Active Drug Research Articles

Discovery of novel VEGFR2 inhibitors against non-small cell lung cancer based on fingerprint-enhanced graph attention convolutional network

Despite the proven inhibitory effects of drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2) on solid tumors, including non-small cell lung cancer (NSCLC), the development of anti-NSCLC drugs solely targeting VEGFR2 still faces risks such as off-target effects and limited efficacy. This study aims to develop a novel fingerprint-enhanced graph attention convolutional network (FnGATGCN) model for predicting the activity of anti-NSCLC drugs. Employing a multimodal fusion strategy, the model integrates a feature extraction layer that comprises molecular graph feature extraction and molecular fingerprint feature extraction. The performance evaluation results indicate that the model exhibits high accuracy and stability in predicting activity. Moreover, we explored the relationship between molecular features and biological activity through visualization analysis, thus improving the interpretability of the approach. Utilizing this model, we screened the ZINC database and conducted high-precision molecular docking, leading to the identification of 11 potential active molecules. Subsequently, molecular dynamics simulations and free energy calculations were performed. The results demonstrate that all 11 aforementioned molecules can stably bind to VEGFR2 under dynamic conditions. Among the short-listed compounds, the top six exhibited satisfactory inhibitory activity against VEGFR2 and A549 cells. Especially, compound Z-3 displayed VEGFR2 inhibitory with IC50 values of 0.88 μM, and anti-proliferative activity against A549 cells with IC50 values of 4.23 ± 0.45 μM. This approach combines the advantages of target-based and phenotype-based screening, facilitating the rapid and efficient identification of candidate compounds with dual activity against VEGFR2 and A549 cell lines. It provides new insights and methods for the development of anti-NSCLC drugs. Furthermore, further biological activity tests revealed that Z1-Z3 and Z6 manifested relatively strong antiproliferative activities against NCI-H23 and NCI-H460, and relatively low toxicity towards GES-1. The hit compounds were promising candidates for the further development of novel VEGFR2 inhibitors against NSCLC.

Mechanistic Insights into Chloride‐Dependent Uncaging Reaction of Propargyl and Allene‐Protected Substrates by Pd‐Complexes

This study investigates the effect of chloride levels on the mode of action of palladium complexes for the activation of propargyl‐ and allene‐protected fluorophores and chemotherapeutic drugs through uncaging reactions. Four Pd(II) complexes were synthesized and characterized using spectroscopic techniques to confirm their structure and electronic properties. Kinetic studies and density functional theory calculations revealed that chloride ions in PBS significantly enhance catalytic efficiency, particularly for allenyl‐protected substrates compared to propargylic counterparts. This enhancement is attributed to the neutral charge nature of the Pd complex. The data suggest that neutral complexes are less prone to chloride exchange by water molecules. Additionally, chloride ligands counterbalance the unusually high stability of the key σ‐bound η1‐Pd intermediates in the aquo complexes in PB, leading to higher reactivity. These results highlight the impact of fine‐tuning the electronic properties of the metal center through both designed ligands and environmental factors. Bench evaluations and tests with living breast cancer cells demonstrated that a Pd catalyst complex with a bidentate ligand effectively activates the prodrugs propargyl‐5‐fluorouracil (Prop‐5FU) and allene‐5‐Fluorouracil (Alle‐5FU), the latter being a novel prodrug. The Pd catalyst successfully released the active drug, inducing cytotoxicity, especially with Alle‐5FU, which operates at lower catalyst concentrations than Pro‐5FU.

Unlocking the Microbial Potential of Intercalated Calcium-aluminum Layered Double Hydroxide-palmitic Acid

Introduction: An efficient and coherent drug delivery system is imperative in detouring a repetitive administration of high doses of the drug to achieve an effective therapeutic effect. This study, therefore, aims to synthesize the nanocomposite (CAPA) utilizing the layered double hydroxide as a drug carrier that can safeguard the medicine and improve its bioavailability while minimizing the adverse impact on the biological process. Method: The Calcium-aluminum Layered Double Hydroxide (CAL) was synthesized via the coprecipitation method followed by integrating palmitic acid (PA) drug into that host employing a similar approach. The successful intercalation was assessed utilizing X-ray diffraction (PXRD) analysis and Fourier transform infrared spectroscopy (FTIR). The characterization of the material was evaluated by using a thermogravimetric-derivative thermogravimetric analysis (TGA-DTG) and accelerated surface area and porosity (ASAP) analyzer. Result: The increment of basal spacing of CAPA (15.21Å) synthesized in this study implies the retainment of PA in the interlayer space of CAL. The FTIR spectra of CAPA, with the elimination of the nitrate ion peak at 1359.87 cm-1 and the appearance of carboxylate ion at 1643.17 cm-1, hint at the existence of PA in the host layer. The surface area of CAPA exhibited a value of 19.8 m2g-1, bigger than that of hosts, while its pore size is within the micropores range. Conclusion: The TGA analysis revealed that the thermal stability of PA was improved following the intercalation process due to the decomposition of the PA core that occurs at 260°C. The antimicrobial activity proposes that the synthesized CAPA can retain the drug's activity against S. aureus, emphasizing the ability of CAL as a potential drug delivery vehicle for PA.

