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Exploring the benefits and limitations of the ZoomLab® virtual assistant in directly compressible formulation development
No full textRazvoj lekova zahteva poznavanje složenih odnosa između karakteristika aktivnih supstanci (AS) i ekscipijenasa, procesnih parametara i ciljnog profila kvaliteta proizvoda, koje je teško pouzdano predvideti. Unapređenje naučnih saznanja u ovoj oblasti, dostupnost velikih baza podataka i primena mašinskog učenja doveli su do razvoja digitalnih platformi sa naprednim algoritmima koji podržavaju i omogućavaju brži razvoj formulacije.
U ovom istraživanju ispitivana je mogućnost primene platforme BASF Virtual Assistant ZoomLab® [1] kao alata za razvoj direktno-kompresibilnih formulacija, uz korišćenje kofeina i rivaroksabana kao model aktivnih supstanci. Sprovedena je uporedna analiza eksperimentalno dobijenih podataka i podataka integrisanih u platformu u okviru aplikacija Tabletabilnost i Procesabilnost aktivne supstance i tabletne smeše, a potom faza razvoja formulacije, korišćenjem aplikacije Formulation Wizard.
Razmatranje svojstava AS u okviru platforme ukazivalo je na slabu procesabilnost, odnosno mogućnost obrade kofeina i rivaroksabana, što implicira na poteškoće prilikom direktne kompresije. Međutim, u aplikaciji Formulation Wizard predložen je sastav formulacija sa dobrom procesabilnošću. Formulacije, odabrane na osnovu predviđene povoljne protočnosti ili tabletabilnosti, pokazale su dobru gustinu, protočnost i kompresibilna svojstva, a izrađene tablete pokazale su zadovoljavajuće mehaničke karakteristike (čvrstina i friabilnost) i kratko vreme dezintegracije.
Zahvaljujući integrisanim algoritmima, kao i bazama podataka AS i ekscipijenasa, ZoomLab® platforma predstavlja koristan alat i vodič za razvoj formulacije. Međutim, baza ekscipijenasa ograničena je na odabrane proizvode kompanije BASF. Iako primena hibridnog pristupa može doprineti razvoju proizvoda u kraćem vremenu, uz manji utrošak materijala, potrebno je kritički razmotriti dostupne podatke i optimizovati sastav formulacije na osnovu sprovedenih eksprimenata.Pharmaceutical development is based on complex relationships between active pharmaceutical
ingredients (APIs) and excipients material properties, process parameters and targeted product
performance which are difficult to model and predict. With advancement of the knowledge base in the
field, availability of large datasets and machine learning, digital platforms have been created providing
advanced algorithms to simplify and accelerate formulation development.
In this study, the applicability of BASF Virtual Assistant ZoomLab® [1], as a tool for development
of directly compressible formulations was investigated, using caffeine and rivaroxaban as model drugs.
Comparative evaluation of the experimentally obtained and built-in data has been performed using the
API and Powder Blend Tabletability and Processability applications followed by Formulation Wizard
guided formulation selection.
Based on API characteristics evaluation, both caffeine and rivaroxaban presented poor
processability, indicating that direct compression into tablets would be challenging. However,
Formulation Wizard identified a number of prospective formulations with good processability. Powder
blends, selected based on predicted favorable flowability or tabletability, exhibited good flowability,
powder density, and compression-related properties. The obtained tablets exhibited good mechanical
properties (hardness and friability), as well as fast disintegration.
