Advanced pharmaceutical bulletin最新文献

Purpose: Breast cancer is a prevalent form of cancer in woman. Vorinostat (VOR) is a chemotherapeutic drug that has been utilized for treatment of breast cancer, but its effectiveness is limited due to low bioavailability and several side effects. The primary aim of this study is to prepare folic acid conjugated pegylated bilosomes containing VOR (FA-PEG- bilosomes) for the selective targeting of breast cancer cells with the FA receptor expression. Accordingly, lithocholic acid was used as a bile acid in bilosomes due to its anti-cancer and anti-proliferation effects.

Methods: VOR loaded bilosomes were prepared using the thin-film hydration method and optimized by applying two-level fractional factorial design. Various properties of the considered bilosomes, including particle size, zeta potential, polydispersity index (PdI), encapsulation efficiency (EE) % and drug loading (DL) %, were then investigated and synthesized FA-PEG-Cholesterol was incorporated in the optimized bilosomes. The anti-cancer efficacy of VOR loaded FA-PEG- bilosomes was also evaluated in vitro using the MCF-7 and 4T1 breast cancer cell lines. Furthermore, drug free FA-PEG-bilosomes and bilosomes were evaluated for biocompatibility in the L929 cell line.

Results: The optimized VOR loaded bilosomes exhibited spherical particles with the size of 305.33±18.50 nm, PdI of 0.37±0.03, zeta potential of -17.66±0.15 mV, EE of 92.91±0.22 % and DL% of 23.64±0.04%. Incorporation of FA-PEG-cholesterol in nanobilosomes increased the particle size and absolute value of zeta potential. In vitro cytotoxicity study also revealed that VOR loaded FA- PEG-bilosomes demonstrated a greater cytotoxic effect, as compared to the free VOR and VOR- bilosomes in both MCF-7 and 4T1 cancer cells.

Conclusion: This showed that FA- PEG-bilosomes could be a promising formulation for the treatment of FA (+) tumors.

Purpose: The objective of this study was to develop and produce a novel fusion protein that combines GLP-1 (glucagon-like peptide-1) and FGF21 (fibroblast growth factor 21), with the aim of achieving synergistic pharmacological effects through the targeting of dual pathways, followed by validation of these effects in a non-alcoholic steatohepatitis (NASH) model.

Methods: We utilized C57Bl/6J mice to establish a high-fat diet (HFD)/CCl₄ NASH model, with the aim of assessing the drug efficacy across low, medium, and high (0.3, 1, 3 mpk) dose groups administered twice a week for 28 days.

Results: The animal pharmacological experiment of HSP763-01 demonstrated a significant reduction in body weight without apparent appetite suppression. Analysis of blood biochemical indicators revealed a marked decrease in triglycerides (TG), serum total cholesterol (TCHO or TC), low-density lipoprotein (LDL), and blood sugar levels with a significant dose-dependent effect. Additionally, Liver tissue analysis indicated notable alleviation of liver fatty degeneration and ballooning degeneration, as well as partial relief of lobular inflammation with a significant dose-dependent effect. However, due to the severe liver fibrosis induced by tetrachloromethane (CCl₄) in mice (3rd grade), HSP763-01 exhibited limited efficacy in alleviating fibrosis.

Conclusion: HSP763-01 exhibited a clear dual target of GLP-1 and FGF21, which has been demonstrated by a robust response to the HFD/CCl₄ model, showing a marked improvement in lipid metabolism, lowering of blood glucose, weight loss, significant alleviation of liver steatosis, ballooning, and partial relief of lobular inflammation and fibrosis.

Purpose: Apoptosis and autophagy play critical roles in the survival and regulation of cancer cells, with key genes serving dual purposes in these processes. Arsenic trioxide (ATO), oxaliplatin (OXA), and docetaxel (DOC) are widely used in the treatment of various cancers. Specifically, ATO inhibits cellular proliferation and induces apoptosis in certain cancer cells, while OXA and DOC, common agents in cancer chemotherapy, continue to be actively studied for their potential therapeutic effects.

Methods: This study investigated the effects of ATO, DOC, and OXA on AGS and MKN-45 gastric cancer cell lines in vitro. The MTT assay was utilized to determine the effective concentrations of these compounds, both individually and in combination. Apoptosis was assessed using Annexin V-FITC staining, and the mRNA levels of genes related to autophagy and apoptosis were analyzed via real-time polymerase chain reaction (PCR).

