Search Results (2,602)

Background: Schistosomiasis impacts over 230 million people globally, with 251.4 million needing treatment. The disease causes intestinal and urinary symptoms, such as hepatic fibrosis, hepatomegaly, splenomegaly, and bladder calcifications. While praziquantel (PZQ) is the primary treatment, its effectiveness against juvenile stages (schistosomula) is limited, highlighting the need for new therapeutic agents, repurposed drugs, or reformulated compounds. Existing microscopy methods for assessing schistosomula viability are labor-intensive, subjective, and time-consuming. Methods: An artificial intelligence (AI)-assisted culture system using YOLOv5 was developed to evaluate compounds against Schistosoma mansoni schistosomula. The AI model, based on object detection, was trained on 4390 images distinguishing between healthy and damaged schistosomula. The system was externally validated against human counters, and a small-scale assay was performed to demonstrate its potential for larger-scale assays in the future. Results: The AI model exhibited high accuracy, achieving a mean average precision (mAP) of 0.966 (96.6%) and effectively differentiating between healthy and damaged schistosomula. External validation demonstrated significantly improved accuracy and counting time compared to human counters. A small-scale assay was conducted to validate the system, identifying 28 potential compounds with schistosomicidal activity against schistosomula in vitro and providing their preliminary LC₅₀ values. Conclusions: This AI-powered method significantly improves accuracy and time efficiency compared to traditional microscopy. It enables the evaluation of compounds for potential schistosomiasis drugs without the need for dyes or specialized equipment, facilitating more efficient drug assessment. Full article

Background/Objectives: The purpose of this study was to develop the gemcitabine-loaded drug-eluting beads (G-DEBs) for transarterial chemoembolization (TACE) in rabbit renal tumors and to evaluate their antitumor effect using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/X-ray computed tomography (¹⁸F-FDG PET/CT). Methods: DEBs were prepared by polyvinyl alcohol-based macromer crosslinked with N-acryl tyrosine and N,N′-methylenebis(acrylamide). Gemcitabine was loaded through ion change to obtain G-DEBs. Their particle size and drug release profile were characterized. VX2 tumors were implanted in the right kidney of rabbits to establish the renal tumor model. The tumor-bearing rabbits received pre-scan by ¹⁸F-FDG PET/CT, followed by targeted transarterial injection of G-DEBs under digital subtraction angiography (DSA) guidance. The rabbits received another ¹⁸F-FDG PET/CT scan 10 or 14 days after the treatment. The therapeutic effect was further validated by histopathological analysis of the dissected tumors. Results: The average particle size of the microspheres was 58.06 ± 0.50 µm, and the polydisperse index was 0.26 ± 0.002. The maximum loading rate of G-DEBs was 18.09 ± 0.35%, with almost 100% encapsulation efficiency. Within 24 h, GEM was eluted from G-DEBs rapidly and completely, and more than 20% was released in different media. DSA illustrated that G-DEBs were delivered to rabbit renal tumors. Compared with the untreated control group with increased tumor volume and intense ¹⁸F -FDG uptake, the G-DEBs group showed significant reductions in tumor volume and maximum standard uptake value (SUV_max) 10 or 14 days after the treatment. Histopathological analysis confirmed that the proliferating area of tumor cells was significantly reduced in the G-DEBs group. Conclusions: Our results demonstrated that G-DEBs are effective in TACE treatment of rabbit VX2 renal tumors, and ¹⁸F-FDG PET/CT provides a non-invasive imaging modality to monitor the antitumor effects of TACE in renal tumors. Full article

Gliomas are a group of primary brain tumors characterized by their aggressive nature and resistance to treatment. Infiltration of surrounding normal tissues limits surgical approaches, wide inter- and intratumor heterogeneity hinders the development of universal therapeutics, and the presence of the blood–brain barrier reduces the efficiency of their delivery. As a result, patients diagnosed with gliomas often face a poor prognosis and low survival rates. The spectrum of anti-glioma drugs used in clinical practice is quite narrow. Alkylating agents are often used as first-line therapy, but their effectiveness varies depending on the molecular subtypes of gliomas. This highlights the need for new, more effective therapeutic approaches. Standard drug-screening methods involve the use of two-dimensional cell cultures. However, these models cannot fully replicate the conditions present in real tumors, making it difficult to extrapolate the results to humans. We describe the advantages and disadvantages of existing glioma cell-based models designed to improve the situation and build future prospects to make drug discovery comprehensive and more effective for each patient according to personalized therapy paradigms. Full article

