Drugs and Drug Candidates

Proteolytic processing of viral polyproteins by virally encoded proteases is essential for the replication of many RNA viruses, including retroviruses and coronaviruses, which are two of the best characterized model systems discussed in this review. These proteases are initially synthesized as polyprotein precursors that possess intrinsic, albeit comparatively low, catalytic activity and undergo tightly regulated autoprocessing to generate the mature enzymes required for viral replication. Accumulating evidence indicates that protease precursors are catalytically and mechanistically distinct from their mature counterparts, exhibiting unique biochemical properties and regulatory features that govern their activation. Therefore, precursor autoprocessing represents a critical checkpoint in viral maturation and an attractive, yet largely unexplored, target for antiviral intervention. This review examines the current understanding of the molecular mechanisms underlying precursor autoprocessing of HIV-1 protease and coronavirus main protease, with particular emphasis on the structural, biochemical, and regulatory features that distinguish precursor enzymes from their mature forms. It also highlights the experimental challenges associated with studying these highly dynamic and conformationally heterogeneous precursors, as well as recent advances in functional screening platforms that have enabled the discovery of proof-of-concept small molecules targeting precursor autoprocessing. Notably, several hit compounds retain activity against HIV-1 variants resistant to clinically approved protease inhibitors (PIs), while also inhibiting the wild-type strain. Together, these findings suggest that protease precursor autoprocessing may serve as a promising antiviral target and provide a conceptual framework for the development of next-generation therapeutics that complement existing mature-protease inhibitors. Full article

Background: Candida albicans can adapt to inhibition of the classical mitochondrial respiratory chain by activating an alternative oxidase (AOX)-dependent pathway, whereas Candida glabrata lacks detectable AOX-mediated respiration under the conditions tested. Identifying compounds that selectively inhibit this alternative pathway may provide new therapeutic strategies against fungal pathogens. Methodology: The antifungal activity of 5-Nitro-1,10-phenanthroline (5-Nitro-Phen) and 1,10-phenanthroline (Phen) was evaluated against C. albicans and Candida glabrata using a diffusion plate assay. Oxygen consumption was measured in intact cells before and after cyanide inhibition of Complex IV, and cyanide-resistant respiration was assessed using salicylhydroxamic acid (SHAM). Metal-chelating activity was evaluated relative to EDTA. Molecular docking was performed using SwissDock, ReverseDock, and PrankDock to predict interactions with AOX1. Results: Both compounds showed greater antifungal activity against C. albicans than C. glabrata, with C. glabrata inhibited only above 350 μM. In C. albicans, cyanide revealed a SHAM-sensitive, AOX-dependent respiratory component that was selectively inhibited by Phen and 5-Nitro-Phen. In contrast, C. glabrata showed no detectable cyanide-resistant or AOX-dependent respiration. Although Phen exhibited greater metal-chelating activity (43% relative to EDTA), both compounds showed similar AOX inhibitory potency (IC₅₀ = 2.7 and 2.9 μM, respectively). Docking predicted favorable binding to AOX1 (−7.39 to −8.395 kcal/mol), involving hydrophobic residues including Phe247, Phe251, Val254, and Phe265. Conclusion: Phen and 5-Nitro-Phen inhibit AOX-dependent respiration in C. albicans, supporting AOX as a promising antifungal target and phenanthroline derivatives as potential scaffolds for AOX-directed inhibitor development. Full article