Results: Our findings demonstrated that the combination of ATO with DOC and OXA significantly reduced the viability of AGS and MKN-45 cells compared to DOC or OXA therapy alone. Notably, the simultaneous administration of all three agents markedly enhanced apoptosis induction. Additionally, the combined use of two drugs showed a more pronounced impact on both cell necrosis and apoptosis compared to the effects of each drug used alone.

Conclusion: The combination of two therapeutic agents represents a promising strategy for inducing autophagy and gene expression related to apoptosis in gastric cancer cells. This approach exerted a more substantial influence on cell apoptosis and necrosis than single-drug treatments, underscoring its potential as an effective therapeutic option.

Purpose: This study aimed to develop sustained-release triamcinolone acetonide (TA) formulations using lipid liquid crystals (LLCs) for ocular drug delivery and to characterize the designed formulations.

Methods: Eighteen dispersed LLC formulations were prepared through a top-down approach, incorporating varying concentrations of TA and different proportions of glyceryl monooleate, deionized water, and pluronic F127. An additional formulation comprising TA: hydroxypropyl beta-cyclodextrin (HPβCD) complex was also developed to investigate the influence of HPβCD on the properties of the formulations. The formulations were evaluated for their rheological properties in room temperature using a rheometer, syringeability by passing them through a 27G needle, size measurements via dynamic light scattering (DLS), and morphology through polarized light microscopy (PLM). Furthermore, the prepared formulations were injected into a dialysis tube and placed in a phosphate buffer at pH 7.4 and 37 °C for in vitro release evaluation. Samples were taken at predetermined intervals and stored in a refrigerator until HPLC analysis. The percentage of Encapsulation efficacy and drug loading were evaluated using an indirect method. A reversed-phase HPLC method was employed to quantify the drug concentrations in the samples.

Results: All selected formulations demonstrated acceptable parameters, including particle size (less than 200 nm), polydispersity index (PDI) ranging from 0.202 to 0.355, and zeta potential values between -14.3 and -32.8 mV. Additionally, the formulations showed good syringeability and achieved 100% drug release within 48 hours (except for the formulation containing HPβCD). PLM analysis revealed the presence of hexosomes and cubosomes, indicating that an increase in hexosomes contributed to a more uniform drug release from the formulations.

Conclusion: Overall, the study findings suggest that liquid crystalline carriers can be a promising formulation for sustained ocular drug delivery of TA.

Cancer, as a complicated disease, is considered to be one of the major leading causes of death globally. Although various cancer therapeutic strategies have been established, however, some issues confine the efficacies of the treatments. In recent decades researchers for finding efficient therapeutic solutions have extensively focused on the abilities of stem cells in cancer inhibition. Mesenchymal stem cells (MSCs) are multipotent stromal cells that can the most widely extracted from various sources such as the bone marrow (BM), placenta, umbilical cord (UC), menses blood, Wharton's jelly (WJ), adipose tissue and dental pulp (DP). These cells are capable of differentiating into the osteoblasts, chondrocytes, and adipocytes. Due to the unique characteristics of MSCs such as paracrine effects, immunomodulation, tumor-tropism, and migration, they are considered promising candidates for cancer therapeutics. Currently, MSCs are an excellent living carrier for delivery of therapeutic genes and chemical agents to target tumor sites. Also, exosomes, the most important extracellular vesicle released from MSCs, act as a strong cell-free tool for cancer therapeutics. MSCs can prevent cancer progression by inhibiting several signaling pathways, such as wnt/β-catenin and PI3K/AKT/mTOR. However, there are several challenges associated with the use of MSCs and their exosomes in the field of therapy that need to be considered. This review explores the significance of MSCs in cell-based therapy, focusing on their homing properties and immunomodulatory characteristics. It also examines the potential of using MSCs as carriers for delivery of anticancer agents and their role in modulating the signal transduction pathways of cancer cells.

Effective optimal pharmacotherapy requires a comprehensive understanding of the drug's pharmacokinetic properties. Chronic kidney disease (CKD) influences medication pharmacokinetics. However, whether sex differences exist in the pharmacokinetics of drugs for children with CKD is unknown. The primary aim of this article was to evaluate the effect of sex on pharmacokinetics of drugs commonly used for CKD treatment in children. Secondary outcome was to address the impact of sex in CKD disease progression. Electronic databases, PubMed, EMBASE, Google Scholar, and Web of Science were searched from inception, using Mesh terms in English for sex differences in the pharmacokinetics of drugs in children with CKD. No studies have documented sex-related differences in the pharmacokinetics of drugs for the treatment of CKD in children. As a consequence, it is difficult to predict the effect of sex on pharmacokinetics by extrapolating data from adult studies to children. Evidence to date suggests that girls generally have a higher prevalence and disease progression of CKD when compared to boys regardless of age. Understanding the pharmacokinetics and pharmacodynamics of drugs provides practical consideration for dosing optimal medication regimens. Future kinetic studies are needed evaluating the effect of sex on the pharmacokinetics and pharmacodynamics of drugs in children with CKD.

