<p>Cilj istraživanja bio je da se utvrdi u kojoj meri dodavanje lanenog ulja u peletirane krmne<br />smje&scaron;e i ishrana tovnog &scaron;arana tako obogaćenom hranom utječe na količinu masti i<br />kompoziciju masnih kiselina u mesu ribe. Krmne smje&scaron;e u svim grupama istraživanja su bile<br />istog sirovinskog sastava, osim dodatka lanenog ulja koje se menjalo (2,0; 3,0; 4,0; 5,0% i 6%<br />u drugom ogledu) i masti (Magnapac) koja je smanjivana za istu postotnu vrednost dodatkom<br />lanenog ulja. Većim delom istraživanog razdoblja fizičko-hemijski parametri vode su u svim<br />ekspermentalnim ribnjacima varirali u pogodnim vrednostima za uzgoj toplovodnih riba. Udio<br />C18:1 cis-9 statistički je značajno najniži u kontrolnoj grupi i iznosi 35,43%. Povećanjem<br />vrednosti lanenog ulja povećava se i udio C18:1 cis-9. Statistički najvi&scaron;a vrednost C20:0 je kod<br />uzoraka hranjenih s dodatkom 5% lanenog ulja. Najniža vrednost C20:3 &omega;-3 je u kontrolnoj<br />grupi i iznosi 0,22% a značajno najvi&scaron;a u grupi koja se hrani s dodatkom 5% lanenog ulja. S<br />obzirom na dodatak lanenog ulja u hrani, nema značajnih razlika kod ukupnih zasićenih,<br />mononezasićenih, polinezasićenih i omega-6 masnih kiselina. Najveći udio &omega;-3 masnih<br />kiselina utvrđen je u uzorcima &scaron;arana kojima je u hranu dodano 5% lanenog ulja (5,41%) U<br />drugom ogledu utvrđena je opravdanost upotrebe lanenog ulja u hrani za ribe u odnosu na<br />efekte koji su dobijeni u mesu. Omjer &omega;-3/&omega;-6 masnih kiselina značajno se povećao u grupama<br />kojima je u hranu dodat veći dio lanenog ulja (0,21 u kontrolnoj grupi do 0,30% u grupi s<br />dodatkom 5% lanenog ulja). Vrednostiholesterola se nisu značajno menjale dodavanjem<br />lanenog ulja u ishrani &scaron;arana.</p> / <p>The aim of this study was to determine to what extent adding flaxseed oil to pellet diet and<br />fattening carp so enriched food affects the amount of fat and the composition of fatty acids in<br />fish meat. Feed mixtures in all the studied groups were the same composition, except for the<br />addition of linseed oil to be changed (2.0; 3.0; 4.0; 5.0% and 6%) and fat (Magnapac), which<br />was reduced by the same percentage value addition linseed oil. During substantial period of<br />research physico-chemical parameters of water in all experimental ponds ranged in values<br />suitable for the cultivation of warm-water fish. Share C18:1 cis-9 was statistically significantly<br />lowest in the control group and amounted 35.43%. By increasing the value of flaxseed oil<br />increases the proportion of C18:1 cis-9. Statistical highest value of C20:0 in the samples fed<br />with the addition of 5% linseed oil. The lowest value of C20:3 &omega;-3 in the control group is<br />0.22% and significantly highest in the group that feeds supplemented with 5% linseed oil. Due<br />to the addition of linseed oil in the food, there is no significant difference in total saturated,<br />monounsaturated, polyunsaturated omega-6 fatty acids. The largest proportion of &omega;-3 fatty<br />acids found in samples of carp which was in food supplemented with 5% linseed oil (5.41%).<br />The experimental results of the second experiment show the usefulleness of using of linseed oil<br />in fish food regearging the meat quality. The ratio &omega;-3/&omega;-6 fatty acid increased significantly in<br />the group that is added to food in a higher proportion of linseed oil (0.21 in the control group<br />to 0.30% in the group with addition of 5% linseed oil). The value of cholesterol was not<br />significantly changed by adding linseed oil to the diet of carp.<br />Accepted on Senate on:<br />AS</p>

<p>Nespu&scaron;teni testis predstavlja odsustvo testisa u skrotumu sa jedne ili obe strane. Faktori rizika za pojavu nespu&scaron;tenog testisa obuhvataju genetsku predispoziciju, prevremeno rođenje, nisku porođajnu masu i prenatalnu izloženost endokrinim disruptorima ili duvanskom dimu. Endokrini disruptori se defini&scaron;u kao egzogene supstance koje imaju uticaj na homeostazu organizma i proizvodnju reproduktivnih hormona. U ovoj grupi nalaze se organofosforni pesticidi koji se &scaron;iroko upotrebljavaju u poljoprivredi. Većina organofosfornih pesticida ima antiandrogeni uticaj i uz činjenicu da živimo u pretežno agrarnoj sredini predmet su na&scaron;eg interesovanja. Cilj istraživanja je da se utvrdi razlika u izloženosti organofosfornim pesticidima kori&scaron;ćenjem upitnika kreiranog po modelu standardizovanog Evropskog upitnika QLK 4-1999-01422 kod osoba koje su rodile zdravu mu&scaron;ku decu i osoba koje su rodile decu sa nespu&scaron;tenim testisom. Pored toga, cilj istraživanja je i da se odredi i uporedi vrednost metabolita organofosfornih pesticida (dimetilfosfat, dimetilditiofosfat, dietilfosfat, dietiltiofosfat i dietilditiofosfat) u urinu majki koje su rodile mu&scaron;ku decu sa nespu&scaron;tenim testisima i majki koje su rodile zdravu mu&scaron;ku decu. Metodologija: Rad je radomizovano, prospektivno, kliničko istraživanje sprovedeno na Klinici za ginekologiju i aku&scaron;erstvo Kliničkog centra Vojvodine i Katedri za farmakologiju i toksikologiju Medicinskog fakulteta, Univerziteta u Novom Sadu. U kliničko istraživanje uključeno je 50 porodilja koje su rodile mu&scaron;ku decu sa nespu&scaron;tenim testisima (eksperimentalna grupa) i 53 porodilje koje su rodile zdravu mu&scaron;ku decu (kontrolna grupa) u periodu od oktobra 2012. godine do aprila 2018. godine. Tokom boravka u porodili&scaron;tu ispitanice su popunjavale upitnik o navikama nakon čega im je uzet uzorak urina radi analiziranja nivoa metabolita OF pesticida. Uzorci urina su pripremljeni metodom koju su opisali Wu i saradnici 2010. godine, a potom analizirani na gasnom hromatografu masenom spektrofotometaru marke Agilent 7890A. Rezultati: Ispitivane grupe se ne razlikuju po starosti ispitanica (prosečna starost kontrolne grupe 29,41 &plusmn; 5,58 godina, a eksperimentalne 30,54 &plusmn; 4,87 godina). U obe grupe prosečno je ispitanicama ovo bila druga trudnoća. Ispitanice se nisu razlikovale ni po načinu porođaja. Prosečna gestacijska nedelja trudnoće na porođaju iznosila je 39,45 &plusmn; 1,38 nedelja za kontrolnu grupu i 39,20 &plusmn; 1,38 nedelja za eksperimentalnu grupu, a porođajna masa novorođenčeta 3527,30 &plusmn; 470,16 g u kontrolnoj grupi i 3404,37 &plusmn; 508,20 g u eksperimentalnoj grupi. Statistički značajna razlika postoji u odnosu na mesto stanovanja (50,9 % ispitanica kontrolne grupe i 77,6 % ispitanica eksperimentalne grupe žive u gradu), jedinicu stanovanja (67,9 % kontrolne i 45,7 % ispitanica eksperimentalne grupe žive u kući) i načinu začeća (6 % ispitanica eksperimentalne i 1,9 % ispitanica kontrolne grupe prijavilo je IVF kao način začeća). Skoro polovina ispitanica obe grupe su pu&scaron;ači, a njih 32,7 % kontrolne grupe i 38,8 % eksperimentalne pu&scaron;ile su i tokom trudnoće. Izloženost pesticidima prijavilo je 50,9 % ispitanica kontrolne i 44 % ispitanica eksperimentalne grupe, a profesionalnu izloženost prijavilo je 3 ispitanice kontrolne i 2 ispitanice eksperimentalne grupe. Ispitanice se ne razlikuju ni po poreklu voća i povrća koje konzumiraju, kao ni po vrsti voća koje su konzumirale tokom trudnoće. Prosečne izmerene vrednosti DMF u kontrolnoj grupi iznose 5,604 &plusmn; 6,103 ug/L, a u eksperimentalnoj 4,815 &plusmn; 6,729 ug/L. Izmerene vrednosti DEF u kontrolnoj grupi su 0,408 &plusmn; 0,447 ug/L, a u eksperimentalnoj 0,461 &plusmn; 0,593 ug/L. Nivo DMDTF u kontrolnoj grupi bio je 0,431 &plusmn; 0,508 ug/L, a u eksperimentalnoj 0,547 &plusmn; 0570 ug/L, a DETF 0,403 &plusmn; 0,606 ug/L u kontrolnoj i 0,529 &plusmn; 0,725 ug/L u eksperimentalnoj grupi. Ni jedan metabolit ne pokazuje statistički značajnu razliku u ispitivanim grupama. Slične vrednosti dobijene su i za vrednosti korigovane za nivo kreatinina. Univarijantna regresiona analiza pokazala je da ispitanice koje žive u gradu imaju 3,3 puta veće &scaron;anse da rode dete sa nespu&scaron;tenim testisom, a one koje žive u stanu imaju 2,5 puta veće &scaron;anse za isti ishod. Statistički značajna razlika primećena je u nivou DEDTF u zavisnosti od starosti ispitanica i jedinici stanovanja. Vi&scaron;e vrednosti DETF dobijene su kod ispitanica koje su bile na hormonskoj terapiji tokom trudnoće. Ispitanice koje su prijavile da su bile izložene pesticidima tokom trudnoće u urinu su imale statistički značajno vi&scaron;e vrednosti DMDTF u odnosu na ispitanice koje su se izjasnile da nisu bile izložene pesticidima. Slični rezultati za vrednost DEDTF dobijeni su kod ispitanica koje su se izjasnile da poseduju kućne ljubimce. Statistički vi&scaron;e vrednosti DEF i DETF korigovano za nivo kreatinina dobijene su kod ispitanica koje nisu konzumirale jabuke, a vi&scaron;e vrednosti DEF i DEDTF dobijene su kod ispitanica koje su konzumirale maline i kupine tokom trudnoće. Ostale grupe nisu pokazale statistički značajnu razliku među ispitivanim grupama. Zaključci: Izloženosti trudnica OF pesticidima nije značajno veća u grupi majki koje su rodile decu sa nespu&scaron;tenim testisom u odnosu na izloženost OF pesticidima kod majki zdrave mu&scaron;ke dece. Vrednosti metabolita OF pesticida (dimetilfosfat, dimetilditiofosfat, dietilfosfat, dietiltiofosfat, dietilditiofosfat) u urinu majki koje su rodile mu&scaron;ku decu sa nespu&scaron;tenim testisima nije vi&scaron;a u odnosu na vrednosti metabolita OF pesticida (dimetilfosfat, dimetilditiofosfat, dietilfosfat, dietiltiofosfat, dietilditiofosfat) izmerene u jutarnjem urinu majki koje su rodile zdravu mu&scaron;ku decu.