Continuous Drug Research Articles

Predicting drug combination response surfaces

Abstract Prediction of drug combination responses is a research question of growing importance for cancer and other complex diseases. Current machine learning approaches generally consider predicting either drug combination synergy summaries or single combination dose-response values, which fail to appropriately model the continuous nature of the underlying dose-response combination surface and can lead to inconsistencies when a synergy score or a dose-response matrix is reconstructed from separate predictions. We propose a novel prediction method, comboKR, that directly predicts the continuous drug combination response surface for a drug combination. The method is based on a powerful input–output kernel regression technique and functional modelling of the response surface. ComboKR belongs to the family of functional output regression methods, where the prediction target is a function, in our case, a non-linear parametric surface. Our method thus avoids predicting discretized forms of the target as scalars, vectors or matrices, and therefore provides better interpolation and extrapolation along the surfaces. As an important part of our approach, we develop a novel normalisation between response surfaces that standardises the heterogeneous experimental designs used to measure the dose-responses, and thus allows training the method with data measured in different laboratories. Our experiments on two predictive scenarios and using two combination datasets highlight the suitability of the proposed approach especially in the traditionally challenging setting of predicting combination responses for new drugs not available in the training data.

Association between stimulant and non-stimulant ADHD medications and completed suicide in adolescents and adults: A population-based nested case-control study.

ADHD has been linked to an increased risk of completed suicide. The aim of this study was to assess the relationship between ADHD medication use and completed suicide. This nested case-control study included individuals aged 12-49 in Quebec, Canada, diagnosed with ADHD and/or dispensed ADHD medication. Suicide cases (n = 472) between 2000 and 2021 were matched with 5 controls each (n = 2360) on date of birth, sex, and continuous public drug insurance coverage for at least 365 days before suicide death (index date). Multivariable conditional logistic regression was used to estimate the association between ADHD medication use and completed suicide. The association between specific ADHD medication types and completed suicide was also assessed. After controlling for potential confounders, no significant association was found between ADHD medication use and completed suicide in the overall sample, in individuals aged 12-24 and 25 to 49 years, and those with a prior ADHD physician diagnosis. No significant differences were found when comparing the use of non-stimulants only (aOR 1.27; 95 % CI: 0.62, 2.63), stimulants and non-stimulants (aOR 1.01; 95 % CI: 0.33, 3.08), and ADHD consultation without medication (aOR 0.94; 95 % CI: 0.69, 1.28) against stimulant-only use. Both stimulants and non-stimulants were not associated with the risk of completed suicide. These findings can inform clinical decision-making.

Lemon-derived nanoparticle-functionalized hydrogels regulate macrophage reprogramming to promote diabetic wound healing

The orderly regulation of immune inflammation and promotion of the regeneration of skin vessels and fibers are key to the treatment of diabetic skin injury (DSI). Although various traditional polypeptide biological dressings continue to be developed, their efficacy is not satisfactory. In recent years, plant-to-mammal regulation has provided an effective approach for chronic wound management, but the development of effective plant-based treatments remains challenging. The development of exosomes from Chinese herbs is promising for wound healing. In this study, plant exosomes derived from lemons (Citrus limon) were extracted, and their biological efficacy was verified. Lemon exosomes regulated the polarization reprogramming of macrophages, promoted the proliferation and migration of vascular endothelial cells and fibroblasts, and thus promoted the healing of diabetic wounds. To solve the problems of continuous drug delivery and penetration depth, Lemon Exosomes were loaded into a hydrogel constructed of Gelatin Methacryloyl (GelMA) and Dialdehyde Starch (DAS) that closely fits to the skin, absorbs water, swells, and is moist and breathable, effectively promoting the sustained and slow release of exosomes and resulting in excellent performance for diabetic wound healing. Our GelMA-DAS-Lemon Exosomes hydrogel (GelMA/DAS/Exo hydrogel) patch represents a potentially valuable option for repairing diabetic wounds in clinical applications.Graphical s

