Search Results (5,387)

Background/Objectives: Goupi plaster (GP) is a traditional black plaster composed of a biphasic fibrous–oil matrix containing multiple bioactive compounds, and it has been widely used for the treatment of musculoskeletal disorders. Representative active compounds include sinomenine, osthole, cinnamaldehyde, and imperatorin, which exhibit anti-inflammatory and analgesic effects. However, due to its heterogeneous matrix structure and multi-component nature, the pharmaceutical delivery behavior of GP remains difficult to evaluate using conventional methods. Therefore, this study aimed to establish an integrated structure–release–permeation–pharmacokinetic evaluation framework to systematically characterize the transdermal delivery behavior of GP. Methods: GP was evaluated using multi-level analysis, including microstructural imaging (FESEM), in vitro release, ex vivo skin permeation, and in vivo dual-site microdialysis. Four representative bioactive compounds (sinomenine, osthole, cinnamaldehyde, and imperatorin) were selected as marker compounds. Release data were fitted to kinetic models, and structure–release relationships were examined using the Higuchi release constant (k_h). Skin-barrier alterations were assessed by attenuated total reflectance–Fourier transform infrared spectroscopy (ATR–FTIR) and differential scanning calorimetry (DSC). Local concentrations in subcutaneous (SC) and intra-articular (IA) compartments were measured by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to explore potential in vitro–in vivo correlation (IVIVC). Results: FESEM revealed a fibrous–oil network structure. GP exhibited sustained, diffusion-dominated release, with k_h = 0.9908–0.9977 and Korsmeyer–Peppas (K–P) release exponents (n) = 0.61–0.66, differing from active pharmaceutical ingredient (API) controls. Fiber area fraction and fiber length density showed negative correlations with k_h (r = −0.91 to −0.99); ex vivo permeation profiles varied among compounds, and ATR–FTIR and DSC analyses showed moderate changes in skin-barrier properties. Dual-site microdialysis demonstrated sustained local exposure, and a positive relationship was observed between in vitro release and in vivo concentrations. Conclusions: This study establishes an integrated structure–release–permeation–pharmacokinetic evaluation framework for traditional black plaster systems. The observed IVIVC is descriptive rather than predictive, reflecting a trend-level association under the current experimental conditions. These findings highlight the importance of integrating in vitro release, skin permeation, and local pharmacokinetics for understanding drug delivery behavior in complex transdermal matrix systems, and provide a methodological basis for quality consistency evaluation of traditional black plaster formulations. Full article

Background: H1-antihistamines are widely used for allergic and upper respiratory conditions; however, several agents included in this class have been associated with cardiac electrophysiological adverse effects, including QT interval prolongation and torsades de pointes (TdP). These effects are largely exposure-dependent and mechanistically linked to inhibition of cardiac ion channels. Chlorpheniramine maleate (CPM), a first-generation H1-antihistamine, has been implicated in arrhythmic events primarily under conditions of increased systemic exposure, prompting interest in whether alternative routes of administration may lower cardiac risk. Methods: This narrative review integrates mechanistic, preclinical, clinical, pharmacokinetic, and regulatory evidence. Information was extracted from PubMed, Google Scholar, and Scielo using search terms such as cardiotoxicity, chlorpheniramine, QT prolongation, intranasal administration, and cardiac arrhythmias, with no language restriction. Results: Comparative pharmacokinetic evidence shows that, on a dose-normalized basis, intranasal and oral chlorpheniramine exhibit comparable bioavailability; however, in a clinical context, intranasal doses (1.12–2.24 mg) are lower than oral daily doses (4–12 mg/day), resulting in a lower systemic exposure (Cmax and AUC) with intranasal administration. Available pharmacovigilance or epidemiological data have not specifically evaluated intranasal chlorpheniramine, and the number of dedicated safety trials remains limited. Conclusions: Preclinical, in vitro, mechanistic studies suggest that intranasal administration of chlorpheniramine should confer superior cardiac safety compared to the oral route. However, clinical data from human studies directly comparing the cardiac safety of intranasal chlorpheniramine versus systemic chlorpheniramine is extremely limited. More data from clinical trials, case–control studies, and regulatory databases are needed to validate these theoretical claims. Full article

