656

Farmakologijaifarmakoterapija

PharmacologyandPharmacotherapy

657

SADRŽAJ–CONTENTS

FFT-P1

UTICAJFORMULACIJEMIKOFENOLNEKISELINENANEŽELJENEEFEKTEKODPACIJENATANAKONTRANSPLANTACIJEBUBREGA

THEINFLUENCEOFMICOPHENOLICACIDFORMULATIONONTHEADVERSEEFFECTSINRENALTRANSPLANTRECIPIENTS

- Ana Spasić, Aleksandra Catić-Đorđević, Nikola Stefanović, Radmila Veličković-Radovanović 660

FFT-P2

EFEKATODABRANIHPREPARATAL‐KARNITINAUMODULACIJIEKSPRESIJEGENAZAHIPOKSIJSKIINDUCIBILNIFAKTOR1αUKULTURILIMFOCITA

EFFECTOFSELECTEDL‐CARNITINEPREPARATIONSONEXPRESSIONOFAGENEFORHYPOXIAINDUCIBLEFACTOR1αINTHELYMPHOCYTECULTURE

- Maja Kuzmanović, Anja Haverić, Naida Lojo-Kadrić, Maida Hadzić, Jasmin Ramić, Sanin Haverić, Lejla Pojskić 662

FFT-P3

GL‐II‐73,POZITIVNIALOSTERNIMODULATORα5GABAARECEPTORA,REDUKUJELIPOPOLISAHARIDOM‐IZAZVANOPONAŠANJESLIČNODEPRESIVNOMKODC57BL/6MIŠEVA

α5GABAARECEPTORPOSITIVEALLOSTERICMODULATIONBYGL‐II‐73REDUCEDLIPOPOLYSACCHARIDE‐INDUCEDDEPRESSIVE–LIKEBEHAVIORINC57BL/6MICE

- Aleksandra Vidojević, Marija Milić, Ivan Jančić, Guanguan Li, Miroslav Savić 664

FFT-P4

NOVIPOZITIVNIMODULATOR4‐GABAARECEPTORA,XHE‐III‐74,SMANJUJEUNOSALKOHOLAUMIŠIJEMMODELU„PIJENJAUMRAKU”

ANOVELPOSITIVEMODULATOROF4‐GABAARECEPTORS,XHE‐III‐74,REDUCESETHANOLINTAKEINMOUSE„DRINKINGINTHEDARK”MODEL

- Tamara Stanković, Bojan Batinić, Anja Santrač, Bojan Marković, Milica Drobac, Jelena Arsenijević, Miroslav Savić 666

658

FFT-P5

BIHEJVIORALNAKARAKTERIZACIJASOCIJABILNOSTIISOCIJALNEMEMORIJE5XFADTRANSGENIHMIŠEVAKAOMODELAALCHAJMEROVEBOLESTI

BEHAVIORALCHARACTERIZATIONOFSOCIABILITYANDSOCIALMEMORYINTHE5XFADTRANSGENICMICEASAMODELOFALZHEIMERDISEASE

- Jovana Aranđelović, Marija Banićević, Aleksandar Obradović, Miroslav Savić 668

FFT-P6

FARMAKOTERAPIJANEUROENDOKRINIHTUMORAPANKREASA

PHARMACOTHERAPYOFPANCREATICNEUROENDOCRINETUMORS

- Bojana Petrović, Predrag Vukomanović 670

FFT-P7

DOZIRANJEAPIKSABANAIRIVAROKSABANAKODPACIJENATASAPLUĆNOMEMBOLIJOM:DALIJEDNADOZAODGOVARASVIMA?

APIXABANANDRIVAROXABANDOSINGINPULMONARYEMBOLISMPATIENTS:DOESONEDOSEFITSALL?

- Jelena Džudović, Marko Antunović, Aleksandra Repić, Boris Džudović 672

FFT-P8

UČEŠĆEHOLINERGIČKIHRECEPTORAUANALGETIČKOMDEJSTVUVORTIOKSETINA

THEINVOLVEMENTOFCHOLINERGICRECEPTORSINTHEANALGESICEFFECTOFVORTIOXETINE

- Milja Vuković, Ana Micov, Uroš Pecikoza, Maja Tomić, Radica Stepanović-Petrović 674

FFT-P9

VORTIOKSETINUBLAŽAVATRIGEMINALNIBOL:UČEŠĆEADRENERGIČKIHRECEPTORA

VORTIOXETINEALLEVIATESTRIGEMINALPAIN:THEINVOLVEMENTOFADRENERGICRECEPTORS

- Ana Micov, Marija Todorović Gerasimoski, Uroš Pecikoza, Maja Tomić, Radica Stepanović-Petrović 676

659

FFT-P10

LOKALNIPERIFERNIANALGETIČKIEFEKATESLIKARBAZEPINACETATAUMODELUTRIGEMINALNOGBOLA:ULOGASEROTONINSKIH5‐HT1B/1DIKANABINOIDNIHCB1/CB2RECEPTORA

THELOCALPERIPHERALANALGESICEFFECTOFESLICARBAZEPINEACETATEINATRIGEMINALPAINMODEL:THEROLEOFSEROTONIN5‐HT1B/1DANDCANNABINOIDCB1/CB2RECEPTORS

- Uroš Pecikoza, Maja Tomić, Ana Micov, Radica Stepanović-Petrović 678

660

Arh.farm 2018;68: 660-662 FFT-P1

UTICAJFORMULACIJEMIKOFENOLNEKISELINENANEŽELJENEEFEKTEKODPACIJENATANAKONTRANSPLANTACIJEBUBREGA

AnaSpasić1,AleksandraCatić‐Đorđević1,NikolaStefanović1,

RadmilaVeličković‐Radovanović1,2

1Katedrazafarmaciju,UniverzitetuNišu‐Medicinskifakultet,2Klinikazanefrologiju,KliničkicentarNiš(Srbija)

Upotrebu imunosupresivnih lekova kod pacijenata sa transplantiranim

bubregompratemnogobrojnineželjeniefekti.Onimoguznačajnodasmanjeadherencupacijenataiutičunapreživljavanjegrafta.Mikofenolnakiselina(MPA)čestojekorišćenimunosupresivni lek koji je na tržištu dostupan u obliku estra (mikofenolat mofetil,MMF) ili u obliku soli (mikofenolat natrijum, EC‐MPS). Cilj istraživanja bio je daprocenimo učestalost i razlike u ispoljenim neželjenim efektima tokom terapijeMMF/EC‐MPSkodpacijenatasatransplantiranimbubregom.

Istraživanje je obuhvatilo 77 pacijenata sa transplantiranim bubregom (53muškarca i 24 žene)koji subili praćeninaKlinici za nefrologiju (Klinički centarNIš,Srbija).Pacijentisuoralnokoristilitakrolimus,kortikosteroide(prednizolon)iMMFiliEC‐MPS. Za procenu neželjenih efekata terapije korišćen je upitnik koju su razvilinefrolozi sa Univerziteta u Bafalu, SAD. Upitnik je obuhvatao osamnaest negativnihefekata koji su podeljeni u gastrointestinalne, estetske i efekte na centralni nervnisistem (CNS). Za statističku analizu podataka korišćen je SPSS 20 softverski paket(Studentovt‐test).Najčešćineželjeniefektibilisugastrointestinalni(80,9%),zatimCNS(71,16%)iestetski(62,66%).PacijentikojisuprimaliMMFimalisuznačajnoizraženijegastrointestinalneneželjeneefekte(0,25±0.19)upoređenjusaonimanaterapijiEC‐MPS(0,16±0.13).Dijarejajebilanajučestalijagastronitestinalnategoba(43,8%).Nijebilo razlike u CNS, estetskim i kumulativnim neželjenim efektima među pacijentimalečenimEC‐MPSiMMF.

