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Computer-Aided Drug Design of novel dual histone deacetylase inhibitors
No full textHistone deacetylases (HDACs) are epigenetic regulators involved in
cancer development. Although several non-selective HDAC inhibitors have been approved, their
clinical use is limited by toxicity and off-target effects. To improve selectivity and efficacy, newer
strategies focus on dual-target inhibitors that modulate other cancer-related signaling pathways
in addition to HDACs. In this study, structure-based modeling and docking were used to
develop novel dual inhibitors targeting HDAC6 or sirtuin2 (SIRT2) in combination with Aurora
kinase A (AURKA), glutaminase (GLS) or WEE1 kinase, guided by pharmacophore models. The
developed compounds showed strong predicted binding and favorable ADMET profiles. We
present nine promising dual inhibitors for HDAC6/WEE1, HDAC6/GLS1 and SIRT2/AURKA
with improved or comparable properties to the reference ligands
Harnessing multiomics technologies and machine learning for advancing personalised theranostic approaches in atherosclerosis
No full textEvidence-based lipid-lowering therapies have significantly reduced, but not eradicated, atherosclerosis-induced cardiovascular disease (ASCVD), which remains a significant cause of morbidity and mortality around the world. This article focuses on precision medicine and examines the transformative potential of multiomics and machine learning (ML) in advancing theranostic approaches for atherosclerosis. The integration of multimodal data, known as Multiomics, encompassing genomics and epigenomics, transcriptomics and epitranscriptomics, proteomics, metabolomics, and lipidomics, can support the comprehensive interrogation of molecular changes associated with disease initiation and progression. ML algorithms are critical for identifying pertinent features of highly diverse and heterogeneous multi-omic datasets. The combination of these new laboratory and data science technologies offers unprecedented opportunities for increasing precision in disease prediction, early detection, and monitoring, as well as more personalised treatments with current and new drugs. This article discusses the implications. It discusses their importance in the development and adoption of personalised medicine based on therapeutic approaches (Figure 1)
Iskustva žena sa upotrebom antibiotika kod urinarnih infekcija - uvidi iz perspektive pacijentkinja
No full textFrom patients’ perspective, the use of antibiotics to treat urinary tract infections (UTIs) in
Serbia is unexplored, and therefore the aim of this study is to examine antibiotic use among these
patients. An online cross-sectional study using snowball sampling was conducted during the
winter of 2020/21 using a validated Google Docs questionnaire. The study included 236 female 299 patients with a mean age of 34.9 ± 14.2 years. Most of the patients perceived UTI symptoms as
severe (62.3%) and disruptive for their daily routines (51.3%). The majority of the patients
(77.1%) used antibiotics by doctors’ prescriptions. Other patients used antibiotics on their own
and their selection. Self-treatment with antibiotics was associated with perceived symptom
severity (p=0.006) and residence (p=0.017). In total, 17 different antibiotics were reported as
being used for UTI treatment and the most frequent were fluoroquinolones (30.3%),
cephalosporins (21.2%), and sulfonamides (15.7%). The highest consistency with national and
European guidelines in doctors’ decisions on antibiotic therapy was observed for treating UTIs in
pregnant women (80.0%). These findings emphasize the need for education of healthcare
professionals and clinical practice improvement in making rational antibiotic prescribing
