Search Results (13,346)

Background/Objectives: Effective communication between medical practices and community pharmacists is essential for safe and efficient outpatient care, yet quantitative evidence from the perspective of community pharmacies regarding the frequency, content, and efficiency of routine pharmacist–physician communication in Germany is limited. This study aimed to investigate, from the perspective of community pharmacies, the reasons for and outcomes of initiating contact with medical practices following the submission of patient prescriptions in routine outpatient care. Methods: In this observational study, 45 community pharmacies in Leipzig and the surrounding region (Germany) documented simultaneously all contacts with medical practices related to prescriptions over a 14-day period (November 2023) using a standardized documentation form. Data included reasons for contact, communication channels, number of contact attempts, outcomes, satisfaction ratings, and case duration. Multivariable linear regression was used to identify factors associated with satisfaction with contact outcomes, and ordinal regression to examine determinants of case duration. Results: In total, 498 documented contacts were analyzed. The most frequent reasons for contact were drug availability issues and formal or content-related prescription errors. Consultations related to drug interactions or contraindications were rare. Overall satisfaction with contact outcomes was high, but lower satisfaction was associated with repeated contact attempts, non-acceptance of pharmacists’ recommendations, and contacts related to formal prescription errors. Case resolution was faster when fewer contact attempts were required and when communicating with general practices rather than specialist practices. Conclusions: Pharmacy-initiated communication with medical practices in outpatient care is largely driven by administrative and logistical issues rather than clinical consultations. Improving prescription quality, enhancing transparency of drug availability, and strengthening efficient communication pathways may reduce workload and increase satisfaction. Full article

Drug resistance remains a significant barrier to achieving durable treatment responses. Traditionally, resistance has been attributed to genetic alterations and clonal selection. However, accumulating evidence suggests that early adaptation to therapy is often mediated by non-genetic state transitions. In this review, we propose a conceptual framework in which resistance emerges through therapy-driven molecular evolution in bladder cancer, characterized by three interconnected axes: non-genetic plasticity, metabolic reorganization, and tumor microenvironment remodeling. Using the Gemcitabine-Resistant Cell (GRC) model as a temporal reference system, we describe a stepwise transition from drug-sensitive states dominated by proliferation to survival-optimized resistant states through a growth–survival trade-off. Early adaptive phases are marked by the attenuation of cell-cycle and glycolytic programs, increased epigenetic flexibility, and metabolic rewiring involving mitochondrial and lipid-associated pathways. Later phases involve the reinforcement of resistance through extracellular matrix remodeling, developmental and stress-response signaling, and immunometabolic interactions within the tumor microenvironment, including adenosine- and lipid-associated mediators. Projecting the GRC score onto a clinical bladder cancer cohort further suggests that these evolutionary patterns may also be reflected in patient tumors. Overall, this framework supports a temporally structured view of chemoresistance and highlights opportunities to therapeutically target transitional adaptive states before resistance becomes stabilized. Full article

Background: Dietitians play a critical role in preventing food–drug interactions (FDIs) and drug–nutrient interactions (DNIs); however, evidence regarding their knowledge, attitudes, and practices (KAP) in Saudi Arabia remains limited. Objective: The aim of this study was to assess dietitians’ KAP regarding FDIs and DNIs and examine their associations with socio-demographic and professional characteristics. Methods: A national cross-sectional study was conducted among 353 dietitians using a validated and modified questionnaire. Knowledge was assessed via 15 multiple-choice items (score range 0–15) and categorized as poor (0–5), moderate (6–10), or good (11–15). Attitudes were assessed using 8 Likert-scale statements (score range 8–40) and classified as negative (8–19), neutral (20–29), or positive (30–40). Practices were assessed via 6 frequency-scale items (score range 6–30) and categorized as poor (6–14), moderate (15–23), or good (24–30). Associations were analyzed using chi-square tests. Results: In total, 65.2% of participants demonstrated poor knowledge. Knowledge level was significantly associated with nationality (p = 0.011), educational qualification (p = 0.042), attendance at FDI/DNI training courses (p = 0.003), and inclusion of related topics during university education (p = 0.013). Higher knowledge levels were also associated with managing digestive diseases (p = 0.001), cardiovascular diseases (p = 0.020), and cancer (p = 0.031). Positive attitudes were reported by 77.6% of participants and were significantly associated with managing cardiovascular disease (p < 0.001) and obesity (p = 0.008). Good practices were observed in 36.3% of dietitians and were significantly associated with younger age (p = 0.024), more recent graduation (p = 0.006), fewer years of professional experience (p = 0.002), and managing obesity (p = 0.016). Knowledge was positively associated with practice (p < 0.001). Conclusions: Despite generally positive attitudes, substantial gaps in knowledge and practice regarding FDIs and DNIs exist among dietitians in Saudi Arabia. Strengthening academic curricula and continuing professional education is essential to enhance competency and improve patient safety. Full article

