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Simulation-guided dissolution testing: Coupling DDDPlus™ and GastroPlus® to predict aripiprazole oral bioperformance
No full textOrally administered weakly basic compounds like aripiprazole (ARI) can precipitate in the small intestine due to limited solubility at intestinal pH. This study aimed to identify in vitro biopredictive dissolution tests conditions for ARI immediate release (IR) tablets using a combined GastroPlus® (G+) and DDDPlus™ (D+) modeling approach. ARI solubility was studied in vitro across various pH levels and in biorelevant media, while passive permeability was evaluated using the PAMPA model. These experimental data were used as inputs to build an ARI-specific G+ model, which was used to estimate the in vivo dissolution profiles of ARI following oral administration of IR tablets. D+ was then used to identify in vitro dissolution test conditions predictive of the G+ simulated in vivo dissolution profiles. The in vitro dissolution data for 10 mg, 15 mg and 30 mg ARI IR tablets in 900 mL of compendial media (pH 1.0, pH 4.5 and pH 6.8) using paddle apparatus at 50 rpm and 75 rpm were employed for D+ model development and validation. Experimental findings classified ARI as a low soluble, borderline highly permeable compound. G+ simulations revealed dose-dependent intestinal precipitation followed by subsequent re-dissolution. A three-stage, pH shift dissolution method using basket apparatus was identified as biopredictive of G+ estimated in vivo dissolution profiles, effectively mimicking the G+ simulated precipitation and re-dissolution. This work illustrates an example of how integrated dissolution and absorption modeling can be leveraged to identify biorelevant in vitro test conditions
The Disruption of Thyroid Gland Homeostasis by the Lead and Polychlorinated-Biphenyls Mixture in Rats
No full textHumans are continuously exposed to a complex mixture of chemicals. While the composition of these mixtures is perpetually changing, most of the risk evaluation is based upon single-component studies. Because both lead (Pb) and polychlorinated biphenyls (PCBs) are ubiquitous chemicals, we investigated whether the environmentally relevant mixture of these chemicals has any effects on thyroid homeostasis and are these changes are dose dependent. Doses of 0.1, 0.5, and 1 mg Pb/kg/day and 0.25, 0.5, and 1 mg PCBs/kg/day were administered to male albino Wistar rats using a 3 × 3 dose design for 28 days. At the end of the mixture treatment period, the measurements of the serum levels of thyroid hormones and thyroid-stimulating hormone (TSH) were performed. In the thyroid gland tissue, oxidative stress parameters were analyzed. The obtained results were used to create the dose–response models in PROAST. An increase in the level of free thyroxine (FT4), total and free triiodothyronine, TSH, total oxidative status (TOS), and sulfhydryl groups was documented. In contrast, a significant decrease in relative thyroid weight (TW) and total antioxidative status (TAS) was observed, while the significant differences in total thyroxine, rat body weight, and albumin serum levels were not confirmed between the control and the exposed groups. The most sensitive parameter was the decrease in the TAS in thyroid gland tissue, while the benchmark dose's lower confidence limit (BMDL) calculated for the FT4 parameter can be used as a reference point. The presented study and available literature suggest that Pb and PCBs in the mixture can act through their toxicological mechanisms on different levels of the hypothalamic–pituitary–thyroid gland axis, including the disruption of oxidative-antioxidative status
RNA modifications in peripheral blood are associated with acute coronary syndrome
No full textAcute coronary syndromes (ACS) trigger inflammatory and immune reactions, yet whether this response is associated with changes in RNA modifications remains poorly understood. We investigated global epitranscriptomic patterns in peripheral blood mononuclear cells (PBMC) from patients with ST-elevation myocardial infarction (STEMI, n = 118), non-ST-elevation myocardial infarction (NSTEMI, n = 22), unstable angina pectoris (UAP, n = 10), and stable angina pectoris (SAP, n = 152). Using liquid chromatography–mass spectrometry, we quantified N1-methyladenosine (m1A), 2′-O-methyladenosine (2′-O-mA), N6-methyladenosine (m6A), N6,2′-O-dimethyladenosine (m6Am), and pseudouridine (Ψ), together with their ratios to unmodified nucleotides. Levels of 2′-O-mA (P = 0.004), m6Am (P < 0.001), and Ψ (P = 0.021) were significantly decreased in STEMI compared with SAP. m6Am was also reduced in UAP (P = 0.037) and NSTEMI (P = 0.012), whereas m1A and m6A did not differ between groups. Among modification ratios, only the m6Am/A ratio declined across ACS subtypes (UAP P = 0.015; NSTEMI P = 0.032; STEMI P = 0.007), indicating relative cap-adjacent hypomethylation. Reduced m6Am correlated inversely with hsCRP (r = −0.19, P < 0.001) and hsTnI (r = −0.24, P < 0.001). In multivariable logistic regression adjusting for age, sex, BMI, and hsCRP, m6Am remained independently associated with STEMI (OR = 0.14, 95% CI 0.02–0.81; P = 0.028). These findings demonstrate selective RNA modification changes in ACS and identify m6Am as an independent epitranscriptomic marker associated with myocardial infarction