Preparation of two new chiral metal-organic frameworks for lipase immobilization and their use as biocatalysis in the enantioselective hydrolysis of racemic naproxen methyl ester

Considering the selective pharmacological activity of chiral drugs, it is important to develop new chiral materials to synthesize them. In this work, two new chiral MOFs (UiO-66@Np and UiO-66@Ib) were prepared by the covalent attachment of the chiral compounds (S-naproxen and S-ibuprofen) to the amine-functionalized Zr-MOF (UiO-66-NH2). Then, Candida rugosa lipase (CRL) was immobilized on these chiral MOFs to fabricate two new biocomposites (UiO-66@Np@CRL and UiO-66@Ib@CRL) as effective biocatalysts, which enable significant enhancement in the catalytic activity and enantioselectivity of lipase. The FTIR, SEM, EDX, TGA, and PXRD analyses were carried out to confirm the formation of the biocomposites. The catalytic performances of the biocomposites (UiO-66@Np@CRL and UiO-66@Ib@CRL) were evaluated in the typical hydrolysis of p-nitro-phenyl palmitate (p-NPP) and the catalytic enantioselective hydrolysis of (R,S)-naproxen methyl ester. Under optimal conditions, UiO-66@Np@CRL showed a higher enantiomeric excess of the substrate (ees) value and a 98 % and 50 % conversion rate, respectively, than that of UiO-66@Ib@CRL. Besides, an excellent enantioselectivity (E) value of 458 was obtained in the presence of the biocomposite (UiO-66@Np@CRL). In addition, it was observed that the catalytic activity, conversion rate and ees value of this composite (UiO-66@Np@CRL) remained almost unchanged in reuse after 6 months. The results showed that in enantioselective reactions, the highest conversion and enantioselectivity could be achieved when the chiral compound bound to the MOF and the model compound used are the same.

MultiADE: A Multi-domain benchmark for Adverse Drug Event extraction

Objective:Active adverse event surveillance monitors Adverse Drug Events (ADE) from different data sources, such as electronic health records, medical literature, social media and search engine logs. Over the years, many datasets have been created, and shared tasks have been organised to facilitate active adverse event surveillance. However, most—if not all—datasets or shared tasks focus on extracting ADEs from a particular type of text. Domain generalisation—the ability of a machine learning model to perform well on new, unseen domains (text types)—is under-explored. Given the rapid advancements in natural language processing, one unanswered question is how far we are from having a single ADE extraction model that is effective on various types of text, such as scientific literature and social media posts. Methods:We contribute to answering this question by building a multi-domain benchmark for adverse drug event extraction, which we named MultiADE. The new benchmark comprises several existing datasets sampled from different text types and our newly created dataset—CADECv2, which is an extension of CADEC (Karimi et al., 2015), covering online posts regarding more diverse drugs than CADEC. Our new dataset is carefully annotated by human annotators following detailed annotation guidelines. Conclusion:Our benchmark results show that the generalisation of the trained models is far from perfect, making it infeasible to be deployed to process different types of text. In addition, although intermediate transfer learning is a promising approach to utilising existing resources, further investigation is needed on methods of domain adaptation, particularly cost-effective methods to select useful training instances.The newly created CADECv2 and the scripts for building the benchmark are publicly available at CSIRO’s Data Portal (https://data.csiro.au/collection/csiro:62387). These resources enable the research community to further information extraction, leading to more effective active adverse drug event surveillance.