Kod pacijenata sa transplantiranim bubregom najčešće su bili prisutnigastrointestinalnineželjeniefekti.OnisubiliznačajnoizraženijikodpacijenatakojisuprimaliMMFuodnosunaEC‐MPS,zarazlikuodostalihtipovaneželjenihefekatakojisenisurazlikovaliuodnosunaformulaciju.ProspektivnopraćenjeneželjenihefekataMPAterapije može da poboljša bezbednost pacijenata i adherencu pacijenata nakontransplantacije.

661

THEINFLUENCEOFMICOPHENOLICACIDFORMULATIONONTHE

ADVERSEEFFECTSINRENALTRANSPLANTRECIPIENTS

AnaSpasić1,AleksandraCatić‐Đorđević1,NikolaStefanović1,RadmilaVeličković‐Radovanović1,2

1DepartmentofPharmacy,UniversityofNiš‐FacultyofMedicine,2Clinicof

Nephrology,ClinicalCentreNiš(Serbia)

After renal transplantation, many patients experience adverse effects from

immunosuppressivedrugs.When theseadverseeffectsoccur,patientadherencewithimmunosuppressionmaybe reduced, impacting allograft survival.Mycophenolic acid(MPA)isawidelyusedimmunosuppressivedrugandit isavailableeitherasanesterprodrug (mycophenolatemofetil,MMF) or as a sodium salt (mycophenolate sodium,EC‐MPS).ThepurposeofthisstudywastodeterminethefrequencyanddifferencesinadverseeffectswithMMF/EC‐MPSinrenaltransplantrecipients.

This prospective study included 77 stable renal transplant recipients (53menand 24 women) who were treated in the Clinic of Nephrology (University ClinicalCentre of Nis, Serbia). Patients received oral MMF or EC‐MPS as part of a tripleimmunosuppressive regimen,which also included corticosteroids (prednisolone) andtacrolimus.Todeterminetheadverseeffectsoftherapyweusedasurveydevelopedbynephrologists at the University of Buffalo, USA. Nephrologists evaluated 18 adverseeffectswhichwereorganized intogastrointestinal, centralnervoussystem(CNS)andaestheticdomains.StatisticalanalysiswasperformedusingSPSSsoftwareversion20(Student t test). The most common adverse effects were gastrointestinal (80.9%),followed by CNS (71.16%) and aesthetic adverse effects (62.66%). Patients treatedwithMMFexperiencedasignificantlypronouncedgastrointestinaladverseeffectratio(0.25 ± 0.19) compared to EC‐MPS (0.16 ± 0.13). Themost frequent gastrointestinaleventwasdiarrhea(43.8%).TherewasnodifferencebetweenpatientstreatedwithEC‐MPSorMMFfortheaesthetic,CNSandcumulativeadverseeffectratios.

Gastrointestinal adverse effects were the most common in renal transplantrecipients. Thenumbers and types of adverse effectswerenot different between thetwo treatments,exceptgastrointestinaladverseeffectswhichweresignificantlymorepronounced in patients treated with MMF. Prospective clinical monitoring of MPAadverse effects may improve patient safety and post‐transplant immunosuppressiveadherence.

662

Arh.farm 2018;68: 662-663 FFT-P2

EFEKATODABRANIHPREPARATAL‐KARNITINAUMODULACIJIEKSPRESIJEGENAZAHIPOKSIJSKIINDUCIBILNIFAKTOR1ΑU

KULTURILIMFOCITA 

MajaKuzmanović1,AnjaHaverić2,NaidaLojo‐Kadrić2,MaidaHadžić2,JasminRamić2,SaninHaverić2,LejlaPojskić2

 1UniverzitetuSarajevu‐Farmaceutskifakultet,2UnivertitetuSarajevu‐Institut

zagenetičkoinženjerstvoibiotehnologiju(BosnaiHercegovina)  

Postoje tvrdnje da brojni dodaci prehrani zbog svojih antioksidativnih iantiinflamatornihefekata imaju sveukupnopozitivneučinkena zdravljepojedinca.L‐karnitinkaosuplementkoristiseurazličitesvrhe:oddodatkauprehrani,urazličitimmedicinskimtretmanimadoreguliranjatjelesnetežine.Ciljovogistraživanjajebiodase procjeni dejstvoL‐karnitina i L‐karnitina sdodatkomvitaminaB6u oksidativnomstresuinvitropraćenjemekspresijegenauključenoguoveprocese.

U ovoj studiji smo testirali dva komercijalno dostupna preparata: jedan kojisadržiL‐karnitinuoblikukapsulaudoziod500mgidrugi,tečnipreparatL‐karnitinsadodatkom vitamina B6 (2,8 mg – 200% RDA). Kulture limfocita su uspostavljenestandardnim postupkom i tretirane tokom 72 sata odabranim koncentracijama L‐karnitina/L‐karnitinasavitaminomB6.Kaonegativnakontrolakorištenisunetretiranilimfociti.UkupnamRNAje izolovana iz tretiranih inetretiranihćelija.RealTime‐PCRmetoda jebilakorištenazaprocjenuekspresijeHIF1Α(eng.hypoxia inducible factor)gena, a kao konstitutivni gen je korišten GAPDH. L‐karnitin je smanjio transkripcijuHIF1α gena u koncentracijama od 50 μmol/l, 250 μmol/l, 500 μmol/l i 1000 μmol/l(p=0,001;p=0,017;p=0,001ip=0,0015,redom).L‐karnitinsavitaminomB6značajnojeredukovaotranskripcijuHIF1αgenaukoncentracijamaod50μmol/li1000μmol/l(p=0,007 i p=0,015, redom), doku koncentracijamaod250μmol/l i 500μmol/l nijeznačajnopovećaotranskripcijuHIF1αgena(p=0,0915ip=0,807,redom).

L‐karnitin je u rasponu koncentracija od 50 μmol/l do 1000 μmol/l smanjioekspresiju gena koji kodira HIF1α gen, što ukazuje na moguću inhibicijuproinflamatornih procesa. Međutim, u kombinaciji sa vitaminom B6, L‐karnitin jesmanjio tranksripciju gena za HIF1α samo u koncentracijama od 50 μmol/l i 1000μmol/l, dok je u koncentraciji od 250 μmol/l imao tendenciju povećanja njegovetranskripcije;smisaoovognalazazahtjevadaljerazjašnjenje.

   

663

   

EFFECTOFSELECTEDL‐CARNITINEPREPARATIONSONEXPRESSIONOFAGENEFORHYPOXIAINDUCIBLEFACTOR1ΑIN

THELYMPHOCYTECULTURE 

MajaKuzmanović1,AnjaHaverić2,NaidaLojo‐Kadrić2,MaidaHadzić2,JasminRamić2,SaninHaverić2,LejlaPojskić2

 1UniversityofSarajevo,Sarajevo–FacultyofPharmacy,2UniversityofSarajevo‐InstituteforGeneticEngineeringandBiotechnology(BosniaandHerzegovina)  

Itisclaimedthatmanynutritionalsupplements,becauseoftheirantioxidantandanti‐inflammatory effects, have an overall positive influence on human health. L‐carnitineasasupplementisusedforvariouspurposes:asfoodsupplement,inmedicaltreatment,orforbodyweightregulation.Theaimofthisstudywastoassesstheeffectof L‐carnitine and L‐ carnitine supplemented with vitamin B6 in oxidative stress invitrobyanalysisofexpressionofageneinvolvedintheseprocesses.

