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Assessment of spatial memory and cognitive flexibility in diabetes type 2 in middle-aged Sprague-Dawley rats of both sexes
No full textMetabolic changes caused by obesity and the development of diabetes type 2 (T2D) can lead to cognitive impairment. Indeed, it occurred to be a common complication of T2D. Thus, problems with spatial memory are one of the first symptoms of memory loss in patients with T2D. In addition, T2D is associated with changes in the hippocampus and prefrontal cortex, which may also underlie executive function impairment. ..
Enzimski i lipidni markeri u proceni rizika za nastanak kardiovaskularnih bolesti kod žena u menopauzi
No full textPostmenopausal women are at an increased risk of cardiovascular disease (CVD), the
leading cause of death worldwide, compared with younger women. Gamma-glutamyl transferase
(GGT) and high-density lipoprotein cholesterol (HDL-c) are linked with oxidative stress,
inflammation, insulin resistance, and CVD risk factors. However, there have been no studies that
examined the relationship between GGT/HDL-c and CVD exclusively in women who are not of
reproductive age. Therefore, we aimed to examine this potential relationship in a cohort of CVD-
free postmenopausal women. A total of 150 disease-free postmenopausal women were
consecutively included. CVD risk was defined according to high sensitivity C-reactive protein
(hsCRP) concentration (hsCRP < 1 mg/L defines low risk and hsCRP ≥ 1 mg/L defines
intermediate and high risk). The GGT/HDL-c was independently associated with intermediate
and high CVD risk in postmenopausal women. As this enzyme/lipid index increased by 1 unit,
the probability of intermediate and high CVD risk rose by 10.3% (OR = 1.103, p = 0.024). The
GGT/HDL-c ratio was independently associated with higher CVD risk, as measured with hsCRP
in postmenopausal women. This cost-effective, easily measured, and widely available index could
be used in everyday clinical practice for estimating CVD risk in postmenopausal women.Žene u postmenopauzi su pod povećanim rizikom od kardiovaskularnih bolesti (KVB),
vodećeg uzroka smrti širom sveta, u poređenju sa mlađim ženama. Gama-glutamil transferaza
(GGT) i koncentracija holesterola u lipoproteinima visoke gustine (HDL-c) povezani su sa
oksidativnim stresom, upalom, insulinskom rezistencijom i faktorima rizika za KVB. Međutim,
ne postoje studije koje su ispitivale odnos između GGT/HDL-c i KVB isključivo kod žena koje
nisu u reproduktivnom dobu. Stoga smo imali za cilj da ispitamo pomenuti potencijalni odnos u
kohorti žena u postmenopauzi bez KVB. Ukupno je uključeno 150 zdravih žena u postmenopauzi.
Rizik od KVB je definisan prema koncentraciji visokosenzitivnog C-reaktivnog proteina (hsCRP)
(hsCRP < 1 mg/L definiše nizak rizik, a hsCRP ≥ 1 mg/L definiše srednji i visoki rizik).
GGT/HDL-c je bio nezavisno povezan sa srednjim i visokim rizikom od KVB kod žena u
postmenopauzi. S povećanjem ovog enzimskog/lipidnog indeksa za 1 jedinicu, verovatnoća
srednjeg i visokog rizika od KVB porasla je za 10,3% (OR = 1,103, p = 0,024). Odnos GGT/HDL-
c je nezavisno povezan sa većim rizikom od KVB, merenim pomoću hsCRP kod žena u
postmenopauzi. Ovaj isplativ, lako merljiv i široko dostupan indeks mogao bi se koristiti u
svakodnevnoj kliničkoj praksi za procenu rizika od KVB kod žena u postmenopauzi
Comparative Leaf Anatomy of Balkan Representatives of Gentiana L. Sect. Ciminalis (Adans.) Dum. (Gentianaceae): Implications for Species Delimitation
No full textThe present study investigates the leaf anatomical traits of representatives of Gentiana section Ciminalis in the Balkan Peninsula, focusing on the ecologically and geographically vicariant species Gentiana acaulis, G. clusii, and G. dinarica. These species are distributed across a variety of mountainous habitats, including calcareous and siliceous rocky grounds, and exhibit pronounced morphological similarities that have led to misidentifications in the past. In order to address the challenges in species delimitation, a comparative analysis of leaf anatomical traits was performed on cross-sections of ten rosette leaves from each population. Statistical data analyses were conducted on 18 morphometric traits. A range of statistical techniques were used to assess variability and identify important discriminating traits, including descriptive statistics, principal component analysis, and discriminant analysis. The results indicate that the species can be distinguished based on leaf anatomy, particularly mesophyll thickness and number of cells that contain calcium oxalate crystals. The leaf of G. acaulis has a smaller mesophyll thickness (mean value: 164.31 μm), G. dinarica a larger mesophyll thickness (mean value: 365.85 μm), while G. clusii lies between these two (mean value: 305.35 μm). Crystal-containing cells are most abundant in G. clusii, where they are distributed throughout the entire leaf mesophyll; followed by G. dinarica, where the distribution of these cells are mainly in the upper half of the leaf; while they are sparse or absent in G. acaulis. These results suggest that leaf anatomy is a valuable diagnostic tool for distinguishing taxa within the section Ciminalis of the genus Gentiana