</p> / <p>Undescended testis is the absence of testis in the scrotum on one or both sides. Risk factors for the occurrence of undescended testis include genetic predisposition, premature birth, low birth weight and prenatal exposure to endocrine disruptors or tobacco smoke. Endocrine disruptors are defined as exogenous substances that can affect homeostasis of the organism and the production of reproductive hormones. In this group are organophosphorus pesticides that are widely used in agriculture. Most of organophosphorus pesticides have anti-androgenic effect and with the fact that we live in a predominantly agricultural area, they are the focus of our interest. The aim of the research: The aim of this study is to determine the difference in exposure to organophosphorous pesticides using questionnaires created by standardized European model questionnaire QLK 4-1999-01422 in individuals who gave birth to a healthy male children and women who gave birth to children with undescended testis. In addition, the aim of this study is to determine and compare the value of metabolites of organophosphorus pesticides (dimethylphosphate, dimethyldithiophosphate, diethylphosphate, diethylthiophosphate and diethyldithiophosphate) in the urine of mothers who gave birth to male children with undescended testis and mothers who gave birth to healthy male children. Methodology: This work is randomized, prospective, clinical research conducted at the Clinic for gynaecology and obstetrics of the Clinical center of Vojvodina and the Department of Pharmacology and toxicology of the Faculty of Medicine, University of Novi Sad. This clinical research includes 50 new mothers that gave birth to male children with undescended testes (experimental group) and 53 new mothers that gave birth to healthy male children (control group) in the period from October 2012 to April 2018. During their stay at the maternity hospital the subjects were asked to fill out a questionnaire about habits and to give a urine sample for analyzing the level of metabolites of organophosphus pesticides. Urine samples were then prepared using the method described by Wu and associates 2010, and analyzed on gas chromatograph with a mass spectrophotometer Agilent 7890A brand. Results: Study groups do not differ according to the age of women (average age of control group is 29.41 &plusmn; 5.58 years, and experimental 30.54 &plusmn; 4.87 years). In both groups this was second pregnancy on average. The subjects did not distinguish either by the way of delivery. The average gestational weeks of pregnancy to childbirth was 39.45 &plusmn; 1.38 weeks for the control group and 39.20 &plusmn; 1.38 weeks for the experimental group, and birth weight of newborn was 3527.30 &plusmn; 470.16 g in control group and 3404.37 &plusmn; 508.20 g in the experimental group. There is no statistically significant difference in relation to the place of residence (50.9 % of the control group and 77.6 % of experimental live in the city), the living unit (67.9 % and 45.7 % of the control and experimental groups are living in the house) and the way of conception (6 % of experimental and 1.9 % of the control group reported IVF as a way of conception). Nearly half of both groups are smokers, and 32.7 % of women in the control group and 38.8 % in experimental smoked during pregnancy. Exposure to pesticides reported 50.9 % of mothers in control and 44 % of mothers in the experimental group. Professional exposure was reported by 3 control subjects and 2 subjects in experimental group. The subjects did not differ according to the origin of fruits and vegetables they were consuming, neither regarding the type of fruits they consumed during pregnancy. Average level of dimethylphosphate in control group was 5.604 &plusmn; 6.103 ug/L, and in experimental 4.815 &plusmn; 6.729 ug/l. Levels of diethylphosphate in control group were 0.408 &plusmn; 0.447 ug/L, and in experimental 0.461 &plusmn; 0.593 ug/l. DMDTP level in the control group was 0.431 &plusmn; 0.508 ug/L, and in experimental 0.547 &plusmn; 0570 ug/L, and the DETP was measured 0.403 &plusmn; 0.606 ug/L in control, and 0.725 &plusmn; 0.529 ug/L in the experimental group. These metabolites showed no statistically significant difference in the examined groups. Similar values are obtained for the adjusted values for creatinine level. Univariate regression analysis showed that the subjects who live in town are 3.3 times more likely to have child with undescended testis, and those who live in the apartment are 2.5 times more likely for the same outcome. Statistically significant difference was noticed in DEDTP level depending on the age of the subject and the living unit. Higher levels of DETP metabolites were detected in subjects that have been on hormonal therapy during pregnancy. The subjects who reported being exposed to pesticides during pregnancy had statistically significantly higher DMDTP values in relation to the subjects that were not exposed to pesticides. Similar results are obtained for the DEDTP level with higher levels in subjects owning pets. Statistically higher levels of DEP and DETP adjusted for creatinine were obtained in subjects that were not reporting eating apples, and higher levels of DEP and DEDTP were obtained in subjects that consumed raspberries and blackberries during pregnancy. Other groups showed no statistically significant difference between the study groups. Conclusion: Exposure of pregnant women to OP pesticides is not significantly greater in the group of mothers who gave birth to children with undescended testis in relation to exposure to OP pesticides in mothers of healthy male children. The level of OP metabolites (dimethylphosphate, dimethyldithiophosphate, diethylphosphate, diethylthiophosphate and diethyldithiophosphate) in the urine of mothers who gave birth to children with undescended testis is not higher in relation to the levels of OP metabolites (dimethylphosphate, dimethyldithiophosphate, diethylphosphate, diethylthiophosphate and diethyldithiophosphate) recorded in urine of mothers who gave birth to healthy male children.</p>

<p>Predmet ovog istaživanja&nbsp; bio je ispitivanje&nbsp;uticaja jona tri te&scaron;ka metala (Ni²⁺, Cu^2+&nbsp;i Cd²⁺)&nbsp;u dve toksične koncentracije u zemlji&scaron;tu na&nbsp;fiziolo&scaron;ke i biohemijske karakteristike&nbsp;<br />odabranih klonova topola, M1, B229 i Pe 19/66.&nbsp;Ispitan je i potencijal odabranih klonova topola&nbsp;da vr&scaron;e fitoekstrakciju-akumulaciju te&scaron;kih&nbsp;metala iz zemlji&scaron;ta u svoje nadzemne delove &scaron;to&nbsp;dovodi&nbsp; do dugoročnog uklanjanja ovih&nbsp;perzistentnih polutanata iz životne sredine.&nbsp;Takođe, ispitan je uticaj te&scaron;kih metala na&nbsp;antioksidantni potencijal, sposobnost&nbsp;<br />neutalizacije slobodnih radikala, aktivnosti&nbsp;antioksidantih enzima kao i&nbsp; na sadržaj&nbsp;slobodnih i konjugovanih poliamina (Put, Spm,&nbsp;Spd),&nbsp; određenih HPLC analizom,&nbsp; i sadržaj&nbsp;biljnih hormona poput indol-3-sirćetne kiseline&nbsp;i&nbsp; abscisinske &nbsp;kiseline,&nbsp; određenih GC/MS&nbsp;analizom, u listovima i korenovima klonova topola.</p><p>&nbsp;</p> / <p>The aim of this study was to estimate and compare phytoextraction capacities of three&nbsp;poplar clones (M1, B229 and Pe 19/66) in soil. Furthermore, the goal was to assess &nbsp;different biological responses among the poplar clones during exposure to different concentration of three heavy metal ions (Ni²⁺, Cu²⁺ i Cd²⁺). In order to track changes in&nbsp; poplars&rsquo;mineral, physiological, biochemical and antioxidant status during the&nbsp; abiotic stress, quantification of physiological properties, free and conjugated polyamines, total phenolics&nbsp; as well as quantification of phytohormones (indol-3-acetic and abscisic acid) was done. Furthermore, assessment of antioxidant potential by tracking radical scavenger capacities (RSC) against DPPH, ABTS, OH and NO radicals and by measuring enzymes activities (SOD, GSH-Px, GPx, GR) in vitro was performed in root and leaves of poplar clones.</p>