ZoomLab® built-in algorithms, as well as the API and excipient databases represent useful
preformulation tool and provide insights which could guide formulation development. However, the
excipients database is limited to the selected BASF products. Relevant outputs should be critically
assessed and further optimized based on experimental observations leading to hybrid approach which
would accelerate product development while minimizing time and resources consumption
Protolytic Equilibria of Cetirizine in the Presence of Micelle-Forming Surfactants
No full textThe acid–base equilibria of cetirizine were investigated with and without the presence of differently charged micelle-forming surfactants (anionic, cationic, nonionic). The pKa values were potentiometrically determined at 25 °C and at a constant ionic strength (0.1 M NaCl). Experimental data were analyzed by applying the computer program Hyperquad 5.2.15. Based on a shift in the ionization constants (∆pKa) in micellar solutions against the pKa values determined in “pure” water under the same conditions, the effects of micelles on the protolytic equilibria of cetirizine were estimated. Applied micelles caused a shift in the protolytic equilibria of all cetirizine ionizable centers, with the piperazine function connected to aliphatic side moiety (∆pKa1 from −0.47 to +1.42), carboxyl group (∆pKa2 from −0.92 to +2.02), and piperazine nitrogen connected to phenyl rings (∆pKa3 from −2.01 to +2.19). Anionic SDS and nonionic Brij 35 micelles caused an increase in the pKa values of the ionizable centers of cetirizine, while a decrease in the pKa values was detected under the influence of cationic CTAB and nonionic TX-100 micelles. The change in the ionization pattern by micelles at pH values with biopharmaceutical significance provides indications of possible interactions of cetirizine with biomolecules of different charge and polarity under physiological conditions
The Potential Role of sPD-L1 as a Predictive Biomarker in EGFR-Positive Non-Small-Cell Lung Cancer
No full textBackground/Objectives: A significant breakthrough in non-small-cell lung cancer (NSCLC) treatment has occurred with the introduction of targeted therapies and immunotherapy. However, not all patients treated with these therapies would respond to treatment, and patients who respond to treatment would acquire resistance at some time point. This is why we need new biomarkers that can predict response to therapy. The aim of this study was to investigate whether soluble programmed cell death-ligand 1 (sPD-L1) could be a predictive biomarker in patients with epidermal growth factor receptor (EGFR)-positive NSCLC. Materials and Methods: Blood samples from 35 patients with EGFR-mutated (EGFRmut) adenocarcinoma who achieved disease control with EGFR tyrosine kinase inhibitor (EGFR TKI) therapy were collected for sPD-L1 analysis. We analyzed sPD-L1 concentrations in 30 healthy middle-aged subjects, as a control population, to determine the reference range. Adenocarcinoma patients were divided into two groups, i.e., a group with low sPD-L1 (≤182.5 ng/L) and a group with high sPD-L1 (>182.5 ng/L). Results: We found that progression-free survival (PFS) was 18 months, 95% CI (11.1–24.9), for patients with low sPD-L1 and 25 months, 95% CI (8.3–41.7), for patients with high sPD-L1. There was no statistically significant difference in PFS between the groups (p = 0.100). Overall survival (OS) was 34.4 months, 95% CI (26.6–42.2), for patients with low sPD-L1 and 84.1 months, 95% CI (50.6–117.6), for patients with high sPD-L1; there was also no statistically significant difference between the groups (p = 0.114). Conclusion: In our study, we found that patients with high sPD-L1 had numerically better PFS and OS, but this has no statistical significance. Further studies with a larger number of patients are needed to evaluate the role of sPD-L1 as a predictive biomarker in patients with EGFRmut NSCLC
Odnos monociti/HDL-holesterol kao rani prognostički marker razvoja komplikacija u trudnoći
No full textPregnancy complications increase the long-term cardiovascular risk for both the mother
and the child. Inflammation is a common mechanism underlying the development of pregnancy
complications and atherosclerosis. This study aims to investigate whether the monocyte/HDL
cholesterol ratio can serve as a predictive marker for the risk of pregnancy complications. A total
of 84 pregnant women participated in this study, 41 of whom had a normal pregnancy course,
while 43 experienced complications. Lipid status parameters were measured using enzymatic
methods and total blood count was measured using a hematology analyzer. In the first trimester
of pregnancies with complications we observed significantly higher levels of total cholesterol
(P < 0.01), low-density lipoprotein cholesterol (LDL-C) (P < 0.01) and triglycerides (P < 0.001)
compared to pregnancies without complications, whereas no differences were observed in high-
density lipoprotein cholesterol (HDL-C). Pregnant women with complications had a significantly
higher proportion of monocytes throughout the entire pregnancy, and lower concentrations of
