In the present research work, graph theory has been used to represent the molecular structures of antiviral drugs corresponding to the influenza strain treatment using degree-based topological descriptors and Laplacian energy to understand their structural and physicochemical behavior. The graph theory-based descriptors are used to construct the quantitative structure property relationship and provide input to an ANN model used to predict various physicochemical properties among the selected antiviral drugs. The comparison shows that the ANN model outperforms the Linear Regression model by demonstrating higher R2 and lower RMSE. The suggested ANN-QSPR model was verified through the 5-fold cross-validation process, showing high prediction efficiency and better robustness regarding various physicochemical properties of antiviral compounds. Moreover, an MCDM approach using the TOPSIS method has been employed to assess and rank the antiviral drugs using both structural and physicochemical aspects. The integrated framework in the present research work offers a comprehensive mathematical and computational platform to perform drug analysis and decision-making in antiviral drug design tasks.
Hospitalization provides an opportunity to improve the Hepatitis C Virus (HCV) cascade of care among people who inject drugs. Little is known about whether this potential opportunity is utilized. We conducted a retrospective chart review at four U.S. academic medical centers among patients hospitalized between 1/1/2018-3/31/2022 with ICD-10 diagnosis codes for both opioid use disorder and acute bacterial or fungal infection. Electronic medical records were reviewed manually to confirm injection drug use-related infection for inclusion in the study. Data abstracted from medical records included baseline HCV status at the time of admission; whether HCV antibody screening and confirmatory viral load testing were performed during hospitalization, and their results; follow up for HCV treatment within the same medical system after discharge; and response to treatment. A total of 1651 patients were included. Seventy-five percent of patients with unknown HCV status at the time of admission were screened for HCV during hospitalization, of whom 66% screened positive. Of those with a confirmatory ribonucleic acid (RNA) test, 62% had a detectable viral load (VL). Seventeen percent of those with detectable VL attended a follow up appointment within 12 months. Fifty-five percent of patients with known prior HCV infection were RNA tested, and 65% of those tested had detectable virus. Results revealed sizeable attrition along the entire HCV cascade of care and missed opportunities to engage people who inject drugs in follow up during hospitalization for other infections. Hospitalized individuals who inject drugs need targeted interventions to improve HCV screening, diagnosis, and care linkage.
This study aimed to establish a novel in vitro model by combining jejunal stem cells from commercially available cryopreserved human intestinal mucosal epithelium (CHIM), which can be used without ethical concerns, with 96-well Vitrigel inserts for high-throughput screening. Jejunal stem cells were successfully isolated from CHIM, and stable long-term expansion in spheroid culture was achieved. The differentiated cells exhibited mRNA expression and function of major pharmacokinetic-related genes. Comparable metabolic and transport activities were maintained even with 96-well Vitrigel inserts instead of the conventional 24-well culture inserts. In a 96-well transcellular transport assay, a significant correlation was observed between the in vitro Papp values and the reported FaFg values (the fraction of orally administered drugs reaching the portal vein) in humans for 10 compounds known to be primarily absorbed via passive diffusion, allowing us to construct a fitting curve. Applying this curve, the FaFg values of transporter substrates could also be estimated with reasonably high accuracy. Furthermore, to estimate human Fg values (the fraction of orally administered drugs escaping from intestinal metabolism), we assessed 5 compounds known to be metabolized by intestinal enzymes. Their predicted Fg values closely matched the reported Fg ones, indicating that our cell model enables their accurate prediction. These findings suggest that a combination of CHIM-derived jejunal stem cells and 96-well Vitrigel inserts provides a practical in vitro model for the quantitative prediction of human intestinal absorption of orally administered drugs. SIGNIFICANCE STATEMENT: In this study, we demonstrated that a combination of commercially available cryopreserved human intestinal mucosal epithelium-derived intestinal stem cells, whose use is free from ethical concerns and restricted tissue availability, and 96-well Vitrigel inserts enables a high-throughput assay that quantitatively predicts human intestinal absorption with high accuracy.
