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Investigation of technological, chemical, biological aspects, and in-silico pharmacokinetic and docking predictions of winter savory (Satureja montana L.) essential oil
No full textHydrodistillation (HD 205 W and 410 W) and microwave-assisted hydrodistillation (MWHD 90–800 W) were used to prepare essential oil samples from winter savory. Isolated essential oils were analyzed to determine their chemical profiles. Carvacrol was the principal compound, followed by p -cymene and γ-terpinene. Biological activity was assessed using six antioxidant assays, an antimicrobial assay (6 different microbes), and a cytotoxic test (4 cell lines). The MWHD 360 W was the most potent antioxidant agent. The HD 205 W and MWHD 360 W showed the best antimicrobial activity, while the HD essential oil samples were the most potent cytotoxic agents. Molecular docking was performed for the eight most abundant compounds on three proteins: E. coli type I signal peptidase (PDB code 1T7D), P. aeruginosa arginine rhamosyltransferase (PDB code 6J7J), and S. aureus penicillin G acyl-Penicillin binding protein 2a (PDB code 1MWT). Carvacryl acetate and trans- caryophyllene provide the most promising results (the lowest binding energy). The ADMET (absorption, distribution, metabolism, excretion, and toxicity) calculations revealed low toxicity, high skin, blood-brain barrier, and CNS permeability, and high intestinal absorption
Structural hybridization as a tool for developing novel biologically active analogues of protulactone A
No full textThe study described in the manuscript includes the synthesis of twelve novel hybrid analogues of protulactone A and the evaluation of their antiproliferative activity against a panel of ten tumour and one normal human cell line (foetal lung fibroblasts, MRC-5). The key step in the synthesis was the Grignard addition of PhMgBr to the aldehyde derived from d -galactose, followed by removal of the 1,2- O -isopropylidene protecting group and cyclocondensation of the resulting lactols with Meldrum's acid to build the [3.3.0]furofuranone core. After routine manipulation with present functional groups, the natural product protulactone A and several new hybrid analogues were obtained, ready for biological testing. Several analogues, particularly compounds 9 , 13 , and 16 , showed IC₅₀ values below 10 μM against leukaemia (K562, HL-60), breast (MCF-7, MDA-MB-231), and cervical (HeLa) cancer cells. Selected derivatives ( 3 , 8 , 11 ) further reduced MRP1 levels and induced apoptosis through Caspase-3 activation in K562 cells, indicating their potential as modulators of multidrug resistance. Structure–activity relationship analysis revealed that the introduction of a phenyl group at the C-7 position and specific stereochemical configurations significantly enhanced cytotoxic potency. Importantly, none of the analogues displayed antibacterial or antifungal activity, underscoring their selectivity for tumour cells. Cellular LC-MS/MS profiling revealed that compound 11 achieves uniform high uptake but remains non-toxic to normal cells, demonstrating true pharmacodynamic cancer selectivity. These findings highlight the structural hybridization of protulactone A and styryl lactone as a rational strategy for designing novel anticancer agents with selectivity and relevance in drug resistance contexts
Newly Synthesized Telmisartan–Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells
No full textTelmisartan, an angiotensin II type 1 receptor (AT1R) antagonist, possesses cytotoxic activity towards BRAF-mutated melanoma cell lines. However, its antihypertensive effects limit its use in the population of normotensive patients. To mitigate this shortcoming, a group of eight telmisartan-amino acid conjugates, designed to have reduced or no AT1R affinity with enhanced cellular uptake, were synthesized by the coupling reaction in yields ranging from 34% to 60%. Their cytotoxicity was tested on BRAF V600E-mutated melanoma cell lines (A375 and 518A2), and compounds 1, 3, and 8 stood out as the best candidates. These three compounds were also tested on the vemurafenib-resistant (A375R) and normal (HaCaT and MRC-5) cell lines, and compound 8 showed better cytotoxicity (IC50 = 8.84 ± 1.24 µM) and selectivity (>3.50) when compared to telmisartan (IC50 = 29.23 ± 3.88, selectivity > 2.40). The cellular uptake of compounds 1 and 8 was significantly higher than telmisartan, with substantial accumulation in the membrane and nuclear compartments. Unlike telmisartan, compounds 1, 3, and 8 did not inhibit angiotensin II-induced Ca2+ signaling, which indicates diminished AT1R binding. All three compounds induced cell cycle arrest and disrupted mitochondrial morphology and membrane potential. These findings highlight their potential as non-antihypertensive telmisartan derivatives for melanoma therapy