HDL-C in the second trimester (P < 0.05). The risk of developing complications in pregnancy
was 11 times higher if the monocyte/HDL-C ratio was elevated in the first trimester (OR: 11.42;
95% CI: 4.05–32.19; P < 0.001). Our results indicate that monocyte/HDL-C ratio could be used
as a simple and cost-effective early prognostic biomarker of pregnancy complications.Pregnancy complications increase the long-term cardiovascular risk for both the mother
and the child. Inflammation is a common mechanism underlying the development of pregnancy
complications and atherosclerosis. This study aims to investigate whether the monocyte/HDL
cholesterol ratio can serve as a predictive marker for the risk of pregnancy complications. A total
of 84 pregnant women participated in this study, 41 of whom had a normal pregnancy course,
while 43 experienced complications. Lipid status parameters were measured using enzymatic
methods and total blood count was measured using a hematology analyzer. In the first trimester
of pregnancies with complications we observed significantly higher levels of total cholesterol
(P < 0.01), low-density lipoprotein cholesterol (LDL-C) (P < 0.01) and triglycerides (P < 0.001)
compared to pregnancies without complications, whereas no differences were observed in high-
density lipoprotein cholesterol (HDL-C). Pregnant women with complications had a significantly
higher proportion of monocytes throughout the entire pregnancy, and lower concentrations of
HDL-C in the second trimester (P < 0.05). The risk of developing complications in pregnancy
was 11 times higher if the monocyte/HDL-C ratio was elevated in the first trimester (OR: 11.42;
95% CI: 4.05–32.19; P < 0.001). Our results indicate that monocyte/HDL-C ratio could be used
as a simple and cost-effective early prognostic biomarker of pregnancy complications
Perceptions and awareness of endocrine disruptors among mothers in Serbia and health implications
No full textEndocrine-disrupting chemicals are significant contributors to various detrimental conditions, mechanistically disrupting the endocrine system and causing adverse health effects. Mounting evidence suggests they can induce multigenerational and transgenerational effects, yet awareness among individuals remain insufficient. This study aimed to assess the knowledge, attitudes and ways of informing mothers in Serbia about endocrine disruptors based on information from 190 women in Serbia. The research was conducted using a survey consisting of multiple-choice questions comprising: The first part aimed to collect sociodemographic data, the second part related to knowledge and attitudes about endocrine disruptors, and the third part focused on the sources of information about endocrine disruptors. Cronbach’s alpha was used to check for scale reliability, and Pearson correlation was used to test the relations between interval variables. ANOVA was employed to test for group differences. The results indicated that mothers in Serbia do not have adequate knowledge about endocrine disruptors (potential sources, categories of substances and alternatives) nor confidence in their ability to mitigate exposure to endocrine disruptors. Also, the estimation of the health risks of exposure to endocrine disruptors was perceived as high, and the mothers thought that they should get additional information about endocrine disruptors before pregnancy. Although with several limitations (i.e. mothers were recruited among those with higher education and mainly from urban areas), the study results highlight the necessity for enhanced maternal education in Serbia regarding endocrine disruptors. Health professionals are deemed most suitable for providing this education, given the respondents’ high level of trust in them
Design of lipid nanoemulsions loaded with CW-02-79-phospholipid complex for targeted brain delivery: focus on stability in protein enriched media
No full textŽivotinjski modeli hronične bolesti bubrega – deo slagalice koji nedostaje za razvoj novih terapijskih mogućnosti
No full textChronic kidney disease (CKD) is considered one of the most important public health
problems today. CKD is characterized by changes in kidney structure and impaired kidney
function (reduced estimated glomerular filtration rate). Data show that more than 13% of the
population suffers from CKD and that it will be the fifth leading cause of death by 2040. To date,
numerous animal models for CKD have been developed. They are used to unravel the
pathophysiological mechanisms of CKD development and represent a very important platform
for the development of new therapeutic strategies. All animal models for CKD can be
systematized in different ways, such as surgical/non-surgical models, subdivisions based on
pathological changes in kidney structure or as subdivisions based on the pathophysiological
mechanisms leading to the development of CKD. In surgical models, part of the kidney tissue is
usually removed, while in non-surgical models, certain substances with nephrotoxic effects are
used. The choice of model depends on the experimental design and the aim of the specific study.
