Journal of Clinical Pharmacy and Therapeutics

Background. Perioperative neurocognitive disorders (PND) are a significant concern, particularly for aged individuals. Sleep fragmentation (SF), a common condition in older adults, is considered a risk factor for PND. The present study explored the impact of SF on cognitive function and its association with microglial activation and iron metabolism. Methods. Adult and aged C57BL/6J mice were subjected to tibial fracture surgery (TFS) and varying durations of SF. Cognitive function was assessed using the Morris water maze and fear conditioning experiments. Microglial activation was evaluated by measuring CD68 protein expression and inflammatory cytokine levels. Iron metabolism and ferroptosis-related proteins were also examined. Results. SF significantly impacted spatial memory and conditioned fear responses in mice, with aged mice showing greater susceptibility. Microglial activation, indicated by changes in CD68 protein expression and inflammatory cytokine levels, was observed in mice exposed to SF. Alterations in iron metabolism, as evidenced by changes in hippocampal iron content and expression of ferroptosis-related proteins, were also observed in these mice. Conclusion. SF can lead to significant cognitive impairment, particularly in aged mice, likely mediated through microglial activation and dysregulated iron metabolism. These findings provide novel insights into the pathogenesis of PND and suggest potential targets for intervention. Significance. This study illuminates the complex interactions between SF, microglial activation, and cognitive function. It highlights the importance of sleep quality for cognitive health in older adults and points to potential therapeutic strategies for preventing PND, including targeting microglial activation and iron metabolism.

Objective. Programmed cell death-1 (PD-1) inhibitors have shown potency for neoadjuvant therapy in several cancers, while their administration combined with concurrent chemoradiotherapy (CCRT) as a neoadjuvant therapy for locally advanced esophageal squamous-cell carcinoma (ESCC) is seldom reported. The current study aimed to investigate the pathological response, survival, and safety of neoadjuvant PD-1 inhibitor plus CCRT in locally advanced ESCC patients. Methods. Twenty-five locally advanced ESCC patients who underwent PD-1 inhibitor plus CCRT neoadjuvant therapy were retrospectively reviewed. Data regarding radiological response, pathological response, disease-free survival (DFS), overall survival (OS), and adverse events were retrieved. Results. Two (8.0%), 14 (56.0%), 9 (36.0%), and 0 (0.0%) patients had a clinical response of complete response, partial response, stable disease, and progressive disease after neoadjuvant therapy by radiological evaluations, respectively. Notably, 25 (100.0%) patients had successful tumor resections, 24 (96.0%) patients realized R0 resection, and 13 (52.0%) patients achieved pathological complete response (pCR) by pathological evaluations. Regarding survival profiles, the 1-year and 2-year accumulating DFS rates were 90.0% and 74.6%, respectively; then, the 1-year and 2-year accumulating OS rates were 95.5% and 90.4%, respectively. The top prevalent adverse events were fatigue (48.0%), nausea and vomiting (40.0%), leukopenia (36.0%), neutropenia (36.0%), and peripheral neuropathy (36.0%). In addition, grades 3-4 adverse events included peripheral neuropathy (12.0%), nausea and vomiting (4.0%), leukopenia (4.0%), neutropenia (4.0%), anemia (4.0%), and pruritus (4.0%). Conclusion. Neoadjuvant PD-1 inhibitor plus CCRT shows a good efficacy and acceptable tolerance for locally advanced ESCC treatment, but further large-scale study validation is needed.

Metformin/glipizide tablets are a compound formulation composed of metformin hydrochloride and glipizide. This study aimed to assess the pharmacokinetics and bioequivalence of two fixed-dose combination (FDC) tablets of metformin/glipizide (500 mg/2.5 mg) in healthy Chinese subjects. We conducted a single-center, open-label, randomized, two-way crossover study with a total of 48 subjects enrolled (24 in each dietary group). The test or reference formulations were given to the subjects at random at a ratio of 1 : 1, with a seven-day washout period. Blood samples, collected at prearranged intervals before and up to 24 hours after dosage, were analyzed using validated LC-MS/MS technology to ascertain plasma concentrations of metformin and glipizide. Finally, 23 subjects completed the fasting and fed studies, respectively. In both studies, the 90% confidence intervals for the geometric mean ratios (test/reference) of the , AUC_0-t, and AUC_0-∞ were all found to fall within the acceptable range for bioequivalence (80%–125%). The exposure of metformin/glipizide FDC tablets in vivo was not significantly affected by food. No serious adverse events were observed. In conclusion, this study demonstrated that both the test and reference metformin/glipizide tablets exhibited bioequivalence and were well tolerated under both fasting and fed conditions. This trial is registered with CTR202686.

