealthofdataon a rangeof treatments andpractices.While this evidence is vital tosupport our knowledge of healthcare delivery, the ability to analyse it is still in itsinfancy. The goal of this lecture is to demonstrate problems and solutions to thechallenges of evidence‐based medicine (EBM) with the innovative tool „PublicationOcean”whichpresentsBigDataanalyticsof theMedical scientific literatue.Access toevidence‐based information is crucial for making decisions using the benefits oftechnologyinordertoachieveitsbestvalueforaparticularhealthconditionandinthatwaytoachieveanefficientandqualitativehealthcaresystem.

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Arh.farm 2018;68:201-202 PP55

INHIBITORIKOTRANSPORTERAZANATRIJUMIGLUKOZUTIPA2KODOBOLELIHODDIJABETESMELITUSATIPA2ISRČANE

INSUFICIJENCIJE:KLINČKIPOGLEDNATERAPIJUKOJAMOŽEDASNIZIMORBIDITETIMORTALITET

MarijaPolovina

KlinikazakardiologijuKliničkogcentraSrbije,UniverzitetuBeogradu‐

Medicinskifakultet(Srbija)Dijabetes melitus tipa 2 (T2DM) i srčana insuficijencija (SI) se smatraju

pandemijamasaozbiljnim javno‐zdravstvenimposledicama.Kodpacijenata saT2DM,SI jeprisutnau10do30%obolelih,audruženoprisustvoobebolesti jepovezanosa1,5‐2putavećimukupnimikardiovasularnimmortalitetomi2,5putavećimrizikomodkardiovaskularnihhospitalizacija.

Optimalno lečenje T2DM u SI i dalje perdstavlja klinički izazov. Primenapreparata sulfonilureje i tiazolidinendiona se povezuje sa porastom mortaliteta kodosobapodrizikomodSIilisavećispoljenomSI.Terapijainsulinomdovodidopovećanatelesne mase i retencije tečnosti što može da umanji pozitivne efekte dobreglikoregulacije u SI. Od novih oralnih hipoglikemika, inhibitor dipeptidil peptidaze‐4(DPP‐4), saksagliptin, je povezan sa 27% višim rizikom za hospitalizaciju zbogpogoršanjaSI,dokdrugiDPP‐4inhibitoriiinkretinskimimeticiimajuneutralanefekatnaSI.

Uskorijevreme,ukliničkupraksujeuvedenanovaklasaoralnihhipoglikemika,atosuinhibitorikotransporterazanatrijumiglukozutipa2(SGLT‐2inhibitori).Udosada završenim randomizovanim studijama, primena empagliflozina i kanagliflozinabilajepovezanasaznačajnimsniženjemnepovoljniihkardiovaskularnihdogađajakodpacijenata sa T2DM. Od posebnog je značaja da su oba leka bila povezana sa >30%nižimrizikomodhospitalizacijezbogpogoršanjaSI.Takođe,upoređenjusaplacebom,postignutojeiznačajnosniženjerizikaodnovo‐nastaleSI,kaoismrtnostzbogSIkodpacijenata sa T2DM. Stoga se SGLT2 inhibitori ispituju u nekoliko randomizovanihstudija kod bolesnika sa SI nezavisno od prisustva T2DM, sa ciljem utvrđivanjaefikasnosti u snižavanju kardiovaskularnog mortaliteta i sprečavanju pogoršanja SI.Oboleli odT2DM i SI imaju visok rizik od nepovoljnih kardiovaskularnih događaja, aprimena SGLT‐2 inhibitora može da sniziti rizik od hospitalizacija zbog SI, kao ikardiovaskularni mortalitet. Iz kliničke perspektive, važno je revidirati politikuparticipacijekakobiovilekovipostalidostupnijivećiniobolelih.

202

SODIUMGLUCOSECONTRANSPORTER‐2INHIBITORSINTYPE‐2DIABETESANDHEARTFAILURE:THECLINICALSTANDPOINTONTREATMENTTHATCANREDUCEMORBIDITYANDMORTALITY

MarijaPolovina

DepartmentofCardiology,ClinicalCenterofSerbia,UniversityofBelgrade–FacultyofMedicine(Serbia)

Type‐2 diabetes mellitus (T2DM) and heart failure (HF) are considered

pandemicswith serious public health consequences. HF is a common comorbidity inT2DM, affecting10‐30%of individuals. ConcomitantT2DMandHFportend1.5 to 2‐fold higher risk of all‐cause and cardiovascular mortality, and increase the risk ofcardiovascularhospitalizationby2.5‐fold.

The optimalmanagementof T2DM inHF remains challenging. Treatmentwithsulphonylureasandthiazolidinedioneshasbeenassociatedwithincreasedmortalityinpatients at risk of, or with known HF. Insulin may promote weight gain and fluidretention, therebypotentially offsettingbenefit of glycemic control inHF.Among thenovel oral anti‐diabetic medications, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor,saxagliptin,hasbeenassociatedwitha27%higherriskofhospitalizationforworseningHF,whileotherDPP‐4inhibitorsandincretinmimeticsdemonstrateaneutraleffectonHFoutcomes.

Recently, a new class of anti‐diabetic medications, the sodium glucose co‐transporter‐2 (SGLT2) inhibitors, has been introduced. In the two completedrandomizedtrialsthat,empagliflozinandcanagliflozinhavedemonstratedasubstantialreduction in adverse cardiovascular outcomes in T2DM patients. In particular, bothmedicationssignificantlyreducedtheriskofHFhospitalizationby>30%.Also,theriskof new‐onset HF and HF‐related mortality were significantly reduced with SGLT‐2inhibitorscomparedwithplacebo.Hence,severalongoingrandomizedtrials,includingpatients with HF, are assessing the efficacy of SGLT2 inhibitors for the reduction ofcardiovascular mortality or HF hospitalization irrespective of T2DM. In conclusion,patientswithT2DMandHFareathighriskofadversecardiovascularoutcomes,andtreatment with SGLT‐2 inhibitors could decrease HF hospitalizations andcardiovascular death. From the clinical perspective, it is of great importance thatreimbursement policies be revised so that thesemedications could be offered to themajorityoftheaffectedpatients.

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Arh.farm 2018;68:203 PP56NOVELANTIDIABETICAGENTSANDCARDIOVASCULARRISK

ManfrediRizzo

BioMedicalDepartmentofInternalMedicineandMedicalSpecialties,UniversityofPalermo(Italy)

Numerousclinicaltrialshavereportedthattreatmentwithnovelclassesoftype

2 diabetes agents reduce and potentially prevent events in patients with type 2diabetes(T2DM)andcardiovascular(CV)disease.Theavailablescientificdataindicatestheireffectsonbodyweightandvariouscardiometabolicmarkers,suchaslipids,bloodpressure,inflammatorymarkers,oxidativestress,butalsoendothelialdysfunction,andsubclinical atherosclerosis. A particular attention is on recent CV outcome studies(CVOTs) and the potential mechanisms beyond glucose‐lowering effects. Briefly,empagliflozin, thesodium‐glucosecotransporter(SGLT)2 inhibitor, in theEMPA‐REGCVOTstudy,markedlyandrapidlyreducedCVdeathandheartfailurehospitalization.Similarly, liraglutide and semaglutide, the glucagon‐like peptide (GLP)‐1 receptoragonists, in the LEADER and SUSTAIN‐6 CVOT study, respectively, reduced CVdeathand major adverse CV events, but did not influence heart failure risks, suggestingdifferent underlying mechanisms. On the other hand, other GLP‐1 receptor agonist,exenatide, in the EXSCEL study, met the goal of CV safety, but failed to show anysignificantCVbenefit.Wearewaitingfortheresultsfromother2CVOTs,withtheuseof dulaglutide (REWIND study) and albiglutide (HARMONY study). However, theunderlyingmechanismsremain largelyunknown.Recently,wehavehypothesizedthemechanismbywhichliraglutidemayhavedirecteffectsontheatherosclerosisplaque,attheearlystageofatherosclerosis,impactingitsformationandprogression.BasedontheavailableCVOTresults,liraglutideandsemaglutideshouldbethepreferredsecond‐linemedicationinT2DMsubjectsinsecondaryCVprevention,asadd‐ontometformintherapy. All these novel therapeutic strategies allow customization of antidiabetictreatment toeachpatient’sneed,providingbettermetaboliccontrolwithreducedCVrisk. Overall, their usage should be expanded in other cardiometabolic disorders aswell.

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Arh.farm 2018;68:204-205 PP57

KONTINUIRANISKORZAMETABOLIČKISINDROMUPOPULACIJIDECEIADOLESCENATA

RadeVuković1,IvanSoldatović2,TatjanaMilenković1,KatarinaMitrović1,SlađanaTodorović1,LjiljanaPlavšić1

1Institutzazdravstvenuzaštitumajkeideteta„DrVukanČupić”,Beograd,

2UniverzitetuBeogradu‐Medicinskifakultet(Srbija)Epidemija gojaznosti u populaciji mladih u Srbiji predstavlja značajan javno

zdravstveni problem, na šta ukazuje trostruki porast prevalencije gojaznosti međumladima u našoj zemlji tokom poslednjih dve decenije. Uporedo sa porastomprevalencije gojaznosti kod mladih uočava se porast učestalosti i ranija pojavakomplikacija gojaznosti kao što su tip 2 dijabetesa melitusa i metabolički sindrom.Definicija metaboličkog sindroma Internacionalne federacije za dijabetes (IDF) jedihotomnog karaktera, što za posledicu ima gubitak podataka i onemogućavakvantifikovanje metaboličkogsindroma, odnosno procenu težine stanja. Do sadakorišćeni kontinuirani skorovi za metabolički sindrom poput sume Z skorova i PCAanalizeomogućavajukvantifikovanjemetaboličkogsindroma,alisuveomakompleksniizahtevajuupotrebunaprednihračunarskihstatističkihprograma.

Novi kontinuirani skor zametabolički sindromupopulaciji dece i adolescenata(PsiMSskor)računasepremasledećojformuli:(2xobimstruka(cm)/telesnavisina(cm))+(glikemija(mmol/l)/5,6)+(trigliceridi(mmol/l)/1,7)+(sistolnikrvnipritisak(mmHg)/130) ‐ (HDL (mmol/l)/1,02). Na ovaj način izračunat skor ima odličnukorelaciju sakompleksnim skorovima, a izuzetno je jednostavan za računanje, što gačini pouzdanim i pogodnim za svakodnevnu primenu u kliničkoj praksi, kao i ukliničkim istraživanjima. PsiMS skor predstavlja praktičan i precizan dijagnostičkimetod za kvantifikovanje metaboličkog sindroma u populaciji gojazne dece iadolescenata.

205

CONTINUOUSMETABOLICSYNDROMESCOREFORUSEIN

PEDIATRICPOPULATION

RadeVuković1,IvanSoldatović2,TatjanaMilenković1,KatarinaMitrović1,SlađanaTodorović1,LjiljanaPlavšić1

MotherandChildHealthCareInstitute„DrVukanČupić”,Belgrade,2University

ofBelgrade–FacultyofMedicine(Serbia)Rising prevalence of obesity in youth in Serbia emphasizes the public health

issueoftheobesityepidemics.Anincreaseintheobesitycomorbidities,suchastype2diabetesandmetabolicsyndrome,aswellasearlieroccurrence,hasalsobeennotedinchildren and adolescents. The International Diabetes Federation (IDF) metabolicsyndrome (MS) definition is dichotomous, which results in loss of data, without thepossibilityofquantifyingtheseverityofthesyndrome.PreviouslyusedcontinuousMSscores, such as sum of Z‐scores and PCA analysis, overcame these issues allowingcontinuousquantificationofMS,howeverthesescoresarecomplex,requiringadvancedstatisticalsoftwareforcalculationofthescores.

Novelcontinuousmetabolicsyndromescoreforuseinthepopulationofchildrenand adolescents (PsiMS score) is calculated using the following formula: (2 x waistcircumference (cm)/height (cm)) + (glycemia (mmol/l)/5.6) +(triglycerides(mmol/l)/1.7) + (systolic blood pressure (mmHg)/130) ‐ (HDLcholesterol (mmol/l)/1.02). PsiMS score correlates highly with more complexcontinuousMSscores,whilebeingsimpletocalculate,makingitareliableandaccuratescore for the evaluation of MS in everyday clinical practice, as well as inclinicalresearch.PsiMSscorerepresentsapracticalandaccuratediagnosticmethodforquantificationofMSinthepopulationofobesechildrenandadolescents.

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Arh.farm 2018;68:206-207 PP58

OPSTRUKTIVNAAPNEJAUSNUIKARDIOMETABOLIČKIRIZIK

JelenaVekić

Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Opstruktivnaapnejausnu(OSA) jehroničnoprogresivnooboljenjesavisokom

prevalencomupopulaciji,koje,bezpravovremenedijagnozeiterapije,možedovestidoznačajnihposledicapokvalitetživotapacijenata.Razvojovogporemećajajepovezansagojaznošću,akarakteriše se rekurentnimepizodamapotpunog iliparcijalnogkolapsagornjih disajnih puteva tokom sna, što se manifestuje apnejom ili hipopnejom iučestalim buđenjima. Tokom epizoda respiratornog kolapsa dolazi do aktivacijesimpatičkog nervnog sistema, što potencira vazokonstrikciju, te dovodi do razvojahipertenzijeiporemećajasrčanograda.Procenjujesedaje60‐90%pacijenatasaOSAgojazno,autvrđenojedasapovećanjemtelesnemaseza10%rizikzarazvojOSAraste6 puta. OSA je čest komorbiditet kod pacijenata sametaboličkim sindromom (MS) ikardiovaskularnim bolestima (KVB) i predstavlja faktor rizika za njihov nastanak.Studije suukazale na vezu izmeđuMS iOSA, te je ovaj fenomenopisankaoposebanporemećaj ‐ sindrom Z. Istraživanje uzročno‐posledične veze između OSA i KVB je uvelikojmeriotežanokompleksnomprirodomsamogoboljenja.KardiometaboličkirizikuOSAjeudružensaarterijskomhipertenzijom,insulinskomrezistencijom,endotelnomdisfunkcijom, inflamacijom, dislipidemijom i oksidativnim stresom. Lečenje OSA sedanas najefikasnije sprovodi neinvazivnom ventilacijom, pomoću uređaja kojiobezbeđujepozitivanpritisakugornjimdisajnimputevima(continuouspositiveairwaypressure, CPAP) i na taj način sprečava pojavu apneja tokom spavanja. Rezultatikliničkih studija su pokazali da CPAP terapija značajno poboljšava hemodinamskeparametre,regulišehipertenziju,povećavaosetljivostnainsulinikorigujedislipidemiju.BudućaistraživanjabitrebalodarasvetledalijeapnejausnufaktorrizikazaKVBperseilijetavezaposledicaširegpatofiziološkogprocesa,čijijedeoiOSA.

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OBSTRUCTIVESLEEPAPNEAANDCARDIOMETABOLICRISK

JelenaVekić

DepartmentofMedicalBiochemistry,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Obstructive sleep apnea (OSA) is a chronic, progressive disorder with a high

prevalence in the population. Without timely diagnosis and therapy OSA cansignificantlyaffectthequalityoflifeofthepatients.DevelopmentofOSAisassociatedwithobesity.Itischaracterizedbyrecurrentepisodesofcompleteorpartialcollapseofthe upper airway during sleep, which is manifested by apnea or hypopnoea andfrequent waking. During the episodes of respiratory collapse activated sympatheticnervoussystemexacerbatesvasoconstriction,leadingtodevelopmentofhypertensionand cardiovascular disorders. It is estimated that 60‐90% of patients with OSA areobese.Also,theriskfordevelopingOSAincreasessixtimesifbodyweightincreasesby10%. OSA is a common co‐morbidity in patientswithmetabolic syndrome (MS) andcardiovasculardisease (CVD)and is a risk factor for theirdevelopment. StudieshavepointedtotherelationshipbetweenMSandOSA,andthisphenomenonwasdescribedassyndromeZ.InvestigationofthecausalrelationshipbetweenOSAandCVDhasbeengreatlyconfoundedbythecomplexnatureofthediseaseitself.CardiometabolicriskinOSA is associated with arterial hypertension, insulin resistance, endothelialdysfunction,inflammation,dyslipidemia,andoxidativestress.ThetreatmentofOSAisnowmosteffectivelyperformedbycontinuouspositiveairwaypressure(CPAP),atypeof non‐invasive ventilation which prevents the onset of sleep apnea. The results ofclinical studies have shown that CPAP therapy significantly improves haemodynamicparameters, regulates hypertension, increases insulin sensitivity, and correctsdyslipidemia.Future investigationsshouldclarifywhethersleepapnea isarisk factorforCVDperseor isaconsequenceofabroaderpathophysiologicalprocess,ofwhichOSAispart.