Inthisstudywetestedtwocommerciallyavailablepreparations:capsulesofL‐carnitineatadosageof500mg,andaliquidL‐carnitinesupplementedwithvitaminB6(2.8mg ‐ 200%RDA). Lymphocyte cultureswere establishedby standardprocedureand treated with selected concentrations of L‐carnitin/L‐carnitine with vitamin B6fromthestartofcultivation.Cultivationlastedfor72hours.TotalmRNAwasisolatedfrom treated and non‐treated cells. Real‐Time PCRwas used to assess relative geneexpression of hypoxia‐inducible factor‐1α (HIF‐1α) and GAPDH as the housekeepinggenefornormalization.

L‐carnitinereducedthetranscriptionoftheHIF1αgeneatconcentrationsof50μmol/l, 250 μmol/l, 500 μmol/l and 1000 μmol/l (p=0.001; p=0.017; p=0.001 andp=0.0015, respectively). L‐carnitine with vitamin B6 significantly reduced thetranscription of the HIF1α gene, at concentrations of 50 μmol/l and 1000 μmol/l(p=0.007 and p=0.015, respectively),while at concentrations of 250 μmol/l and 500μmol/l insignificantly increased the transcription of the HIF1α gene (p=0.0915 andp=0.807,respectively).L‐carnitineintheconcentrationrange50μmol/lto1000μmol/lreducedtheexpressionofthegeneencodingHIF1α,whichindicatespossibleinhibitionofproinflammatoryprocesses.However,whencombinedwithvitaminB6,L‐carnitinereduced the transcriptionof theHIF1αgeneonlyat concentrationsof50μmol/l and1000μmol/l,whileatconcentrationof250μmol/ltendedtoincreaseitstranscription;themeaningofthisfindingneedsfurtherclarification.

664

Arh.farm 2018;68: 664-665 FFT-P3

GL‐II‐73,POZITIVNIALOSTERNIMODULATORα5GABAARECEPTORA,REDUKUJELIPOPOLISAHARIDOM‐IZAZVANOPONAŠANJESLIČNODEPRESIVNOMKODC57BL/6MIŠEVA

AleksandraVidojević1,MarijaMilić1,IvanJančić1,

GuanguanLi2,MiroslavSavić1

1UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija),2Univerzitetu

Viskonsin‐Milvokiju,Milvoki(SAD)

IzmenjenaGABA‐ergička(γ‐aminobuternakiselina)neurotransmisijasedovodi

uvezusaporemećajimaraspoloženja.UovomradujeispitanuticajGL‐II‐73,pozitivnogalosternog modulatora na α5 GABAA receptorima, u lipopolisaharidom (LPS)‐izazvanommišjemmodeluponašanjakojesepovezujesadepresijom.

GL‐II‐73iliketamin(pozitivnakontrolamodela)udoziod10ili6mg/kg,redom,primenjenisumužjacimaC57BL/6miševa(ukupanbroj=75)neposrednopreprimene0.5 mg/kg LPS‐a. Prisustvo bolesnog ponašanja (eng. sickness behavior) je praćenomerenjemtelesnemase(TM),unosahrane(UH) ibrojaulazakaukvadrantetokom5minuta testa spontane lokomotorne aktivnosti (UK).TM iUH sumereni2, 6, 24 i 28sati,aUK2i24satanakonprimenetretmana.Preferencijakasaharozi(SP)uSPtestu(SPT), kao indikator anhedonije, i vreme provedeno u imobilnosti (VI) u testuforsiranogplivanja(FPT),kaoindikatorbihejvioralnogočaja,merenisu24‐28satai28sati nakonprimene tretmana, redom. Životinje koje se nisu razbolele nakonprimeneLPS‐ailikojenisukonzumiralevišeod0,1mltečnostizavremeSPT‐asubileisključeneizanalize.

Uovomradupokazano jeda je tretmanLPS‐om indukovaobolesnoponašanjekao i ponašanje nalik depresivnom kod miševa tako što je snizio TM, UH, UK, SP inastojaodapovećaVI.PretretmansaketaminomjepovratiovrednostiUHuintervalu24‐28 sata,UKposle24h,kao i SP,dok jepretretmansaGL‐II‐73normalizovaoSP iimao tendenciju da smanji VI. Ovi rezultati pokazuju da je ketamin ublažio bolesnoponašanje i anhedoniju kodmiševa bez efekta na bihejvioralni očaj, dok je GL‐II‐73,iako bez efekta na bolesno ponašanje, redukovao anhedoniju i imao tendenciju dasmanjibihejvioralniočaj.

GL‐II‐73, pozitivnimodulator α5 GABAA receptora, redukovao je anhedoniju ibihejvioralni očaj u LPS‐om izazvanom mišjem modelu ponašanja nalik nadepresivnom,štopružapotencijalnonovipristuputretmanudepresivnihporemećaja.

665

α5GABAARECEPTORPOSITIVEALLOSTERICMODULATIONBYGL‐II‐73REDUCEDLIPOPOLYSACCHARIDE‐INDUCEDDEPRESSIVE–LIKE

BEHAVIORINC57BL/6MICE

AleksandraVidojević1,MarijaMilić1,IvanJančić1,GuanguanLi2,MiroslavSavić1

1UniversityofBelgrade‐FacultyofPharmacy(Serbia),2Universityof

Wisconsin‐Milwaukee,Milwaukee(USA)

γ‐Aminobutyricacid(GABA)signalingislikelydisruptedinmooddisorders.We

investigated the influence of GL‐II‐73, an α5 GABAA receptor positive allostericmodulator, in the lipopolysaccharide (LPS)‐inducedmurinemodel of depressive‐likebehavior.

GL‐II‐73orketamine(apositivecontrolofthemodel)dosedat10and6mg/kg,respectively, were administered to male C57BL/6 mice (total N=75) immediatelybefore the application of 0.5 mg/kg of LPS. Sickness behavior was assessed bymeasuringbodyweight(BW),foodintake(FI)andnumberofquadrantentriesduring5minofspontaneouslocomotoractivityassay(QE).BWandFIweremeasured2,6,24and 28 h, andQE2 and 24 h after the treatment administration. Sucrose preference(SP) in SP test (SPT), as an indicatorof anhedonia, and time immobile (TI) in forcedswimtest(FST),asanindicatorofbehavioraldespair,weremeasured24‐28hand28hafter treatment administration, respectively. Animals which did not exhibit sicknessbehavior or consumed less than 0.1 ml of liquid during SPT were excluded fromanalysis.

WedemonstratedthattreatmentwithLPSinducedsicknessanddepressive‐likebehaviorinmicebyultimatelydecreasingBW,FI,QE,SPandtendingtoincreasetheTI.Pretreatmentwith ketamine restoredFI at 24‐28h,QE at 24h and SP, andGL‐II‐73restored SP and tended to restore TI. We showed that ketamine reduced sicknessbehaviorandanhedoniawithnoeffectonbehavioraldespair,whileGL‐II‐73,althoughwith no effect on sickness behavior, reduced anhedonia and tended to reducebehavioraldespair.

GL‐II‐73, an α5 GABAA receptor positive allosteric modulator, reducedanhedonia and behavioral despair in LPS‐induced murine model of depressive‐likebehavior,suggestinganovelapproachinthetreatmentofdepression.

666

Arh.farm 2018;68: 666-667 FFT-P4

NOVIPOZITIVNIMODULATOR4‐GABAARECEPTORA,XHE‐III‐74,

SMANJUJEUNOSALKOHOLAUMIŠIJEMMODELU„PIJENJAUMRAKU”

TamaraStanković1,BojanBatinić2,AnjaSantrač1,BojanMarković3,

MilicaDrobac4,JelenaArsenijević4,MiroslavSavić1

1Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2Katedrazafiziologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,3Katedra

zafarmaceutskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet,4Katedrazafarmakognoziju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)

CiljovestudijebiojedaseispitadaliakutnitretmanligandomXHe‐III‐74,novimpozitivnimmodulatoromα4‐GABAAreceptora,možesmanjitiunosalkoholaumišijemmodelu„pijenjaumraku”(eng.drinkinginthedark–DID).