Background/Objectives: Natural macromolecule-based drug delivery carriers have gained extensive attention for biomedical applications. This study aimed to construct an efficient oral delivery system for the widely used antitumor drug docetaxel (DTX) by utilizing natural nanoparticles derived from Ganoderma (LZ-Nnps). Methods: LZ-Nnps loaded with DTX (LZ-Nnps-DTX) were fabricated via an optimized heat-induced self-assembly approach and characterized for morphology, particle size, zeta potential, stability, drug loading, encapsulation efficiency, and molecular interactions with DTX. Intestinal absorption, pharmacokinetics, and tissue distribution were respectively assessed, while antitumor efficacy, macrophage internalization mechanisms, and immunomodulatory activation were further investigated. Results: The optimized formulation showed a particle size of 361.3 ± 5.3 nm, zeta potential of −39.55 ± 1.31 mV, drug loading of 1.51 ± 0.08%, and near-complete encapsulation efficiency (99.97 ± 0.02%), with favorable stability in gastrointestinal fluids. Hydrogen bonding and hydrophobic interactions effectively kept DTX in a stable amorphous state. LZ-Nnps-DTX markedly improved DTX aqueous solubility, dissolution, and intestinal absorption. In vivo assays showed oral LZ-Nnps-DTX achieved 34-fold higher C_max and 7.8-fold larger plasma AUC_0-t than free DTX, and mainly accumulated in the liver and lung. The nanoparticles entered Caco-2 cells via macropinocytosis and mainly accumulated in the liver. LZ-Nnps-DTX exerted strong cytotoxicity against HepG2, A549, and HCT116 cells, was internalized by RAW264.7 macrophages through caveolae-mediated endocytosis and phagocytosis, and stimulated TNF-α and NO production to suppress tumor growth. Conclusions: These findings demonstrate that LZ-Nnps-DTX effectively enhances oral bioavailability, exerts potent antitumor effects, and activates macrophage-mediated immunity, supporting its promise as an oral DTX delivery system. Full article

Hepatitis E virus (HEV) infection is generally self-limiting in immunocompetent individuals but may progress to chronic infection in immunocompromised patients, underscoring the need for effective antiviral therapies. Although ribavirin is currently used off-label for HEV treatment, its associated adverse effects highlight the need for safer alternatives. In this study, we screened an anti-viral compound library comprising 800 compounds using three HEV reporter systems designed to target distinct stages of the viral life cycle. Candidate compounds were further evaluated in PLC/PRF/5 cells using both acute and chronic infection models with wild-type genotype 3 HEV (HEV-3). Antiviral activity was assessed by measuring HEV RNA levels in culture supernatants. Elbasvir, a known inhibitor of hepatitis C virus (HCV) non-structural protein 5A (NS5A), was identified as the most potent candidate. Although multiple compounds showed inhibitory effects in reporter assays, only elbasvir achieved sustained suppression of HEV growth in long-term culture, reducing HEV RNA levels to below the limit of detection. In a chronic infection co-culture model, elbasvir maintained antiviral activity at non-cytotoxic concentrations. Time-of-addition analysis demonstrated that elbasvir inhibits an early step in the viral life cycle, specifically viral internalization. Furthermore, combination with ribavirin enhanced antiviral efficacy, resulting in sustained viral suppression without detectable cytotoxicity and exhibiting an additive interaction. Collectively, these findings identify elbasvir as a promising candidate for repurposing as an anti-HEV drug and support a combination strategy targeting distinct steps of the viral life cycle. Full article