A Review on Salicylic Acid Ethosomal Gel

The ethosomes are vesicular carrier comprise of hydroalcoholic or hydro/alcoholic/glycolic phospholipid in which the concentration of alcohols or their combination is relatively high. To provide continuous drug infusion through an intact skin, several transdermal therapeutic systems have been developed for topical application onto the intact skin surface to control the delivery of drug and its subsequent permeation through the skin tissue. Transdermal route is promising alternative to drug delivery for systemic effect. An attempt was made to formulate the highly efficient ethosomal drug delivery system and enalapril meleate is used as model drug. The following conclusion are drown from the result and discussion described in the previous chapter. Liposomal formulation was also prepared by the thin film hydration method. The techniques used were simple and reproducible. The prepared ethosomes were spherical and discrete in shape. The size of vesicles were found to be in the range of 3.26-5.79 μm, 0.716-1.301 μm and 5.32 μm for unsonicated ethosomes, sonicated ethosomes and liposomes respectively. However ethosomes prepared by sonication method were more uniform and smaller in size, which is essential for skin permeation. While comparing the entrapment efficiency, ethosomes containing 30% w/w ethanol and prepared by sonication showed highest value with respect to all other formulation, so it is concluded ethosomes prepared by sonication and containing 30% w/w ethanol as the best formulation considering all other aspects. The highest value of transdermal flux for sonicated ethosomes containing 30% w/w ethanol is the indication of complete and rapid penetration through the skin may be because of tiny vesicular size.

Impulse control disorders in Parkinson's disease: What's new?

Impulse Control Disorders (ICDs) are increasingly recognized as a significant non-motor complication in Parkinson's disease (PD), impacting patients and their caregivers. ICDs in PD are primarily associated with dopaminergic treatments, particularly dopamine agonists, though not all patients develop these disorders, indicating a role for genetic and other clinical factors. Studies over the past few years suggest that the mesocorticolimbic reward system, a core neural substrate for impulsivity, is a key contributor to ICDs in PD. Recent advances in neuroimaging have begun to unravel the neurobiological diversity of ICD subtypes. Moreover, recent studies provide valuable insights into the clinical and biologic risk factors for ICDs that could be used as indicators for the development of future preventive strategies or targeted interventions. Indeed, current treatment strategies, which often involve reducing or discontinuing dopamine agonists, are limited in efficacy. Emerging therapies, including behavioral interventions and continuous drug delivery methods, show promise, though further research is needed. This paper provides an updated review of ICD prevalence, mechanisms, assessment, and novel management approaches.

Drug-induced urinary retention: a real-world pharmacovigilance study using FDA and Canada vigilance databases.

Urinary retention (UR) is a clinical condition where patients cannot fully empty their bladder. Although numerous drugs are associated with UR, comprehensive and reliable studies identifying drugs that induce UR are scarce. This study leveraged data from the FDA Adverse Event Reporting System (FAERS) and the Canadian Vigilance Adverse Reaction (CVAR) database to explore adverse events (AEs) related to UR from 2004 to Q1 2024. The top 50 drugs were analyzed for annual reporting trends using linear regression. Disproportionality analysis using the reporting odds ratio (ROR) method, with P-values adjusted via Bonferroni correction, identified significant signals, which were then validated against drug labels and re-evaluated using the CVAR database. Time-to-onset analysis was also performed. From 2004 to Q1 2024, FAERS recorded 17,785,793 AEs, with 16,183 (0.09%) identified as UR cases. The median age among these cases was 65years, with males comprising 53.4%. There were significant annual increases in UR reports associated with antineoplastic agents (0.19% per year) and antidiabetic drugs (0.09% per year), while reports linked to bronchodilators decreased (-0.53% per year). Disproportionality analysis revealed significant signals for 34 drugs (68%), with the highest RORs observed in Fesoterodine, Mirabegron, and Solifenacin. Initial signal detection identified potential new UR signals for Abiraterone, Valacyclovir, Fluoxetine, Empagliflozin, Clopidogrel, and Amlodipine, with CVAR confirming signals for Abiraterone, Fluoxetine, and Empagliflozin. The median time to onset of UR was 29days, with over half of the cases occurring within 30days of initiating medication. The study identifies a rising trend in drug-related UR reports over the past 2 decades. The validation of new signals for Abiraterone, Fluoxetine, and Empagliflozin underscores the critical need for continuous drug safety monitoring and targeted research to better understand the mechanisms behind drug-induced UR.

Drug-Loaded Microspheres on NIR-Responsive PLA/MXene Scaffolds: Controlled Release and Bone Tissue Regeneration.