Long Term Outcome Among HCV-Infected People Who Use Drugs (PWUD) Successfully Treated for HCV Infection with Glecaprevir/Pibrentasvir (G/P)

BackgroundSeveral clinical trials, including the recently published GRAND PLAN study from Vancouver Infectious Diseases Center (VIDC), have demonstrated the efficacy of HCV therapy among active drug users, including those facing significant addiction-related and social challenges. In GRAND PLAN, we documented SVR12 in 108/117 (92.3%) individuals (108/111 (mITT) or 97.3% of those reaching the SVR12 timepoint) receiving an 8-week course of Glecaprevir/Pibrentasvir (G/P), with almost all using fentanyl and over half being unstably housed. Data on the maintenance of this favorable outcome in the long term in such a population with a significant risk of reinfection are limited. We hypothesized that the offer of ongoing multidisciplinary care (including addiction care) after SVR12 was achieved would reduce the likelihood of loss to follow up, HCV reinfection or death and consolidate the gains achieved by initial engagement in care to diagnose and treat HCV infection. MethodsThe inception cohort for this analysis was the 108 individuals achieving a cure of HCV infection within the GRAND PLAN study. All were offered the opportunity to continue to receive care at VIDC. This is a multidisciplinary model of care to address medical, mental health, social and addiction-related concerns on an ongoing basis. This included, if necessary, opiate agonist and safer supply therapy, usually provided by the pharmacy adjacent to our inner-city campus. Among those choosing to be retained in care, the endpoint of this analysis was loss to follow up, mortality and HCV reinfection and their correlates. Reinfection was ascertained by repeat HCV RNA testing every 6 months, more frequently if clinically indicated. ResultsOf the 108 individuals making up the inception cohort for this analysis, all chose to remain in care at VIDC. We note median age 47 (22-75) years, 28% female, 21.3% identifying as indigenous, the majority with mild fibrosis (90.8% F0-F2), slightly more than half with unstable housing. It is of note that we recorded a 20% decrease in fentanyl users among those who were cured compared to the baseline evaluation of the overall study cohort (73.5% vs 94.9%, p < 0.000001). Among the cured individuals, 104 (96.3%) remained alive, while 4 individuals died of opioid overdoses. Out of the 104 patients, 99 (95.2%) remained HCV-free, while 5 (4.8%) were re-infected. All five have recently initiated repeat HCV therapy at VIDC, 2 of whom are already documented to be cured. ConclusionAmong a population of vulnerable inner-city residents cured of HCV infection within a multidisciplinary program of care at VIDC, all accepted the offer to remain in long-term follow up, with a statistically significant reduction in fentanyl use over time. In the setting of an ongoing opioid crisis where 3 deaths/day are recorded in the neighborhood where the study population resides, we documented 4 deaths. Reinfections occurred at a very modest rate, with maintenance in care allowing prompt re-treatment, with a cure already being documented in 2/5 cases, with the other 3 individuals remaining on HCV therapy at VIDC.

Exploring potential natural plant-based antifungal agents in Sri Lanka: A comprehensive review

Recent advances in antifungal drug discovery have prompted a closer inspection of the biology of fungi and the ways in which they adapt to their growing environment. Understanding these findings presents a challenge: developing antifungal agents that can withstand resistance from fungi and effectively combat it. The use of plant-based antifungal agents is gaining momentum within the antifungal drug industry. This review aims to examine the potential to propel current findings on the antifungal activity of selected medicinal plant extracts found in Sri Lanka towards their potential candidacy as novel antifungals. The benefits and adverse effects of fungi are discussed, along with an overview of synthetic and natural antifungal agents. It delves into the modes of action of antifungal agents and the ways in which they encounter resistance from fungi. The review also highlights the classes of phytochemicals in these plant extracts and the mechanisms through which they exhibit antifungal abilities. Furthermore, it summarizes the capability of natural antifungal agents to enhance the antifungal activity of synthetic antifungal drugs through possible synergistic actions. Finally, the barriers to bringing these plant-based antifungal agents to the forefront of the antifungal drug development industry, along with a few suggestions to overcome them, are considered.

Potential anti-schistosomal effect of Daflon, a repurposed drug targeting different stages of Schistosome maturity.

