Journal of Pharmacy and Pharmacology最新文献

Objectives: Tamoxifen is a prodrug that undergoes cytochrome P450(CYP)-mediated bioactivation to its active metabolite endoxifen, primarily due to CYP2D6. We aimed to investigate the clinical impact of CYP2D6 phenotype on the conversion of tamoxifen to endoxifen as well as the interplay of genetic variation and drug interactions.

Methods: Samples were analyzed from a cohort of 932 breast cancer patients on tamoxifen therapy. CYP2D6 phenotype, tamoxifen, endoxifen, 4-hydroxytamoxifen, and N-desmethyl tamoxifen plasma concentrations and antidepressant CYP2D6 inhibitor use were analyzed.

Key findings: There was a significant effect of CYP2D6 phenotype and CYP2D6 inhibitor use on endoxifen concentrations (pinteraction < 0.05). CYP2D6 inhibition was predictive of patients who attained plasma endoxifen concentrations below the 16 nM and 9 nM threshold. CYP2D6 poor metabolizers and CYP2D6 normal or intermediate metabolizers on strong CYP2D6 inhibitors had the largest proportion of patients below an endoxifen threshold of 16 or 9 nM.

Conclusions: Patients on tamoxifen should avoid strong CYP2D6 inhibitors as their endoxifen concentrations are similar to CYP2D6 poor metabolizers. The utility of endoxifen concentrations and which threshold to consider in clinical practice remains unclear. Ultimately, the clinical impact of mild or moderate CYP2D6 inhibitors on CYP2D6 normal or intermediate metabolizer depends on the endoxifen threshold applied.

Introduction: Renal ischemia-reperfusion (RIR) induces inflammation, oxidative stress, and impaired renal function, partly through reduced nitric oxide (NO) availability. Rosuvastatin enhances NO production and has reported organ-protective effects. This study examined whether rosuvastatin confers renoprotection in RIR through NO-dependent mechanisms.

Materials and methods: Five groups of rats (n = 6) were used: control, RIR, RIR + rosuvastatin, RIR + rosuvastatin + L-NAME (NG-Nitro-L-arginine methyl ester), and RIR + rosuvastatin + L-arginine. Drugs were administered once daily from 3 days before ischemia until 24 h after reperfusion. Twenty-four-hour urine, blood, and kidney tissues were collected for analysis. Statistical tests were performed with Prism software.

Results: Rosuvastatin significantly reduced serum urea and creatinine levels versus RIR alone. Glomerular filtration rate increased, though proteinuria remained unchanged. Inflammatory cytokines and oxidative stress decreased markedly, while tissue NO levels rose in the rosuvastatin group. L-NAME co-treatment diminished these effects, whereas L-arginine enhanced them, indicating NO involvement.

Conclusion: Rosuvastatin ameliorated renal injury in RIR, likely through activation of NO signaling. These findings suggest a potential therapeutic role for rosuvastatin in ischemic renal injury.

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.