Background: The leading cause of cancer-related deaths globally is lung cancer, and the P2X7 receptor (P2X7R) is a promising therapeutic target due to its role in the disease progression. Methods: A deep learning-based molecular generation framework that integrates a fragment-based drug method with Relational Graph Convolutional Networks (RGCNs) and a Wasserstein Generative Adversarial Network (WGAN) was employed. Known P2X7R targeting drugs were fragmented to construct a fragment library, which was used to generate new candidate molecules. The generated molecules from the model were evaluated for chemical validity, novelty, Lipinski’s Rule of Five compliance, quantitative estimate of drug-likeness (QED), lipophilicity (LogP), similarity using the Tanimoto coefficient, and binding affinity through molecular docking. Results: The model generated 4498 chemically valid molecules, including 968 unique and 384 novel molecules. Approximately 97% satisfied standard drug-likeness criteria, with QED values predominantly above 0.6 and LogP values within acceptable pharmacokinetic ranges. The novel molecules demonstrated an improved docking score against P2X7R compared to the seed molecules. Conclusions: Despite training on 5000 SMILES due to limited computational resources, the model achieved high validity, strong molecular diversity, and drug-like physicochemical properties, demonstrating the feasibility of a scalable, target-specific AI pipeline for lung cancer drug discovery using fragment-based molecular generation, RGCN and WGAN. Nevertheless, the biological activity of the generated molecules remains experimentally unvalidated, and the findings are based solely on computational analyses. Full article

The global emergence of multidrug-resistant fungal pathogens, including Candida auris, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Pneumocystis jirovecii, poses a growing threat to public health, particularly among immunocompromised individuals. The limited number of available antifungal drug classes and the rapid evolution of resistance mechanisms, including target-site mutations, efflux pump activation, biofilm formation, metabolic adaptation, and stress-response signaling, have substantially reduced treatment efficacy. This review provides a comprehensive overview of current antifungal therapies, their limitations, and emerging molecular targets for next-generation antifungal drug discovery. We highlight promising targets involved in fungal cell wall biosynthesis, membrane integrity, mitochondrial metabolism, virulence regulation, and host–pathogen interactions, emphasizing their interconnected roles within adaptive resistance networks. Attention is given to small-molecule isothiazolone-based inhibitors, including phosphoglucomutase-targeting compounds, as novel candidates capable of disrupting multiple fungal survival pathways. We further discuss advances in combination therapies, anti-virulence approaches, nanotechnology-based delivery systems, and artificial intelligence-driven drug discovery pipelines that integrate multi-omics data, structural modeling, molecular docking, and virtual screening to accelerate therapeutic development. These advances support a transition from conventional single-target strategies toward systems-level, precision-guided antifungal therapies, providing a framework for overcoming multidrug resistance and improving clinical outcomes in invasive fungal infections. Full article

Background/Objectives: This study investigated the effects of a single dose of psilocybin-containing Psilocybe cubensis extract on gut microbiota composition, microbial metabolism, and intestinal immune-related responses. Methods: A single dose of P. cubensis extract (35 mg/L) was subjected to colonic fermentation using the SHIME^® model inoculated with fecal microbiota from individuals with severe anxiety. Psilocybin and psilocin concentrations, microbial metabolites, gut microbiota composition, intestinal barrier integrity, and cytokine responses were evaluated. Results: During colonic fermentation, the concentrations of both psilocybin and psilocin decreased significantly, suggesting their metabolism or degradation within the gut microbial environment. Treatment reduced ammonia production by 19–25% and decreased gamma-aminobutyric acid (GABA) levels. By contrast, the concentrations of the short-chain fatty acids acetic, propionic, and butyric increased by 2.26-, 2.69-, and 2.21-fold, respectively, after 20 h of fermentation. Microbial profiling revealed marked increases in the relative abundances of Bifidobacterium and Lactobacillus after 20 h and 15 days, together with a slight reduction in α-diversity. Fermentation supernatants also altered cytokine profiles and influenced intestinal barrier-related responses, although these effects reflected a complex immunomodulatory pattern rather than a uniform anti-inflammatory response. Conclusions: These findings indicate that psilocybin-containing P. cubensis extract can modulate gut microbiota composition and metabolic activity under in vitro colonic conditions. The observed changes in microbial metabolites, bacterial taxa, and host-related responses support the hypothesis that gut-microbiota-mediated mechanisms may contribute to the broader biological effects of psilocybin. However, these in vitro findings do not establish clinical benefits for intestinal or mental health, and further validation in animal models and well-controlled clinical studies is required. Full article

