Medicine and Pharmacology

Abstract: In a previous review, after recalling the somatic and psychiatric effects of synthetic estrogens in children exposed in utero and their offspring, despite warnings from the moment they were put on the market, we reported that synthetic progestins have similar effects. In the present work, based on data from a retrospective French cohort of patients whose mothers (first generation) were treated with diethylstilbestrol (DES), ethinyl estradiol and/or synthetic progestins during pregnancy, we highlight the presence of congenital malformations, particularly of the musculoskeletal system, in second (directly exposed in utero) and third-generation girls and boys. The analyzed data were from 17 families and included 30 second generation children (20 girls and 10 boys who were prenatally exposed) and 31 third generation grandchildren (7 girls and 24 boys) whose mothers (second generation) some of them received additional hormonal treatment (progestins) to promote fertility or for in vitro fertilization procedures. This is the first time that congenital musculoskeletal malformations have been described in the grandchildren of women treated with xenohormones. The epigenetic and hormonal mechanisms involved in the teratogenic effects of these endocrine disruptors are discussed.

Abstract: Streptococcus pneumoniae remains a major global health threat and is listed by the by the World Health Organization as a pathogen in urgent need of new antimicrobial strategies. While primarily considered as an extracellular pathogen, S. pneumoniae can persist within splenic macrophages in severe disease, creating a protected intracellular niche that may contribute to fulminant sepsis. We recently demonstrated the concept of an mRNA-based therapeutic approach in which host cells produce the pneumococcal bacteriophage endolysin Cpl-1. Here, we investigated whether expression of Cpl-1 in macrophages can target S. pneumoniae residing within host cells. Using the human THP-1 macrophage line, we demonstrated successful translation and intracellular accumulation of bioactive Cpl-1 following IVT-mRNA transfection. Lysates from Cpl-1 mRNA-transfected cells exhibited bacteriolytic activity, and Western blotting as well as immunofluorescent staining confirmed cytosolic endolysin production. Phagocytosis assays using an encapsulated and unencapsulated pneumococcal strain showed a reduction of intracellular bacterial burden in Cpl-1 mRNA-transfected macrophages compared with control and inactive-mutant Cpl-1 mRNA groups, a flow cytometry-based assay further corroborated a decreased intracellular bacterial signal. Together, these findings suggest that mRNA-encoded Cpl-1 enhances intracellular killing of S. pneumoniae and support the feasibility of mRNA-based endolysin therapies to target intracellular pneumococcal reservoirs.

Abstract: The continuous search for new chemical structures more active, less toxic than those currently in practice is justified on the basis of the use of proven pharmacophoric building blocks (benzimidazole heterocycle, sulfonyl group and amidoxime framework in our case). The aim of the work was to synthesize new O-alkylsulfonyl--(benzimidazol-1-yl)propioamidoximes and to test them for in vitro biological activities to identify potential effective agents. Novel O-alkylsulfonylamidoximes were synthesized by the reaction of -(benzimidazol-1-yl)propioamidoxime with alkylsulfonyl chlorides AlkSO2Cl (Alk = CH₃, n-C₃H₇, i-C₃H₇, n-С₄H₉) in a mixture of water : acetone in hydrochloride and base forms. Obtained derivatives were tested for antimicrobial, antifungal and antidiabetic activity. Hydrochlorides and bases of the O-alkylsulfonyl--(benzimidazol-1-yl)propioamidoximes were obtained in moderate to high yields. The structures of the synthesized compounds were established by physicochemical and spectral (FT-IR, NMR and X-ray diffraction) methods. Biological screening found effective samples of amidoximes with antimicrobial and antifungal activities which were near or exceeded the activity of the reference drugs gentamicin and nystatin; in addition, two samples with antidiabetic activity higher than acarbose were found. Results of the present study open new possibilities for the novel -aminopropioamidoxime class as active antimicrobial and antifungal agents, as well as antidiabetics ones.