Antimicrobial Prophylaxis in Elective Orthopaedic Surgical Procedures at the Tertiary Care Hospital: A Prospective Observational Study
No full textObjective: Surgical antimicrobial prophylaxis (SAP) is vital for preventing surgical site infections (SSIs). This study evaluated adherence to local SAP guidelines and assessed SSI-related risk factors in elective orthopaedic surgeries. Methods: A prospective observational study was conducted at a tertiary care hospital between August and October 2023. Patients were categorised into two groups: those receiving guideline-adherent SAP (SAP group) and those with inadequate SAP (ISAP group), defined by incorrect dosing or prolonged duration. Various patient- and procedure-related SSI risk factors were compared between groups. Results: Among 82 patients, 81 received SAP, but only a small proportion received it correctly. Most deviations were due to extended duration and incorrect dosing, resulting in 90.20% non-adherence. Despite this, no significant differences in known SSI risk factors were observed between the two groups, and no SSIs were reported during the study period. Conclusions: Non-adherence to SAP guidelines was widespread, mainly due to extended prophylaxis. Importantly, non-adherence was not associated with increased SSI risk, nor was it linked to higher baseline patient risk factors, suggesting that decisions were influenced more by clinical routine than by patient-specific risk. These findings emphasize the need to strengthen staff education and adherence to guidelines, thereby supporting antimicrobial stewardship in resource-limited settings
Preliminary chemometric assisted spectrophotometric analysis of multicomponent pharmaceutical formulation
No full textAnaliza višekomponentnih formulacija lekova predstavlja značajan izazov koji proizilazi iz kompleksne prirode ispitivanih jedinjenja. Hemometrija i multivarijantne metode mogu olakšati rad i umanjiti doprinos spektralnih smetnji na koje nailazimo u toku primene spektrofotometrije u kvantitativnoj analizi. Cilj ovog istraživanja je primena UV spektrofotometrijskih merenja u kombinaciji sa hemometrijom za kvalitativnu i kvantitativnu analizu tri aktivne farmaceutske supstance: perindopril erbumin, amlodipin besilat i indapamid. Eksperimentalni dizajn koji uključuje procenu uticaja 3 faktora na 5 faktorskih nivoa, izveden uz upotrebu Design Expert 11.0 (Stat Ease, SAD) softvera. Opseg talasnih dužina je bio od 200 do 400 nm, brzina snimanja 800 nm/min, dok je veličina koraka bila podešena na 1,280 nm sa razrezom od 1,5 nm. Osnovni rastvori su bili pripremljeni u smeši etanola i destilovane vode 50/50, a zatim su radni rastvori razblaženi destilovanom vodom do postizanja radnih koncentracija u opsegu 10-50 μg/mL za sve tri aktivne farmaceutske supstance. Spektralni podaci su snimani pomoću Cintra 202 UV spektrofotometra (GBC, Australija) čiji rad podržava Cintral softver, verzija 2.2. Podaci koji se odnose na preklapanja UV spektara su modelovani primenom tehnike parcijalnih najmanjih kvadrata u kombinaciji sa genetskim algoritmom. Ova metodologija je odabrana zbog svoje izuzetne sposobnosti da smanji broj promenljivih tako da zadrži samo one koje poseduju prediktivne sposobnosti, čime se optimizuje tačnost i ponovljivost nagrađenog modela. Razvijena metoda predstavlja isplativiju i vremenski efikasniju alternativu konvencionalnoj HPLC metodi koja se uobičajeno koristi u analitici višekomponentnih smeša.Multidrug analysis presents significant challenges due to the intricate nature of compounds. Chemometrics and multivariate methods effectively mitigate spectral interference encountered in spectrophotometric techniques for pharmaceutical quantification. This research aimed to employ UV spectrophotometric measurements coupled with chemometrics for both qualitative and quantitative analysis of three active pharmaceutical substances: perindopril erbumine, amlodipine besylate, and indapamide. The experimental design was constructed using Design Expert 11.0 (Stat Ease, USA), employing a 5-level-3-factor design. The