Search Results (11,220)

Daptomycin is widely used for serious methicillin-resistant Staphylococcus aureus (MRSA) infections, but it can cause eosinophilic pneumonia, an uncommon and potentially severe adverse drug reaction. We report probable daptomycin-induced eosinophilic pneumonia (DIEP) in a 77-year-old woman receiving intravenous daptomycin with rifampin for a postoperative MRSA foot infection with concern for orthopedic-device involvement and osteomyelitis. Daptomycin had been initiated 10 days before admission, when she developed acute hypoxemic respiratory failure with bilateral ground-glass and consolidative opacities on chest computed tomography and a negative evaluation for infection. Daptomycin was discontinued on the day of admission, yet respiratory failure progressed, requiring mechanical ventilation. Bronchoalveolar lavage performed after corticosteroid exposure demonstrated eosinophilia (9%), and she improved with systemic corticosteroids and supportive care. Although she did not meet strict FDA “most likely/definite” criteria, the temporal association, compatible imaging, exclusion of alternative etiologies, abnormal lavage eosinophilia, and clinical response following drug withdrawal support “probable” DIEP criteria. Clinicians managing complex foot infections should consider DIEP when new respiratory symptoms and infiltrates develop during daptomycin therapy, even early in the treatment course and even when peripheral eosinophilia is absent or minimal. Full article

Background: Amiodarone hydrochloride is an antiarrhythmic agent, primarily classified as a Vaughan Williams Class III antiarrhythmic agent, used for the treatment and prevention of arrhythmia and designated as an essential national drug. Recently, the need to develop formulations suitable for continuous manufacturing, which is gaining significant attention in the pharmaceutical industry, has emerged. Objective: The objective of this study was to evaluate the formulation potential of amiodarone hydrochloride for the development of an oral tablet, with a specific focus on improving the initial dissolution rate to design a formulation optimized for continuous manufacturing. Methods: The primary physicochemical properties of amiodarone hydrochloride were predicted and subsequently validated through experimental characterization. Furthermore, the ratios of the binder and granulation liquid were optimized to facilitate robust and successful production via continuous manufacturing. Results: A new amiodarone hydrochloride tablet formulation, optimized for a continuous wet granulation process, was successfully developed by improving the initial dissolution rate through the optimization of the respective amounts of binder and granulation liquid. Conclusions: The optimal formulation design established in this research provides a critical foundation for enhancing the applicability of a continuous process in the manufacturing of amiodarone hydrochloride tablets. Full article

Seasonal epidemics and high variability of influenza viruses pose a severe threat to global public health security. Neuraminidase, a key functional enzyme in the life cycle of influenza viruses, represents an important target for anti-influenza drug development. Given the continuous emergence of drug-resistant strains against first-line clinical neuraminidase inhibitors (NAIs) such as oseltamivir, there is an urgent need to develop novel, broad-spectrum, and resistance-overcoming NAIs. Natural products, characterized by structural diversity and a wide range of biological activities, provide abundant resources for the discovery of new NAIs. Recent advances in computer-aided drug design, intelligent analytical platforms, and modern screening technologies have accelerated the identification of natural product-derived NAIs. In particular, biosensor-based strategies, including electrochemical, fluorescence, bioluminescence, and surface-enhanced Raman scattering biosensors, have demonstrated significant advantages in sensitivity, selectivity, rapid response, and high-throughput screening. In combination with computational methods and experimental approaches such as affinity ultrafiltration and activity-guided separation, these technologies have promoted the development of intelligent, precise, and multimodal screening platforms. Looking forward, the integration of biosensor-based high-throughput screening platforms with artificial intelligence algorithms is expected to drive the next generation of natural product screening platforms and facilitate the efficient discovery and clinical translation of novel NAIs. This paper systematically reviews the research progress of screening strategies for natural product-derived NAIs; introduces representative natural active NAIs, including phenols, terpenoids, and alkaloids; and prospects future development directions, aiming to provide a scientific reference for the efficient discovery of NAIs from natural products. Full article