Abstract: Metabolic syndrome (MetS) arises from widespread insulin resistance (IR) and endoplasmic reticulum (ER) stress caused by lipid accumulation in metabolic tissues. This study investigates the multi-organ therapeutic effects of Schisandrin B (Sch B), a bioactive compound from Schisandra chinensis, on diet-induced MetS in mice. Over eight weeks, Sch B treatment (10 and 30 mg/kg) effectively counteracted high-fat diet (HFD)-induced weight gain, increased fat mass, high blood sugar, and systemic inflammation (measured by plasma TNF-α). It also significantly improved markers of systemic insulin sensitivity, such as HOMA-IR, QUICKI, and Adipo-IR. Mechanistically, Sch B normalized insulin-stimulated Akt phosphorylation (at Thr308 and Ser473) and reduced lipotoxic ER stress across the liver, adipose tissue, and muscle. This reduction in ER stress was indicated by decreased glucose-regulated protein 78 (GRP78) expression. Additionally, Sch B ameliorated inter-organ endocrine imbalances by improving the plasma adiponectin-to-leptin ratio and lowering plasma levels of harmful hepatokines like FGF21, LECT2, and FGL1. Importantly, these systemic metabolic benefits correlated with increased expression of the active, spliced form of X-box binding protein 1 (XBP-1s) in muscle and adipose tissues. These findings establish Sch B as a powerful, multi-target natural compound that can reverse obesity-related metabolic dysfunction, with non-canonical XBP-1s activation appearing as a key mechanism of its therapeutic action.

Abstract: Biofilms (BFs) bacteria are dramatically intensifying tolerance to conventional antibiotics, no longer effective. Therefore, the research for new antibiofilm (ABF) compounds are noticeably increasing the studies proliferation rate. In this regard, intriguing questions should raise to be debated. To this end, the problematics of BF, mainly in medical setting, have been afforded here in an original way, examining the tension “between efficacy and understanding”. Questions include: are BF mechanistic studies indispensable and strictly required especially at academic levels with poor economic support? When may a purely phenotypic approach still hold scientific value? Could be demonstrate empirical efficacy alone, sufficient for scientific relevance of the study? Do high costs, long times mechanistic insights, also associated to environmental issues, represent the necessary key to defeating BFs and the benchmark that determines the robustness and impact of ABF research? The state of the art of global challenge against BF, responsible for difficult-to-treat and even lethal chronic infection, has been provided. The available armamentarium of best functioning antibiotics/combinations has been discussed, while the correct way to investigate ABF mechanisms has been clarified. Among 102 studies on the ABF activity, considered, distributed in Tables and discussed, mechanistic investigations carried out correctly have been found in only 34 ones. Only efficacy screens, stopping at phenotypic descriptions, as reported in 68 out of 102 papers, are considered essential for discovering efficacious ABF compounds and are welcome by Editors and scientific community. Such approach represents the main trend of most recent literature and is strongly desirable for publication.

Abstract: Background/Objectives: Type 2 diabetes mellitus (T2DM) is a chronic multifactorial metabolic disorder requiring multi-target therapeutic strategies. This study aimed to clarify the potential material basis, key targets and molecular mechanisms by which PuRenDan (PRD) acts against T2DM through an integrated network pharmacology and molecular simulation approach. Methods: Active compounds of PRD were screened from TCMSP, HERB 2.0 and the literature, and compound-related targets were predicted using TCMSP, SwissTargetPrediction and PharmMapper. T2DM-associated targets were collected from OMIM, DrugBank, DisGeNET, HPO, ClinPGx and GeneCards to obtain drug-disease intersection targets. Cytoscape was used to construct herb-compound-target and protein-protein interaction (PPI) networks, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking was performed using AutoDock Vina, and representative ligand-receptor complexes were further assessed by 100 ns molecular dynamics (MD) simulations and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) binding free-energy analysis. Results: A total of 163 active compounds, 597 PRD-related targets, 9138 T2DM-associated targets and 483 intersection targets were identified. β-sitosterol, emodin, quercetin, kaempferol and formononetin were predicted as major active compounds, whereas AKT1, TP53, SRC, IL6, TNF, EGFR and ESR1 were identified as core targets. KEGG enrichment highlighted the PI3K-Akt, MAPK, HIF-1, FoxO, mTOR, AGE-RAGE and TNF signalling pathways. Docking suggested strong multi-target binding potential for β-sitosterol. MD and MM/PBSA analyses further indicated favourable dynamic stability for β-sitosterol-TNF, β-sitosterol-AKT1, β-sitosterol-SRC and emodin-EGFR complexes, with β-sitosterol-TNF showing the lowest binding free energy. Conclusions: PRD may exert therapeutic effects against T2DM through coordinated multi-compound, multi-target and multi-pathway regulation involving inflammation, insulin signalling, oxidative stress and metabolic pathways. β-sitosterol may represent an important candidate material basis of PRD, with TNF, AKT1, SRC and EGFR as potential key targets.

