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N-(9-Acridinyl) Amino Acid Derivatives: Synthesis and In Vitro Evaluation of Anti-Toxoplasma gondii Activity
No full textBackground/Objectives: Acridine, an aromatic heterocyclic compound, serves as a basis for the synthesis of potent bioactive derivatives, displaying a broad spectrum of biological activity, such as antibacterial, antitumor, and antiparasitic activity. With the ability to undergo various types of electrophilic substitutions, introducing different side chains could lead to compounds being active towards various and potentially multiple biotargets. Toxoplasma gondii, a ubiquitous protozoan parasite with worldwide distribution, poses a major health threat, particularly in immunocompromised patients and fetuses. Current treatment options for toxoplasmosis are scarce, with notable limitations, especially regarding side myelotoxicity and inactivity towards T. gondii cysts, causing a need for novel drug candidates. The aim of this study was to evaluate selected N-(9-acrydinil) amino acid derivatives as potential anti-T. gondii agents. Methods: Synthesis of new derivatives was performed using a two-step method, with the initial mixing of 9-chloroacridine with methanol and sodium alkoxide solution and subsequent adding of appropriate amino acids. Cytotoxicity of the tested compounds was evaluated on the Vero cell line using a MTT assay, while their anti-T. gondii activity was investigated using T. gondii RH strain tachyzoites. Results: CC50 values of the derivatives ranged from 41.72 to 154.10 µM. Anti-T. gondii activity, displayed as a reduction in the number of viable tachyzoites compared to the untreated control, ranged from 0 to 33.3%. One of the derivatives displayed activity comparable to the standard treatment option while retaining acceptable cytotoxicity. Esterification, presence of aromatic substituents and the length of the amino acid side chain were identified as key factors that affect both toxicity and activity of these derivatives. Conclusions: Promising results obtained throughout this study provide guidelines for further structural modifications of N-(9-acrydinil) amino acid derivatives in order to synthesize drug candidates competitive to standard treatment options for toxoplasmosis
Stakeholder Consensus on an Interdisciplinary Terminology to Enable the Development and Uptake of Medication Adherence Technologies Across Health Systems:Web-Based Real-Time Delphi Study
No full textBackground: Technology-mediated medication adherence interventions have proven useful, yet implementation in clinical practice is low. The European Network to Advance Best Practices and Technology on Medication Adherence (ENABLE) European Cooperation in Science and Technology Action (CA19132) online repository of medication adherence technologies (MATechs) aims to provide an open access, searchable knowledge management platform to facilitate innovation and support medication adherence management across health systems. To provide a solid foundation for optimal use and collaboration, the repository requires a shared interdisciplinary terminology. Objective: We consulted stakeholders on their views and level of agreement with the terminology proposed to inform the ENABLE repository structure. Methods: A real-time web-based Delphi study was conducted with stakeholders from 39 countries active in research, clinical practice, patient representation, policy making, and technology development. Participants rated terms and definitions of MATech and of 21 attribute clusters on product and provider information, medication adherence descriptors, and evaluation and implementation. Relevance, clarity, and completeness criteria were rated on 9-point scales, and free-text comments were provided interactively. Participants could reconsider their ratings based on real-time aggregated feedback and revisit the survey throughout the study period. We quantified agreement and process indicators for the complete sample and per stakeholder group and performed content analysis on comments. Consensus was considered reached for ratings with a disagreement index of <1. Median ratings guided decisions on whether attributes were considered mandatory, optional, or not relevant. We used the results to improve the terminology and repository structure. Results: Of 250 stakeholders invited, 117 (46.8%) rated the MATech definition, of whom 83 (70.9%) rated all attributes. Consensus was reached for all items. The definition was considered appropriate and clear (median ratings 7.02, IPR 6.10-7.69, and 7.26, IPR 6.73-7.90, respectively). Most attributes were considered relevant, mandatory, and sufficiently clear to remain unchanged except for ISO certification (considered optional; median relevance rating 6.34, IPR 5.50-7.24) and medication adherence phase, medication adherence measurement, and medication adherence intervention (candidates for optional changes; median clarity ratings 6.07, IPR 4.86-7.17; 6.37, IPR 4.80-6.67; and 5.67, IPR 4.66-6.61, respectively). Subgroup analyses found several attribute clusters considered moderately clear by some stakeholder groups. Results