<p>Žučne kiseline (ŽK) su strukturno raznoliki molekuli, koji pored uloge koju ostvaruju putem žuči, deluju i kao signalni molekuli i ostvaruju kako endokrina tako i parakrina dejstva. Činjenica da je do sada u terapijske svrhe primenjivana samo ursodeoksiholna kiselina (UDK), posledica je brojnih ograničenja u mogućnosti primene ostalih prirodnih ŽK, i ističe potrebu za otkrivanjem novih sintetskih ŽK i liganda. Cilj istraživanja bio je ispitivanje sintetske 12-monoketoholne kiseline (MK) i prirodne UDK u modelu holestaze i aloksanom izazvanog dijabetesa. Ispitivanja su vr&scaron;ena na pacovima soja Wistar. Analizirana je telesna masa, glikemija, pokazatelji jetrene funkcije (AST; ALT, &gamma;-GT, ukupni i direktni bilirubin), a iz homogenate jetre određen je intenzitet lipidne peroksidacije i aktivnost antioksidativnih enzima (CAT, GSH-Px, GSH-R, GSH-ST). Isečci tkiva jetre su histolo&scaron;ki obrađeni i bojeni hematoksilin-eozin metodom i histohemijskim metodama (retikulin, Mallory, Periodic Acid Schiff- Alcian Blue (PAS/AB)). Imunohistohemijski je ispitana proliferacija hepatocita (Ki-67), markeri apoptoze (p53, Bcl-2, Bcl-X, Bax) i ekspresija nuklearnog farnesoid X receptora (FXR). Rezultati istraživanja pokazuju da ispitivane ŽK pomažu očuvanje telesne mase u holestazi i dijabetesu, i značajno snižavaju glikemiju kod dijabetičnih jedinki. Parametri jetrene funkcije u holestazi i dijabetesu su regulisani primenom MK i UDK. Obe ŽK u značajnoj meri smanjuju intenzitet lipidne peroksidacije i pojačavaju enzimsku antioksidativnu odbranu hepatocita u holestazi i dijabetesu. Ekspresija markera apoptoze nije značajno promenjena izazvanjem modela holestaze i dijabetesa, kao ni primenom ispitivanih ŽK. Nasuprot tome, izazivanje holestaze i dijabetesa značajno smanjuje proliferaciju hepatocita, dok primena MK i UDK poni&scaron;tava ovaj efekat i značajno povećava proliferaciju hepatocita. Hiperglikemija u aloksanskom dijabetesu nije dovela do pojačane ekspresije FXR. Izazivanje holestaze kod zdravih i dijabetičnih životinja dovelo je do porasta ekspresije FXR, koja je redukovana primenom MK i UDK. Na osnovu dobijenih rezultata može se zaključiti da sintetska 12-monoketoholna kiselina pokazuje slična hipoglikemijska, hepatoprotektivna i antioksidativna dejstva kao i prirodna ursodeoksiholna kiselina.</p> / <p>Bile acids (BAs) are structurally diverse molecules, which have theroles in the digestive system, which are exercised through the bile. Beside those, BAs act as a signaling molecules and achieve endocrine and paracrine effects. In addition to its own metabolism, bile acids modulate the metabolism of lipids and glucose. The fact that so far only ursodeoxycholic acid (UDC) is used for therapeutic purposes, speak clearly about of numerous limitations on the application of other natural BAs, and highlights the need to develop new synthetic Bas and ligands. The aim of this study was to investigate the influence of synthetic 12-monoketocholic acid (MC) and natural bila acid UDC in the model of cholestasis and alloxan-induced diabetes. Tests were performed on male Wistar rats. We analyzed the body mass, glucose, liver function tests (AST, ALT, &gamma;-GT, total and direct bilirubin). Using liver tissue homogenates we determined intensity of lipid peroxidation (by concentration of malondilaldehyde) and the activity of antioxidant enzymes (CAT, GSH-Px, GSH -R, GSH-ST). Liver tissue were histologically processed and stained with hematoxylin-eosin method and histochemical methods (reticulin, Mallory, Periodic Acid Schiff- Alcian Blue (PAS / AB)). Imunohistochemical examination included hepatocyte proliferation (Ki-67), markers of apoptosis (p53, Bcl-2, Bcl-X, Bax), and expression of the nuclear farnesoid X receptor (FXR). Results of the research show that MC prevented decrease in body mass during cholestasis and diabetes, and significantly reduced glycemia in diabetic animals. The liver function tests in cholestasis and diabetes are normalised by MC and UDC aplication. Both BAs significantly reduce lipid peroxidation and enhance enzymatic antioxidant defense of hepatocytes in cholestasis and diabetes. The expression of markers of apoptosis was not significantly changed in models of cholestasis and diabetes, as well as the application of the tested BAs. In contrast, in cholestasis and diabetes model, the proliferation of hepatocytes was significantly reduced, while the use of MC and UDC reversed this effect and significantly increased the proliferation of hepatocytes. Hyperglycemia in alloxan-induced diabetes did not lead to overexpression of FXR. Induction of cholestasis in healthy and diabetic animals resulted in an increase in the expression of FXR, which is reduced by using the MK and the UDC. Based on these results we can conclude that a synthetic 12-monoketocholic acid shows similar hypoglycemic, hepatoprotective and antioxidant effects as natural ursodeoxycholic acid.</p>

<p>U eksperimantalnom postupku disertacije mi&scaron;evi NMRI soja su tretirani infuzom biljke Aristolochia clematitis. Sasu&scaron;eni listovi, grane i plodovi biljke potopljeni su u ključalu vodu i ostavljeni 3-5 sati da stoje, a potom su profiltrirani kroz filter papir. Pravljen je rastvor biljke/vode od 10g/ 1000ml (1%), 20g/ 1000ml (2%) i 40g/ 1000ml (4%). Različite koncentracije infuza su date mi&scaron;evima da piju u neograničenoj količini u periodu od 7 nedelja. Tako su formirane tri ispitne grupe, prva koja je primala 1% infuz, druga 2% infuz i treća 4% infuz i kontrolna grupa koja je dobijala samo vodu da pije. U svakoj grupi je bilo 20 životinja. Tako je razvijen animalni model hronične toksičnosti. Na kraju eksperimenta je urađena patohistolo&scaron;ka analiza bubrega, makroskopski pregled organa i merenje diureze tokom trajanja eksperimenta. Urađena je kompletna analiza urina koja podrazumeva utvrđivanje: boje, izgleda, pH, specifične težine, proteina i sedimenta urina. Analize urina ponavljane su na svakih 7 dana u toku 7 nedelja istraživanja. Na kraju eksperimenta urađena je analiza biohemijskih parametara (glukoza, urea, kreatinin, mokraćna kiselina, ukupni bilirubin, direktni bilirubin, ukupni tj. totalni proteini, natrijum i kalijum) i analiza kompletne krvne slike. Utvrđeno je da je Aristolochia clematitis izrazito nefrotoksična biljka. Utvrđene su patohistolo&scaron;ke promene tubula i intersitcijuma NMRI mi&scaron;a, koje su bile najveće u ispitnoj grupi koja je primala najaču dozu. Ustanovljene&nbsp; patohistolo&scaron;ke promene su slične opisanim patohistolo&scaron;kim promenama tubulointersticijuma bolesnika obolelih od Balkanske endemske nefropatije. Nije ustanovljeno postojanja karcinoma gornjeg urotrakta. Makroskopskim pregledom prilikom obdukcije eksperimentalnih životinja nisu ustanovljene značajnije promene bubrega. Do&scaron;lo je prvo do izrazitog porasta diureze u prvoj, odnosno drugoj nedelji praćenja, kod druge i treće eksperimentalne grupe, da bi nakon 7 nedelja istaživanja diureza u svim ispitnim grupama bila manja od kontrolne grupe. Postoji porast ureje na kraju istraživanja, koji je dvostruko veći u trećoj eksperimentalnoj grupi u odnosu na kontrolnu. Postoji izrazit pad mokraćne kiseline na kraju istraživanja kod eksperimentalne grupe 3. Postoji izrazit pad granulocita u leukocitarnoj formuli u svim ispitnim grupama, a najveći je u trećoj ispitnoj grupi. Kako je do&scaron;lo do pada relativnih vrednosti granulocita, tako je do&scaron;lo do porasta relativnih vrednosti limfocita u prvoj i drugoj ispitnoj grupi. U trećoj ispitnoj grupi je pad granulocita praćen izrazito velikim povećanjem relativnog broja bazofilnih granulocita. Postoji značajan pad specifične težine urina na kraju istraživanja u drugoj i trećoj eksperimentalnoj grupi. Proteinurija je bila čest nalaz svim eksperimentalnim grupama, dok je bila odsutna ili samo u tragu u kontrolnoj grupi. Na kraju eksperimenta je utvrđen znatni porast broja kristala fosfata u eksperimentalnim grupama. Cilindri su se pojavljivali samo u nalazu urina u trećoj ispitnoj grupi. Najveći broj promena urina je utvrđen u trećoj eksperimentlanoj grupi.</p> / <p>In the experimental procedure of dissertation, NMRI strain mice were treated with infusion of plants Aristolochia clematitis. Dried leaves, branches and fruit plants are submerged in boiling water and left to stand for 3-5 hours, and then filtered through filter paper. It was made a solution of the plant / water of 10g / 1000ml (1%), 20g / 1000ml (2%) and 40g / 1000ml (4%). Different concentrations of infusions were given to mice to drink an unlimited amount for a period of 7 weeks. So we formed the three test groups, the first who received 1% infusion, the second received 2% infusion and third received 4% infusion and a control group that received only water to drink. In each group there were 20 animals. Thus, developed an animal model of chronic toxicity. At the end of the experiment was performed histopathological analysis of kidneys, macroscopic examination of organs and measuring urine output during the experiment. We performed a complete analysis of urine, which is the determination of: color, appearance, pH, specific gravity, protein and urine sediment. Urinalysis were repeated every 7 days during the 7 weeks of the study. At the end of the experiment were analyzed for biochemical parameters (glucose, urea, creatinine, uric acid, total bilirubin, direct bilirubin, total proteins, sodium and potassium) and analysis of the complete blood count. It has been found that Aristolochia clematitis is extremely nephrotoxic plant. Identified histopathological changes of tubules and interstitium of NMRI mouse, which were the biggest in the test group receiving biggest dose. Established histopathological changes are similar to those described by pathological changes of tubulointerstitial injury of patients with Balkan endemic nephropathy. Not established the existence of cancer of the upper urinary tract. Macroscopic examination at autopsy of experimental animals, did not determine significant changes in the kidneys. There is first an enormous increase in diuresis in the first and second week of follow-up, in the second and third experimental groups retrospectively, that after 7 weeks of research, diuresis in all test groups was lower than the control group. There is an increase of urea at the end of the research, which is twice higher in the third experimental group compared to the control. There is a marked decrease in uric acid at the end of the research in the experimental group 3. There is a marked decrease in granulocytes in the leukocyte formula in all test groups, and the highest in the third test group. As the decline in the relative values of granulocytes, so there has been a rise in the relative values of lymphocite in the first and second test group. In the third test group, granulocyte drop was accompanied by a extremely large increase in the relative number of basophils. There is a significant drop in specific gravity of urine at the end of the research in the second and third experimental group. Proteinuria is a common finding to all experimental groups, while it was absent or only in traces in the control group. At the end of the experiment was determined to increase significantly the number of phosphate crystals in the experimental groups. The cylinders have appeared only in the urine in the third test group. The greatest number of changes in the urine is determined in the third experimental group.</p>