This study investigated the molecular mechanisms underlying the therapeutic effects of ginsenoside Rh2 (G-Rh2) in coronary heart disease (CHD) through a network pharmacology approach, focusing on identifying key targets and pathways, including those involved in lipid metabolism, metabolism regulation and anti-apoptotic signaling. A multi-target network pharmacology analysis was performed to predict the pharmacoloigical targets and pathways of G-Rh2. Key molecular interactions were validated by molecular docking. In vivo experiments using CHD rat models were conducted to verify and quantify the effects of G-Rh2 on lipid profiles, myocardial pathology, and gut microbiota composition. G-Rh2 significantly ameliorated CHD in rats by reducing serum cholesterol and triglycerides levels, alleviating myocardial fibrosis, suppressing cardiomyocyte apoptosis, and mitigating tissue damage. Mechanistically, G-Rh2 activated the PI3K/AKT signaling pathway, regulated atherosclerosis-associated metabolic pathways (e.g., pentose phosphate and carbon metabolism), and modulated gut microbiota composition by reducing the abundance of harmful bacteria and increasing beneficial microbial populations, thereby enhancing lipid metabolism and energy balance. This study demonstrates that G-Rh2 alleviates CHD through the synergistic activation of the PI3K/AKT pathway, modulation of key metabolic pathways, and restructuring of gut microbiota. These findings underscore the potential of G-Rh2 as a multi-target therapeutic agent for CHD, offering mechanistic insights into its cardioprotective properties and supporting the broader application of G-Rh2 in cardiovascular drug development. Full article

This review offers an in-depth look at the diagnostic and therapeutic potential of MNPs as superparamagnetic and high-surface-area-to-volume entities, considering their applications in MRI, magnetic hyperthermia, and targeted drug delivery. Based on an integrative approach, which includes systematic searches in 3 main bibliographic databases, 870 articles, semantic network analysis, Retrieval-Augmented Generation (RAG), and gap classification (Miles’ taxonomy), our analysis identifies a constant gap between lab performances and in vivo applications, described through eight critical challenges. The development of MNP-based biotechnologies is largely hindered by open issues in terms of safety, standardization, and control of the nanobio interface, mainly incomplete physicochemical characterization and poor methodological harmonization, because the high sensitivity of MNPs to synthesis routes and scale is a major bottleneck for GMP-compatible translation. Moreover, the analysis of in vivo data suggests that, on average, less than 1% of the injected dose accumulates in solid tumors, whereas a substantial fraction is diverted to non-target organs, particularly those associated with the mononuclear phagocyte system, reinforcing concerns regarding off-target sequestration, incomplete clearance, and long-term safety. Other critical challenges include complex interactions with biofluids, lack of unifying conceptual frameworks, limited experimental validation, underexploited methodological integration, and geographical and biological biases. Consequently, successfully overcoming these challenges will require the early and deliberate integration of rigorous materials engineering, mechanistic biological insight, and application-oriented validation for robust, reproducible, and translatable magnetic nanoplatforms. Full article

