Frontiers in Pharmacology最新文献

Background: To evaluate the efficacy and safety of clopidogrel-rivaroxaban combination compared to aspirin-rivaroxaban combination in patients with symptomatic peripheral artery disease (PAD).

Methods: Consecutive patients with symptomatic PAD patients were analyzed from January, 2018 to June, 2022 at Nanjing Drum Tower Hospital. Patients were divided into two groups based on the antithrombotic therapy. The primary efficacy outcome was a composite of major adverse cardiovascular events (MACE) and major adverse limb events (MALE), and the primary safety outcome was major bleeding. Patients were followed until the first occurrence of any outcomes or the study end date (30 June 2024).

Results: A total of 695 patients were enrolled into this study. The clopidogrel-rivaroxaban combination significantly reduced the risk of composite outcome (HR: 0.59, 95%CI: 0.41-0.83) without increasing the risk of major bleeding (HR: 0.68, 95%CI: 0.27-1.69). When analyzed separately, clopidogrel-rivaroxaban combination was associated with a reduced risk of MALE (HR: 0.61, 95%CI: 0.41-0.91), although no significant differences were observed in terms of MACE (HR: 0.64, 95%CI: 0.34-1.20) or all bleeding events (HR: 1.00, 95%CI: 0.52-1.93). In the subgroup analysis, there were no significant interactions between the treatment groups and the subgroups of age, diabetes, lesion sites, Rutherford classifications and renal function for composite outcome, MACE and MALE.

Conclusion: The clopidogrel-rivaroxaban combination in PAD patients may offer enhanced cardiovascular protection without increasing the risk of bleeding complications. These findings suggested that clopidogrel could be a superior alternative to aspirin in dual antithrombotic therapy for PAD management.

Sustained production of reactive oxygen species (ROS) and an imbalance in the antioxidant system have been implicated in the development of cardiovascular diseases (CVD), especially when combined with diabetes, hypercholesterolemia, and other metabolic disorders. Among them, NADPH oxidases (NOX), including NOX1-5, are major sources of ROS that mediate redox signaling in both physiological and pathological processes, including fibrosis, hypertrophy, and remodeling. Recent studies have demonstrated that mitochondria produce more proteins and energy in response to adverse stress, corresponding with an increase in superoxide radical anions. Novel NOX4-mediated modulatory mechanisms are considered crucial for maintaining energy metabolism homeostasis during pathological states. In this review, we integrate the latest data to elaborate on the interactions between oxidative stress and energy metabolism in various CVD, aiming to elucidate the higher incidence of CVD in individuals with metabolic disorders. Furthermore, the correlations between NOX and ferroptosis, based on energy metabolism, are preliminarily discussed. Further discoveries of these mechanisms might promote the development of novel therapeutic drugs targeting NOX and their crosstalk with energy metabolism, potentially offering efficient management strategies for CVD.

Breast cancer is the most commonly diagnosed cancer worldwide. Metal metabolism is pivotal for regulating cell fate and drug sensitivity in breast cancer. Iron and copper are essential metal ions critical for maintaining cellular function. The accumulation of iron and copper ions triggers distinct cell death pathways, known as ferroptosis and cuproptosis, respectively. Ferroptosis is characterized by iron-dependent lipid peroxidation, while cuproptosis involves copper-induced oxidative stress. They are increasingly recognized as promising targets for the development of anticancer drugs. Recently, compelling evidence demonstrated that the interplay between ferroptosis and cuproptosis plays a crucial role in regulating breast cancer progression. This review elucidates the converging pathways of ferroptosis and cuproptosis in breast cancer. Moreover, we examined the value of genes associated with ferroptosis and cuproptosis in the clinical diagnosis and treatment of breast cancer, mainly outlining the potential for a co-targeting approach. Lastly, we delve into the current challenges and limitations of this strategy. In general, this review offers an overview of the interaction between ferroptosis and cuproptosis in breast cancer, offering valuable perspectives for further research and clinical treatment.

Introduction: This study evaluated the relationship between total plasma and free kidney concentrations of amphotericin B (AmB) in healthy and C. albicans-infected Wistar rats using microdialysis and has the potential to significantly impact future research in this field and promote the development of antifungal drugs. The findings of this study, which show that plasma levels are a good predictor for AmB kidney concentrations and can be used to optimize its dosing regimen, underscore the importance of this research.