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Arh.farm 2018;68:209-209 PP59GENETIČKAISPITIVANJAUMETABOLIČKOMSINDROMU

AnaNinić

Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Metabolički sindrom (MetS) je heterogeni poremecaj koji se karakterise

višestrukim metaboličkim abnormalnostima kao što su abdominalna gojaznost,dislipidemija, insulinska rezistencija, hipertenzija i poremecena tolerancija glukoze.Ovoproaterogeno iproinflamatornostanje,kaoglavni faktor rizikaza tip2dijabetesmelitus i kardiovaskularne bolesti, nastaje pod uticajem genetičkih faktora i faktoraživotnesredine.Mnogegenetičkevarijantezajednoisafaktorimaživotnesredinemogudoprineti razvoju MetS. Genomske studije su utvrdile jaku vezu između regionahromozoma 1q41, 2p22.3, 3q27, 7q31.3, 9p13.1, 9q21.1, 10p11.2, 17p12 i 19q13.4 ikliničkihmarkera(telesnemase,obimastrukaikuka,leptina,insulina).99,9%ljudskoggenomajeidentičnozasveljude,takodasugenomskestudijeasocijacijefokusiranenagenetičkevarijacijekaoštosupolimorfizmipojedinačnihnukleotida(SNP).Genomskestudije asocijacije su testirale veliki broj SNP‐ovakao faktora rizika za MetS.IdentifikovalesuznačajneSNP‐ovekojipredstavljaju15lokusapovezanihsajednomilipetkomponenataMetS.VarijantegenaadiponektinairezistinasesvevišeproučavajusaciljemdasepokažekojaodnjihilizajednonajvišeutičunanastanakMetS.Mnogeodnjih su i povezane sa ispoljavanjem MetS. Takođe, nekoliko SNP‐ova povezanih saraspodelomtelesnihmastipokazalojesnažnuinterakcijusafaktorimaživotnesredineiefekte na ispoljavanje MetS. Mnoge studije su izvedene kako bi se utvrdilo kojevarijanteimajujakefekatinterakcijesafaktorimaokoline,alinjihovirezultatinisubilikonzistentni.Profiliekspresijegenauključenihuenergetskuimetaboličkuhomeostazusu, takođe, intenzivno ispitivani. Iako je poznato da jeMetS poligenski poremecaj sasvakomgenetičkomvarijantomkojadoprinosimalimefektima,naukaidaljeimavelikizadatakdaidentifikujeuzročnegeneinjihoveefektenarizikzarazvojMetS.

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GENETICTESTINGFORMETABOLICSYNDROME

AnaNinić

DepartmentofMedicalBiochemistry,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Metabolic syndrome (MetS) is heterogenous disorder characterized by the

multiple metabolic abnormalities such as abdominal obesity, dyslipidemia, insulinresistance, hypertension and impaired glucose tolerance. This proatherogenic andproinflammatory state, as a major risk factor for type 2 diabetes mellitus andcardiovasculardisease, isdeterminedbythegeneticandenvironmental factors.Manygenetic variants together and with environmental factors may contribute to MetSdevelopment. Genome studies have confirmed strong link between chromosomeregions1q41,2p22.3,3q27,7q31.3,9p13.1,9q21.1,10p11.2,17p12,and19q13.4andclinicalmarkers(weight,waistandhipcircumferences,leptin,insulin).99.9%ofhumangenomeisthesameforallpeople,sogeneticassociationstudiesarefocusedongeneticvariationssuchassinglenucleotidepolymorphisms(SNPs).Genome‐wideassociationstudiestestedalargenumberofSNPsforassociationwithriskforMetS.TheyidentifiedsignificantSNPsrepresenting15lociassociatedeithertooneorfiveMetScomponents.Adiponectin and resistin gene variants are extensively studied in order to determinewhich of them or togethermostly influenceMetS development.Many of themwere,indeed, related to MetS occurrence. Also, several SNPs associated to body fatdistribution showed a strong interaction with environmental factors. Many studieswereperformed inorder todeterminewhichvariantshada strong interactioneffectwith environmental factors but their results were inconsistent. Gene expressionpatterns of genes involved in energy and metabolic homeostasis have been alsoextensively studied. Although it is known that MetS is polygenic disorder with eachgeneticvariantcontributingwithsmalleffects,sciencestillhaveamajortasktoidentifythecausalgenesandtheireffectsonriskforMetSdevelopment.

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Arh.farm 2018;68:210-211 PP60

SKORDISLIPIDEMIJE,INFLAMACIJEIOKSIDATIVNOGSTRESAUPROCENIKARDIOVASKULARNOGRIZIKA

JelenaKotur‐Stevuljević,NatašaBogavac‐Stanojević,JelenaVekić,

VesnaKalimanovska‐Spasojević,ZoranaJelić‐Ivanović,SlavicaSpasić

Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Kod oko 20% pacijenata koji dožive akutno ispoljavanje KVB (akutni infarkt

miokarda, moždani udar), kardiovaskularni rizik procenjen preko tradicionalnihfaktora rizika je mali ili umeren. Kod trećine ovih osoba bi mogla da se popravipredikcijarizikauključivanjemodnosaurinarnogalbumina/kreatininailikoncentracijehsCRP. Ovi podaci ukazuju da je značajno ispitivati prisustvo takozvanihnetradicionalnih faktora rizika, pre svega biohemijskih biomarkera (markera u krvi).Predmetovogistraživanjajegrupabiomarkera,biohemijskihparametaraodkojihnekispadajuu tradicionalne faktorerizika(parametri lipidnogstatusa),nekiseubrajajuunove biomarkere čiji je značaj ispitan, potvrđen u velikim studijama i čak uključen unekekalkultorekardiovaskulrnogrizika(markerinflamacije‐hsCRP),aneki jošuveknisu potvrđeni kao nezavisni faktori rizika za kardiovaskularne bolesti (markerioksidativno‐stresnog statusa). Cilj ovog rada je prikaz načina računanja zbirnogkardiovaskularnog rizika koji uključuje tri vrste biohemijskihmarkera: dislipidemiju,inflamaciju ioksidativnistres.Statističkametodakoja jeprimenjenadabiseračunaorizik koji potiče od svakog od faktora je Z‐skor (standardni skor) statistika. Skordislipidemije se računa kao razlika između srednje vrednosti Z skorova zakoncentracije LDL‐holesterola i triglicerida i Z‐skora za HDL‐holesterol. Inflamatorniskor se računa kao Z skor za hsCRP. Oksidativno stresni skor je razlika izmeđuprooksidativnog skora (srednja vrednost Z skorova prooksidativnih parametara) iantioksidativnog skora (srednja vrednost Z skorova antioksidativnih parametara).Ukupnikardiovaskularniskorrizika(KVSR) jezbirdislipidemijaskora, inflamatornogskora i oksidativno‐stresnog skora, nazvanDOI skor (dislipidemija, oksidativni stres,inflamacija).Populacionesrednjevrednostiistandardnedevijacijesudobijeneizbazepodataka zdravih sredovečnih osoba čiji su uzorci analizirani tokom prethodnih 16godina u našoj laboratoriji. Kao ilustracija ovako izračunatog KVSR biće prikazanevrednostipojedinihelemenataskoraupopulacijamapacijenatasaakutnim infarktommiokardaimoždanimudarom.

211

DYSLIPIDEMIA,INFLAMMATIONANDOXIDATIVESTRESSSCOREINCARDIOVASCULARRISKESTIMATION

JelenaKotur‐Stevuljević,NatašaBogavac‐Stanojević,JelenaVekić,

VesnaKalimanovska‐Spasojević,ZoranaJelić‐Ivanović,SlavicaSpasić

DepartmentofMedicalBiochemistry,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Inabout20%ofpatientswithacutecardiovascular(CV)event(acutemyocardial

infarction,stroke),cardiovascularriskestimatedthroughthetraditionalriskfactorsissmallormoderate.Inonethirdpersonswiththisunderscoredrisktheriskpredictioncouldbeimprovedbyurinaryalbumin/creatininerateorhsCRPinclusion.Thesedatasuggest that it is important non‐traditional risk factors assessment, especially blood‐bornmarkers –biochemicalparameters.Themeof this investigation arebiomarkers’group, somebelongs to the traditional risk factors (lipid statusparameters), some tonew,emergingbiomarkersbutwithdocumentedimportanceandpredictivecapabilityinCVdisease,even implemented inriskcalculators(inflammationmarkers–hsCRP),and some still not confirmed as independent factors for CV disease (oxidative stressmarkers).TheaimofthispaperistheexplanationofthelogicandtheequationforthesummaryCV risk calculation,which includes threedifferent kindsof thebiochemicalmarkers:dyslipidemia, inflammationandoxidative stress. Statisticalmethod isbasedon the Z‐score (standardized score statistics. According to ourproposaldyslipidemiascore is calculated as the difference between mean of the Z‐scores for the LDL‐cholesterolandtriglyceridesandZ–scorefortheHDL‐cholesterol.InflammatoryscoreisZ‐scoreforthehsCRP.Oxyscoreisdifferencebetweenprooxidativescore(meanoftheZ‐scoresforthedifferentprooxidants)andtheantioxidativescore(meanoftheZ‐scoresfortheantioxidativeparameters).SummaryCVriskscore(CVRS)issumofthedyslipidemiascore,inflammatoryscoreandoxyscore,entitledDOIscore(dyslipidemia,oxidativestress, inflammation).Populationmeansandstandarddeviationsvaluesarecalculatedfromourdatabasegeneratedduringthelast16yearsinourlaboratoryfromthe samples of the healthymiddle‐aged subjects. As an illustration for theDOI scorecalculation here will be presented results for the patients with acute myocardialinfarctionandacuteischemicstroke.

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Arh.farm 2018;68:212-213 PP 61

HRONIČNATERAPIJA–OČEKIVANJAIZABRINUTOSTNAŠIH

PACIJENATA

BranislavaMiljković

Katedrazafarmakokinetikuikliničkufarmaciju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Stavovi pacijenta i njegovo uključivanje u proces farmaceutske zdravstvene

zaštitemoguznačajnouticatinaadherencu i ishodeterapije.Ciljstudijebio je ispitatiočekivanja i zabrinutost pacijenata na hroničnoj terapiji i starijih pacijenata napolifarmaciji.Prospektivna,opservacionastudijautrajanjuod4mesecajesprovedenauapotekamanateritorijiSrbije.Svakifarmaceutjeregrutovao10uzastopnihodraslihpacijenata sa uvedenim lekom za hroničnu terapiju i/ili 10 starijih pacijenata napolifarmacijiodkojihjetraženodapopuneformular(7pitanjakojiobuhvataju:znanje,očekivanja, problem, zabrinutost, i razlog za prestanak terapije). Druga zakazanakonsultacija zasnovana na odgovorima pacijenata sprovedna je nakon 2‐4 sedmice.Primenjenajedeskriptivnastatistika.

Popunjenudokumentacijujeposlalo44(od73)farmaceutaza391pacijentanahroničnoj terapiji i 440 starijih pacijenata na polifarmaciji. Većina pacijenata nahroničnojterapiji istarijihpacijenatanapolifarmaciji jebilazainteresovanadadobijedodatne informacije (85% vs 59%, redom). Najčešće kategorije očekivanja kodpacijenata na hroničnoj terapiji i starijih pacijenata na polifarmaciji su: kontrolazdravstvenog stanja (46,36% vs 36,1%), unapređenje kvaliteta života (24,32% vs28,4%) i efektivnost (9,32% vs 15,7%), redom. Polovina pacijenata na hroničnojterapijiistarijihpacijenatanapolifarmaciji iskazalisuzabrinutostuvezisaterapijom(55% vs 46%, redom). Najzastupljenija kategorija zabrinutosti kod pacijenata nahroničnoj terapiji i starijih pacijenata na polifarmaciji bila je bezbednost terapije(32,5% vs 19,8%), dužina trajanja terapije (9,8% vs 6,1%), neefikasnost (3,1% vs4,5%), redom. Savetovanje pacijenata unapredilo je razumevanje primene terapije za59,0% pacijenata na hroničnoj terapiji i 75,5% starijih pacijenata na polifarmaciji.Strukturirano savetovanje zasnovano na identifikovanim potrebama i očekivanjimapacijenata može unaprediti pravilnu primenu lekova kod pacijenata koji započinjuhroničnuterapijuikodstarijihpacijenatanapolifarmaciji.

Istraživanje je realizovano u okviru Projekta 175023 finansiranog od strane

Ministarstvaprosvete,naukeitehnološkograzvojaRepublikeSrbije.

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CHRONICTHERAPY–EXPECTATIONSANDCONCERNSOFOURPATIENTS

BranislavaMiljković

DepartmentofPharmacokineticsandClinicalPharmacy,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Patients’attitudesandinvolvementintheprocessofpharmaceuticalcarecould

substantially influence the adherence andoutcomesof therapy.The aimof the studywastoexplorepatients’expectationsandconcernswithmedicationregardingchronictherapyandpolypharmacy.

A four‐month prospective observational study was conducted in communitypharmacies across Serbia. Every pharmacist recruited 10 consecutive adult patientswith the new medication for chronic conditions and/or 10 elderly polypharmacypatients who were asked to fill in the Checklist (7 questions covering: knowledge,expectations, problems, concerns and reason to stop treatment). The consultationappointmentbasedonthepatient’sanswerswasscheduledwithintwo‐to‐fourweeks.Descriptivestatisticalanalyseswasperformed.

Forty‐four pharmacists sent complete documentation from391 patients onchronic therapy and 440 elderly polypharmacy patients. Majority of the patients onchronic therapy and elderly polypharmacy patients were interested to receiveadditional information (85% vs 59%, respectively). Themost prevalent expectationscategory in patients on chronic therapy and elderly polypharmacy patients were:control of the condition (46.36% vs 36.1%), quality of life improvement (24.32% vs28.4%) and effectiveness (9.32%vs 15.7%), respectively. The half of the patients onchronic therapyandelderlypolypharmacypatientswasconcernedabout the therapy(55% vs 46%, respectively). The most prevalent concerns categories among thepatients on chronic therapy and elderly polypharmacy patients were: side effects(32.5%vs19.8%),durationoftherapy(9.8%vs6.1%),ineffectiveness(3.1%vs4.5%),respectively.Thecounsellingwithpharmacistsimprovedpatients’understandingofthemedication use in 59.0% patients on chronic therapy and in 75.5% elderlypolypharmacypatients.Structuredpharmacistcounsellingbasedonidentifiedpatients’concernsandneedscouldimprovetheappropriateuseoftherapyinpatientsstartingwithchronictherapyandelderlypolypharmacypatients.

ThisworkwasconductedasapartoftheProjectNo.175023fundedbytheMinistry

ofEducation,ScienceandTechnologicalDevelopment,RepublicofSerbia.

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Arh.farm 2018;68:214-215 PP62

FARMACEUTIUSRBIJIIDENTIFIKUJUTERAPIJSKEPROBLEMEKODSTARIJIHPACIJENATA‐KOJE,KAKO,KOLIKO?

SandraVezmarKovačević

Katedrazafarmakokinetikuikliničkufarmaciju,UniverzitetuBeogradu‐

Farmaceutskifakultet(Srbija)U kliničkoj praksi razvijenih zemalja uočeni su brojni terapijski problemi kod

starijihpacijenata.Ciljistraživanjajebiodaseutvrdidali, iukojojmerifarmaceutiuSrbijiidentifikujuterapijskeproblemekodstarijihpacijenataupoređenjusarazvijenimzemljama.Dve studije preseka sprovedene su u apotekama primarne zdravstvenezaštiteuperioduoddvegodineucilju identifikacijeterapijskihproblemakodstarijihpacijenata. U okviru jedne studije korišćeni su STOPP/START kriterijumi zaidentifikacijuterapijskihproblemadoksuudrugojstudijifarmaceutisprovodilikliničkipregledlekova.