The resection of bone tumors results in large bone defects with some residual tumor cells, and the treatment of this type of bone defect area often faces a dilemma, namely, the trade-off between bone repair and antitumor after the resection of bone tumors. In order to promote local bone repair, and at the same time inhibit tumor recurrence by continuous and controlled drug administration, we developed a multifunctional NIR-responsive scaffold, whose main components are polylactic acid and MXene, and loaded with PLGA/DOX microspheres, and we hope that the scaffold can take into account both antitumor and bone repair in the bidirectional modulation effect of NIR. The results showed that the scaffold with 1% MXene content had relatively good performance in photothermal therapy (PT) and other aspects, and it could be smoothly increased to 50 °C within 2 min under NIR illumination, and the drug release of microspheres was increased by 10% after illumination compared with that at body temperature. In vivo experiments in animals showed that this scaffold effectively limited the in situ recurrence of tumor cells and lung metastasis and was able to promote osteogenic differentiation under NIR irradiation. Therefore, this scaffold can not only control the release of antitumor drugs but also enhance the antitumor effect through the bidirectional modulation effect of PT and at the same time promote bone formation, which provides a good application solution for the integrated treatment of the bone defect area after bone tumor surgery.

The use of human albumin eye drops as an adjunctive therapy in cases of persistant corneal epithelial defects

Background Albumin eye drops (AED) can be effective in the healing of corneal epithelial defects. Albumin is the main protein component of autologous serum and therefore may be useful in the treatment of ocular surface diseases such as corneal ulcers and epithelial defects. Aim This work aimed to study the effect of human AED as adjunctive therapy in the treatment of persistent corneal epithelial defects (PCEDs). Patients and methods This prospective study was conducted in 20 patients aged 18–60 years, of both sexes, with PCEDs that did not respond to standard medical treatment for 10 to 14 days. All patients underwent slit-lamp examination, fundus examination, intraocular pressure measurement (digital), corneal swab, culture, and sensitivity. Results There was a significant positive correlation between the duration of medical therapy with the persistent antiepithelial defect AED and the size of the persistent epithelial defect at presentation (P<0.05). There was significant improvement in pain sensation, ciliary injection, persistent epithelial defect size, corneal, and stromal infiltration during the study period. There was no significant association between the duration of continuous ant epithelial drug therapy AED and stromal infiltration at presentation (P=0.627). Conclusion The promising therapeutic effects of AED on the corneal epithelium have been demonstrated. Albumin has shown a therapeutic effect in the treatment of PCEDs.

Microbiota-Induced Radioprotection: A Novel Approach to Enhance Human Radioresistance with In-Situ Genetically Engineered Gut Bacteria

The high sensitivity of living organic forms to space radiation remains the critical issue during spaceflight, to which they will be chronically exposed during months of interplanetary or even decades of interstellar spaceflight. In the human body, all actively dividing and poorly differentiated cells are always close to being damaged by radiological or chemical agents. The chronic exposure to ionizing radiation primarily causes changes in blood counts and intestinal damage such as fibrosis, obliterative vasculitis, changes in the gut microbiota, and atrophy or degeneration of muscle fibers. The project “MISS: Microbiome Induced Space Suit” was presented at the Giant Jamboree of the International Genetically Engineered Machine Competition 2021, with the aim to investigate the ability of the novel microbiota-mediated approach to enhance human resistance to ionizing radiation. The key innovative part of the project was the idea to create a novel radioprotector delivery mechanism based on human gut microbiota with the function of outer membrane vesicles (OMVs) secretion. The project concept proposed the feasibility of genetically modifying the human microbiota in situ through the delivery of genetic constructs to the host’s crypts using silicon nanoparticles with chemically modified surfaces. In this perspective, we discuss the advances in modifying microbiota-mediated secretory activity as a promising approach for radioprotection and as an alternative to hormone therapy and other health conditions that currently require continuous drug administration. Future clinical trials of in situ methods to genetic engineering the crypt microbiota may pave the way for indirect regulation of human cells.

Vectorial infectivity screening and epidemiology of schistosomiasis among inhabitants of Zango Kataf local government area, southern Kaduna, Nigeria

Schistosomiasis is a major public health problem in developing countries like Nigeria. This epidemiological study is therefore aimed to determine its transmission status in Zokwa, Kaduna State Nigeria. Methodology: A cross sectional study was conducted from April-September, 2015 among 567 participants from Zokwa community. Fecal and Urine samples were examined using the formalin-ether sedimentation and filtration method. Demographic and risks factors were assessed using a structured questionnaire. Results: The overall prevalence of schistosomiasis was 0% for both Urinary and Intestinal Schistosomiasis. Demographic revealed 287 (50.6%) males and 280 (49.4%) females, people of age bracket (≤20years), 209(36.9%) as students, 327(57.7%) and 21(3.7%) used well water and stream water for domestic use, 281(49.5%) were involved in washing and 35(6.2%)in swimming,248(43.7%) practice open field defecation while128 (22.5%) used water closest. Snail vectors for schistosomiasis were observed absent in screened water bodies during the study period. Retrospective data revealed more males 67(13.4%) than females 58 (10.0%) had gastrointestinal parasite, 6(0.56%) had Schistosoma Mansoni infection recorded in 1 female (0.17%) and 5 males (1.0%). Fasciola sp. 1(0.17%) and Hookworm 56(5.1%) recorded least and highest infection rate. The highest and least helminthic infection rates were recorded in the Months of September 22(26.83%), October 21(24.45%) and March 12(10.53%). There was significant association (p < 0.05) between sex and intestinal helminth infections. Conclusion: The study revealed there is no active transmission of schistosomiasis in Zokwa community in Nigeria. Continuous mass drug administration, health education and community mobilization will serve as important control strategies to attain eradication status.

PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma

BackgroundThe efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.MethodsOur study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.ResultsOur metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.ConclusionsOur results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.

Single-Walled Carbon Nanotubes as Optical Transducers for Nanobiosensors In Vivo.

Semiconducting single-walled carbon nanotubes (SWCNTs) may serve as signal transducers for nanobiosensors. Recent studies have developed innovative methods of engineering molecularly specific sensors, while others have devised methods of deploying such sensors within live animals and plants. These advances may potentiate the use of implantable, noninvasive biosensors for continuous drug, disease, and contaminant monitoring based on the optical properties of single-walled carbon nanotubes (SWCNTs). Such tools have substantial potential to improve disease diagnostics, prognosis, drug safety, therapeutic response, and patient compliance. Outside of clinical applications, such sensors also have substantial potential in environmental monitoring or as research tools in the lab. However, substantial work remains to be done to realize these goals through further advances in materials science and engineering. Here, we review the current landscape of quantitative SWCNT-based optical biosensors that have been deployed in living plants and animals. Specifically, we focused this review on methods that have been developed to deploy SWCNT-based sensors in vivo as well as analytes that have been detected by SWCNTs in vivo. Finally, we evaluated potential future directions to take advantage of the promise outlined here toward field-deployable or implantable use in patients.

Fish Fin-Derived Non-Invasive Flexible Bioinspired Contact Lens for Continuous Ophthalmic Drug Delivery.

Efficient drug delivery is crucial for glaucoma patients. Flexible biomedical devices that enable sustained ocular drug delivery and can regulate the drug release rate according to physiological conditions are highly desirable for glaucoma treatments, addressing both low drug bioavailability and poor patient compliance from manual drug administration, and improving treatment outcomes. Inspired by the structure and reciprocating motion of fish dorsal fins, a drug-eluting contact lens based on deformable microstructures for non-invasive ocular surface drug delivery is developed. Liquid drugs are stored within the interstices of the deformable microstructural units, allowing for continuous drug release through diffusion upon contact with the ocular surface. Finite element analysis is utilized to study the intraocular drug transport dynamics of glaucoma and optimize the overall layout of the device. Microstructural units undergo deformation under loading, altering the interstitial spaces and modulating the drug release rate. This device can adaptively adjust its drug release rate based on changes in intraocular pressure (IOP) and can be proactively regulated in response to cyclic eye loads, accommodating elevated IOP caused by varying body postures and activities. As a flexible, non-invasive, highly dynamic, and adaptive drug delivery platform, it holds significant potential for future biomedical applications.

IMPLEMENTATION OF MONITORING SIDE EFFECTS OF DRUGS IN DRUG-RESISTANT TUBERCULOSIS PATIENTS IN REFERRAL HOSPITALS: A QUALITATIVE STUDY

Drug-resistant tuberculosis (TB) is a public health problem that poses major challenges to patients, health workers, society, and the health care system. This research is a qualitative study to explore the implementation of drug side-effect monitoring and the role of health workers in handling side-effect monitoring medication for tuberculosis patients. We collected data through Focus Group Discussions (FGD) and conducted direct, in-depth interviews. The informants in this study were doctors, pharmacists, and nurses who were directly involved in treating drug-resistant tuberculosis patients. Two drug-resistant TB referral hospitals in the Cirebon area hosted the research. INVIVO 12 was used for qualitative analysis. Both hospitals still need to optimise the mechanism for tracking drug side effects in drug-resistant TB patients in accordance with the technical guidelines. Doctors at both hospitals play a significant role in implementation compared to other health workers. The similar role of doctors in both hospitals in implementation is in initial examination and history taking, determining causality, management, and education regarding drug side effects. Pharmacists have a similar role in managing drug side effects and documenting "unwanted events". The role of nurses in both hospitals is similar, namely providing patients with education on drug side effects. Efforts are needed to increase the implementation of monitoring of drug side effects by conducting assessments of the causality of drug side effects and documentation using specific instruments according to standards, ensuring the ensuring the completeness of manual monitoring forms, and providing continuous drug side effect monitoring training for health workers.

Synthesis of a PVA-GO drug delivery system for sustained release of 4-methyl umbelliferon

Introduction 4-methyl umbelliferon (4MU) is a coumarin with anti-inflammatory, anti-thrombotic, enzyme-inhibiting, and antioxidant properties. Despite the benefits of the compound, it is eliminated very quickly from the blood circulation through the liver, kidney, and digestive system due to its hydrophobic properties. In this study we proposed to improve the durability of 4MU by binding of 4MU to poly vinyl alcohol (PVA) and graphene oxide (GO). Methods The PVA-4MU-GO complex was synthesized and characterized. Release of 4MU from the complex was investigated. H9C2 cells viability was investigated and the entry of complex to the cell was analyzed using flow cytometry. Result UV-Vis and FTIR studies confirmed the interaction of 4MU with PVA and GO. SEM measurement also revealed a particle size around 101 nm for PVA-4MU-GO complexes. The obtained results confirmed the assembly of PVA-4MU-GO. A continuous drug release for 8 d (160 h) was achieved. Cytotoxic studies on H9C2 cell showed that PVA-4MU-GO complex is dependent to the concentration of GO and also the relation of 4MU to GO. Sustained release and penetration of PVA-4MU-GO complex into the H9C2 cell were observed. Conclusion PVA-4MU-GO complex is recommended as an alternative for 4MU. Synthesis the complex of PVA-4MU-GO, verifying the correct binding, showing the in vitro release of the 4MU, as well as checking its toxicity and its gradual entry into the H9C2 cell, were performed in this study.

Humanising and optimising HIV health care for refugees and asylum seekers.

Displaced populations living with HIV, including refugees and asylum seekers, face substantial challenges across various regions globally. The intersection of forced migration and HIV presents both shared challenges and region-specific differences. Key issues include little access to health care, pervasive stigma, discrimination, and disruptions in the continuity of HIV care. Refugees often encounter barriers such as legal, cultural, and economic disparities that impact their overall health outcomes. Although HIV prevalence differs across regions, displaced populations consistently face disproportionate challenges including high-risk environments and little health-care access. Addressing these challenges requires a focus on equitable health-care access, with both actionable local interventions and broader global policy changes and an emphasis on long-term sustainability. Reliable and continuous drug supplies, interagency collaboration, and holistic health-care approaches are essential. International collaboration, robust evidence generation, and comprehensive responses are urgently needed to address the complex interplay between forced migration and HIV among vulnerable populations.

Experimental study on online detection of near-infrared spectroscopy suitable for continuous drug production

Experimental study on online detection of near-infrared spectroscopy suitable for continuous drug production

PD-L1 antibody conjugated dihydrotanshinone I-loaded polymeric nanoparticle for targeted cancer immunotherapy combining PD-L1 blockade with immunogenic cell death

PurposeCombination immune checkpoint inhibitors (ICI) with chemotherapeutic agents has proven to be highly promising in cancer therapy. However, low response rate, immune-related adverse events, and lack of effectively targeted co-delivery strategy are still major hurdles to overcome for this combination therapeutic regimen. Herein, programmed death-L1 (PD-L1) antibody modified and dihydrotanshinone I (DHT) loaded nanoparticle was prepared for tumor targeting drug delivery, thus achieving immune checkpoint blockade (ICB) and immunogenic cell death (ICD) synergistic anti-tumor effects. MethodsThe DHT-loaded nanoparticle (DHT NP) was prepared by the emulsion solvent diffusion method. Atezolizumab (ATEZO) was thiolated with 2-iminothiolane and conjugated to the surface of DHT NP to prepare the ATEZO DHT NP. The drug encapsulation efficiency, drug loading, particle size and drug release were determined. The in vitro cellular uptake, cell proliferation inhibition and apoptosis were evaluated on the HGC-27 tumor cell. The in vivo tumor targeting, anti-tumor efficiency and immune regulation were assessed on tumor bearing mice. ResultsThe optimized ATEZO DHT NP was a spherical nanoparticle of about 250 nm with a continuous drug release profile. It was selectively taken up by the tumor cells through PD-L1 receptor-mediated endocytosis, which resulted in enhanced cytotoxicity and cell apoptosis. In vivo imaging further demonstrated its superior tumor tissue targeting ability. When tumor bearing mice were treated with the ATEZO DHT NP, its synergistic anti-tumor effect was much stronger than that of a single drug. Moreover, the tumor targeting delivery of DHT caused tumor necrosis and initiated ICD with release of tumor-associated antigens, which efficiently up-regulated the population of CD4+ and CD8+ T cells. Notably, there were no obvious system toxicity or tissue damage occur during the whole treatment period. ConclusionThe ATEZO DHT NP could specifically target to tumor and enhance treatment efficiency through combination of PD-L1 blockade with ICD effect.