Acute bipolar depression poses a significant burden and socioeconomic costs. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar depression, considering dose effects across different age groups. We conducted a network meta-analysis (NMA), searching for randomized controlled trials (RCTs) comparing pharmacological interventions against each other/or placebo in patients with acute bipolar depression (Type-I/Type-II/other), indexed in PubMed/MEDLINE, Embase, Web-of-Science/and Scopus (database inception up to 2025.11.25). Co-primary outcomes were change in depressive symptoms/response/and acceptability. Tolerability/remission/change in anxious symptoms/and risk-of-manic/hypomanic switches were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. 103 RCTs, encompassing 71 distinct treatment combinations, included 20,941 participants. Sensitivity analysis including low-risk-of-bias studies only and excluding outliers for possible effect modifiers indicated that lamotrigine 50 mg/day or 200 mg/day, quetiapine extended-release 150 mg/day and 300 mg/day, and lumateperone 42 mg/day outperformed placebo for depressive symptoms, with estimates ranging from -1.53(95%C.I. = -2.13;-0.93) for lamotrigine 50 mg/day, to -0.36(95%C.I. = -0.68;-0.04) for lumateperone 42 mg/day. Several additional drugs might be efficacious, although they emerged as outliers for either mean age of participants/proportion of females/BD-II participants/psychotic features/rapid cycling/baseline severity of depression/and trial duration. No treatment outperformed placebo for response/remission/acceptability/tolerability/and manic/hypomanic switches. Our findings are consistent with previous NMAs and current guidelines, thereby expanding knowledge by concurrently appraising different drugs, doses, and age groups.
Mfd, the canonical bacterial transcription-repair coupling factor, is a highly conserved ATP-dependent DNA translocase with a complex architecture undergoing major rearrangements during its functional cycle. These changes regulate its ATPase and motor activities and are tuned by Mfd interactions with DNA, RNA polymerase and the UvrA subunit of the nucleotide excision repair excinuclease, Uvr(A)BC. Due to its role in accelerating molecular evolution and the development of antibiotic resistance, Mfd is also rapidly emerging as a prime target for the development of anti-evolution drugs to be administered in combination with narrow-spectrum antibiotics to prevent the rise of resistance and combat infection over a wider time window. Here we present the crystal structure of Thermus thermophilus Mfd in its nucleotide-free state. We note the pronounced disorder of the N-terminal UvrB homology module, which was previously seen in Escherichia coli to be engaged in a "clamp" interaction with the C-terminal domain, resulting in autoinhibition of its ATP-dependent functions. Thus, we conclude that the autoinhibitory interdomain interactions, such as the clamp, are not a universal feature of transcription-repair coupling factors. Consistent with this, Thermus thermophilus Mfd, unlike E. coli Mfd, translocates robustly on DNA even in the absence of RNA polymerase and displays DNA binding that is largely nucleotide independent. Our work brings mechanistic insight into the species-specific differences in Mfd structure and function and provides a structural framework for the design of anti-evolution drugs to combat antimicrobial resistance.
Research is needed to establish optimal cutoffs to determine cocaine use via oral fluid testing while considering the possibility of unintentional exposure. We compared detection of cocaine and its metabolites to self-reported use while considering other drug use to determine optimal cutoffs to determine intentional use. In this study, 1819 adults entering randomly selected nightclubs were surveyed about cocaine and other drug use and had their oral fluid analyzed using liquid chromatography quadrupole time-of-flight mass spectrometry. We compared self-reported use to detected exposure. 13.6% of participants reported past 24-hour cocaine use, 43.7% tested positive for cocaine exposure (≥1 ng/mL), and 11.8% tested positive for at least one metabolite. 28.6% either tested positive for or reported past 24-hour use of other drugs, primarily ketamine. Among those testing positive for cocaine exposure (n = 794), only 29.1% reported past 24-hour use. Among positive cases, the optimal cocaine concentration cut-point for predicting self-report was ≥ 26 ng/mL. When focusing on the full sample and a subsample with data on past 48-hour reported use, optimal cut-points were ≥ 6 ng/mL and ≥ 5 ng/mL, respectively. However, detection of metabolites was the strongest predictor of self-reported use. Using self-report as the gold standard, metabolite detection most accurately classified reported use, over and above detection of cocaine or other drugs; however, relying solely on detection of metabolites or higher cocaine concentration thresholds often led to under-detection. In conclusion, relying on detection of metabolites or higher concentrations most accurately detects intentional use, but these lack sensitivity to detect a portion of use.
