Frontiers in Pharmacology最新文献

Introduction: The clinical safety and potential benefits of renin-angiotensin-aldosterone system (RAAS) inhibitors in COVID-19 remain debated, particularly in critically ill populations. Evidence on combined angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy is limited, and the potential interaction with acid-base status has not been sufficiently explored.

Methods: We conducted a retrospective cohort study including adults with PCR-confirmed COVID-19 admitted to the intensive care unit (ICU) at Hospital Dr. Gustavo Fricke (Chile) between March 2020 and December 2021. Patients were categorized according to RAAS therapy at admission (none, ACEI only, ARB only, ACEI + ARB) and arterial bicarbonate (HCO₃ ^-) levels (low <21 mEq/L, normal 21-27 mEq/L, high >27 mEq/L). Changes in HCO₃ ^- during the first 48 h were evaluated. The primary outcome was in-hospital mortality; secondary outcomes included ICU length of stay and duration of mechanical ventilation. Group comparisons used chi-square and non-parametric tests.

Results: Of 2,838 hospitalized patients, 671 required ICU admission and 655 had complete data for analysis. Overall ICU mortality was 34.2%. Combined ACEI + ARB therapy was associated with lower mortality (16.9%) compared with no RAAS blockade (38.3%; p < 0.05), whereas ACEI or ARB monotherapy showed no significant association. Among patients with low or normal admission HCO₃ ^- levels, early increases within 48 h were associated with reduced mortality. Patients with elevated baseline HCO₃ ^- who survived experienced longer ICU stays and prolonged mechanical ventilation.

Discussion: In this observational ICU cohort, dual RAAS blockade was associated with lower in-hospital mortality, although causal inference is limited by the retrospective design and incomplete pharmacologic exposure data. Early bicarbonate increase may reflect renal adaptive capacity and has potential prognostic value. Prospective controlled studies are needed to clarify the clinical relevance of RAAS modulation and metabolic biomarkers in severe COVID-19.

Uncaria rhynchophylla (Miq.) Jacks. (UR), a climbing shrub of the Rubiaceae family, has been a foundational remedy in traditional Chinese medicine for over 1,500 years, and has long been used to treat neurological disorders, hypertension, and inflammatory conditions associated with "Liver Wind" and "Liver Yang Rising." This review summarizes traditional ethnopharmacological knowledge by integrating it with scientific evidence related to UR's chemical composition, pharmacological mechanisms, and therapeutic potential. This systematic narrative review analyzed 78 studies from databases including PubMed, Web of Science, Scopus, CNKI, and Wanfang (2000-2025), focusing on peer-reviewed articles on UR's phytochemistry, pharmacology, and pharmacokinetics. The plant primarily contains monoterpenoid indole alkaloids, triterpenoids, flavonoids, and phenolics. Preclinical studies have demonstrated potential neuroprotective effects against Alzheimer's disease, Parkinson's disease, epilepsy, and depression, though these are largely limited to in vitro and rodent models with methodological flaws such as small sample sizes and lack of blinding. Its antihypertensive effects involve calcium channel antagonism and nitric oxide-mediated vasodilation, while its immunomodulatory, antiviral, and anti-inflammatory effects further extend its therapeutic scope. Pharmacokinetic studies show poor oral bioavailability due to first-pass metabolism via CYP3A4, as well as stereoselective elimination. Despite some evidence linking traditional applications to modern pharmacology, major challenges remain, including difficulties in standardization, poor bioavailability, and a lack of clinical validation. Prioritizing large-scale clinical studies, development of combined formulations, and identification of biomarkers will help advance UR into the realm of evidence-based therapeutics, addressing unmet needs in neurodegenerative and cardiovascular diseases.

Introduction: Although the use of analgesics is generally not recommended during pregnancy, several studies have reported a high prevalence of use among pregnant women. In this study, we assessed the prevalence of early pregnancy use of analgesics in a Brazilian population, as well as potential sociodemographic and lifestyle predictors.

Methods: Pregnant women up to 16 weeks of gestation (N = 275) were recruited in Curitiba, Brazil, and specifically asked about the use of paracetamol, dipyrone, ibuprofen, acetylsalicylic acid, and diclofenac, including common brand names and indications.

Results: The consumption of any analgesic up to the point of recruitment was reported by 61.5% of women, most commonly for the treatment of headaches. Paracetamol was the most used analgesic (55.3%), followed by dipyrone (13.5%) and ibuprofen (12%), and the use of more than one analgesic was reported by 18.5% of participants. The self-reported health status was a significant predictor. Women reporting fair/poor health were more likely to use any analgesic and paracetamol than those who reported good/excellent health status (OR = 3.05; 95% CI = 1.44-6.50). Among paracetamol users, women reporting the consumption of paracetamol and other analgesics ingested more paracetamol pills than those participants who reported the use of paracetamol-only. Similarly, the use of pharmaceuticals other than analgesics was also positively associated with the heavy use of paracetamol (OR = 3.70; 95% CI = 1.08-12.74).

Discussion: Overall, the high prevalence of analgesic use during early pregnancy, particularly paracetamol and the combination of different analgesics, highlights the need for further research across different global regions and their potential implications for maternal and fetal health.

[This corrects the article DOI: 10.3389/fphar.2026.1728183.].

Pathological scarring, a fibroproliferative disorder, imposes a substantial burden on affected individuals. This review explores the pivotal role of the local cutaneous renin-angiotensin system (RAS) in the pathogenesis of pathological scarring. We summarize evidence demonstrating how the pro-fibrotic angiotensin II/angiotensin II type 1 receptor (Ang II/AT1R) axis drives scar formation by promoting fibroblast proliferation, inflammation, and excessive extracellular matrix (ECM) deposition. Concurrently, we examine the interactions between RAS and other fibrotic pathways, as well as inflammation and reactive oxygen species (ROS). Importantly, the review highlights the significant therapeutic potential of targeting this pathway with RAS inhibitors-specifically angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)-particularly in topical formulations. We also outline recent advances in next-generation RAS therapies. Finally, we summarize current limitations and challenges in clinical translation, emphasizing the need for advanced clinical trials and precision medicine strategies to facilitate its clinical adoption.

Psoriasis is a chronic inflammatory skin disorder driven by dysregulation of the Treg/Th17 axis, where enhanced Th17 activity promotes keratinocyte proliferation and inflammation, while impaired Treg function exacerbates immune dysregulation. Emerging evidence highlights peroxisome proliferator-activated receptor γ (PPARγ) as a key regulator of fatty acid oxidation (FAO), a metabolic pathway critical for Treg differentiation and function. PPARγ activation enhances FAO via upregulation of CD36, CPT1, and AMPK signaling, while suppressing glycolysis, thereby skewing the Treg/Th17 balance toward immune tolerance. Concurrently, short-chain fatty acids (SCFAs), microbial metabolites with immunomodulatory properties. ameliorate psoriatic inflammation by promoting Treg expansion, inhibiting Th17 polarization, and modulating innate immune cells (neutrophils, dendritic cells, and macrophages). SCFAs exert their effects through receptor-dependent signaling and epigenetic mechanisms (HDAC inhibition), while derivative compounds and probiotic interventions enhance therapeutic potential. This review summarizes mechanistic insights into PPARγ-driven FAO and SCFA-mediated immunomodulation, proposing novel metabolic and microbiome-targeted strategies for psoriasis treatment.

Background: Locally advanced cervical cancer (LACC) remains a leading cause of cancer-related morbidity and mortality, especially in low- and middle-income countries. While concurrent chemoradiotherapy (CCRT) is the standard of care for LACC, recurrence rates remain high, and the survival outcomes are suboptimal. Recent studies have suggested that immune checkpoint inhibitors (ICIs), such as pembrolizumab and durvalumab, could enhance the therapeutic efficacy of CCRT in LACC patients.

Objective: This systematic review and meta-analysis aim to evaluate the efficacy and safety of ICIs in combination with CCRT for patients with LACC.

Methods: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Cochrane Library from inception to November 2025. Randomized controlled trials (RCTs) and prospective cohort studies assessing the use of ICIs (pembrolizumab, durvalumab, atezolizumab) combined with CCRT for LACC were included. Outcomes analyzed included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), complete response (CR), and treatment-related adverse events (AEs).

Results: Data from five studies involving 1,987 patients were pooled. The addition of ICIs to CCRT significantly improved PFS (HR = 0.76, 95% CI: 0.64-0.91) and ORR (OR = 1.28, 95% CI: 1.06-1.56). Although the CR rate showed an improving trend, it did not reach statistical significance. Immune-related AEs (irAEs) were more common with ICI use (OR = 3.00, 95% CI: 1.68-5.34), but they were generally manageable. Severe irAEs leading to treatment discontinuation occurred in 5%-7% of patients.

Conclusion: This meta-analysis supports the combination of ICIs with CCRT as an effective treatment strategy for LACC, improving PFS and ORR without a significant increase in severe toxicity. However, further studies with mature OS data and exploration of optimal ICI timing are warranted.

Objective: This study aimed to validate and characterize the efficacy of a previously developed anticoagulant-free, single soft-spin centrifugation device for the preparation of autologous fluid-Platelet-Rich Fibrin (f-PRF).

Introduction: f-PRF is generated via one-step soft-spin centrifugation of all blood to produce a platelet-enriched plasma for regenerative medicine use, without the need for additional chemical agents. This study validated the performance of a novel single soft-spin f-PRF preparation system.