were consistent across stakeholder groups and time, yet response variation was found within some stakeholder groups for selected clusters, suggesting targets for further discussion. Comments highlighted issues for further debate and provided suggestions informing modifications to improve comprehensiveness, relevance, and clarity. Conclusions: By reaching agreement on a comprehensive MATech terminology developed following state-of-the-art methodology, this study represents a key step in the ENABLE initiative to develop an information architecture capable of structuring and facilitating the development and implementation of MATech across Europe. The debates and challenges highlighted in stakeholders' comments outline a potential road map for further development of the terminology and the ENABLE repository
Comparison of Drug-Related Problems Identified During a Pharmaceutical Care Model and Physician Consultations in the Geriatric Department
No full textBackground/Purpose: The study aimed to identify common drug-related problems (DRP), their causes and pharmacists' interventions during the pharmaceutical care (PC) model and physician consultations, and to explore the gap between physicians and pharmacists to achieve a better understanding and to provide better cooperation. Methods: We conducted a single-center prospective study at the geriatric department of a tertiary academic hospital. A PC model was implemented and defined a list of pharmacy services, high-risk patients and medications. Data were collected during pharmacist's medication reviews according to the PC model and physician consultations. DRPs, causes and interventions frequency during PC model and physician consultations were compared. Results: Pharmacists identified 197 DRPs during the PC model with primarily adverse drug events (possibly) occurring, followed by untreated indication and unnecessary drug treatment. In line with that, more than half of pharmacists’ interventions were initiation or discontinuation of the drugs, followed by dosage changes. During 107 physician consultations, the most reported DRP was treatement efficacy, which demanded drug or dosage changes. Antibiotics were the top medicines related to DRPs during the PC model and physician consultations. The level of acceptance of pharmacists’ interventions was higher for physician consultations (98.1%) compared to the PC model (68.5%). Conclusion: Physicians consulted pharmacists more on questions related to treatment effectiveness, while pharmacists paid attention to medication safety. The presented results might help physicians better understand the principles of pharmacy care services and guide pharmacists during their daily practice, achieve better cooperation in multidisciplinary teams, and improve the quality of patient care
Telomere length and oxidative stress in small cell lung cancer patients: changes through chemotherapy cycles compared to healthy controls
No full textIntroduction: Small cell lung cancer (SCLC) is an aggressive malignant disease with poor survival outcomes. The aim of this study was to investigate leukocyte telomere length (LTL) and redox status parameters during chemotherapy and evaluate their prognostic potential based on the hypothesis that shorter LTL and oxidative stress burden correlate with poorer survival. Materials and methods: This longitudinal study included 60 SCLC patients and 73 healthy controls. Leukocyte telomere length was measured by quantitative PCR (qPCR) method, while redox status parameters (MDA-malondialdehyde, IMA-ischemia-modified albumin, PON1-paraoxonase 1, redox index) were determined by spectrophotometric methods before, after two and after four cycles of chemotherapy. Results: All measured parameters showed significant differences between patients and controls, except the oxy-score (P < 0.001). Significant differences in IMA, PON1 and redox index were observed between SCLC patient groups at different time points (P < 0.001). Significant differences in IMA and PON1 were observed between SCLC survival groups, with higher values found in survivors after two chemotherapy cycles (P < 0.001). Redox index was the highest in the pre-chemo group (P = 0.019). Among patients who died, PON1 activity differed significantly between those who died within 2 months and after 4 months (P = 0.028). Kaplan-Meier analysis showed that LTL and PON1 were significant predictors of survival, with values below the 25th percentile associated with a higher risk of death. Conclusions: Leukocyte telomere length and PON1 are potential prognostic biomarkers for SCLC survival, suggesting their potential use in non-invasive biomarker panels for improved patient stratification
Memantine reduces the expression of IFN-gamma and IL-17 by CD4+ T cells in aged EAE rats
No full textThe average age of patients with multiple sclerosis (MS) has risen in recent decades. The
incidence of late-onset MS has also increased. More than half of people living with an MS
diagnosis are over 55. Ageing affects the composition and function of N-methyl-D-aspartate
receptors (NMDARs), regardless of whether they are expressed on neuronal or immune cells.