decisions.Upotreba antibiotika u lečenju infekcija urinarnog trakta (IUT) u Srbiji je nedovoljno istražena, posebno iz ugla pacijenata, te je cilj studije da se ispita upotreba antibiotika kod ovih pacijenata. Sprovedena je onlajn studija preseka tokom zime 2020/21. godine, korišćenjem validiranog Google Docs upitnika i tehnike snežne grudve. Studija je obuhvatila 236 pacijenta ženskog pola, prosečne starosti 34,9 ± 14,2 godina. Većina pacijenata smatrala je simptome ozbiljnim (62,3%), i da simptomi ometaju njihove svakodnevne aktivnosti (51,3%). Većina pacijenata (77,1%) je koristila antibiotike propisane na lekarski recept. Ostali pacijenti su koristili antibiotike samostalno, po sopstvenom izboru. Samolečenje antibioticima je bilo povezano sa percepcijom ozbiljnosti simptoma (p=0,006) i prebivalištem (p=0,017). Pacijenti su prijavili upotrebu 17 različitih antibiotika za lečenje IUT, od kojih su najzastupljeniji bili fluorohinoloni (30,3%), cefalosporini (21,2%) i sulfonamidi (15,7%). Najveća usklađenost primene antibiotika sa nacionalnim i evropskim smernicama uočena je kod trudnica (80,0%). Rezultati istraživanja ističu potrebu za edukacijom zdravstvenih profesionalaca i unapređenju kliničke prakse u donošenju odluka o racionalnom propisivanju antibiotika
Development of coated superparamagnetic nanoparticles labeled with 99mTc and 177Lu and testing their efficacy in an experimental model of breast and colon carcinoma
No full textS obzirom na rastuću stopu oboljevanja od malignih bolesti u svetu i nedovoljnu efikasnost postojećih terapija, veliki napori ulažu se u razvoj novih generacija dijagnostičkih i terapijskih lekova, sa smanjenom tendencijom izazivanja neželjenih reakcija. Nedostatak efikasnih strategija lečenja naglašava potrebu i za novim terapijskim pristupima. Poslednje dve decenije, sa ubrzanim razvojem nanostrukturnih materijala i nanomedicine uopšte, donose revolucionarne napretke u medicini i farmaciji.Superparamagnetne nanočestice (SMNČ) na bazi magnetita (Fe3O4) pokazale su značajnu prednost u odnosu na druge nanočestične materijale, zbog svojih povoljnih fizičko- hemijskih karakteristika, sposobnosti generisanja toplote kada se nađu u promenljivom magnetnom polju određene frekvencije, biokompatibilnosti i jednostavnog načina sinteze i funkcionalizacije. Više od jedne decenije, ove nanočestice su u upotrebi u terapiji određenih vrsta tumora magnetnom hipertermijom.Osnovni cilj istraživanja ove doktorske disertacije bio je razvoj novih radiofarmaceutika na bazi obloženih SMNČ obeleženih radionuklidima 99mTc i 177Lu za potencijalnu primenu u dijagnostici i terapiji karcinoma. Ovaj cilj je ostvaren kroz više pojedinačnih ciljeva koji su obuhvatali: sintezu stabilnih biokompatibilnih SMNČ i ispitivanje uslova za njihovo oblaganje biokompatibilnim jedinjenjima (MDP, HEDP i DMSA), fizičko-hemijsku karakterizaciju neobloženih i obloženih SMNČ, određivanje SAR vrednosti obloženih SMNČ, ispitivanje uslova obeležavanja obloženih SMNČ sa 99mTc i 177Lu, ispitivanje biološke raspodele radioobeleženih SMNČ po organima eksperimentalnih životinja (na pacovima i miševima) i in vivo ispitivanje terapijske efikasnosti radioobeleženih SMNČ nakon njihove intratumorske primene u BALB/c miševe sa indukovanim ksenograftima CT-26 i 4T1 mišjeg karcinoma kolona i dojke.Dobijeni rezultati pokazali su da se metodom koprecipitacije sintetišu SMNČ u dobrom prinosu (~ 65% u odnosu na teorijski izračunatu masu), a dobijene čestice su sfernog oblika, ujednačene veličine (prečnika ~11 nm) i morfologije (PdI vrednost od 28,3%), što ovu metodu čini najboljom metodom sinteze ovih SMNČ. Metode fizičko-hemijske karakterizacije su potvrdile da su oblaganjem površine SMNČ sa MDP, HEDP i DMSA dobijene biokompatibilne i stabilne nanosuspenzije, sa visokom vrednošću SAR parametra. Pod optimizovanim uslovima, dobijene su 99mTc i 177Lu radioobeležene SMNČ u visokom prinosu (>95%, odnosno >70%), visoke radiohemijske čistoće i stabilne u humanom serumu i fiziološkom rastvoru na 37 ℃ tokom ispitivanog vremenskog perioda. Rezultati ispitivanja biodistribucije tehnecijumom-99m obeleženih SMNČ nakon i.v. injekcije pacovima soja Wistar pokazali su da je najveći procenat nakupljanja u organima RES-a (>90%). Rezultati biodistribucije 177Lu-DMSA-SMNČ nakon i.t. injekcije BALB/c miševima sa indukovanim ksenograftima CT-26 i 4T1 tumora pokazali su da se radioobeležene čestice zadržavaju u tumorskom tkivu dovoljno dugo da zračenje može da izazove terapijski efekat. Terapijska efikasnost 177Lu-DMSA-SMNČ je zavisila od injektovane doze zračenja, kao i od početne veličine ksenografta.Dobijeni rezultati istraživanja pokazuju da intratumorska primena radioobeleženih nanočestica ima značajan potencijal u terapiji solidnih tumora, zahvaljujući postignutoj visokoj efikasnosti i dobrom bezbednosnom profilu.Vezivanjem radionuklida za različite funkcionalne grupe na