Background: Targeted therapies directed against oncogenic drivers have substantially improved outcomes for patients with epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Despite high initial response rates, most patients ultimately develop acquired resistance to tyrosine kinase inhibitors (TKIs), reflecting complex biological adaptations under therapeutic pressure. Methods: This narrative review synthesizes experimental, translational, and clinical studies examining how environmental and occupational respiratory exposures may influence resistance mechanisms in EGFR- and ALK-driven NSCLC. The review emphasizes exposure-associated signaling plasticity, inflammatory microenvironmental modulation, metabolic reprogramming, and pharmacokinetic alterations. Results: Recent evidence suggests that respiratory exposures, including cigarette smoke, air pollution, diesel exhaust, and occupational inhalational toxicants, can modulate oncogenic signaling networks relevant to resistance to targeted therapies. These mechanisms include aberrant EGFR activation, bypass signaling through the mesenchymal–epithelial transition receptor (MET) and SRC pathways, epithelial–mesenchymal transition (EMT), adaptive kinome remodeling, and exposure-associated inflammatory signaling, all of which may influence tumor evolution and therapeutic response. Conclusions: This review introduces a novel exposome-driven conceptual framework integrating environmental exposures with signaling plasticity and resistance evolution in oncogene-driven NSCLC. These findings support the concept that the respiratory exposome may represent an underrecognized modifier of targeted therapy response. Incorporating structured exposure assessment into precision oncology approaches may refine risk stratification and inform exposure-aware therapeutic strategies. Full article

Background/Objectives: Rebamipide is a gastroprotective agent with poor aqueous solubility and rapid gastrointestinal clearance, leading to reduced therapeutic efficiency. This study aimed to enhance the solubility, mucoadhesion, and sustained oral delivery of Rebamipide through the development of a deep eutectic mixture (DEM)-based bioadhesive controlled-release granule formulation. Methods: In silico hydrogen-bonding interactions between Rebamipide, malonic acid, and urea were analyzed using CCDC tools. A thermodynamically stable DEM (1:3:1) was prepared and incorporated into bioadhesive granules using chitosan and HPMC. Physicochemical characterization was conducted using FTIR, DSC, TGA, and PXRD. Solubility, in vitro dissolution, ex vivo mucoadhesion (sheep gastric mucosa), and in vivo gastric retention (BaSO₄-loaded granules in rats) were evaluated. Results: The optimized DEM significantly enhanced Rebamipide solubility (10.08 mg/mL vs. 0.045 mg/mL). Solid-state analyses confirmed hydrogen-bond formation and reduced crystallinity. DEM granules exhibited sustained drug release over 24 h (99.7 ± 0.8%) with improved dissolution efficiency compared to the marketed tablet (Mucosta®, 100 mg; T₅₀%: 5.03 h vs. 0.82 h). Kinetic modeling indicated non-Fickian anomalous transport (n = 0.47). The bioadhesive force of DEM granules (0.29 ± 0.02 N) was significantly higher than that of the pure drug and physical mixture. In vivo radiographic studies confirmed prolonged gastric retention. Conclusions: The DEM-based bioadhesive granule system effectively improves solubility, dissolution rate, mucoadhesion, and gastric retention of Rebamipide. This approach represents a promising platform for once-daily gastroretentive oral delivery, pending further pharmacokinetic evaluation. Full article