Abstract: 3,4-Methylenedioxyamphetamine (MDMA) has been shown in multiple clinical trials to greatly reduce Post-Traumatic Stress Disorder (PTSD) symptoms, with many patients experiencing lasting improvement. However, recent regulatory rejection based on problems with blinding highlights a contradiction, with regulatory agencies demanding placebo-controlled trials, yet the strong psychoactive effects of MDMA-assisted therapy make true blinding impossible.This paper examines neurofunctional mechanisms and methodological challenges relevant to MDMA-assisted therapy research. First, it introduces the Trauma-Affective Memory Loop (TAML), a simple model of how traumatic memories are stored, reactivated, and reinforced through key brain regions. Second, it explains how MDMA works on a neurofunctional level, by reducing fear signals it creates a temporary “therapeutic window”. In this state, patients can revisit trauma safely, without being overwhelmed, and reprocess the memory in a healthier way.Third, the paper proposes that different types of trauma exposures respond differently to MDMA-assisted therapy. Acute, one-time traumas may often be resolved within one to three MDMA sessions, while complex or developmental trauma, formed over years, may need repeated and carefully structured treatment.Finally, a proposed clinical-trial framework, the Brinzei MDMA-PTSD Protocol (BMPP), is presented. The framework uses a role-separated, quadruple-masked structure intended to reduce expectancy-related bias while preserving therapeutic fidelity. The aim is to move beyond debates about flawed blinding methods and instead design trials that clarify why MDMA works, for whom it works best, and how to deliver it safely and effectively.

Abstract: Chronic Mycobacterium tuberculosis (M.tb) infection reflects failure of sterilizing immunity and persistent pulmonary bacterial burden. While CD4+ T cells and IFN-γ are central to protection, the role of CD8+ T cells in chronic disease remains unclear. This study examined whether CD8+ T cells contribute to immune dysregulation during chronic tuberculosis through IL-10 production. Susceptible CBA/J and resistant C57BL/6 mice were infected with a low-dose aerosol of M.tb Erdman and followed for 150 days. Lung bacterial burden, cytokine responses, and T-cell populations were assessed using high-purity CD8+ T-cell isolation (>97%), ELISA, ELISPOT, and in vivo CD8+ depletion. In susceptible CBA/J mice, chronic infection was associated with progressive pulmonary accumulation of CD8+ T cells, reduced CD4:CD8+ ratios, increased IL-10 levels, and impaired bacterial control. Antigen-experienced CD8+ T cells were a major source of IL-10, which correlated with reduced IFN-γ responses and higher bacterial burden. CD8+ depletion during chronic infection was associated with reduced bacterial burden and increased IFN-γ responses. Resistant C57BL/6 mice showed limited expansion of IL-10-associated CD8+ responses and better bacterial control. These findings support a model in which chronic M.tb infection is associated with expansion of IL-10-producing CD8+ T cells in susceptible hosts and altered immune control. CD8+ T-cell modulation during chronic disease is associated with changes in bacterial burden, suggesting a contributory role in disease outcome. These results highlight CD8+ T-cell functional polarization as a factor to consider in tuberculosis pathogenesis and vaccine design.

Abstract: This study investigates the comparative effects of traditional cigarettes and e-cigarettes on lung health in male Rattus norvegicus over 8 and 12 weeks. Following ARRIVE 2.0 guidelines, 30 rats were divided into six groups to evaluate the impact of nicotine and ascorbic acid aerosols on tracheal and alveolar structures, as well as systemic inflammatory markers (IL-6, TNF-α, SOD-3, MDA). Results indicate that long-term cigarette exposure (12 weeks) and nicotine vaping (8 weeks) significantly stunted weight gain, whereas ascorbic acid vaping caused less growth inhibition. Histological analysis revealed that 8-week cigarette exposure (K3) increased tracheal mucosal thickness and antioxidant activity (SOD-3), while cigarette smoke generally decreased goblet cell counts and induced early emphysema. In contrast, long-term exposure significantly elevated IL-6 and caused severe alveolar wall damage. Notably, vaping ascorbic acid (K6) offered protective benefits, preserving the basement membrane and reducing septal thickening compared to nicotine groups. The findings conclude that while short-term smoking triggers immediate tracheal damage, long-term exposure escalates systemic inflammation and permanent alveolar destruction. Phytochemical-based aerosols, such as ascorbic acid, reduce pulmonary injury compared with nicotine-based products.