U istraživanju jeučestvovalo49 farmaceuta i897pacijenata,prosečne starosti73,1±6,4 godina, od kojih je 56,8% bilo ženskog pola. U proseku su pacijentiprimenjivali6,2±2,1 leka,doksunajčešće indikacijezaprimenu lekovabilearterijskahipertenzija (91,4%), dijabetes melitus (36,3%), primarna prevencijakardiovaskularnog događaja (16,8%) i srčana insuficijencija (12,8%). Ukupno jeidentifikovano 1.567 problema u vezi sa terapijom (u proseku 1,8±1,3 po pacijentu).Značajno veći broj problema u vezi sa terapijom je identifikovani pri kliničkompregledu lekova (p<0,001). Neodgovarajuća primena nesteroidnih antiinflamatornihlekova u terapiji bola (34,9%), dugotrajna primena benzodiazepina (27,7%) ineodgovarajuća primena acetilsalicilne kiseline u primarnoj prevencijikardiovaskularnihdogađaja(22,5%)bilisunajčešćeidentifikovaniterapijskiproblemisa prisutnim lekovima u obe studije. Takođe, identifikovana je nedovoljna primenastatina u terapiji dijabetes melitusa (44,3%), acetilsalicilne kiseline u sekundarnojprevenciji kardiovaskularnih događaja (38,6%) i inhibitora protonske pumpe u ciljuzaštite sluznice gastrointestinalnog trakta (22,6%). U poređenju sa istraživanjima urazvijenim zemljama, farmaceuti u Republici Srbiji su identifikovali slične terapijskeprobleme, ali je u našoj zemlji češće identifikovan nedostatak pojedinih lekova uterapiji, posebno statina i acetilsalicilne kiseline. Problemi u vezi sa terapijompacijenata su često zastupljeni u našoj kliničkoj praksi, a farmaceuti su kompetentnistručnjacikojimoguučestvovatiunjihovojidentifikacijiirešavanju.

Istraživanje je realizovano u okviru Projekta 175023 finansiranog od strane

Ministarstvaprosvete,naukeitehnološkograzvojaRepublikeSrbije.

215

PHARMACISTSINSERBIAIDENTIFYDRUG‐RELATEDPROBLEMSINELDERLYPATIENTS‐WHICH,HOW,HOWMANY?

SandraVezmarKovačević

DepartmentofPharmacokineticsandClinicalPharmacy,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Manydrug‐relatedproblems(DRPs)havebeenreportedinolderpatientsinthe

ambulatory care setting. The goal of this research was to establish if, and to whatextent, pharmacists in Serbia participate in identifying DRPs in older patients,comparedtodevelopedcountries.

Twocross‐sectionalstudieswereconductedinprimarycarepharmaciesduringtwo yearswith the aim of identifying DRPs in older patients. STOPP/START criteriawereusedinonestudy,whereasclinicalmedicationreviewwasperformedtoidentifyDRPsintheother.

Fourty‐nine pharmacists participated in the research as well as 897 patients,averageage73.1±6,4,ofwhom56.8%were female. Inaverage,patientswere treatedwith6.2±2.1medications,mostcommonlyforarterialhypertension(91.4%),diabetesmellitus (36.3%), primary prevention of cardiovascular events (16.8%) and heartfailure (12.8%). In total,1.567DRPswere identified (inaverage1.8±1.3perpatient).Significantly more DRPs were identified by clinical medication review (p<0.001).Inappropriate use of nonsteroidal anti‐inflammatory drugs in the treatment of pain(34.9%),long‐termuseofbenzodiazepines(27.7%)andinappropriateuseofaspirininprimary prevention of cardiovascular events (22.5%) were the most frequentlyidentifiedDRPswithexistingtreatmentinbothstudies.Moreover,lackofuseofstatinsin the treatment of diabetes mellitus (44.3%), aspirin in secondary prevention ofcardiovascular events (38.6%) and proton pump inhibitors for gastrointestinalprotection (22.6%) were commonly identified. Compared to studies in developedcountries, pharmacists in Serbia identified similar DRPs but the occurrence oftreatmentomissionwasmorefrequent,particularlyassociatedwiththeuseofstatinsand aspirin. DRPs occur frequently in the primary care setting and pharmacists arecompetentprofessionalswhocanparticipateintheiridentificationandsolving.

This work was conducted as a part of the Project No. 175023 funded by the

MinistryofEducation,ScienceandTechnologicalDevelopment,RepublicofSerbia.

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Arh.farm 2018;68:216-217 PP63

PRIMENAKONCEPTAFARMACEUTSKEZDRAVSTVENEZAŠTITEKODPACIJENATASAASTMOMIHOBP–MODELPRIMARNE

ZDRAVSTVENEZAŠTITE

MilenaKovačević

Katedrazafarmakokinetikuikliničkufarmaciju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Modelprimarnezdravstvenezaštiteprepoznatjekaoveomaznačajnastrategija

zapoboljšanje ishodapacijenatasahroničnimoboljenjima.Cilj studijebila jeprocenauticaja farmaceuta na implementaciju i efektivnostmodela samokontrole bolesti kodpacijenatasaastmomihroničnomopstruktivnombolešćupluća(HOBP).

Prospektivna studija sprovedena u periodu april‐septembar 2015. uključila jedvanaest samostalnih javnih apoteka/apotekarskih ustanova. Inicijalno, pacijenti supopunjavali zadate upitnike, nakon čega im je pruženo strukturirano savetovanje odstrane farmaceuta. Nakon 3 meseca pacijenti su ponovo popunjavali validiraneupitnike:(1)Morisky8‐item;(2)BeliefsaboutMedicines;(3)KnowledgeofAsthmaandAsthmaMedicines;BristolCOPDKnowledge; (4)AsthmaControlTest;COPDAssessmentTestiModifiedMedicalResearchCouncilDyspneaScale.

U studiji je učestvovalo 90 pacijenata sa astmom i 83 sa HOBP. Procenatpacijenatasadobromkontrolomastmepovećanjeza18%,dokjezaHOBPiznosio6%,odnosno 12%, procenjeno preko CAT i mMRC skora, respektivno (p<0,05). Brojpacijenatasaniskimstepenomadherencesmanjenjeza14%uastmii17%ugrupisaHOBP(p<0,05).Pacijentisupokazaliunapređenjeznanjaobolestiilekovima,sa58,7%na73,6%kodastme, i41,6%na63,1% tačnihodgovora zaHOBP(p<0,05).Značajanrezultatbilojeismanjenjezabrinutostipacijentaupogleduštetnihefekataterapije,dokjeuverenjeokoristiprimeneterapijeunapređeno(p<0,05).Uticajuverenjapacijenataidentifikovanjekaoboljiprediktorstepenaadherenceubrojnimstudijama,negoštosutosociodemografskiilikliničkifaktoripacijenta.

Strukturiranosavetovanjeodstranefarmaceutadovelojedopovećanjastepenaadherence,unapređenjaznanjaobolesti i lekovima,unapređenjastavovapacijenatauvezi sa primenom terapije, i konačno do poboljšanja kontrole astme i HOBP.Pacijentimajepruženapodrškazasprovođenjesamokontrolebolestiedukacijom,štojedovelo do poboljšanja ishoda. Model primarne farmaceutske zdravstvene zaštitepokazanjekaoefektivan,sadodatnomprednošćulakodostupnezdravstvenezaštite.

Istraživanje je realizovano u okviru projekta 175023 finansiranog od strane

Ministarstvaprosvete,naukeitehnološkograzvojaRepublikeSrbije.

217

PHARMACEUTICALCAREMODELINTHECOMMUNITYPHARMACYSETTINGS–FOCUSONASTHMAANDCOPDPATIENTS

MilenaKovačević

DepartmentofPharmacokineticsandClinicalPharmacy,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Theprimarycaremodelhasbeenrecognizedasavaluablestrategyto improve

thequalityof chronicdiseasemanagement.The study sought to assess the impactofcommunitypharmacisteducationonpatientsself‐managementfeasibility.

AprospectivestudywasconductedfromApril1sttoSeptember30th2015in12independent/chain pharmacies in Serbia. The main inclusion criteria was aprescription for asthma/COPD medicine. After recruiting, patients filled out thequestionnaires, received a structured counselling, and after threemonths completedthe questionnaires again. Four groups of validated questionnaires were used: (1)Morisky 8‐item; (2) Beliefs about Medicines; (3) Knowledge of Asthma and AsthmaMedicines;BristolCOPDKnowledge;(4)AsthmaControlTest;COPDAssessmentTestandModifiedMedicalResearchCouncilDyspneaScale.

Atotalof90asthmaand83COPDpatientsenrolledthestudy.Theproportionofpatients with controlled asthma increased for 18%, and controlled COPD for 6%,or12%, regarding toCATandmMRCscore, respectively (allp<0.05).Theproportionoflow adherence decreased for 14% in asthma, and 17% in COPD patients (p<0.05).Patients improved their knowledgeon thedisease andmedications ‐ in asthma from58.7%to73.6%,whereasinCOPDfrom41.6%to63.1%ofcorrectanswers(p<0.05).Adecrease in harm and concern score, as well as an increase in necessity score wasobserved in both asthma and COPD patients (p<0.05). It was shown previously thatpatients’beliefsweremuchstrongeradherencepredictors, thansociodemographicorsocialfactors.

Structured pharmacist‐delivered counselling resulted in improvement ofadherence level,knowledgeonthediseaseandmedicationsused,beliefsandattitudetowardsthetherapy,andfinallyinbetterdiseasecontrol.Improvedpatientsoutcomeswere achieved through self‐management support. Community pharmacists are themost accessible health professionals, able to provide necessary information andempowerpatientstocontroltheirdisease.

This work was conducted as a part of the Project No. 175023 funded by the

MinistryofEducation,ScienceandTechnologicalDevelopment,RepublicofSerbia.

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GERIJATRIJSKOJPOPULACIJI

AleksandraCatić‐Đorđević,NikolaStefanović,RadmilaVeličković‐Radovanović

Katedrazafarmaciju,UniverzitetuNišu–Medicinskifakultet(Srbija)Starenjepratipojavakomorbiditeta iposledičnouvođenjevećegbroja lekovau

terapiju. Potencijal za negativne ishode terapije i pojavu problema udruženih saprimenomlekovausledpolipragmazije jepoznati fenomenugerijatriji.Kriterijumizaprocenu propisane terapije starijim osobama (STOPP) i kriterijumi za upozorenjelekarima o potrebnom tretmanu starijih (START) razvijeni su kako bi se omogućiloidentifikovanje potencijalno neadekvatno propisane terapije i uočila potreba zadopunom terapije. Cilj ovog rada bio je procena pojave polifarmacije i potencijanihneadekvatno propisanih lekova kod ambulantnih (OP) i starijih pacijenata koji susmešteni u dom za brigu o starima (RHP) upotrebom STOPP/START kriterijuma.Izvršenajeiprocenastepenaadherenceispitanika.

UpotrebomSTOPP/STARTkriterijumaobavljenjepregledterapije45pacijenatasmeštenihuGerontološkomcentruNiš,uNišu,Srbijai60ambulantnihpacijenata.Kodsvih pacijenata stepen adherence utvrđen je upotrebom Morisky 8 skale. DobijenipodaciobrađenisupomoćuSPSSsoftvera.

RHPsupokazalivećibroj lekovau terapiji (8,11±3,59vs.3,67±1.,40,p=0,001),prisutnih komorbiditeta (2,8±1,34 vs. 1,72±0,85, p=0,001), kao i STOPP (26 vs. 9,p=0,001) i START (11 vs. 2, p=0,002) kriterijuma. Ipak, gledajući broj STOPPkriterijumapobrojupropisanihlekova,učestalostSTOPPkriterijumajemanjakodRHP(0,18±0,14vs.0,23±0,05,p=0,035).ZaSTARTkriterijumenijenađenaznačajnarazlikaizmeđuposmatranihgrupa.GrupaRHPjepokazalavišistepenadherenceuodnosunaOP (p=0,001). Bez obzira na uočen veći broj lekova i komorbiditeta kod pacijenatasmeštenih u domu za stare, učestalost uočavanja STOPP kriterijuma po brojupropisanih lekova jemanji uz istovremenoviši stepen adherenceu odnosuna grupuambulantnih pacijenata. Konstantan medicinski nadzor je važan u dobijanjupredviđenihzdravstvenihishoda,apregledlekovaodstranefarmaceutamožepomoćiurukovođenjuterapijomivodinjenojoptimizacijiusvakodnevnojkliničkojpraksi.

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STOPP/STARTCRITERIAFOROPTIMIZATIONOFPHARMACOTHERAPYINELDERLY

AleksandraCatić‐Đorđević,NikolaStefanović,

RadmilaVeličković‐RadovanovićDepartmentofPharmacy,UniversityofNiš‐FacultyofMedicine(Serbia)Theagingisoftenassociatedwithcomorbiditiesandfollowingtheintroduction

ofnumerousdrugsineverydaytherapy.Thepotentialfornegativeoutcomesanddrug‐relatedproblemsregardingmultiplemedications inolderpeople iswelldocumented.Screening Tool of Older Person’s Prescriptions (STOPP) and Screening Tool to Alertdoctors to Right Treatment (START) have been developed to identify potentialinappropriate prescriptions and prescribing omissions. The aimwas tomeasure theprevalence rates of polypharmacy and potential inappropriate prescriptions inresidential home care patients (RHP) and outpatients (OP) over 65 usingSTOPP/START criteria. Secondly, we evaluated the level of medication adherencebetweenthosetwogroupsofpatients.

Wereviewedtherapyof45RHPinGerontologicalcenterNis,Serbia,and60OP,using the STOPP/START criteria. Also, we determined their level of medicationadherencebyMorisky8scale.AlldatawerestatisticallyprocessedbySPSSsoftware.

RHP had higher number of drugs (8.11±3.59 vs. 3.67±1.40, p=0.001), morecomorbidities(2.8±1.34vs.1.72±0.85,p=0.001),morepatients identifiedwithSTOPP(26vs.9,p=0.001)andSTART(11vs.2,p=0.002)criteria.Still,RHPhadasignificantlylowerrateofSTOPPcriteriaperdrug(0.18±0.14vs.0.23±0.05,p=0.035).Therewasnodifference inSTARTcriteriaperdrugbetweendefinedgroups.Additionally,RHPhadhigherlevelofmedicationadherencecomparedtoOP(p=0.001).

In spite of the presence of polypharmacy in older patients in the residentialhomecenterandthenumberofSTOPPcriteria,arateofSTOPPcriteriaperdrugwaslow and level of medication adherence was high. Constant medical supervision isimportantforhealthoutcomes,butmedicationreviewbyapharmacistcanbeareliabletoolforoptimizationandmanagementofpharmacotherapyineverydaypractice.

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REGULATIVAODODACIMAISHRANI

IvanStanković

Katedrazabromatologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Dodaci ishrani (dijetetski suplementi) su namirnice koje dopunjuju normalnu

ishranuipredstavljajukoncentrovaneizvorevitamina,mineralailidrugihsupstancisahranljivim ili fiziološkim efektom, pojedinačno ili u kombinaciji, a u prometu su udoziranimoblicimadizajniraneda seuzimajuuodmerenimpojedinačnimkoličinama(kapsule,tablete,kesicepraška,ampuletečnosti,bočicezadoziranjeukapimaisl.).UEU dodaci ishrani regulisani su Direktivom 2002/46/EC i njenim dopunama. EUregulativa koja još uvek nije kompletna sadrži listu dozvoljenih vitamina iminerala,jedinicezanjihovooznačavanje,listusupstancikojesemogukoristitikaonjihoviizvorii posebne zahteve za deklarisanje dodataka ishrani. Na nivou EU još uvek nisuharmonizovane maksimalno dozvoljene količine vitamina i minerala u dnevnoj dozidijetetskihsuplemenata,ostalesupstancesanutritivnimili fiziološkimefektomkaonibiljni dijetetski suplementi i za njih se primenjuju nacionalni propisi zemalja članicakoji se razlikuju. Naš Pravilnik o zdravstvenoj ispravnosti dijetetskih proizvoda („Sl.GlasnikRS”br.45/2010,27/2011,50/2012,21/2015,75/2015i07/2017)usklađenjesa regulativom EU u delu koji se odnosi na dodatke ishrani. Propisana je obaveznaproceduranotifikacija,odnosnoupisubazupodatakakojuvodiMinistarstvozdravljaRS koji se vrši za period od 5 godina, a uključuje dobijanje stručnog mišljenja,kategorizacije i odobrenja teksta deklaracije od strane Farmaceutskog fakulteta,stručnog mišljenja o zdravstvenoj ispravnosti od ovlašćenih laboratorija Zavoda zajavno zdravlje ili Vojnomedicinske akademije i podnošenje zahteva sa kompletnomdokumentacijom Ministarstvu zdravlja Republike Srbije. Predviđenom izmenomZakona o bezbednosti hrane biće omogućeno regulisanje dodataka ishrani posebnimpropisom koji je potrebno usklađivati za izmenama i dopunama regulative EU ododacimaishrani.