Synthesis and cytotoxic evaluation of pyrido-dipyrimidine derivatives: Mechanism of action, DNA and HSA binding studies
No full textThis study presents the synthesis of a novel series of pyrido[2,3-d:6,5-d’]dipyrimidine derivatives ( 4a-v ) via an ‘on-water’ multicomponent reaction, utilizing thiobarbituric acid, diverse aldehydes, and amines at room temperature. The compounds were evaluated for cytotoxic activity against human cancer cell lines (HeLa, K562, LS174, A549) and normal fibroblasts (MRC-5) using MTT assays. Notable potency was observed against HeLa and K562 cells, with IC50 values ranging from 9.82 to 192.47 μM. Compound 4 k exhibited the strongest activity against HeLa (IC50 = 9.82 ± 1.07 μM) with a selectivity index (SI) >12, while 4u was most effective against K562 (IC50 = 17.36 ± 1.39 μM, SI >9). LS174 and A549 showed limited sensitivity. Structure-activity relationship (SAR) analysis revealed that para -hydroxyphenyl substituents at position 5 and thiocarbonyl groups enhanced cytotoxicity, particularly against leukemia cells, via improved hydrogen bonding and target affinity. Mechanistic studies on 4 k and 4u focused on DNA and human serum albumin (HSA) interactions. UV–Vis and fluorescence spectroscopy, including ethidium bromide displacement and viscosity measurements, indicated minor groove binding to CT-DNA (Kb ∼ 104 M−1; Ksv ∼ 104 M−1) with partial intercalation. HSA binding occurred via static quenching at sites I and II (Ksv ∼ 105 M−1; Kb ∼105 M−1), confirmed by competitive assays with Eosin Y and ibuprofen. Cell cycle analysis and AO/EB staining demonstrated apoptosis induction, with increased subG1 populations. Caspase assays showed 4 k activated both intrinsic (caspase-9) and extrinsic (caspase-8) pathways in HeLa cells, leading to caspase-3 execution; 4u induced caspase-independent apoptosis in K562. Molecular docking and dynamics simulations supported minor groove DNA preference and HSA site I/II binding, with stable complexes (ΔGbind ≤ −8 kcal/mol). RMSD, RMSF, and Rg analyses affirmed structural integrity. These derivatives emerge as promising selective anticancer agents targeting DNA and apoptosis, warranting further optimization and in vivo studies
Impact of different extracorporeal blood purification strategies during continuous renal replacement therapy in septic shock patients
No full textBackground: Septic shock with acute kidney injury is associated with high mortality. Hemoadsorption methods
such as CytoSorb®
in conjunction with standard continuous renal replacement therapy (CRRT) and oXiris®-based
CRRT are increasingly used; however, comparative data are scarce. This study assessed the effects of both filters
on vasopressor-free days and key clinical outcomes in septic shock.
Methods: This retrospective single-center cohort included adults with septic shock treated with CytoSorb®
in
conjunction with CRRT or oXiris®-based CRRT between January 2023 and December 2024. The primary endpoint
was vasopressor-free days to day 28, with secondary outcomes including Sequential Organ Failure Assessment
(SOFA) score, lactate levels, norepinephrine equivalent dose (NEED), mean arterial pressure, ventilator-free days,
intensive care unit (ICU) length of stay, and mortality.
Results: A total of 97 patients were included in the analysis. (CytoSorb®
n=75; oXiris® n=22). Both extracorporeal
blood purification modalities were associated with comparable reductions in lactate levels (median [IQR]: −39.7
[−47.2 to −19.3]% vs. 44.5 [−54.0 to −33.3] %, respectively, P=0.14), and NEED (median [IQR]: −36.1 [−66.7 to
−9.1] vs. −56.4 [−83.3 to −12.5] %, respectively, P=0.36), along with similar increases in mean arterial pressure
(9.6 [7.7–18.2]% vs. 9.8 [7.7–16.7] %, respectively, P=0.94). No significant differences were found between the
two modalities. Vasopressor-free days were similar (median [IQR]: 0.0 [0–24] days with CytoSorb®
vs. 20.5 [0–
25] days with oXiris®
, P=0.55). In the multivariable competing-risks analysis, extracorporeal blood purification
modality was not independently associated with vasopressor-free days after adjustment for potential confounders
(subhazard ratio [sHR]=0.97, 95% confidence interval: 0.48–1.94, P=0.93). Ventilator-free days, ICU stay, and
ICU and hospital mortality were likewise comparable.