<p>Mnogi lekovi registrovani za razne druge indikacije mogu da deluju selektivno na tumorske receptore, signalne puteve, metaboličke procese, bioenergetske faktore, enzime, proteine, gene koji reguli&scaron;u proliferaciju, apoptozu i neoangiogenezu tumora ne pogađajući ove procese kod zdravih ćelija. Uvođenje novih lekova je izrazito dug, složen i skup proces istraživanja. Kori&scaron;ćenjem principa otkrivanja antikancerskog efekta kod već registrovanih lekova za druge indikacije, direktno se utiče na skraćivanje vremena i tro&scaron;kova istraživanja. Eksperimentalno je ispitana efikasnost antitumorskog delovanja mebendazola, metformina, itrakonazola, diklofenaka, nitroglicerina i deoksiholne kiseline na fibrosarkom hrčka izazvan BHK21/C13 tumorskom ćelijskom linijom praćenjem veličine i histologije lečenih tumora. Eksperimentalno je ispitana mogućnost primene deoksiholne kiseline, nitroglicerina, kofeina i itrakonazola kao adjuvansa u kombinaciji sa pojedinim ispitivanim lekovima (metformin, itrakonazol, diklofenak) za lečenje fibrosarkoma hrčka. Kako je ispitivanje vr&scaron;eno na mladuncima imladim hrčkovima i kako su sarkomi najče&scaron;ći u dečijem uzrastu, definisanje potencijalne antikancerske uloge ispitivanih lekova se odnosi prvenstveno na njihovu primenu u pedijatriji. Pokazano je da metformin, kombinacije metformina sa kofeinom, metformina sa itrakonazolom i metformina sa nitroglicerinom deluju u pogledu svih ispitivanih parametara tumora antitumorski na fibrosarkom hrčka. Kofein, itrakonazol i nitroglicerin pojačavaju antitumorsko dejstvo metformina na fibrosarkom hrčka. Tokom svih eksperimenata realizovanih u okviru ove disertacije, pokazalo se da nije bilo delotvornog tretmana, koji ne sadrži metformin.</p> / <p>Many drugs registered for various other indications can act selectively to tumor receptors, signaling pathways, metabolic processes, bioenergetic factors, enzymes, proteins, genes that regulate proliferation, apoptosis, and neoangiogenesis of the tumor without affecting these processes in the healthy cells. The introduction of new drugs is a very long, complex and expensive process of research. Using the principle of detecting the anticancer effect in already registered drugs for other indications, directly affects the reduction of time and cost of research. The efficacy of mebendazole, metformin, itraconazole, diclofenac, nitroglycerin and deoxycholic acid antitumor activity on hamster fibrosarcinoma induced experimentally by the BHK21/C13 tumor cell line was tested by monitoring the size and histology of the treated tumors. The possibility of using deoxycholic acid, nitroglycerin, caffeine and itraconazole as an adjuvant in combination with investigated drugs (metformin, itraconazole, diclofenac) for the treatment of hamster fibrosarcoma has been experimentally tested. As the examination was carried out on young cubs and young hamsters and that sarcomas are the most common in childhood, defining the potential anti-cancer role of the investigated drugs relates primarily to their application in pediatrics. Metformin, combinations of metformin with caffeine, metformin with itraconazole and metformin with nitroglycerin have shown antitumor action on the hamster fibrosarcoma in terms of all tested tumor parameters. Caffeine, itraconazole and nitroglycerin increase the antitumor effect of metformin on the hamster fibrosarcoma. During all the experiments carried out within this dissertation, there has been no effective treatment, which does not contain metformin.</p>

<p>Gliklazid je jedan od najče&scaron;će kori&scaron;ćenih lekova u terapiji dijabetes melitusa tip 2. U poslednje vreme, utvrđeno je da gliklazid ispoljava i druge pozitivne farmakolo&scaron;ke efekte kao &scaron;to su imunomodulatorni i anti-koagulacioni efekti, ukazujući na njegovu potencijalnu primenu u terapiji dijabetes melitusa tip 1. Gliklazid se odlikuje varijabilnim stepenom apsorpcije nakon peroralne primene i iz tog razloga pretpostavlja se da bi tehnike njegove ciljane isporuke, kao &scaron;to je mikroinkapsulacija, mogle da dovedu do pobolj&scaron;anja njegove apsorpcije i njegove potencijalne primene u terapiji T1DM. Pokazano je da različite žučne kiseline, uključujući i holnu, imaju stabilizacione efekte u domenu primene mikrovezikula i kontrolisanog osobađanja lekova, te je moguće da bi njihov dodatak u mikrovezikularnu formulaciju gliklazida mogao dodatno da pobolj&scaron;a oslobađanje gliklazida, njegovu apsorpciju i antidijabetičke efekte. S tim u vezi, cilj ovog istraživanja je da se ispita hipoglikemijski efekat gliklazida primenjenog u obliku alginatnih mikrovezikula, sa ili bez dodatka holne kiseline na T1DM modelu pacova. Trideset &scaron;est pacova obolelih od T1DM indukovanog aloksanom i odgovarajuće zdrave kontrolne životinje su nasumično raspoređene u &scaron;est grupa (n=6) i tretirane jednokratnom dozom fiziolo&scaron;kog rastvora, suspenzijom gliklazida, gliklazidom u obliku alginatnih mikrovezikula, samo holnom kiselinom, i mikrovezikulama gliklazida sa ili baz dodatka holne kiseline. Uzorkovana je krv tokom 10 h nakon unete doze i merena je koncentracija glukoze u krvi I koncentracija gliklazida u serumu kori&scaron;ćenjem HPLC metode. Mikrovezikule gliklazida su ispoljile hipo-glikemijski efekat kod pacova obolelih od dijabetesa, uprkos njegovim smanjenim koncentracijama u serumu, dok je dodatak holne kiseline u mikrovezikularnu formulaciju smanjio hipoglikemijski efekat gliklazida. Ovo potvrđuje izostanak sinergističkog efekta između gliklazida i holne kiseline. Takođe, ni proces mikroinkapsulacije niti dodatak holne kiseline nisu doprineli pobolj&scaron;anju apsorpcije gliklazida, &scaron;to ukazuje na činjenicu da su njegovi hipoglikemijski efekti nezavisni od njegove apsorpcije i koncentracije u serumu. Stoga se može pretpostaviti da su hipoglikemijski efekti gliklazida pre pod uticajem crevno-metaboličke aktivacije nego ciljanog oslobađanja u digestivnom traktu sistemske apsorpcije. Mikrovezikule gliklazida ispoljavaju hipoglikemijski efekat kod pacova obolelih od T1DM nezavisno od insulina, te mogu imati potencijalnu primenu u terapiji T1DM. Ovaj rad su podržali: HORIZON 2020 MEDLEM projekat broj 690876; Projekat Sekretarijata naučnog i tehnolo&scaron;kog razvoja Vojvodine broj . 114-451-2072-/2016-02; Projekat Ministarstva obrazovanja, nauke i tehnolo&scaron;kog razvoja Republike Srbije broja 41012.</p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>mladen</o:Author> <o:Version>16.00</o:Version> </o:DocumentProperties> <o:OfficeDocumentSettings> <o:AllowPNG/> </o:OfficeDocumentSettings></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> 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<p>Prema podacima iz 2011 godine, u Srbiji je približno 630 000 ljudi (8,6%) obolelo od dijabetes melitus-a, a procenjuje se da će taj broj porasti na 730 000 (10,2%) do 2030 godine. Preko 90% obolelih ima tip 2 dijabetes melitus (T2DM). Prva linija medikamentne terapije predstavljaju bigvanidi čiji je najznačajniji predstavnik metformin. Prema literaturnim podacima, u oko 10-30% sluĉajeva, kontinuirana upotreba metformina ima za posledicu smanjenu intestinalnu apsorpciju vitamina B12. Tačan patofiziolo&scaron;ki mehanizam koji dovodi do metforminom indukovane malapsorpcije vitamina B12 nije u potpunosti ispitan i poznat i postoji nekoliko aktuelnih teorija s ciljem obja&scaron;njenja ovog kompleksnog problema. Cilj rada je bio utvrđivanje nivoa, dinamike, trenda i učestalosti promena vitamina B12, holotranskobalamina (B12 aktiv), homocisteina i folne kiseline tokom kontinuirane primene metformina tokom godinu dana. Studija praćenja je sprovedena u Centru za laboratorijsku medicinu a u saradnji sa Klinikom za endokrinologiju, dijabetes i bolesti metabolizma, Kliničkog centra Vojvodine. Ovom studijom je obuhvaćeno 50 ispitanika obolelih od T2DM a u momentu uvođenja metformina. Svim ispitanicima je određivana koncentracija vitamina B12, B12 aktiva, homocisteina i folne kiseline, u momentu uvođenja terapije kao i nakon 4, 8 i 12 meseci primene metformina. Za dvanaest meseci kontinuirane primene metformina, utvrđen je kontinuirani pad i redukcija vrednosti ukupnog vitamina B12 za 25.29 %, odnosno vrednosti B12 aktiva za 23.26 %. U toku ispitivanja, utvrđen je kontinuirani trend porasta vrednosti homocisteina u krvi, s statistički značajnim porastom vrednosti homocisteina nakon osam meseci primene metformina. Po&scaron;av&scaron;i od predpostavki da metformin istovremeno blokira apsorpciju vitamina B12 u gastrointestinalnom traktu kao i raspoloživost iz postojećih, tkivnih rezervi, zatečene količine ovog vitamina u ciljnim ćelijama se postepeno redukuju i tro&scaron;e, rezultujući krajnjem snižavanju nivoa metabolički aktivnih oblika kobalamina, te posledičnoj akumulaciji homocisteina kako u ćelijskom, tako i u vanćelijskom prostoru. Na osnovu dobijenih rezultata ispitivanja može se predložiti opservacija nivoa ukupnog vitamina B12 i homocisteina u krvi pre uvođenja metformina u terapiju tipa 2 dijabetes melitusa kao i dvanaest meseci nakon toga. Na osnovu nivoa jednogodi&scaron;njeg pada koncentracija ukupnog vitamina B12, porasta koncentracija homocisteina, kao i drugih kliničkih i laboratorijskih parametara, može se razmatrati opcija uvođenja supstitucione terapije vitaminom B12 ili dalja opservacija nivoa vitamin B12 u krvi i ćelijskom prostoru.