Importance of providing pharmaceutical care for patients using psychotropic medicines in community pharmacy
No full textBackground: Mental health represents a major global public health challenge significantly impacting well-being, quality of life, and mortality. Psychotropic medicines are frequently associated with drug-related problems (DRPs) that may lead to decreased quality of life (QoL), falls, hospitalizations, and increased morbidity, or mortality. Non-adherence, observed in nearly half of patients with psychiatric disorders, remains a critical issue. This study evaluated the real-life impact of community pharmacists in identifying and managing DRPs among patients using psychotropic medicines and examines how sociodemographic factors influence QoL. Methods: The randomized controlled study was conducted in six community pharmacies in the Istrian County (Croatia) among adult patients using psycholeptics or psychoanaleptics. DRPs were documented using the Pharmaceutical Care Network of Europe (PCNE) DRP Classification Version 9.1. QoL was assessed once, prior the intervention, with the WHOQoL-BREF Questionnaire. In the intervention group (A), pharmacists’ intervention followed a standardized protocol, in contrast to common pharmacists’ practice in Croatia provided to the participants in the control group (B). Results: Ninety-seven participants completed the study. Baseline measurement of QoL showed significantly higher scores in Physical health (p = 0.018) and Social interaction (p < 0.001) domains for younger (<65 years) and employed participants. The results of randomized intervention revealed higher median identified DRPs for older, unemployed or retired participants (p = 0.013; p = 0.018) in both groups. The most common manifested DRP was “untreated symptoms or indication,” with significantly higher number of identified potential DRPs in group A (p = 0.015). “Adverse drug event” was the most frequent potential DRP with higher frequency in group A. “Lack of cooperation of patient” was the leading reason for unresolved DRPs in both groups. Conclusion: Community pharmacists play an important role in identifying untreated conditions, adverse drug events and associated causes of DRPs related to psychotropic medicine use. Findings support integration of structured pharmaceutical care into community pharmacy practice to enhance patient safety through prevention of adverse drug events and medication safety surveillance
Multifaceted biological and computational assessment of aromatic and N-heteroaromatic non-substituted thiosemicarbazones
No full textThiosemicarbazones (TSCs) constitute a pharmacologically versatile class of
compounds with documented antimicrobial, antiviral, and anticancer
properties. Despite their therapeutic potential, their biological mechanisms
and pharmacokinetic behaviour remain insufficiently characterized. In this
study, we investigated the biological activity of the library consisting of 28
aromatic and heteroaromatic compounds against twelve cancer cell and two
normal cell lines, and four parasites. Six N-heteroaromatic
thiosemicarbazones based on pyridine (13, 14, and 18), quinoline (24 and
26), and indole (27) moieties show promising anticancer and/or antiparasitic
activity. Density functional theory (DFT) calculations indicated that the
biological activity of 13, 14, 18, 24, and 26 arises from their ability to chelate
d-metals, whereas 27 operates via a distinct mechanism. The passive
gastrointestinal absorption and Human serum albumin (HSA) binding ability of these six compounds were evaluated by the Parallel artificial membrane
permeability (PAMPA) technique and high-performance affinity
chromatography, respectively. Compound 26 emerged as the most potent
and selective anticancer agent and was further examined through cell cycle
profiling, caspase-3/7 activation, DNA double-strand break quantification, 3D
spheroid assays, and an in ovo chorioallantoic membrane (CAM) model,
supported by HSA docking and molecular dynamics simulations. Collectively,
our results indicate that 26 is a selective anticancer agent that exerts
cytotoxic effects preferentially in cancer cells, by inducing apoptosis and
DNA double-strand breaks
Quantitative Analysis of Polyphenols and In Vitro Antioxidant, Antimicrobial and Toxicity Assessments in Needles of Five Pinus Species from Montenegro