Conclusions: CytoSorb®
in addition with CRRT and oXiris®-based CRRT demonstrated similar hemodynamic and
clinical outcomes. Larger prospective studies are needed to define the optimal role of extracorporeal CRRT-based
blood purification in septic shock
An insight into pharmacy users’ habits of using herbal products in Serbia: a cross-sectional study
No full textIntroduction: Medicinal plants have long been used to treat diseases, and their use in herbal products is increasingly
popular, especially for self-medication. This paper aims to assess the prevalence of herbal product use
among pharmacy users in Serbia, as well as the motives and awareness regarding their use.
Methods: A quantitative, nonexperimental survey research was conducted in community pharmacies across
Serbia, involving 2208 respondents. The data were analysed using descriptive statistics (frequencies, percentages)
and inferential techniques (Chi-square test and binary logistic regression).
Results: Nearly all pharmacy users (97.5%) use various herbal products. They most often use them as needed
(39.7%), while 22.8% use them frequently, and a similar proportion use them infrequently (17.9%) or daily
(17.1%). The most common motive for their use is to improve health (76.0%). Over half of the respondents
(58.4%) reported purchasing herbal products from pharmacies. Additionally, 73.1% of respondents consistently
received advice on the use of herbal products from pharmacists. The primary sources of information about herbal
products were pharmacists (44.6%) and then the media (22.8%). Most respondents (58.6%) believe herbal
products are safe but have some side effects, whereas 30.0% believe herbal products are completely free of side
effects. Almost half of the respondents believe herbal products are as effective or more effective than synthetic
medicines.
Conclusion: Strengthening pharmacists’ role in counselling, developing pharmacy-based strategies, enforcing
regulations, promoting pharmacy-based access, and providing pharmacist-led education, together with collaboration
among healthcare professionals, regulators, and the media, is essential to ensure safe and informed use
of herbal products
Population pharmacokinetic analysis for simultaneous fit of clozapine and norclozapine concentrations in adult psychiatric patients
No full textBackground: Clozapine (CLZ) exhibits a high potential for pharmacokinetic interactions due to its extensive and complex metabolism. Additionally, several patient-related factors contribute to the pharmacokinetic variability, making treatment optimization even more challenging. The goal of this study was to develop a parent-metabolite population pharmacokinetic model for CLZ and its primary metabolite norclozapine (NCLZ) and to evaluate sources of variability in a real-world clinical setting. Methods: Data from routine therapeutic drug monitoring (TDM) of 126 adult in- and out-patients with psychiatric disorders were used for the analysis. A nonlinear mixed-effects modeling approach was applied for data analysis to simultaneously fit CLZ and NCLZ concentrations. Results: A one-compartment model for the drug with an additional compartment for NCLZ was used to fit the concentration-time data. The population pharmacokinetic value of oral clearance for CLZ (CL/F) for a typical patient (female, non-smoker) was 26.4 L/h. Male sex and positive smoking status were associated with an increase in CL/F of 25.9 % and 29.2 %, respectively. The estimated value of metabolite clearance (CLm/F) for a typical patient was 29.6 L/h, while male sex and valproic acid (VPA) use were associated with its increases for 45.1 % and 95.5 %, respectively. Conclusion: The developed population pharmacokinetic model describes the simultaneous disposition of CLZ and NCLZ in adult psychiatric patients, accounting for impact of patient and co-therapy factors. In addition to the well-established effects of sex and smoking status on CLZ pharmacokinetics, the model characterizes the significant impact of VPA co-therapy, primarily on NCLZ disposition
Changing Patterns of Psychotropics Use Among Older Adults With Intellectual Disability Over a Decade, With a Focus on Designated Mental Health Conditions