wavelength range was from 200 to 400 nm, the speed is set at 800 nm/min, and the step size is precisely set at 1.280 nm, with a slit width of 1.5 nm. Stock solutions were prepared in a 50/50 mixture of ethanol-distilled water. Subsequently, working solutions were diluted with distilled water to achieve a concentration range of 10-50 μg/mL for the three active pharmaceutical ingredients. Spectral data was collected using a Cintra 202 UV spectrophotometer (GBC, Australia), equipped with Cintral software version 2.2. The UV spectral overlapping was recorded and disentangled employing Partial Least Square (PLS) coupled with Genetic Algorithm (GA). This methodology was selected due to its remarkable ability to reduce the number of variables to those that possess predictive capabilities, thereby optimizing the model accuracy and repeatability. The developed method presents a cost-effective and time-efficient alternative to the conventional HPLC standard method
Inovacije u pakovanju farmaceutskih proizvoda: prednosti i ograničenja
No full textPakovanje farmaceutskih proizvoda značajno utiče na bezbednost, efikasnost, proizvodnju i način primene lekova. Stoga je neophodno da ono bude usklađeno sa propisima i standardima donetim od strane regulatornih tela kao što su EMA, FDA, SZO ili nacionalnih regulatornih tela. Veliki napredak ostvaren je u poslednje dve decenije u oblasti farmaceutskih nauka, razvoju i primeni materijala, elektronskoj informacionoj tehnologiji i inovacijama u razvoju lekova. Sve navedeno dovelo je do dodatnih zahteva koji se postavljaju kada je u pitanju pakovanje farmaceutskih proizvoda koje mora da obezbedi integritet proizvoda, bezbednost pacijenata i sprečavanje falsifikovanja i zloupotrebe. Pored toga, pred savremenu farmaceutsku ambalažu postavljaju se zahtevi kao što su inteligentno pakovanje i održivost proizvoda. Očekuje se da će se propisi koji se odnose na farmaceutske proizvode, uključujući materijale za pakovanje i kontejnere, u budućnosti morati prilagoditi navedenim izazovima, kako bi se uz ostvareni tehnološki napredak poboljšao celokupni lanac snabdevanja i iskustvo pacijenata. Rastuće globalno interesovanje za koncept održivosti proširilo se i na farmaceutski sektor, gde zeleni i održivi materijali za pakovanje, kao što su bioplastika, reciklirani polimeri, monokomponentni laminati i sistemi na bazi papira, nude značajne mogućnosti za smanjenje emisije ugljenika i otpada. Međutim, njihova upotreba je strogo regulisana kako bi se osigurao integritet farmaceutskog proizvoda i bezbednost pacijenata. Međunarodna regulatorna tela zahtevaju da svaki novi materijal pokaže ekvivalentnost u performansama, bezbednosti i stabilnosti u poređenju sa konvencionalnim materijalima. Trenutni okviri, kao što su vodič WHO 902, smernice EMA i FDA naglašavaju potrebu za rigoroznim ispitivanjima, kvalifikacijom dobavljača i procenama zasnovanim na riziku. Iako ova regulatorna tela podržavaju održive inovacije, ekološke prednosti ovih pakovanja nikada ne smeju ugroziti kvalitet leka. Iz tog razloga, potrebno je napraviti balans između održivosti i bezbednosti, što otvara put razvoju novih ekološki odgovornih rešenja za pakovanje lekova. Inovacije u oblasti pakovanja lekova obuhvataju razvoj aktivnih i pametnih sistema koji prevazilaze tradicionalnu zaštitnu funkciju ambalaže. Aktivna pakovanja sadrže komponente koje mogu da apsorbuju vlagu ili kiseonik, oslobađaju regulisane količine konzervansa ili gasova i na taj način direktno utiču na mikroklimu u pakovanju i produžavaju stabilnost leka. Nasuprot njima, pametna pakovanja opremljena su senzorima i indikatorima koji beleže i prikazuju promene spoljašnjih uslova, poput temperature, vlage ili izloženosti svetlosti. Na tržištu su već prisutni sistemi koji uključuju RFID (Radio Frequency Identification) i NFC (Near Field Communication) tehnologiju za digitalnu sledljivost i proveru autentičnosti, kao i indikatore vremena i temperature ili termohromne boje koje vizuelno signaliziraju odstupanja od propisanih uslova čuvanja. U novije vreme razvijaju se i interaktivne etikete koje putem QR ili NFC tehnologije omogućavaju pristup dodatnim informacijama o poreklu i načinu primene proizvoda. Ovakva integracija senzorskih i digitalnih elemenata čini ambalažu aktivnim delom sistema za obezbeđenje kvaliteta lekova i doprinosi većoj bezbednosti, sledljivosti i održivosti u farmaceutskom lancu snabdevanja
Application of statistical approaches in the assessment of rate and extent of absorption and development of a population pharmacokinetic model for clopidogrel and its metabolite clopidogrel carboxylic acid from generic products