No full textThis study aimed to investigate the chemical composition and biological potential of needle extracts from five pine species, including antimicrobial, antioxidant, and cytotoxic activity, as well as their influence on cell cycle progression. Needle extracts were prepared using three extraction methods: conventional maceration (CM), ultrasound-assisted extraction (UAE), and digestion (D). The chemical profile was determined with an emphasis on phenolic acids, flavonoids, and related phenolic compounds. The highest total phenolic content was observed in Pinus sylvestris (3.438 mg/g GAE), followed by Pinus heldreichii (2.732 mg/g GAE). Rutin, ferulic acid, and quercitrin were identified as the predominant phenolic compounds. The highest total flavonoid content was found in Pinus pinea extracts obtained by digestion (1.213 mg/g QE), followed by P. heldreichii (1.074 mg/g QE) and Pinus halepensis (1.074 mg/g QE), both obtained by UAE. Among all examined species, Pinus pinea exhibited the highest TTC values, regardless of the extraction method (7.31–8.21 mg/g GAE). Antibacterial testing showed that P. pinea had an MIC of 19 mg/mL against Enterococcus faecium, while P. sylvestris had the same MIC against Bacillus spizizenii. All extracts exhibited cytotoxic effects using MTT assay against HeLa cells at concentrations of 8%, 16%, and 32%, while LS 174T cells were the least sensitive. Pine needle extracts from Montenegro are a valuable source of phenolic and flavonoid compounds, and they demonstrate antimicrobial and cytotoxic activities. The results support the need for further in vivo studies and elucidation of mechanisms of action in order to assess their potential application as novel bioactive agents
First case report of Shewanella indica isolated from a hospitalized patient in Serbia
No full textOver the past decade, Shewanella spp. have been increasingly recognized as opportunistic pathogens, particularly in patients with malignancies, neutropenia, severe heart failure, renal insufficiency, and hepatobiliary diseases. Shewanella indica is a rarely reported species within the Shewanella genus, and its role in human infection remains poorly documented. In this study, we report the first case of S. indica isolated from the stool of a critically ill 72-year-old man in Serbia with multiple pre-existing comorbidities and co-infections. Initial identification using the VITEK 2 system misclassified the strain as Shewanella algae, while species-level identification by the matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) was inconclusive. However, whole-genome sequencing (WGS) definitively identified the isolate as S. indica and revealed a multidrug-resistant profile together with numerous virulence-associated genes. Minimum inhibitory concentrations (MICs) were determined for 32 antibiotics, although interpretation was constrained by the lack of species-specific breakpoints. This case highlights the diagnostic challenges in differentiating Shewanella indica, discusses its possible clinical roles, and underscores the value of genomic tools for accurate identification. It also reinforces the importance of recognizing rare pathogens in complex clinical scenarios. Copyrigh
Toward Precision Medicine in Atherosclerotic Cardiovascular Disease: Insights from Omics Data into Sex Differences
No full textPurpose of Review: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide. Although there is increasing recognition of sex differences in ASCVD epidemiology, pathogenesis, and clinical outcomes, the underlying biological mechanisms are still insufficiently understood. Women often present with distinct disease phenotypes, such as a higher prevalence of fibrous plaques and microvascular dysfunction, compared with the lipid-rich, inflammatory plaques more typical in men. This review examines recent omics research to clarify the molecular basis of these sex-specific patterns and explores their implications for precision cardiovascular medicine. Recent Findings: Advances in genomics, epigenomics, transcriptomics, proteomics, and metabolomics have shown that sex differences in ASCVD arise from complex hormonal, genetic, epigenetic, and molecular interactions. The variety of available omics approaches offers the potential to discover sex-specific regulatory networks and therapeutic targets, thereby addressing persistent knowledge gaps. However, significant challenges remain, including integrating these diverse omics layers, harmonising datasets across platforms, managing substantial computational demands, and navigating ethical constraints related to data sharing. Summary: Multiomics technologies provide unprecedented opportunities to dissect sex-specific mechanisms in ASCVD and to refine individualised risk stratification and therapeutic strategies. Overcoming current analytical and infrastructural barriers through collaborative efforts, standardised methodologies, and responsible data governance will be critical to unlocking the full potential of multiomics in precision cardiovascular medicine. This review synthesises recent evidence across omics domains and underscores their potential to improve ASCVD prevention and treatment
Direct RNA sequencing identified solute carrier family 2 member 1 to improve neurological outcome prediction after cardiac arrest
No full textBackground Cardiac arrest (CA) is a major cause of mortality and morbidity. Accurate prediction of neurological
outcome and survival remains challenging. In this context, our study aimed to explore novel molecular biomarkers
that could provide additional insights into the pathophysiology of brain injury after CA and potentially distinguish
patients with no brain injury (CPC 1) from those with any degree of neurological damage from moderate injury
up to death (CPC 2–5), and complement existing prognostic tools.