The risk of drug overdose and disease acquisition is highly elevated for those recently initiated into injecting drug use. Despite this, there are few harm reduction interventions developed specifically for new initiates. Further, international technical documents have historically provided little guidance on how to appropriately meet the needs of what is an inexperienced and difficult to engage sub-population. However, the recently updated operational guide for Needle and Syringe Programmes for People Who Inject Drugs from the World Health Organization (WHO), stresses that reaching new initiates requires "tailored, inclusive approaches". In this commentary, we leverage the updated WHO guide to call for renewed focus on new initiates and the development of tailored harm reduction interventions. We describe our recent experiences co-designing interventions for new initiates in Kachin, Myanmar as a case study for how such work may proceed. Finally, we make two key recommendations; 1) that an accepted international definition of new initiates be developed that accounts for risk and opportunity to engage, and 2) that more explicit highlighting and technical guidance on targeting new initiates is made in international documentation. Engaging people who inject drugs as soon as possible after initiation, when vulnerability to blood-borne infections and overdose is greatest, will likely maximise the preventive impact of tailored interventions, thereby providing enduring harm reduction outcomes across injecting careers. The updated WHO guide is the perfect time to re-frame this conversation and re-focus these efforts.
Neuropathic pain is considered the most difficult to manage, with many patients getting inadequate relief from the current pharmacotherapy. While many drugs have been added to the regimen, Lacosamide has emerged as a promising therapeutic option. This systematic review focuses on the efficacy and safety of lacosamide in adult patients with neuropathic pain. Databases such as PubMed, Embase, Scopus, Web of Science, and Cochrane were searched thoroughly for Randomized Controlled Trials (RCTs) published in English through November 2025. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in the included studies. Eight RCTs involving 976 participants with different neuropathic pain conditions met the inclusion criteria. Across the included studies, Lacosamide (200-600 mg/day) provided a modest reduction in their pain scores. However, it didn't have much of a positive impact on quality of life, limited function, adverse effects were common, and a high dropout rate was observed in several trials. Lacosamide might provide a modest analgesic benefit across multiple neuropathic conditions. But its extensive, long-term use requires more research to confirm its benefits, particularly the optimum dosing protocols.
Objective: To construct a reverse genetic system for the genotype ON1 of human respiratory syncytial virus subtype A (HRSV-A) expressing fluorescent reporter genes. Methods: Recombinant plasmids encoding EGFP or mCherry were constructed based on the 2019 Beijing HRSV-A ON1 dominant strain (6914). Recombinant viruses, rescued by co-transfecting BSR/T7-9 cells with helper plasmids, were identified via indirect immunofluorescence, whole-genome sequencing, and Western blot. Biological properties were characterized through fluorescent quantitative RT-PCR (qRT-PCR), immunostaining plaque assay and fluorescent focus assays (FFA). Results: Two recombinant viruses expressing EGFP or mCherry (rRSVA6914-EGFP and rRSVA6914-mCherry) were successfully rescued. Western blot analysis confirmed that the expression levels of key structural proteins (G, F, and N) in the recombinant strains were consistent with the parental virus. Multistep growth