Purpose: Statin therapy is widely used for the management of dyslipidemia and the prevention of cardiovascular diseases (CVDs). However, there is a growing concern about its potential effects on bone metabolism markers and mineral density. The aim of this systematic review and meta-analysis was to investigate the effect of statin therapy on these parameters.

Methods: PubMed/MEDLINE, Scopus, and Clarivate Analytics Web of Science databases were searched from inception to August 2023, using MESH terms and keywords.

Results: After screening 2450 articles, 16 studies that met the inclusion criteria were included, of which 12 randomized controlled trials (RCTs) were used for meta-analysis. The findings showed that statin therapy significantly reduced bone-specific alkaline phosphatase (B-ALP) levels (WMD=-1.1 U/L; 95% CI -2.2 to -0.07; P=0.03; I²=0%,), and bone mineral density (BMD) at different sites (WMD=-0.06 g/cm²; 95% CI -0.08 to -0.04; P<0.001; I²=97.7%, P<0.001). However, this treatment did not have a significant effect on osteocalcin, serum C-terminal peptide of type I collagen (S-CTx), serum N-telopeptides of type I collagen (NTx) concentration, or overall fracture risk.

Conclusion: This systematic review and meta-analysis provide evidence that statin therapy is associated with a significant reduction in B-ALP levels and BMD at different sites of the skeleton. Further studies are needed to investigate the long-term effects of statin therapy on bone health and to identify the potential underlying mechanisms.

Purpose: The HLF and HuH-6 cell lines represent hepatocellular carcinoma (HCC) with different characteristics in chromosome content that may give different drug responses. Here, PGV-1 was intended to challenge the growth-suppressing effect on HLF and HuH-6 and trace the molecular target mechanism of action compared to sorafenib.

Methods: We applied MTT cytotoxic assay, colony forming assay, flow cytometry analysis, immunofluorescence assay and western blot assay.

Results: PGV-1 exhibited cytotoxic effects on HLF and HuH-6 with IC-50 values of 1 µM and 2 µM, respectively, whereas sorafenib showed less cytotoxicity with IC-50 values of 5 µM and 8 µM respectively. PGV-1 suppressed the cell growth permanently but not for sorafenib. Sorafenib did not change the cell cycle profiles on both cells, but PGV-1 arrested the cells at G2/M with the characteristic of senescent cells and mitotic disarrangement. PGV-1 and sorafenib showed the same effect in downregulating p-EGFR, indicating that both compounds have the same target on EGFR activation or as Tyrosine kinase inhibitors. PGV-1 suppressed the MYCN expression in HuH-6 and HLF cells but stabilized cMYC-T58 indicating that even though the MYCN was downregulated, the cells maintained the active form of cMYC. In this regard, PGV-1 also stabilized the expression of PLK-1 and AurA.

Conclusion: PGV-1 elicits stronger cytotoxic properties compared to sorafenib. The lower the MYCN expression, the higher the cytotoxic effect of PGV-1. PGV-1 abrogates cell cycle progression of both cells in mitosis through EGFR inhibition and stabilizes PLK-1 and AurA in correlation with the suppression of MYCN expression.

Premature ovarian failure (POF), is a condition characterized by the early decline of ovulation function. POF is a complex disorder that can be caused by various factors, and the idiopathic form represents a significant proportion of POF patients. Hormone replacement therapy (HRT) is currently considered the first-line treatment for POF. This review aims to provide a comprehensive overview of recent advancements in platelet-rich plasma (PRP), in vitro activation (IVA), stem cell therapy, exosome therapy, microRNAs, and mitochondrial targeting therapies as a promising cell-free therapeutic approach in reproductive medicine. PLT-Exos, a new generation of cells, has been used to treat POF for more than a decade and has been shown to attenuate oocyte morphology and promote the differentiation of theca cells through the upregulation of PI3K/Akt and Bcl2, as well as the downregulation of the Smad and Bax signaling pathways. This review summarizes the current state of the art in the field of PLT-Exos and discusses the advantages and limitations of their potential clinical applications.