Frontiers in Pharmacology最新文献

Onasemnogene Abeparvovec (Zolgensma) is a gene therapy for the treatment of Spinal Muscular Atrophy (SMA) with improved motor neuron function and the potential for a singular treatment. Information on its adverse drug reactions is mainly from clinical trials and real-world studies with extensive sample sizes are lacking. In this study, we analyzed the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) database to assess the drug safety profile of Zolgensma. A total of 1951 adverse event reports associated with onasemnogene abeparvovec (Zolgensma), containing 778 import important medical event (IME) signals, were identified from the FAERS database, and multiple disproportionate analysis algorithms were used to determine the significance of these adverse events. This study identified 281 onasemnogene abeparvovec-related adverse events (AEs), including some significant adverse events not mentioned in the product labelling. Elevated liver enzymes, fever, vomiting, and thrombocytopenia were the most common adverse reactions. Most adverse events manifested within the initial month of onasemnogene abeparvovec use, especially the first 8 days, but some may still occur after 1 year of treatment. Sex-specific scrutiny revealed differing risk levels for adverse events among women and men. Thrombocytopenia and thrombotic microangiopathy are more common in patients weighing ≥8.5 kg, and changes in renal function need to be closely monitored if thrombotic microangiopathy occurs. The above findings provide valuable insights into optimizing the utilization of onasemnogene abeparvovec, improving its effectiveness, and minimizing potential side effects, thereby greatly facilitating its practical application in clinical settings.

Objective: This study aims to evaluate the association between the white blood cell-to-platelet ratio (WPR) and 28-day all-cause mortality among patients experiencing cardiac arrest.

Methods: Utilizing data from 748 cardiac arrest patients in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) 2.2 database, machine learning algorithms, including the Boruta feature selection method, random forest modeling, and SHAP value analysis, were applied to identify significant prognostic biomarkers. Key patient characteristics, encompassing demographic data, comorbidities, hematological and biochemical indices, and vital signs, were extracted using PostgreSQL Administration Tool (pgAdmin) software. The Cox proportional hazards model assessed the impact of WPR on mortality outcomes, while Kaplan-Meier survival curves and restricted cubic spline (RCS) analysis further validated the findings. Subgroup analyses stratified the prognostic value of WPR by demographic and clinical factors.

Results: WPR demonstrated the highest prognostic significance among the variables studied, showing a strong association with 28-day all-cause mortality. In the unadjusted Model 1, hazard ratios (HRs) for WPR quartiles ranged from 1.88 (95% CI: 1.22-2.90) in Q2 to 3.02 (95% CI: 2.04-4.47) in Q4 (Ptrend <0.05). Adjusted models (Models 2-4) confirmed the robustness of these associations, even after accounting for demographic and clinical covariates. Kaplan-Meier and RCS analyses revealed a significant U-shaped relationship between WPR and mortality risk. Subgroup analyses indicated that elevated WPR was particularly associated with increased mortality in males, elderly patients, married individuals, and those with chronic pulmonary disease.

Conclusion: WPR serves as an independent and reliable prognostic biomarker for 28-day mortality in cardiac arrest patients. Its integration into clinical decision-making may enhance the early identification of high-risk patients and guide tailored therapeutic interventions.

Purpose: The present work focused on assessing whether hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and tislelizumab was safe and effective on advanced hepatocellular carcinoma (HCC) showing high tumor burden.

Methods: In the present multicenter retrospective study, treatment-naive advanced HCC patients (BCLC stage C) showing high tumor burden (maximum diameter of intrahepatic lesion beyond 7 cm) treated with lenvatinib and tislelizumab with or without HAIC were reviewed for eligibility from June 2020 to June 2023. Baseline differences between groups were mitigated by propensity score matching (PSM). Our primary endpoint was overall survival (OS); and secondary endpoints included adverse events (AEs), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR) according to RECIST 1.1 criteria, respectively.