Background: To help consumers make healthier choices, the US Food and Drug Administration (FDA) has been charged with developing a front-of-package label (FOPL) to appear on US packaged foods and beverages. One option being explored is the use of “high-in” FOPLs for added sugar, sodium, and saturated fat using a threshold of ≥20% of the recommended daily value (%DV) per portion/serving size to define “high-in”. While research has addressed what FOPL designs are most effective at visually communicating “high-in”, less attention has been paid to the nutrient profile model (NPM) used to decide which products should receive these labels. In addition, several established regional NPMs already exist that identify products that are high in nutrients of concern, but it is unclear how these compare to the FDA’s %DV approach. Methods: We used a dataset of 51,809 US products from Mintel’s Global New Products Database to examine how the FDA’s current definition of “high-in” compares to three established regional NPMs: the Canadian NPM, the Pan American Health Organization (PAHO) NPM, and Chile’s NPM. Results: Overall agreement between the four NPMs was 51% for foods and 72% for beverages, with highest agreement in categories such as sweetened sodas (87%), and lowest agreement in categories such as bread (14%) and salty snacks (29%). The Canadian NPM showed the highest agreement to the FDA “high-in” criteria while the Chilean and PAHO models had lower agreement. For many food categories, the FDA’s definition of “high-in” would require the fewest products to carry a “high-in” label. This issue was particularly pronounced in categories that tend to be served in small portions (e.g., salty snacks, bars), but disappeared or reversed for categories that are served in larger portions (e.g., frozen and non-frozen main dishes). Conclusions: The NPM chosen has important policy implications for an FOPL system’s ability to identify unhealthy foods and incentivize companies to reformulate products. Based on these results, the FDA should consider using a stronger NPM similar to those used elsewhere in the Americas region when deciding the final thresholds for “high-in” for US packaged foods and beverages. Full article

Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown that chronic pain patients have increasingly used other supplements to treat their chronic pain, including cannabidiol (CBD). Up to 50% of chronic pain patients report that they co-use cannabis with their prescribed opioid for pain management, including morphine. Previous work has shown that cannabidiol is a potent inhibitor of UGT2B7, including morphine-mediated metabolism. Co-use of morphine and CBD may result in unwanted drug–drug interactions (DDIs). Methods: Using available physiochemical and clinical parameters, morphine and CBD physiologically based pharmacokinetic (PBPK) models were developed and validated in both healthy and cirrhotic populations. Models for the two populations were then combined to predict the severity and clinical relevance of the potential DDIs during coadministration of both morphine and CBD in both healthy and hepatic-impaired virtual populations. Results: The predictive DDI model suggests that a ~5% increase in morphine exposure is to be expected in healthy populations. A similar increase in exposure of morphine is predicted in severe hepatic-impaired populations with an increase of ~10. Conclusions: While these predicted increases in morphine exposure are below the Food and Drug Administration’s cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5–10% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs. Full article

Background/Objectives: This study aimed to develop a novel nanotechnological slow-release drug delivery platform based on hyaluronic acid Microsponge (MSP) for the subcutaneous administration of methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). RA is a chronic autoimmune disease characterized by joint inflammation and damage, while MTX is a common disease-modifying antirheumatic drug (DMARD), the conventional use of which is limited by adverse effects and the lack of release control. Methods: MSP were synthesized as freeze-dried powder to increase their stability and allow for a facile reconstitution prior to administration and precise MTX dosing. Results: A highly stable and rounded-shaped micrometric MSP, characterized by an open porosity inner structure, achieved both a high MTX loading efficiency and a slow release of MTX after injection. Our drug release assays indeed demonstrated a characteristic drug release profile consisting of a very limited burst release in the first few hours, followed by a slow release of MTX sustained for over a month. By means of a preclinical rat model of RA, the administration of MTX-loaded MSP proved to nearly double the therapeutic efficacy compared to sole MTX, according to a steep reduction in arthritic score compared to control groups. The preclinical study was replicated twice to confirm this improvement in performance and the safety profile of the MSP. Conclusions: This study suggests that the MSP drug delivery platform holds significant potential for clinical use in improving RA therapy by enabling the sustained slow release of MTX, thereby enhancing therapeutic outcomes and minimizing side effects associated with conventional burst-release drug administration. Full article