This paper provides an overview of all currently known animal models for CKD.Hronična bolest bubrega (HBB) se smatra jednim od vodećih zdravstvenih problema današnjice. HBB se karakteriše oštećenjem strukture i funkcije bubrega što se procenjuje na osnovu promene intenziteta glomerularne filtracije. Podaci govore da više od 13% svetske populacije boluje od HBB, kao i da će HBB biti peti vodeći uzrok smrtnosti do 2040. godine. Do danas su razvijeni brojni životinjski modeli HBB. Ovi preklinički modeli su korisni za bolje razumevanje patofizioloških mehanizama nastanka HBB, a takođe predstavljaju i veoma važnu platformu za razvoj novih terapijskih mogućnosti. Svi životinjski modeli HBB se mogu sistematizovati na različite načine kao što su na primer: hirurški/nehirurški modeli, podela na osnovu patoloških promena do kojih dolazi u bubrežnom parenhimu ili podela na osnovu patofizioloških mehanizama uključenih u nastanak HBB. Kod hirurških modela obično se uklanja deo bubrežnog tkiva, dok se kod nehirurških modela koriste određene supstance sa nefrotoksičnim efektom. Izbor modela zavisi od eksperimentalnog dizajna i cilja same studije. U ovom revijskom radu su opisane karakteristike i osnovne prednosti i mane različitih prekliničkih modela HBB
Assessing the safety of thermal mineral water for cosmetic applications: an integrated approach using physicochemical, cheminformatics, and bioinformatics techniques
No full textThermal and mineral waters represent a complex multifunctional natural resource that has been used for various purposes throughout human history. The physico-chemical characterization of thermal and mineral waters is a comprehensive process that integrates knowledge and practice from different scientific fields. When used in direct contact with human skin, whether for bathing or for use in topical products, a toxicological analysis of thermal and mineral waters must also be performed. This work is an example of a multidisciplinary approach to investigate the safety of concrete thermal and mineral water from the Pannonian Basin for use in cosmetics. A detailed physicochemical characterization was performed together with the subsequent safety assessment of the final cosmetic product, coupled with cheminformatics and bioinformatics tools used to predict physicochemical properties, pharmacokinetics, determination of descriptors to assess bioactive potential and evaluation of possible biological pathways and interactions. The results show that the tested thermal and mineral water is a promising resource for use in cosmetic products that can help maintain skin integrity and improve its condition. The toxicological evaluation showed that the tested water is acceptable as an ingredient in a face cream for adults, excluding pregnant and breastfeeding women. The results are discussed in detail and guidance and comments on outstanding issues are provided
Diverging Safety Signals: A Trend Analysis of Suspected Adverse Drug Reactions Reporting for Spinal Muscular Atrophy Therapies in the European Union
No full textBackground/Objectives: The approval of disease-modifying therapies has significantly
improved outcomes for patients with spinal muscular atrophy (SMA), yet their long-term
safety profiles remain under continuous evaluation. This study aimed to assess trends
in the reporting of suspected adverse drug reactions (ADRs) associated with nusinersen,
onasemnogene abeparvovec, and risdiplam across the European Union. Methods: We
conducted a secondary analysis of annual suspected ADR data reported to EudraVig-
ilance from 2017 to 2024 for the three approved disease-modifying therapies for SMA.
On top of general reporting trend, specific adverse reactions of interest included post-
lumbar puncture syndrome for nusinersen, liver toxicity and elevated serum troponin for
onasemnogene abeparvovec, and respiratory and gastrointestinal reactions for risdiplam.