Despite the long history of experimental trials to combat schistosomiasis, it remains a significant burden due to drug resistance and the effectiveness of the standard treatment only against the mature stage, while skipping other early developmental stages thus leading to severe permanent pathological sequelae. Therefore, repurposing a commonly used well-known safe drug would be a wise alternative. We investigated the potential anti-schistosomal drug activity of Daflon® (DAF) against different schistosomal developmental stages. DAF was administrated at a dose of 100 mg/kg/mouse on days zero, 21, and 42 post-infection towards the invasive, immature, and mature stages of Schistosoma mansoni respectively in comparison to the standard anti-schistosomal drug (Praziquantel). All mice were sacrificed on day 49 post-infection. DAF induced a significant reduction in the total and female worm count, hepatic granuloma size, and number, the extent of liver parenchymal injury and fibrosis as well as intestinal and hepatic egg count compared to the infected untreated control. Liver malondialdehyde (MDA) levels significantly decreased in all DAF-treated groups. Scanning electron microscope findings revealed edema, tegumental blebs, cracks, and fissures in male tegument in all DAF-treated groups with distortion of the ventral suckers and disarrangement of the spines of the oral sucker. The female worm from DAF-treated groups showed tegumental edema with loss of the spines at the posterior end. Compared to the documented reduction of testosterone levels and distortion of testicular architecture in the S. mansoni-infected untreated group, DAF significantly restored testosterone levels and testicular architecture.

Resistome phylodynamics of multidrug-resistant Shigella isolated from diarrheal patients.

Multi-drug resistance (MDR) in Shigella continues to pose a significant public health challenge, particularly in developing countries. Recent advances in genomics strengthen the surveillance of MDR-pathogens and antimicrobial resistance (AMR) mediators. However, genome-based investigations into resistome dynamics in Shigella are limited, specifically in Bangladesh. Therefore, we investigated MDR-Shigella resistomes to evaluate their AMR transmission and phylodynamics. Clinical Shigella strains were screened for MDR phenotypes through susceptibility tests against 28 antibiotics from 10 different classes. Whole-genome sequencing (WGS) and bioinformatics approaches were performed to unveil the resistome dynamics: >500 global plasmid entities and >1,000 plasmid-mediated resistance gene clusters from global databases were included in this study. We identified 28 distinct antimicrobial resistance genes (ARGs) from nine antibiotic classes, with 75% originating from plasmids. Notably, two conjugative MDR plasmids included nearly all potential ARGs, conferring resistance to first-line drugs for shigellosis. Two third-generation cephalosporin-resistant [wubC-blaCTX-M-15-ISEcp1 and blaTEM-1] and two macrolide-resistant mobile genomic islands (GIs) [mphA-mrx-mph(R)A-IS6100 and mphE-msrE-IS482-IS6] had emerged in Shigella in Bangladesh. In addition, trimethoprim-aminoglycoside-streptothricin-sulfonamide-resistant dfrA1-sat1-aadA1 and aph3-dfrA14-aph6-sul2 were in conjugative plasmids in Bangladesh. The MDR plasmids and resistant GIs were phylogenetically relevant to Europe, USA, or China-derived isolates, indicating carry-over of the emerging ARGs from heavily industrialized countries and MSM-burdened (men who have sex with men) populations. The global burden of resistance GIs has increased sharply, especially after 2014. Emerging resistance mediators were most frequent (>80%) in human-associated Escherichia coli and Klebsiella pneumoniae. We infer ARGs horizontally propagate among Enteropathogens: informing treatment strategies and supporting policymakers in strengthening AMR-containment efforts utilizing the phylodynamics network.IMPORTANCEThe world is suffering from a high burden of MDR enteropathogens. Healthcare providers in low- and middle-income countries (LMICs) often face trouble finding effective drugs among the many antibiotics introduced in diarrheal treatment. Resistance-mediated drug inactivation is more rapid than the advent of new antimicrobials, leaving enteritis treatment on the edge. In Bangladesh, where one-third of users are self-prescribing antibiotics and thousands are dying due to resistance-related treatment failure, phylogenomic evidence of AMR transmission root is scarce. Therefore, investigating the resistomes of MDR-Shigella, the leading cause of diarrheal deaths in Bangladesh, is crucial. We identified several emerging resistance mediators and their phylogenetic links to global entities, which is significant for improving shigellosis treatment and enhancing AMR containment strategies. Understanding the MDR mechanism in Shigella will help physicians choose effective drugs and anticipate resistance-mediated changes in treatment approaches; the spatiotemporal phylodynamics of AMR mediators aid policymakers in setting effective checkpoints in the AMR transmission network.

Dose-exposure-response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin-angiotensin-aldosterone system in healthy dogs.

