<p>Bor je bilo koji četinar roda Pinus koji pripada porodici Pinaceae. U Republici Srbiji nalaze se prirodne i ve&scaron;tačke &scaron;ume crnog bora Pinus nigra Arnold. Kora bora se vekovima koristila u tradicionalnoj medicini, međutim tek u novije vreme su otkriveni i potvrđeni njeni pozitivni biolo&scaron;ki efekti u medicini. Najpoznatiji komercijalni preparat kore bora je piknogenol, standardizovani ekstrakt kore francuskog primorskog bora Pinus pinaster Aiton, koji raste duţ obale jugozapadne Francuske. Pozitivni efekti koje ispoljava piknogenol, kao &scaron;to su antioksidativno, hipoglikemijsko, hipolipidemijsko delovanje, zasnovani su na njegovom visokom sadržaju fenolnih jedinjenja. Danas, i pored saznanja da je kora bora bogata sekundarnim metabolitima ona najče&scaron;će zavr&scaron;ava kao nusproizvod drvne industrije. Ciljevi ovog rada bili su ispitivanje kvalitativnih i kvantitativnih karakteristika i biohemijskih aktivnosti ekstrakata kore crnog bora Pinus nigra sa Mokre gore i Tare, dobijenih različitim rastvaračima; upoređivanje glikemijskog i lipidnog delovanja ekstrakta kore bora Pinus nigra sa komercijalnim preparatom piknogenol; uticaj ekstrakta kore bora Pinus nigra i piknogenola na delovanje standardnih antidijabetika metformina i gliklazida; kao i uticaj na parametre oksidativnog stresa nakon izlaganja životinja toksičnoj dozi paracetamola. In vitro ispitivanja su uključivala analizu ekstrakata dobijenih različitim rastvaračima. Ukupni sadržaj fenola, tanina, flavonoida i proantocijanidna, kao i ispitivanje antioksidativne aktivnosti kroz pet različitih metoda, određivani su spektrofotometrijski. Vr&scaron;ena je analiza ekstrakata kore bora visokoefikasnom tečnom hromatografijom (HPLC). In vivo ispitivanje je rađeno na 156 albino laboratorijska pacova soja Wistar. Eksperimentalne ţivotinje su tokom 7 dana per os primale ekstrakt kore crnog bora poreklom sa Mokre gore 100 mg/kg, koji je pokazao najbolju aktivnost, piknogenol 50 mg/kg, metformin 100 mg/kg, gliklazid 10 mg/kg, kao i njihove kombinacije. Za ispitivanje uticaja primenjivanih supstanci na glikemiju ţivotinja kori&scaron;ćeni su test oralnog podno&scaron;enja glukoze i indukcija trajne hiperglikemije aloksanom. Od biohemijskih parametara u serumu je određivana koncentracija lipida, kao i parametric pokazatelji funkcije bubrega i jetre. Ex vivo ispitivanja uključivala su određivanje intenzitet lipidne peroksidacije i anktivnosti enzima antioksidativne za&scaron;tite u homogenatu jetre ispitivanih ţivotinja, nakon primene toksične doze paracetamola. HPLC analizom ekstrakata kore crnog bora utvrđeno je da ekstrakti poreklom sa Mokre gore i Tare u najvećoj meri sadrţe taksifolin, a zatim katehin, njegove derivate, kafenu kiselinu i epikatehin. PotvrĎen je visok antioksidativni kapacitet piknogenola, ali takođe i značajan antioksidativni kapacitet ekstrakata kore crnog bora, sa najboljim rezultatima kod ekstrakta poreklom sa Mokre gore. Sedmodnevni tretman ekstraktom kore bora 100 mg/kg, metforminom 100 mg/kg, gliklazidom 10 mg/kg i piknogenolom 50 mg/kg, kod ţivotinja sa aloksanski izazvanim dijabetesom, doveo je do sniženja glikemije u krvi. Uočeno je povećanje konentracije HDL holesterola i značajno sniženje serumskih triglicerida kod dijabetičnih i normoglikemičnih ţivotinja koje su primale piknogenol, ekstrakta kore bora, gliklazid i metformin u poređenju sa kontrolnom grupom ţivotinja. Zajednička primena ekstrakta kore bora i standardnih antidijabetika značajno je snizila vrednosti AST, ALP i direktni bilirubin u grupi dijabetičnih i normoglikemičnih ţivotinja u odnosu na kontrolnu grupu, čime se ukazuje na potencijalno hepatoprotektivno delovanje ekstrakta kore crnog bora. O&scaron;tećenje jetre izazvano toksičnom dozom paracetamola je potvrđeno ispitivanim parametrima, uključujući oksidativni status u homogenatu jetre i histolo&scaron;ka ispitivanja. Rezultati na&scaron;eg istraživanja su pokazali da piknogenol 50 mg/kg, kao i ekstrakt kore crnog bora 100 mg/kg značajno smanjuju nivo MDA u poređenju sa kontrolnom grupom i grupom koja je primala paracetamol. Na osnovu rezultata istraţivanja može se zaključiti da primena piknogenola i ekstrakta kore crnog bora: ublaţava poremećaj homeostaze glukoze, utiče povoljno na lipidni status, značajno potencira antihiperglikemijsko delovanje metformina i hipoglikemijski efekat gliklazida, sprečava poremećaj biohemijskih parametara pokazatelja funkcije jetre i bubrega u serumu ispitivanih životinja i ispoljava značajno in vitro antioksidativno delovanje i sprečava o&scaron;tećenje jetre laboratorijskih životinja izazvano toksičnom dozom paracetamola.