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Assessing potentially inappropriate medication use among older adults in Central and Eastern Europe
No full textObjective: The aim of this study was to examine the prevalence of potentially inappropriate medication (PIM) use and its associated risk factors in community-dwelling older adults from five Central and Eastern European (CEE) countries. Materials and methods: This secondary analysis of a cross-sectional survey, which was part of the Horizon 2020 EuroAgeism ESR7 project, was conducted between February 2019 and March 2020 in Bulgaria, Croatia, Czechia, Estonia, and Serbia. We enrolled older adults aged ≥65 years who visited community pharmacies to acquire medications. The prevalence of PIM use was determined by applying all 282 criteria from the EU(7)-PIM list. Risk and protective factors for PIM use were evaluated using multiple logistic regression. R software version 4.3.2 was used in statistical analysis. Results: Most of the 2,155 participants were women (63.3%) and aged 65–74 years (64.8%). The overall PIM prevalence was 56.0% (95% confidence interval 53.8%–58.1%), ranging from 29.5% in Czechia to 70.0% in Croatia. The most commonly used PIMs were benzodiazepines (16.7% of all PIMs), followed by nonsteroidal anti-inflammatory drugs (14.3%), and proton pump inhibitors taken for more than 8 weeks (14.1%). Multiple logistic regression revealed that residence, increasing comorbidity burden, and polypharmacy were significant risk factors associated with PIM use in older adults. Conclusions: Our findings demonstrate a high prevalence of PIM use among older patients from CEE countries and considerable cross-country differences, underscoring the need to improve medication prescribing for older adults to improve healthcare quality and patient outcomes
Cardiotoxicity of Gaseous Poisons
No full textCardiotoxicity resulting from gaseous pollutants can present diverse symptoms, contingent upon the gas kind, concentration, and exposure length. The issue is a major concern in medicine, especially in nations where air quality fails to meet legal standards and levels of gaseous pollutants exceed permissible limits. Common symptoms of cardiotoxicity due to gaseous poisons include chest pain, a sensation of pressure or tightness in the chest, palpitations, shortness of breath potentially accompanied by a feeling of suffocation, dizziness or lightheadedness resulting from diminished oxygen delivery to the brain, syncope, fatigue or weakness often attributable to reduced oxygen supply and cardiac function, nausea or vomiting, cyanosis, hypotension, and arrhythmias. Some well-known gaseous substances that are cardiotoxic include carbon monoxide (CO), sulfur dioxide (SO2), nitrogen dioxide (NO2), chlorine (Cl), cyanide gas (HCN) etc. Interference with the oxigen transport could affect almost all tissues, while other four mechanisms, direct myocardial damage, electrophysiological alterations, inflammatory responses, and autonomic nervous system disruption could be hazardous, as well, and cause severe carditoxicity
N-3 Fatty Acids (EPA and DHA) and Cardiovascular Health - Updated Review of Mechanisms and Clinical Outcomes
No full textPurpose of Review: We synthesize the latest evidence (published 2020 to 2025) on the role of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in cardiovascular health, emphasizing biological mechanisms and key findings from observational studies and clinical trials related to cardiovascular disease (CVD) risk and outcomes. Recent Findings: EPA and DHA modulate lipid metabolism, inflammation, platelet and endothelial function, the gut-heart axis, ion channels and autonomic function via vagal tone, supporting cardiovascular health. While individual RCTs have produced variable results, updated cohort data and recent meta-analyses consistently link higher intake or circulating levels of EPA and DHA to reduced risk of cardiovascular events. However, evidence from RCTs indicates that high-dose supplementation may be associated with an increase in atrial fibrillation (AF) risk. Summary: Evidence supports a role for EPA and DHA in CVD prevention and treatment, with effects influenced by dose, formulation, and individual variability. Moderate intake appears safe and protective, while high dose EPA may offer added benefits in high-risk individuals but also might increase AF risk