Benazepril exhibits a dose-dependent effect on biomarkers of the circulating renin-angiotensin-aldosterone system (RAAS) in dogs. To characterize the dose-exposure-response relationship of a fixed-dose combination product including benazepril and spironolactone (CARDALIS®) on RAAS biomarkers in dogs. Eighteen purpose-bred healthy beagle dogs. Three groups of 6 dogs received different doses of CARDALIS® for 14 days following induction of RAAS activation by feeding a low-sodium diet: (a) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h (label dose); (b) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h; or (c) benazepril 0.5 mg/kg + spironolactone 4 mg/kg PO q12h. Blood samples were collected at baseline and serial time intervals after CARDALIS® dosing to measure serum RAAS biomarkers and plasma concentrations of active drug metabolites. Time-weighted averages for serum RAAS biomarkers after CARDALIS® dosing at steady state were compared between dosage groups using Wilcoxon rank-sum testing. Compared to the label dose, the highest dose of CARDALIS® was associated with a 30% decrease in angiotensin II (P = .03), 94% increase in angiotensin 1-7 (P = .03), 71% decrease in surrogate activity of ACE (P = .002), and 116% increase in circulating aldosterone (P = .02). CARDALIS® was well-tolerated at all doses with no clinically relevant changes in renal values or serum electrolytes. The combined CARDALIS® product leads to dose-dependent alterations of RAAS metabolites. These results could help inform clinical trials in dogs with heart disease.

Recommendation for Clarifying FDA Policy in Evaluating "Sameness" of Higher Order Structure for Generic Peptide Therapeutics.

Recognizing the approach of a dramatic expansion of peptide therapeutics reaching the marketplace in recent years, led by GLP-1 receptor agonists such as semaglutide and liraglutide, the Center for Drug Evaluation and Research (CDER) branch of the US Food and Drug Administration (FDA) issued a final guidance in 2021 that was intended to assist generic drug producers in meeting Abbreviated New Drug Application (ANDA) obligations to establish "sameness" of their active peptide drug relative to that produced by innovator companies. Research and a published report by FDA scientists on best practices followed, which promulgated the use of nuclear magnetic resonance (NMR) and principal component analysis (PCA) and established a quantitative standard by which "sameness" of higher order structure for the applicant's peptide drug could be judged. A key requirement is that drug product samples be analyzed directly and non-invasively, a condition which in practice restricts sample modification to the addition of a small amount of deuterium oxide to allow signal lock and spectral data alignment (as required for NMR analysis). In the study described herein, data are presented to illustrate that 1) relatively small differences in sample pH can cause significant shifting of certain proton resonances, 2) that such resonance shifting is readily reversible and due to the degree of protonation of specific amino acid residues (rather than reflecting differences in higher order structure), and 3) that small differences in pH variability between sample cohorts can frequently cause failure to meet the quantitative benchmark established by the agency. Methodology is presented by which drug sample pHs can be aligned with minimal impact, and a recommendation is made that minor sample pH adjustments be allowed in assessing "sameness" of peptide drug higher order structure.

Multi-Component, Time-Course screening to develop combination cancer therapies based on synergistic toxicity

Clinical trials in cancer are ideally built on a foundation of sound mechanistic rationale and well-validated drug activity in relevant disease models. The screening of approved and investigational drugs in cell-based phenotypic assays can provide evidence of drug activity, but alternative screening paradigms are needed to develop and optimize multidrug combination regimens. Here, we utilize in vitro screening outcomes across a panel of lymphoma cell lines to dissect the activity of four small-molecule drugs (Venetoclax, Ibrutinib, Prednisolone, and Lenalidomide) currently under investigation within ongoing clinical trials in lymphoma. Data from multiple concentration ranges and time points show that synergistic drug combinations promote apoptosis and cytotoxicity responses at concentrations and time points that are consistent with in vivo drug exposures. To fully map the interaction landscape of these agents in relevant cell models, we developed an in vitro assay format that facilitated time-course evaluations involving concurrent multidrug exposure which further highlighted rapid, synergistic apoptosis induction as a central engine for the activity of this multicomponent targeted therapy. In addition to several instances of exceptional drug+drug synergy, the genetically similar diffuse large B cell lymphoma models also displayed substantial heterogeneity in the degree of synergism between drug pairs. A parallel survey of chemotherapies exhibited limited combination benefit, supporting recent findings that multicomponent chemotherapy outcomes are driven by individual drug activity. Collectively, these data demonstrate how in vitro drug screening data can identify multidrug combinations that exploit drug synergy to overcome the functional diversity of human malignancies.