Abstract: Background: Subcutaneous edema is a common condition seen on ultrasonography, characterized by thickening of the subcutaneous tissue with anechoic or hypoechoic fluid-containing spaces interspersed among fat lobules. The current descriptive term “cobblestone appearance” is used to describe this finding, but the metaphor lacks the vividness of the irregular, reticular pattern we have observed. Observation: We propose the “Cracked Earth Sign” as a novel sonographic sign to describe subcutaneous edema. The sign is defined by thickening of the subcutaneous tissue with irregular, reticular, or branching anechoic or hypoechoic clefts interspersed among fat lobules, resembling cracks in dry, sun-baked earth. Unlike the cobblestone sign, which focuses attention on individual fat lobules, the term “cracked earth sign” emphasizes the reticular network of clefts as a whole, offering a more intuitive visualization of edema distribution. Conclusion: The “Cracked Earth Sign” provides a simple, intuitive sonographic sign for recognizing subcutaneous edema. It may serve as a useful teaching tool for trainees.

Abstract: Introduction: Obesity is a chronic, multifactorial disease associated with significant metabolic and cardiovascular complications. Glucagon-like peptide-1 receptor ago-nists (GLP-1RAs) have emerged as effective pharmacological options for weight man-agement, demonstrating clinically relevant weight loss in controlled trials. However, real-world evidence is essential to assess their effectiveness and safety under routine clinical conditions and to verify if trial results are reproducible in diverse populations. Objective: To evaluate the effectiveness and safety of GLP-1RAs in terms of weight loss in real-world clinical practice and to compare outcomes among different available agents, focusing on their impact on obesity management. Method: A cross-sectional, observational pilot study was conducted in Spain. Adult patients receiving GLP-1RAs for at least four weeks were included. Data collected included sociodemographic vari-ables, treatment characteristics, anthropometric measurements, and adverse effects. Weight loss outcomes were analyzed using descriptive statistics, ANOVA for in-ter-drug comparisons, and multivariate ANCOVA to adjust for confounders. This pilot study also validated the protocol for a subsequent nationwide multicenter study. Re-sults: A total of 32 patients (62.5% women; mean age 58.2 years) were analyzed. Mean weight loss was 2.97 kg (3.17%). Significant differences between drugs were observed (p = 0.005), with semaglutide 2.4 mg (Wegovy) showing the greatest reduction (11.0 kg). Patients without diabetes achieved significantly greater weight loss than those with diabetes (5.0 vs. 0.8 kg; p = 0.021). Treatments were well tolerated, with 53.1% re-porting no adverse effects; most side effects were mild gastrointestinal symptoms. Conclusions: GLP-1RAs are effective and well-tolerated for obesity treatment in re-al-world clinical practice, although weight loss is more modest than in pivotal clinical trials. Differences between agents persist after adjustment, with specific formulations like semaglutide 2.4 mg showing superior effectiveness. These findings support the need for individualized treatment strategies in obesity care. This pilot study success-fully validated the methodology for an ongoing nationwide investigation

Abstract: Antisense oligonucleotides (ASOs) are a class of nucleic acid therapeutics that modulate gene expression through diverse mechanisms. Since their initial demonstration in inhibiting viral genes, advances in medicinal chemistry, pharmacology, and delivery have enabled robust and durable target engagement across multiple tissues. Chemical modifications to the backbone, ribose, and nucleobases have improved nuclease resistance, binding affinity, and pharmacokinetics, while conjugation and delivery technologies have expanded tissue accessibility. Beyond classical RNase H–mediated RNA degradation, ASOs regulate gene expression via splicing modulation, microRNA inhibition, transcriptional activation, and translation modulation, supporting both gene silencing and upregulation strategies. Multiple ASO drugs are now approved, particularly for genetic diseases, with many more in clinical development. This review outlines the evolution of antisense technology, key chemical and delivery innovations, ASO pharmacokinetics and intracellular trafficking, the mechanisms underlying gene regulation, and current clinical applications and future opportunities.