Eksperimenti su sprovedeni na odraslim miševima soja C57BL/6. Mogućesedativno dejstvo XHe‐III‐74 (0,5; 2 ili 5 mg/kg, i.p.) ispitano je u testu spontanelokomotorne aktivnosti (SLA). Prvog dana jednog ciklusa DID eksperimenta svakaživotinjaimalajedvočasovnipristupalkoholu(etanol20%,v/v).Drugogdanatretmanje primenjivan 20 minuta pre pristupa alkoholu, a trećeg dana pacovi nisu tretiraniničim.UsvimDIDeksperimentimasvakaživotinjajeprošlakrozčetiriciklusatakodajeu svakomprimila jednuod tri doze tretmana ili placebo.UprvomDIDeksperimentutestirali smoefekatXHe‐III‐74(0,8;2 ili5mg/kg)naunosvode(n=12,podozi),doksmo u drugom testirali efekat istih doza na unos alkohola (n=14). Ekekat referetnogleka, naltreksona (1; 4 ili 16 mg/kg) testiran je u trećem eksperimentu.USLAtestu,nijednaododabranihdozaXHe‐III‐74nijesmanjilapređeniputživotinje(F3,20=0,48;p=0,703).UprvomDIDeksperiementu, tretmanXHe‐III‐74nijeuticaonaunos vode (F3,33=0,39; p=0,763). Unos alkohola,meren u drugomDID eksperimentu,izmenjenjepoddejstvomXHe‐III‐74tretmana(F3,39=7,41;p<0,001),gdejedozaXHe‐III‐74 od 5 mg/kg značajno smanjila unos u poređenju sa kontrolom (p<0,001). Utrećem eksperimentu, naltrekson je značajno smanjio unos alkohola (F60,3=22.18;p<0,001), i to u sve tri doze: 1 mg/kg (p<0,001); 4 mg/kg (p<0,001) i 16 mg/kg(p<0,001).

Uz očekivani izostanak sedativnog dejstva, XHe‐III‐74, pozitivnimodulator α4‐GABAA receptora, ispoljio je evidentan potencijal za smanjenje unosa alkohola umišijemDIDmodelu,kojisemožeporeditisaonimpostignutimprimenomnaltreksona,referentnoglekauterapijiporemećajaunosaalkohola.

667

ANOVELPOSITIVEMODULATOROF4‐GABAARECEPTORS,XHE‐III‐74,REDUCESETHANOLINTAKEINMOUSE

„DRINKINGINTHEDARK”MODEL

TamaraStanković1,BojanBatinić2,AnjaSantrač1,BojanMarković3,MilicaDrobac4,JelenaArsenijević4,MiroslavSavić1

1DepartmentofPharmacology,UniversitiyofBelgrade‐FacultyofPharmacy,2DepartmentofPhysiology,UniversitiyofBelgrade‐FacultyofPharmacy,

3DepartmentofPharmaceuticalChemistry,UniversitiyofBelgrade‐FacultyofPharmacy,4DepartmentofPharmacognosy,UniversitiyofBelgrade‐Facultyof

Pharmacy(Serbia)

ThepresentstudyaimedtoinvestigatewhetheracutetreatmentwithXHe‐III‐74,anovelpositivemodulatorofα4‐GABAAreceptors,mayreducealcoholintakeinmousemodelof„drinkinginthedark”(DID).

All experiments were conducted on adult C57BL/6 mice. Potential sedativeproperties of XHe‐III‐74, (0.5, 2 or 5 mg/kg, i.p.) were assessed using spontaneouslocomotoractivity(SLA)test.Onthe1stdayofoneDIDcycleeachanimalhad2‐haccesstoethanol(20%,v/v),onthe2nddaytreatmentwasgiven20minbeforetheaccesstoethanol, while on the 3rd day the animal was not treated in any way. In all DIDexperiments each animal passed through four cycles and respectively receive one ofthreetreatmentdosesorsolventineachcycle.InExperiment1wetestedwhetherXHe‐III‐74(0.8,2or5mg/kg)hadanyeffectsonwater intake(n=12pertreatmentdose),whileinExperiment2,thesamedoseswereusedtotestpotentialdecreaseofethanolintake (n=14). Effects of the reference drug, naltrexone (1; 4 and 16 mg/kg) weretested inExperiment3 (n=21). In theSLA test,noneof theselectedXHe‐III‐74dosesdecreasedthedistancetraveled(F3,20=0.48;p=0.703).InDIDExperiment1,XHe‐III‐74treatmentdidn’taffectwaterintake(F33,3=0.39;p=0.763).Ethanolintake,measuredinExperiment2,wasaffectedbyXHe‐III‐74treatment(F39,3=7.41;p<0.001),with5mg/kgXHe‐III‐74significantlyreducingtheintakerelativetocontrol(p<0.001).InExperiment3,naltrexonesignificantlyaffectedtheintakeofethanol(F60,3=22.18;p<0.001),withallthreedosesreducingtheintake:1mg/kg(p<0.001);4mg/kg(p<0.001)and16mg/kg(p<0.001).

With expected lack of sedative actions,XHe‐III‐74, a positivemodulator ofα4‐GABAARs,exhibitedaclearpotentialfordecreasingethanolintakeinmouseDIDmodel,comparable to that of naltrexone, a reference drug in alcohol use disorder.

668

Arh.farm 2018;68: 668-669 FFT-P5

BIHEJVIORALNAKARAKTERIZACIJASOCIJABILNOSTIISOCIJALNE

MEMORIJE5XFADTRANSGENIHMIŠEVAKAOMODELAALCHAJMEROVEBOLESTI

JovanaAranđelović,MarijaBanićević,AleksandarObradović,MiroslavSavić

Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)

Kod pacijenata koji boluju od Alchajmerove bolesti dolazi do poremećaja u

socijalizaciji i socijalnoj memoriji. 5xFAD miševi predstavljaju široko korišćenprogresivni model u ispitivanju ove bolesti, u kome socijalna interakcija i socijalnoprepoznavanjenisudetaljnoistraženi.Ciljradabiojedasebihejvioralnookarakterišusocijabilnost i socijalnamemorija obapola5xFADživotinjauperiodu samogpočetkastvaranjaplaka.

U eksperimentu su korišćeni transgeni (11 mužjaka, 11 ženki) i netransgeni(kontrolna grupa; 13 mužjaka, 12 ženki) 5xFAD miševi starosti 2 meseca koji supodvrgnute testu tri komore. Protokol obuhvata tri uzastopne faze: habituaciju,socijalnuinterakcijuisocijalnoprepoznavanje.

Nalokomotornuaktivnostživotinja,procenjenuufazihabituacije,neutičunipolnigenotip.Utestusocijalneinterakcije,kontrolnimužjacisuprovelistatističkiznačajnoviševremenaukomorisamišemičešćesuulaziliuovu,uodnosunapraznukomoru,štonijebioslučajkodkontrolnihženki.Ni transgenimužjacini transgeneženkenisurazlikovali praznu i komoru sa mišem, što ukazuje da 5xFAD genotip može da imanepovoljan uticaj na socijabilnost. U testu socijalnog prepoznavanja, samo sunetransgenimužjaci,alineinetransgeneženke,niti transgeneživotinjediskriminisalipoznatog i novog miša, što je pokazano statistički značajno dužim vremenomprovedenimsanovimmišem,kaoivećimbrojemulazakauzonusanovimuodnosunazonusapoznatimmišem.