Second-generation anticoagulant rodenticides (SGARs) were developed to overcome warfarin resistance in rodent populations; however, their prolonged hepatic retention has raised concerns regarding secondary poisoning of non-target wildlife. All major SGARs exist as cis–trans isomeric pairs, and differences in biological half-life between isomers have been reported, yet the molecular basis for such isomer-dependent pharmacokinetic behavior remains poorly understood. In this study, we conducted an integrated evaluation of cis and trans isomers of SGARs using in vivo, in vitro, and in silico approaches, with vitamin K epoxide reductase (VKOR) serving as the molecular target. The individual compounds exhibited distinct isomer-dependent profiles in hepatic retention, inhibitory potency (IC₅₀), and VKOR interaction-related properties. Molecular dynamics simulations further revealed isomer-dependent differences in torsional flexibility around specific rotatable bonds and in ligand–VKOR interaction fractions. For flocoumafen and bromadiolone, the presence of an ether oxygen was associated with increased torsional and orientational flexibility and enhanced hydrogen-bonding potential, which may facilitate metabolic processing and contribute to the relatively faster elimination of cis isomers. Collectively, these results suggest that isomer-specific VKOR interaction patterns may contribute, in a compound-dependent manner, to isomer-dependent pharmacokinetic behavior, offering structural perspectives for the design of rodenticides with reduced ecological risk. Full article

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, and its co-occurrence with psychiatric disorders poses significant therapeutic challenges. This narrative review examines the safe use of psychopharmacological agents in patients with HF, focusing on mood stabilizers (particularly lithium) and antipsychotics. We summarize clinically relevant pharmacokinetic and pharmacodynamic interactions between these agents and guideline-directed HF therapies, including ACEIs, ARBs, ARNIs, beta-blockers, MRAs, SGLT2 inhibitors, and diuretics. Lithium is particularly prone to interactions due to its narrow therapeutic index and dependence on renal sodium handling, with RAAS inhibitors, thiazide diuretics, and SGLT2 inhibitors increasing the risk of toxicity. Antipsychotics are associated with QT prolongation, orthostatic hypotension, and electrolyte disturbances, with substantial variability between agents. This review highlights key clinical risks, provides a practical summary of drug interactions, and outlines principles for individualized, multidisciplinary management. Care requires coordinated cardiology–psychiatry collaboration, careful drug selection, and assessment of renal function, electrolytes, drug levels, and ECG parameters. Further studies and improved guideline integration are needed. Full article

Flavonoids are a broad class of polyphenolic compounds with well-established biological and therapeutic relevance; however, their clinical application is often limited by unfavorable pharmacokinetic properties, including low solubility, poor bioavailability, and extensive metabolism. Enzymatic modification has emerged as a promising strategy to overcome these limitations, enabling regio- and stereoselective structural changes under mild and environmentally sustainable conditions. This study presents a systematic review conducted in accordance with the PRISMA 2020 guidelines, covering studies published between 2015 and 2025 on the enzymatic modification of flavonoids and their effects on physicochemical properties and bioavailability, with emphasis on biological activity and therapeutic potential. The literature search was performed in PubMed, Scopus, and Web of Science, complemented by citation searching and exploratory bioinformatics analysis. Evidence from in vitro, in vivo, and clinical studies indicates that enzymatic modifications such as glycosylation, deglycosylation, acylation, hydroxylation, methylation, and prenylation can improve stability, absorption, and biological activity. Despite promising results in experimental models, clinical evidence remains limited. Overall, enzymatic modification represents a promising strategy for improving flavonoid properties; however, most available evidence is derived from in vitro and in vivo studies, and further well-designed clinical trials are required to confirm their therapeutic potential in humans. Full article

Intranasal administration is a promising drug delivery route enabling precise and rapid central nervous system targeting. In our previous work, twelve hybrid colloidal dispersions were developed, consisting of synthetic poly(ethylene-oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) block copolymers with an increasing proportion of the hydrophobic PCL segment, Tween 80 (Tw80) and β-cyclodextrin derivatives (βCD), either methyl-β-CD (MβCD) or hydroxy-propyl-β-CD (HPβCD) for IN delivery of ropinirole hydrochloride (RH). Colloidal dispersions were prepared at different weight ratios (system/RH equal to 10:1 and 10:5), characterized and evaluated in vitro. The aim of this study is to evaluate the ex vivo permeation through rabbit nasal mucosa and determine the pharmacokinetic parameters of RH, when administered intranasally as a colloidal dispersion, compared with oral and intranasal RH solutions in C57BL/6J mice. Ex vivo permeation studies showed that all formulations significantly enhanced RH permeation compared to the pure RH solution (0.5 mg/mL, pH 5.6). Among them, F4 [(PEO-b-PCL₁/Tw80/HPβCD)/RH 10:5] was selected for further investigation. Pharmacokinetic analysis showed that F4 significantly enhanced both systemic and brain exposure of RH, achieving higher serum AUC and C_max values, despite a 3-fold lower administered dose compared to the oral dose. It showed high systemic (F_rel(Serum) = 1815%) and brain (F_rel(Brain) = 363%) relative bioavailability compared with oral administration, underscoring its potential as an intranasal delivery system for efficient CNS targeting. Full article

