Search Results (6,346)

Background/Objectives: The work investigates the effect of the estragole complex encapsulated in beta-cyclodextrin (ES/β-CD) in modulating bacterial resistance, specifically in Staphylococcus aureus strains expressing NorA and MepA efflux pumps. Efflux pumps are mechanisms that bacteria use to resist antibiotics by expelling them from the cell. Methodology: Several compounds and antibiotics, such as ciprofloxacin and norfloxacin, were used to evaluate the antimicrobial activity and the ability of the ES/β-CD complex to reverse resistance. Methods: The study included scanning electron microscopy assays, minimum inhibitory concentration (MIC) determination, and efflux pump inhibition tests. Results: The ES/β-CD complex did not show significant direct antibacterial activity. However, it modulated the action of norfloxacin, decreasing the MIC when combined with this antibiotic in the 1199B (NorA) strain. These results suggest a potential for synergy but not a direct inhibition of efflux pumps. Conclusion: ES/β-CD can potentiate the efficacy of some antibiotics but does not directly act as an efflux pump inhibitor; it is more of an antibiotic potentiator than a direct solution to bacterial resistance. The molecular docking simulation data suggest its high affinity for forming the ES/β-CD complex. The pharmacokinetic predictions based on MPO suggest that the compound has moderate lipophilicity, highly effective cellular permeability, and low incidence of organic toxicity, pointing to a promising pharmacological principle with controlled daily oral dosing. Conclusions: These results indicate this complex’s possible and relevant association as an adjuvant in antibiotic therapy to reduce multidrug-resistant bacteria; however, new in vivo assays are necessary to confirm this effect. Full article

Anticoagulants can complicate the interpretation of routine and specialised coagulation assays. Several methodologies have been developed to minimise or eliminate anticoagulant-associated interferences; however, no ‘universal methodology’ that encompasses different anticoagulant classes is currently available. Ciraparantag is a promising reversal agent that can bind both direct oral anticoagulants (DOACs) and heparin-like anticoagulants. As such, we aimed to investigate whether ciraparantag could be employed as a ‘universal’ anticoagulant chelator in vitro. Human plasma was spiked with ascending concentrations of ciraparantag, with or without DOACs or heparin, and assayed for routine coagulation parameters. Ciraparantag had minimal effects on coagulation testing when added to human plasma at concentrations similar to pharmacokinetic maxima; however, ciraparantag did not remove DOAC- or heparin-associated activities in vitro, which was likely due to the preferential chelation of anionic substances in the coagulation reagents. In contrast, DOAC-Stop™, a commercial activated charcoal-based adsorbent, efficiently removed both DOAC- and ciraparantag-associated interferences. In conclusion, although ciraparantag is not effective as a ‘universal’ anticoagulant chelator in vitro, we report that activated charcoal-based adsorbents may be clinically useful in situations where laboratory investigations are complicated by the presence of DOACs and/or ciraparantag. Full article

It is imperative to comprehend the mechanisms that underlie drug toxicity in order to enhance the efficacy and safety of novel therapeutic agents. The capacity to identify molecular pathways that contribute to drug-induced toxicity has been significantly enhanced by recent developments in omics technologies, such as transcriptomics, proteomics, and metabolomics. This has enabled the early identification of potential adverse effects. These insights are further enhanced by computational tools, including quantitative structure–activity relationship (QSAR) analyses and machine learning models, which accurately predict toxicity endpoints. Additionally, technologies such as physiologically based pharmacokinetic (PBPK) modeling and micro-physiological systems (MPS) provide more precise preclinical-to-clinical translation, thereby improving drug safety assessments. This review emphasizes the synergy between sophisticated screening technologies, in silico modeling, and omics data, emphasizing their roles in reducing late-stage drug development failures. Challenges persist in the integration of a variety of data types and the interpretation of intricate biological interactions, despite the progress that has been made. The development of standardized methodologies that further enhance predictive toxicology is contingent upon the ongoing collaboration between researchers, clinicians, and regulatory bodies. This collaboration ensures the development of therapeutic pharmaceuticals that are more effective and safer. Full article