Rano odraslo doba predstavlja period u kome postoji izmenjena socijabilnostkod5xFADmužjaka.Netransgeneženkenisupokazaleočekivanusocijalnuinterakcijuiprepoznavanje, što onemogućava izvođenje zaključaka o transgenim ženkama.Potrebno je nastaviti karakterizaciju socijalnog ponašanja ovih miševa tokomprogresijestvaranjaplakairazvojaostalihsimptomabolesti.

669

BEHAVIORALCHARACTERIZATIONOFSOCIABILITYANDSOCIALMEMORYINTHE5XFADTRANSGENICMICEASAMODELOF

ALZHEIMERDISEASE

JovanaAranđelović,MarijaBanićević,AleksandarObradović,MiroslavSavić

DepartmentofPharmacology,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)

PatientssufferingfromAlzheimerdiseaseexperiencedesocializationandsocial

memory impairment. Transgenic 5xFAD mice represent a widely used progressivemodelofthisdisease,inwhichsocialinteractionandsocialrecognitionhavenotbeenthoroughlyexploredyet.Ouraimwastocharacterizethesociabilityandsocialmemoryofbothgendersof5xFADanimalsattheveryonsetofplaquedeposition.

Twomonthsoldtransgenicmice(11males,11females)andtheirnon‐transgeniclittermates(controlgroups;13males,12females)wereassessedinthethree‐chambertest.Theprotocolconsistedofsuccessivephasesofhabituation,socialinteractionandsocialrecognition.

The general locomotor activity, as assessed in the habituation phase, was notsignificantly affected by genotype or gender. In the social interaction phase, asexpected, control males spent more time and entered more frequently the chamberwiththecon‐specific thantheemptyone;however, thiswasnotthecasewith femalecontrols. Both, transgenic males and females did not distinguish between these twochambers,whichindicatesthatthe5xFADgenotypemighthaveanadverseimpactonsociability. In the social recognition phase, only non‐transgenic male, but not non‐transgenicfemaleortransgenicmice,discriminatedbetweenfamiliarandnovelmouse,asdemonstratedby the increased time the animal spent in, andagreaternumberofentriesintothezonewithanovelversusthefamiliarmouse.

Theearlyadulthoodrepresentsaperiodinwhichsociabilityin5xFADmalemiceisaltered.Femalenon‐transgenicanimalsdidnotshowexpectedsocialinteractionandrecognition,whichprecludesanyconclusionsaboutthebehavioroftransgenicfemales.It isnecessarytocontinuecharacterizingthesocialbehaviorofthesemiceduringtheprogressionofplaquegenerationanddevelopmentofothersymptoms.

670

Arh.farm 2018;68: 670-671 FFT-P6

FARMAKOTERAPIJANEUROENDOKRINIHTUMORAPANKREASA

BojanaPetrović,PredragVukomanović

Visokazdravstveno‐sanitarnaškolastrukovnihstudija„Visan”,Beograd(Srbija)

Neuroendokrini tumori pankreasa (pNET), na osnovu funkcionalne aktivnosti

(vrste hormona koje tumor sekretuje) obuhvataju insulinom, VIP‐om, glukagonom,somatostatinom, kao i tumore koji sekretuju hormone koji se ne produkuju upankreasu ‐ gastrinom, kortikotropinom, gonadotropinom i dr.Najbolji vid lečenja jehirurško odstranjivanje tumora, koje je često neprimenljivo zbog nepristupačnihlokalizacija, kasnog postavljanja dijagnoze i metastatskog širenja. Medikamentoznaterapijauključujeprimenuanalogasomatostatina(SSA‐oktreotid,lanreotid,vapreotid,pasireotid), alkilirajućih agenasa (streptozocin, temozolomid, dakarbazin), platine,radioobeleženih peptida, kao i savremenih terapeutika‐sunitiniba, everolimusa ibevacizumaba.RadimazaciljdaprikažerazlikeizmeđukonvencionalnihisavremenihlekovauterapijipNET‐a.Urađena jekomparativnaanalizaefikasnostirazličitihgrupalekovauterapijipNET‐a.

U terapiji metastatskih i neoperabilnih pNET‐a u novije vreme su indikovanisunitinib,everolimus,bevacizumab,uvidumono‐ilikombinovaneterapije.

Za razliku od tradicionalnih, ovi lekovi imaju ciljna dejstva, inhibirajućiangiogenezu tumorskih ćelija. Inhibicijom angiogeneze sprečavaju rast tumorapankreasa i proliferaciju endotelnih ćelija, fibroblasta i glatkih mišićnih ćelija.EverolimusjeselektivaninhibitormTOR,smanjujenivoVEGF(vaskularnogendotelnogfaktora rasta koji potencira angiogenezu tumora). Bevacizumab, anti‐VEGF antiteloprepoznajeiblokiraspecifičneproteineprisutneutumorskimćelijama.Sunitinibdelujedvostruko na maligne ćelije: sprečava njihovo umnožavanje i rast krvnih sudovainhibicijom receptorskih tirozin‐kinaza: c‐kit, RET, CSF‐1R, Flt3, PDGFR i VEGFR.Budući da ovi lekovi selektivno inhibiraju stvaranje novih krvnih sudova, oni manjeoštećujunormalnećelijeodtradicionalnihcitostatika,jerpostojećikrvnisudoviostajuočuvani za snabdevanje normalnih ćelija. Pored toga, mnogobrojne studije pokazujunjihovu izrazito povoljniju farmakovigilancu i duže preživljavanje pacijenata.Multidisciplinarnipristup,razvoj iprimenaselektivnijih lekovauterapijipNET‐a,kojipoboljšavajukvalitetživotapacijenata,odsuštinskogjeznačaja,naročitokadaseimauvidučinjenicadaseradioretkiminedovoljnoproučenimentitetima.

671

PHARMACOTHERAPYOFPANCREATICNEUROENDOCRINETUMORS

BojanaPetrović,PredragVukomanović

MedicalSanitarySchoolofAppliedSciences„Visan”,Belgrade(Serbia)

Pancreaticneuroendocrinetumors(pNETs),basedonthetypeofhormonethat

is secretedaredivided into: insulinoma,VIPoma,glucagonoma, somatostatinomaandnonpancreatic hormone tumors (gastrinoma, gonadotroph, corticotroph adenomas).The most effective treatment is surgical removal of tumors, which is often notapplicable due to inaccessible localization, late diagnosis and metastatic spread.Pharmacotherapy includes administration of somatostatin analogues (SSA‐octreotide,lanreotide, vapreotide, pasireotide), alkylating agents (streptozocin, temozolomide,dacarbazine),platinum,apeptidereceptorradionuclidetherapy,aswellasthemoderntherapeutics‐sunitinib, everolimus, bevacizumab. The paper aims to show thedifferencesbetweenconventionalandmoderndrugsinthepNETstreatment.

ComparativeanalysisoftheefficiencyofdifferentpharmacologicalgroupsinthetreatmentofpNETswasperformed.

In recent years, sunitinib, everolimus, and bevacizumab, as mono‐ orpolytherapy,areindicatedforthetreatmentofmetastaticandinoperablepNETs.Unliketraditional therapy, these drugs have a target of action, inhibition of angiogenesis oftumorcells,tumorgrowthandproliferationofendothelialcells,fibroblasts,andsmoothmuscle cells.Everolimus isa selectivemTOR inhibitor that reduces the levelofVEGF(vascularendothelialgrowth factor).Bevacizumab,ananti‐VEGFantibody,recognizesandblocksspecificproteinspresentintumorcells.Sunitinibactsdoublyonmalignantcells: prevents their multiplication, and the angiogenesis by inhibition of receptortyrosine kinases: c‐kit, RET, CSF‐1R, Flt3, PDGFR, and VEGFR. Since these drugsselectively inhibit angiogenesis, they less damage normal cells than traditionalcytostatics, as existing blood vessels remain preserved for normal cell supply. Inaddition,numerousstudieshaveshowntheirfarmoresuitablepharmacovigilanceandlonger patient survival. Multidisciplinary approach, development and application ofselectivedrugsinthetreatmentofpNETswhichimprovethequalityoflifeofpatientsisessential considering the fact that pNETs are rare and insufficiently investigatedentities.

672

Arh.farm 2018;68: 672-673 FFT-P7

DOZIRANJEAPIKSABANAIRIVAROKSABANAKODPACIJENATASAPLUĆNOMEMBOLIJOM:DALIJEDNADOZAODGOVARASVIMA?

JelenaDžudović1,MarkoAntunović2,AleksandraRepić3,BorisDžudović1

1Klinikazakardiologijuiurgentnuinternumedicinu,Vojnomedicinska

akademija,Beograd,2NacionalniCentarzakontrolutrovanja,Vojnomedicinskaakademija,Beograd,3InstitutzamedicinuradaSrbije,(Srbija)

Apiksaban i rivaroksaban su direktni oralni antikoagulansi (DOAK) koji

inhibirajufaktorkoagulacijeXaičestosepropisujupacijentimasaplućnomembolijom(PE). U fiziološkimuslovima, kada je očuvana bubrežna funkcija i ukoliko ekstremneosobinepacijenatanisuudružene,svakiodovadvalekaimajedinstvenodoziranjebezobziranatelesnumasu,godineživotailipol.Ipak,mnogestudijenisuuključivalestarijeiliekstremnogojaznepacijente,takodapodacioefikasnostiibezbednostiovihlekovazaovupopulacijunedostaju.Ciljovestudijebiojedaseuporedianti‐XaaktivnostkodpacijenatasaPEuzavisnostiodnjihovogindeksatelesnemase,godinaživotaipola.

U ovoj retrospektivnoj, opservacionoj studiji preseka jedne zdravstveneustanove,konsekutivnipacijentisaPEsusvrstaniugrupukojajedobijalaapiksabanilirivaroksaban nakon otpusta. Nakon jednomesečne stabilne terapije, u uzorku krvidobijenojvenepunkcijomodređivanajeanti‐Xaaktivnost.Usvakojodgrupavrednostianti‐Xa su poređene između pacijenata sa normalnom telesnom masom i gojaznih,zatimizmeđumlađihistarijihod75godinaživotaiizmeđumuškaracaižena.

U studiju je bilo uključeno 167 pacijenata, 56 (33,5%) na apiksabanu i 111(66,5%) na rivaroksabanu. U grupi pacijenata lečenih apiksabanom nije postojalaznačajnarazlikauanti‐Xaaktivnostiizmeđupacijenatasanormalnomtelesnommasomi gojaznih (p=0,285),mlađih i starijihod75godina (p=0,663) ili izmeđumuškaraca ižena (p=0,092). Takođe, ni u grupi pacijenata lečenih rivaroksabanom nije postojalaznačajna razlikau anti‐Xa aktivnosti za iste kriterijume (p=0,938, p=0,885 i p=0,102,redom). Kod pacijenata sa PE, nakon jednomesečne terapije bilo apiksabanom ilirivaroksabanom, telesna masa, godine života ili pol ne utiču značajno na anti‐Xaaktivnost.

673

APIXABANANDRIVAROXABANDOSINGINPULMONARYEMBOLISM

PATIENTS:DOESONEDOSEFITSALL?

JelenaDžudović1,MarkoAntunović2,AleksandraRepić3,BorisDžudović1

1ClinicforCardiologyandEmergencyInternalMedicine,MilitaryMedicalAcademy,Belgrade,2NationalPoisonControlCenter,MilitaryMedicalAcademy,

Belgrade,3SerbianInstituteofOccupationalHealth,Belgrade(Serbia)

Apixaban and rivaroxaban are direct oral anticoagulants (DOACs)which block

coagulation factor Xa and are commonly prescribed to the patients diagnosed withpulmonaryembolism(PE).Innormalconditions,withpreservedkidneyfunctionandifextreme patients’ characteristics are not combined, each drug has the same dosageregardless of age, body mass or sex. However, many trials did not include elderlypatientsorthosewithextremeobesity,sodataofdrugefficacyandsafetywithsingleandpredefineddosageinsuchpopulationisstilllacking.Theobjectiveofthisstudywasto compare an anti‐Xa activity in PE patients considering their different body massindex,ageandsex.

In this single‐center retrospective, observational cross‐sectional study,consecutive PE patients were allocated to either apixaban or rivaroxaban groupregardingtheDOACtheyreceivedafterhospitaldischarge.Afteronemonthonstabletherapy,anti‐Xaactivitywasmeasuredinthebloodcollectedbyvenepunctureduringthe trough drug concentration. In each of apixaban and rivaroxaban group anti‐Xaactivityvalueswerecomparedbetweennormalweightedandobese,youngerandolderthan75yearsofage,malesandfemales.

Overall 167 patients were involved in this study, 56 (33.5%) in the apixabangroupand111(66.5%)intherivaroxabangroup.Intheapixabangroup,thedifferencein anti‐Xa activitywas not significant between normalweighted and obese, youngerandolderthan75yearsofage,andmalesandfemales(p=0.285,p=0.663andp=0.092,respectively). In therivaroxabangroup,nosignificantdifferencewas foundeither forthe same criteria (p=0.938, p=0.885, and p=0.102, respectively). In PE patients, afteronemonthoftreatmentwithasinglerecommendeddosageofapixabanorrivaroxaban,anti‐Xaactivityisnotsignificantlyinfluencedbypatient’sbodymass,ageorsex.

674

Arh.farm 2018;68: 674-675 FFT-P8

UČEŠĆEHOLINERGIČKIHRECEPTORAUANALGETIČKOMDEJSTVU

VORTIOKSETINA

MiljaVuković,AnaMicov,UrošPecikoza,MajaTomić,RadicaStepanović‐Petrović

Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)

Vortioksetin je noviji antidepresiv samultimodalnimmehanizmom dejstva. Za

razliku od većine antidepresiva poseduje prokognitivna svojstva, čemu verovatnodoprinosi potenciranje holinergičke neurotransmisije. Poznato je da se antidepresivikoriste u lečenju različitih bolnih stanja, uključujući i ona trigeminalnog porekla.Nedavno smo pokazali da vortioksetin ostvaruje efikasnost u orofacijalnomformalinskom testu u miševa, modelu trigeminalnog bola. Kako bismo razjasnilimehanizamanalgetičkogdejstvavortioksetinauovommodelubola, ciljnašegrada jebio da se ispita potencijalno učešće holinergičkih (muskarinskih i α7‐nikotinskih)receptora,imajućiuvidunjihovznačajumodulacijibola.

Bolna preosetljivost orofacijalnog regiona miševa izazivana je supkutanominjekcijom rastvora formalina (2 %, 20 μl). Merni parametar je ukupno vremeprovedenoubolnomponašanju(trljanjenjuške)tokomprve(0‐9minnakonformalina)i druge (9‐45 min nakon formalina) faze testa. Najpre smo potvrdili efikasnostvortioksetina u ovom testu, a potom smo pratili uticaj atropina (neselektivnogantagoniste muskarinskih receptora) i metillikakonitina (selektivnog antagoniste α7‐nikotinskih receptora) na analgetičko dejstvo fiksne, efektivne doze vortioksetina.Vortioksetin je primenjivan peroralno (p.o.), a antagonisti intraperitonealno (i.p.) 60minprerastvoraformalina.