Background/Objectives: Alzheimer’s disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1–40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10⁻⁵ mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation. Full article

Background: Prostate cancer (PCa) is the leading male urinary malignancy globally. Our previous article demonstrated the anti-PCa activity of Euphorbia humifusa Willd water extract (EHW) and some of its compounds via downregulating AR expression, but the anti-PCa active compounds from Euphorbia humifusa Willd (EH) and their mechanisms of action are yet to be clarified. Thus, the current article studied the in vitro anti-PCa effects of 3,3′-di-O-methylellagic acid (3,3′-di-O-Me-EA) derived from EHW and the related mechanism involved. Methods: 3,3’-di-O-Me-EA was isolated from EHW applying bioassay-guided fractionation. The spectroscopic methods were used to determining the structure of 3,3′-di-O-Me-EA. The drug-likeness and ADMET properties (absorption, distribution, metabolism, excretion, and toxicity) of 3,3′-di-O-Me-EA were analyzed in silico. Molecular docking and real-time surface plasmon resonance (SPR) analysis were performed to measure the interaction of 3,3′-di-O-Me-EA and VDAC1 protein. The viability and apoptosis of 22RV-1 and DU145 PCa cells were determined using MTT and Annexin V-FITC staining assay, respectively. q-PCR and Western blot experiments were used to analyzing the gene and protein expressions of VDAC1. Results: 3,3′-di-O-Me-EA was isolated and purified from EHW with a purity of ≥90.06%, and its structure was identified by HRTOF mass, NMR, and an authentic standard. In silico ADMET analysis indicated its favorable drug-like and pharmacokinetic properties. Molecular docking and SPR results confirmed that 3,3′-di-O-Me-EA could bind with the VDAC1 protein. Moreover, 3,3′-di-O-Me-EA dose- and time-dependently inhibited 22RV-1 and DU145 PCa cell viability, and induced apoptosis in a dose-dependent manner (p < 0.05). RT-qPCR and Western blot results showed that 3,3′-di-O-Me-EA dose-dependently up-regulated VDAC1 gene and protein expression levels in 22RV-1 and DU145 cells (p < 0.05). Meanwhile, in VDAC1-depleted 22RV-1 and DU145 cells, 3,3′-di-O-Me-EA down-regulated VDAC1 gene and protein expression levels, increased cell viability, and inhibited apoptosis compared to 22RV-1 and DU145 cells (p < 0.05). Furthermore, 3,3′-di-O-Me-EA enhanced VDAC1 gene and protein expression levels, inhibited cell viability, and induced apoptosis in VDAC1-overexpressed 22RV-1 and DU145 cells compared with 22RV-1 and DU145 cells (p < 0.05). Overall, EH active compound 3,3′-di-O-Me-EA may inhibit viability and induce apoptosis of 22RV-1 and DU145 PCa cells via up-regulating VDAC1 gene and protein expression levels. Conclusion: The results indicated that the 22RV1 and DU145 PCa cell viability inhibitory effects of 3,3′-di-O-Me-EA isolated from EH may be mediated by induction of apoptosis through up-regulation of VDAC1 gene and protein expression levels. Full article