Danofloxacin is a fluoroquinolone antibiotic approved for use in fish. It can be used for bacterial infections in fish of all body sizes. However, physiological differences in fish depending on size may change the pharmacokinetics of danofloxacin and therefore its therapeutic efficacy. In this study, the change in the pharmacokinetics of danofloxacin in rainbow trout of various body sizes was revealed for the first time. The objective of this investigation was to compare the plasma and tissue pharmacokinetics of danofloxacin in rainbow trout of different body sizes. The study was conducted at 14 ± 0.5 °C in fish of small, medium, and large body size and danofloxacin was administered orally at a dose of 10 mg/kg. Concentrations of this antimicrobial in tissues and plasma were quantified by high performance liquid chromatography with ultraviolet detector. The plasma elimination half-life (t_1/2ʎz), volume of distribution (V_darea/F), total clearance (CL/F), peak concentration (C_max), and area under the plasma concentration–time curve (AUC_0–last) were 27.42 h, 4.65 L/kg, 0.12 L/h/kg, 2.53 µg/mL, and 82.46 h·µg/mL, respectively. Plasma t_1/2ʎz, AUC_0–last and C_max increased concomitantly with trout growth, whereas CL/F and V_darea/F decreased. Concentrations in liver, kidney, and muscle tissues were higher than in plasma. C_max and AUC_0–last were significantly higher in large sizes compared to small and medium sizes in all tissues. The scaling factor in small, medium, and large fish was 1.0 for bacteria with MIC thresholds of 0.57, 0.79, and 1.01 µg/mL, respectively. These results show that therapeutic efficacy increases with body size. However, since increases in danofloxacin concentration in tissues of large fish may affect withdrawal time, attention should be paid to the risk of tissue residue. Full article

Background: Artemisia annua, a plant with antiviral potential, has shown promise against various viral infections, yet its mechanisms of action are not fully understood. This study explores A. annua’s antiviral effects using network pharmacology and molecular docking, focusing on key active compounds and their interactions with viral protein targets, particularly within the JAK-STAT signaling pathway—a critical mediator of immune responses to viral infections. Methods: From the TCMSP database, we identified eight active compounds and 335 drug targets for A. annua, with 19 intersecting targets between A. annua compounds and viral proteins. A protein–protein interaction (PPI) network highlighted 10 key hub genes, analyzed further through Gene Ontology (GO) and KEGG pathways to understand their immune and antiviral roles. ADMET properties of the active compound Patuletin (MOL004112) were assessed, followed by 200 ns molecular dynamics simulations to examine its stability in complex with JAK2. Results: PPI analysis identified JAK2, MAPK3, MAPK1, JAK1, PTPN1, HSPA8, TYK2, RAF1, MAPT, and HMOX1 as key hub genes, with JAK2 emerging as a critical regulator of immune and antiviral pathways. ADMET analysis confirmed Patuletin’s favorable pharmacokinetic properties, and molecular dynamics simulations showed a stable Patuletin-JAK2 complex, with FEL analysis indicating minimal disruption to JAK2’s intrinsic flexibility. Conclusions: These findings highlight JAK2 as a promising target in the antiviral activity of A. annua compounds, particularly Patuletin, supporting its potential as an antiviral agent and providing a foundation for further research on A. annua’s therapeutic applications. Full article

Objective: The aim of this study was to develop quantitative structure–pharmacokinetics relationship (QSPKR) models for a group of xanthine derivatives with proven pharmacological activity and to investigate its applicability for the prediction of the pharmacokinetics of these compounds. Methods: The SYBYL-X, KowWin, and MarvinSketch programs were employed to generate a total of fourteen descriptor variables for a series of new compounds: 7- and 7,8-substituted theophylline derivatives (GR-1–GR-8) and three well-known methylxanthines. Pharmacokinetic profiles of all compounds were determined after intravenous administration of studied compounds to cannulated male rats. Pharmacokinetic parameters were calculated using noncompartmental analysis. Results: Multiple linear regression revealed that logD was the main determinant of the variability in V_ss, λ_z, and CL of the studied compounds. Moreover, λ_z and CL depended on LUMO and HEFO, while for V_z COAR was the only explanatory variable. The developed QSPKR models accounted for most of the variation in V_ss, λ_z, CL, and fraction unbound (f_u) (R² ranged from 0.68 to 0.91). Cross-validation confirmed the predictive ability of the models (Q² = 0.60, 0.71, 0.34, and 0.32 for V_ss, λ_z, CL, and f_u, respectively). Conclusions: The multivariate QSPKR models developed in this study adequately predicted the overall pharmacokinetic behavior of xanthine derivatives in rats. Full article

Finding new molecules to prevent the growth of antimicrobial resistance is a hot topic for scientists worldwide. It has been reported that some raw bioproducts containing Monascus polyketides have antimicrobial activities, but extensive studies on this effect have not been conducted. In this context, our studies aimed to evaluate the antimicrobial properties of six raw bioproducts containing three classes of microbial polyketides biosynthesized by three Monascus strains through solid-state biosynthesis. As a methodology, we performed in silico predictions using programs such as PyMOL v3.0.4 and employed ESI-MS techniques to provide evidence of the presence of the six studied compounds in our bioproducts. The results obtained in silico were validated through in vitro studies using the Kirby-Bauer diffusion method on bacteria and fungi. The test performed in silico showed that Monascorubramine has the highest affinity for both Gram-positive and Gram-negative bacteria, followed by yellow polyketides such as Ankaflavin and Monascin. The estimated pharmacokinetic parameters indicated high gastrointestinal absorption and the potential to cross the blood-brain barrier for all studied compounds. However, the compounds also inhibit most enzymes involved in drug metabolism, presenting some level of toxicity. The best in vitro results were obtained for S. aureus, with an extract containing yellow Monascus polyketides. Predictions made for E. coli were validated in vitro for P. aeruginosa, S. enterica, and S. marcescens, as well as for fungi. Significant antibacterial properties were observed during this study for C. albicans, S. aureus, and fungal dermatophytes for crude bioproducts containing Monascus polyketides. In conclusion, the antimicrobial properties of Monascus polyketides were validated both in silico and in vitro. However, due to their potential toxicity, these bioproducts would be safer to use as topical formulations. Full article