Methods: Sixteen healthy volunteers (94% female, ages 23-52) donated blood for a comparative analysis between Exprecell™ and Arthrex ACP^® Double-Syringe systems. f-PRF was prepared using standardized centrifugation (420xg, 5 min) and characterized for cellular composition, platelet function, growth factors, and extracellular vesicles (EVs). Platelet activation was assessed via P-selectin expression and GPIIb/IIIa activation following stimulation using flow cytometry.

Results: Exprecell™ yielded 20% more f-PRF volume (6.5-10.5 vs. 5.5-9.0 mL) with excellent cellular depletion (>99% erythrocyte, >95% leukocyte reduction). Platelet counts and function were similar between systems, with preserved in vitro agonist responses in terms of P-selectin expression and GPIIb/IIIa activation. Most growth factors remained below detection limits, and those detectable showed no differences between the devices. EV profiles from different cell types were also comparable.

Conclusion: These findings support the Exprecell™ single soft-spin methodology, demonstrating that anticoagulant-free f-PRF preparation achieves functional equivalence to conventional methods while providing a statistically significant increase in volume yield and procedural simplicity. The closed system design reduces contamination risk and Luer-lock compatibility facilitates integration into clinical workflows. Maintained in vitro biological activity supports clinical utility for this innovative point-of-care f-PRF preparation device. Future studies are needed to demonstrate the clinical benefit of the f-PRF obtained.

Introduction: The development of novel anticancer agents targeting DNA replication and repair mechanisms remains a priority in leukemia therapy. In this study, newly synthesized derivatives incorporating bis-indole and pyrazolo[3,4-b]pyridine scaffolds were evaluated for their antiproliferative potential against leukemia cell lines.

Methods: The antiproliferative activity of the synthesized compounds was assessed in four cancer cell lines, including acute myeloid leukemia (MV4-11) and chronic myeloid leukemia (K562). Growth inhibition (GI₅₀) values were determined. DNA relaxation assays were performed to evaluate inhibition of topoisomerase I and IIα activities. Cell cycle distribution, apoptosis induction, and DNA damage response markers were analyzed using cellular and molecular assays. Combination studies were conducted using CHK1, ATR, and PARP-1 inhibitors.

Results: Compounds 7b, 7d, and 7e demonstrated the most potent antiproliferative activity, with GI₅₀ values below 2.5 μM in leukemic cell lines. Compound 7e exhibited notable cytotoxicity, with GI₅₀ values of 1.1 μM (MV4-11) and 2.7 μM (K562). Compounds 7b and 7e significantly inhibited topoisomerase I activity and effectively suppressed topoisomerase IIα-mediated DNA relaxation. Cellular studies revealed S-phase cell cycle arrest, activation of apoptotic pathways (caspase cleavage and PARP-1 degradation), and induction of DNA damage response markers (γH2AX, p-CHK1, p53). In MV4-11 cells, combination treatment with CHK1 or ATR inhibitors resulted in pronounced synergistic cytotoxicity, whereas co-treatment with a PARP-1 inhibitor produced minimal synergy.

Discussion: These findings identify bis-indole and pyrazolo[3,4-b]pyridine derivatives, particularly compound 7e, as potent dual topoisomerase inhibitors with significant antileukemic activity. Their ability to induce DNA damage and enhance cytotoxicity in combination with DNA damage response inhibitors highlights their potential therapeutic value, especially in combination strategies targeting replication stress pathways in leukemia.

In the era of artificial intelligence (AI) and Industry 4.0, pilot-scale platforms for small molecule chemical drugs are undergoing a transformative digital evolution. These platforms serve as a critical link between early-stage laboratory research and full-scale pharmaceutical manufacturing, ensuring process feasibility, scalability, and regulatory compliance. This review offers a comprehensive and forward-looking analysis of the structure, function, and strategic importance of pilot-scale systems within the modern pharmaceutical landscape. Focusing on the integration of AI and intelligent automation, the study highlights innovations such as AI-driven process optimization, predictive maintenance, data integration, digital twin technologies, and continuous manufacturing. These technologies are reshaping conventional production paradigms by enhancing efficiency, improving quality control, and reducing environmental impact. The convergence of computational pharmaceutics and green chemistry is also examined as a key driver of sustainable and intelligent drug development. Moreover, the review addresses the industry's transition toward Industry 5.0, characterized by human-machine collaboration, data-centric innovation, and an emphasis on sustainability. Persistent challenges such as equipment standardization gaps, data-sharing limitations, and outdated infrastructure are critically discussed. Drawing from industrial case studies, academic research, and best practices, this paper explores both the opportunities and constraints associated with AI-enabled pilot platforms. Ultimately, the review aims to inform future strategies in digital pharmaceutical manufacturing by underscoring the importance of technological innovation, regulatory alignment, and collaborative ecosystems in advancing the development, efficiency, and sustainability of small molecule drug production.