Abstract: Anemia management in chronic kidney disease patients is a significant challenge for modern healthcare professionals. Anemia in chronic kidney disease patients has multiple causes which include erythropoietin deficiency, abnormal iron metabolism, resistance to erythropoietin signaling, bone marrow suppression, blood loss, inflammation, nutrition deficiencies and oxidative stress. Vadadustat (a stabilizer of hypoxia-inducible factor (HIF) is indicated for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis. Evidence-based pharmaceutical care services are of great importance for chronic kidney disease patients because they provide safe, effective and economic care for patients. In the present article, we outline the most important pharmaceutical aspects that may affect the efficacy and safety of drug therapy with vadadustat and other HIF stabilizers. We conclude that evidence-based pharmaceutical care is one of the criteria that promotes management of vadadustat therapeutic efficacy and safety. Such an approach will contribute to improving patient adherence to treatment and, consequently, quality of life. Special attention is paid to structure-derived side effects of widely used HIF stabilizers, including their advantages and disadvantages. Based on all available safety and efficacy data for vadadustat, the overall risk-benefit profile remains positive for the approved indications for use.

Abstract: Inflammatory rheumatic diseases exhibit dynamic and heterogeneous inflammatory activity, yet clinical monitoring remains episodic and temporally sparse, limiting early intervention and delaying treatment adjustment. Advances in biosensing technologies, wearable monitoring, and computational modeling offer opportunities to transition toward continuous, data-driven disease assessment. In this review, we synthesize evidence across rheumatology, immunology, biosensing, and digital health to examine how multimodal measurement approaches can support clinically actionable decision-making. We introduce a structured framework—the “Measurement Stack”—that links three components: biological signal domains (systemic, synovial, imaging-derived, and physiological), sensing platforms with distinct temporal and specificity trade-offs, and computational inference layers including feature extraction, multimodal data integration, and predictive modeling. We emphasize that the clinical value of biomarkers depends not on association alone but on actionability, defined by temporal sensitivity, repeatability, robustness to heterogeneity and signal noise, and alignment with clinical decisions. Key methodological considerations include feature engineering for sparse and continuous data, handling missingness and signal drift, calibration-aware validation, temporal and external validation, and decision-curve analysis for clinical utility. A decision-centric mapping aligns measurement and modeling strategies with clinical tasks such as early flare detection, differentiation of flare from infection, therapy switching or tapering, and monitoring of treatment response. By integrating biosensing advances with clinically grounded evaluation standards, this review outlines pathways toward interpretable, deployment-ready monitoring systems enabling proactive and personalized management of inflammatory rheumatic disease.

Abstract: Drug recall is a critical regulatory mechanism implemented to protect public health by removing defective, unsafe, or non-compliant pharmaceutical products from the market. Despite stringent regulatory approval processes, issues related to manufacturing defects, contamination, labeling errors, stability failures, and post-marketing safety concerns may lead to drug recalls. Regulatory authorities across the world, including the Central Drugs Standard Control Organization (CDSCO), the United States Food and Drug Administration (US FDA), the European Medicines Agency (EMA), and other national agencies, have developed structured recall guidelines and rapid alert systems to ensure timely withdrawal of defective products. Drug recalls are typically classified based on the level of health risk and may be executed at different levels of the distribution chain, including wholesale, retail, and consumer levels. Effective recall management involves risk assessment, recall communication, product traceability, documentation, and recall effectiveness checks. Pharmacovigilance systems also play an important role in identifying adverse drug reactions and quality defects that may lead to product recalls. This review article provides a comprehensive overview of drug recall systems, including causes of recalls, regulatory frameworks in India and other countries, recall classification, recall procedures, rapid alert systems, and global recall trends. The article also discusses challenges in recall implementation and provides recommendations to strengthen drug recall systems and regulatory coordination worldwide.