Background: Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. Methods: This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. Results: The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein–ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6–ligand complexes, confirming the stability of their interactions. Conclusions: The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems. Full article

The glycosylation profile of therapeutic proteins significantly influences their efficacy, stability, and immunogenicity. Sialylation is crucial for the biological activity and pharmacokinetics of fusion proteins used in treating angiogenic disorders, making sialic acid levels a critical quality attribute in the development and production of biologics. In this study, we employed a mass spectrometry-based approach to assess sialylation levels through site-specific N-glycosylation analysis. To validate the method’s effectiveness, IEF fractions (acidic, main, and basic) obtained from the production media of the VEGFR-IgG fusion protein and anticipated to exhibit varying sialylation levels were analyzed. Our analytical method successfully evaluated the sialylation levels of each domain—IgG, VEGFR-1, and VEGFR-2—within the Fc-fusion protein. The results confirm that the overall sialylation level of the Fc-fusion protein correlated with the levels observed across the IEF fractions. This finding highlights the value of LC-MS/MS-based sialylation monitoring as a crucial tool for biosimilar development and quality control, particularly in optimizing target protein production. Additionally, glycopeptide-based LC-MS analysis enables site-specific sialylation evaluation, ensuring consistent profiles for robust quality assurance. Full article

Objective: To establish and validate an LC-MS/MS method for the simultaneous determination of curcumin (CUR) as well as its glucuronide conjugate (COG) and sulfate conjugate (COS) in rat plasma. The method was employed to evaluate and compare the pharmacokinetic behaviors of curcumin following oral and intratracheal administration in rats. Methods: Rat plasma samples were separated by chromatography on a C18 column after protein precipitation with acetonitrile. Gradient elution with a mobile phase of 0.5 mM ammonium acetate in acetonitrile was utilized. Mass spectrometry detection incorporated an electrospray ionization (ESI) source, multiple reaction monitoring (MRM), and dual-mode (positive and negative) scanning for quantitative analysis. A total of 12 SD rats were randomly divided into two groups and were orally (20 mg/kg) or intratracheally (10 mg/kg) administrated curcumin, respectively. CUR, COG, and COS concentrations in plasma were measured to assess pharmacokinetic disparities. Results: The method demonstrated linearity within the ranges of 2–400 ng/mL for CUR and COS and 5–1000 ng/mL for COG. Intratracheal administration significantly elevated CUR plasma concentrations compared to oral administration. The exposure of COG was higher than COS following oral administration. Conversely, intratracheal administration resulted in markedly higher COS exposure, with no significant difference in COG exposure after dose normalization between oral and inhalation routes. Conclusions: The established LC-MS/MS method provides a reliable tool for the simultaneous measurement of CUR, COG, and COS in rat plasma, facilitating preclinical pharmacokinetic investigations. The study reveals distinct pharmacokinetic profiles for CUR following oral versus intratracheal administration, suggesting that inhalation may offer superior therapeutic efficacy. Full article

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD₃) and its three major metabolites, 25-hydroxyvitamin D₃ (25D₃), 1,25-dihydroxyvitamin D₃ (1,25D₃), and 24,25-dihydroxyvitamin D₃ (24,25D₃), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects (n = 29) were administered one dose of oral VitD₃ (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD₃ and its metabolites. The simultaneous fit of a two-compartment model for VitD₃ and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD₃ and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD₃ and metabolites. This is the first reported population pharmacokinetic modeling of VitD₃ and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D₃ concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD. Full article

