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Utilization of Parallel Artiicial Membrane Permeability Assay and Chemometric Modeling for Predicting Blood–Brain Barrier Permeability of Protein Kinase Inhibitors for Brain Anticancer Therapy
No full textThis study investigates the passive diffusion of protein kinase inhibitors across the blood- brain barrier (BBB) for brain anticancer therapy and develops a predictive model for their permeability. ..
Uticaj hidrolata smilja (Helichrysum italicum (Roth) G. Don) i hidrolata lavande (Lavandula angustifolia Mill.) na parametre oksidativnog stresa i antioksidantne zaštite u humanom serumu
No full textA number of studies suggest that different antioxidants play important roles in the body's
antioxidant defense system. Hydrolates, by-products of essential oils, commonly obtained by
steam distillation, are recognized to possess remarkable pharmacological activities, in particular
an antioxidant activity. This study aimed to investigate and compare the antioxidant properties of
immortelle hydrolate (IH) and lavender hydrolate (LH) using an ex vivo platform, i.e. human
serum. To assess their impact on oxidative stress / antioxidative parameters, spectrophotometric
biochemical assays were applied. The GC/MS analysis revealed that the main constituents were
italidione I (17.2%), linalool (15.6%), α-terpineol (13.7%), terpinen-4-ol (6.3%) and nerol (5.2%)
in IH, and linalool (19.6%), terpinen-4-ol (17.0%), α-terpineol (13.6%) and borneol (5.8%) in
LH. The results showed that serum samples with LH, along with tert-butyl hydroperoxide as a pro-oxidant, had lower concentrations of the TOP (total oxidant potency) parameter, and slightly
higher concentrations of the TAC (total antioxidant capacity) and SHG (total sulfhydryl groups)
parameters compared to IH samples. Moreover, a significant difference in the OSI (oxidative
stress index) parameter was observed (IH vs. LH – 49 (41–58) vs. 70 (61–75), p<0.05). The
current ex vivo platform demonstrated IH and LH distinct antioxidant potency, highlighting LH
as a potentially stronger antioxidant than IH.Brojne studije ukazuju da različiti antioksidansi igraju važnu ulogu u antioksidantnom odbrambenom sistemu organizma. Poznato je da hidrolati, nusproizvodi koji se dobijaju tokom ekstrahovanja etarskih ulja destilacijom vodenom parom, poseduju različite farmakološke aktivnosti, a posebno antioksidantnu. Cilj ovog istraživanja bilo je ispitivanje i upoređivanje antioksidantne aktivnosti hidrolata smilja (IH) i hidrolata lavande (LH) u humanom serumu kao ex vivo platformi. Za evaluaciju njihovog uticaja na parametre oksidativnog stresa i antioksidantne zaštite, korišćeni su spektrofotometrijski biohemijski testovi. GC/MS analizom utvrđeno je da su glavni sastojci italidion I (17,2%), linalol (15,6%), a-terpineol (13,7%), terpinen-4-ol (6,3%) i nerol (5,2%) u IH, i linalol (19,6%), terpinen-4-ol (17,0%), a-terpineol (13,6%) i borneol (5,8%) u LH. Rezultati su pokazali da su u uzorcima seruma sa LH, u prisustvu terc-butil hidroperoksida kao prooksidansa, utvrđene manje koncentracije parametra TOP (total oxidant potency), i nešto veće koncentracije parametara TAC (total antioxidant capacity) i SHG (total sulfhydryl groups) u odnosu na uzorke sa IH. Štaviše, primećena je statistički značajna razlika u vrednostima parametra OSI (oxidative stress index) (IH u poređenju sa LH - 49 (41-58) : 70 (61-75), p<0,05). Korišćenjem ove ex vivo platforme, otkriveni su različiti antioksidantni potencijali IH i LH, pri čemu je LH istaknut kao potencijalno snažniji antioksidans od IH
A computational framework for the design and development of ERK2 and multi-target ERK2/HDAC inhibitors