Results: After eligibility reviewed, total 162 patients treated with lenvatinib and tislelizumab were enrolled: 63 patients with HAIC (HTP group), and the remaining 99 patients without HAIC (TP group). After PSM 1:1, 47 cases were evenly divided into each group. Of them, HTP group showed significant prolonged median OS compared with TP group (16.6 versus 21.0 months; hazard ratio [HR]: 0.26, 95% confidence interval [CI]: 0.35-0.98; p = 0.039), and median PFS of HTP group was also prolonged (8.9 versus 11.6 months; HR: 0.55, 95% CI: 0.34-0.87; p = 0.010). Higher DCR and ORR could be observed in HTP relative to TP groups (ORR: 53.2% versus 17.0%, p < 0.001; DCR: 87.2% versus 61.7%, p = 0.004). The severe AEs (grade 3/4) and all grades were comparable between the groups, while all of these AEs could be controlled, and AEs of grade 5 were not reported.

Conclusion: HAIC combined with lenvatinib and tislelizumab is the candidate treatment for advanced HCC patients because of its improved prognosis and acceptable safety.

Herbal medicine are an invaluable reservoir of bioactive compounds, offering immense potential for novel drug development to address a wide range of diseases. Among these, Caesalpinia sappan has gained recognition for its historical medicinal applications and substantial therapeutic potential. This review explores the ethnopharmacological significance, phytochemical composition, and pharmacological properties of C. sappan, with a particular focus on its anticancer activities. Traditionally, C. sappan has been utilized for treating respiratory, gastrointestinal, and inflammatory conditions, demonstrating its broad therapeutic scope. The plant's rich array of bioactive compounds-flavonoids, triterpenoids, phenolic acids, and glycosides-forms the basis of its potent antioxidant, anti-inflammatory, and pharmacological effects. Modern pharmacological research has further substantiated its versatility, revealing anticancer, anti-diabetic, anti-infective, and hepatoprotective properties. However, significant challenges remain, including the need to unravel the precise molecular mechanisms underlying its anticancer effects, refine extraction and isolation methods for bioactive compounds, and validate its safety and efficacy through well-designed clinical trials. Particularly noteworthy is C. sappan's potential in combination therapies, where it may synergistically target multiple cancer pathways, enhance therapeutic outcomes, and mitigate adverse effects. This review synthesizes the findings from the past decade, providing a comprehensive evaluation of C. sappan's pharmacological promise while identifying critical areas for future research. By addressing these gaps, C. sappan could serve as a cornerstone for innovative therapeutic strategies, offering hope for improved management of cancer and other complex diseases.

Background: Acute lung injury (ALI) is a severe condition characterized by inflammation, tissue damage, and persistent activation of the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) pathway, which exacerbates the production of pro-inflammatory mediators and promotes the progression of ALI. Specific inhibition of this pathway has been shown to alleviate ALI symptoms. Kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside (KAE), an active compound found in the flowers of Angelica acutiloba Kitagawa, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the molecular mechanisms through which KAE regulates the cGAS-STING pathway in the context of ALI.

Methods: ALI was induced using LPS. Lung damage and anti-inflammatory/antioxidant effects were assessed by H&E staining, lung edema index, and SOD, MDA, and ELISA assays. NO release and mitochondrial membrane potential (MMP) were measured by JC-1 and Griess methods. The impact of KAE on the cGAS-STING pathway and PANoptosis was analyzed using flow cytometry, Western blot, and immunofluorescence.

Results: KAE significantly alleviated lipopolysaccharide-induced pulmonary injury by reducing inflammatory cell infiltration, alleviating pulmonary edema, enhancing antioxidant capacity, and decreasing levels of inflammatory cytokines in mouse lung tissues. In both in vitro and in vivo analyses, KAE downregulated the expression of key components of the cGAS-STING pathway, including cGAS, STING, p-TBK1, and nuclear factor-κB. KAE also reduced the assembly and activation of the PANoptosome, thereby attenuating apoptosis, necroptosis, and pyroptosis. Additionally, KAE inhibited cGAS activation by restoring the MMP, which reduced the release of cytosolic DNA.

Conclusion: KAE improve ALI by inhibiting the release of cytosolic DNA and suppressing cGAS-STING pathway activation, thereby protecting cells from PANoptosis. Our findings provide valuable insights for the development and application of novel therapeutic strategies for ALI.