The 33^rd Annual Conference of the Group for the Promotion of Pharmaceutical Chemistry in Academia (GP₂A), held in Nantes from 11 to 13 June 2025, marked a significant expansion of the organization’s scope and collaborative efforts. Building on the success of the previous meeting in Coimbra, the 2025 edition brought together 168 participants and featured a comprehensive scientific programme comprising 102 abstracts. A key highlight of this year’s conference was the collaboration with COST Action OneHealthdrugs and the Paul Ehrlich (PE) Euro-PhD Network, fostering interdisciplinary exchange and identifying future research synergies. The event included 1 computational workshop and 8 keynote lectures by international experts, alongside a strong emphasis on early-career researchers, with 25 oral presentations and 25 flash poster communications. In addition, 77 posters were presented across three dedicated sessions. All the presentations were eligible for 18 conference awards. Staying true to the GP₂A and PE mission, the conference provided a dynamic platform for young scientists to engage with established researchers. Full article

Background. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used treatments for mild to moderate pain and fever in pediatric patients. Notwithstanding, greater caution and awareness of their distinct safety profiles is warranted, especially in children with comorbidities. Expert opinion. Herein, expert opinion is presented on the use of these drugs in this setting. Paracetamol is suggested as first-line treatment for managing fever in pediatric patients. For pain, paracetamol is suggested for acute mild-to-moderate pain, whereas NSAIDs are preferred for pain associated with inflammatory conditions. A fixed-dose combination of paracetamol and ibuprofen may be considered for moderate pain, which allows effective analgesia while potentially reducing the risk of adverse events associated with monotherapy. Based on opinion and clinical experience, suggestions were made for pediatric patients considering a large variety of comorbidities. For example, in patients with infection/influenza, the panel concluded that paracetamol should be preferred over NSAIDs. In pediatric patients with inflammatory bowel disease, it was suggested to avoid long-term or high-dose NSAID treatment, particularly in those with active disease. In the presence of skin and soft tissue infections, it was suggested to limit the use of NSAIDs and prioritize paracetamol as first-line therapy. It was also recommended to exercise caution when using NSAIDs in pediatric patients with diabetes. Lastly, shared therapeutic flowcharts were developed that facilitate the patient journey of pediatric patients with comorbidity and fever or pain, which may help promote therapeutic appropriateness and reduce the risk of adverse events, providing practical guidance for general practitioners and pediatricians. Full article

Hypertension is a major global health concern affecting over one billion people worldwide and is a leading risk factor for cardiovascular diseases, stroke, and kidney failure. Plant-derived bioactive compounds provide promising natural strategies for hypertension management by improving endothelial function, promoting vasorelaxation and diuresis, reducing oxidative stress, and modulating key molecular pathways. This review focuses on some important traditional medicinal plants from Northeast India with potential antihypertensive activity, summarizing their phytochemical constituents, pharmacological evidence, and proposed mechanisms of action. Northeast India lies within the Eastern Himalayas and Indo-Burma biodiversity hotspots and is recognized for its rich plant diversity. We conducted a systematic literature search using PubMed, Google Scholar, ScienceDirect, and Scopus following PRISMA guidelines. We further evaluated identified compounds for ADMET using open-source computational tools. Ten medicinal plants: Clerodendrum colebrookeanum, Moringa oleifera, Garcinia dulcis, Centella asiatica, Terminalia bellirica, Hibiscus sabdariffa, Citrus limon, Passiflora edulis, Garcinia cowa, and Solanum torvum yielded 22 bioactive compounds with notable antihypertensive activity. These compounds exhibited antioxidant, anti-inflammatory, and vasorelaxant effects via nitric oxide synthase activation, MAPK/NF-κB inhibition, ACE inhibition, calcium channel modulation, and reactive oxygen species scavenging. ADMET profiling indicated favorable pharmacokinetics, with vitexin, isovitexin, isoquercetin, and nobiletin showing low predicted toxicity and high stability. Full article