površini obloženih, biokompatibilnih SMNČ dobija se potencijalni multifunkcionalni dijagnostički, terapijski i teranostički agens.In view of the growing rate of malignant diseases in the world and the insufficient effectiveness of existing therapies, great efforts are being invested in the development of new generations of diagnostic and therapeutic medicines with a lower tendency to adverse effects. The lack of effective treatment strategies underlines the need for new therapeutic approaches. The last two decades have brought revolutionary advances in medicine and pharmacy with the accelerated development of nanostructured materials and nanomedicine in general.Superparamagnetic nanoparticles based on magnetite (Fe3O4) (SPIONs) have shown a significant advantage over other nanoparticle materials, due to their favorable physical and chemical characteristics, the ability to generate heat when they are in a variable magnetic field of a certain frequency, biocompatibility and simple method of synthesis and functionalization. For more than a decade, these nanoparticles have been used in the therapy of certain types of tumors with magnetic hyperthermia.The main goal of the research of this doctoral dissertation was the development of new radiopharmaceuticals based on coated SPIONs labeled with radionuclides 99mTc and 177Lu for potential application in cancer diagnosis and therapy. This goal was achieved through a number of individual goals that included: synthesis of stable biocompatible SPIONs and examination of conditions for their coating with biocompatible compounds (MDP, HEDP and DMSA), physicochemical characterization of uncoated and coated SPONs, determination of SAR values of coated SPIONs, examination of labeling conditions coated SPIONs with 99mTc and 177Lu, examining the biological distribution of radiolabeled SPIONs in the organs of experimental animals (on rats and mice) and in vivo investigation of the therapeutic efficacy of radiolabeled SPIONs after their intratumoral administration in BALB/c mice with induced xenografts of CT-26 and 4T1 colon and murine mammary carcinomas.Based on the obtained results, it is considered that the coprecipitation method has a great advantage because it enables the synthesis of SPIONs in a good yield (~ 65% compared to the theoretically calculated mass), and spherical particles of uniform size (diameter ~11 nm) and morphology (PdI~28,3%). Physico-chemical characterization methods confirmed that biocompatible and stable nanosuspensions, with a high value of the SAR parameter, were obtained by coating the surface of SPIONs with MDP, HEDP and DMSA.Under optimized conditions, 99mTc and 177Lu radiolabeled SPIONs of high yield (>95% or >70%) and high radiochemical purity, stable in human serum and saline at 37℃ during the investigated time, were obtained. Results of the biodistribution study of technetium-99m labeled SPIONs after i.v. injections in Wistar rats showed that the highest percentage of accumulation was in the RES organs (>90%). Results of biodistribution of 177Lu-DMSA-SPIONs after i.t. injections into BALB/c mice with induced CT-26 and 4T1 tumor xenografts showed that the radiolabeled particles persisted in the tumor tissue long enough for the radiation to induce a therapeutic effect. The therapeutic efficacy of 177Lu- DMSA-SPION depended on the injected dose of radiation, as well as on the initial size of the xenograft. The obtained research results show that the intratumoral application of radiolabeled nanoparticles has a significant potential in the therapy of solid tumors, thanks to the achieved high efficiency and good safety profile.By binding radionuclides to different functional groups on the surface of coated, biocompatible SPIONs, a potential multifunctional diagnostic, therapeutic and theranostic agent is obtained
Primena proširenog termodinamičkog pristupa za opisivanje efekta katjona haotropnih agenasa i modifikatora jonske jačine na retenciono ponašanje protonovanih analita baznih osobina u haotropnoj hromatografiji
No full textIn this study, the extended thermodynamic approach was used to quantitatively explain the
effect of counterions, both of chaotropic agents and ionic strength modifiers, in variable (vI) and
constant ionic strength (cI) systems on the retention behavior of 23 fully protonated basic analytes.