Zadovoljstvo korisnika uslugama u javnim apotekama
No full textCustomer satisfaction reflects the quality of pharmaceutical services and depends on
various factors, such as the quality of services, pharmacists’ skills and customer’ demographic
characteristics. Positive experiences strengthen customer trust and loyalty. Research into user
satisfaction is an important tool for improving services. The aim of the work was the analysis of
user satisfaction with pharmacy services in Serbia over the last twelve years. Annual reports on
user satisfaction in pharmacies from 2013 to 2024 were analyzed. Based on key indicators, a
report was prepared comparing satisfaction over the years, taking into account various factors and
service quality. With the exception of 2020, public, private and health center pharmacies
participated every year. The highest response rate was recorded in 2015. More than 60% of users
visit a pharmacy more than five times a year, usually waiting less than five minutes. The highest
level of satisfaction with the availability of medicines was recorded in 2021, while overall
satisfaction with services peaked in 2022. User satisfaction has remained stable, indicating good
availability and quality of pharmaceutical services. The results may contribute to further
improvement in practice.Zadovoljstvo pacijenata odražava kvalitet farmaceutskih usluga i zavisi od više faktora, kao što su kvalitet usluge, veštine farmaceuta i demografske karakteristike korisnika. Pozitivna iskustva jačaju poverenje i lojalnost pacijenata. Istraživanja zadovoljstva korisnika su važan alat za unapređenje usluga. Cilj rada bila je analiza zadovoljstva korisnika apotekarskim uslugama u Srbiji tokom poslednjih dvanaest godina. Analizirani su jednogodišnji izveštaji o zadovoljstvu korisnika u apotekama u periodu od 2013. do 2024. godine. Na osnovu ključnih indikatora izrađen je izveštaj koji poredi zadovoljstvo po godinama, uzimajući u obzir različite faktore i kvalitet usluge. Osim 2020. godine, svake godine su učestvovale apoteke u državnom i privatnom vlasništvu kao i apoteke u okviru domovima zdravlja. Najveći odziv ispitanika zabeležen je 2015. godine. Više od 60% korisnika godišnje poseti apoteku više od pet puta, uz čekanje kraće od pet minuta. Najveće zadovoljstvo snabdevenošću zabeleženo je 2021. godine, a ukupnim uslugama 2022. godine. Zadovoljstvo korisnika je stabilno, što ukazuje na dostupnost i kvalitet farmaceutskih usluga. Rezultati mogu doprineti daljem unapređenju prakse
Izrada oralno-disperzibilnih filmova metodom 3D štampanja ekstruzijom polučvrstog materijala - fleksibilan pristup izradi farmaceutskih oblika
No full textOrodispersible films (ODFs) emerged as a patient-friendly dosage form that is particularly
suitable for pediatric therapy, where swallowing difficulties often interfere with adherence to
therapy. In this study, the preparation of ODFs using semi-solid extrusion (SSE) 3D printing was
investigated as an alternative to the conventional solvent casting method. Four hydrophilic
polymers – hydroxypropyl cellulose (HPC), polyethylene glycol-polyvinyl alcohol graft
copolymer (PVA-PEG), maltodextrin (MDX) and sodium alginate (SA) – were used either
individually or in binary blends, with caffeine selected as the model active ingredient. Films were
printed on an Ultimaker 2+ system and evaluated for uniformity, thickness, porosity, moisture
content, mechanical strength, disintegration and drug release. Formulations containing only MDX
or PVA-PEG exhibited poor printability due to leakage and spreading, while other systems
showed reproducible film deposition and satisfactory dimensional stability. Binary blends
generally resulted in increased film thickness. SA-based films showed the lowest porosity and
moisture absorption, while HPC films exhibited favorable mechanical properties. The
investigated samples achieved rapid disintegration and complete release of the caffeine. These