Methods Whole blood samples collected 48 h after return of spontaneous circulation were analyzed by RNA
sequencing in a subgroup of 50 CA patients from the monocenter North Pole cohort, and by quantitative PCR in 233
patients from the same cohort as well as in 511 patients from the multicenter TTM trial. The association of gene
expression changes with 6-month neurological outcome (assessed by the Cerebral Performance Category (CPC)
score) and survival was studied.
Results In a discovery phase with a subset of 50 patients from the North Pole cohort (25 CPC 1 and 25 CPC 5), direct
RNA sequencing identified the solute carrier family 2 member 1 (SLC2A1), a gene encoding a major glucose trans-
porter at the blood–brain barrier (GLUT1), as significantly upregulated in CPC 5 patients (dead with severe neuro-
logical impairment) compared to survivors without neurological sequelae (CPC 1). This upregulation was confirmed
by quantitative PCR and extended to the entire North Pole cohort (p < 0.001). SLC2A1 was an independent predictor
of neurological sequelae or death in this cohort. In the TTM trial, SLC2A1 was also upregulated in patients with neu-
rological sequelae or death (p < 0.001) and was an independent predictor of neurological sequelae or death, provid-
ing an incremental predictive value to a baseline clinical model (odds ratio = 2.06, 95% confidence interval 1.31–3.4,
p = 2.82E-03, and likelihood ratio test p < 0.001).
Conclusion Blood level of SLC2A1 is a tentative blood biomarker that may aid in neurological outcome prediction
after CA and also provide new insights into post-CA injury mechanisms
Ispitivanje citotoksičnosti i sposobnosti uklanjanja ROS-a metanolnih ekstrakata Teucrium montanum L. u HaCaT ćelijama
No full textTeucrium montanum L. (TM) is a perennial species of the Lamiaceae family, traditionally used in folk medicine for its diverse therapeutic properties. Although previous studies have explored the biological activity of TM extracts, their effects on skin cells have not been investigated. This study examined the cytotoxic and antioxidant effects of two methanolic extracts of T. montanum (TM1 and TM2), obtained from serpentinite and limestone, across a concentration range of 12.5–400 μg/mL on human keratinocyte (HaCaT) cells. Both extracts showed a concentration-dependent cytotoxic effect in the MTT assay, with no significant impact on cell survival up to 100 μg/mL. At higher concentrations (200 and 400 μg/mL), cell viability decreased significantly, with TM1 exhibiting greater cytotoxicity than TM2. Antioxidant potential was assessed by the H2DCFDA assay, revealing that neither extract altered basal reactive oxygen species (ROS) levels, but higher concentrations increased ROS formation under H2O2 induced oxidative stress. These results suggest that TM1 and TM2 are well tolerated at lower concentrations, but may induce oxidative stress and cytotoxicity at higher concentrations. The findings highlight the importance of dose optimisation for potential therapeutic or cosmetic applications of TM extracts and further phytochemical characterisation to identify the active constituents responsible for these effects.Teucrium montanum L. (TM) je višegodišnja vrsta iz porodice Lamiaceae, koja se
tradicionalno koristi u narodnoj medicini zbog svojih raznovrsnih terapeutskih svojstava. Iako su
prethodne studije ispitivale biološku aktivnost TM ekstrakata, njihovi efekti na ćelije kože nisu
istraženi. U ovoj studiji su ispitani citotoksični i antioksidativni efekti dva metanolna ekstrakta T.
montanum (TM1 i TM2), sa serpentinita i krečnjaka, u opsegu koncentracija od 12,5–400 μg/mL
na ćelije humanih keratinocita (HaCaT). Oba ekstrakta su pokazala koncentraciono zavisan
citotoksični efekat u MTT testu, bez uticaja na preživljavanje ćelija do koncentracije od 100
μg/mL. Pri višim koncentracijama (200 i 400 μg/mL), vijabilnost ćelija je značajno smanjena, pri
čemu je TM1 pokazao veću citotoksičnost od TM2. Antioksidativni potencijal je procenjen
H 2 DCFDA testom, koji je pokazao da nijedan ekstrakt nije promenio bazalne nivoe reaktivnih
vrsta kiseonika (ROS), ali su više koncentracije ekstrakta povećale nivo ROS-a pod oksidativnim
stresom izazvanim vodonik-peroksidom. Ovi rezultati ukazuju na to da ćelije tolerišu TM1 i TM2
u nižim koncentracijama, ali da više koncentracije mogu izazvati oksidativni stres i biti
citotoksične. Rezultati ukazuju na važnost optimizacije doze pri potencijalnoj terapeutskoj ili
kozmetičkoj primeni ekstrakata TM kao i na potrebu za daljom fitohemijskom karakterizacijom
kako bi se identifikovali njihovi aktivni sastojci