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REGULATIONONFOODSUPPLEMENTS

IvanStanković

DepartmentofBromatology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Food supplements are foodstuffs the purpose of which is to supplement the

normaldietandwhichareconcentratedsourcesofnutrientsorothersubstanceswithanutritional or physiological effect, alone or in combination, marketed in dose form,namely forms suchas capsules, tablets, sachetsof powder, ampoules of liquids, dropdispensingbottles,andothersimilarformsofliquidsandpowdersdesignedtobetakeninmeasured small unit quantities. In the EU, food supplements are regulated by theDirective2002/46/ECanditsamendments.EUregulationonfoodsupplements,thatisnot yet completed, includes a list of permitted vitamins andminerals, their labelingunits,a listofsubstancesthatcanbeusedastheirsourcesandspecificrequirementsforthelabelingoffoodsupplements.AttheEUlevel,themaximumallowableamountsof vitamins andminerals in the daily dose of dietary supplements, other substanceswithnutritionalorphysiologicaleffects,aswellasherbaldietarysupplements,arestillnotharmonizedandtheyaresubjecttothenationalregulationsoftheMemberStates.Our rule book on the health safety of dietary products („Official Gazette of RS” No.45/2010, 27/2011, 50/2012, 21/2015, 75/2015 and 7/2017) is in linewith the EUregulation in the part referring to food supplements. The mandatory notificationprocedure for a period of 5 years includes the obtaining of expert opinion,categorizationandapprovalofthetextonthelabelbytheFacultyofPharmacy,opiniononthefoodsafetyfromtheauthorizedlaboratoriesoftheInstitutesforPublicHealthorMilitaryMedicalAcademyandsubmittingofapplicationwithcompletedocumentationtotheMinistryofHealthoftheRepublicofSerbia.

TheforeseenamendmenttotheFoodSafetyActwillallowforthenewseparaterule book on food supplements that need to be periodically harmonized withamendmentstotheEUregulationonfoodsupplements.

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KORISTISUPLEMENTACIJEUPROMOCIJIZDRAVLJA

BrižitaĐorđević1,NevenaIvanović1,IvanaBaralić2,3

1Katedrazabromatologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2Kliničko‐bolničkicentarZvezdara,Beograd,3Udruženjezamedicinusporta,

Beograd(Srbija)

Poslednjih decenija dijetarne intervencije pod kojim se podrazumeva

potenciranjeilieliminacijaodređenihnutrijenatailinamirnicaizishrane,kaoiprimenaodređenih nutrijenata u koncentrovanom obliku, u formi dijetetskih suplemenata,dobijajusvevišenaznačaju.Iakosestručnajavnostuglavnomslažedaseodgovarajućiunos nutrijenata može obezbediti dobro izbalansiranom ishranom, postoje stanja ukojima je upotreba suplemenata korisna i poželjna, kao što su starije osobe,pedijatrijska populacija, osobe sa poremećajem ishrane…U skladu sa izvornomdefinicijom,dijetetski suplementi obezbeđujudodatniunosnutrijenata.Naime,poredvitamina imineralakojisu inajčešćisastojcisuplemenata,uovimproizvodimamogubiti prisutni i čitav niz drugih nutrijenata, kao što su pojedine masne kiseline,aminokiseline i izolovani proteini i peptidi, pojedini ugljeni hidrati, ali i veliki brojnenutritivnihsupstancizakojanaučna istraživanjapružajudokazedasukorisna idapovoljnodelujunaorganizam(karotenoidi,probiotskimikroorganizmi,koenzimQ10,bioflavonoidiidr).Kakoseposlednjihgodinauopštojpopulacijibeležiizuzetnovisokaprevalencakorišćenjadijetetskihsuplemenata,veomačestosepostavljapitanjekojajestvarnakoristodsuplementacije.Ononaštarezultatiistraživanjaukazujujestedajeuzemljamaukojimajeupotrebadijetetskihsuplemenataraširena,nutritivnistatusopštepopulacijepovoljniji,apojavadeficitaređa.Takođe,velikibrojstudijagovoriuprilogdijetarnihintervencijasuplementacijom.Kodnajvećegbrojaovihstudijaosnovniciljjekorigovanjedeficitanutrijenata,aliiopštapromocijazdravljausmislusmanjenjarizikaod hroničnihnezaraznih bolesti. Tako u literaturi postoje jasni dokazi o promotivnojulozi određenih biološki aktivnih jedinjenja ‐ vitamina D, gvožđa, kalcijuma, cinka,omega‐3 masnih kiselina, dok, s druge strane, za neka druga jedinjenja protektivnauloga još nije sasvim razjašnjena. Na kraju, zaključak o efikasnosti određenogsuplementa, ali i sigurnosti i uslovima njegove primene, mora biti donet na osnovuvrsteikoličinedokazadobijenihuadekvatnosprovedenimstudijama.

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DIETARYSUPPLEMENTINHEALTHPROMOTION

BrižitaĐorđević1,NevenaIvanović1,IvanaBaralić2,3

1DepartmentofBromatology,UniversityofBelgrade‐FacultyofPharmacy,2ZvezdaraUniversityMedicalCentar,Belgrade,3Sportsmedicineassociationof

Serbia,Belgarde(Serbia)

In the former few decades the dietary interventions designed to potentiate or

eliminate certain nutrients or whole foods from the diet, yet another designed toincludesomenutrientsinaconcentrated,dietarysupplementform,arebecomingmoreand more important. Although professional public in the most cases agree thatappropriate intake of nutrients could be satisfied by well balanced diet, there areconditions in which use of supplement is useful and desirable such as use in olderpopulation, pediatric population, peoplewithnutritiondisorders. In accordancewiththe original definition, dietary supplements should provide additional intake ofnutrients. Namely, besides vitamins and minerals which are the most commoningredients of supplements, a variety of other nutrients can be present in theseproducts, suchas certain fatty acids, aminoacids and isolatedproteins andpeptides,certaincarbohydrates,aswellasalargenumberofnon‐nutritivesubstancesforwhichscientificresearchprovidesevidencethattheyareusefulandfavorableforthehumanwell‐being(carotenoids,probioticmicroorganisms,coenzymeQ10,bioflavonoids,etc.).As in recent years in the general population has been reported an extremely highprevalence of dietary supplements use, the question arises whether there are realbenefits of supplements use. Literature data indicate that in countries where use ofdietary supplements iswidespread, the dominant status of the general population ismore favorable, and the occurrence of the deficit is lower. Also, a large number ofexistingstudiespointtothebenefitofsupplementusage.Inmostofthesestudies,themaingoalwascorrectionofnutrientdeficiencies,butalsoageneralhealthpromotionintermsofreducingtheriskofchronicnon‐communicablediseases.Thus,thereisclearevidence in the literature for role of certain biologically active compounds in healthpromotion‐vitaminD, iron,calcium,zinc,omega‐3fattyacids.Ontheotherhand,forsome other compounds, the protective role has not been yet clarified. In the end,conclusion on the effectiveness of certain supplements, as well as the safety andconditions of its application, must be based on the type and amount of evidenceobtainedinadequatelyconductedstudies.

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ZDRAVSTVENIRIZICIUPOTREBEDIJETETSKIHSUPLEMENATA

ZoricaBulat

Katedrazatoksikologiju„AkademikDaniloSoldatović”,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Primena suplemenata se generalno smatra sigurnom što doprinosi njihovoj

široko rasprostranjenoj upotrebi. Rizik od pojave eventualnih štetnih ili toksičnihefekatajeveomamaliinajčešćepotičeodnepravilneprimene,upotrebefalsifikovanihpreparatakojisadrženedozvoljenesupstancenpr.steroide,prisustvanečistoćakaoštosutoksičnimetaliitd.

Izvestanbroj trovanja,kojasuujedno inajteža,posledicasuakutne izloženostivisokimdozamasuplemenata,biloda jerečoslučajnimtrovanjima ili samoubilačkimnamerama.Centrizakontrolutrovanjakonstantnobeležeizvestanbrojslučajevaovihtrovanja,pričemusevećinaslučajevarelativnolakozapažajuikarakterišeihblagadoumerenoteškakliničkaslika.Verovatnovećiproblempredstavljanepravilna,slučajnailitendenciozna,upotrebajednogilivišesuplemenata,samih,ilizajednosalekovima.Uovimslučajevimaeventualništetnii/ilitoksičniefektiseteškozapažajuiretkodovodeuvezusaupotrebomsuplemenata.Nepravilnaupotrebaseogleda,kakouunosuvišihdoza, tako i u primeni u dužem vremenskom periodu u odnosu na preporuke, a saciljem da se postigne željeni efekat. U ovim slučajevima, osobe koje ih koriste, čestosvesno ili nesvesno ne informišu lekara o upotrebi ovih preparata. Nekontrolisanaupotreba pojedinih suplemenata koji mogu da interreaguju, među sobom ili saesencijalnim supstancama, pored rizika od prekomernog unosa per se, mogurezultovati i suprotnim efektima, odnosno interakcijama koje vode ka smanjenojraspoloživostisupstancineophodnihorganizmu.

Da bi se sprečili eventualni štetni efekti upotrebe suplemenata, pored pažljivekontroleovihproizvodaodstraneproizvođačairegulatornihtela,neophodnojedasepodignesvest,kakoosobakojiihupotrebljavaju,takoizdravstvenihradnika,označajunjihovepravilneupotrebe.Naročitotreba imatiuviduda istovremenaprimenavećegbrojasuplemenatamožeproizvestibrojneteškosaglediveefekte,oddeficitasupstancineophodnihorganizmu,dopojavetoksičnihefekata.

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DIETARYSUPPLEMENTS‐HEALTHRISK

ZoricaBulat

DepartmentofToxicology„AkademikDaniloSoldatović”,Universityof

Belgrade‐FacultyofPharmacy(Serbia)

Useofsupplementsisgenerallyregardedassafe;hencetheiruseiswidespread

nowadays.Theriskofharmfulortoxiceffects isvery lowandmostoftenarisesfromthe improper use, intake of counterfeit preparations containing unauthorizedsubstances,e.g.steroids,orthepresenceofimpuritiessuchastoxicmetals,etc.

Acertainnumberofpoisoningcasesare theconsequenceofacute ingestionofhighdoses,whetheraccidentalor suicidal, and thesecasesare themost severeones.The PoisonControl Centers are consistently recording certain number of such cases,and majority can be easily recognized and are characterized bymild to moderatelysevereclinicalpresentations.Inappropriate,unintentionalorintentional,useofoneormoresupplements,aloneorincombinationwithdrugsrepresentsbiggerissue.Insuchcases,harmfuland/or toxiceffectsaredifficult todetectandcanrarelybeassociatedwiththeuseofsupplements. Inadditiontooverdose, improperuseofsupplements isalso reflected by the duration of use which is in some instances longer thanrecommended.Moreover,rarelydothesepatientsinformtheirmedicaldoctorsaboutthe use of such products. Uncontrolled use of supplements that can interact amongthemselves, or with some essential substances, in addition to the risk of excessiveintake per se, also can result in interactions leading to reduced availability ofsubstancesessentialforphysiologicalfunctions.

To prevent possible harmful effects of the supplements’ use, in addition tocareful control of these products by manufacturers and regulatory bodies, it isnecessary to raise patient and health professional’s awareness on the importance oftheir appropriateuse. Special attentionshouldbegiven to the fact that simultaneousintakeofmanysupplementscanproduceseveraleffectswhicharedifficulttoforeseesuchasdeficitofessentialsubstancesnecessaryforphysiologicalfunctionsandvarioustoxiceffects.

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ANALIZADIJETETSKIHSUPLEMENATAKOJEKORISTESPORTISTIUSRBIJI

NenadDikić1,MarijaAnđelković2,MilicaVukašinovićVesić2,

BrižitaĐorđević3

1UniverzitetSingidunum‐Fakultetzafizičkukulturuimenadžmentusportu,2AntidopingagencijaRepublikaSrbije,3Katedrazabromatologiju,Univerzitetu

Beogradu‐Farmaceutskifakultet(Srbija)

AntidopingagencijaRepublikeSrbije(ADAS) jesaciljeminformisanjasportista

popitanjuprisustavasupstancesaListezabranjenihsupstanci,od2011.godineuvelainstitucijedavanjamišljenjao lekovimaisuplementima.Dabise izbeglinesporazumi,svamišljenja o lekovima i suplementima sudatapisano, a nakon elektronskogupita.Ciljovogradajeprikazsuplemenatazakojesubilizainteresovanisportisti.Urađenajeanaliza svih izdatih mišljenja u periodu od 2011. do 2017. godine prema grupamalekovaisuplemenata.Uovomradućebitipredstavljenisuplementi.

Prvih deset grupa suplemenata od 380 izdatih mišljenja na zahtev sportistaprema različitim grupama suplemenata su: sagorevači masti (9,47%), whey protein(8,95%),NOreaktori (8,68%),multikomponentnipreparati(6,58%),kreatin(6,05%),tribulus (5,79%), biljni preparati (4,74%), aminokiseline – kompleks (4,21%),povećanjeenergije‐ugljenihidrati(3,9%),povećanjetelesnetežine–gejneri(3,95%)itd.KompletnalogistikaodstraneADASkojajepruženasportistimanijesamoservis,već,ipresvega,autentičanvidsaradnjeuborbiprotivdopingausportu,kojikaotakav,ne postoji na svetu. Kompleksnost problema sigurno zahteva dublju farmakološkuanalizu, ali i samo nasumični pogled na tabelu sa grupama suplemenata koje koristesportistiSrbijeukazujenaneophodnostrazumevanjasuplemenatakojisportistumogudauveduuozbiljanzdravstveniproblem,iprekršajdopingpravila.

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ANALYSISOFDIETARYSUPPLEMENTSUSEDBYSERBIANATHLETESNenadDikić1,MarijaAnđelković2,MilicaVukašinovićVesić2,

BrižitaĐorđević3

1SingidunumUniversity‐FacultyofPhysicalEducationandManagementinSport,2AntidopingagencyofSerbia,3DepartmentofBromatology,Univeristyof

Belgrade‐FacultyofPharmacy(Serbia)

TheAnti‐DopingAgencyoftheRepublicofSerbia(ADAS)hasintroducedservice

on giving opinions on medicines and supplements since 2011, with the aim ofinformingtheathleteabout thepresenceof thesubstance fromtheListofprohibitedsubstances. In order to avoid misunderstandings, all opinions on drugs andsupplementsaregiveninwriting,afteranelectronicinquiry.Theaimofthispaperistopresentthesupplementsissuedattherequestofathletes.Ananalysisofallpublishedopinionsintheperiodfrom2011.to2017.wascarriedoutaccordingtogroupsofdrugsandsupplements.Inthisworksupplementswillbepresented.