The aim of this study was to investigate the effects of memantine, a non-competitive NMDAR
antagonist, on CD4+ T lymphocytes in young and aged rats immunized for experimental
autoimmune encephalomyelitis (EAE). Memantine was administered by oral gavage to 3- and
24-month-old female Dark Agouti rats for 7 consecutive days from the first day
post-immunization (dpi) or from the 7th dpi. Mononuclear cells were isolated from the lymph
nodes draining the site of immunization or the spinal cord and analysed by flow cytometry. A
histopathologic analysis of the spinal cord was performed. Memantine administration more
effectively reduced the mean neurological score and histological score in aged rats. Memantine
reduced the expression of IFN-gamma and IL-17 by CD4+ T lymphocytes derived from draining
lymph nodes or the spinal cord to a greater extent in aged rats. On the other hand, there was no
difference in apoptosis of CD4+ T lymphocytes between control and memantine-treated young
rats, whereas apoptosis of these cells was significantly reduced in memantine-treated aged rats.
NMDARs have a greater effect on IFN-gamma and IL-17 synthesis by CD4+ T cells and
apoptosis of these cells in aged than in young EAE rats
Assessment of X Chromosome Centromere Instability in Alzheimer’s Disease: A Quantitative FISH Approach
No full textChromosomal instability in Alzheimer’s disease (AD) neurons has been previously reported. This pilot study aimed to establish a quantitative technique for assessing X chromosome centromere signals using fluorescence in situ hybridization (FISH). Hippocampal brain tissue was collected at autopsy from sporadic AD patients and age- and gender-matched controls. FISH was utilized to detect and measure the intensity of hybridization signals for X chromosome centromeres in the interphase nuclei of hippocampal brain cells. The premature centromere division (PCD) phenomenon, marked by a close bipartite signal appearing as two separated FISH spots, was examined to see if the hybridized DNA amount in each spot matched the expected centromere DNA amount. The technique effectively distinguished between PCD+ and PCD− signals. The average PCD frequency of the X chromosome in the AD group was 7 ± 1%, compared with 3.2 ± 0.84% in the controls. This quantitative approach supports qualitative analyses of FISH centromere spots, reinforcing findings of chromosomal instability in AD. The presence of a double signal at the centromere of a single X chromosome indicates re-entered cell cycles, DNA replication, and PCD in hippocampal neurons. This technique provides a reliable method for identifying PCD + signals and contributes to understanding chromosomal instability in AD
Selective Laser Sintering of Atomoxetine Tablets: An Innovative Approach for Small-Scale, Personalized Production
No full textBackground/Objectives: The growing interest in personalized medicine has accelerated the exploration of three-dimensional (3D) printing technologies in pharmaceutical applications. This study investigates the potential of selective laser sintering (SLS) as a flexible, small-scale manufacturing method for atomoxetine tablets tailored for individualized therapy, comparing it with conventional direct compression. Methods: Atomoxetine tablets were produced using SLS 3D printing with varying laser scanning speeds and compared to tablets made via a compaction simulator. Formulations were based on hydroxypropyl methylcellulose (HPMC) as the primary matrix former. The physical properties, drug content, disintegration time, and dissolution profiles were evaluated. The structural and chemical integrity were assessed using SEM, FTIR, DSC, and XRPD. Results: The SLS tablets exhibited comparable mechanical properties and drug content to those made by compaction. Lower laser speeds produced harder tablets with slower disintegration, while higher speeds yielded more porous tablets with ultra-rapid drug release (>85% in 15 min). All tablets met the European Pharmacopoeia dissolution criteria. No significant drug–excipient interactions or changes in crystallinity were detected. Conclusions: SLS printing is a viable alternative to traditional tablet manufacturing, offering control over drug release profiles through parameter adjustment. The technique supports the development of high-quality, patient-specific dosage forms and shows promise for broader implementation in personalized pharmaceutical therapy
Multiomics in atherosclerotic cardiovascular disease
No full textBackground and aims: Atherosclerotic cardiovascular disease (ASCVD) is among the leading causes of death worldwide, and technological advances have made it possible to expand the repertoire of biomarkers used in diagnostics and treatment of ASCVD. These include different omics (genomics, epigenomics, transcriptomics, proteomics, and metabolomics). We introduce the various layers of omic data and how they can be used in diagnostics and treatment of ASCVD. Further, we discuss future possibilities of combining multiomic data with machine learning (ML) and artificial intelligence (AI) to develop algorithms for facilitating precision medicine. Methods: we reviewed the current literature on omic data in ASCVD and its integration with ML/AI. Results: Genomics has been used to generate polygenic risk scores (PRS), which have shown promising results in risk prediction of ASCVD. Key epigenetic changes implicated in atherosclerosis include deoxyribonucleic acid (DNA) methylation. Transcriptomics has been used to identify transcripts, including micro ribonucleic acid (miRNAs), implicated in atherosclerosis progression. Proteomic risk scores have shown independent predictive information and outperformed clinical risk models, and within the metabolomics field, lipidomics has emerged as a promising predictive tool. The combination of multiomic data analysis with ML and AI methods has already demonstrated potential in the development of clinical models. Conclusions: A major effort is necessary to bring omic data and technologies to the clinical field. Further support will be offered by the generation of clinically applicable/approved AI/ML algorithms able to translate large datasets into valuable information for accurate precision medicine approaches
Da li je primarna prevencija dostupna studentima?