No full textThe Ras-Raf-MEK-ERK/MAPK signaling pathway regulates important cellular processes such as proliferation, differentiation, apoptosis, development and stress responses. This signaling pathway is overexpressed in various types of cancer, with ERK2 (Extracellular signal - Regulated Kinase 2) serving as the final effector component. Current inhibitors of this pathway, including ERK2 inhibitors, face challenges such as safety concerns, limited efficacy and resistance, highlighting the need for new therapeutic candidates. In this study, ML-QSAR (Machine Learning - Quantitative Structure-Activity Relationships) and 3D-QSAR (Three-Dimensional Quantitative Structure-Activity Relationships) models and molecular docking of the investigated compounds were used to identify key structural features related to ERK2 inhibitory activity. This computational framework formed the basis for a fragment-based drug design that enabled the development and evaluation of new ERK2 inhibitors from two distinct structural classes, pyrimidine-2-pyridone and pyrazolyl-pyrrole derivatives. Molecular dynamics simulations were performed for the best designed ERK2 inhibitor. The developed computational framework was successfully used for the design and evaluation of multi-target ERK2/HDAC inhibitors as a basis for future cancer therapies
Costs of Treating Onasemnogene Abeparvovec-Xioi-Induced Liver Injury
No full textAims were to reveal types of onasemnogene abeparvovec-xioi (OA)-induced liver injury, their treatment patterns, utilization of healthcare, and treatment costs. This study employed secondary research to analyze OA-induced liver injury using data from the EudraVigilance database, published case reports, cohort studies, and clinical trials. The extracted data were analyzed to define real-life clinical entities that could be clearly outlined as syndromes resulting from the OA-induced liver injury, and further used in guiding the development of healthcare utilization matrices. Serbian healthcare costs were calculated by multiplying utilization figures by local unit prices, converted to Euros using exchange rates and adjusted by price level indices. A spreadsheet model with uniform distributions simulated costs for 1000 virtual patients, providing mean values and standard deviations for Serbia and the EU. From 1566 adverse event reports in the EudraVigilance database following OA therapy, 231 were hepatobiliary dis- orders, predominantly hypertransaminasaemia (30.7%; 71/231). Liver injury largely manifested as mild-to-moderate biochemical abnormalities, rarely progressing to severe complications, and was effectively managed with corticosteroid therapy. Economic analysis highlights the manageable burden of OA-induced liver injury. In the EU, mild-to-moderate cases cost €823.7, while severe cases average €1638.6. Medication costs range from €26.8 for prednisone to €695.4 for severe cases requiring additional immunosuppressive agents like tacrolimus and mycophenolate mofetil. To conclude, OA-induced liver injury, though notable, is clinically manageable with immunosuppressive therapy and rarely causes severe complications like encephalopathy or liver failure. Its modest costs do not undermine OA's cost-effectiveness, supporting its transformative role in spinal muscular atrophy treatment
Potential of two innovative acrylate derivatives for gelation of fragile low-energy nanoemulsions
No full textThis research closely examined the internal structure of nanoemulsion gels after gelation of a nanoemulsion with two different innovative acrylate derivatives: Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer (SeppinovTM EMT 10) and Polyacrylate Crosspolymer-6 (Sepimax ZenTM). ..