Background: Cenobamate is a novel antiseizure medication with potential interactions involving cytochrome P450 enzymes, including CYP2C19. Genetic variability in CYP2C19 may influence drug metabolism and tolerability, although its clinical relevance in cenobamate-treated patients remains unclear. Methods: We conducted a single-center retrospective study including 48 adults with drug-resistant epilepsy treated with cenobamate. Patients were stratified by concomitant use of CYP2C19-substrate ASMs (patients with CYP2C19 substrates vs. patients without CYP2C19 substrates). CYP2C19 genotype was classified into metabolizer phenotypes. Adverse events (AEs) were categorized as potentially CYP-mediated or likely unrelated to CYP-mediated pharmacokinetic mechanisms based on clinical assessment, temporal association, and known pharmacological interaction profiles. Associations were explored using descriptive statistics and regression models. Results: Overall, 58.3% of patients received CYP2C19-substrate ASMs. AEs were more frequent among patients with CYP2C19 substrates (71.4% vs. 20.0%; p = 0.001), with potentially CYP-mediated AEs observed only in this group (32.1% vs. 0%; p < 0.001). Intermediate metabolizers showed a higher proportion of potentially CYP-mediated AEs (87.5%; p < 0.001). This pattern was not observed in patients without CYP2C19 substrates. Regression analyses suggested increased risk in intermediate metabolizers, although estimates were imprecise and should be considered exploratory. Conclusions: An exploratory association between CYP2C19 variability and AE occurrence was observed in patients treated with cenobamate combined mainly with clobazam and other CYP2C19-substrate ASMs. Intermediate metabolizers may represent a higher-risk subgroup, but these preliminary findings require prospective confirmation with pharmacokinetic monitoring. Full article

Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG trinucleotide in the exon 1 of the huntingtin gmodellerene. This abnormal expansion produces a mutant huntingtin (mHTT) protein with extended polyglutamine (polyQ) tracts. Although the molecular mechanisms underlying HD onset and progression remain poorly understood, aberrant folding, aggregation, and membrane interactions of mHTT are considered central to disease pathogenesis. In this study, we used molecular dynamics (MD) simulations to investigate the structural properties, dimerization propensity, and membrane lipid interaction of mHTT carrying 70 polyQ repeats (mHTT-Q70). Our analyses revealed that mHTT-Q70 retains partially structured α-helical conformations with increased flexibility within the polyQ domain, thus being predisposed to misfolding. Coarse-grained MD simulations further revealed a strong tendency of mHTT-Q70 to dimerize, indicating that early oligomerization may represent a critical step in protein aggregation. Interestingly, we show that membrane cholesterol content dose-dependently promotes dimeric mHTT-Q70—but not monomeric mHTT-Q70—association with neuronal membrane models, which was observed for 70% of simulation time at 40% cholesterol content. Such a cholesterol-dependent membrane binding of dimeric mHTT-Q70 suggests that membrane lipid composition may represent a critical checkpoint in the early stages of mHTT-Q70 aggregation, and of cytotoxicity thereof. Moreover, distinct neuronal membrane lipids like phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine differently contributed to mHTT-Q70 binding, highlighting the complexity of such a lipid-dependent modulation. Taken together, these findings underscore the dynamic interplay between polyQ-driven misfolding, dimerization, and membrane lipids in HD pathogenesis, suggesting that modulation of membrane composition, and in particular of cholesterol levels, may be a novel action point to design therapeutic drugs for HD. Full article

The photothermal conversion capability of polydopamine (PDA) was exploited to load the anticancer drug doxorubicin (DOX) onto its surface via π-π stacking and hydrogen-bond interactions, yielding a PDA-DOX complex. In this study, biocompatible poly-L-lactic acid (PLLA) was employed as a shell material to fabricate multifunctional PLLA composite PDA-DOX (PLLA@PDA-DOX) nanobubbles with integrated functions of ultrasound imaging, photothermal therapy, and chemotherapy. The fabricated nanobubbles exhibited a uniform mean diameter of 489.30 ± 6.96 nm with a Polydispersity index (PDI) of 0.226 ± 0.01 and a DOX loading efficiency of 3.27%. Acute toxicity evaluation in mice revealed that the maximum tolerated dose of PLLA@PDA-DOX nanobubbles was markedly higher than the clinical equivalent dose, showing no detectable toxicity or allergic reactions. Under near-infrared (NIR) laser irradiation, the inhibition rate of HCCLM3 cells increased from 50.1% to 64.45%, indicating enhanced therapeutic efficacy through the combined effects of photothermal therapy and chemotherapy. Moreover, compared with the free DOX group, the survival rate of LX-2 cells in the composite nanobubble group significantly increased from 18.9 ± 1.56% to 68.8 ± 3.08%, suggesting that the PLLA@PDA-DOX nanobubbles effectively reduced the direct cytotoxicity of DOX by preventing its immediate contact with cells. Collectively, the results confirm that PLLA@PDA-DOX nanobubbles possess excellent biocompatibility, robust ultrasound imaging performance, and enhanced antitumor efficacy under NIR irradiation. This multifunctional nanosystem demonstrates promising potential as an integrated platform for simultaneous cancer diagnosis and therapy. Full article