Background: Neurofibromatosis type 1 (NF1) is a rare neurogenetic disorder with limited treatment options. Selumetinib, a MEK1/2 inhibitor, has emerged as a promising therapy for inoperable NF1-related plexiform neurofibromas.

Methods: Our retrospective pharmacovigilance study utilized the FDA Adverse Event Reporting System (FAERS) to comprehensively evaluate Selumetinib's safety profile in real-world settings. Data from the third quarter of 2020 to the fourth quarter of 2023 were analyzed, identifying 498 adverse event reports with Selumetinib as the primary suspect drug.

Results: Statistical analysis revealed disproportionate signals for skin and subcutaneous tissue disorders, eye disorders, and various congenital, familial, and genetic disorders. The most common adverse events were elevated blood creatine phosphokinase, rash, and acneiform dermatitis. Notably, several adverse events, including rhabdomyolysis, were identified but not listed on the Selumetinib product label, based on a comparison with the FDA drug labeling.

Conclusion: The study underscores the importance of early detection and management of adverse reactions associated with Selumetinib, particularly within the initial month of treatment. These findings provide valuable insights for clinicians and regulators to ensure the safe and effective use of Selumetinib in NF1 patients.

Radix Codonopsis (Dangshen), derived from the dried root of plants in the Campanulaceae family, is a widely used Chinese herbal medicine. It is renowned for its pharmacological effects, including tonifying the middle qi, invigorating the spleen, benefiting the lungs, enhancing immunity, and nourishing the blood. Codonopsis extract is frequently incorporated into health products such as tablets and capsules, making it accessible for daily health maintenance. Additionally, it is commonly used in dietary applications like soups, teas, and porridges to nourish qi, enrich blood, and promote overall vitality. In recent years, increasing attention has been given to the anti-cancer potential of Radix Codonopsis. Studies have identified key active components such as luteolin, stigmasterol, polyacetylenes, lobetyolin, and glycitein, which exhibit anti-tumor properties through mechanisms like inhibiting cancer cell growth and proliferation, suppressing epithelial-mesenchymal transition (EMT), and inducing apoptosis. This review highlights the research progress on Radix Codonopsis, including its active constituents, anti-cancer mechanisms, and its role in the convergence of medicine and food in modern life. By doing so, it aims to provide valuable insights and references for future scientific studies and clinical applications of Radix Codonopsis.

Background: In the Kazakh community of Xinjiang, China, fermented camel milk has been traditionally used to manage diabetes. This study evaluates the effects of composite probiotics derived from fermented camel milk (CPCM) on metabolic disturbances in a rat model of Type 2 diabetes (T2DM).

Methods: T2DM was induced in Wistar rats using streptozotocin. Experimental groups included a diabetic control, Metformin, and low- and high-dose CPCM. Measurements over 6 weeks included body weight (BW), fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), C-peptide (CP), lipid profiles, inflammatory markers, fecal short-chain fatty acids (SCFAs), and tight junction protein expression in colonic tissues.

Results: High-dose CPCM significantly increased BW by 22.2% (p < 0.05) and reduced FBG by 6.5 mmol/L (p < 0.001). The OGTT AUC decreased by 40.1% (p < 0.001), and HbA1c levels fell by 22.9% (p < 0.01). CP levels rose by 21.8% (p < 0.05). Lipid profiles improved: TC decreased by 40.0%, TG by 17.1%, and LDL-C by 30.4% (all p < 0.001). Fecal SCFAs, including acetate (75.4%, p < 0.001), methyl acetate (18.9%, p < 0.05), and butyrate (289.9%, p < 0.001), increased, with total SCFAs rising by 89.7% (p < 0.001). Inflammatory markers IL-1β (12.7%, p < 0.01), TNF-α (16.7%, p < 0.05), and IL-6 (17.3%, p < 0.01) were significantly reduced. Tight junction protein expression (ZO-1, occludin, claudin-1) and mucin (MUC2) in colonic tissues increased (p < 0.05). CPCM treatment also reduced serum total bile acids by 24.9%, while hepatic and fecal bile acids increased by 114.0% and 37.8% (all p < 0.001). CPCM lowered serum DAO, D-lactate, and LPS levels (all p < 0.001). mRNA levels of TGR5 and CYP7A1 in the liver, and TGR5 and FXR in the colon, were markedly elevated (all p < 0.001). Histological examinations revealed reduced pancreatic inflammation and hepatic steatosis, with restored colonic structure.