</p> / <p>A pine is any conifer in the genus Pinus of the family Pinaceae. In the Republic of Serbia there are natural and artificial forests of black pine Pinus nigra Arnold. Pine bark has been used for centuries in traditional medicine, but only recently its positive biological effects has been revealed and confirmed in medicine. The most famous commercial pine bark product is Pycnogenol, a standardized extract of the French maritime pine bark (Pinus pinaster Aiton), which grows along the coast of southwestern France. The positive effects of Pycnogenol, such as antioxidant, hypoglycemic, hypolipidemic, are based on its high content of phenolic compounds. Nowdays, despite the knowledge that the pine bark is rich in secondary metabolites, it usually ends up as a by-product of the wood industry. The objectives of this dissertation were to investigate the qualitative and quantitative characteristics and biochemical activities of the black pine (Pinus nigra) extracts from Mokra gora and Tara, obtained by different solvents; comparison of glycemic and lipid action of Pinus nigra bark extract with commercial product Pycnogenol; the influence of black pine bark extract and Pycnogenol on the action of standard antidiabetics metformin and gliclazide; as well as the influence on the parameters of oxidative stress in animals exposed to the toxic dose of paracetamol. In vitro analyses included the analysis of extracts obtained with different solvents. The total phenolic, tannin, flavonoid and proanthocyanidin content, as well as the antioxidant activity tests, were determined spectrophotometrically. High-efficiency liquid chromatography (HPLC) was performed in order to determine black pine bark extract content. In vivo analyses was performed on 156 albino Wistar laboratory rats. Experimental animals received for 7 days per os: black pine bark extract obtained from Mokra gora 100 mg/kg, which showed the best activity; Pycnogenol 50 mg/kg; metformin 100 mg/kg; gliclazide 10 mg/kg; and their combinations. An oral glucose tolerance test and the aloxan-induced hyperglycaemia were used to examined the effects of the substances on experimental animals. Biochemical parameters, the lipids concentration and parameters of the kidney and liver function, were determined in animal serum. Ex vivo analyses included determination of lipid peroxidation activity and the activity of antioxidant protection enzymes in liver homogenates of the test animals, after administration of a toxic dose of paracetamol. HPLC analysis of black pine bark extracts obtained from Mokra gora and Tara showed the greatest content of taxifolin, then catechin, and its derivatives, caffeic acid and epicatechin. A high antioxidative capacity of Pycnogenol was confirmed, but also a significant antioxidant capacity of black pine bark extract, with the best results in the extract obtained from Mokra gora. Seven-day treatment in aloxan-induced diabetes animals with 100 mg/kg black pine bark extract, metformin 100 mg/kg, gliclazide 10 mg/kg and Pycnogenol 50 mg/kg led to a decrease of serum glycemic index. There was an increase in the HDL cholesterol concentration and a significant reduction in serum triglycerides in diabetic and normoglycemic animals which received Pycnogenol, black pine bark extract, gliclazide and metformin compared to the control group. Concomitant usage of the black pine bark extract and standard antidiabetics significantly reduced the levels of AST, ALP and direct bilirubin in the group of diabetic and normoglycemic animals compared to the control group, indicating the potential hepatoprotective action of the black pine bark extract. Damage to the liver caused by the toxic dose of paracetamol was confirmed by the liver homogenate oxidative status and histological examination. The results of our study have shown that Pycnogenol 50 mg/kg, as well as 100 mg/kg black pine bark extract significantly reduce the level of MDA in comparison with the control and the paracetamol treated group. Based on the results of the dissertation, it can be concluded that the use of Pycnogenol and black pine bark extract alleviate glucose homeostasis disorder; positively affects the lipid status; significantly increases the antihyperglycemic effect of metformin and the hypoglycemic effect of gliclazide; prevents impairment biochemical parameters of the liver and kidney function in the serum of the experimental animals; significantly exhibits in vitro antioxidant activity and prevents liver damage caused by toxic dose of paracetamol in experimental animals.