GATNM: Graph with Attention Neural Network Model for Mycobacterial Cell Wall Permeability of Drugs and Drug-like Compounds

Mycobacterium tuberculosis cell wall has complexity and unusual organization. These conditions make the nutrients and antibiotics difficult to penetrate this wall which affects the low activity of several antimycobacterial drugs in mycobacteria cells. Based on this information, the cell wall permeability prediction in some compounds becomes important and would help develop novel antitubercular drugs. Recently, there have been many predictions helped by computational technology using the Simplified Molecular Input Line Entry System (SMILES) input drug compounds. In this study, we applied computational technology to predict the permeability of cell walls to some compounds or drugs. We evaluated several common machine learning models for their ability to predict cell wall permeability. However, none of these models achieved satisfactory performance. We investigated a Graph with Attention Neural Network (GATNN) model to address this challenge. In the case of permeability detection, to the best of our knowledge, the GATNN model is considered a new approach to improve the prediction performance of the penetration ability of some compounds to the cell wall of the mycobacterial. Additionally, we optimized the accuracy value to get the best hyperparameter and the best model by Optuna. After getting the optimal model, by using the benchmark dataset, this model has slightly increased the performance over the previous model in accuracy and specificity to 78.9% and 81.5%. As a complementary, we also provided an ensemble model and generated the interpretability of the model. The code and materials of all experiments in this paper can be accessed freely at this link: https://github.com/asw1982/MTbPrediction.

Macamides as Potential Therapeutic Agents in Neurological Disorders.

Therapeutic treatment of nervous system disorders has represented one of the significant challenges in medicine for the past several decades. Technological and medical advances have made it possible to recognize different neurological disorders, which has led to more precise identification of potential therapeutic targets, in turn leading to research into developing drugs aimed at these disorders. In this sense, recent years have seen an increase in exploration of the therapeutic effects of various metabolites extracted from Maca (Lepidium meyenii), a plant native to the central alpine region of Peru. Among the most important secondary metabolites contained in this plant are macamides, molecules derived from N-benzylamides of long-chain fatty acids. Macamides have been proposed as active drugs to treat some neurological disorders. Their excellent human tolerance and low toxicity along with neuroprotective, immune-enhancing, and and antioxidant properties make them ideal for exploration as therapeutic agents. In this review, we have compiled information from various studies on macamides, along with theories about the metabolic pathways on which they act.

Pulrodemstat, a selective inhibitor of KDM1A, suppresses head and neck squamous cell carcinoma growth by triggering apoptosis

BackgroundChemotherapy is often ineffective as a first-line treatment for head and neck squamous cell carcinoma (HNSCC), and a more precise and effective therapeutic option is urgently needed.MethodsHigh-throughput screening of a histone demethylase inhibitor library was performed to identify potential drugs for treating HNSCC. The Cancer Genome Atlas (TCGA) and single-cell sequencing were used to evaluate the potential diagnostic value and expression distribution of candidate drug targets. Colony formation, transwell assays, and flow cytometry analyses were used to assess the antitumor function of the potential drugs. The CCK-8 assay was used to compare the antitumor activity of the candidate drug and the traditional chemotherapy drug. Bioinformatic analysis based on TCGA database was used for unveiling the upstream signaling.ResultsPulrodemstat, a selective KDM1A inhibitor that is ongoing clinical trial, stood out as the most effective candidate anti-HNSCC drug based on the high-throughput screening. IC50 analysis revealed that Pulrodemstat might possess stronger anti-tumor activity than 5-Fu. Additionally, Pulrodemstat dramatically suppressed HNSCC cell proliferation and migration without inducing toxicity in normal cells. TCGA analysis revealed that KDM1A is positively associated with tumor proliferation, DNA repair, and DNA replication in HNSCC. Consistent with these results, Pulrodemstat substantially induced apoptosis in the HNSCC cells. Furthermore, TCGA analysis revealed that KDM1A was aberrantly overexpressed in HNSCC, positively correlated with malignancy, and negatively associated with the clinical outcomes of HNSCC patients. Notably, single-cell analysis indicated that KDM1A was mainly distributed in the malignant cells of HNSCC samples, highlighting that Pulrodemstat may be a more precise therapeutic option for HNSCC. In addition, methylation occupancies in the KDM1A promoter were substantially low in HNCC tumors, and low methylation occupancies in the KDM1A promoter predicted poor clinical outcomes in HNSCC. These data are consistent with the KDM1A expression in HNSCC. Moreover, TET3, a DNA demethylase, was strongly and positively correlated with KDM1A expression.ConclusionsPulrodemstat is an effective therapeutic drug for HNSCC. Thus, the TET3/KDM1A axis may account for the malignant phenotype of HNSCC.