curve analysis revealed that the replication kinetics of the two recombinant viruses in HEp-2 cells did not differ significantly from those of the parental strain. Two recombinant viruses exhibited substantial neutralizing activity against both palivizumab and nirsevimab used in clinical settings. Furthermore, the viral titer of rRSVA6914-mCherry in A549 cells [(1.19±0.05)×105 PFU/ml] was significantly higher than in HEp-2 cells [(7.60±0.79)×104 PFU/ml] (P<0.001). For rRSVA6914-EGFP, the viral titers determined by immunostaining plaque assay and FFA methods were (1.15±0.17)×105 PFU/ml and (1.36±0.19)×105 FFU/ml. For rRSVA6914-mCherry, the corresponding titers were (3.50±0.23)×104 PFU/ml and (3.37±0.07)×104 FFU/ml. There was no statistically significant difference between the immunostaining plaque assay and FFA methods (both P>0.05). Conclusion: The HRSV-A genotype ON1 reverse genetic system expressing fluorescent reporter genes has been successfully constructed and systematically verified, providing a scientific tool for investigating the pathogenic mechanism of genotype ON1 and for screening antiviral drugs. 目的： 构建携带荧光报告基因的人呼吸道合胞病毒A亚型（HRSV-A）ON1基因型反向遗传学系统。 方法： 利用2019年北京地区分离的HRSV-A优势流行株ON1基因型6914株，构建携带增强型绿色荧光蛋白（EGFP）或红色荧光蛋白（mCherry）报告基因的重组质粒。通过与辅助质粒共转染至BSR/T7-9细胞拯救重组病毒；利用间接免疫荧光、全基因组测序、Western blot等方法鉴定病毒；基于荧光定量RT-PCR、免疫染色空斑试验及荧光灶形成试验（FFA）评价其生物学特性。 结果： 成功拯救出携带EGFP或mCherry报告基因的两株重组病毒（rRSVA6914-EGFP与rRSVA6914-mCherry）。Western blot证实重组病毒关键结构蛋白（G、F、N）表达水平与亲本株一致。多步生长曲线分析显示，两株重组病毒在HEp-2细胞中的复制动力学与亲本株基本一致。重组病毒对临床使用的帕丽珠单抗和尼塞韦单抗均表现出显著的中和活性。rRSVA6914-mCherry在A549细胞［（1.19±0.05）×105 PFU/ml］中的病毒滴度高于HEp-2细胞［（7.60±0.79）×104 PFU/ml］（P<0.001）。rRSVA6914-EGFP采用免疫染色空斑试验法和FFA法测得的病毒滴度为（1.15±0.17）×105 PFU/ml和（1.36±0.19）×105 FFU/ml，rRSVA6914-mCherry为（3.50±0.23）×104 PFU/ml和（3.37±0.07）×104 FFU/ml，两种方法测得的病毒滴度差异均无统计学意义（均P>0.05）。 结论： 成功构建并系统验证了携带荧光报告基因的HRSV-A ON1基因型反向遗传系统，可为ON1基因型致病机制研究及抗病毒药物筛选提供科学工具。.
Brazil is a continental country with socioeconomic inequities, hampering access to essential goods and services, including health care. Brazil's Unified Health System (SUS) is a universal, publicly funded health system, warranting free access to health care, including medicines. Significant advances followed the creation of SUS, the implementation of the National Medicines Policy (PNM) and the National Pharmaceutical Services Policy (PNAF) between 1990 and 2000, such as country-wise organization and management of pharmaceutical services and provision of high-cost medicines, a segment including most medicines for rare diseases. The National Policy for Comprehensive Care for Individuals with Rare Diseases has fostered discussion and action on comprehensive care for individuals with rare conditions. However, insufficient funding, setbacks in provision, shortages and the pressures of innovation, patents and prices of medicines have burdened access initiatives. The paper presents the Brazilian scenario and discusses the main pathways for access to medicines for rare diseases in the country, beginning by a comprehensive description of administrative routes, as marketing authorization and incorporation into the health system, which constitute the more straightforward and norm-adherent paths. However, the alternative pathway, litigation for access, guaranteed by the Brazilian Constitution that upholds the right to health, has consolidated itself in the last 20 years, taking an enormous toll on expenditures and appropriate use of medicines. To overcome these challenges and expand access to drugs for rare diseases Brazil must ensure robust evidence-based use for adequate indications, monitoring and managed entry of new medicines and ethical allocation of resources.
Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8 + T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.