Powder bed fusion–laser beam (PBF-LB) three-dimensional (3D) printing: Fun shaped oral dosage forms with desloratadine
No full textSince the introduction of the first 3D-printed drug called Spritam®, it has been recognised that there is an unmet need in the pharmaceutical field for technologies that enable the production of dosage forms that are specifically tailored to the needs of the individual patient while containing a precise dose of an active pharmaceutical ingredient (API)[1]. For this reason, intensive research has been conducted into various three-dimensional printing (3DP) technologies. One of these is laser sintering (LS), also known as powder bed fusion laser beam (PBF-LB), which delivers solid dosage forms by selectively fusing powder particles under the thermal energy of a laser beam using a well-known layer-on-layer mechanism[1,2]. To confirm that PBF-LB 3DP offers promising potential for the production of patient-specific drugs, the aim of this study was to formulate and manufacture complex, fun-shaped oral dosage forms with desloratadine (DSL) as the API, specifically tailored for the paediatric population
Constitutive androstane receptor, liver pathophysiology and chemical contaminants: current evidence and perspectives
No full textIntroduction: The Constitutive Androstane Receptor (CAR) (NR1I3), a pivotal member of the xenosensor family, plays a key role in the hepatic detoxification of xenobiotic and endobiotic chemicals through the induction of the expression of drug-metabolizing enzymes and transporters. CAR’s involvement extends beyond detoxification, influencing gluconeogenesis, lipogenesis, bile acid regulation, and cellular processes such as proliferation, tissue regeneration, and carcinogenesis. This review explores CAR regulation by various factors, highlighting its role in mediating metabolic changes induced by environmental contaminants. Methods: A literature search was conducted to identify all articles on the PubMed website in which the CAR-contaminant and CAR-hepatic steatosis relationship is analyzed in both in vitro and in vivo models. Results: Numerous contaminants, such as perfluorooctanoic acid (PFOA), Zearalenone mycotoxin, PCB, triazole fungicide propiconazole can activate hepatic nuclear receptors contributing to the development of steatosis through increased de novo lipogenesis, decreased fatty acid oxidation, increased hepatic lipid uptake, and decreased gluconeogenesis. Indirect CAR activation pathways, particularly involving PFOA, are discussed in the context of PPARα-independent mechanisms leading to hepatotoxicity, including hepatocellular hypertrophy and necrosis, and their implications in nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD). The prevalence of NAFLD, a significant component of metabolic syndrome, underscores the importance of understanding CAR’s role in its pathogenesis. Conclusions: Experimental and epidemiological data suggest that endocrine disruptors, especially pesticides, play a significant role in NAFLD’s development and progression via CAR-regulated pathways. This review advocates for the inclusion of modern toxicological risk assessment tools, such as New Approach Methodologies (NAMs), Adverse Outcome Pathways (AOPs), and Integrated Approaches to Testing and Assessment (IATA), to elucidate CAR-mediated effects and enhance regulatory frameworks
Spectroscopic, Thermally Induced, and Theoretical Features of Neonicotinoids’ Competition for Adsorption Sites on Y Zeolite
No full textThe competitive retention of pollutants in water tables determines their environmental fate and guides routes for their removal. To distinguish the fine differences in competitive binding at zeolite adsorption centers, a group of neonicotinoid pesticides is compared, relying on theoretical (energy of adsorption, orientation, charge distribution) and experimental (spectroscopic and thermogravimetric) analyses for quick, inexpensive, and reliable screening. The MOPAC/QuantumEspresso platform was used for theoretical calculation, indicating close adsorption energy values for acetamiprid and imidacloprid (−2.2 eV), with thiamethoxam having a lower binding energy of −1.7 eV. FTIR analysis confirmed hydrogen bonding, among different dipole-dipole interactions, as the dominant adsorption mechanism. Due to their comparable binding energies, when the mixture of all three pesticides is examined, comparative adsorption capacities are evident at low concentrations, owing to the excellent adsorption performance of the FAU zeotype. At higher concentrations, competition for adsorption centers occurs, with the expected thiamethoxam binding being diminished due to the lower bonding energy. The catalytic impact of zeolite on the thermal degradation of pesticides is evidenced through TG analysis, confirming the adsorption capacities found by UV/VIS and HPLC/UV measurements. Detailed analysis of spectroscopic results in conjunction with theoretical calculation, thermal profiles, and UV detection offers a comprehensive understanding of neonicotinoids’ adsorption and can help with the design