Future Pharmacology

The progress of contemporary pharmacology is deeply linked to pharmacokinetics (PK) and its quantitative exploration through PK modeling. By offering a robust mathematical framework to describe and predict drug absorption, distribution, metabolism, and excretion (ADME), PK modeling is essential for designing and optimizing safe and effective dosing regimens and for advancing personalized medicine and model-informed drug development (MIDD). The reliability of population PK (popPK) and physiologically based PK (PBPK) models depends on high-quality experimental data to estimate PK parameters. Traditional PK data sources include clinical studies, preclinical animal models, and human-derived cell lines. Although considered gold standards, these sources have significant drawbacks. Clinical trials are often restricted by ethical, logistical, and financial challenges and often include homogenous populations that fail to reflect real-world interindividual variability. Similarly, animal and cell-based models lack the physiological complexity of humans, leading to discrepancies between preclinical predictions and clinical outcomes. These constraints have stimulated interest in alternative platforms that more faithfully recapitulate human physiology and interindividual diversity. This review explores the potential of organoids as a novel or complementary source of PK-relevant data. Organoids, three-dimensional (3D) stem cell-derived structures, mimic the cellular architecture, functional heterogeneity, and physiological responses of human tissues. In particular, intestinal, liver, and kidney organoids preserve essential cellular features of ADME processes, positioning them as promising tools for integration into popPK and PBPK modeling frameworks.

Background/Objectives: Fungal keratitis (FK) is a current challenge in ophthalmology due to its association with severe visual impairment and the limitations of current antifungal therapies. We aim to evaluate the antifungal activity of essential oils (EOs) from the aromatic and medicinal plants Cymbopogon citratus and Lavandula pedunculata against selected FK pathogens collected from FK patients in two Portuguese hospitals. Methods: The antifungal activity of the EOs was tested at concentrations of 25%, 50%, 75%, and 100% for up to 7 days using the solid-phase disk diffusion in vitro assay. Results: Candida albicans was the most prevalent pathogen (28.6%), followed by Candida parapsilosis (21.4%) and Dicyma olivacea (14.2%). The other identified species were Aspergillus fumigatus and Scedosporium boydii (7.1%). Clinical diagnostic methodologies showed agreement with the molecular identification. Cymbopogon citratus EO showed higher antifungal activity than Lavandula pedunculata EO. The highest antifungal activity was observed against Aspergillus fumigatus and Scedosporium boydii (inhibition zone diameter, IZD = 90.0 mm) after 7 (Cymbopogon citratus EO) or 3 days of incubation (Lavandula pedunculata EO). While the antifungal activity of Cymbopogon citratus EO was maintained during the study (for Aspergillus fumigatus, Candida albicans, and Scedosporium boydii), the antifungal activity of Lavandula pedunculata EO decreased with time. Conclusions: Cymbopogon citratus EO and Lavandula pedunculata EO showed optimal antifungal activity against molds (Aspergillus fumigatus and Scedosporium boydii) after 3 days of incubation. Against yeasts (Candida albicans and Candida parapsilosis), the EOs showed lower activity. Our study sheds light on the development of new pharmacological strategies for FK based on EOs extracted from aromatic and medicinal plants.

Background: Rapidly growing mycobacteria (RGM) are microorganisms with variable pathogenicity, which can cause different clinical forms of mycobacterioses. They can form structured communities at the liquid-air interface and adhere to animate and inanimate solid surfaces, characterizing one of their most powerful mechanisms of resistance and survival, named biofilms. Objectives: Here, a novel series of sulfamethoxazole (SMTZ) Schiff bases were obtained by the condensation of the primary amine from SMTZ core with six different aldehydes to evaluate their antimicrobial and antibiofilm activities, as well as physicochemical and in silico characteristics. Methods: The compounds L1–L6 included: pyridoxal hydrochloride (L1), salicylaldehyde (L2), 3-methoxysalicylaldehyde (L3), 2-hydroxy-1-naphthaldehyde (L4), 3-allylsalicylaldehyde (L5), and 4-(diethylamino)salicylaldehyde (L6). MIC determination was performed against standard strains and seven clinical isolates. Time-kill assays, biofilm inhibition assays, atomic force microscopy, and peripheral blood mononuclear cell cytotoxicity assays were carried out. Density functional theory (DFT) calculations using quantum descriptors, Mulliken charges, Fukui functions, non-covalent interactions (NCI), and reduced density gradient (RDG), along with molecular docking calculations to DHS, LasR, and PqsR, supported the experimental trend. Results: The compounds L1–L6 showed a significant capacity to inhibit the growth of RGM, with MIC values in the range of 0.61 to 1.22 μg mL⁻¹, which are significantly lower than those observed for the parent compound SMTZ, demonstrating superior antimicrobial potency. To deepen antimicrobial activity assays, L1 was chosen for further evaluations and showed a significant ability to inhibit the growth of RGM in both planktonic and biofilm forms. In addition, atomic force microscopy views great changes in topography, electrical force, and nanomechanical properties of microorganisms. The cytotoxic assays with the peripheral blood mononuclear cell model suggest that the new compound may be considered as an antimicrobial alternative, as well as a safe substance showing selectivity indexes in the range of efficacy. Conclusions: Density functional theory (DFT) calculations were performed to obtain quantum descriptors, Mulliken charges, Fukui functions, non-covalent interactions (NCI), and reduced density gradient (RDG), which, with molecular docking calculations to DHS, LasR, and PqsR, supported the experimental trend.