Joinpoint regression analysis was used to evaluate annual percent changes and identify
statistically significant trend segments for each medicine. Results: The reporting of sus-
pected ADRs for nusinersen showed an initial increase, followed by a significant decline
after 2019. Onasemnogene abeparvovec exhibited a continued but decelerating increase
in suspected ADRs, while risdiplam demonstrated a consistent upward trend across all
reported reactions. Conclusions: Diverging patterns in adverse reaction reporting sug-
gest a stabilizing safety profile for nusinersen and potential emerging safety signals for
risdiplam and onasemnogene abeparvovec, underscoring the need for ongoing continued
pharmacovigilance (e.g., post-authorization studies and spontaneous reporting)
Determination of the pharmacophore structure, design, synthesis and in vitro evaluation of dual inhibitors of histone deacetylases (HDAC) and Rho-associated protein kinases (ROCK)
No full textDuktalni adenokarcinom pankreasa (pancreatic ductal adenocarcinoma, PDAC) i trostruko-negativni karcinom dojke (triple-negative breast cancer, TNBC) spadaju u tumore sa najlošijom prognozom što naglašava hitnu potrebu za novim terapijskim strategijama u cilju poboljšanja terapijskog ishoda. Epigenetički i kinazni signalni putevi imaju bitnu ulogu u tumorogenezi i progresiji ovih maligniteta. U tom kontekstu, histon-deacetilaze (histone deacetylases, HDAC) i Rho-vezane protein kinaze (Rho-associated coiled-coil kinases, ROCK) se ističu kao relevantni targeti u tretmanu različitih vrsta karcinoma, uključujući TNBC i PDAC. S obzirom na prednosti multitarget terapijskih pristupa, zabilježene sinergističke efekte između HDAC i ROCK inhibitora u in vitro i in silico studijama, kao i njihov značaj u patogenezi ovih tumora, dizajn i razvoj dualnih HDAC/ROCK inhibitora predstavlja inovativnu i obećavajuću strategiju za liječenje ovih agresivnih maligniteta.U ovoj doktorskoj disertaciji istraživanje je sprovedeno u četiri faze. Prvo, primjenom kvantitativnih studija odnosa strukture i aktivnosti (Quantitative structure-activity relationship, QSAR) i molekulskog dokinga, razvijena je farmakofora ROCK1/ROCK2 inhibitora, na osnovu koje su dizajnirani novi ROCK inhibitori. Identifikovan je region fasudila, poznatog ROCK inhibitora, koji nije esencijalan za interakcije sa ROCK enzimima, što je omogućilo njegovu strukturnu modifikaciju i integraciju HDAC farmakofore. Na ovaj način su po prvi put dizajnirani dualni HDAC/ROCK inhibitori. U drugoj fazi istraživanja, dizajnirani ROCK i HDAC/ROCK inhibitori su sintetisani, nakon čega je u trećem segmentu istraživanja ispitana njihova enzimska aktivnost, kao i antitumorska svojstva u dvodimenzionalnim i trodimenzionalnim ćelijskim kulturama TNBC (MDA-MB-231, MDA-MB-468) i PDAC (MiaPaCa-2, Panc-1). Finalno, na osnovu svih prethodnih rezultata, u četvrtoj fazi je uspostavljen detaljan in silico protokol za budući dizajn i optimizaciju strukture dualnih HDAC/ROCK inhibitora. Dati protokol se zasniva na kombinaciji metoda dizajna zasnovanog na strukturi ciljnog mjesta dejstva (Structure-based drug desing, SBDD) i dizajna zasnovanog na strukturi liganda (Ligand-based drug design, LBDD) koje uključuju molekulski doking, 2D-QSAR modele formirane koriščenjem algoritama mašinskog učenja i računanje slobodne energije vezivanja MM-GBSA metodom.Među dizajniranim ROCK inhibitorima, jedinjenje C-19 se izdvojilo po svojoj inhibitornoj aktivnosti na ROCK1 (IC50 = 4,22 μM) i ROCK2 (IC50= 6,13 μM), kao i po citotoksičnom efektu na MiaPaCa-2 i Panc-1 ćelijama (IC50= 19,10 μM i 35,03 μM). Takođe, C-19 je ispoljilo anti-migratorna i anti-invazivna svojstva, uporediva sa fasudilom.Najperspektivnije među sintetisanim HDAC/ROCK dualnim inhibitorima je jedinjenje C-9, koje je pokazalo snažnu inhibiciju ROCK1 (IC50 = 800 nM), ROCK2 (IC50 = 700 nM) i HDAC6 (IC50 = 185 nM). U ispitivanjima citotoksičnosti, C-9 je pokazalo značajno bolju aktivnost od poznatih inhibitora fasudila i tubastatina A, sa IC50 vrijednostima od 5,81 μM za MDA-MB-231, 3,87 μM za MiaPaCa-2 i 19,57 μM za Panc-1. Pored toga, C-9 je demonstrirao visok stepen efikasnosti u 3D tumorskim