This Health Policy compares the current recommendations from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for new treatments in rheumatoid arthritis, highlighting where they align, where they differ, and how harmonisation could make drug development more efficient. We examined the EMA's Guidelines on Clinical Trials of Medicinal Products for the Treatment of rheumatoid arthritis and the FDA's draft guidance rheumatoid arthritis Development of Drugs for Treatment, together with relevant cross-indication FDA guidelines and labelling decisions in rheumatoid arthritis in the last two decades. The key aspects of trial design, including study populations, endpoints, safety requirements, and statistical considerations were analysed. The findings were reviewed and interpreted by a panel of rheumatologists, who proposed strategies for aligning regulatory expectations. The FDA and EMA agree on several core principles such as the use of composite clinical endpoints, validated patient-reported outcomes, the importance of preventing structural joint damage, need for adequate long-term safety exposure, and limits on placebo duration. The EMA, however, favours remission or low disease activity as the preferred primary endpoints, generally requires two pivotal trials in distinct rheumatoid arthritis populations, and background methotrexate unless contraindicated. The FDA offers more flexibility in primary endpoint selection, allows for a single pivotal trial if supported by strong confirmatory evidence, and places greater emphasis on early dose-response characterisation. Greater alignment between FDA and EMA requirements could help reduce duplication, streamline global data interpretation, and speed patient access to effective rheumatoid arthritis therapies globally.
Patients with type 2 diabetes mellitus (T2DM) usually accompany with the occurrence of high blood pressure, necessitating a combination of treatments. This includes sodium-glucose co-transporter 2(SGLT2) inhibitors like empagliflozin, ertugliflozin, and henagliflozin, and antihypertensives like telmisartan. Both classes interact with transporters like P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), with telmisartan further inhibiting several, including organic anion transporting poly-peptide (OATP) 1B1/1B3. Despite their common use, pharmacokinetic interactions between these drugs remain underexplored. This study aims to investigate the potential pharmacokinetic interaction between three specific SGLT2 inhibitors and telmisartan. Rats were divided into twelve groups, with six rats per group, and received different combinations of empagliflozin, ertugliflozin, henagliflozin, and telmisartan. Drug concentrations were measured using ultra-performance liquid chromatography-tandem mass spectrometry, and mRNA expressions through quantitative reverse transcription polymerase chain reaction (RT-qPCR). Our study manifested that telmisartan increased the plasma concentration-time curves (AUC0-t and AUC0-∞) and the maximum plasma concentrations (Cmax) of empagliflozin, whereas the apparent clearance (CLz/F) and apparent volume of distribution (Vz) significantly decreased(all p ＜ 0.05). Similarly, telmisartan increased the AUC0-t, AUC0-∞ and Cmax of henagliflozin and decreased the CLz/F(all p ＜ 0.05). When coadministered with ertugliflozin or henagliflozin, the AUC0-t and AUC0-∞ of telmisartan decreased significantly and the CLz/F increased significantly(all p ＜ 0.05). Furthermore, PCR results demonstrated that telmisartan decreased the expression of BCRP expression in liver, intestines and kidney, P-gp expression in the intestines and kidney and OATP1B2 expression in liver tissue. Our findings highlight the importance of these drug interactions, which could inform dose adjustments to enhance safety in patients with T2DM and hypertension.
This study reports the fabrication of pH-sensitive hydrogel beads composed of β-cyclodextrin-ionic liquid/chitosan modified with glycidyl methacrylate/sodium alginate (CD-IL/CTS-GMA/Alg), cross-linked by calcium chloride (CaCl2) to improve the loading and delivery of poorly soluble drug amlodipine (AML). Chitosan was first modified with glycidyl methacrylate to obtain CTS-GMA, while CD-IL was synthesized by reacting mono-6-(p-toluenesulfonyl)-6-deoxy-cyclodextrin (CD-OTs) with vinyl imidazole. An aqueous solution of alginate containing AML was mixed with CD-IL/CTS-GMA copolymer, and the final solution was added dropwise into CaCl2 (3%) to form hydrogel beads at room temperature via the "egg-box" gelation model. Structural and morphological characterization was performed using FTIR, 1H NMR, and SEM. The CD-IL/CTS-GMA/Alg beads exhibited significantly enhanced AML loading efficiency (~99%) compared to Alg/CTS beads (~67%). The β-cyclodextrin moiety facilitated inclusion complexation with AML, improving solubility and stability, while the ionic liquid component further enhanced drug incorporation. Electrostatic interactions between alginate and chitosan imparted pH sensitivity. Drug release was limited under acidic conditions (pH 1.2, ~20% after 96 h) but markedly higher under near-neutral conditions (pH 7.4, ~86% after 96 h), demonstrating controlled and pH-dependent release. Cytotoxicity assays confirmed biocompatibility across 10-1000 μM. Overall, CD-IL/CTS-GMA/Alg hydrogel beads show strong potential as effective carriers for hydrophobic drugs.