Gastric cancer remains a highly heterogeneous malignancy in which chemotherapy response is limited by intrinsic and acquired resistance, cumulative toxicity, and the restricted predictive value of conventional preclinical models. This review critically synthesizes evidence on selected medicinal plants and their bioactive phytocompounds as adjuncts to standard chemotherapy for gastric cancer, with an emphasis on mechanistic plausibility, preclinical synergy, and translational barriers. Across the reviewed literature, phytocompounds from Curcuma longa, Scutellaria baicalensis, Camellia sinensis, Syzygium aromaticum, Glycyrrhiza glabra, Allium sativum, Marsdenia tenacissima, and Rhus verniciflua showed anticancer or chemopreventive activity through multitarget effects on apoptosis, proliferation, invasion, inflammation, oxidative stress, and resistance-associated signaling. The most convincing chemosensitizing evidence involved curcumin, wogonin, baicalein, EGCG, which enhanced the activity of fluoropyrimidines, platinum agents, paclitaxel, doxorubicin, or related antitumor regimens in selected gastric cancer models. However, the evidence base remains heterogeneous and is constrained by variable extract standardization, incomplete dose reporting, poor bioavailability, insufficient pharmacokinetic/pharmacodynamic integration, and underuse of clinically relevant model systems. Overall, medicinal plant bioactives remain promising adjunct candidates in gastric cancer. Still, meaningful translation will require chemically defined interventions, rigorous synergy analysis, interaction-aware study design, and validation in advanced preclinical and clinical settings. Full article

Human serum albumin (HSA) binding critically influences drug distribution and pharmacokinetics. In this study, HSA affinity chromatography was integrated with machine-learning-based quantitative structure–retention relationship (QSRR) modeling to elucidate structural determinants of albumin binding in a library of 115 fluoroquinolone (FQs) derivatives. Experimentally determined logk_HSA values were obtained using biomimetic chromatography, and these were then used as modelling endpoints. Following descriptor reduction via Least Absolute Shrinkage and Selection Operator (LASSO) and systematic benchmarking of 42 regression algorithms, support vector regression (SVR) and nu-support vector regression (ν-SVR) with radial basis function kernels demonstrated superior predictive performance. A parsimonious 12-descriptor ν-SVR model achieved strong calibration and validation metrics (R² = 0.916, Q²_test = 0.823, concordance correlation coefficient (CCC) = 0.899) and satisfied Organisation for Economic Co-operation and Development (OECD) criteria, including applicability domain assessment. Shapley Additive exPlanations (SHAP)-based interpretation revealed that albumin binding is governed by a balance between hydrophobic surface area and distributed electronic properties, whereas excessive localized polarity and quaternary ammonium functionalities reduce affinity. This experimentally anchored and interpretable modeling framework provides mechanistic insight into HSA binding in fluoroquinolones and offers a robust tool for rational pharmacokinetic optimization. Furthermore, in order to make the model easily accessible to users, we have packaged it in the form of an online application. Full article

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which B-cell dysregulation plays a central pathogenic role beyond autoantibody production. Advances in B-cell biology have led to the development of targeted therapies, including inhibition of the B-cell activating factor (BAFF) pathway. Belimumab, a monoclonal antibody that neutralizes soluble BAFF, modulates B-cell survival signals upstream, promoting progressive immunologic remodeling rather than rapid depletion. This review integrates current knowledge on BAFF-dependent B-cell biology with mechanistic, pharmacokinetic, and clinical data to provide a comprehensive framework for understanding belimumab’s effects in SLE and lupus nephritis (LN). Belimumab preferentially reduces transitional and naïve B cells, while memory B cells show a relative transient increase followed by a gradual return to baseline levels, reflecting redistribution rather than expansion, and long-lived plasma cells are largely unaffected. These effects result in progressive remodeling of B-cell compartment dynamics and contribute to broader modulation of adaptive immune amplification pathways. Pharmacokinetic data support a threshold-based model of BAFF neutralization, with exposure influenced by disease-related factors such as proteinuria in LN. Clinical response is primarily determined by baseline disease biology, with greater benefit observed in patients with serologically active disease and less established organ involvement. Across clinical trials and real-world studies, belimumab reduces disease activity and flares, enables glucocorticoid tapering, and slows organ damage accrual. In LN, it improves renal outcomes and reduces the risk of kidney-related events. Collectively, these findings support belimumab as a disease-modifying therapy in SLE. Further research is needed to refine patient selection and optimize treatment sequencing and combination strategies. Full article