The top ten groups of supplements of 380 opinions issued at the request ofathletesaccordingtodifferentgroupsofsupplementsintheperiodfrom2011to2017are:fatburners(9.47%),wheyprotein(8.95%),NOreactors(8.68%),multicomponentpreparations (6.58%), Creatine (6.05%), Tribulus (5.79%), herbal products (4.74%),aminoacids– complex (4.21%),energygainers (3.9%),bodyweightgainers (3.95%)etc.ThecompleteADASlogisticsprovidedtoathletesisnotjustaservice,butaboveallanauthentictypeofcooperationinthefightagainstdopinginsport,whichassuchdoesnot exist in the world. The complexity of the problem certainly requires a deeperpharmacological analysis, but even a random view of the table with the groups ofsupplements used by athletes in Serbia points the necessity of understanding thesupplementsthatcanbringtheathleteintoaserioushealthproblemandaviolationofdopingrules.

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APOTHECARYPROFESSIONANDPHARMACEUTICALACTIVITIESINTHEHEALTHCARESERVICEATTHEENDOFTHEFIRSTWORLD

WAR

AdrianaElenaTaerel

„CarolDavila”UniversityofMedicineandPharmacy,Buchurest(Romania)The innovative trends in the pharmaceutical industry at the end of the 19th

century and before the FirstWorldWar have become significant in the present‐daypharmacy,determiningpharmaco‐historianstoconsiderthe20thcenturyastheageofmedicine at European and international level. Favoured by the development of thechemistry and pharmaceutical technology, as well as by the modernisation of themanufacturingprocesses,thedrugindustryhasseenanincreasingdevelopment.Ithadgenerated the appearance of the large factories and chemical‐pharmaceuticalmonopoliesindevelopedEuropeancountrieslikeGermany(Bayer,Hoechest),England,Netherlandsetc.

Materials referring to the period under review were studied, with a focus onaspectsrelatedtotheprogressandstagnation,respectively,oftheEuropeanpharmacypracticeandapothecaryservice.

Asregardsthepharmaceutical industry,production laboratoriesarestartingtoopeninmanyEuropeancountries,Romaniaasexample,withupto176labsfunctioningbymid‐20thcentury. Themodern pharmacist education required the introduction ofnew subjects in the curriculumplan. Themodern healthcare laws enacted in severalEuropean countries before 1914 and between the two World Wars were not fullyenforced.Althoughtheypromotedmodernorganisationandpharmaceuticalassistance,thehealthcarelawsinRomaniahadseriousdrawbacks.

During the historical period we observed, the overall pharmacy developmentfollowedanunevenupwardstrend,howevermarkedbysetbacksandlagging.ThiswasthecaseinmanycountriesacrosstheEurope.Thepharmaceuticalresearchhasgainedmomentum on an international scale although the two World Wars devastated thesocialandpoliticallifeoneverylevel.

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JAČANJEPROFESIONALIZMAUAPOTEKARSKOJPRAKSI:ČEMUNASUČEAPOTEKARSKEZAKLETVEODNAJSTARIJIHDOSAVREMENIH

DušankaKrajnović

Katedrazasocijanufarmacijuifarmaceutskozakonodavstvo,Univerzitetu

Beogradu–Farmaceutskifakultet(Srbija)Rutter i Duncan (2010) upućivali su na to da je „profesionalizam skup

strukturalnih, karakternih i bihejvioralnih osobina”, dok Hammer (2006)profesionalizam definiše njegovim ispoljavanjem u praksi, koje se „očituje krozprofesionalnu socijalizaciju, gde pojedinac može da usvoji vrednosti, osobine ipraktičnoponašanjekojejeodrazprofesionalizma”.Krenuli smoodistorijskeanalizekoja je pokazala da se razvoj farmaceutske prakse, a posebno apotekarske prakse,menjaoimoraodaseprilagodisvezahtevnijimdruštvenimpromenama.

U radu je istraženo kako su se očekivanja, veštine, karakteristike i zahtevanemoralneosobineapotekaramenjalekroz vreme.Metodakoju smokoristili uključujeanalizu sadržaja odabranih apotekarskih zakletvi, od onih prvih iz 12. veka dosavremenih, poput FIP‐ove zakletve farmaceuta. Izabrali smo zakletvu kao formuetičkog normativa zbog toga što je najstarija i zbog toga što se održala dodanas.Odsrednjegvekadopočetkaprošlogveka,karakterneosobineapotekara,kaohipotetičkapolazištazaprihvatljivoponašanje,bilesuuosnovizahtevasvihanaliziranihtekstovazakletvi.Unjima semožepratiti i promenaprofesionalne filozofije i društveneulogeapotekara, od majstora umeća izrade lekova, preko snabdevača i onoga ko izdajelekove,dopružaocauslugezapacijenta.Farmaceutisushodnoovompreokretuimalituprednostdabuduosnaženinizomnovihzahtevaiveštinakoje jetrebalousvojiti.Kaošto nas upućuju tekstovi savremenih apotekarskih zakletvi, ovaj posao mora da seobavlja dostojanstveno, celishodno i s ponosom kako bi se ostvarila dva značajnamoralnaprincipa:kaoprvo„nenanetištetu”(primumnonnocere)idrugo,dužnostdasestarajuzapacijenta.Princip„raditiunajboljeminteresupacijenta”uosnovi jesvihanaliziranih tekstova i iskazan jekrozvišezahteva,odkojih je samo jedankonstantoprisutan‐atojeočuvanjepoverenjakojepacijentimaufarmaceutakaozdravstvenogprofesionalca.

Istraživanje je realizovano u okviru Projekta 14004 finansiranog od strane

Ministarstvaprosvete,naukeitehnološkograzvojaRepublikeSrbije.

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REINFORCINGPROFESSIONALISMINAPOTHECARYPRACTICE:WHATCOULDWELEARNFROMTHEAPOTHECARIES’OATHSFROM

THEPASTTOTHEMOSTCONTEMPORARY

DušankaKrajnović

DepartmentofSocialPharmacyandPharmaceuticalLegislation,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Rutter and Duncan (2010) suggested that „professionalism is a complex

composite of structural, attitudinal andbehavioral attributes”,whileHammer (2006)argued that professionalism is defined by its demonstration in practice and is„manifested through professional socialization, when one can learn to adopt to thevalues,attitudesandpracticalbehaviorsthatareseenasrepresentingprofessionalism.”We took the point of history analysis which showed that pharmacy profession,apothecary in particular, has had to adapt to accommodate to the imposedrequirementsofsociety.

Thispaper examinedhowexpectations, skills, characteristics and the requisitemoral character of apothecarists changed over time, by using the text analysis ofseveralapothecaryoaths.Wechoseoathsastheoldestformofethicalnormativewhichhas been persisted for almost twomillennia. The oldest analyzed apothecary oath isfrom the 12thcentury, while the contemporary one is the FIP oath/promise of apharmacist.Fromthemiddleagestheconceptof„character”wasemphasizedasthesetof assumptions about the proper behavior rather historically and culturally specific.Shiftingoftheroleofpharmacistfromatechnician,compounderandsellerofdrugstoacareerofpatients, ledtotheevolutionofpharmacyfromoccupationaltoprofessionalstatusandtheadoptionofanewphilosophyofpracticeaccountableforpharmaceuticalcare in an ethical context. Pharmacists benefited from this change with a set ofexpectationsandasetofskillstobeacquired.Asreflectedincontemporaryoathsthisservicemustbecarriedoutwithdignity, integrityandhonor inorder toachieve twoimportantmoralprinciples:„nottodoharm”andtoprovide„dutyofcare”.

This researchwas supported by the grant ofMinistry ofEducation, Science and

TechnologicalDevelopmentinSerbia,GrantNumber41004.

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QUALITYINDICATORSOFPHARMACEUTICALCARESERVICES

MitjaKos

FacultyofPharmacy,UniversityofLjubljana(Slovenia)A basic concept which should underlie all health care services and pharmacy

practiceisthatofassuringthequalityofpatientcareactivities.Donabediandefinedthethree elements of quality assurance in health care as being structure, process andoutcome(DonabedianA.,1980).Qualityindicatorsaddressmeasurablequalityaspectsofthethreeelements.Theyprovideaninsightintotheperformanceofcareprovidersand are used to stimulate continuous improvement of patient care. They areinformative to healthcare providers, payers and patients.With the development andimplementation of new pharmacy‐led services, pharmacists are challenged to formspecific indicators that will reflect the main goals of their services. For example,medicationusereviewserviceaimstoimprovemedicationadherenceofpatients,theirknowledge about medicines and the appropriateness of use. Therefore, we wouldexpectqualityindicatorsreflecttheabovestatedgoalsoftheservice.Qualityindicatorsshouldbe implemented into thesystemstepbystepandshouldbeginwith themostactualandprofessionallyrelevantones.

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Arh.farm 2018;68:232-233 PP72ANALIZAFARMACEUTSKIHUSLUGAUEVROPIISRBIJI–MODALITETIRAZVOJAUSVETLUNOVIHTEHNOLOGIJA

IvanaTadić

Katedrazasocijanufarmacijuifarmaceutskozakonodavstvo,Univerzitetu

Beogradu–Farmaceutskifakultet(Srbija)Farmaceutske usluge koje se pružaju u apotekama razlikuju se u državama

Evropeusledkulturološkihrazlika i različitih sistemazdravstvenezaštite.Promeneufarmaceutskojregulativiiprimenanovihzdravstvenihtehnologijautičunapromeneupružanju farmaceutskih usluga kao i uloge farmaceuta u društvu.Velika studijasprovedena tokom 2012. i 2013. godine, sa ciljem da se analizira stepen pružanjafarmaceutskihusluga,obuhvatilajefarmaceuteiz16državaEvrope.Podaciouslugamaprikupljeni su pomoću „Behavioral Pharmaceutical Care Scale” (BPCS) upitnika.Učešćemustudiji,poprviputjeomogućenodasefarmaceutskeuslugekojesepružajuu Srbiji porede sa farmaceutskim uslugama drugih zemalja. Prosečan BPCS skorfarmaceuta (n=374) iz Srbije iznosio je 77,5±25,5. Najveći BPCS skor zabeležen je uŠvajcarskoj(82,7±22,8)dokjenajnižizabeleženuLitvaniji(60,4±20,8).Maliprocenatfarmaceuta Srbije (3,7%) pripao je kategoriji „pružaoci farmaceutskih usluga”(farmaceutičiji je skorbiourasponunajviših20%vrednostiukupnogBPCSskora).Uponovljenoj studiji sprovedenoj 2018. godine u Apoteci Beograd (učestvovalo 59farmaceuta)ukupanprosečanBPCSskoriznosioje84,3±22,1,dokje8,5%farmaceutapripaokategoriji„pružaocifarmaceutskihusluga”.UposlednjihpetgodinazabeleženjeporastukupnogBPCSskorafarmaceutaizSrbije.Tokomovogperiodamnogizakonskiakti od značaja za farmaceutsku praksu pretrpeli su izmene ili su usvojeni novi.Implementirane zdravstvene tehnologije omogućile su izdavanje lekova putemobnovljivih elektronskih recepata, olakšano pružanje informacija o lekovima (načinuupotrebelekova,interakcijamaizmeđulekova,kaoiinterakcijamalekovasahranomilidijetetskim suplementima, adherenci), olakšanu saradnju farmaceuta sa drugimzdravstvenimradnicima,kaoiedukacijufarmaceutaputemelektronskihplatformi.Sveovepromeneznačajnosuuticalenapromenuulogefarmaceutaudruštvu.

233

ANALYSISOFPHARMACEUTICALSERVICESPROVIDEDIN

COMMUNITYPHARMACIESINEUROPEANDSERBIA‐MODALITIESFORFUTUREDEVELOPMENTINTHELIGHTOFNEWTECHNOLOGIES

IvanaTadić

DepartmentofSocialPharmacyandPharmaceuticalLegislation,Universityof

Belgrade‐FacultyofPharmacy(Serbia)The pharmaceutical services are different across European countries due to

country specific practice, culture and systems of health delivery. Changes inpharmaceutical regulations and implementationof newhealth technologies influencetheevolutionofpharmaceuticalservicesandcommunitypharmacists’role.Intheyears2012 and 2013 the large study, with the aim to assess the degree of provision ofpharmaceutical services by community pharmacists, was conducted across Europeusing the Behavioral Pharmaceutical Care Scale ‐ BPCS. For the first time,pharmaceutical services in Serbian community pharmacies were compared with theservicesofother15Europeancountriesthatparticipatedinthestudy.ThetotalBPCSaverage score achieved by Serbian pharmacists (n=374 pharmacists) was 77.5±25.5(the highest score was 82.7±22.8 of Switzerland pharmacists and the lowest was60.4±20.8ofLithuanianpharmacists).Only3.7%Serbianpharmacistswerecategorizedas„providersofpharmaceuticalcare”accordingtotheclassificationofthetop20%ofthe total BPCS score.In repeated study conducted in 2018 year in Serbia within thePharmacyBelgrade(n=59pharmacists),theoverallBPCSaveragescorewas84.3±22.1and8.5%Serbianpharmacistswerecategorizedas„providersofpharmaceuticalcare”.

The overall BPCS score of the Serbian pharmacists increased in the last fiveyears.During thisperiodmanypharmaceutical regulationshavebeen changed, somehave been adopted and new technologies have been implemented. New healthtechnologies enabled dispensing medicines on repeatable prescriptions, easierprovision of information about medicines (medication use; interactions with othermedicines,foodanddietarysupplements;adherence),easierreferralandconsultationactivitiesaswellason‐lineeducationofpharmacists.Allofthesechangessignificantlyinfluencedthechangeofthepharmacists’roleinthesociety.

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UNAPREĐENJEZDRAVSTVENEZAŠTITETRUDNICAIDOJILJA–ULOGAFARMACEUTAIDOPRINOSFARMACEUTSKIHUSLUGA

MarinaOdalović

Katedrazasocijanufarmacijuifarmaceutskozakonodavstvo,UniverzitetuBeogradu–Farmaceutskifakultet(Srbija)

Značajan doprinos farmaceuta u unapređenju zdravlja majki prepoznat je od

straneSvetskefarmaceutskefederacije(InternationalPharmaceuticalFederation‐FIP).Ulogafarmaceutaopisanajeuokviruvišeintervencijaiuključujesledeće:informisanjetrudnica i dojilja o vitaminskim i drugim dijetetskim proizvodima, uključujući folnukiselinu i proizvode koji sadrže gvožđe; promovisanje odvikavanja od pušenja iupotrebe alkohola; evaluacija primene potencijalno teratogenih lekova i savetovanjeadekvatne promene terapije (npr. kod terapije epilepsije). Dodatno, opisano je višefarmaceutskih usluga tokom postpartalnog perioda kao što su: pomoć kod dojenja(preporukaodgovarajućeformulezaodojčekadamajkanijeumogućnostidadojidete,ikadajeovakavnačinishraneprihvatljiv,izvodljivibezbedanzabebu);skriningženapod rizikom od postpartalne depresije; obezbeđenje suplemenata sa vitaminom A.Uprkos preporukama FIP‐a, tradicionalno, farmaceuti nisu direktno uključeni ustruktuirane usluge zdravstvene zaštite namenjene trudnicama i dojiljama.Međutim,trudnice navode farmaceute kao jedan od najkorisnijih izvora informacija u vezi sarazličitim zdravstvenim problemima u trudnoći. Sa druge strane, farmaceuti opisujurazličite barijere sa kojima se susreću pri savetovanju trudnica. Nedostatak znanja oterapijispecifičnihstanjautrudnoći,kaoinedostatakrelevantnihizvorainformacijaobezbednosti lekova i drugih proizvoda pri primeni u trudnoći prepoznati su kaonajčešćiproblemiupraksi.Kursevikontinuiraneedukacijeposvećeniupotrebilekovautrudnoći predstavljaju za farmaceute značajan izvor korisnih informacija. Dobroinformisani farmaceuti mogu dati značajan doprinos u unapređenju zdravlja majki ibeba. Razvoj informacionih centara o teratogenosti lekova zajedno sa specifičnimkursevimakontinuiraneedukacijemogubitiveomakorisnizafarmaceute.