No full textKlopidogrel je inhibitor agregacije trombocita, prolek koji se posle p.o. primene brzo resorbuje i intenzivno metaboliše, pre svega presistemski u jetri, pri čemu se veći deo primenjene doze konvertuje do neaktivnog metabolita klopidogrel karboksilne kiseline, a manji deo, oko 15%, do aktivnog metabolita klopidogrel tiola, preko koga klopidogrel ostvaruje svoj efekat. Na tržištu je prisutno više generičkih lekova, za koje je potvrđena biološka ekvivalentnost sa istim referentnim lekom, dok između samih generičkih lekova nije direktno potvrđena. Budući da klopidogrel ima varijabilnu farmakokinetiku, kao i odgovor na terapiju ovim lekom, za kliničku praksu mogu biti značajne informacije o eventualnim razlikama između generičkih lekova u brzini i stepenu resorpcije, zbog kojih kod pacijenata potencijalno može da se poveća rizik od pojave neželjenih reakcija. Cilj prvog dela disertacije bio je poređenje brzine i stepena resorpcije između 19 generičkih lekova klopidogrela, metodama indirektnog i direktnog poređenja, pri čemu su korišćeni rezultati studija biološke ekvivalentnosti koji uključuju primarne i/ili sekundarne podatke za klopidogrel i klopidogrel karboksilnu kiselinu. Cilj drugog dela istraživanja bio je karakterizacija procesa resorpcije i dispozicije klopidogrela, kao i njegove konverzije do klopidogrel karboksilne kiseline, kroz razvoj i validaciju združenog populacionog farmakokinetičkog modela, uz razmatranje faktora varijabilnosti, korišćenjem koncentracija klopidogrela i klopidogrel karboksilne kiseline i drugih dostupnih relevantnih primarnih podataka iz dve studije biološke ekvivalentnosti. Metodom prilagođenog indirektnog poređenja obrađeni su podaci za klopidogrel i klopidogrel karboksilnu kiselinu iz 19 studija biološke ekvivalentnosti i utvrđene su kombinacije generičkih lekova klopidogrela koje se mogu smatrati međusobno biološki ekvivalentnim i potencijalno zamenjivim u kliničkoj praksi (76%), kao i one za koje se zamena ne preporučuje. Direktnim poređenjem farmakokinetičkih parametara iz dve studije biološke ekvivalentnosti korišćenjem Student t-testa, utvrđena je sličnost između generičkih lekova ispitivanih u ovim studijama u pogledu stepena resorpcije kopidogrela i njegove konverzije do klopidogrel karboksilne kiseline, ali ne i u pogledu brzine ovih procesa. Budući da je klinički značaj stepena resorpcije veći u odnosu na brzinu ovog procesa, može se smatrati da između ova dva generička leka nema statistički značajne razlike u biološkoj raspoloživosti. Metodom nelinearnog modelovanja kombinovaniah efekata razvijen je i validiran združeni semi-fiziološki populacioni farmakokinetički model kopidogrela i klopidogrel karboksilne kiseline, koji uključuje linearnu resorpciju sa 2 tranzitna prostora, hepatički prostor za opisivanje presistemskog metabolizma do metabolita, jednoprostorni model za klopidogrel, dvoprostorni model za klopidogrel karboksilnu kiselinu, linearnu eliminaciju ovog metbolita, alomerijsko skaliranje klirensa i volumena distribucije. Razvijeni model daje čvrstu osnovu za potencijalna buduća poboljšanja pri građenju složenijeg modela. Sprovedeno istraživanje koristi savremene metode analize sekundarnih i/ili primarnih podataka dostupnih za generičke lekove klopidogrela i pruža dodatne informacije o međusobnoj zamenjivosti lekova, koje mogu biti od koristi u kliničkoj praksi, te predstavlja iskorak u pravcu primene alternativnih metoda u svrhu poređenja biološke raspoloživosti lekova kod kojih nije pogodan standardni pristup predviđen aktuelnom regulativom.Clopidogrel, a platelet aggregation inhibitor, is a prodrug that undergoes rapid absorption and extensive hepatic first-pass metabolism after p.o. administration. The majority of the dose is metabolized into the inactive metabolite clopidogrel carboxylic acid, while only about 15% is converted into the active metabolite clopidogrel thiol, responsible for the clopidogrel therapeutic effect. Given its variable pharmacokinetics and therapeutic response, understanding differences in the rate and extent of absorption between generic products is crucial, as these differences could potentially impact patient safety or therapeutic outcomes. Although generic products are individually bioequivalent to the reference drug, bioequivalence between generics has not been directly assessed. The dissertation aimed to address this gap through two main objectives. In the first part of the dissertation the aim was to compare the rate and extent of absorption between 19 generic clopidogrel drugs, using indirect and direct comparison methods, analyzing primary and/or secondary data for clopidogrel and clopidogrel carboxylic acid originated from