Antimicrobial resistance demands intensive research on new nonantibiotics and drug repurposing to expand the arsenal of antimicrobial agents. The present work analysed the combination of diclofenac (DFNAC) and cannabidiol (CBD) and evaluated its potentiation and its biocompatibility. The formulation’s potency has been tested against Staphylococcus epidermidis (S. epidermidis), Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and P. aeruginosa. The DFNAC-CBD combination showed an evident synergistic effect, a significant decrease in the minimum inhibitory concentration against Staphylococcus epidermidis, and an additive effect against Staphylococcus aureus, indicating the levels of cooperation between the two compounds. All tested treatments exhibited MBC/MIC ratios ≤ 4, indicating bactericidal activity according to accepted interpretative criteria. Overall, the DFNAC-CBD combination accelerated bacterial killing relative to the individual compounds and exhibited a clear time-dependent antibacterial effect. The combination exhibited no antibacterial activity against Gram-negative strains such as E. coli and Pseudomonas aeruginosa. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays demonstrated that the antibacterial concentration (3.906 µg/mL) preserves cell viability and membrane integrity. Live/dead staining confirms cell viability and normal morphology. The results indicate that the DFNAC-CBD combination achieves antimicrobial efficacy through bactericidal rather than merely bacteriostatic activities and without inducing significant cytotoxicity. Therefore, the proposed DFNAC-CBD combination has significant potential as a nonantibiotic formula, which with further profile analysis can develop into formulations that can control the use and dosage of common antibiotics. Full article

Background: Bladder dysfunction is a complicated condition that substantially impairs quality of life for both men and women. Due to the adverse effects and limited efficacy of current therapies, new strategies must be rapidly developed. Female bladder dysfunction arises from multifaceted etiologies distinct from the predominantly male benign prostatic hyperplasia (BPH) that is the focus of existing drug development. In this study, we investigated the therapeutic potential of Quisqualis indica extract (QIE), a traditional medicinal herb that attenuates BPH-induced lower urinary symptoms (LUTS), to elucidate its underlying mechanisms in a female bladder dysfunction model. Methods and Results: A bladder dysfunction model was established by inducing partial bladder outlet obstruction (pBOO) in female Sprague Dawley rats, followed by the oral administration of QIE for 7 weeks. Voiding pattern analysis and cystometry were conducted to evaluate indicators such as voiding frequency, voiding volume, and intravesical pressure. Histological analysis of excised bladder tissue quantified smooth muscle hypertrophy and collagen deposition. Gene expression profiling of inflammatory cytokines and fibrosis-related markers within the bladder tissue was performed to assess tissue remodeling. Furthermore, pharmacological contraction studies examined the direct effects of QIE on detrusor muscle responsiveness to muscarinic and purinergic agonists. QIE administration significantly improved the elevated voiding pressure and abnormal inter-contraction intervals observed in the pBOO rats, restoring normal voiding patterns. Histological examination revealed a marked decrease in muscle hypertrophy and collagen deposition. Expression levels of pro-inflammatory cytokines (TNFα, IL-1β) and fibrosis-associated genes (TGF-β, α-SMA) were downregulated. Pharmacological contraction assays demonstrated that QIE attenuated the hypercontractile response of bladder smooth muscle to a muscarinic agonist, with concurrent reduced expression of muscarinic receptors (M₂, M₃) at the mRNA level. Conclusions:QIE ameliorates key aspects of bladder dysfunction, voiding abnormalities, inflammation, fibrosis, and hypercontractility by modulating muscarinic receptor signaling and fibrotic pathways. This study suggests that QIE warrants further investigation as a natural product-based therapeutic candidate for female bladder dysfunction. Full article

Objectives: The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the current treatment limitations—particularly the emergence of drug resistance and the reduced efficacy of some existing drugs against new variants—highlight the need for novel antiviral strategies with novel action mechanisms. Fusion inhibitors that disrupt six-helix bundle (6-HB) formation during viral entry represent a promising approach. Posaconazole, an antifungal agent, has been identified as a weak fusion inhibitor, but suffers from poor membrane permeability and modest activity. This study aimed to enhance its antiviral potency by conjugating it with cell-penetrating polyarginine peptides and to investigate the mechanism of action. Methods: A series of posaconazole-polyarginine conjugates were synthesized via click chemistry. Antiviral activity was evaluated using pseudotyped SARS-CoV-2 Omicron XDV in HEK293T cells. Mechanisms were investigated by circular dichroism, native PAGE, size-exclusion HPLC, molecular docking, and isothermal titration calorimetry. Metabolic stability was assessed using hepatic microsomes. Results: Posa-R8 exhibited potent antiviral activity comparable to the clinical candidate EK1, with minimal cytotoxicity. Mechanistic studies confirmed that Posa-R8 binds the HR2 region of the spike protein, disrupts 6-HB formation, and inhibits membrane fusion. It also showed strong lipid bilayer affinity and improved phase I metabolic stability over EK1. Conclusions: Polyarginine conjugation enhances the membrane-binding affinity and antiviral efficacy of posaconazole. Posa-R8 represents a promising lead for developing next-generation SARS-CoV-2 fusion inhibitors. Full article

