Controlled Drug Research Articles

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.

Local Controlled Delivery of IL-4 Decreases Inflammatory Bone Loss in a Murine Model of Periodontal Disease.

Chronic inflammatory diseases are a leading global health problem. In many of these diseases, the consistent presence of systemic low-grade inflammation induces tissue damage. This is true in conditions such as diabetes, arthritis, and autoimmune disorders, where an overactive and uncontrolled host immune response is a major driver of immunopathology. Central to this overactive and destructive host response are macrophages, the major phagocytic cells within the innate immune system. These cells exhibit a dual role in both host defense against invading pathogens and promotion of tissue repair during inflammation resolution. Those unique characteristics make macrophages an excellent target for therapeutic interventions in many chronic inflammatory conditions. Using periodontal disease as a model of chronic inflammation, we sought to assess the feasibility of using a controlled drug delivery strategy to target macrophages within the oral cavity. To that end, IL-4 was encapsulated within a biodegradable polymer carrier and locally delivered into the inflamed periodontal tissues. Our data indicate that local sustained delivery of IL-4 decreased inflammatory bone loss and promoted bone gain in the diseased mouse periodontium. Those effects correlated with a shift of local macrophage population toward a prorepair phenotype. Using single-cell RNA sequencing technology, we found that IL-4 delivery reversed several proinflammatory pathways associated with tissue destructive macrophages. Together, our data suggest that sustained delivery of IL-4 may be a viable therapeutic option for chronic diseases characterized by immune-mediated tissue damage.

A Review of Advanced Hydrogel Applications for Tissue Engineering and Drug Delivery Systems as Biomaterials

Hydrogels are known for their high water retention capacity and biocompatibility and have become essential materials in tissue engineering and drug delivery systems. This review explores recent advancements in hydrogel technology, focusing on innovative types such as self-healing, tough, smart, and hybrid hydrogels, each engineered to overcome the limitations of conventional hydrogels. Self-healing hydrogels can autonomously repair structural damage, making them well-suited for applications in dynamic biomedical environments. Tough hydrogels are designed with enhanced mechanical properties, enabling their use in load-bearing applications such as cartilage regeneration. Smart hydrogels respond to external stimuli, including changes in pH, temperature, and electromagnetic fields, making them ideal for controlled drug release tailored to specific medical needs. Hybrid hydrogels, made from both natural and synthetic polymers, combine bioactivity and mechanical resilience, which is particularly valuable in engineering complex tissues. Despite these innovations, challenges such as optimizing biocompatibility, adjusting degradation rates, and scaling up production remain. This review provides an in-depth analysis of these emerging hydrogel technologies, highlighting their transformative potential in both tissue engineering and drug delivery while outlining future directions for their development in biomedical applications.

Xanthine Oxidase Inhibition by Monoterpene-Chalcone Conjugates from Kaempferia subglobosa and Molecular Docking Insights.

Kaempferia subglobosa is a perennial medicinal plant in the Zingiberaceae family, identified as a new species in January 2024. To uncover the biological benefits of K. subglobosa and its compounds, investigation of the metabolites of the roots and rhizomes, yielded three new monoterpene-chalcone conjugates, the globosones A-C, representing a rare metabolite group within the Zingiberaceae, along with six known compounds. The biogenetic pathway for the globosones involves an oxidative [3+2] cycloaddition between α-phellandrene and 4'-methoxy-4,2',6'-trihydroxychalcone. Biological testing revealed potent xanthine oxidase (XO) inhibition by globosones A and B, with IC50 values of 7.0±1.0 and 3.0±0.2 μM, respectively, surpassing the positive control drug allopurinol (IC50 7.2±0.1 μM). Globosones A-C also showed good aromatase inhibition (IC50 3.0-3.5 μM). Molecular docking studies indicated that globosones A and B may inhibit xanthine oxidase through binding at the FAD domain site. The physicochemical properties of these isolates suggest that they possess characteristics suitable for additional biological assessment in more advanced test systems. This study enhances an understanding of monoterpene-chalcone conjugate inhibitors of XO, and offers preliminary insights into the metabolites and bioactivities of K. subglobosa, uncovering potent biological activities associated with this newly discovered plant species.

Dan'e fukang decoction reduces hemorrhage in a rat model of mifepristone induced incomplete abortion and may correlate with cell adhesion molecule signaling interference

Ethnopharmacological relevanceDan'e fukang decoction(DFD) is a traditional Chinese medicine formula. DFD obtains 10 herbs, including Salvia yunnanensis C.H.Wright (Zidanshen) , Curcuma zedoaria (Christm.) Roscoe (Ezhu), Angelica sinensis (Oliv.) Diels (Danggui), Cyperus rotundus L. (Xiangfuzi), Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu, Bupleurum marginatum Wall. ex DC. (Yanhusuo), Sparganium stoloniferum (Buch.-Ham. ex Graebn.) Buch.-Ham. ex Juz. (Sanleng), Panax notoginseng (Burkill) F.H.Chen (Sanqi), Paeonia lactiflora Pall. (Shaoyao) and Glycyrrhiza uralensis Fisch. (Gancao). DFD is now clinically used for the treatment of menstrual irregularities, dysmenorrhea and menstrual discomfort caused by blood stasis and easing of endometriosis. Based on this, it is reasonable to presume that DFD may be effective in treating incomplete abortion and reducing postpartum bleeding, but no specific studies have been reported so far. Aim of the studyTo investigate the efficacy of Dan'e fukang decoction (DFD) in reducing prolonged vaginal bleeding followed by mifepristone induced incomplete abortion and explore the mechanisms of action of DFD in treating incomplete abortion. MethodsAn incomplete abortion model of rat was established by single intragastrically administered 8.5 mg/kg mifepristone on the 7th day of pregnancy. From the 8th day of pregnancy, the abortive rats were administered solvent, a positive control drug, or different doses of DFD, respectively for seven consecutive days. The efficacy of DFD was assessed by measuring the vaginal bleeding volume of the rats. Four coagulation parameters and platelet counts were measured. Hematoxylin and eosin (HE) staining was performed to evaluate pathological changes in the uterine embryos. Serum levels of progesterone and estrogen were measured using ELISA. Network pharmacology and transcriptomics were used to predict potential targets and pathways for DFD to reduce hemorrhage. The levels of mRNA related to cell adhesion molecules (CAMs) were detected by RT-qPCR. The levels of progesterone and estrogen receptors and the proteins associated with CAMs pathway in uterine tissues were detected by Western Blot. ResultsDFD significantly reduced the volume of vaginal bleeding of the abortive rats and significantly downgraded the pathological scores of uterine embryos. DFD significantly increased serum levels of E2, and had no impact on serum levels of P4 and the protein expression of ER and PR in the uteri of the abortive rats. Pathways in cancer, lipid, focal adhesion and immune-related signaling were predicted to be influenced by DFD via the analysis of network pharmacology. The CAMs signaling was found the most critical pathway regulated by both mifepristone and DFD via RNA-seq assay, followed by axon guidance, basal cell carcinoma, hippo signaling pathway and neuroactive ligand-receptor interaction. Combining the two analytical methods, ICAM-1 was predicted likely the key targeted gene by DFD. Finally, DFD was validated to decrease the protein expression of ICAM-1, ITGB2, ITGB7 and RASSF5 in the uterine tissues, which correlated to suppress the CAMs signaling pathway. ConclusionDFD significantly reduced hemorrhage. DFD significantly increased the serum levels of E2 and inhibited CAMs signaling pathway, which was likely to be involved in the mechanism of action of DFD facilitating residual uterine embryo expulsion in the rat model of incomplete abortion.

Synthesis, XRD structural analysis and theoretical studies of a potential inhibitor against rheumatoid arthritis (RA).

This work focused on analyzing the properties of N-(5-nitrothiazol-2-yl)furan-2-carboxamide (C8H5N3O4S, NTFC) as a possible inhibitor of the rheumatoid arthritis process. The synthesis of NTFC was carried out and good-quality crystals were obtained and studied by NMR (1H and 13C), DEPT 135, UV-Vis, IR, MS and single-crystal X-ray diffraction. The structure of NTFC consists of two rings, thiazole and furan, and a central C-N-C(=O)-C segment, which appears to be planar. This central amide segment forms angles of 2.61 (10) and 7.97 (11)° with the planes of the thiazole and furan rings, respectively. The crystal structure of NTFC exhibits N-H...N, N-H...O and C-H...O hydrogen bonds, and C-H...π and π-π interactions that facilitate self-assembly and the formation of hydrogen-bonded dimers, which implies the appearance of R22(8) graph-set motifs in this interaction. The stability of the dimeric unit is complemented by the formation of strong intramolecular C-S...O interactions of chalcogen character, with an S...O distance of 2.6040 (18) Å. Hirshfeld surface (HS) analysis revealed that O...H/H...O interactions were dominant, accounting for 36.8% of the total HS, and that N-H...N interactions were fundamental to the formation of the dimeric structure. The molecular electrostatic potential (MEP) map showed a maximum energy of 46.73 kcal mol-1 and a minimum of -36.06 kcal mol-1. The interaction energies of molecular pairs around NTFC are highest for those interactions linked by N-H hydrogen bonds. The properties of the NTFC ligand as a potential inhibitor of the DHODH (dihydroorotate dehydrogenase) enzyme were evaluated by molecular docking, showing coupling energies very close to those obtained with the control drug for rheumatoid arthritis, i.e. leflunomide.

Therapeutic effect of topical tamoxifen in murine cutaneous leishmaniasis caused by Leishmania major.

Iran is one of the endemic regions of cutaneous leishmaniasis (CL) caused by Leishmania major. There is no protective vaccine available against CL available, and the most effective strategy is a definitive treatment. Topical medications can be an excellent option for this purpose. Tamoxifen, a cancer control drug, has properties such as inducing cell apoptosis and anti-parasitic activity, which can be useful in controlling eukaryotic parasites such as Leishmania. The present study was conducted to investigate this theory in experimental CL caused by L. major. Forty female BALB/c mice aged 4 to 6 weeks were infected by injecting 1 × 106 L. major metacyclics (MRHO/IR/75/ER) in the base of the tail. After the appearance of Leishmania nodules, mice were divided into five test and control groups. Two drug formulations were used: tamoxifen 1% in ethanol and tamoxifen citrate ointment 0.1%. The effectiveness of each formula was evaluated by determining the mean size of the ulcers and parasite burden after a 28-day treatment period. Both formulations showed reduced ulcer mean sizes. However, only the tamoxifen citrate ointment group demonstrated a statistically significant reduction (P = 0.049). The parasite burden decreased by 40.83% for the ointment group and 33.67% for the ethanol solution. Other control groups showed lesser reductions. This study partially demonstrated the effectiveness of topical tamoxifen on CL lesions in a murine model. It can provide a basis for further research on the therapeutic effects of different topical tamoxifen formulations.

Effect of heart rate control with ivabradine on hemodynamic in patients with sepsis: study protocol for a prospective, multicenter, randomized controlled trial

IntroductionSepsis, a life-threatening syndrome, is often accompanied by tachycardia in spite of hypovolemia and hypotension have been corrected. Recently, relevant studies have shown that sustained tachycardia in sepsis was related to high mortality, and appropriate control of heart rate (HR) could improve prognosis. Ivabradine reduces HR directly without a negative inotropic effect through inhibition of the If ionic current, which is different from the traditional rate control drug (beta-blockers).Methods and analysisThis is a prospective, multicenter, randomized, open label study designed to investigate the effect of heart rate control with ivabradine on hemodynamic in patients with sepsis. Our study will enroll 172 patients with sepsis as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria with sinus rate of 95 bpm or higher despite a hemodynamic optimization. Patients will be randomly assigned to standard treatment group (GS) or ivabradine group (GI, standard treatment for sepsis plus enteral ivabradine). Patients in GI will receive ivabradine to maintain HR between 70 and 94 bpm. The primary outcome is the difference of a reduction in HR below 95 bpm and the effect of ivabradine on hemodynamics between GI and GS group within the first 96 h after randomization. The secondary outcomes include organ function measures, the difference in SOFA score, incidence of adverse events, need for organ support, length of ICU stay, and 28-day overall mortality.DiscussionThere are limited studies on ivabradine to control heart rate in patients with sepsis. Our study aims to evaluate whether direct sinus node inhibition can improve hemodynamics, as well as its impact on organ function and prognosis in patients with sepsis, so as to provide evidence for the safe usage in clinical practice.Trial registrationClinicalTrials.gov NCT05882708. Registered on May 11, 2023, https://clinicaltrials.gov/ct2/show/NCT05882708.

Drug conjugates crosslinked bioresponsive hydrogel for combination therapy of diabetic wound

Basic fibroblast growth factor (bFGF) has proved to be effective for wound healing, yet its effectiveness is extremely retarded in diabetic wounds due to the severe oxidative stress in wound beds. To solve this issue, herein a novel combination therapy of bFGF and N-acetylcysteine (NAC, antioxidant) was devised for improved diabetic wound repair. To avoid rapid loss of both drugs in the wound beds, a bioresponsive hydrogel (bFGF-HSPP-NAC) was engineered by incorporating bFGF and NAC into polymer-drug conjugates (HSPP) via thiol-disulfide exchange reactions. In response to oxidative stress (e.g., reactive oxygen species), the disulfide bonds (SS) within the hydrogel are broken into thiol groups (-S-H), thereby promoting hydrogel degradation and enabling controlled drug release. Initially, NAC is released to scavenge free radicals and ameliorate oxidative damage. Subsequently, bFGF is released to expedite tissue regeneration. This combinatorial strategy is tailored to the specific characteristics of the wound microenvironment at various stages of diabetic wound healing, thereby achieving therapeutic efficacy. The results indicate that the bFGF-HSPP-NAC hydrogel markedly enhances re-epithelialization, collagen deposition, hair follicle regeneration, and neovascularization. In conclusion, the bioresponsive bFGF-HSPP-NAC hydrogel demonstrates significant potential for application in combinatorial therapeutic approaches for diabetic wound healing.

Evaluation of a weight‐based process for real‐time accurate confirmation of oral liquid controlled drug balances

AbstractTo meet legislative requirements in Australia, the balance of controlled drugs (CDs) must be confirmed after completion of each transaction. This is particularly challenging for liquid CD formulations, and over the years, health organisations have implemented various methods of performing this task, including the use of visual aids or conversion of bulk formulations to individual unit doses. These methods have a number of limitations. Therefore, this study aimed to evaluate the accuracy and feasibility of a weight‐based method for confirming oral liquid CD balances packed in multidose containers. This study was conducted in a palliative care ward of a metropolitan hospital over a 41‐day period. Morphine mixture 5 mg/1 mL transactions and balance checks were confirmed using weight calculations of the product bottle. The weights were then converted to volume using a locally developed electronic application, which was recorded in the relevant CD registers. The acceptable tolerance per transaction (±0.1 mL) was determined prior to commencement based on 80 test transactions. Throughout the trial period, 407 transactions were undertaken, among which there were no CD discrepancies. Nine nurses provided feedback via an anonymous online survey after the trial, mostly reporting that the new method was more accurate. However, participants also reported that it took on average 3 min longer to complete each transaction. In conclusion, utilising a weight‐based method of confirming liquid CD balances may present a feasible method of meeting legislative requirements related to the recording and accountability of CDs. This project was exempt due to the local policy requirements that constitute research by the Eastern Health Office of Research and Ethics (Reference no: QA24‐100‐111698). The justification for this ethics exemption was as follows: the study conformed with the National Health and Medical Research Council (NHMRC) Ethical considerations in quality assurance and evaluation activities and did not directly affect patient care; written consent was not required from participants per local requirements, however staff were provided verbal and written project information and were informed their participation in the survey was voluntary and anonymous.

A pH-Responsive Ti-Based Local Drug Delivery System for Osteosarcoma Therapy.

Osteosarcoma is one of the major bone cancers, especially for youngsters. The current treatment usually requires systemic chemotherapy and the removal of bone tumors. Titanium (Ti)-based implants can be modified as local drug delivery (LDD) systems for controllable and localized chemotherapeutic drug release. In this work, a pH-responsive Ti-based LDD prototype was designed by introducing polydopamine (PDA) to release doxorubicin (DOX) around osteosarcoma cells with low pH. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and a contact angle meter were applied for surface characterization. Both direct and indirect cell culture modes were performed for biocompatibility and biofunction assessments. The results indicate that the Ti-based LDD prototype exhibits significant pH-dependent DOX release. The cumulative release can reach up to approximately 40% at pH = 6.0 after 72 h, but only around 20% at pH = 7.4. The Ti-based LDD implant shows good biocompatibility with approximately 93% viability of MC3T3 cells after direct culture in vitro for 24 h. Both direct and indirect culture modes verify the good anti-osteosarcoma function of the LDD implant, which should be attributed to the pH-responsive release of DOX.

Combining ion-pair strategy and percutaneous permeation enhancers to develop sustained-release paliperidone patch

In this study, a sustained-release paliperidone (PAL) patch was developed using a combination of ion-pair strategy and percutaneous permeation enhancers (PPEs). The ion-pair strategy was used to improve drug-adhesive miscibility and control drug release. PPEs were used to break SC barrier function to facilitate drug skin permeation. The in vitro skin permeation experiments using single-factor experiments and Box-Behnken design gave the optimized formulation, a 55 μm adhesive thickness patch with 7 % (w/w) PAL-LA (Lauric acid), 9.7 % (w/w) Plurol® Oleique CC 497 (POCC). Moreover, the pharmacokinetic study confirmed its potential in sustained-release transdermal patch with longer MRT0-t (18.35 ± 3.11 h) and higher BA (63.14 %) than the gavage group (Cmax = 6.64 ± 2.61 μg/mL, MRT0-t = 2.88 ± 1.06 h, BA = 45.70 %) without significant increasing Cmax. The mechanism study revealed that forming ion-pairs effectively modulated drug’s physicochemical properties and doubly ionic H-bond strength to improve drug miscibility in patches. To summarize, a sustained-release patch of PAL was successfully developed, which provided a strategy for sustained-release patches with good drug-polymer miscibility, drug controlled-release, and feasible drug utilization features.

Light/pH dual controlled drug release "nanocontainer" alleviates tumor hypoxia for synergistic enhanced chemotherapy, photodynamic therapy and chemodynamic therapy

Light/pH dual controlled drug release "nanocontainer" alleviates tumor hypoxia for synergistic enhanced chemotherapy, photodynamic therapy and chemodynamic therapy

Processing Solid Hydrogels into Hollow Structures by Infrared Laser Light for Highly-Efficient Drug Loading and Controlled Release.

Hollow hydrogels, characterized by their three-dimensional networks akin to biological tissues, are extensively utilized in artificial blood vessels, drug delivery, and nerve conduits due to their superior biocompatibility and fluid-transportation capacity. Nonetheless, the fabrication of hollow hydrogels presents significant challenges, including intricate steps, costly equipment, and structural instability. Consequently, refining the preparation techniques for hollow hydrogels remains paramount to surmounting the limitations of conventional methods. This research introduces an innovative approach that markedly diverges from traditional techniques, offering notable convenience and efficiency in the creation of hollow hydrogel structures. The central novelty of this method lies in employing laser light to induce an in situ photothermal effect, leading to the formation of hollow configurations. This laser-driven transformation of solid hydrogels into hollow structures addresses numerous shortcomings associated with traditional methods. For instance, conventional chemical approaches often necessitate several days to yield hollow hydrogels, and the resultant structures tend to be fragile and susceptible to damage under external pressure. In contrast, the laser-assisted technique facilitates the formation of hollow structures within 240 s, significantly outpacing traditional methods. To achieve controlled drug release, silk fibroin was integrated into the wall of the hollow hydrogels, enabling modulation of wall permeability and directing the drug release process.

Synthesis of novel indazole derivatives as inhibitors of diabetics II along with molecular docking and simulation study

In the light of the pharmacological significance of the indazole and 1, 3, 4-thiadiazole scaffold, hybrid analogs of indazole and 1, 3, 4-thiadiazole (1–14) were synthesized, identified using HREI-MS, 1H, and 13CNMR, and their capability for inhibition of α-amylase and α-glucosidase enzymes was evaluated. Generally, most of the synthesized derivatives of the series exhibited good inhibition activity in comparison to the reference drug acarbose with IC50 value of 10.30 ± 0.20 for α-amylase, and 9.80 ± 0.20 for α-glucosidase. Amongst the synthesized derivatives, fluoro substituted analog 10 appeared to be the most potent inhibitor having IC50 value of 9.90 ± 0.30 for α-amylase and 9.20 ± 0.30 for α-glucosidase. A structure activity relationship (SAR) for the series was established based on electronic effects and the positions of various groups on the phenyl ring. To comprehend the chemicals' binding interactions, molecular docking along with simulation study were also carried out. Compound 10 was ranked top in the series based on docking score and interactions with receptors. Compound 10 establish more H-bond contacts with the active site's residue of alpha-amylase and α-glucosidase as compared to all other compounds. Furthermore, 10 was found to be highly stable throughout 50 ns MD simulation. As compared to the control drug, 10 revealed high stability with both α-amylase and α-glucosidase enzymes during molecular dynamics simulation.

Proteins-Based Nanoparticles for Benznidazole Enteric Delivery.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects millions worldwide, particularly in Latin America. Despite its prevalence, treatment options remain limited. Current drugs, such as benznidazole, cause adverse effects possibly due to ineffective administration. In this context, nanoparticles offer a promising solution to target and control drug delivery by leading the effector site and minimizing side effects. This article focuses on zein-casein-based nanoparticles (Bioparticles, BP) coated with Eudragit L100-55 (BP:EU) for enteric delivery of benznidazole. BP:EU structures are synthesized to minimize premature drug release in the stomach, promoting release in the small intestine. Physical characterization confirmed the successful synthesis of BP:EU and their pH-responsive trigger for drug release. These findings suggest that this material can be a promising approach for Chagas disease treatment, addressing challenges in benznidazole delivery that can lead to improved therapeutic responses.