OBJECTIVE:Histone deacetylase 1 (HDAC1) exacerbates ventricular remodeling and heart failure by promoting myocardial peroxidative damage. Thus, this study aimed to investigate whether the HDAC1 inhibitor mocetinostat alleviates pathological cardiac hypertrophy via suppressing ferroptosis and to elucidate the potential mechanisms involving the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. METHODS:Primary cardiomyocytes were stimulated with phenylephrine (PE) to induce hypertrophy and ferroptosis in vitro, with or without mocetinostat treatment. The Nrf2 inhibitor ML385 was used to verify pathway specificity. In vivo, a mouse model of pressure-overload-induced cardiac hypertrophy was established using a transverse aortic constriction (TAC)-induced approach. Mocetinostat was administered to evaluate its therapeutic effects. Ferroptosis markers including lipid peroxidation, iron accumulation, and levels of ferroptosis-related proteins, were assessed. The acetylation and nuclear translocation of Nrf2, as well as the expression of the associated downstream targets (Solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroportin, ferritin heavy chain 1 (FTH1), heme oxygenase-1 (HO-1)), were analyzed. RESULTS:Mocetinostat treatment significantly ameliorated PE-induced cardiomyocyte hypertrophy and ferroptosis in vitro and attenuated TAC-induced cardiac hypertrophy and fibrosis in vivo. Mechanistically, mocetinostat facilitated Nrf2 acetylation and promoted Nrf2 nuclear translocation, leading to the transcriptional activation of downstream antioxidant targets and subsequent inhibition of lipid peroxidation. The protective effects of mocetinostat were abrogated by the Nrf2 inhibitor ML385. CONCLUSION:This study demonstrates that mocetinostat attenuates pathological cardiac hypertrophy by inhibiting ferroptosis through activation of the Nrf2 pathway . These findings indicate the potential of mocetinostat as a therapeutic strategy for delaying heart failure progression.
BACKGROUND:Switching from branded to generic extended-release (ER) metoprolol formulations is common practice due to cost considerations. Although generics are approved as bioequivalent, subtle differences in formulation, such as coating composition, may influence drug release under real-life conditions across patients. OBJECTIVE:This study aimed to evaluate potential differences in drug release between the originator product Beloc-Zok 95 mg and randomly selected generic ER metoprolol succinate formulations available on the German market. METHODS:Formulations were assessed under variable, interindividual, physiologically relevant in vitro conditions simulating gastrointestinal transit. RESULTS:All formulations demonstrated controlled drug release; however, the release profiles were not fully overlapping. One generic formulation consistently exhibited slightly slower release across all test scenarios. These findings indicate that minor differences in release behavior can occur even among bioequivalent ER formulations. While such variations are generally clinically negligible, they may contribute to pharmacokinetic and pharmacodynamic differences in sensitive individuals, potentially explaining reported adverse effects such as bradycardia, hypotension, chest pain, or increased blood pressure when switching to generic products. CONCLUSIONS:The results underscore the importance of considering patient-specific variability when switching from branded to generic formulations. Incorporating physiologically relevant in vitro studies combined with physiologically based pharmacokinetic and pharmacodynamic modeling in future research may improve predictions of in vivo performance and support safer therapeutic decisions.
BACKGROUND:β-lactam allergy labels (BALs) are commonly found in patient records but are often inaccurate. This can lead to suboptimal antibiotic selection, increased healthcare costs, and antimicrobial resistance. Most existing risk assessment tools were developed in Western settings and are not applicable in Chinese clinical contexts. This study developed and pilot-tested a pharmacist-led BAL risk assessment tool tailored to the Chinese healthcare environment. METHODS:The study was conducted in three phases: (1) A systematic review of 90 studies to identify key β-lactam allergy risk factors; (2) Grounded theory and text co-occurrence analysis to extract high-risk features and construct the assessment framework; and (3) A pilot implementation in a tertiary hospital to evaluate the tool's feasibility, clinical impact, and patient outcomes using a quasi-experimental design. RESULTS:The final tool comprised eight dimensions, 35 subdimensions, and over 1328 distinct coded nodes. Of the 289 patients involved in the pilot, 18.7% were classified as high risk. Compared with patients with BALs but without high-risk features, those at lower risk had significantly shorter hospital stays (8.5 ± 4.3 vs. 10.6 ± 5.5 days; p < 0.001), reduced hospitalization costs (17,800 ± 6200 vs. 21,000 ± 7500; p = 0.0011), and lower allergy event rates (0% vs. 6.5%; p = 0.002). β-lactam use increased (75.3% vs. 40.3%; p < 0.001), whereas second-line antibiotic use decreased (24.7% vs. 59.7%; p < 0.001). The tool also demonstrated high feasibility, achieving a 100% completion rate and strong adherence among pharmacists. CONCLUSION:This pharmacist-led risk assessment tool has strong potential for accurately identifying high-risk β-lactam allergy patients and optimising antimicrobial stewardship in Chinese hospitals. Further large-scale validation is warranted.
BACKGROUND:Prophylactic opioid rescue therapy is often used to manage cancer-related pain. However, the effect of prophylactic rescue therapy in suppressing increases in breakthrough pain due to body movements has not yet been investigated. Therefore, this study aimed to compare the efficacy and safety of prophylactic rescue therapy before and after administration. METHODS:This multicenter, retrospective survey was conducted in Japan. Participants were patients with cancer who received prophylactic strong opioid rescue therapy for the first time. The primary endpoint was the suppression of an increase in pain, assessed using a Numerical Rating Scale (NRS), before and after administration of prophylactic rescue due to body movement. RESULTS:The overall analysis (193 cases) showed that prophylactic rescue suppressed the increase in the median NRS value by 3.00 (interquartile range: 1.00-4.00, p < 0.001). In addition, subgroup analysis by purpose (meals/bathing/rehabilitation/radiation therapy/others) also showed a significant reduction in the increase in NRS, with all categories exhibiting a decrease of 2.00 or more. CONCLUSIONS:Prophylactic opioid rescue with appropriate patient selection can effectively suppress breakthrough pain caused by body movement.
BACKGROUND:The placenta plays important roles in pregnancy maintenance and fetal development, and chemical-induced functional or structural abnormalities can lead to adverse pregnancy outcomes. However, information on the placental effects of chemicals remains limited. To help address this gap, this study aimed to investigate the effects of two model chemicals, phenytoin and phenobarbital, on syncytialization (the fusion of cytotrophoblasts into multinucleated syncytiotrophoblasts), a critical process in placental development, using the human choriocarcinoma cell line BeWo. METHODS:Phenytoin and phenobarbital, anticonvulsant drugs known to cause major congenital malformations, were each co-treated with forskolin, which promotes syncytialization in BeWo cells, for 48 h. RESULTS:Evaluation of cell fusion showed that phenytoin significantly suppressed forskolin-induced luciferase activity, whereas phenobarbital did not. Enzyme-linked immunosorbent assay showed that the concentration of human chorionic gonadotropin beta (hCGβ) in the cell culture supernatant was decreased in phenytoin-treated syncytialized BeWo cells but increased in phenobarbital-treated cells. Western blotting also showed a similar pattern in the hCG protein expression level. CONCLUSION:Collectively, these results indicate that phenytoin suppresses the process of syncytialization, whereas phenobarbital does not affect cell fusion and instead enhances hCG production.