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PREGNANTANDBREASTFEEDINGWOMENHEALTHCARE

IMPROVEMENT‐THEROLEOFPHARMACISTS

MarinaOdalović

DepartmentofSocialPharmacyandPharmaceuticalLegislation,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Significant contributionofpharmacists in improvementofmaternalhealthhas

beenwellrecognizedbytheInternationalPharmaceuticalFederation(FIP).Theroleofpharmacists has been described within the following interventions for pregnantwomen: educate mothers on and supply vitamins and nutritional supplements,including folic acid and iron supplements; promote cessation of alcohol and nicotineuse;evaluationofpotentialteratogenicmedicines;adviceonalternativedrugregimensifteratogenicityofcurrenttreatmentisknownorareductioninriskisrequired(e.g.inepilepsy). Additionaly, pharmaciusts interventions for posnatal period has also beendescribedandinclude:supportbreastfeeding(whenreplacementfeedingisacceptable,feasible, affordable, sustainable and safe); identify women at risk of postpartumdepression;providingofvitaminAsupplementation.InspiteofFIPrecommendations,traditionally, pharmacists have not provided speciality services to pregnant andbreastfeedinf women. However, pregnant women has reported that they seepharmacistasoneofthemostusefulsourcesofinformationabouthealthissuesrelatedto pregnancy. On the other side, different areas of concerns and barriers related tocounselling of pregnant women have been described by pharmacists. Gaps inknowledgerelatedtospecificconditiontreatmentinpregnancy,anddeficitofrelevantsources of drug safety data for use in pregnancy have been reported as a commonproblems in practice. Continuing professional development courses have beenrecognizedasimportantforcontributiontotheknowledgebaserelatedtothisspecificanddemandingissue.Wellinformedpharmacistscouldgiveimportantcontributiontoimprovement of maternal and nowborn health. Development of teratogenicinformationservicealongwithcountinuingeducationcoursescouldbeveryusefulforpharmacists.

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KOLIKOKOŠTAFARMACEUTSKAUSLUGA?

DraganaLakić

Katedrazasocijanufarmacijuifarmaceutskozakonodavstvo,UniverzitetuBeogradu–Farmaceutskifakultet(Srbija)

PremasadašnjemPravilnikuocenamazdravstvenihusluga(bezobzirada li se

radi o primarnom, sekundarnom ili tercijarnom nivou), gotovo nijedna farmaceutskausluga nije prepoznata za plaćanje od strane Republičkog fonda za zdravstvenoosiguranje.

Farmaceutske usluge predstavljaju sve usluge koje pruzaju farmaceuti u ciljuobezbeđenja adekvatne farmaceutske zdravstvene zastite. Ovo uključuje kakoaktivnostiusmerenenanabavku,snabdevanjeiizdavanjelekovaidrugihproizvodakojise mogu naći u apoteci, tako i aktivnosti usmerene u cilju promocije zdravlja, kao iproceskomunikacijeipružanjesavetaoadekvatnojprimenilekabilopacijentimabilodrugim zdravstvenim radnicima. Cilj pružanja farmaceutske usluge je dostizanjeoptimalnihishodaterapijepacijentaipoboljšanjepacijentovogkvalitetaživota.

Uprezentacijićebitiprikazanekonomskiaspektpružanjafarmaceutskeuslugeuapoteci. Istraživanja iz sveta, ali i Srbije pokazuju da su pacijenti spremni zaizdvajanjem određenog novčanog iznosa za farmaceutske usluge. Neophodno jepokazati značaj i vrednost farmaceuta i farmaceutske usluge i donosiocima odluka uzdravstvu.

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HOWMUCHDOESTHEPHARMACEUTICALSERVICECOST?

DraganaLakić

DepartmentofSocialPharmacyandPharmaceuticalLegislation,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

According to the currentOrdinance onprices of health services (regardless of

whetheritisaprimary,secondaryortertiarylevel),almostnoneofthepharmaceuticalservicesarerecognizedforpaymentbytheNationalHealthInsuranceFund.

Pharmaceuticalservicesrepresentallservicesprovidedbypharmacistsinorderto provide adequate pharmaceutical care. This includes both activities aimed at theprocurement,supplyanddispensingofmedicinesandotherproductsthatcanbefoundinthepharmacy,aswellasactivitiesaimedatpromotinghealth,andalsotheprocessofcommunication and providing advice on the adequate use of the drug to patients orotherhealthprofessionals.Thegoalofprovidingpharmaceuticalservicesistoachievetheoptimaloutcomeofthepatient'streatmentandtoimprovethepatient'squalityoflife.

The presentation will show the economic aspect of providing pharmaceuticalservices in the pharmacy. Research from the world as well as Serbia shows thatpatientsarereadytoallocateacertainamountofmoneyforpharmaceuticalservices.Itis necessary to show the importance and value of pharmacists and pharmaceuticalservicestodecision‐makersinhealthcare.

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PATIENTCENTRICDOSAGEFORMDESIGN

AndreasZimmer1,SvenStegemann2

1UniversityofGraz,InstituteofPharmaceuticalSciences,DepartmentofPharmaceuticalTechnologyandBiopharmacy,2GrazUniversityofTechnology,

InstituteofProcessandParticleEngineering(Austria)Sincethereisgrowingevidencethatpatientcentricdosageformdesignplaysa

key role in achieving effectiveness and minimizing medication errors, many drugdeliverysystemsareconsideredtomeetpatientsneeds.Whenreviewingtheliteraturewithregardtotheclinicalevidenceforsuchclaims,theresultsareverydisappointing.Themainreasonsareafocusonasingleproductfeatureoutsidetheentirecontextualframeworkandthelackofspecificmethodologytoinvestigatepatientcentricproductdesign.

Patientcentricdosageformdesignfollowsthelogicofapatientasamedicallayperson, based on prior learnings, perception, intuition and capabilities within thepersonaldailycontextandenvironment.Even thoughthere isnotasingleorasetofmethodology specifically developed for patient centric drug product design, severalmethodsareappliedbyotherdisciplinesandindustriessuccessfully.

Understanding the patient journey from symptom recognition through toeffective disease management will be the starting point to identify and prioritizepatientneedswithregardtodrugproductdesigndevelopment.Thepatientneedswillhave to be integrated into the Target Product Profile (TPP). Potential approaches toaddresstheseneedshavetobeverifiedwithintherelevantpatientmedicationuseandprocessincomparativetrialstoachievethedesiredendpoints.Otherindustrieshavealong time established process to design products for specific user groups, severalmethodologies can be used in a similar way by the pharmaceutical industry. Whilepatient centric drug product design is considered being a mind‐set, pharmaceuticalorganizations might have to adapt their existing development processes early on toincrease effectiveness andpatient safety throughpatient centricdrugproductdesignwithoutimpactingondevelopmenttimelines.

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INCREASEDPATIENTSAFETYBYREADY‐TO‐USE/READY‐TO‐ADMINISTERPARENTERALSPREPAREDINHOSPITALPHARMACIES

IreneKrämer

UniversityMedicalCenter,JohannesGutenberg‐UniversityMainz(Germany)

Mostmedicinalproductswhichareadministeredparenterallyareapprovedand

marketed as injection concentrate or powder for injection. Prior to administration,these products must be reconstituted, diluted and equipped with an administrationdevice by health care professionals. According to the European Resolution CM/Res2016, the risks associated with the reconstitution should be assessed. High‐riskproducts should be prepared in the pharmacy department either as ready‐to‐administer or ready‐to‐use parenterals in patient‐individual or standard doses.Antineoplastic drug solutions and parenteral nutrition admixtures are commonlyprepared for individual patients in individualized doses. Antibiotics, antifungals,continuousinjectionsfor intensivecarepatients,analgesics,andemergencydrugsaremostly prepared batch‐wise in standardized doses or concentrations. Premises,facilitiesandpharmaceuticalknowledgemustbeappropriateforthereconstitutionorthe preparation of unlicensed medicinal products for the special needs of patients.Appropriatequalityassurancesystemsaretobeimplemented.

Examples for the different types of pharmacy preparations and their addedvalue,especiallyincreasedpatientsafety,willbegiven.

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FORMULACIJAFARMACEUTSKIHOBLIKALEKOVAZAPRIMENUUPEDIJATRIJSKOJPOPULACIJI‐ASPEKTI

PRIHVATLJIVOST/ADHERENCA

JelaMilić,SandraCvijić,IvanaPantelić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Formulacija lekova za pedijatrijske pacijente predstavlja poseban izazov za

farmaceute. Mnogi lekovi nisu dostupni u odgovarajućem farmaceutskom obliku zapedijatriski uzrast i često se propisuju na način koji nije predviđen sažetkomkarakteristikaleka,odnosno,pristupaseneodobrenoj(off‐label)upotrebileka.Takođe,registrovani lekovi za odrasle se često različitim postupcima „prilagođavaju” zaprimenu kod dece, čime se povećava rizik od pojave neželjenih reakcija, greški udoziranjuilineprihvatljivostileka.

Prilikom formulacije lekova za decu potrebno je odabrati odgovarajućifarmaceutski oblik leka za određeni uzrast i pažljivo razmotriti izbor pomoćnihsupstanci i „nosača” za isporuku leka. „Lek prilagođen uzrastu” treba da budeprihvatljiv od strane pacijenta i dovoljno jednostavan za primenu od straneroditelja/starateljailimedicinskogosoblja.Pritometrebarazmotritiputprimeneleka,lakoću primene, preciznost i fleksibilnost doziranja, veličinu i disperzibilnostfarmaceutskogoblikalekaimogućnostkorigovanja/„maskiranja”ukusakodpreparatazaoralnuprimenu.Značajovakvogpristupajeprepoznatodstraneregulatornihorganakoji su dali preporuke za procenu prihvatljivosti i odabir farmaceutskog oblika/putaprimenelekauzavisnostioduzrastadeteta.

Uporedo sa razvojem farmaceutskih oblika lekova za pedijatrijski uzrast,razvijajuseiuređaji/priborkojiomogućavajupreciznodoziranje.No,uprkosnaporimadasepovećadostupnostkomercijalnihpreparatazadecu,idaljepostojivelikapotrebazanjihovomizradomuapotekama,zaodređenegrupepedijatrijskihpacijenata.Uciljuunapređenja ovog segmenta rada u apoteci nedavno je pokrenut projekat za izraduPanevropskih pedijatrijskih formula namenjenih farmaceutima koji se bave izradommagistralnih lekova za pedijatrijske pacijente. Pedijatrijske formule treba da pružiinformacije o sastavu, načinu izrade, pakovanju i uslovima čuvanja lekova za decuprilagođenihuzrastu,kojinisudostupninatržištu.Očekujesedaćenovaistraživanjaiodgovarajuće smernice regulatornih/stručnih tela pomoći u naporima da se ubudućnosti proizvede/izradi veći broj bezbednih i efikasnih lekova, prihvatljivih zaprimenukoddece.

241

FORMULATIONOFPAEDIATRICDOSAGEFORMS‐ACCEPTABILITYISSUES/COMPLIANCE

JelaMilić,SandraCvijić,IvanaPantelić

DepartmentofPharmaceuticalTechnologyandCosmetology,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Formulation of paediatric medicines is associated with numerous challenges.

Many drugs are not available in suitable dosage forms for paediatric patients,whichoftenleadstooff‐labelandunlicenseduseofadultmedicines.Also,adultdosageformsare often modified/manipulated to enable drug administration in children, whichincreasetheriskofadversedrugreactions,dosingerrorsandnon‐complianceissues.

When developing paediatric formulations, it is necessary to select appropriateage‐adapteddosageforms,andcarefullyconsiderthechoiceofexcipientsanddeliverydevices. An „age‐appropriate medication” should be acceptable/suitable for use inchildren and easy to administer by parents/caregivers or healthcare professionals.Somepointstoconsiderincludedosingroute,easeofuse,doseaccuracy/flexibility,andalso size, dispersibility and taste masking ability for oral dosage forms. In order toassistinthedevelopmentofpaediatricformulations,regulatoryauthoritieshaveissuedrecommendationsonacceptabilityratingandtheselectionofmostappropriatedosageform/dosingrouteinrelationtochildage.

Inparallelwiththedevelopmentofpaediatricdosageforms,newdosingdevicesarebeingdesigned.Butdespitetheeffortsto improveavailabilityofcommercialdrugproductsforchildren,thereisstillawidespreadneedforcompoundedpreparationsforcertain paediatric age groups. In order to facilitate compounding of paediatricformulations,aprojecttodevelopPan‐Europeanformularyhasbeenlaunchedrecently.This formulary is intended to provide clinicians and pharmacists with compilinginformationonthecomposition,preparation,containersystemsandstorageconditionsregardingextemporaneouspreparationofnon‐licensedmedicinesforchildren.

Futureresearchonpediatricformulationsandappropriateregulatory/scientificguidelines are expected to result in an increased number of safe and effectiveauthorised/compounded,age‐appropriatemedicinesforchildren.

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CANCERIMMUNOTHERAPY:WHEREDIDITSPRECISIONCOMEFROMANDWHEREWILLITGO?

FarzinFarzaneh

DivisionofCancerStudies,DepartmentofHaematologicalMedicine,Kings

CollegeLondon(UnitedKingdom)

TheNobelPrizeinPhysiologyorMedicine2018wasawardedtoJamesP.Allison

and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negativeimmuneregulation".Bythisaccomplishment,cancerimmunotherapyhascomeofage,approximatelyhalfacenturyafterclassicalexperimentsthatdistinguished"self"from"non‐self",andtheseminalfindingsthathumoralimmunity,effectedbyBlymphocytes,is inextricably complemented by cellular immunity, effected by T lymphocytes. Themajorgoalofcancerimmunotherapyistoreversethetolerantstatethatenablescancercells to evade immune detection and destruction. Contemporary immunologicstrategies for targeting tumors encompass mechanisms that target T cells: directlyactivatingthem,orinhibitingmoleculesthatsuppressT‐cellactivation,ormodifyingTcells genetically to allow them to recognize and kill tumor cells either in an MHC‐dependent (TCR‐modified T cells) or MHC‐independent manner, by geneticallyengineeredChimericAntigenReceptorModifiedTcells(CARTcells).Inthisfield,majorbreakthroughs in clinical practice have been achieved with immune checkpointblockade. This refers to the suppression of inhibitory pathways activated by cancercells, and comprises antibodies directed against the components of the pathwayinvolvedinadaptiveimmunesuppression,namelyProgrammedCellDeath‐1receptor(PD‐1, expressed on activated T cells) and Ligand (PD‐L1, expressed on antigenpresenting cells). Currently, five PD‐1/PD‐L1 immune checkpoint inhibitors areapprovedforcancerimmunotherapy:atezolizumab,avelumab,durvalumab,nivolumaband pembrolizumab. Another approach with substantial potential is to developtherapeuticcancervaccines.Byemployingthestrategiesofadjuvantactivationoftoll‐likereceptors,suchvaccineswouldaimtopredominantlyengagethecellularimmunityinawaythatcancontrolthelocation,magnitudeanddurationoftheelicitedresponse,andarehopedtoleadtofurtherbreakthroughsinthefieldofcancerimmunotherapy.

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PRECIZNAMEDICINAUONKOLOŠKOJPRAKSI:PROCENAKORISTIIRIZIKA

IvanaBožović‐Spasojević

Institutzaonkologijuiradiologiju,Beograd(Srbija)

"Zavisnost od onkogena", kada nastanak i rast tumora kontinuirano zavise odsignala onkogena, predstavlja ključno načelo u onkologiji. Koncept je potvrđen nabrojnim onkogenima u kliničkim i pretkliničkim ispitivanjima, i smatra se opštimnačelom odabira ciljane terapije u onkologiji. Međutim, dostupni vodiči i dalje nepreporučujurutinskogenomskotestiranjetumorazbogograničenihdokazaokliničkojupotrebiiselekcijisistemsketerapijekodpacijenatasaodmaklommalignombolešću.Sdruge strane, rezultati genomskog testiranja mogu biti relevantni za utvrđivanjepodobnosti pacijenata za klinička ispitivanja sa agensima od interesa. Preciznaonkologija u pristupu utvrđivanja varijabilnosti gena koristi različite metode, odimunohistohemijedosekvencioniranjatumora,ispitivanjamolekularneabnormalnostiuDNK tumorau ciljuutvrđivanja terapijskemete.Kliničkaprimenjivostovihmetodasuočava se sa važnim izazovima: odabira najreprezentativnijeg tkiva za testiranje,ponavljanja testiranja tokom lečenja i praćenja pacijenta (vremenska i prostornaheterogenost tumora), tumačenja i razumevanja rezultata i njihovog stavljanja ukliničkikontekstkojijerelevantanzapacijenta,prioritizacijeonkogenihsignalakadaihimaviše,cenetestiranjairazumevanjapacijenataoneophodnostiiznačajutestiranja.