Non-steroidal anti-inflammatory drugs (NSAIDs) are used globally for their pain-relieving and fever-reducing properties. However, excessive intake of NSAIDs can have harmful effects on multiple body systems, including the cardiovascular, gastrointestinal, hepatic, renal, and nervous systems. The anti-inflammatory activity of 34 derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline was investigated in vivo. A relationship between the activity of the compounds and the nature of their substituents, as well as their positional and mutual arrangement in the C ring (1-Ar-), was established. In silico modeling of these 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives’ interaction with the COX-2 (PDB ID: 1PXX) active site revealed that the nitro-derivatives exhibited the highest stability owing to their superior capacity for electrostatic and hydrogen bond formation compared to brominated compounds. These data on the effects of the substituents –NH₂, –OH, and –OCH₃ in ring C (1-Ar-) of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines on anti-inflammatory activity promote the search for new, highly effective derivatives within this series. Full article

A series of 1,2,3-triazole-linked-thiazolidine-2,4-dione hybrids (SDP1–SDP15) were designed, synthesized, and evaluated for their antidiabetic potential. All structures were characterized by FT-IR and NMR spectroscopy (¹H and ¹³C). All derivatives exhibited significant in vitro inhibition of α-glucosidase (IC₅₀: 24.17–46.41 µg/mL) and α-amylase (23.25–50.66 µg/mL), comparable to the standard drug acarbose (IC₅₀: 25.18 and 32.53 µg/mL) and superior to the reference drug pioglitazone (IC₅₀: 84.24 and 79.74 µg/mL) for α-glucosidase and α-amylase, respectively. Molecule SDP8 emerged as the most potent with an IC50 of 24.17 and 23.25 µg/mL for α-glucosidase and α-amylase, respectively. Further, SDP8 exhibited a higher docking score of −10.7 kcal/mol and −10.4 kcal/mol against α-glucosidase and α-amylase than pioglitazone (−8.1 kcal/mol and −7.7 kcal/mol, respectively), suggesting that interaction with these two enzymes may be the cause for its antidiabetic activity. Furthermore, DFT analysis revealed favorable electronic properties with a low HOMO-LUMO energy gap, whereas ADMET predictions revealed moderate drug-like characteristics with some limitations, such as poor solubility, relatively high lipophilicity, and partial noncompliance with drug-likeness regulations. Overall, these results highlight triazole-linked thiazolidinedione hybrids as promising candidates for further development in T2DM, with SDP8 serving as a preliminary lead requiring additional optimization and validation. Full article

Glioblastoma recurrence remains nearly universal despite maximal safe surgical resection and multimodal adjuvant therapy. Beyond tumor debulking, resection induces profound local brain microenvironment alterations, including sterile neuroinflammation, blood–brain barrier disruption, extracellular matrix remodeling, and rapid activation of innate immune pathways. Among resident immune populations, microglia emerge as central regulators of the post-resection microenvironment, influencing inflammatory signaling, tissue repair, and tumor–host interactions. Activated microglia accumulate at the resection margin, where they adopt highly plastic functional states shaped by cytokine gradients, metabolic stress, hypoxia, and tumor-derived mediators. This dynamic activation landscape establishes bidirectional crosstalk with residual glioblastoma cells, promoting invasion, angiogenesis, maintenance of stem-like phenotypes, and suppression of anti-tumor immunity. As a result, microglial responses contribute to a permissive microenvironment that supports therapeutic resistance and tumor regrowth. Importantly, the perioperative period represents a short but important opportunity to modify microglial activity. Targeted therapeutic strategies, including pharmacologic modulation, local drug delivery systems, immunometabolic approaches, and gene- and cell-based therapies, may help alter the tumor microenvironment. This narrative review synthesizes current mechanistic insights into microglial dynamics following glioblastoma resection and evaluates emerging therapeutic strategies targeting microglial function. We further discuss integration with standard-of-care treatments and highlight evolving biomarker platforms for monitoring microglial states. Ultimately, targeting microglial plasticity represents a biologically grounded and clinically actionable strategy to improve outcomes after glioblastoma surgery. Full article