of future adsorbents.The competitive retention of pollutants in water tables determines their environmental fate and guides routes for their removal. To distinguish the fine differences in competitive binding at zeolite adsorption centers, a group of neonicotinoid pesticides is compared, relying on theoretical (energy of adsorption, orientation, charge distribution) and experimental (spectroscopic and thermogravimetric) analyses for quick, inexpensive, and reliable screening. The MOPAC/QuantumEspresso platform was used for theoretical calculation, indicating close adsorption energy values for acetamiprid and imidacloprid (−2.2 eV), with thiamethoxam having a lower binding energy of −1.7 eV. FTIR analysis confirmed hydrogen bonding, among different dipole-dipole interactions, as the dominant adsorption mechanism. Due to their comparable binding energies, when the mixture of all three pesticides is examined, comparative adsorption capacities are evident at low concentrations, owing to the excellent adsorption performance of the FAU zeotype. At higher concentrations, competition for adsorption centers occurs, with the expected thiamethoxam binding being diminished due to the lower bonding energy. The catalytic impact of zeolite on the thermal degradation of pesticides is evidenced through TG analysis, confirming the adsorption capacities found by UV/VIS and HPLC/UV measurements. Detailed analysis of spectroscopic results in conjunction with theoretical calculation, thermal profiles, and UV detection offers a comprehensive understanding of neonicotinoids’ adsorption and can help with the design of future adsorbents
Dual-Mechanism Gastroretentive Tablets with Encapsulated Gentian Root Extract
No full textBackground/Objectives: This study aimed to develop gastroretentive tablets based on mucoadhesive–floating systems with encapsulated gentian (Gentiana lutea, Gentianaceae) root extract to overcome the low bioavailability and short elimination half-life of gentiopicroside, a dominant bioactive compound with systemic effect. The formulation also aimed to promote the local action of the extract in the stomach. Methods: Tablets were obtained by direct compression of sodium bicarbonate (7.5%) and solid lipid microparticles (92.5%), which were obtained with lyophilizing double emulsions. A quality by design (QbD) was employed to evaluate the impact of formulation factors and processing parameters on emulsion viscosity, powder characteristics (moisture content, encapsulation efficiency, flowability), and tablet characteristics (floating lag time, gentiopicroside release, and assessment of dispersibility during in vitro dissolution). Results: The trehalose content and high-shear-homogenization (HSH) time of primary emulsion were critical factors. Trehalose content positively influenced emulsion viscosity, moisture content, floating lag time, encapsulation efficiency, and the release rate of gentiopicroside. HSH time positively affected powder stability and negatively gentiopicroside release. The selected powder had a high gentiopicroside encapsulation efficiency (95.13%), optimal stability, and good flowability. The developed tablets exhibited adequate floating lag time (275 s), mucoadhesive properties, and gentiopicroside biphasic release (29.04% in 45 min; 67.95% in 6 h). Furthermore, the optimal tablet formulation remained stable for 18 months and was primarily digested by duodenal enzymes. Conclusions: Dual-mechanism gastroretentive tablets with encapsulated gentian root extract were successfully developed. The in vitro digestion study demonstrated that the optimal formulation effectively resisted gastric enzymes, ensuring the release of its contents in the small intestine, even in the case of premature gastric evacuation
Spectroscopic and Morphological Examination of Co0.9R0.1MoO4 (R = Ho, Yb, Gd) Obtained by Glycine Nitrate Procedure
No full textThe glycine nitrate procedure (GNP) is a method that proved to be the easiest and most effective method for controlling the composition and morphology during the synthesis of Co0.9R0.1MoO4 (R = Ho, Yb, Gd). This method of the combustion process achieves control of stoichiometry, homogeneity, and purity. Metal nitrates and glycine were mixed in the appropriate stoichiometric ratios to produce Co0.9R0.1MoO4 (R = Ho, Yb, Gd). The samples obtained by the mentioned method were further subjected to different characterization methods such as differential thermal analyses (DTA), X-ray diffraction (XRD), Fourier transform infrared spectrum (FTIR), spectroscopy, field emission scanning electron microscopy (FESEM), and nitrogen adsorption method. A high level of anisotropy of the shape and size of particles in the form of agglomerates was found. Also, there are noticeable differences in the microstructure and plate crystals. The color of the synthesized sample changes from darker to lighter shades after thermal treatments. There are pronounced changes in the dominant wavelength (nm) and color purity between the initial sample and the sample after heating (1100 °C) due to the concentration of Co