Cytisine is a plant-derived quinolizidine alkaloid found, among other sources, in the seeds of the common laburnum (Laburnum anagyroides). It has properties that enable it to act as a partial agonist of brain nicotinic α4β2 receptors, which play a key role in the development and maintenance of nicotine addiction. Clinical studies have shown that cytisine is a more effective smoking cessation aid than nicotine replacement therapy and at least as effective as varenicline in treating tobacco cigarette addiction. It may also be an effective agent in treating addiction to electronic cigarettes. Cytisine is also significantly cheaper than other anti-nicotine medications. This is of great importance for the population of smokers in developing countries, who cannot afford anti-nicotine treatment. In recent years, the role of cytisine in the pharmacotherapy of nicotine addiction worldwide has increased significantly. This drug is becoming available in an increasing number of countries, and in 2025 the World Health Organization (WHO) added cytisine to the list of essential medicines. The need for further development of the drug poses additional challenges for scientists, including the creation of new pharmaceutical forms, optimization of dosing regimens, and expansion of indications to include the treatment of nicotine addiction supplied into the body in forms other than traditional tobacco products. This review describes the use of cytisine in the treatment of nicotine addiction, the drug’s mechanism of action, pharmacokinetics, efficacy, safety of use, and the available pharmaceutical preparations. It also presents research directions on cytisine related to the development of innovative pharmaceutical products, new dosing regimens, and new indications associated with the treatment of addiction to various nicotine-containing products. Conclusions indicate that cytisine has a difficult dosing regimen, which is why patients do not adhere to it, limiting the effectiveness of the therapy. This necessitates optimizing the dosage of existing capsules and tablets or introducing, for example, new extended-release forms of the drug containing cytisine. Full article

Background/Objectives: Ustekinumab has been approved for the treatment of moderate to severe ulcerative colitis. Real-world data regarding its efficacy and the discovery of predictive factors of response need to be studied further. We aimed to evaluate the efficacy and identify predictors of response to induction treatment with ustekinumab in patients with ulcerative colitis. Methods: This is a multicenter, prospective cohort study. Clinical response (CR) at week 16 was the primary endpoint, and steroid-free clinical remission (SFCRem) and endoscopic response were the secondary endpoints. Baseline histology, mucosal gene expression, and pharmacokinetics were studied for their effect on response to treatment. Results: We included 123 patients (mean age = 50.3 years). CR was recorded in 70.8% (75/106), SFCRem in 48% (59/123), endoscopic improvement in 71.4% (40/56), and mucosal healing in 28.6% (16/56). Higher PRO-stool frequency (OR = 0.49, p = 0.027), concomitant use of 5-ASA (OR = 3.69, p = 0.021), platelet number of ≥284 × 10⁹/L (OR = 6.52, p = 0.001) at baseline, and a drop in the total count of platelets by 10⁸/L (OR = 1.23, p = 0.022) at week 8 were independently associated with CR. Elevated trough levels of ustekinumab at week 16 were associated with a higher probability of endoscopic improvement (median difference = 3784 ng/mL, p = 0.013), with an optimal cut-off value of 3500 ng/mL (AUC = 0.82, 95% CI: 0.66–0.96). Increased mucosal mRNA expression for IL-23 (p = 0.007) and IL-23R (p = 0.031) at baseline was associated with increased probability of CR. Higher continuous Geboes scores at baseline were associated with a lower probability of CR (OR = 0.80, p = 0.045), with an optimal cut-off value of 14 (AUC = 0.75, 95% CI: 0.57–0.93). Conclusions: Clinical, laboratory, and molecular markers may identify patients with ulcerative colitis who are more likely to respond to ustekinumab. Full article