results confirm the potential of SSE 3D printing as a versatile manufacturing platform for
customizable ODFs that enable precise dosing and patient-centric design for pediatric drugs.Oralno-disperzibilni filmovi (ODF) predstavljaju farmaceutski oblik posebno pogodan za primenu kod pedijatrijskih pacijenata gde poteškoće pri gutanju često utiču na adherencu. U ovom radu je ispitana mogućnost izrade ODF korišćenjem 3D štampanja metodom ekstruzije polučvrstog materijala (SSE) kao alternativne metode konvencionalnom izlivanja disperzija. Korišćena su četiri hidrofilna polimera - hidroksipropilceluloza (HPC), polietilenglikol-polivinil alkohol graft kopolimer (PVA-PEG), maltodekstrin (MDX) i natrijum-alginat (SA) - pojedinačno ili u binarnim mešavinama, a kofein je izabran kao model aktivna supstanca. Filmovi su štampani korišćenjem 3D štampača Ultimaker 2+ i procenjivana je njihova uniformnost, debljina, porozitet, sadržaj vlage, mehaničke karakteristike, raspadljivost i brzina oslobađanja kofeina iz filmova. Formulacije koje sadrže samo MDX ili PVA-PEG nisu bile pogodne za štampanje usled curenja disperzije iz mlaznica, dok su druge formulacije štampane nanošenjem uniformnih slojeva i imale su zadovoljavajuću strukturnu stabilnost. Binarne mešavine su generalno dovele do povećanja debljine filma. Filmovi izrađani sa SA imali su niske vrednosti poroziteta i sadržaja vlage, dok su HPC filmovi pokazali povoljne mehaničke karakteristike. Ispitani uzorci su se brzo raspadali i imali potpuno oslobađanje kofeina. Dobijeni rezultati potvrđuju potencijal SSE 3D štampe kao fleksibilne metode za izradu ODF koji omogućavaju precizno doziranje i dizajn usmeren na pojedinačnog pacijenta, posebno za pedijatrijske lekove
Comparison of different approaches to the design space computation: example of stability-indicating method for citalopram tablets
No full textNa osnovu definicije iz ICH Q14, prostor dizajna za analitičke metode može se opisati kao podskup ispitivanih eksperimentalnih uslova za koje se može, sa dovoljnom verovatnoćom, pokazati da metoda ispunjava unapred definisane kriterijume [1]. Distribucija odgovora treba da se simulira, a eksperimentalni uslovi, za koje je verovatnoća da se ključni atributi kvaliteta (CQA) nalaze unutar prihvatljivog regiona iznad željenog nivoa kvaliteta (p), treba da budu uključeni u prostor dizajna. Mogu se primeniti Monte Karlo simulacije, bootstrap metode i Bajesova analiza [2], pri čemu se poslednji pristup preferira jer uzima u obzir i nesigurnost parametara modela i korelacije podataka [3]. Cilj ove studije bio je da se ispitaju razlike između tri pristupa za određivanje prostora dizajna hromatografske metode za ispitivanje stabilnosti citaloprama u tabletama. Kao CQAs (Y) izabrani su retencioni faktor nečistoće A (k) i rezolucija između citaloprama i nečistoće E (Rs), a kao kritični procesni parametri (X) sadržaj acetonitrila koncentracija perhlorata u mobilnoj fazi, kao i temperatura kolone. Prihvatljivi region za CQAs definisan je kao ���� = {(����,��������):���� > 1,�������� > 2}, a prostor dizajna kao DS = {x∈����|����(Y∈����)≥����}, pri čemu je p = 0,9. Kontur dijagrami koji prikazuju zavisnost verovatnoće od sadržaja acetonitrila i temperature kolone pri pet različitih koncentracija perhlorata nisu pokazali značajne razlike, što se može pripisati niskoj nesigurnosti parametara modela (0,0015-0,0240) i slaboj korelaciji regresionih reziduala (-0,26). Potrebne je ispitati veći opseg nesigurnosti parametra, korelacije reziduala i slično, kako bi se utvrdile oblasti praktične ekvivalentnosti ispitivanih pristupa.Based on the ICH Q14 definition, design space for analytical methods can be described as a subset
of investigated experimental conditions for which it can be demonstrated, with sufficient probability, that
method fulfills predefined criteria [1]. The response distribution should be simulated and the
experimental conditions, for which the probability that the critical quality attributes (CQAs) are within
acceptance region is above the desired quality level (π), should be included in the design space. Monte-
Carlo simulations, bootstrapping, and Bayesian analysis [2] can be applied, with the last approach