Conclusion: CPCM treatment significantly improved metabolic dysregulation in the T2DM rat model, reducing blood glucose and lipid levels, enhancing intestinal barrier function, and increasing insulin secretion. These findings highlight the therapeutic potential of CPCM in T2DM management and probiotics' role in metabolic health.

Objective: To explore the current research status and trends of potassium-competitive acid blockers (P-CABs) in the treatment of acid related diseases (ARDs) using bibliometric analysis.

Materials and methods: We collected publications related to P-CAB in the treatment of acid-related diseases in the Web of Science (WOS) Core Collection from the establishment of the database to 30 June 2024. We evaluated the publication volume and citation status over the years using the WOS platform, and visualized the authors, countries, institutions, keywords, and citations of the publications using CiteSpace and VOSviewer.

Results: This study included a total of 455 articles. The number of publications and citations related to research has been increasing year by year. The results show that the scholars with the highest number of publications mainly come from South Korea and Japan. Scholars such as Geun Seog Song, Bongtae Kim, and Nobuhiro Inatomi produced many works in related fields. The most popular drug in this field was vonoprazan, and research on this drug mainly focused on the effectiveness and safety evaluation of ARDs such as Helicobacter pylori infection, gastroesophageal reflux disease, peptic ulcers, etc. Researchers were concerned about the evaluation of treatment regimens and efficacy comparison between P-CABs and traditional proton pump inhibitors (PPIs) in the treatment of ARDs. At the same time, researchers are also closely monitoring the potential adverse reactions and long-term adverse outcomes of clinical application of P-CABs for ARDs.

Conclusion: The clinical application of P-CABs, represented by vonoprazan, in ARDs is receiving widespread attention from researchers. The exploration of the application of this type of drug in ARDs is constantly expanding, and it is a research field with great clinical value and research potential.

Introduction: Cigarette smoking is a well-established risk factor for renal dysfunction. Smoking associated with renal damage bears distinct physiological correlations in conditions such as diabetic nephropathy and obesity-induced glomerulopathy. However, the cellular and molecular basis of such an association remains poorly understood. High mobility group box 1(HMGB1) is a highly conserved non-histone chromatin associated protein that largely contributes to the pathogenesis of chronic inflammatory and autoimmune diseases such as sepsis, atherosclerosis, and chronic kidney diseases. Hence, the present study tested whether HMGB1 contributes to nicotine-induced podocyte injury.

Methods and results: Biochemical analysis showed that nicotine treatment significantly increased the HMGB1 expression and release compared to vehicle treated podocytes. However, prior treatment with glycyrrhizin (Gly), a HMGB1 binder, abolished the nicotine-induced HMGB1 expression and release in podocytes. Furthermore, immunofluorescent analysis showed that nicotine treatment significantly decreased the expression of podocyte functional proteins- podocin and nephrin as compared to control cells. However, prior treatment with Gly attenuated the nicotine-induced nephrin and podocin reduction. In addition, nicotine treatment significantly increased desmin expression and cell permeability compared to vehicle treated podocytes. However, prior treatment with Gly attenuated the nicotine-induced desmin expression and cell permeability. Mechanistic elucidation revealed that nicotine treatment augmented the expression of toll like receptor 4 (TLR4) and pre-treatment with Gly abolished nicotine induced TLR4 upregulation. Pharmacological inhibition of TLR4 with Resatorvid, a TLR4 specific inhibitor, also attenuated nicotine induced podocyte damage.

Conclusion: HMGB1 is one of the important mediators of nicotine-induced podocyte injury through TLR4 activation.