</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>Iako je dijabetes melitus (DM) tip 2 je hronično oboljenje čija se stopa značajno povećala poslednjih decenija, podaci o odnosu pacijenta prema leku i lečenju dijabetes melitusa su retki i odnose se na pojedine aspekte terapije. Glavni kamen spoticanja u lečenju dijabetesa jeste nepridržavanje pacijenata propisanim lekovima, &scaron;to otežava održavanje normalne glikoregulacije i doprinosi razvoju te&scaron;kih komplikacija koje značajno utiču na kvalitet života pacijenata sa DM. Raspolaganje tačnim podacima o upotrebi antidijabetičnim lekova, kao i uvidom u realno stanje o odnosu pacijenata prema leku u lečenju DM tipa 2, omogućava pobolj&scaron;anje farmakoterapijske prakse i kreiranje intervencije za pobolj&scaron;anje adherencije pacijenata Ciljevi ovog istraživanja bili su: 1) analiza obima potro&scaron;nje i strukture antidijabetičnih lekova na teritoriji Republike Srpske i njihovo poređenje sa upotrebom i strukturom propisivanja u okolnim zemljama kao i državama sa razvijenom farmakoterapijskom praksom; 2) analiza obima potro&scaron;nje i strukture antidijabetičnih lekova u op&scaron;tini Foča i poređenje sa savremenim farmakoterapijskim smernicama; 3) određivanje procenta pokrivenosti antidijabetičnom terapijom pacijenata sa DM tip 2 tokom jedne godine u op&scaron;tini Foča; 4) određivanje adherencije pacijenata sa DM tipa 2 prema antidijabetičnoj terapiji metodom brojanja tableta/doza insulina i putem validiranog upitnika; 5) određivanje kvaliteta života povezanog sa zdravljem pacijenata sa DM tipa 2 u op&scaron;tini Foča primenom validiranog upitnika SF-36v2; 6) određivanje prediktora neadherenije kod primene obe metode merenja adherencije u odnosu na karakteristike i kvalitet života pacijenata sa DM tip 2 u op&scaron;tini Foča. Ispitivanje se sastojalo iz dva dela. U prvom delu sprovedeno je retrospektivno farmakoepidemiolo&scaron;ko praćenje upotrebe antidijabetičnih lekova kao i određivanje strukture ovih lekova na teritoriji Republike Srpske u periodu od 01.01.2013. do 31.12.2013.godine i izvr&scaron;eno je poređenje sa upotrebom i strukturom propisivanja u okolnim zemljama kao i državama sa razvijenom farmakoterapijskom praksom. U drugom delu ispitivanja sprovedeno je farmakoepidemiolo&scaron;ko ispitivanje primene antidijabetičnih lekova na nivou same op&scaron;tine Foča u okviru koje je pored analize obima potro&scaron;nje i strukture antidijabetičnih lekova u istom periodu kao i na teritoriji Republike Srpske i poređenja sa savremenim farmakoterapijskim smernicama, određivan i procenta pokrivenosti antidijabetičnom terapijom mereno redovno&scaron;ću ponovnih popunjavanja recepata od strane lekara op&scaron;te prakse tokom jednogodi&scaron;njeg perioda. Takođe je sprovedeno i ispitivanje adherencije prema antidijabetičnim lekovima primenom dve različite metode merenja kao i kvalitet života pacijenata sa DM tip 2 između 01.01.2015. i 31.12.2015.godine. Ukupna upotreba antidijabetika za lečenje dijabetesa tip 1 i tip 2 na teritoriji Republike Srpske iznosila je 38,29 DDD/1000st/dan. Upotreba insulina i analoga iznosila je 11,28 DDD/1000st/dan. Ukupna upotreba oralnih lekova koji snižavaju glukozu i krvi, isključujući insuline iznosila je 27,01 DDD/1000st/dan, a metformin je najče&scaron;će kori&scaron;ćeni predstavnik. Sličan obim i struktura upotrebe antidijabetičnih lekova utvrđena je i u op&scaron;tini Foča. Procenat pokrivenosti antidijabetičnom terapijom pacijenata sa DM tip 2 tokom jedne godine u op&scaron;tini Foča iznosio je vi&scaron;e od 94,91%. Adherencija određivana metodom brojanja tableta/doza insulina iznosila je 52,3%, a merena primenom validiranog upitnikom iznosila je svega 44,9%. Statistički značajni prediktori neadherencije određivane primenom metode brojanja tableta/doza insulina su doplata cena leka kao i niži skor dimenzije mentalnog zdravlja kada je u pitanju kvalitet života. Prediktori neadherencije merene primenom validiranog upitnikom bili su mu&scaron;ki pol, kao i niži skor dimenzije mentalnog kao i fizičkog zdravlja kada je u pitanju kvalitet života. Na osnovu ovih saznanja, intervencije za pobolj&scaron;anje adherencije pacijenata bi bile usmerene na edukaciju pacijenata mu&scaron;kog pola, zatim na smanjivanje izdataka pacijenata za lekove, &scaron;to će doprineti i boljem kvalitetu života ovih pacijenata.</p> / <p>Although diabetes mellitus (DM) type 2 is a chronic disease whose rate has increased significantly in recent decades, data on the patient&#39;s attitudes towards the medicine and the treatment of diabetes mellitus are rare and relate to individual aspects of the therapy. The main stumbling block in the treatment of diabetes is not taking prescribed drugs regularly, which makes it difficult to maintain normal glycoregulation and contribute to the development of severe complications that significantly affect the quality of life of patients with DM. The disposition of accurate data on the use of antidiabeticdrugs, as well as the insight into the real state of the patient&#39;s relationship with the medication in the treatment of DM type 2, enables the improvement of pharmacotherapeutic practice and the creation of an intervention to improve patient adherence.<br />The objectives of this research were:<br />1) analysis of the volume of consumption and structure of anti-diabetic medicines on the territory of the Republic of Srpska and their comparison with the use and structure of prescribing in the surrounding countries as well as countries with developed pharmacotherapeutic practice;<br />2) analysis of the volume of consumption and structure of antidiabetic drugs in the municipality of Foča and comparison with modern pharmacotherapeutic guidelines;<br />3) determining the percentage of coverage with antidiabetic therapy of patients with DM type 2 during one year in the municipality of Foča;<br />4) determining the adherence of patients with DM type 2 in antidiabetic therapy by the method of pill counts /volume of insulin and by validated questionnaire;<br />5) determining the quality of life associated with the health of patients with DM type 2 in the municipality of Foča using the validated questionnaire SF-36v2;<br />6) determination of the predictor of nonadherence in the application of both methods of adherence measurement in relation to the characteristics and quality of life of patients with DM type 2 in the municipality of Foča.<br />The investigation consisted of two parts.<br />In the first part, a retrospective pharmacoepidemiological monitoring of the use of antidiabetic drugs was carried out, as well as determining the structure of these drugs in the territory of the Republic of Srpska in the period from January, 1st 2013 until December, 31st 2013, and a comparison was made with the use and prescription structure in neighboring countries as well as countries with developed pharmacotherapeutic practices. In the second part of the study, a pharmacoepidemiological study was carried out on the use of antidiabetic drugs at the level of the municipality of Foča itself, in which, besides analyzing the volume of consumption and structure of anti-diabetic drugs in the same period as in the territory of the Republic of Srpska and comparison with modern pharmacotherapeutic guidelines, the percentage of coverage by antidiabetic therapy was measured by the regularity of the prescription prescribed by the general practitioner over a one-year period. Medication adherence to antidiabetic drugs was also carried out using two different methods of measurement as well as the quality of life of patients with DM type 2 between January, 1st 2015 and December, 31st 2015. The total use of antidiabetic for the treatment of type 1 diabetes and type 2 in the territory of the Republic of Srpska was 38.29 DDD / 1000st / day. The use of insulin and analogs was 11.28 DDD / 1000st / day. The total use of blood glucose lowering drugs , excluding insulins, was 27.01 DDD / 1000st / day, and metformin is the most commonly used representative. A similar volume and structure of the use of anti-diabetic drugs was also determined in the municipality of Foča. The percentage of coverage of antidiabetic therapy of patients with DM type 2 during one year in the municipality of Foca amounted to more than 94.91%. Adherence determined by the pill counts and the volume of insulin method was 52.3%, and measured by applying the validated questionnaire was only 44.9%. Statistically significant predictors of nonadherence determined by the method of pill counts/volume of insulin are copayment, a fix fee for prescription made by patients as well as the lower score of the mental health dimension when it comes to quality of life. The non-adherence predictors measured using the validated questionnaire were the male sex, as well as a lower score of the mental dimension as well as physical health when it comes to quality of life. Based on these findings, interventions to improve patient adherence would focus on health education of male patients, and policy changes regarding availability of antidiabetic medication through copayment reductions , which will contribute to a better quality of life for these patients.</p>