Vitiligo is a multifaceted autoimmune skin disease characterized by the loss of epidermal melanocytes, yet its molecular basis remains poorly understood. To address the need for a specialized systems biology interface, we present VIRdb v3.0, an integrative database combining curated transcriptomics-based datasets with differentially expressed genes, a protein-protein interaction network highlighting regulatory hubs, and an enriched library of natural compounds and FDA-approved drugs targeting vitiligo-related proteins. The platform supports pathway enrichment, molecular docking, and cross-disease comparisons with autoimmune disorders to identify shared molecular signatures. Backend redevelopment using the Django framework enables scalability and real-time data integration. The updated platform now also supports z-score normalization of expression data, multi-gene pathway enrichment queries, and comparative gene-gene interaction networks for vitiligo and its comorbid autoimmune conditions. VIRdb v3.0 facilitates hypothesis generation, biomarker discovery, and therapeutic exploration, advancing vitiligo systems biology. The database is freely accessible at https://virdb.sbdaresearch.in/.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), enters host cells via interaction between the receptor-binding domain of the spike protein (RBDSP) and the peptidase domain (PD) of the host angiotensin-converting enzyme 2 (ACE2). However, no drugs that directly inhibit this interaction have been clinically approved. To discover novel inhibitors, we developed an artificial intelligence (AI)-guided virtual screening approach focused on medium-sized synthetic compounds ≥500 Da. One hit compound inhibited the RBDSP-PDACE2 interaction and suppressed SARS-CoV-2 infection. Nuclear magnetic resonance (NMR) titration revealed direct binding to PDACE2, not RBDSP. ACE2 forms dimers that interconvert between tight and loose conformations, with the tight form stabilized by inter-subunit hydrogen bonds. Extensive NMR analysis using isotopically-labeled PDACE2 identified a putative compound-binding region near the PDACE2 dimer interface, distinct from the RBDSP-binding site. Docking simulations and infection assays using ACE2 mutants deficient in inter-subunit hydrogen bonding provided further evidence for a model in which compound binding is compatible with the loose dimer conformation and may shift the conformational equilibrium away from the tight dimer state, thereby impairing viral entry. These findings uncovered a previously unrecognized allosteric regulatory region within ACE2, which can be targeted by medium-sized molecules to modulate ACE2 conformational equilibrium to inhibit SARS-CoV-2 infection.
Protein kinases continue to be the primary therapeutic targets in cancer therapy because they mediate proliferation, survival, angiogenesis, metastasis, and resistance to treatment. Among these scaffolds, coumarins and hydroxycoumarins have emerged as highly versatile platforms for anticancer drug design due to their rigid benzopyran-2-one core, tunable substitution patterns, and potential for hybridization with kinase-privileged heterocycles. With an interest in medicinal chemistry, structure-activity relationships, and target binding and mechanisms, this review discusses the recently published primary literature on hydroxycoumarins and coumarin-derived derivatives developed as kinase-targeted anticancer agents. Existing evidence demonstrates that coumarin analogs have been considered against receptor tyrosine kinases (EGFR and VEGFR), survival-associated signaling nodes (PI3K/Akt/mTOR signaling), and cell cycle control kinases (CDKs and CK2). These subclasses exhibit various hydroxylation patterns and substitutions at key ring positions, linker architecture, heteroaryl fusion, and heteroaryl-aryl hybrid pharmacophores, each influencing ATP-pocket recognition, hinge-region interactions, and downstream biological responses, such as apoptosis, cell cycle arrest, and anti-migratory effects. Overall, coumarins have the potential to be used as a flexible scaffold family for the discovery of kinase-targeted anticancer drugs. However, further research is warranted to enhance the biochemical validation, optimize the selectivity, and facilitate the translational development of these compounds.