the bioequivalence studies. The aim of the second part of the research was to characterize the process of absorption and disposition of clopidogrel, as well as its conversion to clopidogrel carboxylic acid, through the development and validation of a joint population pharmacokinetic model, considering also variability factors. Clopidogrel and clopidogrel carboxylic acid concentrations as well as other available relevant primary data from two bioequivalence studies were used for model development. Data for clopidogrel and clopidogrel carboxylic acid from 19 bioequivalence studies were analyzed using adjusted indirect comparison method, which allowed the identification of combinations of generic clopidogrel drugs that can be considered mutually bioequivalent and potentially interchangeable in clinical practice (76%), as well as those for which substitution is not recommended. A direct comparison of pharmacokinetic parameters from two bioequivalence studies using Student t-test showed similarity between the generic drugs from these studies in the extent of clopidogrel absorption and its conversion to clopidogrel carboxylic acid, but not in terms of the rate of these processes. Since the extent of absorption is clinically more important compared to the rate of this process, these differences were deemed not statistically significant. A joint semi-physiological population pharmacokinetic model for clopidogrel and clopidogrel carboxylic acid was developed and validated using the nonlinear mixed effects modeling approach. Model included linear absorption with 2 transit compartments, hepatic compartment for describing clopidogrel presystemic metabolism to metabolites, one-compartment model for clopidogrel, two-compartment model for clopidogrel carboxyl acid, linear elimination of this metabolite, allomeric scaling of clearance and volume of distribution. The developed model provides a solid base for potential future improvements in building a more complex model. This research uses state-of-the-art methods for analyzing secondary and/or primary data available for generic clopidogrel drugs and provides additional information on interchangeability of these drugs, especially for cases where traditional regulatory approaches may not suffice. It provides additional data that can inform clinical decision-making and optimize the use of generic clopidogrel products in practice
Prevalence of fermented foods consumption in a Serbian young adult population
No full textAlthough it is known that fermented foods have a long tradition in human nutrition, there is
not much available data on the prevalence of their consumption in general and specific
population groups ..
A linear solvation energy relationship analysis of selected imidazoline derivatives in reversed-phase thin-layer chromatography
No full textA linear solvation energy relationship (LSER) analysis of 19 selected imidazoline derivatives was performed using retention data obtained from four different thin-layer chromatography (TLC) systems with the same mobile phase consisting of methanol‒water‒ammonia and with different polarities of the stationary phase (CN, RP2, RP8, and RP18). Stepwise multiple linear regression and partial least square regression were applied to examine the most significant Abraham’s descriptors affecting retention under the investigated conditions. The results obtained showed that the Abraham descriptors with the most significant contribution to the retention mechanism in all studied TLC systems were molecular volume (V) and solute basicity (B), with V having a positive influence and B a negative influence on retention. All models created met very strict internal and external validation criteria, indicating their high reliability in predicting the retention behavior of compounds containing the imidazoline scaffold. Furthermore, correlation studies between retention data and pharmacokinetic properties, such as volume of distribution, rate of brain penetration, and blood‒brain partition coefficient revealed the potential of the examined reversed-phase systems as an alternative biomimetic tool for the rapid profiling of novel imidazoline analogs
Single subanesthetic dose of ketamine exerts antioxidant and antidepressive-like effect in ACTH-induced preclinical model of depression
No full textHyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive N-methyl-D-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, ip) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, sc, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O2·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O2.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression