Controlled Drug Research Articles

Endogenous/exogenous stimuli‐responsive smart hydrogels for diabetic wound healing

AbstractDiabetes significantly impairs the body's wound‐healing capabilities, leading to chronic, infection‐prone wounds. These wounds are characterized by hyperglycemia, inflammation, hypoxia, variable pH levels, increased matrix metalloproteinase activity, oxidative stress, and bacterial colonization. These complex conditions complicate effective wound management, prompting the development of advanced diabetic wound care strategies that exploit specific wound characteristics such as acidic pH, high glucose levels, and oxidative stress to trigger controlled drug release, thereby enhancing the therapeutic effects of the dressings. Among the solutions, hydrogels emerge as promising due to their stimuli‐responsive nature, making them highly effective for managing these wounds. The latest advancements in mono/multi‐stimuli‐responsive smart hydrogels showcase their superiority and potential as healthcare materials, as highlighted by relevant case studies. However, traditional wound dressings fall short of meeting the nuanced needs of these wounds, such as adjustable adhesion, easy removal, real‐time wound status monitoring, and dynamic drug release adjustment according to the wound's specific conditions. Responsive hydrogels represent a significant leap forward as advanced dressings proficient in sensing and responding to the wound environment, offering a more targeted approach to diabetic wound treatment. This review highlights recent advancements in smart hydrogels for wound dressing, monitoring, and drug delivery, emphasizing their role in improving diabetic wound healing. It addresses ongoing challenges and future directions, aiming to guide their clinical adoption.

Nanobiopolymers in cancer therapeutics: advancing targeted drug delivery through sustainable and controlled release mechanisms.

Nanobiopolymers have emerged as a transformative frontier in cancer treatment, leveraging nanotechnology to transform drug delivery. This review provides a comprehensive exploration of the multifaceted landscape of nano-based biopolymers, emphasizing their diverse sources, synthesis methods, and classifications. Natural, synthetic, and microbial nanobiopolymers are scrutinized, along with elucidation of their underlying mechanisms and impact on cancer drug delivery; the latest findings on their deployment as targeted drug delivery agents for cancer treatment are discussed. A detailed analysis of nanobiopolymer sources, including polysaccharides, peptides, and nucleic acids, highlights critical attributes like biodegradability, renewability, and sustainability essential for therapeutic applications. The classification of nanobiopolymers based on their origin and differentiation among natural, synthetic, and microbial sources are thoroughly examined for inherent advantages, challenges, and suitability for cancer therapeutics. The importance of targeted drug release at tumour sites, crucial for minimizing adverse effects on normal tissues, is discussed, encompassing various mechanisms. The role of polymer membrane coatings as a pivotal barrier for facilitating controlled drug release through diffusion is elucidated, providing further insight into efficient methods for cancer treatment and thus consolidating the current knowledge base for researchers and practitioners in the field of nanobiopolymers and cancer therapeutics.

Nanoemulsion and nanoemulgel-based carriers as advanced delivery tools for the treatment of oral diseases.

Oral diseases rank among the most widespread ailments worldwide posing significant global health and economic challenges affecting around 3.5billion people, impacting the quality of life for affected individuals. Dental caries, periodontal disease, bacterial and fungal infections, tooth loss and oral malignancies are among the most prevalent global clinical disorders contributing to oral health burden. Traditional treatments for oral diseases often face challenges such as poor drug bioavailability, breakdown of medication in saliva, inconsistent antibiotic levels at the site of periodontal infection as well as higher side effects. However, the emergence of nanoemulgel (NEG) as an innovative drug delivery system offers promising solutions where NEG combines the advantages of both nanoemulsions (NEs) and hydrogels providing improved drug solubility, stability, and targeted delivery. Due to their minuscule size and ability to control drug release, NEGs hold promise for improving treatment of oral diseases, where versatility of these delivery systems makes them suitable for various applications, including topical delivery in dentistry. This review concisely outlines the anatomy of the oral environment and investigates the therapeutic potential of NE-based gels in oral disorder treatment. It thoroughly examines the challenges of drug delivery in the oral cavity and proposes strategies to improve therapeutic efficacy, drawing attention to previous research reports for comparison. Through comprehensive analysis, the review highlights the promising role of NEGs as a novel therapeutic approach for oral health management via research advancements and their clinical translation. Additionally, it provides valuable insights into future research directions and development opportunities in this area.

Nanomotors as Therapeutic Agents: Advancing Treatment Strategies for Inflammation-Related Diseases.

Inflammation is a physiological response of the body to harmful stimuli such as pathogens, damaged cells, or irritants, involving a series of cellular and molecular events. It is associated with various diseases including neurodegenerative disorders, cancer, and atherosclerosis, and is a leading cause of global mortality. Key inflammatory factors, such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 (IL-1), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1/CCL2), RANTES (CCL5), and prostaglandins, play central roles in inflammation and disease progression. Traditional treatments such as NSAIDs, steroids, biologic agents, and antioxidants have limitations. Recent advancements in nanomaterials present promising solutions for treating inflammation-related diseases. Unlike nanomaterials that rely on passive targeting and face challenges in precise drug delivery, nanomotors, driven by chemical or optical stimuli, offer a more dynamic approach by actively navigating to inflammation sites, thereby enhancing drug delivery efficiency and therapeutic outcomes. Nanomotors allow for controlled drug release in response to specific environmental changes, such as pH and inflammatory factors, ensuring effective drug concentrations at disease sites. This active targeting capability enables the use of smaller drug doses, which reduces overall drug usage, costs, and potential side effects compared to traditional treatments. By improving precision and efficiency, nanomotors address the limitations of conventional therapies and represent a significant advancement in the treatment of inflammation-related diseases. This review summarizes the latest research on nanomotor-mediated treatment of inflammation-related diseases and discusses the challenges and future directions for optimizing their clinical translation.

Gas Chromatography-Mass Spectrometry and Fourier Transform Infrared Spectroscopy Analysis of Potential α-Glucosidase Inhibitors from Terminalia catappa Leaf Extracts

Aims: Postprandial hyperglyceamia is often caused by insulin insufficiency or cellular glucose uptake complications, and conventional treatments often yield undesirable side effects. The aim of the current work was to assess the α-glucosidase inhibitory activities of T. catappa leaf extracts and use spectroscopic techniques to partially characterize possible inhibitors. Study Design: Phytochemical screening, enzyme inhibition assay and spectrometric and spectroscopic characterization of bioactive compounds from leaf extract and fractions of T. catappa. Place and Duration of Study: The entire work was carried out at the Department of Applied Chemistry and Biochemistry, University for Development Studies, Ghana within nine months. Methodology: T. catappa leaf extract and fractions were qualitatively screened for phytochemicals and their biological activity assessed in α-glucosidase inhibition assay. The potential enzyme inhibitors were characterized by Gas Chromatography-Mass Spectrometry (GC-MS) and Fourier Transform Infrared (FT-IR) Spectroscopy. Results: Phytochemical screening of the extract and the various solvent fractions revealed the presence of alkaloids, flavonoids, saponins, flavanol glycosides, phenolics, and terpenoids. The α-glucosidase inhibition potential of the crude leaf extract was concentration-dependent with a half-maximal inhibitory concentration (IC50) of 337.5 µg/ml. Solvent fractions from the crude extract demonstrated α-glucosidase inhibitory activity with IC50 values ranging from 170.40 µg/ml for ethyl acetate (EtOAc) fraction to 71.90 µg/ml for n-hexane (n-Hex) fraction. Acarbose, the control drug, demonstrated significant α-glucosidase inhibition activity in a similar pattern with IC50 of 6.16 µg/ml. The enzyme inhibition kinetics parameters, specifically the Michaelis constant (KM) and Maximum reaction velocity (Vmax) values, suggested that the inhibition of α-glucosidase by T. catappa extract followed a competitive mode. GC-MS and FT-IR analysis of the n-Hexane fraction identified the compounds Eugenol, Urs-12-en-24-oic acid, 3-oxo-, methyl ester (+)-, phytol, trans-isoeugenol, α-amyrin, and squalene as the potential antidiabetic agents that might be responsible for reducing postprandial blood glucose levels. Conclusion: These findings show that T. catappa leaf extract contains α-glucosidase inhibitors and therefore serves as a valuable resource in the discovery of natural anti-diabetic agents.

Neurodevelopmental Outcome in Infants of Gestational Diabetic Mother in a Tertiary Care Hospital, Dhaka, Bangladesh

Background: Diabetes Mellitus (DM) is one of the most common metabolic complications of pregnancy, with negative influences on maternal and fetal health. Infants of Diabetic Mothers (IDMs) are prone to develop both early and late complications. Evidences shows that diabetes in pregnancy have strong association with long-term adverse effects on brain development in babies born to mothers with gestational diabetes mellitus. Very few studies were done in this subcontinent regarding association of gestational diabetes mellitus and infant’s neurodevelopmental outcome. This study will help to find out this associations and thus to reduce poor neurodevelopmental outcome in infants of diabetic mothers by early detection and providing proper early childhood stimulation. Objective: To assess the neurodevelopmental outcome of infants born to mother with gestational diabetes mellitus. Methodology: This prospective observational study was conducted in the department of Neonatology and Institute of Pediatric Neurodisorder and Autism (IPNA), BSMMU, from March 2022 to September 2023. Neonates (N= 52) born at or after 34 weeks of gestation and born to gestational diabetic mother were enrolled in this study. Consent was taken from guardians. The newborns fulfilling the inclusion criteria were followed up for neurodevelopmental assessment at their 9 months of age by clinical psychologists assigned from Institute of Pediatric Neurodisorder and Autism (IPNA), BSMMU, who were blinded about infant’s diagnosis. Bayley scales of infant and toddler development (BSID III) was used for developmental assessment. In the Bayley III, cognitive development, expressive and receptive language and fine and gross motor development all were evaluated at 9 months of age. All data were recorded in a preformed questionnaire and analyzed by Statistical Package for Social Sciences (SPSS), version 25. Results: According to inclusion and exclusion criteria 58 newborn were enrolled and their blood samples were sent at 24 to 48 hours of age to see the laboratory parameters of metabolic and hematological profile. Among them 6 patients lost to follow up, so 52 infants were followed up for neurodevelopmental outcome at 9 months of age. Among the baseline characteristics of mother and neonate 48% mother needed drugs for glycemic control, while others were on dietary modification and 75% of the mothers had good glycemic control. Most of the neonate were born at term and were age appropriate, 18 patients needed NICU admission. Among the neonatal laboratory parameters hyperbilirubinemia was most common (30.8%) and hypoglycemia was second most common found in 15.4% of newborns. The most common morbidity was sepsis (17.3%). Overall adverse neurodevelopmental outcome was found among 14 (26.9%) neonate and 38 (73.1%) neonates had favorable outcome. Use of drugs and poor maternal glycemic control were found statistically significant in between adverse and favorable groups. (p-value- 0.041 and 0.000). Among the neonatal clinical parameters only hypoglycemia was found statistically significant in between these two groups. (p-value- 0.014) Multivariate logistic regression among these predictive factors showed only maternal poor glycemic control was significantly associated with adverse neurodevelopmental outcome (p-value=0.001). Conclusion: Maternal gestational diabetes can adversely affect on their infants neurodevelopment. Among the adverse outcome of three domains language delay was most common. Neonatal hypoglycemia, maternal poor glycemic control and use of drugs for GDM are significant predictors of adverse neurodevelopmental outcome in infants of gestational diabetic mother. Among them maternal poor glycemic control was significantly associated with adverse neurodevelopmental outcome.

A Study on the Stability of High Drug Solubility Characteristics of Hydroxyphenyl Adhesives under the Interference of CPEs.

Novel hydroxyphenyl adhesives (HP-PSAs) could significantly increase drug solubility and control drug release through a doubly ionic hydrogen bond (DIH bond) in the patch. However, chemical penetration enhancers (CPEs) always destroy the performance of most adhesives. As a result, this work investigated the stability of both the HP-PSA features and the DIH bond under the interference of the CPEs. Donepezil (DON) was chosen as the model drug, and CPEs with hydroxyl, carboxyl, amido, and ester groups were selected as model CPEs. Unlike the commonly used neutral H-bond, the DIH bond between DON and the HP-PSA was still stable under the interference of the CPEs, resulting in the 2-3-fold drug solubility in the HP-PSA, which was higher than that in the nonfunctional PSA, which reduced the drug crystallization risk and the difficulty of formulation design. FT-IR, 1H NMR, XPS, dynamic simulation, and molecular docking revealed the mechanism of the stability feature of both the DIH bond and the high drug solubility of the HP-PSA, which was that the formed neutral H-bond interaction caused by CPEs is weaker than that of the DIH bond between DON and the HP-PSA. Furthermore, the drug release, skin permeation, and CPE release study showed that the newly formed weak H-bond and strong ionic H-bond interaction promoted or controlled both DON and CPE release, respectively, thereby influencing drug skin permeation, which provided a theoretical basis for drug release regulation. To summarize, besides the reversible, strong features of the DIH bond in our previous study, the stability of the interaction made the HP-PSA's high drug solubility potential to be applied in the TDDS.

Design of Remote-Controllable Diels-Alder Platform on Magnetic Nanoparticles via Layer-by-Layer Assembly for AC Magnetic Field-Triggered Drug Release.

Diels-Alder chemistry was exploited to develop a remote-controllable drug release platform on magnetic nanoparticles (MNPs). For this purpose, MNPs were decorated with anionic poly(styrenesulfonic acid-co-furfuryl methacrylate) (poly(SS-co-FMA)) and cationic poly(allylamine hydrochloride) by layer-by-layer assembly. The decorated MNPs successfully underwent DA reaction to produce covalent bonding between FMA (diene) and maleimide (dienophile)-terminated model drug. Thermal treatment above 80 °C caused the retro Diels-Alder reaction (rDA) between FMA and the drug, resulting in drug release. The retro DA could be also achieved by applying an alternating-current (AC) magnetic field to the decorated MNPs. This could spatially limit the heat generation around MNP without heating entire system. Drug release could be also accelerated with the irradiation time when a threshold temperature was met or exceeded the required energy for rDA reaction. Our results highlight the potential of DA chemistry as a new strategy to provide a remote controllable drug release platform for improving the therapeutic efficiency.

Advancements in cyclodextrin-based controlled drug delivery: Insights into pharmacokinetic and pharmacodynamic profiles

Advancements in cyclodextrin-based controlled drug delivery: Insights into pharmacokinetic and pharmacodynamic profiles

Anti-cancer and anti-microbial drug encapsulated lipid vesicles as drug delivery systems: Calorimetric and spectroscopic study

Lipid-based drug delivery systems (DDS) have attracted considerable interest for their capacity to achieve controlled drug release and encapsulate a variety of drug molecules—hydrophobic, hydrophilic, and amphiphilic—enabling diverse therapeutic applications. The research focuses on the structural and functional aspects of lipid-based vesicles that encapsulate both anti-cancer and anti-microbial drugs. The study employs ultrasensitive isothermal titration calorimetry and differential scanning calorimetry to gain mechanistic insights into the partitioning of drugs in the lipid-based DDS, release mechanisms, and binding interactions with serum proteins after the release.The structural properties of 5-fluorouracil (5-FU) suggest that the drug can partition into the outer region of the bilayer, where it forms hydrogen bonds with the polar heads of the amphiphilic lipid chains. Kanamycin indicates strong partitioning into liposomes as it displays a binding constant of the order of 106. Erythromycin exhibits limited partitioning into the bilayer, as assessed by fitting ITC data using a sequential two-binding site model. The values of change in enthalpy and entropy reflect the interaction nature and desolvation process during the drug's partitioning into liposomes. Thermodynamic signatures and transition temperatures obtained from ITC and DSC studies indicate that no diffusion-based drug release occurs from DPPC and DSPC-based liposomes. The interaction heat between the released drug and carrier serum albumin protein is very low and shows no consistent pattern. This suggests that the drugs are stably encapsulated in the drug delivery system (DDS), with no significant leakage over time. Insights from such studies on the influence of drug molecule structure on its partitioning into various lipid vesicles and further release of the same drugs from it guide in criteria for developing improvised drug delivery systems.

Integrated Gut Microbiome and UHPLC-MS Metabolomics to Reveal the Prevention Mechanism of Pidanjiangtang Granules on IGT Rats

IntroductionPidanjiangtang (PDJT) is a traditional Chinese medicine formula empirically used to treat impaired glucose tolerance (IGT) based on the "Pidan" theory from the classic ancient book Nei Jing. However, the mechanism of PDJT intervention for IGT remains to be studied. ObjectiveThis study aims to explore the mechanism of PDJT granules intervention in IGT by integrating gut microbiome and UHPLC-MS untargeted metabolomics. Materials and methodsThe IGT model was established in 6-week-old male Sprague-Dawley (SD) rats by feeding them a high-fat diet and using an STZ injection. The low, medium, and high doses of PDJT were used for six weeks. Metformin was used as the positive control drug. The efficacy of PDJT was evaluated using fasting blood glucose (FBG), blood glucose maximum (BGmax), blood lipid, and inflammatory factor levels. Finally, 16S rDNA gut microbiome sequencing with metabolomics analysis was used to explore the pharmacological mechanism of PDJT intervention in IGT. ResultsPDJT could reverse the phenotype of IGT rats, reduce blood glucose levels, improve lipid metabolism disorder, and reduce inflammatory response. Gut microbiome analysis found that PDJT can improve gut microbiota composition and abundance of three phyla (Firmicutes, Bacteroidota, Desulfobacterota) and four genera (unclassified_f__Lachnospiraceae, Ruminococcus, Allobaculum, Desulfovibrio), which play an important role in the process of PDJT intervention on glucose metabolism and lipid metabolism in IGT rats. UHPLC-MS untargeted metabolomics showed that PDJT could regulate the levels of 258 metabolites in lipid metabolism pathways, inflammatory response pathways, fat and protein digestion, and absorption. The combined analysis of the two omics showed that improving the body's metabolism by gut microbes may be the possible mechanism of PDJT in treating IGT. Thus, this study provides a new method to integrate gut microbiome and UHPLC-MS untargeted metabolomics to evaluate the pharmacodynamics and mechanism of PDJT intervention in IGT, providing valuable ideas and insights for future research on the treatment of IGT with traditional Chinese medicine.

Synthesis and Study Biological Activity of Some New Substituted Thiazolidin-4-one Derivatives

The microwave (MW) method was used to create a series of new thiazolidin-4-one derivatives containing benzothiazole and azo groups. Azoaldehyde derivative A was synthesized via the coupling reaction of 2-aminobenzothiazole diazonium ions and 2-hydroxybenzaldehyde. The resultant azoaldehyde A was then subjected to condensation reactions with the primary aromatic amines using the MW method to give azoimines derivatives S1-S5. Finally, compounds S1-S5 were reacted with α-mercaptoacetic acid by the MW method to generate the thiazolidin-4-one derivatives T1-T5. The novel-produced compounds T1-T5 were identified by FT-IR, 1H NMR, and 13C NMR spectroscopy. The DPPH was used to determine the antioxidant activity of the novel-produced compounds T1-T5. The obtained results for T1 and T5 were excellent as antioxidants in comparison with ascorbic acid, while in the antibacterial study, it was discovered that T2, T3, and T5 were found to be more successful than Gentamycin as a control drug against Staphylococcus aureus in an antibacterial investigation, while T3 was found to be more effective than the reference drug against Escherichia coli.

Cu2+-mediated telomeric dimeric G-quadruplex DNAzyme for highly sensitive colorimetric detection of deferasirox

Deferasirox (DEF) is an important iron chelator for treatment of iron overload–related diseases. Monitoring DEF concentration in human serum will provide some valuable information for clinical diagnosis and therapy of such diseases. In this study, we developed a peroxidase-mimicking colorimetric sensor for the detection of DEF by simple assembly of a telomeric dimeric G-quadruplex DNAzyme with Cu2+. The DNAzyme–catalyzed oxidation of 3,3′,5,5′-tetramethylbenzidine in the presence of H2O2 can generate a quantitative colorimetric signal, and the color change can be discerned by the naked eye. Compared with the reaction rate of the monomeric G-quadruplex–Cu2+ DNAzyme, the reaction rate of the dimeric G-quadruplex–Cu2+ (G2–Cu2+) DNAzyme is significantly accelerated, and the reaction rate gradually increases and then reaches a plateau with increasing number of TTA spacers. Herein, the G2–Cu2+ DNAzyme is chosen for the highly sensitive detection of DEF based on the DEF–Cu2+ complex–induced inhibition of its peroxidase-mimicking activities. The limit of detection (LOD) of DEF is achieved as low as 0.03 μM, and the linear range is from 0.05 to 1.2 μM. The proposed strategy exhibits excellent selectivity in the presence of potential interferents, such as metal ions and small molecules. Importantly, the G2–Cu2+ DNAzyme is further expanded to detect DEF in dispersible tablets and human serum samples. Overall, this G2–Cu2+ DNAzyme provides a simple, low-cost, and rapid platform for DEF detection. This novel strategy is the first example of DEF analysis by utilizing signal amplification technology based on the G-quadruplex DNAzyme and holds great potential for DEF quality control and therapeutic drug monitoring.

Revolutionizing Eye Care: Exploring the Potential of Microneedle Drug Delivery

Microneedle technology revolutionizes ocular drug delivery by addressing challenges in treating ocular diseases. This review explores its potential impact, recent advancements, and clinical uses. This minimally invasive technique offers precise control of drug delivery to the eye, with various microneedle types showing the potential to penetrate barriers in the cornea and sclera, ensuring effective drug delivery. Recent advancements have improved safety and efficacy, offering sustained and controlled drug delivery for conditions like age-related macular degeneration and glaucoma. While promising, challenges such as regulatory barriers and long-term biocompatibility persist. Overcoming these through interdisciplinary research is crucial. Ultimately, microneedle drug delivery presents a revolutionary method with the potential to significantly enhance ocular disease treatment, marking a new era in eye care.

Chemical and Biological Prospection of Marine Sponges Belonging to the Class Demospongiae: A Review.

Marine sponges belonging to the class Demospongiae have shown to be promising sources of bioactive compounds. This review aimed to compile studies on the biological activities and chemical components of sponge species from this class, highlighting the structure/activity relationship. Data collection was conducted using the Science Direct, PubMed, Scielo, Web of Science and Google Scholar databases, employing the following descriptors: antimicrobial marine sponges, antioxidant marine sponges, and biological activity of marine sponges. The inclusion criteria were: (1) publications from the year 2022 onwards; (2) written in English or Portuguese; and (3) that evaluated biological activities. Exclusion criteria included: (1) duplicate studies; (2) studies that were not within the scope; and (3) studies that did not evaluate biological activities. As a result of this survey, it was possible to isolate and identify 262 compounds from different metabolic classes, with terpenes, lipids, and alkaloids being highlighted. The extracts, fractions, and isolates were investigated for their antioxidant, antimicrobial, anti-inflammatory, and cytotoxic properties. The sponges demonstrated broad-spectrum antimicrobial potential and cytotoxic potential against various cancer cell lines. Based on data analysis, it is concluded that the studied compounds show promise for the development of drugs for microorganism control and cancer treatment, acting through different mechanisms of action.

Frailty and anticoagulant prescription in older hospitalized patients with atrial fibrillation: a multi-centred observational study

Abstract Background Evidence of the impact of frailty on anticoagulant prescription in older people with atrial fibrillation (AF) is conflicting. Some studies suggested that oral anticoagulants (OACs) were underutilized in older people with frailty while others have not found this. Aims The primary aim of this study was to examine the prevalence of frailty in hospitalized older patients with AF and the association between frailty and OAC prescription during admission. The secondary aim was to examine the association between frailty and prescription of rate/rhythm control medications during admission. Methods This is a retrospective observational cohort study. Adults aged ≥65 years with AF admitted to six hospitals in Australia between 1 June 2022 and 31 August 2022 were eligible for this study. Frailty was defined by a Frailty Index constructed using information from the electronic medical records. Logistic regression models were applied to examine the association between frailty and the prescriptions of OACs, rate control drugs and rhythm control drugs during admission. Results are presented as odds ratios and 95% confidence intervals. Results A total of 685 patients were included in this analysis. They had a mean age of 82.6, and 49.8% were female. Using the cut-off point of 0.25, 42.8% of the patients were identified as being frail. Overall, 75.6% of the patients were prescribed OACs (67.9% in the frail compared to 81.4% in the non-frail, p<0.001), 37.7% received rate control drugs (42.0% in the frail versus 34.4% in the non-frail, p=0.044), while 27.3% received rhythm control drugs (22.9% in the frail compared to 30.6% in the non-frail, p=0.024). The adjusted odds ratios of frailty on prescriptions during admission were 0.53 (95%CI 0.37 – 0.78) for OACs, 1.45 (95%CI 1.05 – 1.99) for rate control drugs, and 0.79 (95%CI 0.55 – 1.13) for rhythm control drugs. Conclusion Our study found a high prevalence of frailty in older inpatients with AF and frailty was associated with a reduced likelihood of receiving OACs. Further studies are needed to understand the reasons for under-coagulation in frail patients with AF.Prescriptions of OACs during admission

Persistence and predictors for non-persistence to edoxaban therapy in patients with atrial fibrillation: 4-year follow-up data from the ETNA-AF-Europe study

Abstract Background Non-persistence to non-vitamin K antagonist oral anticoagulants (NOACs) is associated with increased stroke risk in atrial fibrillation (AF) patients. To date, most NOAC persistence studies have been retrospective and often did not include patients receiving edoxaban. Identifying predictors for non-persistence may be useful when considering the design of future studies and help develop strategies to reduce non-persistence in clinical practice. Purpose To define and describe patients who did not reach the end of the study period and were non-persistent to edoxaban during the 4-year follow-up of ETNA-AF-Europe. Methods ETNA-AF-Europe was a prospective, observational study conducted in AF patients receiving edoxaban. In this subanalysis, patients not reaching the end of the study period and patients who were non-persistent (defined as permanent discontinuation of edoxaban) after 4 years of treatment were examined, including patients switching to other NOACs and reasons for discontinuation. Baseline predictors for not reaching the end of the study period and baseline predictors for non-persistence with edoxaban treatment during 4 years of follow-up were also examined. Persistent patients may have missed dose/interruption. Results Overall, 13,164 patients were included in the analysis. During the whole study period, 14.3% died. At the end of the study, 27.3% of patients prematurely terminated the study and 71.5% were classified as completing the study. Of patients who left the study (n=3598), 30.2% were lost-to-follow-up, 6.9% withdrew consent, and 5.9% transferred to another institution. Of patients who completed the study (n=9417), 87.4% were classified as persistent within the 4 years. Only 6.2% permanently discontinued edoxaban without switching to another NOAC (Table). Following backwards elimination, baseline characteristics associated with premature study termination (excluding death) were male sex, low body mass index, low renal function, chronic hepatic disease, long standing persistent/permanent AF, smoking, low compliance as judged by investigator, vitamin K antagonist-naïve, and no rate/rhythm control drug at baseline. Characteristics associated with non-persistence were increasing age, male sex, body weight extremes, low renal function, heart failure, vascular disease, chronic hepatic disease, alcohol use, perceived frailty, chronic obstructive pulmonary disease, smoking, current AF symptoms, and ablation (Figure). The criterion for backward elimination was p=0.05. Conclusions Most patients in ETNA-AF-Europe reached the end of the study. Less than a quarter were classified as non-persistent during the 4-year follow-up. The majority of patients who were non-persistent switched to another NOAC with a small number completely stopping anticoagulant therapy. Male sex, low renal function, chronic hepatic disease, and smoking were associated with both treatment discontinuation and non-persistence.Termination and persistence

Prediction of atrial fibrillation recurrence after ablation: the impact of machine learning and recurrence during the blanking period

Abstract Introduction Pulmonary vein isolation is superior to antiarrhythmic drugs for rhythm control in patients with atrial fibrillation (AF). Nevertheless, recurrences within the first year are still significant. Several clinical risk scores were developed to predict AF recurrence; however, despite good results in development cohorts, the results in external validation are usually poor, limiting the general applicability of these scores. Purpose We aimed to develop machine learning (ML) models to predict AF recurrences within the first year after catheter ablation and compare their performance with conventional risk scores. Methods We used a retrospective dataset of a tertiary hospital center, including all consecutive patients submitted to the first AF ablation between 2017 and 2021. The dataset included 76 features: patient characteristics, medical history, baseline echocardiography, calcium score, procedure variables, and early recurrence (ER) during the 90-day blanking period. The outcome was defined as the occurrence of an electrocardiographically documented late recurrence (LR) of atrial tachycardia/AF > 30s between 3-12 months. Three different supervised ML models (penalized logistic regression, random forests, and XGBoost) were developed on the training cohort, and hyperparameters were tuned using 10-fold cross-validation. A testing dataset was held out to estimate the final performance (25%). The following risk scores were calculated: APPLE, CAAP-AF, and BASE-AF2 (the last includes ER). Areas under the curve (AUC) of receiver operating characteristic curves were compared using DeLong’s test. Results 679 patients were included: 62.7% males, median age of 59±16 years, and 78.2% with paroxysmal AF. The median time from diagnosis to ablation was 2±4 years. 74.2% underwent radiofrequency ablation and the remaining cryoablation. ER occurred in 12.5%, and most of these patients also experienced LR (68.7 vs 19.6% in those without ER, p<0.001). LR was observed in 25.6%. The XGBoost model showed the best performance with an AUC 0.774, 95% confidence interval (CI) 0.688–0.844) outperforming existing scores (picture 1): APPLE score AUC 0.607, 95% CI 0.562–0.653, p-value<0.001; CAAP-AF score AUC 0.622, 95% CI 0.576–0.668, p-value=0.002; BASE-AF2 AUC 0.628, 95% CI 0.581–0.675, p-value= 0.003. Variable importance analysis showed a significant drop in the performance of the models when ER was not considered, indicating its high importance in predicting LR (picture 2). Conclusions Recurrence during the blanking period was the most important predictor of LR in our population. The ML model was superior to conventional risk scores. ML models might be an essential tool to improve the prediction of outcomes and clinical decision-making for optimal follow-up.ROC curvesFeature Importance