Antimicrobial resistance (AMR) represents a global threat that affects all populations and ecosystems equally, partly driven by the massive and improper use of antibiotics since their discovery in the 20th century. While microorganisms' ability to develop resistance is a natural adaptation mechanism, human practices have dramatically accelerated this process, compromising the therapeutic efficacy of these drugs and generating health, economic, and political consequences on a global scale. In this context, the "responsible use of antimicrobials" emphasizes the commitment, shared responsibility, and conscious action of all actors involved in the life cycle of these medications, as part of an urgent and sustained systemic response to this crisis. This narrative review explores the impact of AMR in Latin America and Argentina, the use of antimicrobials in animal health, and its impact on the environment, proposing various strategies for change. This document serves as a compelling call to action, recognizing the ubiquitous involvement of all stakeholders -the community (including the environment) and the healthcare sector- as both contributors to and potential mitigators of AMR. Ensuring a future where antimicrobials remain effective tools for human, animal, and environmental health is a collective mission for all. La resistencia a los antimicrobianos (RAM) constituye una amenaza global que afecta a todas las poblaciones y ecosistemas por igual, impulsada en parte por el uso masivo e inadecuado de antibióticos desde su descubrimiento en el siglo XX. Aunque la capacidad de los microorganismos para desarrollar resistencia es un mecanismo natural de adaptación, las prácticas humanas han acelerado dramáticamente este proceso, comprometiendo la eficacia terapéutica de estos fármacos y generando consecuencias sanitarias, económicas y políticas a escala planetaria. En este contexto, el "uso responsable de antimicrobianos" enfatiza el compromiso, la corresponsabilidad y la acción consciente de todos los actores involucrados en la cadena de vida de estos medicamentos, como parte de una respuesta cultural urgente y sostenida frente a esta crisis. En esta revisión narrativa se explora el impacto de la RAM en Argentina, el uso de antimicrobianos en salud animal y su impacto en el ambiente proponiendo diferentes estrategias para el cambio. Este documento es una convocatoria a la acción de todos como parte de un problema, la RAM, y parte de la solución, en la comunidad, en el ámbito de la salud o en el medioambiente. Asegurar un futuro donde los antimicrobianos sigan siendo herramientas eficaces para la salud humana, animal y ambiental es una misión de todos para todos.
Ifosfamide is an antineoplastic alkylating agent associated with neurotoxicity, which is conditioned by predisposing factors and manifests up to one week after infusion, with a variable clinical spectrum. The indications for complementary studies and treatment is controversial. The objective was to describe the clinical manifestations associated with ifosfamide, identify risk factors, evaluate complementary studies, and determine the need for treatment during the acute phase and/or prophylactically phase. Observational and retrospective study of 10 cancer patients evaluated for neurotoxicity secondary to ifosfamide at the Comprehensive Care Center for Hematology- Oncology Patients during the period 2017-2021. Patients who received ifosfamide and developed neurological symptoms were included, while those with previous neurological pathology or symptoms secondary to another etiology were excluded. Ten patients who manifested neurological symptoms associated with ifosfamide were evaluated, with symptoms occurring most frequently within the first six hours after infusion and after the third dose. Generalized motor seizures were the predominant manifestation, requiring anticonvulsants; two patients had recurrence. Neuroimaging was normal. Five electroencephalograms were performed, one of which was abnormal. No patient developed subsequent neurological comorbidity. Treatment with ifosfamide is associated with acute and/or delayed neurological manifestations, with seizures being the most frequent, related to the number of doses and infusion time; risk factors include hypoalbuminemia and concomitant treatment with nephrotoxic drugs. Therefore, knowledge and early detection. Therefore, awareness and early detection are essential for proper treatment. Introducción: La ifosfamida es un agente alquilante antineoplásico, asociado a neurotoxicidad, la cual está condicionada por factores predisponentes, manifestándose hasta una semana post infusión, con un espectro clínico variable. La indicación de estudios complementarios y tratamiento son controvertidos. El objetivo fue describir las manifestaciones clínicas asociadas a ifosfamida, identificar factores de riesgo, evaluar los estudios complementarios y determinar la necesidad de tratamiento durante el cuadro agudo y/o profiláctico. Materiales y métodos: Estudio observacional y retrospectivo de 10 pacientes oncológicos evaluados por neurotoxicidad secundaria a ifosfamida en el Centro de Atención Integral del Paciente Hemato-Oncológico, durante el periodo 2017‐2021. Se incluyeron pacientes a quienes se infundió ifosfamida y desarrollaron síntomas neurológicos, se excluyeron aquellos con enfermedad neurológica previa o sintomatología secundaria a otra etiología. Resultados: Se evaluaron 10 pacientes que manifestaron síntomas neurológicos asociados a ifosfamida, presentándose con mayor frecuencia dentro de las primeras seis horas post infusión y tras la tercera dosis. Las convulsiones motoras generalizadas fueron la manifestación predominante, requiriendo anticonvulsivantes; dos pacientes presentaron recurrencia. Las neuroimágenes fueron normales. Se realizaron cinco electroencefalogramas, siendo uno patológico. Ningún paciente desarrolló comorbilidad neurológica posterior. Conclusión: El tratamiento con ifosfamida se asocia a manifestaciones neurológicas agudas y/o tardías, siendo las convulsiones la más frecuente, relacionándose con el número de dosis y tiempo de infusión. Los factores de riesgo fueron la hipoalbuminemia y el tratamiento concomitante con fármacos nefrotóxicos. Por ello, su conocimiento y detección temprana son esenciales para un tratamiento adecuado.