Backgrounds: Astragalus membranaceus (AM), a traditional Chinese medicinal herb, has garnered interest for its potential in anticancer therapy. Preclinical evidence suggests that AM inhibits tumor growth and could mitigate the adverse effects associated with conventional treatments. However, a comprehensive review of its efficacy across various cancer types is lacking. Objectives: This systematic review evaluates the preclinical evidence for the antitumor efficacy of AM and its active components to inform future clinical translation. Methods: A systematic literature search was conducted in PubMed, EMBASE, and Web of Science from their earliest records to February 2026 to identify relevant studies. Studies reporting on the antitumor effects of AM or its constituents in murine models were included. Results: Seventy-six studies met the inclusion criteria. The most frequently investigated compounds were formononetin (21 studies), Astragaloside IV (20 studies), and Astragalus polysaccharide (16 studies). The evidence indicates that these compounds, both as monotherapies and in combination with standard chemotherapy, can inhibit tumor growth and potentiate antitumor efficacy. Conclusions: AM and its bioactive constituents exhibit promising anticancer effects against solid tumors, including breast, lung, hepatocellular, and colorectal carcinomas in preclinical models. Clinical investigation is warranted to confirm the utility of AM for cancer therapy. Full article

Background: Geraniol is an acyclic monoterpene widely distributed in the essential oils of aromatic species such as Cymbopogon citratus, Pelargonium graveolens, and Rosa damascena, It is known for its antioxidant, anti-inflammatory, neuroprotective, and antitumor activities. Methods: This study aimed to investigate, through network pharmacology and computational ADMET modeling, the molecular mechanisms and pharmacological potential of geraniol, integrating drug-likeness parameters, toxicity prediction, and multitarget interactions. Results: A total of 25 core targets were identified, mainly involved in inflammation, oxidative stress, apoptosis, and transcriptional regulation. Geraniol exhibited a favorable drug-likeness profile, high predicted intestinal absorption, and low systemic toxicity, supporting its pharmaceutical applicability. Mechanistically, it modulates the Nrf2/HO-1 ↔ NF-κB axis, reducing reactive oxygen species, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and apoptotic markers (caspases, Bax), while enhancing antioxidant enzymes (SOD, CAT, GPx) and antiapoptotic proteins (Bcl-2). Conclusions: These findings confirm its multitarget and pleiotropic nature, highlighting its potential as a therapeutic candidate for inflammatory, metabolic, and neurodegenerative disorders. Furthermore, this study provides a robust mechanistic rationale for future in vitro and in vivo validation, as well as for the design of nanostructured formulations to improve geraniol’s bioavailability and therapeutic safety. Full article

Carbapenem-resistant Acinetobacter baumannii (CRAB) is classified by the World Health Organization among the critical-priority pathogens, reflecting high mortality, near-ubiquitous nosocomial spread, and a depleted therapeutic pipeline. No antibiotic chemical class with a genuinely novel target and activity against A. baumannii reached patients for more than fifty years, and current options—sulbactam–durlobactam, cefiderocol, polymyxins, high-dose ampicillin–sulbactam and tetracyclines—are constrained by toxicity, inconsistent efficacy, or emerging resistance. Against this background, zosurabalpin (RG6006), the first member of the tethered macrocyclic peptide (MCP) class, represents a potentially important conceptual advance. Identified through whole-cell phenotypic screening of nearly 45,000 macrocyclic peptides and optimized into a zwitterionic clinical candidate, zosurabalpin inhibits the LptB₂FGC complex, the inner-membrane ATP-binding-cassette transporter that initiates lipopolysaccharide (LPS) export. By trapping LPS within the transporter, the drug causes lethal accumulation of the molecule at the inner membrane. This mechanism is structurally distinct from that of every clinically used antibiotic and, in preclinical studies, is not affected by the major currently recognized CRAB resistance mechanisms. Zosurabalpin shows potent, narrow-spectrum activity essentially restricted to the Acinetobacter baumannii–calcoaceticus complex, retaining activity in vitro against isolates resistant to cefiderocol and last-line agents; its clinical efficacy in patients, however, remains to be established. Here we review the discovery, structural mechanism, microbiological spectrum, and clinical development of zosurabalpin, and we situate it within a broader revival of pathogen-specific (narrow-spectrum) antibiotic development, discussing the diagnostic, stewardship, and economic implications of this paradigm. Full article