Metabolic pathway modeling, essential for understanding organism metabolism, is pivotal in predicting genetic mutation effects, drug design, and biofuel development. Enhancing these modeling techniques is crucial for achieving greater prediction accuracy and reliability. However, the limited experimental data or the complexity of the pathway makes it challenging for researchers to predict phenotypes. Deep learning (DL) is known to perform better than other Machine Learning (ML) approaches if the right conditions are met (i.e., a large database and good choice of parameters). Here, we use a knowledge-based model to massively generate synthetic data and extend a small initial dataset of experimental values. The main objective is to assess if DL can perform at least as well as other ML approaches in flux prediction, using 68,950 instances. Two processing methods are used to generate DL models: cross-validation and repeated holdout evaluation. DL models predict the metabolic fluxes with high precision and slightly outperform the best-known ML approach (the Cubist model) with a lower RMSE (≤0.01) in both cases. They also outperform the PLS model (RMSE ≥ 30). This study is the first to use DL to predict the overall flux of a metabolic pathway only from variations of enzyme concentrations. Full article

Background: This study explored the potential of MCM-48 mesoporous silica matrices as a drug delivery system for metformin hydrochloride, aimed at improving the therapeutic management of type 2 diabetes mellitus. The objectives included the synthesis and characterization of MCM-48, assessment of its drug loading capacity, analysis of drug release profiles under simulated physiological conditions, and the development of a multifractal dynamics-based theoretical framework to model and interpret the release kinetics. Methods: MCM-48 was synthesized using a sol–gel method and characterized by SEM-EDX, TEM, and nitrogen adsorption techniques. Drug loading was performed via adsorption at pH 12 using metformin hydrochloride solutions of 1 mg/mL (P-1) and 3 mg/mL (P-2). In vitro dissolution studies were conducted to evaluate the release profiles in simulated gastric and intestinal fluids. A multifractal dynamics model was developed to interpret the release kinetics. Results: SEM-EDX confirmed the uniform distribution of silicon and oxygen, while TEM images revealed a highly ordered cubic mesoporous structure. Nitrogen adsorption analyses showed a high specific surface area of 1325.96 m²/g for unloaded MCM-48, which decreased with drug loading, confirming efficient incorporation of metformin hydrochloride. The loading capacities were 59.788 mg/g (P-1) and 160.978 mg/g (P-2), with efficiencies of 99.65% and 89.43%, respectively. In vitro dissolution studies showed a biphasic release profile: an initial rapid release in gastric conditions followed by sustained release in intestinal fluids, achieving cumulative releases of 92.63% (P-1) and 82.64% (P-2) after 14 hours. The multifractal dynamics-based theoretical release curves closely matched the experimental data. Conclusions: MCM-48 mesoporous silica effectively enhanced metformin delivery, offering a controlled release profile well-suited for type 2 diabetes management. The multifractal theoretical framework provided valuable insights into drug release dynamics, contributing to the advancement of innovative drug delivery systems. Full article

Background/Objectives: The combination of isoniazid (INH) and rifampicin (RIF) is indicated for the treatment maintenance phase of tuberculosis (TB) in adults and children. In Brazil, there is no current reference listed drug for this indication in children. Farmanguinhos has undertaken the development of an age-appropriate dispersible tablet to be taken with water for all age groups from birth to adolescence. The primary objective of this work was to develop and validate a physiologically-based biopharmaceutics model (PBBM) in GastroPlus^TM, to link the product’s in vitro performance to the observed pharmacokinetic (PK) data in adults and children. Methods: The PBBM was developed based on measured or predicted physico-chemical and biopharmaceutical properties of INH and RIF. The metabolic clearance was specified mechanistically in the gut and liver for both parent drugs and acetyl-isoniazid. The model incorporated formulation related measurements such as dosage form disintegration and dissolution as inputs and was validated using extensive literature as well as in house clinical data. Results: The model was used to predict the exposure in children across the targeted dosing regimen for each age group using the new age-appropriate formulation. Probabilistic models of efficacy and safety versus exposure, combined with real world data on children, were utilized to assess drug efficacy and safety in the target populations. Conclusions: The model predictions (systemic exposure) along with clinical data from the literature linking systemic exposure to clinical outcomes confirmed that the proposed dispersible pediatric tablet and dosing regimen are anticipated to be as safe and as effective as adult formulations at similar doses. Full article