Background: Drug–drug interactions (DDIs) occur when two or more drugs are administered concomitantly, changing the pharmacokinetics or pharmacodynamics of a drug’s characteristics. Despite the advances in health technology, DDIs remain a concern to patient safety. This study aimed to (1) assess the knowledge, attitude, and practice of hospital and community pharmacists toward DDIs in Saudi Arabia and (2) examine factors associated with their practice. Methods: A cross-sectional study was conducted using an online self-administered questionnaire targeting hospital and community pharmacists working in Saudi Arabia. The study questionnaire consisted of five sections: demographics, knowledge, attitude, and practice toward DDIs, as well as pharmacy characteristics. Descriptive statistics were used to summarize the characteristics of participants as count and percentage. Chi-square tests were used to examine associations between practice variables and other independent variables. Results: A total of 131 pharmacists participated in the study. The majority were males (81.7%), aged 26–35 years (64.9%), and worked in community pharmacies (81.7%). Nearly half of the participants reported optimal practice regarding checking drug interactions before dispensing any drug. Factors associated with the practice of checking DDIs were found to be gender, perceived workload, perceived knowledge, and attitude variables. Regarding the practice of asking patients about their prescription and OTC drugs, there were statistically significant differences between hospital and community pharmacists. Conclusions: Our findings on both community and hospital pharmacists in Saudi Arabia reveal that pharmacists’ attitudes and perceived knowledge might influence the practice of pharmacists toward DDIs. Full article

Cryptococcal infection commonly begins as an opportunistic infection in humans, however, this can escalate to a systemic or life-threatening form in immunocompromised individuals. Here, we aim to identify novel antifungal molecules from plants resources. Sclareolide, a phytochemical classified as a sesquiterpene lactone, was assessed against Cryptococcus neoformans H99. Sclareolide exhibited promising antifungal properties with a minimum inhibitory concentration (MIC) of 16 µg/mL. Additionally, the C. neoformans growth rate was significantly affected by sclareolide treatment in a concentration-dependent manner, as observed through a time killing assay, with a significant reduction at MIC × 8 compared to the control by 48 h. To elucidate the underlying mechanisms of sclareolide antifungal activity, fluorescence-based methods were employed. Propidium iodide (PI) accumulation assay indicated a reduction in C. neoformans membrane integrity, with values as low as 6.62 ± 0.18% after treatment. Moreover, sclareolide at MIC × 4 and MIC × 8 significantly increased the production of reactive oxygen species (ROS) and reduced the mitochondrial membrane potential (MMP), suggesting oxidative stress and mitochondrial dysfunction in C. neoformans. Sclareolide did not induce caspase-dependent apoptosis, suggesting a non-apoptotic mechanism. Further, a checkerboard experiment was performed to assess potential synergistic interaction with Amphotericin B, however, no synergism was observed. Moving on, sclareolide at 128 µg/mL did not exhibit toxicity in Galleria mellonella, further supporting its potential as a safe antifungal agent. These findings suggest that the antifungal activity of sclareolide against C. neoformans is mediated by oxidative stress. Further in vivo and pharmacokinetic studies are recommended to explore the potential of sclareolide as a prototype for the development of novel anti-cryptococcal therapies. Full article

Tamibarotene is a synthetic retinoid that inhibits tumor cell proliferation and promotes differentiation. We previously reported on the safety and tolerability of tamibarotene in patients with recurrent or refractory solid tumors. Therefore, in this study, we aimed to evaluate the pharmacokinetic properties of tamibarotene and construct a precise pharmacokinetic model. We also conducted a non-compartmental analysis and population pharmacokinetic (popPK) analysis based on the results of a phase I study. Targeted pediatric and young adult patients with recurrent or refractory solid tumors were administered tamibarotene at doses of 4, 6, 8, 10, and 12 g/m²/day. Serum tamibarotene concentrations were evaluated after administration, and a popPK model was constructed for tamibarotene using Phoenix NLME. During model construction, we considered the influence of various parameters (weight, height, body surface area, and age) as covariates. Notably, 22 participants were included in this study, and 109 samples were analyzed. A two-compartment model incorporating lag time was selected as the base model. In the final model, the body surface area was included as a covariate for apparent total body clearance, the central compartment volume of distribution, and the peripheral compartment volume of distribution. Visual prediction checks and bootstrap analysis confirmed the validity and predictive accuracy of the final model as satisfactory. Full article

Zanthoxylum species have long been utilized in traditional medicine; among their various properties, they provide an analgesic effect. Central to this medicinal application are alkamides, a class of alkaloids characterized by their unsaturated fatty acid chains. These compounds are particularly noted for their distinctive alleviation of tingling and numbing effects, which are beneficial in dental pain management and local anesthesia. This review synthesizes the existing phytochemical research on alkamides derived from 11 Z. species, focusing on their chemical properties, pharmacodynamics and clinical implications. The analysis includes an examination of the structure–activity relationships (SARs), pharmacokinetics and mechanisms by which these compounds modulate sensations such as pungency and numbness, contributing to their analgesic and local anesthetic efficacy. This systemic review identifies significant research gaps, including the need for comprehensive evaluations of alkamide efficacy, detailed explorations of their pharmacological mechanisms and expanded clinical applications. These areas represent key opportunities for future investigations to enhance the understanding and utilization of alkamides in medical treatments. Full article