Drug recall is a critical regulatory mechanism implemented to protect public health by removing defective, unsafe, or non-compliant pharmaceutical products from the market. Despite stringent regulatory approval processes, issues related to manufacturing defects, contamination, labeling errors, stability failures, and post-marketing safety concerns may lead to drug recalls. Regulatory authorities across the world, including the Central Drugs Standard Control Organization (CDSCO), the United States Food and Drug Administration (US FDA), the European Medicines Agency (EMA), and other national agencies, have developed structured recall guidelines and rapid alert systems to ensure timely withdrawal of defective products. Drug recalls are typically classified based on the level of health risk and may be executed at different levels of the distribution chain, including wholesale, retail, and consumer levels. Effective recall management involves risk assessment, recall communication, product traceability, documentation, and recall effectiveness checks. Pharmacovigilance systems also play an important role in identifying adverse drug reactions and quality defects that may lead to product recalls. This review article provides a comprehensive overview of drug recall systems, including causes of recalls, regulatory frameworks in India and other countries, recall classification, recall procedures, rapid alert systems, and global recall trends. The article also discusses challenges in recall implementation and provides recommendations to strengthen drug recall systems and regulatory coordination worldwide. The review additionally summarizes major official sources of recall information, including recall alerts, safety communications, and regulatory databases maintained by the Food and Drug Administration (FDA), EMA, CDSCO, Medicines and Healthcare products Regulatory Agency (MHRA), and World Health Organization (WHO), and provides a comparative global perspective on contemporary pharmaceutical recall practices. Full article

One of the most pressing challenges facing healthcare today is the rise of biofilm infections and antibiotic-resistant bacteria, which demand entirely new therapeutic strategies beyond conventional antibiotic reliance. A biofilm is a structured community of microorganisms encased in a self-produced extracellular polymeric substance (EPS) matrix, which confers resistance to host immune defenses and antimicrobial agents. Accumulating evidence demonstrates that plant-derived secondary metabolites—including flavonoids, phenolic acids, tannins, terpenoids, and alkaloids—exert potent antibacterial and antibiofilm activities through diverse mechanisms of action. These natural compounds inhibit biofilm formation by disrupting bacterial adhesion, suppressing quorum sensing, degrading the EPS matrix, and impairing bacterial motility. Beyond independent bioactivity, phytochemicals demonstrate significant synergistic potential when combined with conventional antibiotics, revitalizing antimicrobial efficacy against drug-resistant pathogens. Nanoformulation and biogenic carrier technologies further enhance the bioavailability and therapeutic potency of these compounds. Despite these advances, critical challenges persist, including poor bioavailability, physicochemical instability, dose-dependent toxicity, and the risk of resistance development. This review presents a critical and integrative analysis of the pharmacological mechanisms of plant secondary metabolites, with particular emphasis on their role in combating biofilm-associated infections and antibiotic resistance, and discusses translational opportunities including structure–activity relationship (SAR)-guided optimization, high-throughput screening platforms, and advanced drug delivery systems. Collectively, plant secondary metabolites represent a scientifically compelling and clinically relevant pipeline for the development of next-generation antimicrobial and antibiofilm therapeutics. Full article

Background: Microbiome-oriented therapies, including fecal microbiota transplantation (FMT), phage therapy, and live biotherapeutic products (LBPs), represent a promising direction in modern biomedicine for addressing antimicrobial resistance (AMR), recurrent Clostridioides difficile infection (rCDI), and dysbiosis-associated conditions. Despite encouraging clinical outcomes, their integration into routine clinical practice remains limited due to regulatory heterogeneity and unresolved ethical challenges. Objective: This review aims to analyze international regulatory approaches to microbiome-based therapies and to identify key bioethical issues associated with their clinical application. Main content: The paper summarizes current scientific evidence and regulatory frameworks governing microbiome therapies in the United States, the European Union, Ukraine, and selected Asia-Pacific countries. Particular attention is given to differences in classification, approval pathways, and safety requirements. The review also examines major ethical concerns, including informed consent, donor screening, biosafety, data protection, and equitable access to innovative treatments. Conclusions: The analysis demonstrates that microbiome therapies have significant potential for improving clinical outcomes and supporting antimicrobial stewardship. However, their broader implementation requires the harmonization of regulatory frameworks, strengthening of biosafety standards, and development of clear ethical guidelines. International cooperation and accumulation of clinical evidence are essential for the safe and effective integration of microbiome-based interventions into healthcare systems. Full article