Vortioksetin (5‐20 mg/kg; p.o.) je značajno i dozno‐zavisno smanjio vremeprovedenounociceptivnomponašanjuudrugojfazitestasamaksimalnimefektomod75%. Atropin (2,5 i 5 mg/kg; i.p.) i metilikakonitin (1 i 6 mg/kg; i.p.) su značajnoinhibiralianalgetičkodejstvovortioksetina(15mg/kg;p.o.)nadozno‐zavisannačinudrugoj fazi testa. Maksimalna inhibicija iznosila je 92% i 100% za atropin imetillikakonitin,redom.

Prikazani rezultati ukazuju da je analgetičko dejstvo vortioksetina u modelutrigeminalnog bola u miševa posredovano, barem delimično, muskarinskim i α7‐nikotinskimholinergičkimreceptorima.

OvajradjefinansiranodstraneMinistarstvaprosvete,naukeitehnološkograzvoja

RepublikeSrbije(Projekatbr.175045).

675

THEINVOLVEMENTOFCHOLINERGICRECEPTORSINTHE

ANALGESICEFFECTOFVORTIOXETINE

MiljaVuković,AnaMicov,UrošPecikoza,MajaTomić,RadicaStepanović‐Petrović

DepartmentofPharmacology,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)

Vortioxetine is a novel antidepressant with multimodal activity. Unlike most

other antidepressants, it possesses procognitive properties and the enhancement ofcholinergic neurotransmission probably contributes to this effect. Antidepressantshavebeenused to treat variouspain conditions, including thoseof trigeminal origin.We have recently demonstrated that vortioxetine exerts the analgesic effect in theorofacialformalintestinmice(modeloftrigeminalpain).Toelucidatethemechanismofvortioxetine’sanalgesiceffectinthispainmodel,theaimofourstudywastoexaminetheinvolvementofcholinergic(muscarinicandα7‐nicotinic)receptorsinvortioxetine‐inducedantinociception,giventheirimportantroleinpainmodulation.

Trigeminal nociception was induced by a subcutaneous injection of formalinsolution(2%,20µL)intotheperinasalareaofmice.Timespentinnociceptivebehavior(facerubbing) inthe firstphase(0‐9minpost‐formalin)andsecondphase(9‐45minpost‐formalin) of the test was measured. Firstly, we confirmed the efficacy ofvortioxetine in this test, and then the influence of atropine (nonselectivemuscarinicreceptorantagonist)andmethyllicaconitine(selectiveα7‐nicotinicreceptorantagonist)on the analgesic effect of a fixed, effective dose of vortioxetine was monitored.Vortioxetine was administered perorally (p.o.), and antagonists were appliedintraperitoneally(i.p.),60minbeforeformalininjection.

Vortioxetine(5‐20mg/kg;p.o.)significantlyanddose‐dependentlyreducedtimespent innociceptivebehavior in thesecondphaseof the testwithmaximumeffectof75%. In antagonist study, atropine (2.5 and 5mg/kg; i.p.) andmethyllycaconitine (1and6mg/kg;i.p.)significantlydecreasedtheanalgesiceffectofvortioxetine(15mg/kg,p.o.) inadose‐relatedmanner in thesecondphaseof the test.Thevaluesofmaximalinhibition were 92% and 100% for atropine and methyllycaconitine, respectively.Presentedresultssuggest thattheanalgesiceffectofvortioxetine inatrigeminalpainmodelismediated,atleastinpart,bymuscarinicandα7‐nicotiniccholinergicreceptors.

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

TechnologicalDevelopment(Grant175045).

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Arh.farm 2018;68: 676-677 FFT-P9

VORTIOKSETINUBLAŽAVATRIGEMINALNIBOL:UČEŠĆE

ADRENERGIČKIHRECEPTORA

AnaMicov,MarijaTodorovićGerasimoski,UrošPecikoza,MajaTomić,RadicaStepanović‐Petrović

Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)

Utrigeminalnojregijise javljajunekaodnajčešćihionesposobljavajućihbolnihstanja. U lečenju bolova trigeminalnog porekla neretko se poseže za alternativnimanalgeticima,kaoštosuantidepresivi.Vortioksetin jeantidepresivnovijegdatumasajedinstvenim farmakološkim profilom. Prethodno smo pokazali da vortioksetinostvaruje efikasnost u orofacijalnom formalinskom testu u miševa (modeltrigeminalnog bola), ali mehanizam njegovog analgetičkog dejstva nije razjašnjen.Poznatojedavortioksetinpovećavanivoekstracelularnognoradrenalinauodređenimregijamamozga,uključujućiionekojesuodznačajazatrigeminalnunocicepciju.Stogaje cilj našeg rada bio da ispitamo učešće adrenergičkih (α2 i β1) receptora uanalgetičkomdejstvuvortioksetinaumodelutrigeminalnogbola.

Trigeminalnanocicepcijajeizazivanasupkutanominjekcijomrastvoraformalina(2%,20μl)uperinazalnuregijumiševa.Merniparametarjeukupnovremeprovedenoubolnomponašanju(trljanjenjuške)tokomprve(0‐9minnakonformalina)idruge(9‐45 min nakon formalina) faze testa. Najpre smo potvrdili efikasnost vortioksetina uovom testu, a potom smo pratili uticaj johimbina (selektivnog antagoniste α2–adrenergičkih receptora) i metoprolola (selektivnog antagoniste β1–adrenergičkihreceptora)naanalgetičkodejstvo fiksne,efektivnedozevortioksetina.Vortioksetin jeprimenjivanperoralno(p.o.),aantagonistiintraperitonealno(i.p.)60minprerastvoraformalina.

Vortioksetin (5‐20mg/kg; p.o.) je statistički značajno i dozno‐zavisno smanjiovremeprovedenoubolnomponašanjuudrugojfazitesta.Analgetičkiefekatizraženuprocentima iznosio je35‐75%.Adrenergičkiantagonisti, johimbin(1 i2mg/kg; i.p.) imetoprolol(1i2mg/kg;i.p.),značajnosuidozno‐zavisnoinhibiralianalgetičkodejstvovortioksetina (15mg/kg; p.o.) u drugoj fazi testa.Maksimalna inhibicija analgetičkogdejstva vortioksetina iznosila je 79% za johimbin i 90% za metoprolol. Rezultatiukazuju da su u analgetičko dejstvo vortioksetina u modelu trigeminalnog bolauključeni,baremdelimično,α2‐iβ1‐adrenergičkireceptori.

OvajradjefinansiranodstraneMinistarstvaprosvete,naukeitehnološkograzvoja

RepublikeSrbije(Projekatbr.175045).

677

VORTIOXETINEALLEVIATESTRIGEMINALPAIN:THEINVOLVEMENTOFADRENERGICRECEPTORS

AnaMicov,MarijaTodorovićGerasimoski,UrošPecikoza,

MajaTomić,RadicaStepanović‐Petrović

DepartmentofPharmacology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Some of the most prevalent and debilitating pain conditions arise from the

trigeminal region. In the treatment of trigeminal pain alternative analgesics, such asantidepressants, are commonly used. Vortioxetine is a novel antidepressant with aunique pharmacological profile.Wehave recently shown that vortioxetine exerts theanalgesiceffectintheorofacialformalintestinmice(modeloftrigeminalpain),butthemechanismof itsantinociception isnotelucidated.Vortioxetine increases the levelofextracellular noradrenaline in certain brain regions, including those relevant fortrigeminalnociception.Therefore,theaimofourstudywastoexaminetheinvolvementofadrenergic(α2iβ1)receptorsinvortioxetine‐inducedanalgesiainatrigeminalpainmodel.