Abstract: Modern dietary debates remain highly polarized among competing nutritional paradigms, including low-fat, Mediterranean, plant-based, vegan, low-carbohydrate, ketogenic, and animal-based dietary models. Despite decades of nutritional guidelines and extensive epidemiological research, chronic diseases—including obesity, type 2 diabetes mellitus (T2DM), atherosclerotic cardiovascular disease (ASCVD), autoimmune disorders, cancer, and neurodegenerative diseases—continue to rise globally. These trends raise an important question: are prevailing nutritional frameworks adequately aligned with human physiology, metabolic biology, and long-term systems resilience?This paper proposes an Integrative Orthomolecular Medicine (IOM) Systems Medicine framework for evaluating human diets based not solely on caloric intake or macronutrient composition, but on broader biological principles including metabolic compatibility, metabolic flexibility, nutrient density and bioavailability, mitochondrial energetics, inflammatory regulation, biological barrier integrity, oxidative-reduction balance, and cumulative toxicological burden.We first examine evolutionary and physiological foundations of human nutrition, emphasizing omnivorous adaptation, fuel-switching physiology, fasting metabolism, and the evolutionary importance of energetic resilience during periods of food scarcity, migration, hunting, and prolonged physical exertion. Particular attention is given to the human capacity for metabolic flexibility—the ability to transition between glucose utilization, fatty acid oxidation, and ketone metabolism according to energetic demands and nutrient availability. We propose the Energetic Resilience Principle, which suggests that nutritional systems should be evaluated not solely according to glycemic control, but also according to their effects on mitochondrial energetics, fuel adaptability, endurance capacity, fasting tolerance, and long-term physiological resilience. Particular attention is also given to the absence of a clearly established minimum dietary carbohydrate requirement in the presence of adequate protein and fat intake.We then compare major dietary models—including the Standard American Diet (SAD), Mediterranean, plant-based and vegan, low-carbohydrate, ketogenic, and carnivore/elimination-based approaches—across multiple domains relevant to metabolic health and systems biology. Particular attention is given to the potential consequences of chronic dependence on highly refined, continuously fed, hyperinsulinemic metabolic states, including impaired metabolic flexibility, mitochondrial stress, oxidative imbalance, and reduced physiological adaptability.Special attention is given to the nutritional and toxicological characteristics of both plant- and animal-derived foods. While plant foods provide fiber, phytonutrients, vitamins, and numerous bioactive compounds, they may also contain naturally occurring defense compounds such as lectins, oxalates, phytates, alkaloids, and gluten-related proteins, in addition to agricultural contaminants including pesticides, herbicides, and microplastics. Conversely, animal-derived foods may bioaccumulate persistent fat-soluble pollutants and environmental contaminants. The paper further proposes that plant-heavy and animal-heavy dietary systems may differ in dominant toxicological exposure profiles, including relative tendencies toward water-soluble agricultural contaminants and plant defense compounds versus fat-soluble bioaccumulated environmental pollutants. Accordingly, this paper proposes that no modern dietary system is entirely toxin-free, and that dietary strategies should instead be evaluated according to cumulative toxicological burden, nutrient sufficiency, metabolic effects, mitochondrial support, and biological compatibility.Finally, this paper proposes a hierarchical IOM Systems Nutrition framework emphasizing: • low glycemic burden, • low ultra-processing burden, • low cumulative toxicological burden from both natural and industrial exposures, • nutrient sufficiency, • metabolic flexibility, • mitochondrial support, • preservation of energetic resilience, • and long-term physiological adaptability.Within this framework, nutrition is viewed not merely as a source of calories or macronutrients, but as a systems-level regulator of mitochondrial energetics, metabolic resilience, endocrine signaling, inflammatory regulation, biological integrity, adaptive stress responses, and long-term physiological resilience. The framework proposed is intended as a comparative systems-based model for evaluating dietary compatibility with human physiology and adaptive metabolism, rather than a universal prescription for any single dietary pattern.

Abstract: Cancer drug development still relies heavily on preclinical models that often fail to predict clinical efficacy. Although two-dimensional (2D) cell cultures and animal models have contributed significantly to cancer research, they do not adequately capture the complexity, heterogeneity, and microenvironmental conditions of human tumors. As a result, pharmacological findings generated with these systems frequently show limited clinical translation. This review discusses the conceptual distinction between drug activity and predictive pharmacology, arguing that successful target modulation in simplified experimental systems does not necessarily predict therapeutic benefit in patients. The limitations of conventional preclinical approaches, including homogeneous drug exposure in 2D cultures and species-specific differences in animal models, are briefly examined. This review further highlights the potential of human-relevant models, such as patient-derived organoids and microphysiological systems, to improve the predictive value of preclinical testing. These platforms allow more realistic evaluation of drug response, resistance mechanisms, and functional biomarkers under conditions that better resemble human tumor biology. Altogether, the integration of functionally informative models into drug development pipelines may support more accurate and clinically relevant pharmacological decision-making.