Many species of actinomycete bacteria synthesise glycosylated polyene macrolides that have potential as antifungal drugs. The sugar residues of these compounds have profound effects on potency, toxicity and water-solubility. The medically important antibiotics amphotericin B and nystatin A1 have a single D-mycosamine sugar on C19 of the polyene macrolactone. A few naturally occurring polyenes have a second sugar residue. This may be attached to C35 of 38-membered macrolactones like nystatins or to the equivalent C27 of 30-membered pentaenes like selvamicin. The recently discovered mandimycin has a C35 disaccharide that changes the mode of action, reduces adverse side effects, and delays the emergence of resistance in laboratory cultures of fungal pathogens. Glycosyltransferases that can modify the C27 and C35 positions are of interest to synthetic biologists. The GloSV enzyme is predicted to add a 2,6-dideoxy-D-hexose to C27 of a pentaene in Saccharopolyspora gloriosae. Here we assess GloSV in strains of the amphotericin producer, Streptomyces nodosus. Low levels of new amphotericin analogues modified with D-oliose or D-digitoxose were identified through HR-LCMS. The identification of this glycosyltransferase will assist the development of streptomycete systems for production of non-toxic polyene glycoanalogues. Full article

Antimicrobial polymers are a potential and viable alternative to antibiotic therapies, whose effectiveness is increasingly compromised by the onset of antimicrobial resistance and antibiotic persistence. Antimicrobial polymers also have potential in the formulation of new drug delivery systems. Difficulties in finding new naturally derived compounds and classes of antimicrobials pose a major threat to public health and have made finding an alternative crucial. The aim of this review is to provide a comprehensive overview of the antimicrobial polymers currently available, whether of natural or synthetic origin, and to explore their use in pharmaceutical formulations, including a brief description of their preparation methods. Furthermore, a critical assessment of the advantages, limitations, and potential future developments of these systems will be presented, with particular attention to their clinical applicability, safety profiles, and role in combating antimicrobial resistance. Finally, the review highlights key challenges and future directions for the clinical translation of antimicrobial polymer-based systems, with a focus on safety, scalability, and their potential role in addressing antimicrobial resistance. Full article

Plant extracts and plant-derived bioactive compounds are considered important natural agents in cancer research due to their antiproliferative, pro-apoptotic, antioxidant, anti-inflammatory, and anti-angiogenic effects. However, the low solubility, limited bioavailability, instability, and challenges in their standardization directly limit their therapeutic use. Therefore, the development of new delivery systems has become necessary. In this context, hydrogels are among the biomaterial platforms gaining attention in cancer treatment. This review provides a comprehensive assessment of the potential of hydrogel systems containing plant extracts and plant-derived bioactive compounds in cancer treatment. The article discusses cancer types, the limitations of current treatments, mechanisms of action of plant-derived bioactive compounds against cancer, stimulus-responsive hydrogel systems, and the design criteria for extract-loaded hydrogels. In addition, hydrogel systems containing plant-derived components and combination approaches that use these components alongside anticancer drugs have been investigated. According to the literature, these compounds may increase anticancer activity through local, prolonged release, reduce the toxicity of chemotherapeutic agents in some cases, and exhibit complementary or synergistic antitumor effects with chemotherapeutic drugs. They also point out the potential of treatment strategies targeting the tumor microenvironment. However, researchers need to conduct more comprehensive studies on extraction standardization, biosafety, release kinetics, in vivo efficacy, and clinical scalability. In conclusion, hydrogel systems containing plant extracts and plant-derived bioactive compounds should be considered not as direct alternatives to cancer treatments but as rational biomaterial platforms that enable controlled release, local application, and combination therapies. 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