Background/Objectives: Course-based Undergraduate Research Experiences (CUREs) represent a form of student crowdsourcing in which individuals perform authentic discovery-based research in a class setting with interest to outside stakeholders. Here, the renowned Tiny Earth (TE) CURE is being utilized to teach microbiology and perform natural product discovery research by students in the course. Methods: In our TE CURE, students collect soil samples from their hometown and characterize bacteria that can inhibit plant and animal pathogens. This unique growing collection of isolates from across Ohio has provided opportunities to facilitate drug discovery and establish biotechnology collaborations. Results: In this study, we describe two outcomes using our environmental strain collection that initiated biotechnology collaborations and identified bacterial candidates for drug discovery. Results from one project led to a partnership with an aquaculture company. A novel biosynthetic gene cluster involved in antagonistic activity was identified, whose product inhibits Aeromonas pathogens, which cause disease in freshwater fish. The other project involves a collaboration with a global commercial cleaning and equipment company to identify lipase activity among Bacillus strains for its potential use in bioremediation. Conclusions: The unique strain collection generated by students in the CURE led to collaboration with biotechnology companies, which contributed to natural product discovery of an antimicrobial product and active enzymatic activity, all of which benefit education and scientific discovery. Full article

Obesity is a growing public health concern linked to poor dietary habits, physical inactivity, and metabolic disturbances, which can be evaluated using complementary laboratory tests. Among pharmacological interventions, semaglutide, a GLP-1 receptor agonist, has shown promise by acting on the central nervous system to reduce appetite and stimulate insulin secretion, thereby improving the lipid profile and reducing inflammation biomarkers. This review focused on changes in lipid parameters and C-reactive protein (CRP) levels in overweight or obese individuals treated with semaglutide, based on phase 3 studies from the STEP program (“Semaglutide Treatment Effect in People with Obesity”). The STEP clinical trial program was conducted across 36 countries, reflecting a broad and diverse geographic representation. Key findings include significant reductions between placebo vs. semaglutide in body weight (−1.3 vs. −13.0 Kg), body mass index (−0.69 vs. −4.72 kg/m²), and waist circumference (−2.79 × −11.81 cm). Additionally, there were notable decreases in triglycerides (−0.67 vs. −20.89%), VLDL-C (−0.99 vs. 20.82%), and CRP levels (−15.45 vs. −55.55%). These changes reflect improvements in both inflammatory and metabolic markers. The observed benefits suggest that semaglutide may contribute to reducing comorbidities associated with metabolic syndrome and to the prevention of cardiovascular disease. Current evidence also supports its potential role in individualized treatment strategies based on patients’ clinical and biochemical profiles. However, despite these promising findings, further long-term studies are required to confirm the efficacy and safety of semaglutide across diverse populations. Full article