Retrospective Analysis of Pregnant Cases in Terms of Drug-Drug interactions and Teratogenic risks

Objective: While teratogenic risks in pregnant women are frequently discussed, polypharmacy and drug-drug interactions (DDI) are topics with little known information. The aim of this study is to determine the polypharmacy status, DDI, and teratogenic risk profile during pregnancy. Method: A retrospective cohort study was conducted covering the year 2023 on pregnant women who were referred for pharmacology consultation due to a history of drug use. Investigation of DDI was performed through the Micromedex and Medscape online query modules. Results: It was found that 113 pregnant women used a total of 71 different active ingredient drugs from 24 diverse pharmacological groups. The average number of drugs used per individual was 2.97. Analgesics, antibiotics, and gastric acid inhibitors were the most used medications, respectively. 11.6% of the women had a comorbidity, and cardiovascular diseases were the most common. It was determined that 28.3% of women had a serious or moderate DDI. The rate of drugs in categories D and X, which are particularly risky in terms of teratogenicity, was found to be 40.8%. Conclusion: In addition to teratogenic effects, polypharmacy and DDI are also significant risk factors in pregnant women. There is still a crucial need for evidence on the medications prescribed in pregnancy, how it specifically affects women with comorbidities, and related benefits and harms.

Esterase-Responsive Self-Immolative Prodrugs for the Sustained Delivery of the Anticancer Drug 5-Fluorouracil with Turn-On Fluorescence.

Stimuli-responsive prodrugs of anticancer drugs are advantageous for the selective delivery of drugs to cancer cells with minimized off-target side effects. In the present study, esterase-activatable fluorogenic prodrugs of the chemotherapeutic drug 5-fluorouracil (5-FU) have been rationally designed and synthesized using multi-step organic synthesis. While 5-FU was connected directly with the fluorophore via a C-N bond in the prodrug BJ-50, an additional self-immolative benzylic spacer with a carbonate linker was incorporated in the prodrug BJ-92. Although absorption and emission spectroscopic studies revealed the activation of both the prodrugs by porcine liver esterase (PLE), reverse-phase HPLC studies confirmed the inability of BJ-50 to release the active drug 5-FU. In contrast, a sustained release of 5-FU and Cou-OH was observed from BJ-92 in the presence of PLE. The endogenous esterase-mediated activation of the prodrug BJ-92 was validated by the turn-on fluorescence in A549 cells and the anti-proliferative activities in A549, and HEK-293 cells. Modulation of the expression of a few cancer marker proteins by BJ-92 and 5-FU was studied to evaluate their anticancer activities. As esterases are overexpressed in cancer cells, the prodrug in the present study would be helpful in selectively delivering 5-FU to cancer cells with reduced off-target side-effects.

How far are we? Assessing progress in hepatitis C response towards the WHO 2030 elimination goals by the civil society monitoring in 25 European countries, period 2020 to 2023

BackgroundWith the advent of direct acting antivirals (DAAs) the World Health Organisation (WHO) adopted global strategy to eliminate hepatitis C virus (HCV) infection by 2030. In Europe, people who inject drugs (PWID) account for the majority of new cases, however testing and treatment remain suboptimal. The aim was to monitor progress in HCV policy and cascade-of-care for PWID, led by the civil society organisations (CSO) that provide harm reduction services for PWID across Europe.MethodsIn period 2020–2023, CSOs representing focal points of Correlation-European Harm Reduction Network were annually invited to complete online questionnaire on use/impact of HCV test-and-treat guidelines for PWID, availability/functioning of continuum-of-care, and role/limitations of harm reduction services for PWID. A retrospective longitudinal analysis of responses to questions answered each year by the same respondents was performed, and a comparison among the studied years was made.ResultsTwenty-five CSOs from cities in 25 European countries were included and responded to 25 questions. Between 2020 and 2023, there was positive trend in number of HCV treatment guidelines, separate guidelines for PWID, and their positive impact on acess to testing/treatment (24/25, 5/25, and 16/25 in 2023, respectively). DAAs were available in all countries, predominantly prescribed by specialist physicians only (slight increase at primary care), with restrictions including active drug use, stage of liver fibrosis or/and reimbursement policies (2/25, 4/25, and 3/25 in 2023, respectively). A decrease in HCV testing sites was noted. Treatment was consistently most common at clinical settings, however an increase outside the specialist settings was detected, particularly in prisons (12/25 and 15/25 in 2020–2021, respectively). Comparing 2022–2023, number of HCV-testing services increased in many cities with positive dynamic in nearly all the settings; increase in treatment at harm reduction services/community centres was noted (6/25 to 8/25, respectively). Between 2020 and 2023 the frequency of various limitations to CSOs addressing HCV was oscillating, presenting an increase between 2022 and 2023 (9/25 to 14/25, respectively).ConclusionThe overall progress towards WHO HCV elimination goals across Europe remains insufficient, most probably also due to the influence of Covid-19 pandemic. Further improvements are needed, also by including CSOs for PWID in continuum-of-care services, and in monitoring progress.