</p> / <p>According to data from 2011, in Serbia, approximately 630.000 people (8.6%) were diagnosed with diabetes mellitus, and it is estimated that this number will increase to 730.000 (10.2%) by 2030. Over 90% are type 2 diabetes mellitus (T2DM) patients. The first line of medication therapy is metformin. According to the literature data, in about 10-30% of cases, continuous use of metformin causes impared intestinal absorption of vitamin B12. The exact pathophysiological mechanism leading to metformin induced malabsorption of vitamin B12 has not been fully known, and there are several current theories to explain this complex problem. The aim of this study was to determine the level, dynamics, trend and frequency of changes in blood levels of total vitamin B12, holotranscobalamin (B12 active), homocysteine and folic acid during continuous application of metformin, over a year. The study was carried out at the Center of Laboratory Medicine in cooperation with the Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Vojvodina. This study included 50 T2DM patients at the time of the introduction of metformin therapy. Levels of vitamin B12, holotranscobalamin, homocysteine and folic acid are determined before and after 4, 8 and 12 months of metformin administration, to all subjects. After a year of metformin use, the level of total vitamin B12 has been reduced by 25.29%, as well as holotranskobalamin by 23.26%. During the study, a continuous elevation of homocysteine levels was determined, with statistically significant increase in homocysteine values after eight months of metformin administration. Starting from the assumption that metformin blocks the absorption of vitamin B12 in the gastrointestinal tract as well as the availability of existing tissue reserves, the amount of this vitamin in the target cells is gradually reduced, resulting in an extremely low level of metabolically active forms of this vitamin and the consequent accumulation of homocysteine in intracellular and extracellular space. On the basis of the obtained test results, it may suggest observation of the level of total vitamin B12 and homocysteine prior to the introduction of metformin in T2DM therapy and after one year thereafter. Based on the level of one-year decline of total vitamin B12 and the increase of homocysteine concentrations, as well as other clinical and laboratory parameters, substitution therapy with vitamin B12 or further monitoring of laboratory parameters of vitamin B12 metabolism may be proposed.</p>

<p>Grupno-strukturna analiza naftnih kiselina izolovanih iz srednjih uljnih&nbsp;komercijalnih frakcija vojvođanske nafte &bdquo;Velebit&rdquo; rađena je analizom IR-,&nbsp;¹H- i&nbsp;¹³C NMR- i ESI-MS spektara niske rezolucije. Određeno je &scaron;est klasa&nbsp;karboksilnih kiselina op&scaron;te molekulske formule C_nH_2n-ZO₂. To su karboksilne&nbsp;kiseline u opsegu masa 240-466 sa 15-31 C atoma u molekulu koje su&nbsp;grupisane u pet cikloalkil Z-serija: monociklična- (C_nH_2n-2O₂, 14.72%),&nbsp;biciklična- (C_nH_2n-4O₂, 34.63%), triciklična- (C_nH_2n-6O₂, 25.03%), tetraciklična- (C_nH_2n-8O₂, 10.04%), pentaciklična klasa karboksilnih kiselina (C_nH_2n-10O₂, 4.99%) i jedna alkanska klasa kiselina sa alkil grupama otvorenog niza (C_nH_2nO₂, 10.57%).</p><p>Razdvajanjem na bazi različite kiselosti i njihove rastvorljivosti u vodi na&nbsp;određenim pH vrednostima u rasponu od pH 2-10 dobijeno je devet užih&nbsp;frakcija kiselina. Ekstrakcijom sa etrom u vodi nerastvornih kiselina u rasponu&nbsp;od po jedne pH jedinice dobijena je sledeća distribucija masa: 9.57% (pH 10),&nbsp;12.69% (pH 9), 5.91% (pH 8), 4.85% (pH 7), 2.44% (pH 6), 11.71% (pH 5),&nbsp;23.94% (pH 4), 16.76% (pH 3) i 10.12% (pH 2). Razdvajanjem kiselina na bazi&nbsp;njihove kiselosti oko 50% mase kiselina ekstrahovano je od pH 2-4, znači u&nbsp;grupi jačih kiselina. Masenom spektrometrijom niske rezolucije ESI-MS na&nbsp;pH 4 vidi se da su u sme&scaron;i kiselina skoncentrisane kiseline sa vi&scaron;e prstenova u&nbsp;alkilnom delu sa maksimumom na tricikličnim kiselinama (36.50%), dok su&nbsp;pojedinačno najzastupljenije tetraciklične strukture kiselina C₂₀H₃₂O₂(4.43%) i&nbsp;C₂₁H₃₄O₂(4.56%). Na pH 8 biciklične- i triciklične strukture su zastupljene&nbsp;ukupno sa 65.02% sa maksimalno zastupljenim kiselinama sa 20-26 C atoma&nbsp;u molekulu, a izdvajaju se C₂₂H₃₈O₂ (5.26%)&nbsp;biciklične- i C₂₄H₄₂O₂(7.01%)&nbsp;triciklične strukure, a od tetracikličnih struktura kiselina izdvaja se C₂₄H₄₀O_2&nbsp;(4.77%). Na pH 10 najzastupljenije izolovane kiseline su aciklične, odnosno&nbsp;masne kiseline zastupljene sa 25.28%, a najdominantnije su strukture&nbsp;C₂₁H₄₂O₂ (4.83%), dok su ostale klase kiselina ujednačene po svom masenom&nbsp;udelu u odnosu na sastav u ukupnoj polaznoj sme&scaron;i kiselina.&nbsp;Drugi deo rada obuvata derivatizaciju izolovanih prirodnih naftnih kiselina.&nbsp;Sintetizovani su funkcionalni kiseonični metil-, etil-, n-butil-,&nbsp; terc-butil- i&nbsp;benzil-derivati naftnih kiselina kao i funkcionalni azotni derivati: amidi i anilidi&nbsp;naftnih kiselina. Sinteze navedenih estara rađene su klasičnim postupcima i&nbsp;modifikovanom metodom esterifikacije u kiselo-katalizovanim uslovima&nbsp;upotrebom mikrotalasa kao ko-katalizatora, &scaron;to je imalo za cilj skraćenje&nbsp;reakciong vremena i pobolj&scaron;anje ekolo&scaron;kih sintetskih uslova.<br />Modifikacijom sinteze metilnaftenata MT-zagrevanjem 48 puta je skraćeno&nbsp;vreme trajanja sinteze, prinosi ni promenom reakcionih parametara (vreme,&nbsp;snaga MT) nisu bitno promenjeni. Strukturnom analizom ESI-MS spektra&nbsp;polaznih kiselina i metilnaftenata dobijenih metilovanjem naftnih kiselina&nbsp;utvrđeno je da je odnos klasa u dobroj podudarnosti. Prinos estara u ovoj&nbsp;sintezi je 95.47%. Esterifikacija naftnih kiselina etil alkoholom rađena je u&nbsp;uslovima kisele katalize uz konvencionalno zagrevanje (91.76%), a&nbsp;modifikacijom metode MT-zagrevanjem (150 W) reakciono vreme je skaćeno&nbsp;96 puta (92.19%). Esterifikacija naftnih kiselina n-butil alkoholom rađena je uz&nbsp;sumpornu kiselinu kao katalizator i uz konvencionalno zagrevanje (94.24%), a&nbsp;u uslovima MT-zagrevanja (150 W) 72 puta je skraćeno reakciono vreme&nbsp;(61.15%). Sinteza terc-butilnaftenata rađena je prevođenjem naftnih kiselina u&nbsp;hloride a zatim reakcijom sa terc-butil alkoholom nastaju terc-butilnaftenati&nbsp;(80.17%). Modifikovanom metodom klasične reakcije esterifikacije naftnih&nbsp;kiselina terc-butil alkoholom katalizovanom sumpornom kiselinom u uslovima&nbsp;MT-zagrevanja (150 W) ostvaren je prinos od 85.49% a vreme trajanja reakcije&nbsp;je 5 minuta. Sinteza benzilnaftenata rađena je prevođenjem naftnih kiselina u&nbsp;hloride a zatim reakcijom sa benzil alkoholom nastaju benzilnaftenati&nbsp;(84.43%), a modifikovanom metodom klasične kiselo-katalizovane&nbsp;esterifikacije naftnih kiselina benzil alkoholom u uslovima MT-zagrevanja&nbsp;(150 W) ostvaren je prinos od 85.49% uz reakciono vreme od 5 minuta.&nbsp;Sinteza amida naftnih kiselina rađena je iz hlorida reakcijom sa amonijakom.&nbsp;Prinos čistih amida je 65.74%, a reakcija amidacije sa amonijakom trajala je&nbsp;15 minuta. Strukturnom analizom ESI-MS spektra amida naftnih kiselina&nbsp;utvrđen je grupno-strukturni sastav amida. Među strukturama amida naftenskih&nbsp;kiselina takođe su dominantne biciklične- i triciklične strukture, kao i u sme&scaron;i&nbsp;slobodnih kiselina. Sinteza anilida naftnih kiselina rađena je iz hlorida reakcijom sa anilinom. Prinos čistih anilida je 96.48%, a reakcija amidacije anilinom trajala je 30 minuta. Strukturnom analizom ESI-MS spektra anilida naftnih kiselina utvrđen je grupno-strukturni sastav proizvoda, anilida. Među strukturama anilida naftenskih kiselina takođe su dominantne biciklične- i triciklične strukture kao i u sme&scaron;i slobodnih kiselina.</p><p>U trećem delu ovog rada ispitivana je biolo&scaron;ka aktivnost naftnih kiselina&nbsp;auksinskog i giberelinskog tipa, njihov uticaj na ožiljavanje reznica,&nbsp;ukorenjivanje bočnih grana i mikroizdanaka biljaka, na aktivnost biljnih&nbsp;hormona, kao i na usvajanje metalnih jona kod biljaka.&nbsp;</p><p>Aktivnost naftenskih kiselina utvrđena je pomoću tri in vitro&nbsp; biolo&scaron;ka testa.&nbsp;&bdquo;Koleoptil test&rdquo;, rađen je na dva supstrata, odnosno na semenu ozime p&scaron;enice&nbsp;novosadske sorte Partizankai jare p&scaron;enice takođe novosadske sorte Venera.