No full textBackground: Psychotropics (sometimes off-label), mental health diagnoses and behaviours of concern are common in older adults with intellectual disability. Guidelines recommend non-pharmacological interventions and regular medication review. This study examined changes in psychotropics among older adults (≥ 40) with intellectual disability. Methods: Longitudinal data were obtained from the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA) at two timepoints [Wave 1(2009/10); Wave 4(2019/20)]. Post hoc analysis, Chi-squared tests and univariate binary logistic regression were conducted. Results: Overall, psychotropics decreased (59.2% to 56.5%). Significant decreases in antipsychotics (43.1%–40.1%) and sedatives/hypnotics (13.6%–8.1%) and significant increase in antidepressants (26.2%–31.8%) were found. Nearly half of antidepressant users reported depression at Wave 1, compared with under 30% at Wave 4. Antipsychotics and antidepressants were common (75% and 60%, respectively) among those with behaviours of concern, after excluding clinical indications. Conclusion: Psychotropic prescribing remained consistent, though class-specific patterns shifted, with some decreases or increases observed
Computational profiling of toxic mixtures associated with type 2 diabetes mellitus development: identification of key protective agents
No full textThe aim of the current research was to assess the association between the exposure to plastic-related chemicals and toxic metals with the development of type 2 diabetes mellitus using an in silico approach, while also exploring the protective potential of antioxidant vitamins and phytochemicals, including Vitamin C, Vitamin E, sulforaphane, resveratrol, curcumin, naringin, and quercetin. CTD database, GeneMANIA server, and Toppgene portal were used as the main in silico tools in this study. Six common genes (BAX, CASP3, CAT, IL6, SOD1, TNF) were identified for all toxic substances, indicating potential shared mechanisms of toxicity (apoptosis, inflammation, oxidative stress). Additionally, phthalates and bisphenols affected cell growth, lipid and energy metabolism, and vascular functions, while toxic metals were linked to apoptosis regulation, DNA repair, insulin regulation, and glucose uptake. All tested protective substances, except naringin, affected all six common genes for all toxic substances, with vitamin C, vitamin E, and sulforaphane showing the most consistent protective effects. This study highlights the complex mechanisms in type 2 diabetes pathogenesis induced by toxic substances and provides a foundation for further research on the preventive effects of tested protective substances, emphasizing their varying protective potentials depending on the toxic compounds
Effect of Oxidative Stress Intensity on Inflammatory, Bone Turnover, and Haemostasis Biomarkers in Patients with Spinal Osteoarthritis
No full textOsteoarthritis is associated with chronic inflammation, which contributes to a hypercoagulable state. Oxidative stress may further disrupt homeostatic balance, thereby promoting thrombotic events. This study evaluated the association between biomarkers of oxidative stress, inflammation, haemostasis, and bone metabolism in patients with spinal osteoarthritis. A total of 48 patients were included. The levels of inflammatory, bone turnover, haematological, and coagulation biomarkers were determined using standard laboratory methods. Redox status was assessed via prooxidant–antioxidant balance (PAB) and superoxide dismutase (SOD) activity. Patients with elevated PAB showed significantly higher erythrocyte sedimentation rate (ESR) (p = 0.005), alkaline phosphatase (ALP) (p = 0.003) and fibrinogen levels (p = 0.006) and platelet count (p = 0.040), along with lower 25-OH vitamin D levels (p = 0.045) and shortened PT (p = 0.008) and aPTT (p = 0.017). In low oxidative stress states (PAB < 100 U/L), significant correlations were observed among redox, coagulation, and bone turnover markers, whereas in high oxidative stress (PAB ≥ 100 U/L), it was characterised by predominant associations between redox and bone turnover biomarkers. Patients with grade V disc degeneration had a significantly higher probability of elevated D-dimer levels compared to those with grade IV (OR = 5.440; p = 0.009). In addition, elevated D-dimer levels were associated with increased ESR (p = 0.015), IL-6 (p = 0.016) and ALP levels (p = 0.034). The associations between biomarkers of redox status, inflammation, coagulation and bone turnover are influenced by the extent of oxidative stress. Our results suggest that PAB and D-dimer may serve as potential biomarkers for disease severity and thrombotic risk. Further studies are needed to confirm these preliminary findings