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

Oncology conditions are increasingly defined by their molecular profiles, and drug repurposing exploits this new evidence to identify new therapeutic uses of authorized/investigational medicinal products outside their original indication(s). This scoping review mapped original research published between January 2022 and December 2024 to determine the impact of automated processes and artificial intelligence in generating oncology candidates for drug repositioning, and 42 individual projects met the eligibility criteria and were analyzed. The included studies demonstrate extensive use of computational approaches for candidate prioritization, large-scale data integration, and hypothesis generation in oncology drug repurposing, creating opportunities for positive impact on efficiency. The included projects most commonly were target-oriented and disease-oriented and used multiple databases and computational validation procedures, while experimental and clinical validation were less frequently reported. The available open-access literature suggests substantial activity in China and India, which can support the notion that digitalization represents an important instrument in healthcare systems of low- and middle-income countries but should be interpreted cautiously. While the search was limited to PubMed and open-access English-language publications, we identified a relatively small number of drug-oriented projects, the importance of providing publicly accessible source code to reduce development costs, and the predominant role of academic institutions. Full article

Tacrolimus is an immunosuppressant drug commonly used in transplantation. Although multiple studies have demonstrated that polymorphisms in the CYP3A5 gene impact the metabolism of tacrolimus, routine pre-transplant testing for these markers is still not broadly implemented. TacroType™—a new laboratory-developed test implemented by One Lambda Laboratories—utilizes a qPCR-based six-plex assay for CYP3A5 genotyping and detects the three most common genetic variants (*3, *6 and *7) associated with loss of CYP3A5 protein function and reduced tacrolimus metabolism. TacroType was optimized to address known sources of protocol, technical or sample variability to achieve accurate and reproducible genotyping results. An analytical performance study was completed following CLSI guidelines. Accuracy was confirmed for each possible CYP3A5 genotype involving six target alleles using 32 well-characterized reference samples. TacroType exhibited accurate performance within a broad range of DNA concentrations and quality. Precision studies indicated consistent genotyping results across four operators, two instrument types and five lots of reagents. Accurate and reproducible assay performance was demonstrated using whole blood from 95 donors and buccal swabs from 65 donors. The analytical performance of TacroType was evaluated in 4014 total qPCR reactions, with a report rate of 99.8% and genotyping accuracy of 100% (95% confidence interval of 99.9%). Full article

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recently developed effective CFTR modulator drugs have substantially altered the disease trajectory of people with CF (pwCF) with access to these new therapies. Yet globally, this transformation to causal treatment remains profoundly unequal, with a substantial proportion of pathogenic CFTR variants in populations of non-European ancestry neither detectable by widely used genetic CF screening panels nor approved for or responsive to modulator therapies. This narrative review organizes the current global treatment realities along three axes: pwCF with access to CFTR modulator therapy; pwCF experiencing structural barriers in proper diagnosis and drug access; and those pwCF with biological realities not predisposing to currently approved effective CF drugs. Full article

Type 2 diabetes (T2D), a major global health challenge, represents approximately 96% of all cases of diabetes worldwide. Epidemiological forecasts indicate the prevalence of this disease could rise by almost 45% over the next 25 years. T2D is a chronic metabolic disorder characterised by insulin resistance and progressive impairment of β-cell function. Untreated T2D can lead to serious microvascular and macrovascular complications. Traditional therapies have focused primarily on glycaemic control, whereas modern treatment strategies are increasingly centred on the broader pathophysiology of T2D. Among new therapeutic approaches, triazine derivatives have gained significant attention as versatile scaffolds for the development of antidiabetic drugs. This article provides a comprehensive review of triazines (mainly 1,2,4-triazines and 1,3,5-triazines) as promising compounds for the treatment of T2D and its complications. Three databases (Scopus, PubMed, and Web of Science) were searched for the period of 2000–2025. Over the past 25 years, numerous compounds have been described. They were primarily investigated as inhibitors of digestive enzymes and factors that cause diabetic complications. The individual sections discuss the biological activity of these compounds, focusing on SAR analysis and the studies conducted (in vitro, in silico, and in vivo). During this period, two compounds, fotagliptin and imeglimin, have entered clinical use. The results show that triazines have great potential to become antidiabetic drugs. They can not only regulate blood sugar levels (by acting on digestive enzymes, insulin secretion or glucose transport) but also directly prevent serious complications of diabetes. Full article