Nine series of experiments (at three pH values for NaPF 6 , KPF 6 and NH4 PF 6 ) with vI and nine
series of experiments (at three pH values for NaPF6 , KPF 6 and NH4PF 6 ) with ionic strength kept
constant with NaCl, KCl and NH4 Cl were performed. The experimentally determined retention
factors were modeled using the extended thermodynamic approach and the processes occurring
in the stationary phase and in the mobile phase and their influence on retention in the investigated
chaotropic chromatography systems were rationalized. In both vI and cI systems, ion pair
formation in the stationary phase proved to be dominant over ion pair formation in the mobile phase. In the KPF 6 _vI systems, these interactions with the stationary phase were even more
pronounced than in the other systems. Although both K+ and NH 4+ are chaotropic in nature, the
formation of ion pairs in the stationary phase was favored by the presence of NH4+ only at its
rather high concentrations as in cI systems.U ovom radu, primenjen je prošireni termodinamički pristup kako bi se kvantitativno
objasnio efekat katjona haotropnih agenasa i modifikatora jonske jačine, u sistemima varijabilne
(vI) i konstantne jonske jačine (cI) na retenciono ponašanje 23 potpuno protonovana analita
baznih osobina. Sprovedeno je devet serija eksperimenata (pri tri pH vrednosti za NaPF6 , KPF6 i
NH4PF6 ) sa vI i devet serija eksperimenata (pri tri pH vrednosti za NaPF6 , KPF6 i NH4PF6 ) sa
jonskom jačinom koja je održavana konstantnom sa NaCl, KCl i NH4Cl. Eksperimentalno
određeni retencioni faktori modelovani su primenom proširenog termodinamičkog pristupa i
objašnjeni su procesi koji se odigravaju na stacionarnoj fazi i u mobilnoj fazi, kao i njihov uticaj
na retenciju u ispitivanim sistemima haotropne hromatografije. Pokazalo se da je, i u vI i u cI
sistemima, formiranje jonskih parova na stacionarnoj fazi dominantno u odnosu na formiranje
jonskih parova u mobilnoj fazi. U sistemima KPF6_vI ove interakcije sa stacionarnom fazom bile
su još izraženije nego u drugim sistemima. Iako su i K + i NH4 + haotropne prirode, formiranje
jonskih parova na stacionarnoj fazi je favorizovano prisustvom NH4 + samo pri visokim
koncentracijama ovog katjona kao što je u cI sistemima
Comparative analysis of conventional and novel inflammatory biomarkers in Familial Mediterranean fever during attack-free periods
No full textBackground: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory condition accompanied with periodic attacks of fever. The clinical utility of some novel inflammatory parameters has not been well explored in FMF. Hence, the aim of this study was to explore the accuracy of a variety of inflammatory indexes in patients with an FMF-attack-free period and without a complication of amyloidosis. Methods: This cross-sectional study included a total of 114 patients with FMF (of them, 43.8% were men) and 97 controls (of them, 43.3% were men). Complete blood count, albumin, fibrinogen, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A (SAA) were measured. Other parameters were calculated [i.e., platelet-albumin ratio (PAR), HALP score, systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV)]. Receiver operating characteristic (ROC) curve analysis was used to test the discriminative ability of each marker between patients with FMF and those without FMF. Results: The area under the ROC curve for fibrinogen [AUC = 0.710, 95% CI (0.644–0.770)], CRP [AUC = 0.780 (0.718–0.834)], fibrinogen/albumin [AUC = 0.722 (0.657–0.782)], and CRP/albumin [AUC = 0.782 (0.720–0.836)] indicated satisfactory clinical accuracy. The AUCs for SAA [AUC = 0.844 (0.788–0.890)], SAA/albumin [AUC = 0.856 (0.801-0.900)], and PLT/SAA [AUC = 0.810 (0.750–0.861)] indicated good clinical accuracy. There was no difference between AUCs for SAA and SAA/albumin (P = 0.073), whereas the AUCs for these 2 parameters were significantly higher than the AUC for PLT/SAA (P = 0.033 and P = 0.005, respectively). Conclusion: SAA and SAA/albumin ratio are the most reliable biomarkers in discriminating patients with FMF from healthy individuals
Characterization of atorvastatin calcium liquisolid tablets prepared with Neusilin® US2 and Syloid® XDP 3050 as carries
No full textAtorvastain calcium (ATC) is a BCS class II drug known for its low absolute bioavailability (12%), which is due to its poor solubility in gastrointestinal fluids [1]. The technology of liquisolid systems (LSS) has been shown to improve the bioavailability of a number of poorly soluble drugs, primarily due to the increased surface area available for dissolution and the presence of the hydrophilic liquid vehicle, resulting in faster drug release [2]. The aim of this study was to investigate the possibility of using the LS technique to improve the dissolution rate of ATC. Two novel porous excipients with high absorption capacity were selected as carriers to formulate LS tablets with high liquid phase content and suitable mechanical properties as well as acceptable disintegration times and improved dissolution rate