preferred as it accounts for both model parameter uncertainty and data correlations [3]. This study aimed
to investigate differences between the three approaches to derive the design space for a chromatographic
stability-indicating method for citalopram tablets. Retention of impurity A (k) and resolution between
citalopram and impurity E (R s) were selected as CQAs (Y), while acetonitrile content, perchlorate
concentration in the mobile phase, and column temperature were critical process parameters (X). The
acceptance region for CQAs was set as = {(, ): > 1, > 2} and the design space as DS =
{x ∈ ∣ (Y ∈ ) ≥ } with π = 0.9. Contour plots showing the dependence of the probability on
acetonitrile content and column temperature at five different perchlorate concentrations showed no
significant differences, which can be attributed to the low uncertainty of the model parameters (0.0015–
0.0240) and weak correlation of regression residuals (–0.26). A wider range of parameter uncertainties,
residual correlations, etc. need to be investigated to determine areas of practical equivalence of the
examined approaches
Sustainability by design – A new paradigm for drug product life-cycle management
No full textThe essential principle of sustainable development is to “meet the needs of the present without compromising the ability of future generations to meet their own needs” [1]. In order to achieve this, a paradigm shift is necessary in the way we think and act as citizens and professionals. Scientists in different disciplines are expected to integrate sustainability principles in their work, investigate topics associated with sustainable development and provide solutions for sustainability challenges [2, 3].
The Sustainability by Design (SbD) in pharmaceutical sciences emphasizes the integration of sustainability principles across the entire drug product life cycle. In this work, key dimensions of SbD in different stages of pharmaceutical product life cycle, relevant tools and points of action are reviewed:
• Research and development based on: (i) predictive modelling of pharmaceutical safety and efficacy, (ii) green chemistry principles, (iii) patient-centric product design, and (iv) early environmental impact assessment.
• Manufacturing and distribution incorporating the principles of ecological footprint minimization through employment of: (i) renewable resources and waste minimization, (ii) biodegradable, recyclable active pharmaceutical ingredients, excipients and packaging materials, and (iii) process digitalization.
• Clinical use guided by: (i) rational prescribing; (ii) precision dosing, (iii) enhanced adherence, and (iv) incorporation of digital health tools, leading to therapy optimisation and improved health outcomes, while avoiding pharmaceuticals overuse and reducing waste.
SbD paradigm in pharmaceutical sciences is an advanced, interdisciplinary concept which extends beyond the laboratory benchtop and manufacturing site to align pharmaceutical innovation with the broader objectives of environmental stewardship, pharmacoeconomic efficiency, and improved patient health outcomes.Koncept održivog razvoja zasniva se na principu da “se potrebe sadašnjeg društva zadovolje bez ugrožavanja mogućnosti budućih generacija da ostvare svoje potrebe” [1]. Ostvarivanje ovog principa zahteva promenu načina razmišljanja i postupanja, kako na ličnom, tako i na profesionalnom planu. Od istraživača u svim oblastima nauke očekuje se integracija principa održivosti u naučni i stručni rad, proučavanje tema povezanih sa održivim razvojem i formulisanje rešenja usmerenih ka prevazilaženju izazova u postizanju održivosti [2, 3].
Paradigma “Održivost kroz dizajn” u farmaceutskim naukama podrazumeva integraciju principa održivog razvoja u sve faze životnog ciklusa leka. U ovom radu razmatrane su ključne dimenzije koncepta “Održivost kroz dizajn” u različitim fazama životnog ciklusa leka, odgovarajući alati i aktivnosti:
• Istraživanje i razvoj zasnovani na: (i) prediktivnom modelovanju efikasnosti i bezbednosti, (ii) primeni principa zelene hemije, (iii) dizajnu proizvoda usmerenom na pacijenta, (iv) ranu procenu uticaja na životnu sredinu.