Percutaneous Coronary Intervention (PCI) is a treatment method that involves reopening narrowed arteries with a balloon catheter that delivers a cylindrical, mesh-shaped implant device to the site of the stenosis. Currently, by applying a coating to a bare metal stent (BMS) surface to improve biocompatibility, the main risks after PCI, such as restenosis and thrombosis, are reduced while maintaining the basic requirements for the mechanical behavior of the stent itself. In this work, for the first time, the development and optimization process of the spatial structure of the Co-Cr stent (L-605) with a graphene-based coating using cold-wall chemical vapor deposition (CW-CVD) to ensure uniform coverage of the implant was attempted. The CW-CVD process allows the coating of 3D structures, minimizing thermal stress on the surrounding equipment and allowing the deposition of coatings on temperature-sensitive materials. It produces uniform and high-purity films with control over the thickness and composition. The reduced heating of the chamber walls minimizes unwanted reactions, leading to fewer impurities in the final coating. The graphene layers obtained using Raman spectroscopy at different parameters of the CW-CVD process were verified, their properties were investigated, and the functional mechanical behavior of the studied graphene-covered stent was confirmed. In vitro, graphene-coated stents promoted rapid endothelial cell repopulation, an advantage over gold-standard drug-eluting stents delaying re-endothelialization. Also, full-range biocompatibility studies on potential allergic, irritation, toxicological, and pyrogenic reactions of new material in vivo on small animal models demonstrated excellent biocompatibility of the graphene-coated stents. Full article

The simulation of gas flow in the bronchial tree using computational fluid dynamics (CFD) has become a useful tool for the analysis of gas flow mechanics, structural deformation, ventilation, and particle deposition for drug delivery during spontaneous and assisted breathing. CFD allows for new hypotheses to be tested in silico, and detailed results generated without performing expensive experimental procedures that could be potentially harmful to patients. Such computational techniques are also useful for analyzing structure–function relationships in healthy and diseased lungs, assessing regional ventilation at various time points over the course of clinical treatment, or elucidating the changes in airflow patterns over the life span. CFD has also allowed for the development and use of image-based (i.e., patient-specific) models of three-dimensional (3D) airway trees with realistic boundary conditions to achieve more meaningful and personalized data that may be useful for planning effective treatment protocols. This focused review will present a summary of the techniques used in generating realistic 3D airway tree models, the limitations of such models, and the methodologies used for CFD airflow simulation. We will discuss mathematical and image-based geometric models, as well as the various boundary conditions that may be imposed on these geometric models. The results from simulations utilizing mathematical and image-based geometric models of the airway tree will also be discussed in terms of similarities to actual gas flow in the human lung. Full article

Ventricular assist devices (VADs) are designed to provide sufficient blood flow to patients with severe heart failure. Once implanted, the patient becomes dependent on the VAD, making it essential to prevent situations that could harm the patient while receiving circulatory support. VADs are classified as critical systems (CS), and adverse events (AEs) can lead to serious consequences, including hospitalization or even death. At present, patient care is provided through in-person consultations, with incidents reported via medical device reports (MDRs) to the Food and Drug Administration (FDA). However, there is no real-time monitoring of AEs or oversight of these events. In response to this gap, a system for supervising critical adverse processes in patients with implanted VADs (SCVAD) is proposed, based on horizontally and vertically integrated architecture. This system aims to address the complexity of AEs by considering multiple domains of operation: the device, the patient, and the medical team, as well as the interactions between these entities. In this context, the formalism of Petri nets (PN) is used to develop models that represent adverse processes based on the actions recommended by the medical team. These models allow for the mapping of events with the potential to cause harm to the patient. Therefore, the medical team will be able to monitor adverse processes, as the models in interpreted PN can be isomorphically transcribed into computable algorithms that can be processed on compatible devices, enabling the tracking of complications caused by adverse processes. Full article