sferoidnim modelima, inhibirajući formiranje i vijabilnost Panc-1 i MiaPaCa-2 sferoida. Takođe, C-9 je nadmašilo fasudil u smanjenju migracije i invazije MDA-MB-231 i MiaPaCa-2 ćelija, što ga definiše kao obećavajućeg kandidata za dalju prekliničku evaluaciju u tretmanu metastatskih karcinoma.Na osnovu ovih rezultata, C-9 je identifikovan kao vodeći molekul (lead) i njegova struktura je dalje optimizovana u skladu sa prethodno definisanom ROCK farmakoforom, što je dovelo do dizajniranja i sinteze novih HDAC/ROCK dualnih inhibitora. Primjenom metoda SBDD razvijena je serija novih dualnih HDAC/ROCK inhibitora...Pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) are among the most aggressive malignancies with extremely poor prognoses, highlighting the urgent need for innovative therapeutic strategies to improve treatment outcomes. Epigenetic mechanisms and kinase signaling pathways play a crucial role in the tumorigenesis and progression of these cancers, with histone deacetylases (HDACs) and Rho-associated protein kinases (ROCKs) emerging as relevant therapeutic targets. Given the advantages of multi-target therapeutic approaches, the observed synergistic effects between HDAC and ROCK inhibitors in in vitro and in silico studies, and their critical roles in the pathogenesis of these tumors, the design and development of dual HDAC/ROCK inhibitors represent an innovative and promising strategy for treating these aggressive malignancies.This research was conducted in four phases. Initially, using quantitative structure-activity relationship (3D-QSAR) studies and molecular docking, a pharmacophore model for ROCK1/ROCK2 inhibitors was developed, leading to the design of novel ROCK inhibitors. A non-essential region of fasudil, a known ROCK inhibitor, was identified by molecular docking study, enabling its structural modification and the incorporation of an HDAC pharmacophore while preserving ROCK inhibitory activity. This approach resulted in the first-ever designed dual HDAC/ROCK inhibitors. In the second phase, the designed ROCK and HDAC/ROCK inhibitors were synthesized, followed by the third phase, which involved evaluating their enzymatic activity and anticancer properties using two-dimensional and three-dimensional cell culture models of TNBC (MDA-MB-231) and PDAC (MiaPaCa-2, Panc-1). Finally, based on all previous findings, the fourth phase established a comprehensive in silico protocol for the future design and structural optimization of dual HDAC/ROCK inhibitors. This protocol integrates structure-based drug design (SBDD) and ligand-based drug design (LBDD) methodologies, incorporating molecular docking, 2D-QSAR models developed using machine learning algorithms, and binding free energy calculations performed using the MM-GBSA approach.Among the designed ROCK inhibitors, compound C-19 demonstrated notable inhibitory activity against ROCK1 (IC50 = 4.22 μM) and ROCK2 (IC50 = 6.13 μM), as well as cytotoxic effects on MiaPaCa-2 and Panc-1 cells (IC50 = 19.10 μM and 35.03 μM). Additionally, C-19 exhibited significant anti-migratory and anti-invasive properties, comparable to fasudil.The most promising of the synthesized HDAC/ROCK dual inhibitors was C-9, which showed potent inhibition of ROCK1 (IC50= 800 nM), ROCK2 (IC50= 700 nM), and HDAC6 (IC50 = 185 nM). In cytotoxicity assays, C-9 demonstrated significantly higher activity than the well-known inhibitors fasudil and tubastatin A, with IC50 values of 5.81 μM for MDA-MB-231, 3.87 μM for MiaPaCa-2, and 19.57 μM for Panc-1. Moreover, C-9 exhibited strong efficacy in 3D tumor spheroid models, effectively inhibiting the formation and viability of Panc-1 and MiaPaCa-2 spheroids. Additionally, C-9 outperformed fasudil in reducing the migration and invasion of MDA-MB-231 and MiaPaCa-2 cells, establishing itself as a promising candidate for further preclinical evaluation in the treatment of metastatic cancers.Based on these results, C-9 was identified as the lead compound, and its structure was further optimized according to the previously defined ROCK pharmacophore model. Structure-based drug design (SBDD) was used to develop a series of novel HDAC/ROCK dual inhibitors..