Nove neinvazivne metode obećavaju prevazilaženje navedenih mana, dajućikompleksniju i sveobuhvatniju slikumalignebolesti. To su tečnebiopsijekoje izkrvimogu ispitivati cirkulišuću tumorskuDNK i tumorske ćelije, analize urina, pljuvačke,stolice ali i izdaha u kome se ispituju isparljive organske komponente. Ove metodeprevazilaze tradicionalnu analizu tumorskog tkiva i omogućavaju ponavljano,prospektivno,longitudinalnopraćenjetumorskogodgovora,rezistencijeiprogresijenaordiniranuterapiju.

Uporedo sa tehnološkim napretkom desio se pomak u sprovođenju kliničkihispitivanjakojazahtevajunovi,adaptabilnidizajninačinsprovođenja.Sobziromdajekoličinapodatakadobijenabioinformatičkomanalizomomics tehnologijavelika,trendjedapodacibudusačuvaninazajedničkimplatformamaizatimjavnodostupnizadaljeanalize.

Svedocismorazvojaimunoterapijeuonkologiji.Oduvođenjaanti–CTLA‐4ianti–PD‐1/PD‐L1monoklonskihantitelakaostandardneterapijezalečenjemnogihtumora,validiranojenekolikobiološkihmarkera.TosunivoekspresijePD‐L1,mikrosatelitskanestabilnost, i u skorije vreme opterećenje tumorskom mutacijom, kao prediktivnimarkeriodgovoranaimunoterapiju.

Uzevšiuobzirodnoskoristi irizika,kliničarimaostaje izazovodabiranajboljihgenetskihimolekularnihoruđauodabiruisprovođenjuterapije.

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PRECISIONMEDICINEINONCOLOGYPRACTICE:

BENEFIT‐RISKASSESSMENT

IvanaBožović‐Spasojević

InstituteforOncologyandRadiology,Belgrade(Serbia)A key principle underlying treatment selection is "oncogene addiction." This

means that tumors are continuously addicted to the driving growth signal from anoncogene.Thisconceptisvalidatedacrossplentifuloncogenesinclinicalandpreclinicalcontexts, and represents general principle underlying selection of targeted therapy.Availableclinicalpracticeguidelinesdonotrecommendgenomic testingof tumors inroutine practice because of limited evidence of clinical utility to guide selection ofsystemictherapyforpatientswithadvancedcancer.However,genomictestingresultsmaybe relevant to determine eligibility for clinical trialswith investigational agents.Precisiononcologyusesmultipletestingtechniquestoidentifymolecularabnormalitiesin a patient's DNA with the aim of identifying therapeutic targets. However, clinicalpracticefacesbarriersinimplementingprecisionmedicine,suchasunderstandingthebest tissueformoleculartests, identifyingthemostprecisemoleculartestsandwhentissueshouldbetested,interpretingthetestresults,understandingtheroleofgeneticcounselling,patientattitudesandfinancialconcerns.

Novel noninvasive cancer diagnostics platforms, like liquid biopsy, used tointerrogatectDNAorcirculatingtumorcells,urine,salivaandstoolandbreathbiopsy,whichmeasuresvolatileorganiccompounds,havecontinuedtoevolveinrecentyears.Thesenoninvasivemoleculardiagnosticsassaysfundamentallytransformthepotentialutilities of cancer diagnostics to enable repeat, prospective, and serial longitudinalbiopsiestomonitordiseaseresponse,resistanceandprogressionontherapies.

Alongside these technology advances, a lot of trials with precision medicineprincipleswereinitiated.Precisionmedicinetrialsraisenewanddifferentchallengesintheirdesignandconduction,requiringnewstrategiesforsuccessfulimplementationinclinicalpractice.

Wealso facetherecentadventofcancer immunotherapies.Since thearrivalofanti–CTLA‐4 and anti–PD‐1/PD‐L1 cancermonoclonal antibodies, a few genomic andtissuebiomarkershavebeenvalidatedandapprovedforcancerimmunotherapy.Theseinclude tumoral PD‐L1 expression levels and microsatellite instability status.Furthermore,strongevidenceoftumormutational loadhasbeenfoundtosupport itsuseasapredictiveimmuno‐oncologybiomarker.

Forphysicians,determiningwhenandhowtoincorporategeneticandmoleculartoolsintoclinicinacost‐effectivemanneriscritical.

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MOLECULARPATHWAYSTHATOPERATEINMLL‐ASSOCIATEDLEUKEMIATOOVERCOMERESISTANCETOANTICANCERDRUGS

BobanStanojević

DepartmentofHaematologicalMedicine,DivisionofCancerStudies,King's

CollegeLondon(UnitedKingdom),LaboratoryforRadiobiologyandMolecularGenetics,„Vinča”InstituteofNuclearSciences,UniversityofBelgrade(Serbia)

Deregulation of gene expression can cause devastating cancers. Fusion of the

mixed‐lineage leukemia (MLL) gene (also known as KMT2A,MLL1, ALL‐1, or HTRX)and various partners causes aggressive leukemia. To date,more than 70 genes havebeen reported to fusewithMLL. The sequence of theMLL genewas revealed in theearly 1990s. Since then, a series of technological breakthroughs such asDNA arrays,shRNA library screening, proteomic and deep sequencing have provided us with amuchdeeperunderstandingof themolecularbasisof leukemogenesiscausedbyMLLmutations. Advances in technology and the ongoing development of new targetedtherapieshaveopenedupnewopportunitiestocombatdrugresistanceaswell.Wearenow able to characterize the signalling pathways involved in regulating tumour cellresponse to chemotherapy more completely than ever before. Based on theunderstanding of these molecular mechanisms, several small molecules that inhibitcriticalprocessesofleukemogenesishavebeendevelopedasmolecularly‐targeteddrugcandidates.IhereinreviewthenormalbiologicalrolesofMLL1anditsfusionpartners,how these roles are hypothesized to be dysregulated in the context of MLL1rearrangements, the clinicalmanifestations of this group of leukemiaswith a specialfocusonmolecularpathwaysthatoperatetopreventresistancetoanticancerdrugs.

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PRECIZNEANTIKANCERSKETERAPIJE:KAKOFARMACEUTSKATEHNOLOGIJADAJEDOPRINOS?

SnežanaSavić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐

Farmaceutskifakultet(Srbija)Precizna/personalizovana medicina teži da individualizuje terapijske

intervencije/isporuku leka na osnovu ex vivo i in vivo informacija o pacijentu ispecifičnih karakteristika bolesti. Primena nanotehnologije, povezano sa humanimzdravljem(nanomedicina),usvetlupreciznedijagnoze/tretmanarazličitihtumoraimaveć duže vreme istaknuto mesto u ovom kontekstu. Dok su hirurgija i radioterapijaprimarnitretmanikojisekoristezalokalizovane,nemetastatskekancere,antikancerskilekovi (hemioterapeutici, hormoni, biološki lekovi, imunoterapija) predstavljajuaktuelnipristuputerapijimetastatskihkancera.Neselektivnadestrukcijazdravihćelija,toksičnost konvencionalnih citotoksičnih lekova, kao i razvoj multiple rezistencijepodržavaju ideju za pronalaženjem novih efektivnih opcija ciljne terapije, koji suzasnovani na izmeni molekulskih bioloških mehanizama tumorskih ćelija. Osnovnikoncept za dizajniranje nano‐antikancerskih lekova kroz niz prethodnih godinazasnovan na „efektu poboljšanja permeabilnosti i zadržavanja” (EPR), opšte‐prihvaćenom kao „zlatni standard” u polju ciljne isporuke antikancerskih lekova(koncept pasivne ciljne isporuke), u međuvremenu je delom osporen, pošto kliničkirezultatinepodržavajuprekliničkenalazenaanimalnimmodelima.Stoga,svečešćesepostavljapitanje validnosti tvrdnji o efikasnosti terapijenabaziEPRefekta, odnosnopitanje o budućnosti nanomedicine bez EPR efekta, te razvoja klinički relevantnogmodelaEPRefekta?

Ipak, interes na polju daljeg specijalizovanja nano‐antikancerskih lekova neopada,štopodržavaiodređeni(madamali)brojFDA‐odobrenihiliterapijaurazličitimfazama kliničkih ispitivanja iz grupe PEG‐ilovanih liposoma, polimernihmicela/konjugata/nanočestica, dendrimera, karbonskih nanotuba, koji uglavnom težeda isporučehemioterapeutikdomolekulskihmetakojesuspecifičnoeksprimiranenapovršini tumorskih ćelija; ovi nanonosači treba da transportuju hemioterapeutik dotumora, izbegavajući normalna tkiva i redukujući mu toksičnost, citostatik štite oddegradacije,produžujupolu‐vremeeliminacije,poboljšavajurastvorljivostiefektivnostleka, smanjuju renalni klirens. Dodatno, u obzir se uzimaju posebnosti tumorskogmikro‐okruženja, kroz razvoj nanonosača responsivnih na endogenu stimulaciju (pHvarijacije, redoks gradijent, kocentracija enzima, promena temperature), ili uzudruženuprimenu sa egzogenim stimulacijama (ultrazvuk,magnetno polje, svetlost),štozahtevaskupuopremu.

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PRECISEANTI‐CANCERTHERAPIES:HOWDOESPHARMACEUTICALTECHNOLOGYCONTRIBUTETOTHEM?

SnežanaSavić

DepartmentofPharmaceuticalTechnologyandCosmetology,Universityof

Belgrade‐FacultyofPharmacy(Serbia)Precision/Personalized medicine aims to individualize therapeutic

interventions/drugdeliveryonthebasisofexvivoandinvivoinformationonpatient‐and disease‐specific characteristics. Use of nanotechnology associated with humanhealth(nanomedicine)inthelightofprecisediagnosis/treatmentofvarioustumorshasforalongtimeanindispensableplaceinsuchcontext.Whilesurgeryandradiotherapyare the primary treatments used for local and non‐metastatic cancers, anti‐cancerdrugs (chemotherapeutics, hormones, biologics, imunotherapies) present the currentapproach in metastatic cancers. The indiscriminate destruction of normal cells, thetoxicityof conventional chemiotherapeutics, thedevelopmentofmultidrugresistancesupporttheideatofindneweffectivetargetedtherapies,basedonthechangesinthemolecularbiologyoftumorcells.Themayorunderlayingconceptinthedesignofanti‐cancernanomedicines for longerwasbasedonEnhancedPermeabilityandRetentioneffect(EPR),widelyacceptedas„goldstandard”inthefieldofcancerpassivetargeting,butinmeantimewaspartialyhandeddown,asitworkedinrodentsbutnotinhumans.Therefore,asthequestiononvalidityofclaimingtheefficacyofanti‐cancertherapyviatheEPReffectcameout,itisprobablytimetoaskwhatisthefutureofnanomedicinewithout theEPReffectandpossibility todevelopanewclinically relevantEPReffectmodel?

Still, the interest in the field of further specialized development of nano‐anti‐cancer drugs don't subside, supported by several (although only few) FDA‐approvedtargeted therapies or those undergoing different phases of clinical trials (PEG‐ylatedliposomes, polymeric micelles/conjugates/nanoparticles, dendrimers, carbonenanotubes), mainly tending to deliver cytotoxic drugs to molecular targetsoverexpressedonthetumorcellssurface;thesenanocarriersshouldnotonlytransportchemotherapeutictotumor,avoidingnormaltissuesandreducingitstoxicity,butalsoprotect it from degradation, increase the half‐life, payload and solubility and reducerenal clearance. In addition, somepecularities of tumormicroenvironment are takeninto consideration through the development of endogenous stimuli‐responsivenanocarriers (pH variations, redox gradient, enzyme concentration, temperaturechange), or accompanied with exogeneous stimuli application (ultrasound, magneticfield,light),thatrequiresexpensiveequipment.

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SAVREMENIPRISTUPIUKONTROLIKVALITETABIOLOŠKIHLEKOVA

BorutŠtrukelj

Farmaceutskifakultet,UniverzitetuLjubljani(Slovenija)

Za razvojproizvodnogprocesa i za razvoj rutinskihanalizakoje seprimenjuju

tokom proizvodnje bioloških lekova potrebno je primeniti veliki broj specifičnihanalitičkih metoda, kao što su različite gel elektroforeze (PAGE), jono‐izmjenjivačkahromotografija (IEC), cirkularni dihroizam (CD), ekskluziona hromatografija (SEC),kapilarna zonska elektroforeza (SDS‐PAGE), florescentna spektroskopija, natrijum‐dodecilsulfatpoliakrilamidgelelektroforeza(SDS‐PAGE),cepanjelaserskimsnopomimasenaspektrometrijauzmatrikspotpomognutomjonizacijomlaserskomdesorpcijom(MALDI‐TOF), micelarna elektrokinetska hromatografija, hidrofobna interakcija ireverznofaznehromatografije(HIC,RPC),ćelijskiienzimsko–imunskitestovi(ELISA).Nabrojaneanalitičkemetodekoristesezaanalizubiološkeaktivnostiiuovomradućebiti predstavljen kritički osvrt na iste. Biološki lekovi mogu izazvati imunološkereakcijekojemogudatiozbiljnukliničkuslikuiozbiljneneželjenereakcije.Potencijalnaimunogenost kao i neželjene reakcije koje su posledica heterogene strukture mAbspredstavljajunajnepoželjnijereakcijeizazvaneprimenombiološkihlekova.Razvilismoopštuplatformuzasnovanunaćelijskojtehnologiji,kojaseoslanjanaispitivanjeranihDC‐vođenihdogađajakojimaseiniciraCD‐4T‐ćelijskizavistanhumaniadaptivniimuniodgovor,uključenupraćenjepotencijalneimunogenosti.

U prvom delu istraživanja pretražena je literature. Za otkrivanje potencijalneimunogenosti primenjeno je in vitro određivanje DC‐sazrevanje i DC‐stimulacija namAbs i PBMC, praćenjem proliferacije mAbs strukturnih varijanti. Određen jepotencijalnikapacitetagregatamAbsdapodstaknu(indukuju)sazrevanjedendritičnihćelija.DCiPBMCćelijskoodređivanjebilojeoptimizovano,amAbsstrukturnevarijanteproizvedene su podvrgavanjem mAb1 uzoraka stresnim uslovima svetlosti izamrzavanja. Testirani su sledećimarkeri: CD40, CD80, CD86, CCR7 i HLA‐DR, kao icitokini: IL‐1β,IL‐6, IL‐8, IL‐10,IL‐12p70iTNF‐α.Pokazanojedarazvijenaplatformapruža dovoljno informacija na osnovu kojih je moguće predvideti imunogenost. Zaodređivanje fizičko‐hemijskih, strukturnih i bioloških karakteristika bioloških lekovapotrebno je primeniti čitav set modernih analitičkih tehnika. Mi smo razvili brzu,specifičnuipouzdanumetoduzadetekcijupotencijalneimunogenostibiološkihlekova,kojajeposledicavarijabilnostiunjihovojstrukturi.

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CONTEMPORARYAPPROACHESINBIOLOGICALDRUGSQUALITYCONTROL

BorutŠtrukelj

FacultyofPharmacy,UniversityofLjubljana(Slovenia)

Productionprocessdevelopmentandroutineanalysisduringtheproductionof

biologicals incorporatea largenumberofspecificanalyticalmethods,suchasvariousgel electrophoresis (PAGE), ion‐exchange chromatography (IEC), circular dichroism(CD), size‐exclusion chromatography (SEC), capillary zone electrophoresis (CZE),fluorescence spectroscopy, sodium‐dodecyl sulphate polyacrylamide gelelectrophoresis(SDS‐PAGE),laser‐lightscatteringandmatrix‐assistedlaser‐desorptionionization time of flight (MALDI‐TOF) mass spectrometry, micellar electrokineticchromatography,hydrophobicinteractionsandreversedphasechromatographies(HIC,RPC) and cell‐based and enzyme‐linked immunoassays (ELISA) to study biologicalactivity. In present paper, the critical review of such methods will be elucidated.Biologicalmedicinalproductsmayinduceimmuneresponsesleadingtoseriousclinicalside effects. Potential immunogenicity as well as other side‐effects due to theheterologousmAbsstructureisoneofthemostundesirableeffects.Wedevelopedthegeneral platform using a cell‐based technology, which relies on interrogation of theearlyDC‐drivenevents that initiateCD‐4T‐celldependenthumoraladaptive immuneresponses,integratedintothemonitoringofpotentialimmunogenicity.