The study investigates the development and characterization of dual-loaded niosomes incorporated into ion-sensitive in situ gel as a potential drug delivery platform for ophthalmic application. Cannabidiol (CBD) and epigallocatechin-3-gallate (EGCG) simultaneously loaded niosomes were prepared via the thin film hydration (TFH) method followed by pulsatile sonication and were subjected to comprehensive physicochemical evaluation. The optimal composition was included in a gellan gum-based in situ gel, and the antimicrobial activity, in vitro toxicity in a suitable corneal epithelial model (HaCaT cell line), and antioxidant potential of the hybrid system were further assessed. Dual-loaded niosomes based on Span 60, Tween 60, and cholesterol (3.5:3.5:3 mol/mol) were characterized by appropriate size (250 nm), high entrapment efficiency values for both compounds (85% for CBD and 50% for EGCG) and sustained release profiles. The developed hybrid in situ gel exhibited suitable rheological characteristics to enhance the residence time on the ocular surface. The conducted microbiological studies reveal superior inhibition of methicillin-resistant Staphylococcus aureus (MRSA) adhesion by means of the niosomal in situ gel compared to the blank gel and untreated control. Regarding the antioxidant potential, the dual loading of CBD and EGCG in niosomes enhances their protective properties, and the inclusion of niosomes in gel form preserves these effects. The obtained outcomes indicate the developed niosomal in situ gel as a promising drug delivery platform in ophthalmology. Full article

Endothelial cells (ECs) are crucial for vascular health, regulating blood flow, nutrient exchange, and modulating immune responses and inflammation. The impairment of these processes causes the endothelial dysfunction (ED) characterized by oxidative stress, inflammation, vascular permeability, and extracellular matrix remodeling. While primary ECs have been widely used to study ED in vitro, their limitations—such as short lifespan and donor variability—pose challenges. In this context, induced iECs derived from induced pluripotent stem cells offer an innovative solution, providing an unlimited source of ECs to explore disease-specific features of ED. Recent advancements in 3D models and microfluidic systems have enhanced the physiological relevance of iEC-based models by better mimicking the vascular microenvironment. These innovations bridge the gap between understanding ED mechanisms and drug developing and screening to prevent or treat ED. This review highlights the current state of iEC technology as a model to study ED in vascular and non-vascular disorders, including diabetes, cardiovascular, and neurodegenerative diseases. Full article

Enterotoxigenic Escherichia coli (ETEC) is a major pathogen causing diarrhea in humans and animals, with increasing antimicrobial resistance posing a growing challenge in recent years. Lytic bacteriophages (phages) offer a targeted and environmentally sustainable approach to combating bacterial infections, particularly in eliminating drug-resistant strains. In this study, ETEC strains were utilized as indicators, and a stable, high-efficiency phage, designated vB_EcoM_JE01 (JE01), was isolated from pig farm manure. The genome of JE01 was a dsDNA molecule, measuring 168.9 kb, and a transmission electron microscope revealed its characteristic T4-like Myoviridae morphology. JE01 effectively lysed multi-drug-resistant ETEC isolates. Stability assays demonstrated that JE01 retained its activity across a temperature range of 20 °C to 50 °C and a pH range of 3–11, showing resilience to ultraviolet radiation and chloroform exposure. Furthermore, JE01 effectively suppressed ETEC adhesion to porcine intestinal epithelial cells (IPEC-J2), mitigating the inflammatory response triggered by ETEC. To investigate the in vivo antibacterial efficacy of phage JE01 preparations, a diarrhea model was established using germ-free mice infected with a drug-resistant ETEC strain. The findings indicated that 12 h post-ETEC inoculation, intragastric administration of phage JE01 significantly reduced mortality, alleviated gastrointestinal lesions, decreased ETEC colonization in the jejunum, and suppressed the expression of the cytokines IL-6 and IL-8. These results demonstrate a therapeutic benefit of JE01 in treating ETEC-induced diarrhea in mice. Additionally, a fluorescent phage incorporating red fluorescent protein (RFP) was engineered, and the pharmacokinetics of phage therapy were preliminarily assessed through intestinal fluorescence imaging in mice. The results showed that the phage localized to ETEC in the jejunum rapidly, within 45 min. Moreover, the pharmacokinetics of the phage were markedly slowed in the presence of its bacterial target in the gut, suggesting sustained bacteriolytic activity in the ETEC-infected intestine. In conclusion, this study establishes a foundation for the development of phage-based therapies against ETEC. Full article