Journal of Pharmacy and Pharmacology最新文献

Objectives: Dabigatran etexilate (DAB), a direct thrombin inhibitor, exhibits limited oral bioavailability (6%-7%), mostly attributable to pH-dependent solubility. To address this issue, Eudragit S100 (EU)-coated liposomes were engineered to safeguard DAB-loaded nanocarriers in the stomach and provide targeted release in the intestine, where absorption occurs through several mechanisms.

Methods: Liposomal vesicles were prepared using the conventional thin film hydration method. The developed formulations were subjected to physicochemical characterization, which included Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), zeta potential analysis, particle size measurement, polydispersity index (PDI) assessment, entrapment efficiency (EE%), and transmission electron microscopy (TEM).

Key findings: The selected formulation, EU@DAB-Lip4, exhibited advantageous properties: minimal particle size (136.9 nm), high EE (92.67%), and colloidal stability (zeta potential -17.3 mV). In vitro release demonstrated pH-responsive behaviour, with low gastric release (12.8% at 2 hr) and enhanced intestinal release (75.5% at pH 7.4). Pharmacokinetic studies in rats demonstrated a 5.6-fold and 2.7-fold enhancement in bioavailability for EU@DAB-Lip4 relative to DAB-Lip and DAB suspension, respectively, as indicated by elevated Cmax (2664 vs. 891 and 554 ng/ml) and AUC₀-∞ (21 020 vs. 7236 and 3749 ng.hr/ml).

Conclusions: EU-coated liposomes constitute a viable platform for enhancing DAB bioavailability and therapeutic efficacy.

Background: Late-stage prostate cancer is treated with hormonal therapy. While initially effective, development of drug resistance is common. Hypoxia, a local-environmental occurrence in tumours, is known to trigger hormone-independence and concurrent drug resistance in cancer cells.

Methods: Here we analyse single-cell transcriptomes of LNCaP cells throughout drug treatment. These cells were exposed to chronic hypoxia and treated with Enzalutamide, a hormonal drug which inhibits the androgen receptor, both with and without Tazemetostat, an epigenetic drug that inhibits EZH2 catalytic activity, which renders Enzalutamide-resistant clones partially sensitive to hormonal therapies. We identify genes characterizing the resistant clone and assess clinical relevance.

Results: We characterize a resistant cluster present with Enzalutamide treatment but not with combination therapy. The top 10 upregulated genes in this cluster included genes previously linked to resistance: DDIT3, MDM2, and CDKN1A, and one previously proposed as a pan-cancer hallmark (HSP90B1). Analysis of clinical databases showed expression of CDKN1A, POLH, and GADD54 to be significantly upregulated in association with neuroendocrine prostate cancer.

Conclusion: This work characterizes at a single-cell level the Enzalutamide resistant clone and the impact of epigenetic inhibitors on resistance development. This characterization may enable the identification of resistant and non-resistant cells by their gene expression profile.

Objective: This review comprehensively summarizes the botany, traditional applications, phytochemistry, pharmacological activities, toxicology, and quality control of Sedum sarmentosum, aiming to provide a reference for its further research and development.

Methods: Research articles and materials were retrieved from databases including Web of Science, PubMed, Google Scholar, CNKI, and related academic publications.

Key findings: To date, 174 chemical constituents have been isolated and identified from S. sarmentosum, including volatile oils, flavonoids, terpenoids, phenolics, glycosides, and others. Modern pharmacological studies have revealed diverse bioactivities such as hepatoprotective, nephroprotective, antitumour, and antioxidant effects. Ten proprietary Chinese medicines primarily composed of S. sarmentosum have been developed for the treatment of liver diseases.

Conclusions: This review provides a comprehensive overview of the traditional Chinese clinical applications, phytochemical identification, and pharmacological mechanisms of S. sarmentosum, offering insights and references for subsequent Traditional Chinese Medicine research and development, as well as in-depth studies on natural active products and pharmacological mechanisms. Current research suggests that its terpenoid components directly associated with its significant hepatoprotective effects. Moreover, the specific mechanisms underlying its hepatoprotective actions still require further investigation.

Objectives: Drug-resistant epilepsy affects 30% of patients, where antiseizure medications (ASMs) are non-effective. A possible mechanism is the presence of the P-glycoprotein (P-gp) transporter in the blood-brain barrier (BBB), which may cause ASM efflux and limit bioavailability. Therefore, this study aimed to evaluate the potential of ASMs as P-gp substrates.