• Proizvodnja i distribucija sa minimizovanim uticajem na životnu sredinu kroz: (i) upotrebu obnovljivih resursa i smanjenje otpada, (ii) primenu biorazgradivih aktivnih farmaceutskih supstanci i ekscipijenasa, kao i reciklabilnih materijala za pakovanje, (iii) digitalizaciju procesa.
• Klinička primena koja podrazumeva: (i) racionalno propisivanje lekova, (ii) precizno doziranje, (iii) unapređenje adherence i (iv) integraciju digitalnih alata, što omogućava optimizaciju terapije i poboljšanje zdravstvenih ishoda uz izbegavanje prekomerne upotrebe lekova, kao i smanjenje otpada.
Paradigma “Održivost kroz dizajn” u farmaceutskim naukama predstavlja savremen, interdisciplinarni koncept koji prevazilazi okvire laboratorijskih istraživanja i tradicionalnih proizvodnih procesa, sa ciljem da se inovacije usklade sa širim prioritetima očuvanja životne sredine, farmakoekonomske efikasnosti i unapređenih zdravstvenih ishoda pacijenata
The influence of the type and ratio of hydrophilic polymers on the pharmaceutical-technological and biopharmaceutical characteristics of solid dispersions with clopidogrel hydrogen sulfate
No full textRazvoj formulacija lekova je poslednjih godina postao posebno izazovan zbog novih aktivnih supstanci koje imaju zahtevna fizičkohemijska svojstva, zbog potrebe farmaceutskih kompanija da se lekovi što pre plasiraju na tržište, kao i zbog sve strožijih zahteva regulatornih tela. Preko 40% aktivnih supstanci, koje se koriste u terapiji i preko 60% onih koji se nalaze u nekoj od faza istraživanja, spada u grupu slabo rastvorljivih aktivnih supstanci. Formulacija čvrstih disperzija je jedan od aktuelnih pristupa za povećanje rastvorljivosti i brzine rastvaranja slabo rastvorljivih aktivnih supstanci. Klopidogrel je inhibitor aktivacije i agregacije trombocita. Najčešće se koristi u obliku soli, klopidogrel-hidrogensulfata, koja ima nisku i pH-zavisnu rastvorljivost, što ograničava njegovu bioraspoloživost i terapijsku efikasnost. Klopidogrel je pro-lek, samo oko 2% primenjene doze klopidogrela se metaboliše u aktivni oblik i dospeva u sistemsku cirkulaciju, a uz to ima i izraženu interindividualnu varijabilnost. Iz navedenih razloga, cilj istrаživаnjа ove doktorske disertаcije bila je formulаcijа, izrаdа i fаrmаceutsko-tehnološkа i biofаrmаceutskа kаrаkterizаcijа čvrstih disperzijа sа slаbo rаstvorljivom model аktivnom supstаncom, klopidogrel-hidrogensulfаtom, u cilju povećаnjа brzine rаstvаrаnjа nаvedene аktivne supstаnce.U prvoj fazi eksperimentalnog rada formulisano je i izrađeno dvadeset čvrstih disperzija sa različitim hidrofilnim polimerima (kopovidon, makrogol 6000, poloksamer 407 i povidon K30) i različitim odnosima aktivna supstanca/polimer (1:1, 1;2; 1:3; 1:5 i 1:9), u cilju povećanja brzine rastvaranja aktivne supstance. Rezultati in vitro ispitivanja brzine rastvaranja su pokazali da vrsta i udeo hidrofilnog polimera imaju bitnu ulogu u povećanju brzine rastvaranja klopidogrel-hidrogensulfata. Najveći procenat klopidogrel-hidrogensulfata (96,38%, nakon 60 minuta) se rastvorio iz čvrste disperzije sa poloksamerom 407, pri udelu aktivna supstanca/polimer 1:9.U drugoj fazi istraživanja sprovedena je karakterizacija odabranih čvrstih disperzija primenom metoda diferencijalne skenirajuće kalorimetrije (DSC), infracrvene spektrofotometrije sa Furijeovom transformacijom (FT-IR) i difrakcije X-zraka na prašku (PXRD), kao i određivanje sadržaja klopidogrela. U svim ispitivanim uzorcima potvrđeno je prisustvo klopidogrel-hidrogensulfata u amorfnom obliku, a sadržaj klopidogrela je bio u dozvoljenim granicama odstupanja (± 5%). Rezultati ponovljenih ispitivanja, nakon 12 meseci skladištenja uzoraka pod kontrolisanim uslovima (25 ± 2 °C i vlažnost vazduha 60 ± 5%), ukazali su na njihovu dobru stabilnost. Međutim, rezultati ispitivanja in vitro brzine rastvaranja klopidogrel-hidrogensulfata iz čvrstih disperzija sa makrogolom 6000 su pokazali da je nakon 12 meseci došlo do velikog smanjenja količine rastvorenog klopidogrel-hidrogensulfata. Ovi rezultati su ukazali na neprihvatljivu stabilnost, odnosno na neprihvatljiv kvalitet čvrstih disperzija sa makrogolom 6000, pri odnosima aktivna supstanca/polimer 1:5 i 1:9.U trećoj fazi istraživanja ispitivane su karakteristike čvrstih disperzija prihvatljive stabilnosti (sa kopovidonom i poloksamerom 407, pri udelima aktivna supstanca/polimer 1:5 i 1:9) značajne za njihovu dalju obradu u finalni farmaceutski oblik (tablete i kapsule). Dobijeni rezultati ispitivanja veličine i raspodele veličina čestica, stvarne, nasipne i tapkane gustine, određivanja protočnosti, kompresibilnosti, poroziteta, sadržaja vlage i reoloških parametara su ukazali da ispitivane čvrste disperzije imaju prihvatljive osobine za obradu u finalni farmaceutski oblik.U četvrtoj fazi istraživanja, primenom kompjuterskog programa GastroPlus™, uspešno je razvijen i validiran klopidogrel-specifični, fiziološki zasnovan biofarmaceutski (PBBM) model, koji na odgovarajući način opisuje apsorpciju i distribuciju klopidogrela nakon intravenske i peroralne primene. Izgrađeni PBBM model je korišćen za ispitivanje uticaja vrste i udela hidrofilnih polimera na apsorpciju, distribuciju i posledično, bioraspoloživost aktivne supstance...The development of drug formulations has become a particular challenge in recent years, as the physico-chemical properties of new active pharmaceutical ingredients are becoming increasingly complex, the pharmaceutical industry is demanding a rapid market launch and regulatory requirements are becoming ever stricter. More than 40 % of marketed active pharmaceutical ingredients and over 60 % of drug candidates in development belong to the class of poorly soluble substances. The formulation of solid dispersions is one of the current approaches to increasing the solubility and dissolution rate of poorly soluble active substances. Clopidogrel is an inhibitor of platelet activation and aggregation. It is most commonly used in the form of a salt, clopidogrel hydrogen sulfate, which has a low and pH-dependent solubility, limiting its bioavailability and therapeutic efficacy. Clopidogrel is a pro-drug, only about 2% of the clopidogrel dose administered is converted to an active form and enters the systemic circulation, and there is marked inter-individual variability. For these reasons, the research objective of this dissertation was the formulation, preparation and pharmaceutical-technological and biopharmaceutical characterization of solid dispersions with a poorly soluble model drug, clopidogrel hydrogen sulfate, in order to increase the dissolution rate of the listed active substances.In the first phase of the experimental work, twenty solid dispersions were formulated and prepared with different hydrophilic polymers (copovidone, macrogol 6000, poloxamer 407 and povidone K30) and different drug/polymer ratios (1:1, 1;2; 1:3; 1:5 and 1:9) to increase the dissolution rate of the drug. The results of the in vitro dissolution rate test showed that the type and ratio of hydrophilic polymer play an important role in increasing the dissolution rate of clopidogrel hydrogen sulfate. The highest percentage of clopidogrel hydrogen sulfate (96.38%, after 60 minutes) was dissolved from the solid dispersion with poloxamer 407 at a drug/polymer ratio of 1:9.In the second phase of the study, the characterization of the selected solid dispersions was carried out using the methods of differential scanning calorimetry (DSC), Fourier transform infrared spectrophotometry (FT-IR) and powder X-ray diffraction (PXRD), as well as the determination of the clopidogrel content. The presence of clopidogrel hydrogen sulfate in amorphous form was confirmed in all samples analysed, and the clopidogrel content was within the acceptable limits (± 5%). The results of repeated tests after 12 months of storage of the samples under controlled conditions (25 ± 2 °C and 60 ± 5 % RH) indicated their good stability. However, the results of testing the in vitro dissolution rate of clopidogrel hydrogen sulfate from solid dispersions with macrogol 6000 showed that there was a sharp decrease in the amount of dissolved clopidogrel hydrogen sulfate after 12 months. These results indicate an unacceptable stability, i.e. an unacceptable quality of the solid dispersions with macrogol 6000 at drug/polymer ratios of 1:5 and 1:9.In the third phase of the research, the characteristics of solid dispersions with acceptable stability (with copovidone and poloxamer 407, at a 1:5 and 1:9 drug/polymer ratio) were studied, which are important for further processing into the final pharmaceutical form (tablets and capsules). The results of testing the particle size and distribution of particle size, true density, bulk and tapped density, determination of flowability, compressibility, porosity, moisture content and rheological parameters showed that the solid dispersions tested had acceptable properties for processing into the final dosage form.In the fourth phase of the research, a clopidogrel-specific physiologically based biopharmaceutical model (PBBM) was successfully developed and validated using GastroPlus™ software. The model adequately described the absorption and distribution of clopidogrel after both intravenous and oraladministration..
Vortioxetine in inflammatory pain models: mechanism of action, effect on cognitive abilities and redox status of cardiomyocytes
No full textBol je kompleksno, multidimenzionalno iskustvo koje oblikuju biološki, psihološki i socijalni faktori. Među najčešćim bolnim stanjima izdvajaju se inflamatorni bolovi, uključujući osteoartritis.Ciljevi ovog rada su bili ispitivanje efekata i mehanizama dejstva vortioksetina u modelima inflamatornog bola, kao i uticaja leka na kognitivne performanse, opštu dobrobit, redoks status i histološke promene kardiomiocita kod mužjaka i ženki pacova sa osteoartritisom.Efekti vortioksetina su ispitani u modelima akutnog inflamatornog trigeminalnog, visceralnog i somatskog bola, kao i u modelu osteoartritisa. Mehanizam dejstva vortioksetina u modelu trigeminalnog bola je ispitan primenom odgovarajućih receptorskih antagonista. U modelu osteoartritisa, praćen je uticaj leka na molekularne markere bolne preosetljivosti, parametre oksidativnog stresa u kolenu pacova, kognitivne performanse i opštu dobrobit životinja, kao i na parametre redoks statusa i histološke promene kardiomiocita.Vortioksetin je ostvario značajne efekte u svim ispitivanim modelima bola. U modelu trigeminalnog bola je pokazano učešće serotonergičkih 5-HT1B/1D, α2/β1 adrenergičkih, muskarinskih, α7 nikotinskih, kanabinoidnih CB1/CB2, adenozinskih A1 receptora. Vortioksetin je smanjio ekspresiju Ngf i nivo markera oksidativnog stresa u kolenu pacova oba pola; smanjio je ekspresiju iRNK za markere neuroinflamacije u spinalnim gangljima i kičmenoj moždini mužjaka, ali ne i ženki pacova. Dodatno, vortioksetin je poboljšao kognitivne performanse životinja sa osteoartritisom bez štetnog uticaja na opštu dobrobit životinja i redoks status i histološke promene kardiomiocita.Rezultati ukazuju da bi vortioksetin mogao biti efikasan u terapiji inflamatornih bolnih stanja, sa korisnim efektima na kognitivnu funkciju.Pain is a complex, multidimensional experience shaped by