Development of Stable and Intensified Mixing Processes for the Precise and Scalable Production of Uniform Drug Delivery Nanocarriers.

Nanocarriers show great promise in drug delivery but face challenges in stability, uniformity, and morphology control. This work introduces an enhanced mixing process to overcome these obstacles, specifically aiming to produce consistently sized poly(lactic-co-glycolic) acid (PLGA) nanoparticles loaded with anti-tumor drugs. By innovatively integrating a pulsation dampener into the microfluidic channels of a continuous flow preparation system, the flow stability of piston pumps is improved nearly tenfold. Consequently, large-scale production of uniformly sized nanoparticles with customizable dimensions is achieved through nanoprecipitation. Furthermore, incorporating terminal double-bond-functionalized poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-maleimide (PLGA-PEG-Mal) enables these nanoparticles to act as nano-crosslinkers. This facilitates in situ crosslinking with thiolated hyaluronic acid via a spontaneous thiol-ene coupling reaction under physiological conditions, allowing for minimally invasive drug administration and significantly enhancing localized drug retention. The material's degradability in the presence of endogenous enzymes ensures controlled drug release, as demonstrated with the anti-tumor drug doxorubicin (DOX). Validation in a murine breast cancer model shows reduced toxicity and a substantial reduction in tumor weight compared to the free DOX group. These findings confirm the approach's effectiveness for breast cancer treatment and pave the way for innovative solutions in nanomedicine, providing a practical microfluidic mixing system for the design and large-scale production of nanomedicines.

Effect of catheter ablation vs medical therapy on cardiovascular outcomes in hypertrophic cardiomyopathy with atrial fibrillation

Abstract Background Atrial fibrillation (AF) increases the risks of stroke and mortality. AF ablation in patients with heart failure (HF) was associated with a lower risk of death and hospitalisation for worsening HF. Whether AF ablation is beneficial to improve cardiovascular outcomes in patients with concomitant hypertrophic cardiomyopathy (HCM) and AF remains unclear. Objective To investigate whether AF ablation is more effective than conventional medical therapy for improving outcomes in HCM. Methods 2,281 patients with HCM and AF undergoing catheter ablation or medical therapy (antiarrhythmic drugs or rate control drugs) in 2005–2015 were identified from the Korean National Health Insurance Service database. The primary composite outcome of death from cardiovascular causes, ischaemic stroke, hospitalization for worsening HF, or acute myocardial infarction was compared between catheter ablation and medical therapy using propensity score overlap weighting. The time-at-risk was counted from the first medical therapy, and catheter ablation was analysed as a time-varying exposure. Results Of the included (41.1% female; median age: 66 years), 145 (6.1%) underwent catheter ablation for AF during the study period. During a mean follow-up of 3.1 (IQR 1.3–5.8) years, a total of 831 composite outcomes occurred including 292 cardiovascular deaths and 401 strokes. Catheter ablation, compared with medical therapy, was associated with lower risks of the primary composite outcome (weighted incidence rate: 3.84 vs. 6.43 per 100 person-years; weighted HR 0.61, 95% CI 0.38–0.96) and ischaemic stroke (weighted HR 0.43, 95% CI 0.19–0.97). The association between ablation and a lower risk of composite outcome was more pronounced in cases of ablation success whereas no significant difference was observed in cases of ablation failure. Conclusions In patients with AF and HCM, catheter ablation was associated with a lower risk of adverse cardiovascular outcomes than medical therapy.