Methods: The study was conducted using the BBB model cell line human cerebral microvascular endothelial cells (hCMEC/D3). Ten widely used ASMs were assessed for their interaction with P-gp through in vitro assays: ATPase, competitive substrate efflux, and bidirectional transport assay, followed by quantification using HPLC or liquid chromatography-tandem mass spectrometry.

Key findings: Valproic acid, lamotrigine, and topiramate stimulated basal ATPase activity of P-gp. In a competitive substrate efflux assay, valproic acid, lamotrigine, and topiramate increased rhodamine123 intracellular accumulation, thereby influencing its P-gp-mediated efflux. Valproic acid and lamotrigine exhibited an efflux ratio > 1.5 in a bidirectional transport assay, which was significantly reduced in the presence of a P-gp inhibitor (P < .01).

Conclusions: The findings support that valproic acid and lamotrigine are likely substrates of P-gp at the BBB. Thus, targeting the P-gp-mediated efflux may represent a promising strategy for managing drug-resistant epilepsy against these ASMs.

Objectives: Pazopanib is an anti-angiogenic small molecule tyrosine kinase inhibitor approved for use in the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma. This review provides an overview of pazopanib pharmacokinetics and therapeutic drug monitoring.

Key findings: Pazopanib exhibits a multifaceted pharmacokinetic profile characterized by low and pH-dependent solubility, non-linear absorption, and time-dependent decreases in systemic exposure. Research to date has revealed numerous intrinsic and extrinsic factors significantly influencing pazopanib pharmacokinetics, including food interactions, use of gastric acid suppressants, drug-drug interactions with concomitant medications and genetic polymorphisms. Pazopanib plasma trough concentrations > 20.5 and ≥ 27 μg/ml are associated with improved efficacy in patients with renal cell carcinoma and soft tissue sarcoma, respectively, and increased pazopanib systemic exposure is associated with increased incidence of drug-related adverse events (e.g. hypertension).

Conclusion: Pazopanib exhibits large variability in systemic exposure and consequently, achieving systemic exposures within a therapeutic range for optimal efficacy while minimizing toxicity, can be challenging when a fixed dose is used. Therefore, therapeutic drug monitoring may be a promising tool to optimize the efficacy of pazopanib while limiting drug-related toxicities, through personalized dose adjustments guided by monitoring plasma pazopanib concentrations. Further exploration into the influence of additional factors on pazopanib pharmacokinetics is essential for advancing pharmacokinetic-guided dosing strategies and improve treatment outcomes.

Objectives: Although HER2 overexpression is observed in only 2%-3% of colorectal cancer (CRC) patients, its amplification can function as a compensatory mechanism that drives CRC resistance to targeted therapy. 1,2,3,4,6-Penta-O-galloyl-β-d-glucose (PGG) has been reported to possess anti-tumor and anti-metastatic activities in CRC. Nevertheless, the molecular targets through which PGG exerts its effects in CRC remain unclear. This study aimed to evaluate the role of HER2 as a potential molecular target of PGG in CRC.

Methods: Ultra performance liquid chromatography-mass spectrometer (UPLC-MS) was employed to determine the cellular uptake of PGG in HCT116 cells. Potential PGG targets were predicted using STITCH and molecular operating environment platforms. Functional rescue assays were performed with lapatinib, a HER2 inhibitor. Direct PGG-HER2 interactions were validated by drug affinity responsive target stability and thermal shift assays. Downstream signaling effects were examined by assessing HER2 expression and its downstream pathway by Western blotting.

Key findings: UPLC-MS analysis confirmed the accumulation of PGG (204.5 ± 19.1 ng) in HCT116 cells after 40 μM PGG treatment for 12 h. Computational predictions suggested ErbB2 (HER2) as a potential binding target. Rescue experiments showed that the combination of lapatinib and PGG failed to further reduce cell viability when compared with lapatinib alone, implying HER2 as a molecular target of PGG. Both drug affinity responsive target stability and thermal shift assays verified that PGG protects HER2 from pronase-induced degradation and enhances its stability upon thermal challenge, indicating direct binding. Mechanistically, PGG suppressed HER2 expression and inhibited the PI3K-Akt-mTOR pathway, a canonical downstream pathway of HER2.