Background/Objectives: Upper respiratory tract infections (URTIs), including common cold and influenza, remain a major global health burden, and their symptomatic management often includes the use of herbal medicines alongside conventional therapies. The aim of this study was to evaluate the real-world use of herbal medicines as drug candidates in the management of URTIs in Estonia, with a focus on differences between pharmacy customers and pharmacy professionals. Methods: A cross-sectional survey was conducted among 905 participants, including 400 pharmacy customers and 505 pharmacy professionals (pharmacists and pharmacy assistants). Standardized questionnaires were used to assess the frequency of use, perceived effectiveness, and safety considerations of commonly used herbal substances and home remedies in adults and children. Results: Herbal medicines and home remedies were widely used, reported by 68% (95% CI: 63.4–72.6%) of pharmacy customers and 71% (95% CI: 67.0–75.0%) of pharmacy professionals. The most commonly used herbal substances included lemon (79%), ginger (57%), garlic (56%), raspberry (55%), and chamomile (50%). While most respondents perceived these remedies as effective for symptom relief, notable discrepancies were observed between customer and professional assessments of efficacy. The use of several herbal substances in children did not consistently align with European Medicines Agency recommendations, highlighting potential safety concerns. The findings demonstrate that widely used herbal substances represent real-world candidates for supportive URTI management; however, their perceived effectiveness and patterns of use are not always supported by regulatory guidance or clinical evidence. These results underscore the need for further pharmacological and clinical studies, as well as improved evidence-based communication between healthcare professionals and patients. Conclusions: The results allow the identification and prioritization of herbal substances as real-world drug candidates for further pharmacological and clinical development. Full article

The therapeutic landscape for heart failure (HF), particularly in patients with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF), has historically been characterized by limited effective disease-modifying options. The recent approval of nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), specifically finerenone, represents a major paradigm shift. This review synthesizes contemporary evidence, including the landmark FINEARTS-HF trial, which demonstrated significant reductions in cardiovascular death and heart failure hospitalizations in patients with left ventricular ejection fraction (LVEF) ≥ 40%. These findings contrast with the neutral overall results and subgroup limitations observed with steroidal MRAs such as spironolactone in the TOPCAT trial. Mechanistic distinctions, cardiorenal benefits, and emerging metabolic effects of finerenone are explored alongside its complementary role with sodium–glucose cotransporter-2 (SGLT2) inhibitors. Practical considerations for implementation, including patient selection, dosing, monitoring, and combination therapy strategies, are discussed. Overall, nsMRAs establish a new foundation for the management of HFmrEF and HFpEF and represent a critical advancement in contemporary heart failure therapeutics. Full article

Background/Objectives: Achillea millefolium is a well-known plant used in traditional medicine for the treatment of inflammation, gastrointestinal disorders, respiratory diseases, hypertension, and diabetes, among others. These effects are attributed to the metabolite content of flavonoids and terpenes such as achillin (1) and leucodin (2). Thus, the current investigation aims to standardize the extracts from A. millefollium based on the presence of 1 and 2 and relate them to their relaxant effect in ex vivo assays. Methods: A validated High-Performance Liquid Chromatography (HPLC) method was used to determine the concentration of the main compounds, employing standard molecules previously isolated from the same species and characterized by nuclear magnetic resonance (NMR) and X-ray diffraction. Also, the relaxant effects of both compounds and their combinations were assayed on aortic and tracheal rat rings in an organ bath. Results: Compounds (1) and (2) are the main compounds in hexane, dichloromethane, and hydroalcoholic extracts, present in different proportions. The relaxant effects in ex vivo models of the aorta and trachea showed that the sesquiterpene lactones achillin (1) [Trachea, maximum effect (Emax): 67.67 ± 5.01%, medium effective concentration (EC50): 304.44 ± 2.61 µM; Aorta: Emax: 63.94 ± 6.28%, EC50: 225.73 ± 4.49 µM)] and leucodin (2) (Trachea: Emax: 76.71 ± 4.73%, EC50: 266.40 ± 2.05 µM; Aorta, Emax: 72.96 ± 1.73%, EC50: 163.29 ± 2.99 µM) are responsible for the relaxant effects shown by the extracts. The observed effect is proportional to the concentration of these molecules, with hexane extracts being more active. Additionally, we demonstrate the safety of molecules 1 and 2 through toxicological studies recommended by the OECD. Conclusions: The isolated compounds achillin and leucodin are the primary constituents in the flowers of A. millefolium, with higher concentrations found in hexane extracts, particularly of achillin, which shows a correlation of 2.33 with respect to leucodin. This correlation is closely related to their relaxant effect, as these compounds are the main contributors to the relaxant response in the trachea and aorta, being more effective when used together. Full article