Objective. To identify gender differences in the adverse events (AEs) of ketamine, reduce the AEs among patients, and contribute to the advancement of personalized medicine. Methods. A normalized dataset from 2004 Q1 to the 2022 Q4 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) was analysed. The reporting odds ratio (ROR), proportional reporting ratio (PRR), and value were used to detect the risk signals from the data in the FAERS database and quantify the presence and extent of gender differences in ketamine AEs. Results. Totally, 5,477 ketamine (female/male (2507/1795)) AE reports were analysed, and sedation (ROR 1.30 (1.07, 1.58)), suicidal ideation (ROR 1.30 (1.03, 1.64)), nausea (ROR 1.37 (1.05, 1.78)), depression (ROR 1.22 (1.13, 1.61)), dizziness (ROR 2.25 (1.78, 2.90)), anxiety (ROR 1.48 (1.09, 1.99)), and other adverse events were found to be significantly more frequent in male patients than in female patients. Conclusion. Using FAERS, we identified gender as factors associated with ketamine-related AEs. With the limitations inherent to this open data source, our data need prospective validation but elucidate potential factors for a personalized side effect profiling.

Cervical cancer significantly impacts women’s health due to its high mortality rate and increasing prevalence among younger individuals, thereby posing a severe threat. Echinatin is the primary active component of licorice in traditional Chinese medicine. However, studies on its use in cervical cancer treatment are limited. In our study, 198 targets of Echinatin were identified by some databases. Among these, 40 core targets related to cervical cancer were selected. Enrichment analyses revealed that Echinatin operated through genes associated with cell cycle, apoptosis, senescence, and various cancer-related signaling pathways. Differential expression of intersecting targets was verified in the GEO database, and molecular docking also indicated a strong binding capacity between active compounds and identified targets. Moreover, the results of western blot provided further evidence at the protein level. Echinatin hindered the proliferation, migration, and invasion of HeLa and SiHa cells while increasing their apoptosis. This study predicted the potential targets and beneficial effects of Echinatin in cervical cancer treatment, which provides a new avenue for further research into the molecular mechanisms underlying the role of Echinatin in cervical cancer treatment.

Gastrointestinal cancers account for a significant health concern as the existing treatment modalities, such as surgery, chemotherapy, and radiation therapy, exhibit considerable drawbacks, including a high probability of recurrence, insufficient drug specificity, and severe adverse effects. Hence, novel therapeutic approaches and enhanced tissue-specific targeting are required. Nanomedicine is a field of medicine that uses nanoscale carriers for targeting and administering drugs or diagnostic agents to particular tissues. In the field of nanomedicine, chitosan nanoparticles are well-established delivery technologies used as polymeric carriers. Chitosan is a natural carbohydrate that is biocompatible, biodegradable, polycationic, and mucoadhesive. Chitosan has shown promise in the administration of chemotherapeutic drugs, gene therapy, and immunotherapy for the treatment of gastrointestinal cancers. The limited water solubility of chitosan is one of its major disadvantages as a drug delivery system. Thus, solubility may be increased by chemically treating chitosan. Chitosan derivatives improve the activity, selectivity, biocompatibility, and therapeutic dose reduction of anticancer drugs when used in hydrogel, emulsion, surfactant formulations, and nanoformulation. Chitosan and its derivatives have shown effectiveness in nanoparticle production and exhibit unique surface properties, enabling them to interact selectively with gastrointestinal tumors through both active and passive targeting mechanisms. This review focuses on the molecular signaling pathways of chitosan nanoparticles and their derivatives as potential anticancer agents. The potential of future chitosan applications in gastrointestinal cancers is additionally highlighted.