Conclusions: Our findings provide a strong preclinical rationale for future clinical trials of PGG as a HER2-targeted drug in CRC and highlight its considerable potential as a novel therapeutic for CRC treatment.

Background: Drug resistance critically impedes renal cell carcinoma therapy. A dual-targeted liposomal system that codelivered resveratrol (RES) and paclitaxel (PTX) with αvβ3 integrin-targeting was developed to overcome multidrug resistance (MDR).

Methods: RGDfC peptide-functionalized liposomes (PTX/RES-RGDfC-Lip) were synthesized via film hydration-ultrasound methods. The particle size, zeta potential, drug encapsulation efficiency, and release kinetics were evaluated. P-glycoprotein (P-gp) modulation, cellular uptake, and chemosensitization in PTX-resistant A498 cells (PTX-res-A498) and in vivo antitumor efficacy were studied in xenograft models.

Results: The RGDfC ligand enables selective tumor delivery by binding to αvβ3 integrins that are overexpressed in the renal carcinoma vasculature, whereas RES enhances PTX efficacy by modulating P-gp-mediated drug efflux. Liposomes were synthesized via film hydration-ultrasound methods and systematically characterized for size (109.8 ± 4.2 nm), zeta potential (-8.91 ± 0.75 mV), dual-drug encapsulation efficiency (RES: 90.56 ± 4.30%; PTX: 90.23 ± 4.66%), and sustained release kinetics. In vitro studies demonstrated 3.19-fold greater cellular uptake in resistant renal carcinoma cells (PTX-res-A498 cells) than in nontargeted formulations. In vivo, PTX/RES-RGDfC-Lip resulted in 70.2% tumor reduction in xenograft models. Mechanistic studies confirmed the RES-mediated downregulation of P-gp expression and the restoration of chemosensitivity.

Conclusion: This dual-targeted codelivery system represents a promising strategy for overcoming MDR in advanced renal carcinoma.

Objectives: The primary aim was to characterize the influence of diet-induced obesity on the stereoselective pharmacokinetics of racemic bupivacaine in male and female rats.

Method: Rats were fed either a standard diet (StdD) or high-fat diet (HFD) for 12 weeks. A stereoselective assay was used to measure plasma concentrations after subcutaneous injection of racemic bupivacaine. A rich sampling protocol was initially employed for cannulated rats, while a sparse sampling in non-cannulated rats, coupled with Bayesian forecasting, was used in dietary assessment.

Key findings: Clearance (CL) of both enantiomers was significantly reduced in males fed HFD. StdD females had lower peak concentrations and longer elimination phases than StdD males. Stereoselectivity was modest, with the d-enantiomer displaying marginally higher CL than antipode. There was an apparent late-absorption peak with rich sampling.

Conclusion: Bupivacaine exhibits modest stereoselectivity in rats, with diet and sex influencing CL. The application of Bayesian forecasting in sparse sampling models in rats proved to be a robust tool for pharmacokinetic assessment, aligning with the goals of reducing numbers, refining experimental design and replacing invasiveness of procedures in the use of animals.

Objective: To investigate the mechanism and pharmacological activity of (Xiaoyaosan decoction) XYSD in the treatment of NAFL (nonalcoholic fatty liver) by proteomic techniques.

Methods: C57BL/6 mice NAFL model was induced by HFD (high fat diet), and observed biochemical indicators and histopathological changes. We employed TMT (tandem mass tag) quantitative proteomics and conducted bioinformatics analysis. Additionally, an in vitro model using unsaturated FFA (free fatty acid)-induced lipid accumulation was established to discover the effect of XYSD on lipid accumulation in HepG2 cells.

Results: The results showed that XYSD improved liver index and biochemical indexes, and reversed the characteristics of liver steatosis in NAFL mice. Based on the results of in vivo proteomic enrichment analysis, we hypothesize that the activation of the PPARα signaling pathway may be a potential mechanism underlying the therapeutic effect of XYSD in treating NAFL. XYSD remarkably improved protein and gene expression of Fads2 (fatty acid desaturase 2), Hmgcs2 (3-hydroxymethylglutaryl-CoA synthase 2), Fabp1 (fatty acid-binding protein 1) and PPARα. This hypothesis has been further confirmed in our in vitro experiments.

Conclusion: The study shows that XYSD improves lipid accumulation by activating PPARα signaling pathway, and finally achieves the effect of NAFL.