Methods: Microdialysis probe recovery rates were determined by dialysis and retrodialysis in vitro, as well as by retrodialysis in vivo. The intravenous (i.v.) administration of 2.5 × 10⁶ CFU/mL of C. albicans ATCC induced the infection. A 2.5 mg/kg i.v. bolus was used in healthy and C. albicans-infected rats (n = 6/group). Plasma and microdialysate samples were analyzed using HPLC-diode-array detection. AmB tissue penetration was analyzed using the ratio between the total plasma and kidney concentrations and population pharmacokinetics (PopPK) to assess the impact of the infection on the pharmacokinetic parameters. The chosen flow rate was set to 1.5 μL/min, and there was no statistical difference between the relative recovery values when changing AmB concentrations.

Results and discussion: The in vivo relative recovery was determined to be 10.9% ± 3.7%. The antifungal tissue penetration was 0.77 and 0.71 for the healthy and infected animals, respectively. The structural PK model with two compartments and linear elimination describes the concentration versus time profile of AmB simultaneously in the plasma and tissue. Infection by C. albicans does not interfere with AmB kidney penetration. AmB protein binding is demonstrated to be nonlinear and dependent on the AmB concentration in the plasma of healthy and infected animals.

Introduction: Follicular lymphoma (FL) is a common type of non-Hodgkin lymphoma that is incurable but often follows an indolent course. While survival is improving thanks to advances in diagnosis, supportive care, and new therapies, understanding outcomes and their impact on overall survival is still limited. There are few studies on FL in Brazil, so this study aims to evaluate the patient's profile, morbidity and mortality treated by the Brazilian national health service (SUS) and evaluate risk factors associated with treatment failure.

Methods: This is a nationwide 16 years cohort with patients that underwent chemotherapy in the SUS (2000-2015). The Kaplan-Meier method was used to estimate survival until treatment failure, and the Cox proportional hazards model was used to evaluate risk factors.

Results: The cohort included 10,009 patients and survival rates were 73.3%, 45.3%, and 30.7% for the first, fifth and 10th year respectively. The median overall survival was approximately 4.1 years. The most used regimen was CHOP (13%), followed by CVP (9.7%) and R-CHOP (3.3%). Four hundred and ninety-eight patients (4.9%) used rituximab-containing regimens. Univariate analysis indicated worse survival rates for male patients, those over 65 years of age, clinical stage III or IV and those using non-rituximab-containing regimens. The health technology performance assessment related to oncology schemes for FL suggests that rituximab-based regimens has shown best survival probability (0.52 CI 0.39-0.69) in 78 months of follow up with a HR 1.5 times better than other schemes (HR 0.67; CI 0.55-0.81).

Discussion: In light of the substantial advancements achieved by the SUS, there is a need for CONITEC to expedite decision-making processes in order to enhance patients access to new oncology drugs. This should be done while upholding health technology assessment standards. Timely integration and sufficient funding for oncology services have the potential to save lives, especially when compared to the treatments available within SUS at that time.

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and mitigating oxidative stress is crucial in managing MI. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in combating oxidative stress and facilitating cardiac remodeling post-MI. Here, we engineered Cerium oxide (CeO₂) nanoparticle-guided assemblies of ceria/Nrf2 nanocomposites to deliver Nrf2 plasmids. The CeO₂/Nrf2 nanocomposites effectively activated the Nrf2/antioxidant response element (ARE) signaling pathway both in vivo and in vitro. In a mouse MI model induced by permanent ligation of the left anterior descending artery (LAD), CeO₂/Nrf2 nanocomposites were administered via tail vein injection, predominantly targeting circulating monocytes and macrophages which will be recruited to the heart post MI due to the acute inflammatory response. We demonstrated that CeO₂/Nrf2 nanocomposites alleviated cardiac systolic dysfunction and significantly reduced infarct size and scar fibrosis post-MI. Furthermore, CeO₂/Nrf2 nanocomposites effectively mitigated MI-induced oxidative stress and downregulated Nrf2-regulated inflammatory genes (tumor necrosis factor-α, IL-6, and inducible nitric oxide synthase), thereby reducing cardiomyocyte apoptosis. These findings indicate that CeO₂/Nrf2 nanocomposites significantly enhance Nrf2 signaling activation and confer protection against MI. This study identifies CeO₂/Nrf2 nanocomposites as a promising strategy for post-MI therapy.

Background: In the past few decades, selective serotonin reuptake inhibitors (SSRIs) became widely used antidepressants worldwide. Therefore, the adverse reactions of patients after SSRI administration became a public and clinical concern. In this study, we conducted a pharmacovigilance study using the Adverse Event Reporting System (FAERS) database of the US Food and Drug Administration. Our main goal was to evaluate adverse events related to SSRIs, with a particular focus on abnormal weight gain and glucose/lipid metabolism disorders.