&nbsp;Referentna aktivnost u testu rađena je sa -naftilsirćetnom 3-indolsirćetnom&nbsp;kiselinom. U oba testa ustanovljen je približno isti odnos aktivnosti rastvora&nbsp;naftenskih kiselina i aktivnosti standardnih biljnih hormona. &bdquo;Test inhibicije&nbsp;klijanja&rdquo; semena rađen je sa semenom crne slačice, Brasscia nigra. Najveći&nbsp;uticaj naftenskih kiselina na inhibiciju klijanja postignut je u rasponu&nbsp;koncentracija kiselina od 10^-7&nbsp;-10^-8&nbsp;mol/L (0.05-0.01 mg/L). Testovi za &scaron;est užih&nbsp;frakcija dobijenih iz sme&scaron;e ukupnih kiselina razdvajanjem na bazi različite&nbsp;rastvorljivosti pri različitim pH vrednostima pokazuju istu aktivnost kao&nbsp;3-indolsirćetna kiselina (0.5 mg/L), a da je frakcija izdvojena iz vodenog&nbsp;rastvora na pH 7 takođe aktivna ali u poređenju sa 3-indolsirćetnom kiselinom&nbsp;to je 10 puta niža aktivnost. Hormonska aktivnost giberelenskog tipa ispitivanih&nbsp;kalijumovih soli naftenskih kiselina utvrđena je &bdquo;Endosperm testom&rdquo;, u kojem je&nbsp;određivana aktivnost amilaze spektrofotometrijskim praćenjem povećanja&nbsp;koncentracije redukujućih &scaron;ećera u endospermu semena tretiranog ječma i&nbsp;poređena sa aktivno&scaron;ću rastvora giberelinske kiseline (GA3). Rezultati ovih&nbsp;testova pokazuju da delovanjem vodenih rastvora užih frakcija naftenskih&nbsp;kiselina u koncentraciji 1.0 mg/L (3.5 x 10^-6mol/L)frakcija izolovana pri pH 8&nbsp;ima aktivnost koja je približno u opsegu aktivnosti giberelina koncentracije&nbsp;10^-2-10^-3&nbsp;mg/L.&nbsp;</p><p>Natrijum-naftenati u koncentraciji od 10^-6&nbsp;<br />do 10^-8&nbsp;mol/L stimuli&scaron;u formiranje&nbsp;adventivnih korenova kod reznica suncokreta pa je broj korenova po biljci 40&nbsp;puta veći kod biljaka koje su bile potopljene u rastvor natrijum-naftenata u&nbsp;odnosu na one koje su bile potopljene u vodu, a sličan efekat utvrđen je i pri&nbsp;tretiranju bočnih grana suncokreta.&nbsp;</p><p>Ožiljavanje drvenastih biljaka rađeno je na reznicama bele topole (Populus&nbsp;alba) i reznicama američke crne topole (Populus deltoides). Uočen je jasan&nbsp;inhibitomi efekat na rast korenčića i izbojka u vodenom medijumu sa 10^-4&nbsp;mol/L&nbsp;naftenskih kiselina, dok je tretman od 24 časa doprineo većem broju korenčića&nbsp;na donjih 5 cm reznice, kao i ukupnog broja korenčića nego kod kontrole.&nbsp;</p><p>U testu ukorenjivanja mikroizdanaka kod hrizantema najveći broj korenova&nbsp;dobijen je nakon tretmana sa rastvorom koji sadrži 10 &micro;mol/L ukupnih naftenata&nbsp;i tretmanom sa 50 &micro;mol/Lfrakcijom kiselina izolovanom pri pH 7. Oba rezultata&nbsp;su na nivou aktivnosti 3-indolbuterne kiseline koncentracije 10 &micro;mol/L&scaron;to znači&nbsp;da u ovom slučaju frakcionacija nije neophodna.&nbsp;</p><p>Efekti natrijum-naftenata na ukorenjivanje praćeni su merenjem nivoa totalnih&nbsp;peroksidaza i amilaze, &nbsp;kao i sadržaja redukujućih &scaron;ećera i ukupnih proteina u&nbsp;bazalnim delovima reznica bagrema(Rozaszin-AC).&nbsp; Nakon 1; 3 i 6 dana&nbsp;reznice su uzete za biohemijske analize. U svakom slučaju, aktivnosti&nbsp;IAA-oksidaze i amilaze su se povećavale do trećeg dana, &nbsp;a zatim smanjuje.&nbsp;Efekat je bio jače izražen posle tročasovnog tretmana sa natrijum-naftenatima&nbsp;u poređenju sa &scaron;estočasovnim tretmanom i kontrolom. Sadržaj rastvornih&nbsp;proteina je bio povećan jedan dan posle tretmana, smanjen trećeg i ponovo povećan &scaron;estog dana, osim za &scaron;estočasovni tretman natrijum-naftenatima, kada je efekat bio sasvim suprotan.</p><p>Test uticaja naftnih kiselina na nivo kadmijuma u biljkama pokazuje fiziolo&scaron;ko delovanje naftnih kiselina na snižavanje nivoa te&scaron;kih metala u biljci, u ovom slučaju kadmijuma. Ispitivan je efekat niske koncentracije natrijum-naftenata (10^-7&nbsp;mol/L) na ukupan sadržaj Cd u pojedinim frakcijama interćelijskog prostora kao i unutar ćelija, kao i na neke fiziolo&scaron;ke i biohemijske parametre kod mladih biljaka soje koje su uzgajane u prisustvu kadmijum-hlorida koncentracije 1 mmol/L. Prisustvo naftenata smanjuje sadržaj ukupnog kadmijuma kako u korenu tako i u stablu i listovima u proseku za oko 40% i ublažava &scaron;tetne efekte kadmijuma na aktivnost nitrat-reduktaze kao i na sadržaje fotosintetskih pigmenata.</p><p>Tretman biljaka niskim koncentracijama natrijum-naftenata utiče na&nbsp;akumulaciju nekih esencijalnih elemenata kod mladih biljaka soje. Prisustvo&nbsp;naftenata (10^{-7 &nbsp;}mol/L) značajno povećava sadržaj Mn, Fe, Zn i Ni u korenu, ali&nbsp;u stabljici i listovima samo sadržaj Fe i Mn. U korenu, sadržaj Mn je četiri puta&nbsp;veći a sadržaji Fe, Zn i Ni su povećani 17%, 60% i 68%, respektivno.&nbsp;</p><p>Ispitivanja na celeru i mrkvi su potvrdila da uticaj naftenata na mineralnu&nbsp;ishranu zavisi od primenjenog elementa i da je način preuzimanja određenih&nbsp;jona različit, &scaron;to ima za posledicu ili povećanje ili smanjenje sadržaja pojedinih&nbsp;jona u nekim delovima biljaka. Mlade biljke celera i mrkve, gajene u hranljivom&nbsp;medijumu, tretirane su natrijumovim solima naftenskih kiselina (10^-7&nbsp;mol/L)&nbsp;folijarno ili prisustvom u hranljivom medijumu. Jedino je tretman putem&nbsp;prisustva naftenata u hranljivom medijumu smanjio svežu masu korena i&nbsp;nadzemnog dela oko 20% kod obe biljke.Oba tretmana uticala su na sadržaj&nbsp;Fe, Cu, Mn, Mg i Ca kod biljaka celera i Fe, Mn, Zn i Na kod biljaka mrkve.&nbsp;Kod biljaka celera do&scaron;lo je do smanjenja sadržaja navedenih nutrienata dok je&nbsp;u korenu biljaka mrkve do&scaron;lo do povećanja sadržaja Fe za 45%, Mn za 70% i&nbsp;Zn za 37%. Kod ovih biljaka prisustvo naftenata u hranljivom medijumu dovelo&nbsp;do smanjenja mase korenova i nadzemnih delova, &scaron;to je potpuno suprotno od&nbsp;rezultata dobijenih kod biljaka soje.&nbsp; Folijarnim tretmanom je značajno<br />povećana masa nadzemnog samo kod celera.</p> / <p>Group-structural analysis of naphthenic acids isolated from middle&nbsp;commercial fractions of Vojvodina oil &bdquo;Velebit&rdquo; was performed with the&nbsp;analysis of IR-,<br />¹H- and&nbsp;¹³C NMR- and ESI-MS low resolution spectrums.&nbsp;Six classes of carboxylic acids of the general molecular formula C_nH_2n-ZO_2&nbsp;were determined. These are carboxylic acids with mass range of 240-466&nbsp;with 15-31 C atoms in molecule which are grouped in five cycloalkyl&nbsp;<span style="font-size: 12px;">Z-series: monocyclic- (C_nH_2n-2O₂, 14.72%), bicyclic- (C_nH_2n-4O₂, 34.63%),&nbsp;</span><span style="font-size: 12px;">tricyclic- (C_nH_2n-6O₂, 25.03%), tetracyclic- (C_nH_2n-8O₂, &nbsp;10.04%), pentacyclic&nbsp;</span><span style="font-size: 12px;">class of carboxylic acids (C_nH_2n-10O₂, 4.99%) and one alyphatic class of&nbsp;</span><span style="font-size: 12px;">acids with open chain alkyl groups (C_nH_2nO₂, 10.57%).</span></p><p>By fractioning on the basis of different levels of acidity and their solubility in&nbsp;water with pH values ranging from pH 2-10 nine subfractions of acids were&nbsp;obtained. By extraction with ether in water undissolved acids in the range of&nbsp;one pH unit the following distribution of mass was performed: 9.57%&nbsp;(pH 10), 12.69% (pH 9), 5.91% (pH 8), 4.85% (pH 7), 2.44% (pH 6), 11.71%&nbsp;(pH 5), 23.94% (pH 4), 16.76% (pH 3) and 10.12% (pH 2). By fractioning&nbsp;acids on the basis of their acidity about 50% of acid &nbsp;mass was extracted at&nbsp;pH 2-4, i.e., in the group of stronger acids. Low resolution mass&nbsp;spectrometry ESI-MS shows that at pH 4 acids with more rings in the alkyl&nbsp;<br />section were concentrated in the mixture with maximum at tricyclic acids&nbsp;(36.50%), while individually tetracyclic acid structures C₂₀H₃₂O₂ (4.43%) and&nbsp;C₂₁H₃₄O_2&nbsp;(4.56%) were most prominent. At pH 8 bicyclic- and tricyclic&nbsp;structures are represented &nbsp;together by 65.02% with acids with 20-26 C&nbsp;atoms in molecule being represented the most, and C₂₂H₃₈O₂&nbsp; (5.26%)&nbsp;bicyclic- and C₂₄H₄₂O₂(7.01%) tricyclic structures stand &nbsp;out, while with&nbsp;tertacyclic acid structures C₂₄H₄₀O₂ (4.77%) stands out. At pH 10 most&nbsp;represented isolated acids are acyclic, i.e., fatty acids which are&nbsp;represented by 25.28%, with the most dominant C₂₁H₄₂O_2&nbsp;structures&nbsp;(4.83%), while the other classes &nbsp;of acids are well balanced in their mass&nbsp;share in relation to the composition of the overall initial acid mixture.</p><p>The second part of this work deals with derivatization of the isolated natural&nbsp;naphthenic acids. Functional oxygen methyl-, ethyl-, n-butyl-, tert-butyl and&nbsp;benzyl-derivatives of naphthenic acids as well as functional nitrogen&nbsp;derivatives: amides and anilides of naphthenic acids were synthesized. The&nbsp;syntheses of the above mentioned esters were performed by conventional&nbsp;methods and by a modified method of esterification in acid-catalyzed&nbsp;conditions using microwaves as a co-catalyst with the aim of shortening the&nbsp;reaction time and improving the ecological synthetic conditions.&nbsp;</p><p>By modification of methyl naphthenates synthesis using MT-heating the&nbsp;time period for synthesis is reduced 48 times and the yield does not&nbsp;significantly change even after the reaction parameters (time, MT power)&nbsp;have been altered. Using structural analysis of ESI-MS spectrum of initial&nbsp;carboxylic acids and the methyl naphthenates obtained through methylation&nbsp;of naphthenic acids it was establishedthat the class ratio shows great&nbsp;compatibility. The esters yield in this synthesis is 95.47%. The esterification&nbsp;of naphthenic acids with ethyl alcohol done under the conditions of acid&nbsp;catalysis with conventional heating (91.76%), and with the modified method&nbsp;MT-heating (150 W) the reaction time is reduced 96 times (92.19%). The&nbsp;esterification of naphthenic acids with n-butyl alcohol was performed using&nbsp;sulphuric acid as a catalyst with conventional heating (94.24%), and under&nbsp;MT-heating conditions (150 W) reaction time was 72 times&nbsp; shorter&nbsp;(61.15%). The synthesis of&nbsp; tert-butyl naphthenates was performed by&nbsp;conversion of naphthenic acids into chlorides, followed by the reaction with&nbsp;tert-butyl alcohol which resulted in tert-butyl naphthenates (80.17%). By the&nbsp;modified method of conventional reaction of esterification of naphthenic&nbsp;acids using tert-butyl alcohol catalysed with sulphuric acid in MT-heating&nbsp;conditions (150 W) the yield was 85.49% and reaction time was 5 minutes.