Journal of Pharmacy and Pharmacology最新文献

Purpose: The aim of this study was to evaluate the novel rhein derivative Y01 for its anti-HCC activity and potential molecular mechanisms, thereby positioning it as a promising candidate for HCC therapy.

Methods: CCK-8, EdU incorporation and clone formation assay were employed to assess the impact of Y01 on the cell viability and proliferation of HCC cells. While apoptosis was assessed through flow cytometry and western blotting techniques. Additionally, the impact of Y01 on cell mobility was evaluated via wound healing and transwell migration assays, with western blotting analyses providing further insights. Mechanistically, transcriptomics and western blotting assays were used to explore the potential signaling pathways.

Results: Y01 markedly suppressed the growth, colony formation, and migratory capacity of HCC cells, induced apoptosis and affected the expression of apoptosis-related proteins. Transcriptomics initially pointed toward the PI3K/AKT/mTOR pathway as a potential target, which was corroborated by western blotting results showing decreased levels of phosphorylated PI3K, AKT, and mTOR following Y01 treatment, highlighting its role in mediating the compound's anticancer effects.

Conclusions: Y01 inhibited the proliferation, migration, and induced apoptosis of HCC cells possibly by blocking PI3K/AKT/mTOR signaling pathway.

Objectives: Palbociclib (PBB) is an oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for the treatment of HR+/HER2- breast cancer. However, poor adherence and limited tolerability of oral administration often compromise its therapeutic effectiveness, especially in palliative care for metastatic conditions. Dose reductions are frequently required to manage toxicity, but lower doses can still provide effective tumour control with reduced neutropenia risk, thereby improving quality of life and progression-free survival. Developing a long-acting injectable (LAI) formulation of PBB offers significant advantages for sustained therapy in advanced-stage cancer management.

Methods: This study focuses on dose selection, release profile optimisation, and the design of sterile PBB-loaded PLGA microsphere suspensions for intramuscular (IM) administration using physiologically based pharmacokinetic (PBPK) modelling and simulations. The PBPK model, developed and validated with data from oral and intravenous routes, enabled the prediction of IM pharmacokinetics. Clinical target product profiles were defined based on IC50 and minimum steady-state concentration (Css, min).

Key findings: The dose optimisation study revealed that the rational selection of dose for both strengths, with an optimised sustained-release profile (Target 2, showing minimal initial burst and controlled release reaching ~55% by day 10.5 and ~90% by day 21), achieved the desired clinical quality target product profiles.

Conclusions: The developed model will further support polymer selection, specification setting, and drug-to-polymer ratio. Incorporating PBB's physicochemical properties and host response helps guide rational formulation design.

Objectives: To clarify the antipyretic efficacy of Capilliposide (LC) and investigate its antipyretic mechanism.

Methods: Dry yeast was used to establish rats fever model. Five hours after inoculation, 60 and 80 mg/kg LC was given to rats (i.g.). Rectal temperatures were measured at 2.5 h after administration. Then, the rats were sacrificed and blood and brain tissues were collected. The levels of cytokines tumor necrosis factor-α , interleukin (IL)-1β, and IL-6 were determined in serum, and prostaglandin E2 expression was measured in the hypothalamic suspension. Additionally, nitric oxide (NO) production and pyrogenic cytokines were detected in the supernatant of RAW 264.7 cells with or without LC treatment. Transcriptional analysis was performed and verified using western blot analysis.

Key findings: LC treatment significantly decreased the rectal temperature compared to that in the fever model at 5 h. The levels of pyrogenic cytokines were reduced following LC treatment. LC alleviated the pathological damage of hypothalamus caused by fever. LC treatment also significantly reduced NO production in vitro. Western blot results showed that LC inhibited the nuclear factor kappa-B and mitogen-activated protein kinase (MAPK) signaling pathways.

Conclusions: In summary, our results demonstrated that LC exhibited excellent anti-inflammatory and anti-pyretic effects in vivo and in vitro through MAPK/inducible nitric oxide synthase/NF-κB pathway.

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.