Method: The adverse event data for representative SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) was extracted from the FAERS database from 2004Q1 to 2023Q4. The reporting odds ratio and proportional reporting ratio were employed to explore relevant adverse event reports (ADEs) signals. Univariate logistic regression analysis was utilized to explore factors associated with glucose/lipid metabolism abnormality following SSRIs treatment.

Results: We identified 143,744 ADE reports associated with SSRIs and revealed significant abnormal signals related to weight gain and glucose/lipid metabolism in depressed patients. Variations were observed among different SSRIs medications. Specifically, citalopram was associated with abnormal weight gain (ROR: 4, 95% CI: 3.1-5.2) and hepatic steatosis (ROR: 2.8, 95% CI: 2.1-3.6); escitalopram was correlated with gestational diabetes (ROR: 9.1, 95% CI: 6.6-12.4) and cholestasis (ROR: 2.4, 95% CI: 1.75-3.38); fluoxetine was associated with obesity (ROR: 2.8, 95% CI: 2.08-3.78); fluvoxamine was linked to arteriospasm coronary (ROR: 13.87, 95% CI: 4.47-43.1); and sertraline was implicated in neonatal jaundice (ROR: 16.1, 95% CI: 12.6-20.6). Females and younger age are important risk factors for the development of associated adverse effects.

Conclusion: Our study screened for adverse effects associated with abnormal glucose/lipid metabolism, such as abnormal body weight and fatty liver, in depressed patients taking selective serotonin reuptake inhibitors by utilizing FAERS database. This provides valuable insights for healthcare professionals in accepting and managing patients treated with SSRIs.

Background: Migraine represents a chronic neurological disorder characterized by high prevalence, substantial disability rates, and significant economic burden. Its pathogenesis is complex, and there is currently no cure. The rapid progress in multi-omics technologies has provided new tools to uncover the intricate pathological mechanisms underlying migraine. This systematic review aims to synthesize the findings of multi-omics studies on migraine to further elucidate the complex mechanisms of disease onset, thereby laying a scientific foundation for identifying new therapeutic targets.

Methods: We conducted a comprehensive systematic review, specifically focusing on clinical observational studies that investigate various aspects of migraine through the integration of genomics, transcriptomics, proteomics, and metabolomics. Our search encompassed multiple databases including PubMed, EMBASE, the Web of Science Core Collection, the Cochrane Library, China National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database, the Wanfang database, and the China Biology Medicine Database to cover studies from database inception until 20 March 2024., The scope of our review included various aspects of migraine such as ictal and interictal phases; episodic or chronic migraine; menstrual-related migraine; and migraine with or without aura (PROSPERO registration number: CRD42024470268).

Results: A total of 38 studies were ultimately included, highlighting a range of genetic variations, transcriptional abnormalities, protein function alterations, and disruptions in metabolic pathways associated with migraine.These multi-omics findings underscore the pivotal roles played by mitochondrial dysfunction, inflammatory responses, and oxidative stress in the pathophysiology of migraine.

Conclusion: Multi-omics approaches provide novel perspectives and tools for comprehending the intricate pathophysiology of migraine, facilitating the identification of potential biomarkers and therapeutic targets.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=470268, identifier CRD42024470268.

Objectives: To assess the pharmacokinetics and pharmacodynamics of imipenem in a retrospective cohort of hospitalized Chinese older patients.

Methods: A population pharmacokinetic (PPK) model was constructed utilizing a nonlinear mixed-effects modeling approach. The final model underwent evaluation through bootstrap resampling and visual predictive checks. Additionally, a population pharmacokinetic and pharmacodynamic analysis was conducted employing Monte Carlo simulations to investigate the impact of commonly used dosing regimens (0.25 g every 6 h, 0.5 g every 6 h, 0.5 g every 8 h, 1 g every 6 h, 1 g every 8 h, and 1 g every 12 h) on the likelihood of achieving the target therapeutic outcomes.

Results: A total of 370 observations available from 142 patients were incorporated in the PPK model. A two-compartment PPK model with linear elimination best predicted the imipenem plasma concentrations, with the creatinine clearance as a significant covariate of clearance. Typical estimates for clearance, inter-compartmental clearance, central and peripheral volume were 13.1 L·h^-1, 11.9 L·h^-1, 11.7 L, 29.3 L, respectively.

Conclusion: The pharmacokinetics of imipenem in elderly patients were effectively characterized by the established PPK model, which includes creatinine clearance as a key covariate. This research will enhance our understanding of imipenem elimination and support precision dosing in this patient demographic.