&nbsp;The synthesis of benzyl naphthenates was performed by conversion of&nbsp;naphthenic acids into chlorides, followed by a reaction with benzyl alcohol&nbsp;which produces benzyl naphthenates (84.43%), whereas the modified&nbsp;method of conventional acid-catalysed esterification of naphthenic acids&nbsp;using benzyl alcohol under MT-heating (150 W) conditions the yield was&nbsp;85.49% with the reaction time of 5 minutes.&nbsp;</p><p>The synthesis of naphthenic acid amides was done from chlorides by&nbsp;reaction with ammonia. The yield of pure amides was 65.74%, and the&nbsp;reaction of amidation with ammonia lasted for 15 minutes. The structural&nbsp;analysis of ESI-MS spectrum of naphthenic acid amides determined the&nbsp;group-structural composition of amides. With the structures of amides of&nbsp;naphthenic acids bicyclic- and tricyclic structures are also dominant, as in&nbsp;the mixture of free acids. The synthesis of naphthenic acid anilides were&nbsp;performed from chloride by reacting with aniline. The yield of pure anilides&nbsp;<br />was 96.48%, and the reaction of amidatation lasted for 30 minutes. The&nbsp;structural analysis of ESI-MS spectrum of naphthenic acid anilides&nbsp;determined the group-structural composition of anilide products. With the&nbsp;structures of anilides of naphthenic &nbsp;acids bicyclic- and tricyclic structures&nbsp;are also dominant, as in the mixture of free acids.</p><p>The third part of this work tests the biological activity of naphthenic acids of&nbsp;auxine and gibberellinic type, their influence on the rooting of cuttings,&nbsp;lateral branches and microshoots of plants, on the activity of plant&nbsp;hormones as well as on the metal ions uptake by plants.&nbsp;</p><p>The activity of naphthenic acids was determined using three in vitro&nbsp;biological tests. &bdquo;Koleoptil test&rdquo;, was done on two substrates, namely the&nbsp;seed of winter wheat of the Partizankasort and the spring wheat of the&nbsp;Venerasort. The referential activity in the test was performed with&nbsp;&alpha;-naphthylacetic- and 3-indolacetic acid. Both tests showed approximately&nbsp;the same ratio of activity of naphthenic acid solutions and standard plant&nbsp;hormones. &bdquo;Germination Inhibition Test&rdquo; of the seed was performed using&nbsp;<br />Brasscia nigraseed. The greatest influence of naphthenic acids to&nbsp;germination inhibition was achieved in the acid concentration ranging from&nbsp;10^-7-10^-8&nbsp;mol/L (0.05-0.01 mg/L). The tests for six narrow fractions obtained&nbsp;from the overall mixture of acids through fractioning on the basis of different&nbsp;solubility at different pH values show the same activity as 3-indolacetic acid&nbsp;(0.5 mg/L), with the fraction isolated from the aqueous solution at pH 7 also&nbsp;active but in comparison to 3-indolacetic acid this activity was 10 times&nbsp;lower. Hormone activity of gibberellinic type of the potassium salts of&nbsp;naphthenic acids was determined using &ldquo;Endosperm Test&rdquo; where amylase&nbsp;<br />activity was determined by spectrophotometric measuring of the increase of&nbsp;the concentration of reducing sugars in endosperm in the treated barley&nbsp;seed which was then compared to the activity of the gibberellic acid solution&nbsp;(GA3).&nbsp; The results of these tests indicate that the activity of aqueous&nbsp;solutions of narrow fractions of naphthenic acids in the concentration of&nbsp;1.0 mg/L (3.5 x 10^-6&nbsp;mol/L)the fraction isolated &nbsp;at pH 8 has the activity&nbsp;which is approximately within the range of activities of gibberellin of the&nbsp;concentration of 10^-2-10^-3&nbsp;mg/L.&nbsp;</p><p>Sodium salts of naphthenic acids in concentrations of 10^-6&nbsp;do 10^-8&nbsp;mol/L&nbsp;stimulated formation of adventitious roots in&nbsp;<span style="font-size: 12px;">sunflower cuttings even by a&nbsp;</span><span style="font-size: 12px;">factor of 40 compared with control, the effect being also observed lateral&nbsp;</span><span style="font-size: 12px;">branches of interspecies sunflower hybrids. The obtained results suggest&nbsp;</span><span style="font-size: 12px;">the possibility of using naphthenic acids as a means for rooting of plant&nbsp;</span><span style="font-size: 12px;">cuttings.</span></p><p>Rooting of hardwood plants was investigated on the cuttings of white poplar&nbsp;(Populus alba) and black poplar (Populus deltoides). The distinct inhibitory&nbsp;effect on the root and shoot growth in water culture was detected in the&nbsp;concentration of naphtenic acids 10^-4&nbsp;mol/L, but 24-hour treatment raised&nbsp;the number roots on undermost 5 cm of the cutting, as well as the total&nbsp;number of roots, comparing to the control.</p><p>In the test of rooting microshoots ofchrysanthemum the highest number of&nbsp;<span style="font-size: 12px;">roots was achieved after the treatment with solution containing 10 &micro;mol/L of&nbsp;</span><span style="font-size: 12px;">total napthenates, as &nbsp;well as after the treatment with fraction of naphthenic&nbsp;</span><span style="font-size: 12px;">acids which was isolated at pH &nbsp;7 in concentration of 50 &micro;mol/L. Both results&nbsp;</span><span style="font-size: 12px;">are on the level of activity of 3-ndolbutyric acid in concentration of 10 &micro;mol/L&nbsp;</span><span style="font-size: 12px;">which suggests that in this case ractionation is not necessary.</span></p><p>The effects of sodium naphthenates on rooting were investigated by&nbsp;measuring the level of total peroxidases and amylase, along with the&nbsp;contents of reducing sugars and total proteins in basal parts of cuttings of&nbsp;black locust (Rozaszin-AC). After 1; 3 and 6 days cuttings were taken for&nbsp;biochemical analysis. In all cases, the activities of IAA-oxidase and amylase&nbsp;increased to the third day and showed a decrease afterwards. The effect&nbsp;was more pronounced after the three-hour treatment with sodium&nbsp;naphthenates, compared to the six-hour treatment and control. The content&nbsp;of soluble proteins increased one dayafter the treatment and decreased to&nbsp;the third and again increased to the sixth day, an exception being the&nbsp;six-hour treatment with sodium naphthenate, when the effect was&nbsp;completely opposite.</p><p>The test of naphthenic acids influence on the level of cadmium in plants&nbsp;showed physiological activity of naphthenic acids on the decrease of the&nbsp;level of heavy metals, &nbsp;in this case cadmium, in the plant. The effect of low&nbsp;concentrations (10^-7&nbsp;mol/L) of sodium naphthenate on total content of Cd in&nbsp;the intercellular space and inside cells, as &nbsp;well as on some physiological&nbsp;and biochemical parameters of young soybean plants grown in the&nbsp;presence of 1 mmol/L solution of cadmium chloride was investigated.&nbsp;Presence of naphthenate reduced in average by 40 % content of total and&nbsp;intracellular Cd in root, stem and leaves and alleviated the harmful effect of&nbsp;<br />Cd on activity of nitrate reductase and content of photosynthetic pigments.</p><p>Treatment of soybean plants with low concentrations of sodium&nbsp;naphthenate influenced the accumulation ofsome essential elements by the&nbsp;young plants. The presence of naphthenates (10^-7&nbsp;mol/L) significantly&nbsp;increased content of Mn, Fe, Zn and Ni in root, but in stem and leaves&nbsp;increased only contents of Fe and Mn. Inroot, the content of Mn increased&nbsp;four times while contents of Fe, Zn and Ni increased by 17%, &nbsp;60% and 68%&nbsp;respectively compared to the control.</p><p>Investigations on celery and carrot&nbsp; confirmed that the influence of&nbsp;naphthenates on mineral nutrition depends on the applied element and that&nbsp;the way of uptake of certain ions is different, which results in either increase&nbsp;or decrease of the contents of some ions in certain parts of plants. Young&nbsp;plants of celery and carrot, were grown in the nutrient medium and treated&nbsp;with sodium salts of naphthenic acids (10^-7&nbsp;mol/L) over the leaves or with its&nbsp;presence in the nutrient medium. Only the treatment based on the &nbsp;presence&nbsp;of naphthenates in the nutrient medium resulted in the decrease of the fresh&nbsp;mass of root and aboveground part by about 20% for both plants. Both&nbsp;treatments had influence on the content of Fe, Cu, Mn, Mg and Ca in the&nbsp;plants of celery and Fe, Mn, Zn and Na in the plants of carrots. In the plants&nbsp;of celery the content of the mentioned nutrients was decreased, while in the&nbsp;root of plants of carrot &nbsp;the content was increased, Fe by 45%, Mn by 70%&nbsp;and Zn by 37%. With these plants &nbsp;the presence of naphthenates in the&nbsp;nutrient medium caused the reducing roots and aboveground parts, which is&nbsp;completely opposite from the results obtained with soybean plants. The&nbsp;treatment by leaves significantly increased the mass of aboveground part&nbsp;only with celery.</p>