Redox behavior of amsacrine: a pathway to understanding its biological action
No full textInvestigating the redox characteristics of the anticancer agent amsacrine (AMS) is crucial for understanding its biological activity and interactions with key biomolecules. A comprehensive electrochemical study was performed using cyclic, differential pulse, and square-wave voltammetry at a glassy carbon electrode (GCE). The effects of pH and scan rate were thoroughly examined. The results show that AMS undergoes independent oxidation and reduction processes. Its oxidation involves two distinct pathways: a reversible, two-electron, low-potential oxidation of diarylamine and methanesulfonamide facilitated by the electron-donating 3′-OCH3 substituent, leading to the formation of a quinone diimine; and a higher-potential, two-electron oxidation of the acridine ring, proceeding via radical cation formation followed by dimerization. Additionally, the acridine ring can undergo one-electron reduction. The electron-donating properties and relatively low oxidation potential of the diarylamine (which is believed to be sufficiently low to permit facile oxidation in vivo) appear to be directly relevant to AMS's biological activity and its interactions with biologically significant molecules. The oxidation mechanism established at the GCE was further applied to develop a simple and efficient screening method for probing AMS interactions with biomolecules. Using an un-doped GCE setup, interactions with human serum albumin (HSA) and DNA were successfully assessed, demonstrating the potential of voltammetric techniques as effective tools in drug–biomolecule interaction studies
Design of lipid-polymer hybrid nanoparticles for lymphotropic delivery of GL-ll-73: comparison of conventional and microfluidic synthesis methods
No full textThe aim of this research was developing lipid-polymer hybrid nanoparticles (LPHNPs) to facilitate lymphotropic delivery of GL-II-73, the novel positive allosteric modulator of α5GABAA receptors. The tested LPHNPs consisted of poly(D,L-lactide-co-glycolide) (PLGA) hydrophobic core and soybean lecithin and DSPE-PEG2000 as stabilizers. Two production methods, the conventional nanoprecipitation method based on self-assembly and the innovative microfluidic synthesis based on a herringbone micromixer (TAMARA, Inside Therapeutics, France) were tested to obtain LPHNPs with a particle size (10-100 nm) and drug loading (at least 2 mg/ml) required for efficient accumulation in the lymphatic system
Development of co‑processed excipient from wheat harvest residue‑derived microcrystalline cellulose suitable for formulation of immediate release tablets containing high‑dose drug
No full textThe isolation of microcrystalline cellulose (MCC) from agricultural waste is one of the approaches to improve waste management and avoid potential problems due to its accumulation. Although MCC is the most common tablet diluent, its low solubility can cause problems, such as prolonged tablet disintegration and slow drug dissolution, especially in formulations containing drugs with low water solubility. This study investigates the potential to improve the characteristics of wheat harvest residue-derived MCC (MCC HR) by co-processing with mannitol, crospovidone and colloidal silicon dioxide with the aim of developing immediate-release tablets containing ibuprofen as a model of high-dose drug. Co-processing with mannitol, crospovidone and colloidal silicon dioxide led to change in particle morphology and the formation of spherical particles, but without the formation of covalent bonds and/or new chemical entities. The changes in particle size and shape did not lead to improved powder flowability. Prolonged tablet disintegration and slow drug dissolution were observed when MCC HR or samples co-processed with silicon dioxide were used in formulation of tablets containing 50% or 70% ibuprofen. The mixture obtained by co-processing MCC HR with mannitol, crospovidone and colloidal silicon dioxide was only suitable for the preparation of tablets with an ibuprofen content of up to 50%, which fulfil pharmacopoeial requirements for disintegration of immediate release tablets and ibuprofen release from such tablets