Neuroinflammation plays a key role in epileptogénesis, with interleukin 6 (IL-6) implicated in drug-resistant epilepsy (DRE). The objective was to compare serum IL-6 levels between patients with DRE and non-drug-resistant epilepsy (n-DRE) and to evaluate their relationship with the use of anti-seizure drugs (ASDs). Retrospective multicentre study (March 2019 to April 2022) in two hospitals in Buenos Aires. Patients >18 years of age with epilepsy, at least 2 years of follow-up and no seizures in the last 2 weeks were included. Serum IL-6 was measured by ELISA. Demographic, clinical and treatment data were collected. Comparisons were made using the t-test, Mann-Whitney test, chi-square test, or Fisher's exact test. 121 patients were included (43 with DRE and 78 with n-DRE). The median IL-6 levels did not differ significantly between the two groups. Focal epilepsy and focal seizures with altered consciousness were more frequent in patients with DRE (p = 0.039). In monotherapy, higher IL-6 levels were observed in patients receiving valproic acid (p = 0.027), especially in women (p < 0.05). In this cohort, IL-6 levels were not associated with drug resistance. However, IL-6 concentrations varied according to ASD and sex. Future studies are needed to clarify the role of cytokines in epileptogénesis and their possible value as prognostic biomarkers. Introducción: La neuroinflamación desempeña un papel clave en la epileptogénesis, estando la interleucina 6 (IL-6) implicada en la epilepsia farmacorresistente (EFR). El objetivo fue comparar los niveles séricos de IL-6 entre pacientes con EFR y epilepsia no resistente a los fármacos (n-EFR), y evaluar su relación con el uso de drogas anticrisis (DAC). Materiales y métodos: Estudio multicéntrico retrospectivo (marzo de 2019 a abril de 2022) en dos hospitales de Buenos Aires. Se incluyeron pacientes mayores de 18 años con epilepsia, al menos con 2 años de seguimiento y sin convulsiones en las últimas 2 semanas. La IL-6 sérica se midió mediante ELISA. Se recopilaron datos demográficos, clínicos y de tratamiento. Las comparaciones se realizaron mediante la prueba t, Mann-Whitney, chi-cuadrado o la prueba exacta de Fisher. Resultados: Se incluyeron 121 pacientes (43 con EFR y 78 con n-EFR). La mediana de los niveles de IL-6 no difirió significativamente entre ambos grupos. La epilepsia focal y las crisis focales con alteración del estado de conciencia fueron más frecuentes en los pacientes con EFR (p = 0.039). En monoterapia, se observaron niveles mayores de IL-6 en pacientes que recibían ácido valproico (p = 0.027), especialmente en mujeres (p < 0.05). Conclusión: En esta cohorte, los niveles de IL-6 no se asociaron con la resistencia a los fármacos. Sin embargo, las concentraciones de IL-6 variaron según las DAC y el sexo. Futuros estudios son necesarios para esclarecer el papel de las citocinas en la epileptogénesis y su posible valor como biomarcadores pronósticos.