Efficacy of Antidepressants in Management of Depressive Symptoms in Dementia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: Dementia is associated with a complex array of neuropsychiatric manifestations which require consideration as they worsen the course of illness, especially in neurodegenerative etiologies. Depression and subsyndromal depressive symptoms are common in dementia, usually managed with antidepressants, but evidence is weak. Objective: The objective is to study the efficacy of antidepressants compared to placebo in management of depressive symptoms in dementia. Methodology: Electronic databases such as PubMed, MEDLINE, PsychINFO, ClinicalTrials.gov, BASE, and MedNar were searched from their date of inception to March 18, 2024, with appropriate search-terms. Randomized controlled trials (RCTs) that are double-blind in nature with placebo as comparator of dementia patients (Alzheimer’s disease [AD], Frontotemporal, Lewy body, and Parkinson disease dementia) treated with antidepressants for at least ≥ 4 weeks with severity of depressive symptoms measured on standardized rating scales were included. Studies with nonrandomized/nondouble-blind design, active drug or brain stimulation methods as comparator and nonneurodegenerative etiologies of dementia were excluded. Cochrane tool for risk of bias assessment, Covidence and Microsoft Excel for data extraction and review manager version 5.4.1 for data analysis were used. Results: Our search yielded 13(N) RCTs for systematic review, majority of which reported on AD (n = 12), selective serotonin reuptake inhibitors as intervention (n = 7), and high risk of bias (n = 9). Efficacy analysis using forest-plot with seven RCTs showed no statistically significant treatment effect (standardized mean differences [SMD] = −0.04, 95%confidence interval [−0.36, 0.27], Z = 0.26, P = 0.79) between intervention and placebo group. Substantial significant heterogeneity (I 2 = 74%, P &lt; 0.001) was noted across studies. Discussion: Antidepressants administered for 6–13 weeks and different rating scales used to measure outcome in RCTs were possible reasons for heterogeneity. We conclude that antidepressants have not been found to be efficacious compared to placebo in management of depressive symptoms in dementia. Findings cannot be generalized to other etiologies as our analysis found limited data majorly on AD and RCTs with high risk or some concerns in the bias, thus throws a light on need for robust RCTs in this area.

Metagenomics insights into bacterial diversity and antibiotic resistome of the sewage in the city of Belém, Pará, Brazil.

The advancement of antimicrobial resistance is a significant public health issue today. With the spread of resistant bacterial strains in water resources, especially in urban sewage, metagenomic studies enable the investigation of the microbial composition and resistance genes present in these locations. This study characterized the bacterial community and antibiotic resistance genes in a sewage system that receives effluents from various sources through metagenomics. One liter of surface water was collected at four points of a sewage channel, and after filtration, the total DNA was extracted and then sequenced on an NGS platform (Illumina® NextSeq). The sequenced data were trimmed, and the microbiome was predicted using the Kraken software, while the resistome was analyzed on the CARD webserver. All ecological and statistical analyses were performed using the. RStudio tool. The complete metagenome results showed a community with high diversity at the beginning and more restricted diversity at the end of the sampling, with a predominance of the phyla Bacteroidetes, Actinobacteria, Firmicutes, and Proteobacteria. Most species were considered pathogenic, with an emphasis on those belonging to the Enterobacteriaceae family. It was possible to identify bacterial groups of different threat levels to human health according to a report by the U.S. Centers for Disease Control and Prevention. The resistome analysis predominantly revealed genes that confer resistance to multiple drugs, followed by aminoglycosides and macrolides, with efflux pumps and drug inactivation being the most prevalent resistance mechanisms. This work was pioneering in characterizing resistance in a sanitary environment in the Amazon region and reinforces that sanitation measures for urban sewage are necessary to prevent the advancement of antibiotic resistance and the contamination of water resources, as evidenced by the process of eutrophication.