biological, psychological, and social factors. Among the most prevalent pain conditions are inflammatory pain conditions, including osteoarthritis.The aim of this study was to investigate the effects and mechanisms of action of vortioxetine in models of inflammatory pain, as well as the drug’s impact on cognitive performance, general well-being, redox status, and histological changes in cardiomyocytes in male and female rats with osteoarthritis.Vortioxetine's effects were evaluated in models of acute inflammatory trigeminal, visceral, and somatic pain, as well as in a model of osteoarthritis. In the trigeminal pain model, its mechanism of action was assessed using selective receptor antagonists. In the osteoarthritis model, the drug’s influence was monitored on molecular markers of pain hypersensitivity, oxidative stress parameters in the rat knee, cognitive performance, general well-being, as well as on redox status and histological alterations in cardiomyocytes.Vortioxetine achieved significant effects in all pain models tested. In the trigeminal pain model, involvement of serotonergic 5-HT1B/1D, α2/β1-adrenergic, muscarinic, α7-nicotinic, cannabinoid CB1/CB2, and adenosine A1 receptors was demonstrated. Vortioxetine reduced Ngf expression and oxidative stress markers in the knees of both sexes; it also decreased mRNA expression of neuroinflammatory markers in the spinal ganglia and spinal cord of male, but not female rats. Additionally, vortioxetine improved cognitive performance in osteoarthritic animals without negative effects on general well-being, redox status, or cardiomyocyte histology.The results suggest that vortioxetine may be effective in treating inflammatory pain conditions, with beneficial effects on cognitive function
Klinički aspekti terapijskog praćenja ciklosporina u pedijatrijskoj populaciji pacijenata sa transplantiranim bubregom
No full textCyclosporine A (CsA) is an immunosuppressive used in both children and adult transplant
recipients, as well as patients with autoimmune diseases such as nephrotic syndrome. Therapeutic
drug monitoring (TDM) of CsA is essential due to its significant interindividual and
intraindividual pharmacokinetic variability, narrow therapeutic index and the risk of organ
rejection or autoimmune disease relapse at subtherapeutic levels, as well as the potential for
serious adverse effects with overexposure. In pediatric patients, CsA pharmacokinetics can be
significantly influenced by developmental physiological factors, necessitating even greater
attention to TDM in this vulnerable population. This paper explores the key challenges associated
with TDM in children, the clinical rationale for its use, clinical settings where it is applied and
future perspectives, including the potential of model-informed precision dosing (MIPD).Ciklosporin A (CsA) je imunosupresiv koji se koristi kod dece i odraslih pacijenata sa
transplantiranim organom, kao i kod pacijenata sa autoimunim bolestima kao što je nefrotski
sindrom. Terapijsko praćenje ciklosporina (TDM) je ključno za optimizaciju terapije zbog velike
interindividualne i intraindividualne farmakokinetičke varijabilnosti, uskog terapijskog indeksa,
rizika od odbacivanja organa ili recidiva autoimune bolesti ukoliko su nivoi CsA preniski, ili
pojave neželjenih efekata usled prekomerne izloženosti leku. Kod dece, farmakokinetika CsA
može biti izmenjena zbog razvojnih fizioloških faktora, tako da treba posvetiti više pažnje
sprovođenju TDM u ovoj osetljivoj populaciji. U ovom radu biće opisani ključni izazovi
sprovođenja TDM u pedijatrijskoj populaciji, razlog zbog koga se i kada sprovodi u kliničkoj
praksi, kao i savremene strategije za optimizaciju terapije kao što je doziranje zasnovano na
upotrebi modela