For the first part of the study, the literature survey was applied. For thedetection of potential immunogenicity, In‐vitro DC maturation and DC stimulationassays on mAb and PBMC proliferation assay on mAb structural variants was used.Potential capacity of themAb aggregates to inducematuration of dendritic cells hasbeen determined. Both DC and PBMC cell assay was optimised and mAB structurevariants were produced by using light stressed and freeze/thaw stressed mAb1samples.Thefollowingmarkersweretested:CD40,CD80,CD86,CCR7andHLA‐DR,aswellascytokines:IL‐1β,IL‐6,IL‐8,IL‐10,IL‐12p70andTNF‐α.Itwasdemonstratedthatthe developed platform is enough informative for the prediction of immunogenicity.The complex toolbox of modern analytical techniques are required for thedeterminationofphysico‐chemical,structuralandbiologicalcharacteristicofbiologicalmedicinalproducts.Wedevelopedfast,specificandreliablemethodforthedetectionofpotentialimmunogeniceffectofbiologicalsduetotheirvariationinstructure.

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MICRO‐PHOTOGRAMMETRYASANOVELTOOLFORCHARACTERISATIONOFDISSOLUTIONBEHAVIOUROF

PHARMACEUTICALDOSAGEFORMS

AlessandraD'Angelo1,MikeReading2,MilanAntonijevic1

1DepartmentofPharmaceutical,ChemicalandEnvironmentalSciences,UniversityofGreenwich,2UniversityofHuddersfield(UnitedKingdom)Manynovelandenhanceddrugdeliverysystemsareinthedevelopmentorhave

been developed in recent years. Such rapid development of formulations demands abetter and more rigorous analytical support and assessment. Work presented hereaims at the development of an innovative analytical technique for the 3Dchemicalmapping of pharmaceutical dosage forms, via simultaneous topographiccharacterisationanddissolutionanalysisofsoliddrugdeliverysystems.

The system is composed of micro‐photogrammetry apparatus, dissolutionsystemandsoftwarefordataanalysis.Micro‐photogrammetryconsistsofamicroscopewhichisheldbymagnetsinpositiononasemi‐circularsupport.Thesampleisplacedon rotating platform that moves under computer control as the images are taken.Obtainedimagesareprocessedbysoftwarewhichdelivers3Dimageoftheobjectfromwhich further analysis can be carried. Dissolution system consists of assembly thatallowsperiodicie.stepwisedissolutionwheresampleissubjectedforcertainperiodoftimetoamediumafterwhichmediumiscollectedandanalysedbyHPLCandsamplelefttodryandanalysedusingphotogrammetry.Thesestepsarethenrepeatedmultipletimestogainafulldissolutionprofile.Thismethodologyallowsin‐depthanalysisoffastdissolution processes by subjecting sample to a small portion ofmedium for a verylimited period of time, usually 10‐60seconds. Dissolution of Ibuprofen sugar coatedtablets(BristolLaboratories)wasconductedinsevendiscontinuoussteps.Analysed3Dmodels of the formulations revealed a small volume displacement induced by thedissolution of the Sucrose outer layer, followed by a significant variation of tabletvolume after exposure of the product components underlying the outer sugar layer.Volumetric analysis revealed that diffusion controlled the initial stages of thedissolutionprocess,followedbyerosion.Novelmethodologypresentsagreatpotentialinevaluatingdissolutionprofilesofdiversepharmaceuticalsystems.

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Arh.farm 2018;68:251-252 PP84KONCEPTUALNIMODELZAUNAPREĐENJESISTEMATSKE

KONTROLE

GordanaPejović

AgencijazalekoveimedicinskasredstvaSrbije,Fakultetorganizacionihnauka,UniverzitetuBeogradu(Srbija)

Substandardni lekovi na tržištu su veliki rizik u lečenju. Stoga nacionalni

regulatorni autoriteti za lekove preduzimaju različite mere za kontrolu lekova natržištu.Posebnapažnjasepoklanjasistematskojkontroli,kojasesprovodinasumičnimuzorkovanjemlekovasanacionalnihtržišta.

Izvršena je sveobuhvatna analiza regulative u oblasti lekova u regionujugoistočneEvropekakobisesagledaloregulatornookruženjezanadzornadtržištem.

Predložen je konceptualnimodel za unapređenjeprocesa sistematske kontrolena regionalnom tržištu lekova, kojim su opisane i obuhvaćene sve važne regulatorneinstitutcije na evropskom i regionalnom nivou. Opisana je i moguća harmonizacijaregulatornih mehanizama koja bi usledila nakon usvajanja opisanog konceptualnogmodela.Mogućipristupzaunapređenjesistematskekontrolenaregionalnomtržištujeosnivanje regionalnog centra za ispitivanje osposobljenosti, koji će upravo bitinamenjensistematskojkontroli.Tobimoglabiti jednaodagencijazalekoveuregion,kojibirazvilaposebnešemezaispitivanjeosposobljenostizakontrolukvalitetalekovana tržištuu region. Sistematskakontrola jeključna regulatornamera zaunapređenjekvaliteta lekovana tržištu,kojomseosiguravada lekovi substandardnogkvalitetanebududostupnipacijentima.

252

CONCEPTUALMODELFORTHEIMPROVEMENTOFMARKET

SURVEILLANCEPROCESS

GordanaPejović

MedicinesandMedicalDevicesAgencyofSerbia,FacultyofOrganisationalSciences,UniversityofBelgrade(Serbia)

Substandardqualityofmedicinesonthemarketposessignificantriskfordisease

treatment.Therefore,nationalmedicinesregulatoryauthorities(NMRAs)areapplyingvarious regulatory mechanisms to control authorised medicines on the market. Thespecialemphasisisgiventothemarketsurveillanceprocess,whichisintendedforthequalitycontrolofrandomlysampledmedicinesfromthenationalmarket.

A comprehensive review of medicines legislation in South East Europe (SEE)countries was undertaken to summarize regulatory framework for national marketsurveillance.

The conceptual model for the improvement of regional market surveillanceprocess was developed, describing all the important regulatory institutions atEuropean and regional level. The possible harmonisation of regulatory mechanismsresulting from the implementation of described conceptual model is described. Thepossibleapproachisto improvetheregionalmarketsurveillanceprocessthroughtheintroductionofregionalproficiencytesting(PT)centre,aimedatmarketsurveillance.This centre couldbeoneofNMRAs in the region,whichwoulddevelopa specificPTschemes aimed at quality control of marketed medicines in the region. Marketsurveillanceisthekeyregulatorymeasurefortheimprovementofmedicinesqualityonthemarket,assuringthatthesubstandarddrugsarenotavailabletopatients.

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ANALITIKAPOLARNIHSUPSTANCIPRIMENOMMETODETEČNEHROMATOGRAFIJEHIDROFILNIHINTERAKCIJA

BiljanaJančićStojanović

Katedrazaanalitikulekova,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)Poslednjihgodina,tečnahromatografijahidrofilnihinterakcija(eng.Hydrophilic

interaction liquid chromatography‐HILIC) pojavljuje se kao korisna alternative zarevezno‐faznu tečnuhromatografijuu analizi polarnih jedinjenja. Cilj ovog rada jedaprikažeprimenljivostHILICmetodeufarmaceutskojanalizirazličitihpolarnihanalita.

U HILICmetodi korsite se umereno polarne kolone i polarnemobilne faze savisokimprocentomorganskograstvarača(običnovišeod50%organskograstvarača).HILICretencionimehanizmisuveomakompleksniimoguuključitivišeprocesakaoštosu: raspodela analita između adsorbovane vode na površini stacionarne faze i bulk‐amobilne faze, adsorpcije analita napovršini stacionarne faze i jonske izmene izmeđunaelektrisanoganalita isuprotnonaelektrisanihgrupanapovršinistacionarnefaze.Ukojoj meri učestvuju navedeni procesi zavisi od značajnog broja faktora kao što su:vrstastacionarnefaze,polarnostistepenjonizacijeanalita,kaoisastavmobilnefaze.Iztograzloga,retencioniprocesiuHILIC‐ujošnisudobroproučeniipredmetsubrojnihkontraverznih tumačenja. Uzimajući u obzir navedene činjenice neophodan je pažljivizbor HILIC uslova za analizu svakog polarnog analita. Kao rezultat rastućepopularnosti HILIC‐a poslednjih godina je uloženo puno truda kako u teorijskaistraživanjaHILIC‐a tako i u process razvojaHILICmetode. Time, u ovoj studiji krozvišeeksperimentalnihprimeraprikazanajespecifičnostrazvojaHILICmetode.

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HYDROPHILICINTERACTIONLIQUIDCHROMATOGRAPHY(HILIC)ASAVALUABLEALTERNATIVEFORREVERSED–PHASELIQUIDCHROMATOGRAPHY(RP–LC)INTHEANALYSISOFPOLAR

COMPOUNDS

BiljanaJančićStojanović

DepartmentofDrugAnalysis,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Hydrophilic interaction liquid chromatography (HILIC) has emerged in recent

years as a valuable alternative to reversed–phase liquid chromatography (RP–LC) inthe analysis of polar compounds. The aim of this study is to present applicability ofHILICmethodinpharmaceuticalanalysisofdifferentpolaranalytes.Analysisofcertainpolaranalytesusingdifferentpolarstationaryphaseshasbeenperformed.

In HILIC, polar or moderately polar columns and less polar aqueous–highlyorganic mobile phases (usually above 50% of the organic solvent) are used. HILICretentionmechanismisrathercomplexandcaninvolveseveralprocesses:partitionoftheanalytebetweentheadsorbedwater–enrichedlayeronthesurfaceofthestationaryphase and thebulk mobile phase, adsorption of the analyte on the stationary phasesurfaceandion–exchangebetweenthechargedanalyteandoppositelychargedgroupson the stationary phase surface. The involvement of each process depends onconsiderablenumberoffactorsthatarerelatedto:thetypeofthestationaryphase,thepolarity and ionizationof the analytes and themobile phase composition. Therefore,HILIC retention process is still insufficiently elucidated and a subject of manycontroversialinterpretations.Consideringallthosefacts,carefulinvestigationofHILICconditionsforanypolaranalyteisnecessary.

AsaresultofagrowingpopularityofHILICinrecentyearsalotofeffortisputintoboth, theoretical investigationsofHILICsystemsandHILICmethoddevelopmentprocess.Thus,inthisstudythroughseveralexperimentalexamplesspecificityofHILICmethoddevelopmentispresented.

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Arh.farm 2018;68:255-256 PP86

MOGUĆNOSTIPRIMENEEKOLOŠKIPRIHVATLJIVIHHROMATOGRAFSKIHMETODAUKONTROLILEKOVA

AnaProtić,NevenaMaljurić,BiljanaOtašević,MiraZečević

Katedrazaanalitikulekova,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)Upotreba toksičnih organskih rastvarača, u prvom redu acetonitrila zbog

njegovogpovoljnoguticajanahromatografskuefikasnost, jenezaobilaznakodmetodareverzno‐faznetečnehromatografije(RP‐HPLC).Nažalost,acetonitrilporedpovoljnihfizičko‐hemijskih osobina poseduje i druge, ne tako dobre osobine, kao što sutoksičnost, zapaljivost i štetnostpoživotnusredinu. Iz tograzlogasvevišeseradinapronalaženjurazličitihstrategijakakobiseovemetodepreveleuekološkiprihvatljiveikakobiseutrošaktoksičnogorganskograstvaračasveonanajmanjumogućumeru.CiljovogradajeispitivanjerazličitihnačinanakojeRP‐HPLCmetodemogupostatiekološkiprihvatljive,kaoimogućnostprimeneovogkonceptaukontrolilekovaposmatranosaregulatornogaspekta.

GradijentnaRP‐HPLCmetodazaispitivanjestabilnostidronedaron‐hidrohloridamodifikovanajeuUHPLCimicelarnuHPLCmetodu(MLC).ThermoscientificcalculatorprimenjenjeprigeometrijskomtransferuHPLCuUHPLCmetodu,dokjemetodologijapovršineodgovoraprimenomDesignExpert7.0.0.softveraiskorišćenazavizuelizacijueksperimentalnogprostora irazvojMLCmetode.Stepenekološkeprihvatljivostinovopredloženihmetodaispitanjepomoćuvrednostianalitičkogekološkogskora.

PrilikomgeometrijskogtransferaHPLCuUHPLCmetoduukazalasepotrebazadodatnimmodifikacijamakakobisezadržalaefikasnaseparacijaispitivanihsupstanci.Sa druge strane MLC metoda je zahtevala potpuno novi razvoj shodno drugačijimretencionim mehanizmima. Konstruisanje 3D‐grafikona omogućilo je predlaganjenajoptimalnijihuslova.EkološkianalitičkiskorzagradijentuUHPLCmetodu iznosio je83poena, dok je zaMLCmetodu iznosio90poenaodukupnih100. Sadruge strane,modifikacija hromatografske metode uslovljava prijavu varijacije kao i određivanjevrstevarijacijeiobimizmeneregistracionedokumentacije.

PokazanojedajeMLCmetodaekološkiprihvatljivijanaosnovuvećegekološkoganalitičkogskora,madasuobabilavećaod70štoobemetodekvalifikujekaoekološkiprihvatljive. Bilo kakva promena metode zahteva prijavu varijacije regulatornimorganima.UkolikosedokaženjenoznačajnopoboljšanjevarijacijabibilatipaIA.

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PROSPECTSOFECOLOGICALLYACCEPTABLECHROMATOGRAPHICMETHODSINDRUGCONTROL

AnaProtić,NevenaMaljurić,BiljanaOtašević,MiraZečević

DepartmentofDrugAnalysis,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)Toxicorganicsolventsarewidelyusedwhenworkingwithreversed‐phaseliquid

chromatography (RP‐HPLC). Acetonitrile is the most commonly used regarding itsoutstanding chromatographic efficiency and other beneficial physical‐chemicalcharacteristics. Unfortunately, acetonitrile is very toxic, flammable and harmful forlivingworld.Forthisreasonthescientistsarelookingfordifferentwaysoflimitingtheconsumptionofthissolvent.Theaimofthisworkistoinvestigatedifferentpossibilitiesof greening RP‐HPLC methods and to evaluate whether this concept could beincorporatedintotheanalyticalmethodsusedfordrugcontrol.

Stability‐indicating RP‐HPLC method with gradient elution for the analysis ofdronedarone‐hydrochloridewasmodifiedtoUHPLCandmicellarHPLCmethod(MLC).Thermo scientific calculatorwasusedduring geometrical transferofHPLC toUHPLCmethod,whileResponseSurfaceMethodology(RSM),performedinDesignExpert7.0.0,was applied for the visualizationof the experimental space anddevelopmentofMLCmethod.Ecologicalacceptabilityofthesemethodswasevaluatedusingeco‐scalescore.

Duringgeometrical transferUHPLCmethod,theadditionalmodificationsofthechromatographicconditionswerenecessaryinordertopreserveefficientseparationofallinvestigatedcompounds.Ontheotherside,differentretentionmechanismsinvolvedin MLC demanded development of new chromatographic method. 3D‐graphiconconstruction enabled definition of optimal chromatographic conditions and eco‐scalescorewas83and90pointsoutof100forUHPLCandMLCmethod,respectively.Fromthe regulatory point of view, modification of chromatographic conditions involvesdenunciationofthevariation,determiningtypeofthevariationandlevelofregistrationdocumentation change. Eco‐scale score pointed out that MLC is more ecologicallyacceptable than UHPLC method. However, eco‐scale score above 70 points for bothmethods indicates its green character. Any change of the analytical method leads todenunciation of the variation to the regulatory affairs. If method`s significantimprovementisdemonstratedthevariationtypecouldbeIA.