No full textThe college years are critical to students' health as they face various challenges, including
social influences and unhealthy lifestyles. Limited access to health services in residence halls
increases the risk of unhealthy behaviours. The aim of this study was to investigate students'
attitudes towards public health services for primary prevention in dormitories and to make
suggestions for improvement. A cross-sectional study was conducted using a questionnaire
among students living in halls of residence. The survey explored students' views on healthcare
and the availability of preventive services for students living away from home. A total of 996
students participated (response rate 99.1%). Most were unemployed (83.9%). The most frequent
preventive visits were to dentists (34.4% twice a year, 24.7% once a year), while 37.7% never
visited a gynaecologist/urologist. The majority (68.6%) stated that a pharmacy was necessary in
their dormitories. Basic health services include general practitioners (82.3%) and psychologists
(21.4%). Attitudes towards health centres varied significantly by place of residence (p<0.001).
Primary prevention should be improved by health centres with student-friendly opening hours
and additional activities that promote access to healthcare and awareness of prevention.Period studiranja je ključan za zdravlje studenata, jer se suočavaju sa različitim izazovima,
uključujući društvene uticaje i nezdrav način života. Ograničen pristup zdravstvenim uslugama u
studentskim domovima povećava rizik od nezdravih ponašanja. Ova studija imala je za cilj da
istraži stavove studenata o javno-zdravstvenim uslugama za primarnu prevenciju u studentskim
domovima i predloži poboljšanja. Sprovedena je studija preseka korišćenjem upitnika među
studentima koji žive u domovima. Anketa je procenjivala stavove studenata o zdravstvenoj zaštiti
i dostupnosti preventivnih usluga za one koji studiraju van mesta prebivališta. U istraživanju je
učestvovalo 996 studenata (stopa odziva 99,1%). Većina je bila nezaposlena (83,9%). Najčešće
preventivne posete bile su stomatološke (34,4% dva puta godišnje, 24,7% jednom godišnje), dok
37,7% nikada nije posetilo ginekologa/urologa. Većina (68,6%) smatra da je apoteka neophodna
u studentskom domu. Najvažnije zdravstvene usluge uključuju lekare opšte prakse (82,3%) i
psihologe (21,4%). Stavovi o zdravstvenim centrima značajno su se razlikovali u zavisnosti od
postojanja takvog centra u domu (p<0,001). Primarna prevencija treba da se poboljša kroz
zdravstvene centre sa prilagođenim radnim vremenom i dodatne aktivnosti koje poboljšavaju
pristup zdravstvenoj zaštiti i podižu svest o značaju prevencije
Minerals and microelements in commercial baby foods and food supplements consumed in Serbia
No full textThe mineral content of 147 commercially available baby foods and food supplements consumed in Serbia was analyzed. The content of elements (Na, K, Ca, Mg, Se, Fe, Mn, Cu, Zn) was determined by optical emission spectrometry with inductively coupled plasma (ICP OES) method and flame atomic absorption spectrometry (FAAS) method. Sample preparation was performed by dry ashing and wet digestion. The analytical procedure was optimized and validated. The results show that only K, Na and Ca were within the permissible tolerance limits. Outside the defined tolerance range were 15 % of formulations for special medical purposes (for Se, Fe, Cu, Zn, Mn); 5 % of infant and follow-on formulae (for Mn, Mg, Fe), while 9 % of food supplements were outside the defined tolerance range (for Zn).The percentage of banned deviations is not worrying, but more extensive investigations are needed, covering more samples and the entire territory of Serbia, so that the results give as realistic a picture as possible of these products on the national market. Methods utilized in this study obtained acceptable precision (CV: <5 %) and accuracy (recovery: 80–101 %) through validation process, and are straightforward enough for routine work