Background: The pharmacological management of type 2 diabetes mellitus has become increasingly complex due to expanding therapeutic options and the high prevalence of multimorbidity in affected patients. As a result, the risk of drug–drug and drug–disease interactions has grown significantly, with potential implications for glycemic control, safety, and treatment outcomes. Objective: This narrative review provides a comprehensive, class-based overview of clinically relevant interactions associated with antidiabetic medications, highlighting their mechanisms, clinical consequences, and practical management strategies. Methods: A targeted literature search was conducted using major medical databases to identify clinical studies, meta-analyses, pharmacovigilance reports, and evidence-based guidelines concerning interactions related to key antidiabetic drug classes. Interactions were categorized as pharmacokinetic, pharmacodynamic, or disease-related. Results: Significant variability exists across antidiabetic drug classes in terms of interaction profile and clinical relevance. Metformin presents interaction risks mainly through renal impairment or co-administration with drugs affecting lactate metabolism. Sulfonylureas and glinides are strongly associated with hypoglycemia-enhancing interactions. DPP-4 inhibitors generally exhibit a low interaction burden, whereas GLP-1 receptor agonists may interact through delayed gastric emptying. SGLT2 inhibitors require caution in patients with diuretics or conditions predisposing them to dehydration or ketoacidosis. Insulin remains highly sensitive to pharmacodynamic interactions with a broad spectrum of therapies. Underlying renal, hepatic, and cardiovascular conditions further modify the interaction risk. Conclusions: Understanding class-specific interaction profiles is essential for personalized and safe diabetes management. Careful medication review, close metabolic monitoring, and individualized dose adjustments can mitigate the risk of harmful interactions. Further research is needed to elucidate interactions in populations with advanced multimorbidity and polypharmacy. Full article

Research on oxazolones, particularly 4-alkynyloxazolones, has garnered increasing interest due to the presence of an alkynyl group, which facilitates molecular conjugation and enables diverse chemical modifications. In this study, three representative 4-alkynyloxazolone derivatives (L1–L3) were synthesized and structurally characterized through single-crystal X-ray diffraction and computational analysis to obtain a reliable structure of L1–L3 to subsequently predict in silico interactions with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. The crystallographic results revealed high molecular planarity and multifurcated hydrogen bonding. Considering the obtained crystallographic structure, theoretical descriptors such as HOMO–LUMO energy gaps and electrostatic potential maps indicated that these compounds exhibit favorable electronic reactivity, particularly for L3, with favorable drug-like predictions. The lack of methoxy groups in L2 and L3 makes these compounds have lower predicted toxicity parameters than L1. Molecular docking calculations targeting SARS-CoV-2 spike glycoprotein in three different feasible conformations in a biological matrix, i.e., three receptor-binding domains (RBD) in down conformation, two RBD in down and one in up conformation, as well as RBD bound to the human receptor angiotensin-converting enzyme 2 (ACE2), suggested strong binding affinities and specific interactions with the RBD moiety, mainly in the up conformation. Overall, this work integrates crystallographic and computational approaches to establish the structural and in silico evaluation of spike-binding properties of early substituted 4-alkynyloxazolones, suggesting L3 as a candidate for future in vitro antiviral assays. Full article