Trigeminal nociception was induced by a subcutaneous injection of formalin(2%,20µL) into theperinasalareaofmice.Timespent innociceptivebehavior (facerubbing) inthefirstphase(0‐9minpost‐formalin)andsecondphase(9‐45minpost‐formalin)ofthetestwasmeasured.Firstly,weconfirmedtheefficacyofvortioxetineinthis test, then the influence of yohimbine (selectiveα2–adrenoceptor antagonist) andmetoprolol (selective β1‐adrenoceptor antagonist) on the analgesic effect of a fixed,effective dose of vortioxetinewasmonitored. Vortioxetinewas administered by oral(p.o.) gavage, and antagonists were applied intraperitoneally (i.p.) 60 min beforeformalininjection.

Vortioxetine(5‐20mg/kg;p.o.)significantlyanddose‐dependentlyreducedtimespent innociceptivebehavior in thesecondphaseof the test.Theanalgesiceffectsofvortioxetine ranged from 35% to 75%. Adrenergic antagonists, yohimbine (1 and 2mg/kg;i.p.)andmetoprolol(1and2mg/kg;i.p.)significantlydecreasedtheanalgesiceffectofvortioxetine(15mg/kg,p.o.)inadose‐relatedmannerinthesecondphaseofthe test. Themaximum inhibition of the analgesic effect of vortioxetinewas79% foryohimbineand90%formetoprolol.Theresultsofthepresentstudyshowthatα2‐andβ1‐adrenergic receptors are involved, at least partially, in the analgesic effect ofvortioxetineinatrigeminalpainmodel.

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

TechnologicalDevelopment(Grant175045).

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Arh.farm 2018;68: 678-679 FFT-P10

LOKALNIPERIFERNIANALGETIČKIEFEKATESLIKARBAZEPIN

ACETATAUMODELUTRIGEMINALNOGBOLA:ULOGASEROTONINSKIH5‐HT1B/1DIKANABINOIDNIHCB1/CB2RECEPTORA

UrošPecikoza,MajaTomić,AnaMicov,RadicaStepanović‐Petrović

Katedrazafarmakologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Eslikarbazepinacetat(ESL) jenovpredstavnikdibenzazepinskihantiepileptika,

kojijepokazaoefikasnostuublažavanjutrigeminalnogbolauprekliničkimikliničkimstudijama. Međutim, tačno mesto i mehanizam analgetičkog dejstva ESL nisu upotpunosti razjašnjeni. Prethodno smo pokazali da se analgetički efekat peroralnoprimenjenogESL,umodelutrigeminalnogbola,možeinhibiratisistemskomprimenomantagonista serotoninskih5‐HT1B/1D i kanabinoidnihCB1/CB2 receptora.Uovomradusmo hteli da proširimo postojeće rezultate i ispitamo efikasnost ESL u modelutrigeminalnog bola (orofacijalni formalinski test) nakon lokalne periferne primene, iuloguperifernihserotoninskih5‐HT1B/1DikanabinoidnihCB1/CB2receptoraunastankulokalnogefektaESL.

Trigeminalni bol je izazivan supkutanom injekcijom rastvora formalina uperinazalnu regijumiševa. Nakon injekcije formalinamerili smo vreme provedeno unociceptivnomponašanjuuprvoj i drugoj fazi testa. ESL je primenjivan supkutanouperinazalnuregiju,20minpreformalina.Dodatno,ispitalismoefektenajvećetestiranedozeESLnakonkontralateralneprimene(uodnosunastranuformalinskeinjekcije),ucilju potvrde lokalne prirode efekta. Ulogu perifernih receptora smo ispitali tako štosmopratiliuticajantagonistaserotoninskih5‐HT1B/1D(GR127935),kanabinoidnihCB1(AM251) ili CB2 receptora (AM630) na analgetički efekat fiksne, efikasne doze ESL(antagonistisuprimenjenisupkutano,zajednosaESL).

Lokalna primena ESL (7,5‐30 µg/mišu)je proizvela značajan, dozno‐zavisananalgetički efekat od 35‐60% u drugoj fazi testa. Kontralateralna primena najvećetestirane doze ESL (30 µg/mišu) nije imala značajan efekat u orofacijalnomformalinskomtestu.AntagonistiGR127935(2,5i5µg/mišu),AM251(3i7,5µg/mišu)iAM630(1 i2,5µg/mišu)doveli sudoznačajne,dozno‐zavisne inhibicijeanalgetičkogefekta ESL (15 µg/mišu). Stepeni inhibicije analgetičkog efekta ESL za veće dozeantagonistasubili69%zaGR127935,99%zaAM251i89%zaAM630.ESLispoljavaanalgetičkiefekatnakonlokalneperiferneprimeneumodelutrigeminalnogbolakojijeposredovan,bardelom,perifernim serotoninskim5‐HT1B/1D i kanabinoidnimCB1/CB2receptorima.

OvajradjefinansiranodstraneMinistarstvaprosvete,naukeitehnološkograzvoja

RepublikeSrbije(Projekatbr.175045).

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THELOCALPERIPHERALANALGESICEFFECTOFESLICARBAZEPINEACETATEINATRIGEMINALPAINMODEL:THEROLEOFSEROTONIN

5‐HT1B/1DANDCANNABINOIDCB1/CB2RECEPTORS

UrošPecikoza,MajaTomić,AnaMicov,RadicaStepanović‐Petrović

DepartmentofPharmacology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Eslicarbazepineacetate(ESL)isanoveldibenzazepineantiepilepticdrug,which

has demonstrated efficacy against trigeminal pain in preclinical and clinical studies.However, the exact site andmechanism of ESL’s analgesic action are not completelyunderstood.We have previously demonstrated that the analgesic effects of perorallyadministeredESL, inatrigeminalpainmodel,canbeinhibitedbysystemicapplicationofserotonin5‐HT1B/1DandcannabinoidCB1/CB2receptorantagonists.Inthisstudy,weaimed to expand the existing data and examine the efficacy of locally peripherallyadministeredESLinatrigeminalpainmodel(theorofacialformalintest)andtheroleofperipheral serotonin 5‐HT1B/1D and cannabinoid CB1/CB2receptors in mediating thelocaleffectsofESL.

Trigeminalpainwasinducedwithasubcutaneousinjectionofformalinsolutioninto the perinasal region ofmice. After the formalin injectionwemeasured the timespent in nociceptive behavior in the first and second phase of the test. ESL wasadministered subcutaneously into the perinasal region, 20 min before the formalininjection. Additionally, we examined the effects of the highest tested ESL dose aftercontralateral application (with respect to the side of formalin injection) in order toconfirmthelocalnatureofitseffect.Theroleofperipheralreceptorswasexaminedbyevaluating the influence of a serotonin 5‐HT1B/1D (GR127935), cannabinoid CB1(AM251)orCB2receptorantagonist(AM630)ontheanalgesiceffectofafixed,effectivedoseofESL(theantagonistsweresubcutaneouslycoadministeredwithESL).

Local application of ESL (7.5‐30 µg/mouse) produced a significant and dose‐dependent analgesic effect of 35‐60% in the second phase of the test. ContralateralapplicationofthehighesttesteddoseofESL(30µg/mouse)hadnosignificanteffectintheorofacial formalin test.The antagonistsGR127935 (2.5 and5µg/mouse),AM251(3 and 7.5 µg/mouse) and AM630 (1 and 2.5 µg/mouse) produced a significant anddose‐dependent inhibitionof theanalgesiceffectofESL (15µg/mouse).The levelsofinhibitionofESL’sanalgesiceffectachievedwiththehigherantagonistdoseswere69%forGR127935,99%forAM251and89%forAM630.ESLproducesananalgesiceffectinatrigeminalpainmodelafter localperipheralapplicationthat ismediated, inpart,byperipheralserotonin5‐HT1B/1DandcannabinoidCB1/CB2receptors.

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

TechnologicalDevelopment(grant175045).