Abstract: Objectives: The aim of our study was to investigate the in vitro activity and in vivo effica-cy of rezafungin, anidulafungin, caspofungin and micafungin against Candida auris iso-lates belonging to clade V. Methods: Five clinical isolates were evaluated (IFRC2087, IFRC4050, MRL40, TMML616 and TMML617). Echinocandin MICs and killing activities were determined in RPMI-1640. In the survival and fungal tissue burden experiments (heart, kidney and brain), neutro-penic mice were infected intravenously (107 CFU/mouse). Treatment was initiated 24 hours post-infection with intraperitoneal dosing of 20 mg/kg of rezafungin on days 1, 3 and 6 or once-daily dosing for 6 days with 3 mg/kg of caspofungin, 5 mg/kg of micafungin or 5 mg/kg of anidulafungin. Results: MIC ranges of rezafungin, anidulafungin, caspofungin, and micafungin were 0.06-0.25, ≤0.03-0.12, 0.12-0.5 and ≤0.03-0.12 mg/L, respectively. The four echinocandins at ≥1 mg/L were fungicidal only against isolate MRL40. All echinocandin regimens im-proved the survival in mice infected with isolates MRL40 and IFRC4050 (P-values were ≤0.0002 and 0.0006, respectively), but only rezafungin was effective against isolate TML617 (P=0.0049). All four echinocandins induced more than 3 logs mean CFU/gram decreases in the kidneys and hearts of mice infected with the three isolates compared to control mice, some of which were not statistically significant. Fungal growth, regardless of the isolate tested, was poorly inhibited by echinocandins in the brain. Histopathology showed large aggregates of pseudohyphae in the hearts, kidneys and brains in control mice. In echinocandin treated mice only blastoconidia were found. Conclusions: In vitro activity and in vivo efficacy of the four echinocandins against the fifth clade of C. auris was echinocandin- and isolate-specific. Pseudohyphal production was common in controls, but not in echinocandin treated mice. Rezafungin activity was comparable to or better than the three previously approved echinocandins.

Abstract: Background: Finerenone is associated with a lower, yet clinically relevant, risk of hyperkalemia compared with steroidal mineralocorticoid receptor antagonists in diabetic kidney disease (DKD) trials. However, real-world data on hyperkalemia and its associated factors are lacking. Methodology: FINE-TURK is a national, observational cohort of DKD patients who were initiated on finerenone. Eligible adults were included; demographic, clinical, and laboratory data were evaluated. The primary outcome (PO) was hyperkalemia risk signal (potassium ≥ 5.0 mEq/L), and the secondary outcome (SO) was clinically meaningful hyperkalemia (potassium ≥ 5.5 mEq/L). Multivariate logistic regression (LR) was used to define features associated with both PO and SO. LR, random forest (RF), gradient boosting, and CatBoost classifiers were used to define important features associated with the PO. Results: 699 patients were included. 259 (37.1%) reached the PO, and 51 (7.3%) reached the SO. Baseline potassium and estimated glomerular filtration rate (eGFR) were the most important variables associated with both outcomes and were consistently identified as the top features across all models. Thiazide use, presence of diabetic retinopathy, and diabetes duration were also associated with the PO. LR demonstrated the highest recall; random forest achieved the highest precision in performance. Discussion: Real-world data suggest that the risk of clinically meaningful hyperkalemia is similar to that in the clinical trials. In parallel with the safety analysis of clinical trials, baseline potassium and eGFR were consistently the most important factors associated with hyperkalemia risk.

Abstract: Poor drug bioavailability remains a major challenge in pharmaceutical development, primarily due to low aqueous solubility, limited membrane permeability and rapid met-abolic degradation, which significantly reduce therapeutic efficacy. In this context, nanocarrier-based drug delivery systems have emerged as an effective strategy to over-come these limitations. This review summarizes the main types of nanocarriers, including lipid-based, polymeric, inorganic and hybrid systems, and discusses their design and functional properties. Nanocarriers enhance drug performance by improving solubility, protecting active compounds from degradation, enabling controlled and sustained re-lease, and facilitating targeted delivery to specific tissues. The influence of physicochemi-cal parameters, such as particle size, surface charge and functionalization, on pharmaco-kinetics and pharmacodynamics is also addressed. Representative case studies illustrate the successful application of nanocarrier formulations in improving bioavailability and therapeutic outcomes. Despite these advances, challenges related to toxicity, large-scale production and regulatory approval remain. Overall, nanocarrier-based systems represent a versatile and promising platform for enhancing drug bioavailability and advancing modern pharmaceutical therapies.