DDEL-15. PHARMACOKINETIC ANALYSIS OF CARBOPLATIN AND FLUORESCEIN BRAIN PENETRATION AND PERMANENCE FOLLOWING ULTRASOUND-BASED BLOOD-BRAIN BARRIER OPENING ON GLIOBLASTOMA CLINICAL TRIAL

Abstract The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving drug delivery to the brain. The implication of this transient BBB opening on parenchymal drug permanence is unknown. We compared the parenchymal levels and permanence/retention of temozolomide, carboplatin, and fluorescein, and investigated in a clinical trial (NCT04528680) the effect of LIPU/MB on the permanence of carboplatin and fluorescein in the human brain. Four patients underwent intraoperative LIPU/MB (SonoCloud-9, Carthera) with intravenous carboplatin and fluorescein infusion. Microdialysis catheters were implanted into sonicated and non-sonicated brain for continuous drug measurement over 24 hours. Published data from a microdialysis study of temozolomide were used for comparison. Temozolomide and carboplatin exhibited similar brain-to-plasma AUC ratios (17.8 ± 13.3%; 16.3 ± 8.2%, respectively) which were higher than that of fluorescein (10.4 ± 6.9%). Parenchymal half-life was the longest for fluorescein (13.6 ± 11.0 hours), followed by carboplatin (5.1 ± 1.9 hours) and temozolomide (2.9 ± 1.6 hours). LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in AUC for both carboplatin (P = 0.02), and fluorescein (P = 0.04), and higher parenchymal than systemic drug levels starting at 21 hours and 7 hours for these drugs respectively (P < 0.05), timepoints where these drugs had mostly cleared from the plasma. Fluorescein exhibits prolonged permanence in the brain parenchyma and may be “trapped” by the BBB. In the context of transient BBB opening by LIPU/MB, parenchymal carboplatin and fluorescein concentrations remain elevated over time, supporting the notion that the BBB exhibits a bi-directional restriction of drug passage. Future studies are warranted to explore the efficacy of drug trapping to achieve prolonged/sustained exposure of cytotoxic drugs for brain tumor therapy.

Prevalence and antibiotic resistance of Staphylococcus aureus in wound infections: a hospital study in Hawassa, Ethiopia.

Wound infections are common nosocomial infections associated with increased morbidity and mortality. Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), is a major cause of hospital-acquired wound infections. This study aimed to determine the burden and antimicrobial susceptibility pattern of S. aureus and MRSA, among patients with wound infections at Hawassa University Comprehensive Specialized Hospital (HUCSH), Hawassa, Ethiopia. A hospital-based cross-sectional study was conducted on 246 admitted patients with wound infections at HUCSH from April to August 2021. Wound swabs were aseptically collected and cultured for bacterial isolation and drug susceptibility testing. Data were analyzed using SPSS version 20, and descriptive statistics were computed. Among the 246 clinical specimens analyzed, S. aureus was isolated from 57 (23.2%), of which 5 (8.8%) were identified as MRSA. All S. aureus strains were sensitive to linezolid. The highest resistance was observed for penicillin (52 strains, 91.2%), and 24.6% of S. aureus strains were found to be multidrug resistant. All MRSA strains were isolated from patients with no history of past wound infection, and all of them were sensitive to vancomycin. This study identified S. aureus (23.2%) and MRSA (8.8%) along with their antimicrobial resistance among patients with wound infections at HUCSH. A substantial proportion (24.6%) of S. aureus exhibited multidrug resistance. However, all MRSA isolates were sensitive to vancomycin. Continuous drug resistance monitoring (drug surveillance) is crucial to manage and prevent resistance spread in the hospital.