<p>Raloksifen je predstavnik selektivnih modulatora estrogenih receptora koji se koristi u terapiji osteoporoze i invazivnog oblika raka dojke u postmenopauzi. Raloksifen se relativno dobro resorbuje iz gastrointestinalnog trakta, ali pri prvom prolasku kroz jetru podleže biotransformaciji u značajnom procentu, &scaron;to je uzrok njegove niske biolo&scaron;ke raspoloživosti. Bioraspoloživost kod ljudi iznosi 2%, a kod Wistar pacova 39%. Različite supstance se koriste da bi se pobolj&scaron;ala bioraspoloživost lekova. Žučne kiseline, kao &scaron;to je deoksiholna kiselina, omogućavaju bolji prolazak kroz biolo&scaron;ke membrane drugim supstancama, te mogu povećati bioraspoloživost lekova. Apigenin je &scaron;iroko rasprostranjeni flavonoid koji inhibi&scaron;e različite metaboličke puteve i na taj način može usporiti metabolizam i eliminaciju i povećati koncentraciju lekova u krvi. Ciljevi ovog istraživanja su bili da se ispita da li apigenin i natrijum-deoksiholat mogu povećati bioraspoloživost raloksifena, njihov uticaj na biohemijske parametre i parametre hemostaze, kao i da se ispita antioksidativni potencijal apigenina. Ispitan je i uticaj apigenina na akutno o&scaron;tećenje jetre usled primene toksične doze paracetamola. U istraživanju su kori&scaron;ćeni zdravi, beli pacovi mu&scaron;kog roda, soja Wistar. U ogledu su ukupno kori&scaron;ćene 84 eksperimentalne životinje. Sva ispitivanja na životinjama je odobrila Etička komisija Univerziteta u Novom Sadu. Raloksifen je primenjen intravenski i per os, dok su natrijum-deoksiholat i apigenin aplikovani peroralno. Uzorci krvi, urina i fecesa su kori&scaron;ćeni za određivanje farmakokinetskih parametara, dok su za određivanje biohemijskih, hemostatskih i parametara oksidativnog stresa kori&scaron;ćeni serum i uzorci jetre laboratorijskih životinja. Pretretman natrijum-deoksiholatom je doveo do smanjenja koncentracije raloksifena u krvi zbog olak&scaron;anog i brzog prodora raloksifena u periferne kompartmane. Time je značajno produženo poluvreme eliminacije i srednje vreme zadržavanja raloksifena i značajno je povećan volumen distribucije raloksifena. Apigenin je doveo do manjeg pada koncentracije raloksifena u prvim satima nakon intravenske primene raloksifena, dok su koncentracije raloksifena bile značajno vi&scaron;e nakon osmog časa od primene leka. Uticaj raloksifena na biohemijske parametre je bio značajno veći nakon intravenske nego nakon peroralne primene. Nakon intravenske primene raloksifena je značajno povećana aktivnost enzima jetre, ALP, ALT, AST i GGT, dok su pokazatelji funkcije bubrega, urea, mokraćna kiselina i kreatinin bili sniženi. U grupama koje su pretretirane natrijum-deoksiholatom i apigeninom vrednosti ovih parametara bile su niže u odnosu na grupu tretiranu samo raloksifenom. Statistički najznačajniji uticaj je imala primena trojne kombinacije, raloksifena, natrijum-deosiholata i apigenina, koja je dovela do značajnog pada aktivnosti enzima jetre, i u odnosu na grupu tretiranu raloksifenom i u odnosu na kontrolnu grupu. Kod životinja tretiranih kombinacijom apigenina i paracetamola pokazatelji toksičnosti su bili značajno niži, naročito vrednosti ALT i ALP, u odnosu na grupu koja je dobijala samo paracetamol. Hepatotoksičnost izazvana toksičnom dozom paracetamola je potvrđena i histopatolo&scaron;kim promenama na jetri, koje nisu primećene u grupi životinja tretiranih kombinacijom apigenina i paracetamola. Ispitivanjem je utvrđeno da apigenin može da spreči paracetamolom indukovano povećanje nivoa MDA, &scaron;to ukazuje da apigenin pozitivno utiče na očuvanje integriteta ćelije. Aktivnost enzima CAT i GR u homogenatima jetre je bila značajno povećana nakon primene toksične doze paracetamola u odnosu na kontrolnu grupu. Aktivnost enzima CAT i GR u grupi tretiranoj kombinacijom apigenina i paracetamola je bila približna vrednostima u kontrolnoj grupi. Na osnovu rezultata istraživanja može se zaključiti da natrijum-deoksiholat i apigenin značajno utiču na farmakokinetiku raloksifena. Primena natrijum-deoksiholata dovela je do pada koncentracije raloksifena u krvi, značajnog prelaska raloksifena iz krvi u periferne kompartmane i povećanja njegovog volumena distribucije, dok je apigenin značajno usporio metabolizam i eliminaciju raloksifena i doveo do njegovog produženog zadržavanja u krvi. Natrijum-deoksiholat i apigenin su pokazali pozitivan uticaj na biohemijske parametre, parametre hemostaze i smanjenje nivoa oksidativnog stresa. Kombinacija natrijum-deoksiholata i apigenina je pokazala sinergistički uticaj na navedene parametre, odnosno dovela je do značajnih promena u odnosu na pojedinačnu primenu ovih supstanci. Rezultati ispitivanja ukazuju na to da apigenin smanjuje stepen lipidne peroksidacije i da dovodi do značajnog povećanja enzimskih antioksidantnih mehanizama odbrane kod pacova kod kojih je hepatotoksičnost indukovana paracetamolom.</p> / <p>Raloxifene is selective estrogen receptor modulator used in treatment of osteoporosis and invasive breast cancer in postmenopausal women. Raloxifene is well absorbed from the gastrointestinal tract, but undergoes extensive first-pass metabolism, which results in very low bioavailability of raloxifene, 2% in humans, and 39% in Wistar rats. Various supstances are used for increasing bioavailability of other drugs. Bile acids, such as deoxycholic acid, promote transport of other supstances through biological membranes, and consequently, may increase their bioavailability. Apigenin is a widespread flavonoid, which inhibits different metabolic pathways. Thus, apigenin can slow down metabolism and elimination of drugs, and raise drug concentration in blood. Aims of this study were to investigate if apigenin and sodium deoxycholate could increase bioavailability of raloxifene, their influence on biochemical and hemostasis parameters, and to investigate antioxidative potential of apigenin. Furthermore, influence of apigenin on acute liver damage after toxic dose of paracetamol was examined. In vivo experiments were performed on 84 laboratory healthy male Wistar rats. All experiments were approved by Ethics Committee of University of Novi Sad. Raloxifene was applied intravenously and per os, while sodium deoxycholate and apigenin were given perorally. Blood, urine and feces samples were used for pharmacokinetic parameters measurement, whereas serum and liver samples were used for evaluation of biochemical, hemostasis and oxidative stress parameters. Pretreatment of sodium deoxycholate led to raloxifene blood concentration decrease due to easier penetration of raloxifene in peripher compartments. As a result, raloxifene half-life and mean residence time were significantly longer and volume of distribution was increased. Apigenin caused lower decrease in raloxifene concentration in first few hours after raloxifene intravenous application, while raloxifene concentrations after apigenin pretreatment were significantlny higher 8 hours after raloxifene application. Influence of raloxifene on biochemical parameters was more significant after intravenous than after per os application. Intravenous application of raloxifene led to increased activity of liver enzymes, ALP, ALT, AST and GGT, while parameters of kidney function, urea, uric acid and creatinine were decreased in comparison to the control group. In experimental groups pretreated with sodium deoxycholate and apigenin these parameters were lower than in the group treated only with raloxifene. Statistically the most significant effects were in the group treated with combination of raloxifene, sodium deoxycholate and apigenin, which caused significant decrease in activity of liver enzymes compared both with raloxifene and control group of animals. In experimental animals treated with combination of apigenin and paracetamol bioindicators of paracetamol toxicity were significantly lower, especially activity of ALT and ALP, in comparison to the group treated only with paracetamol. Hepatotoxicity induced by toxic dose of paracetamol was also confirmed by histopathological alterations in liver, which were not observed in the experimental group treated with combination of apigenin and paracetamol. In this study it was confirmed that apigenin could prevent paracetamol-induced MDA level increase, which suggests that apigenin have positive effects on cell integrity. Activity of CAT and GR in liver homogenates was significantly increased after toxic dose of paracetamol in comparison to the control group, while activity of these enzymes in the group treated with apigenin and paracetamol was similar to values in the control group. Results of this study showed that sodium deoxycholate and apigenin can significantly change pharmacokinetic parameters of raloxifene. Sodium deoxycholate caused signicant decrease in raloxifene blood concentration, extensive distribution from blood to peripheral compartments and increase of raloxifene volume of distribution. Apigenin inhibited metabolism and elimination of raloxifene and thus prolonged half-life and mean residence time of raloxifene. Sodium deoxycholate and apigenin showed positive effects on biochemical and hemostasis parameters and decreased the level oxidative stress. Combination of sodium deoxycholate and apigenin showed synergistic effects on these parameters in comparison to effects of separate application of sodium deoxycholate and apigenin. The result of our study indicates that apigenin inhibits the level of lipid peroxidation and significantly increase the enzyme antioxidant defence mehanisms in paracetamol induced hepatotoxicity in rats.</p>