High Drug Concentrations Research Articles

Ultrasound Irradiation as a Candidate Procedure to Improve the Transdermal Drug Delivery to the Tail Edema of a Mouse Model

Drug therapy for secondary lymphedema has not yet been established. Conventional oral and intravenous administration is difficult to administer in sufficient doses due to adverse events. Therefore, it is necessary to develop a transdermal delivery system that can deliver high concentrations of drugs to the edema area. In this study, we examined the efficacy of transdermal drug delivery in a mouse model of tail edema using ultrasound irradiation (sonication method). Ultrasound irradiation can deliver high-molecular-weight substances subcutaneously, and the percutaneous administration of clobetasol propionate to the mouse tail edema model prevented the enlargement of lymphatic vessels with reduced tail volume. Therefore, steroid administration utilizing ultrasound irradiation is effective in decreasing tail swelling in a mouse tail edema model. Thus, ultrasound irradiation could have the potential to innovate the treatment of secondary lymphedema by directly administering the drug to the edema.

Subcutaneous versus intravenous infliximab therapy - a real-world study: toward higher drug concentrations.

Recently, a formula of subcutaneous infliximab (SC-IFX) has been approved for inflammatory bowel disease (IBD), demonstrating a better pharmacokinetic and immunogenic profiles, compared to intravenous infliximab (IV-IFX), with similar efficacy and safety. The aim of this study is to evaluate the clinical, biochemical, and pharmacological outcomes of IBD patients in clinical remission, who switched from IV-IFX to SC-IFX, with a follow-up period of 6 months. Retrospective cohort study, including IBD patients in clinical remission, previously medicated with IV-IFX, who switched to SC-IFX 120 mg every other week. Biochemical parameters were evaluated before the switch and 6 months after, namely infliximab serum concentrations, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin. Included 41 patients in clinical remission, 32 with Crohn's disease (78.0%) and 9 with ulcerative colitis (22.0%). All patients maintained clinical remission during the 6 months after the switch, with a treatment persistence rate of 100%, and no patients requiring corticosteroid therapy, switching back to IV-IFX, or IBD-related hospitalization. The mean infliximab serum concentrations were significantly higher after 6 months of SC-IFX (17.3 ± 6.6 vs. 9.1 ± 5.5 µg/ml, P < 0.001). However, there were no differences between values of ESR, CRP, and fecal calprotectin, before and after the switch ( P = 0.791, P = 0.246, and P = 0.639). Additionally, none of the patients developed antibodies to infliximab. Switching from IV-IFX to SC-IFX in IBD patients in clinical remission is effective and leads to higher infliximab serum concentrations, regardless of the combination with immunomodulatory therapy.

Region-independent active CNS net uptake of marketed H+/OC antiporter system substrates

The pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter system facilitates the active net uptake of several marketed organic cationic drugs across the blood-brain barrier (BBB). This rare phenomenon has garnered interest in the H+/OC antiporter system as a potential target for CNS drug delivery. However, analysis of pharmacovigilance data has uncovered a significant association between substrates of the H+/OC antiporter and neurotoxicity, particularly drug-induced seizures (DIS) and mood- and cognitive-related adverse events (MCAEs). This preclinical study aimed to elucidate the CNS regional disposition of H+/OC antiporter substrates at therapeutically relevant plasma concentrations to uncover potential pharmacokinetic mechanisms underlying DIS and MCAEs. Here, we investigated the neuropharmacokinetics of pyrilamine, diphenhydramine, bupropion, tramadol, oxycodone, and memantine. Using the Combinatory Mapping Approach for Regions of Interest (CMA-ROI), we characterized the transport of unbound drugs across the BBB in specific CNS regions, as well as the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). Our findings demonstrated active net uptake across the BBB and BSCB, with unbound ROI-to-plasma concentration ratio, Kp,uu,ROI, values consistently exceeding unity in all assessed regions. Despite minor regional differences, no significant distinctions were found when comparing the whole brain to investigated regions of interest, indicating region-independent active transport. Furthermore, we observed intracellular accumulation via lysosomal trapping for all studied drugs. These results provide new insights into the CNS regional neuropharmacokinetics of these drugs, suggesting that while the brain uptake is region-independent, the active transport mechanism enables high extracellular and intracellular drug concentrations, potentially contributing to neurotoxicity. This finding emphasizes the necessity of thorough neuropharmacokinetic evaluation and neurotoxicity profiling in the development of drugs that utilize this transport pathway.

Effects of Inosine-5′-monophosphate Dehydrogenase (IMPDH/GuaB) Inhibitors on Borrelia burgdorferi Growth in Standard and Modified Culture Conditions

Borrelia burgdorferi’s inosine-5′-monophosphate dehydrogenase (IMPDH, GuaB encoded by the guaB gene) is a potential therapeutic target. GuaB is necessary for B. burgdorferi replication in mammalian hosts but not in standard laboratory culture conditions. Therefore, we cannot test novel GuaB inhibitors against B. burgdorferi without utilizing mammalian infection models. This study aimed to evaluate modifications to a standard growth medium that may mimic mammalian conditions and induce the requirement of GuaB usage for replication. The effects of two GuaB inhibitors (mycophenolic acid, 6-chloropurine riboside at 125 μM and 250 μM) were assessed against B. burgdorferi (guaB+) grown in standard Barbour–Stoenner–Kelly-II (BSK-II) medium (6% rabbit serum) and BSK-II modified to 60% concentration rabbit serum (BSK-II/60% serum). BSK-II directly supplemented with adenine, hypoxanthine, and nicotinamide (75 μM each, BSK-II/AHN) was also considered as a comparison group. In standard BSK-II, neither mycophenolic acid nor 6-chloropurine riboside affected B. burgdorferi growth. Based on an ANOVA, a dose-dependent increase in drug effects was observed in the modified growth conditions (F = 4.471, p = 0.001). Considering higher drug concentrations at exponential growth, mycophenolic acid at 250 μM reduced spirochete replication by 48% in BSK-II/60% serum and by 50% in BSK-II/AHN (p &lt; 0.001 each). 6-chloropurine riboside was more effective in both mediums than mycophenolic acid, reducing replication by 64% in BSK-II/60% serum and 65% in BSK-II/AHN (p &lt; 0.001 each). These results demonstrate that modifying BSK-II medium with physiologically relevant levels of mammalian serum supports replication and induces the effects of GuaB inhibitors. This represents the first use of GuaB inhibitors against Borrelia burgdorferi, building on tests against purified B. burgdorferi GuaB. The strong effects of 6-chloropurine riboside indicate that B. burgdorferi can salvage and phosphorylate these purine derivative analogs. Therefore, this type of molecule may be considered for future drug development. Optimization of this culture system will allow for better assessment of novel Borrelia-specific GuaB inhibitor molecules for Lyme disease interventions. The use of GuaB inhibitors as broadcast sprays or feed baits should also be evaluated to reduce spirochete load in competent reservoir hosts.

Effect of drugs of various groups on the pharmacokinetics of cefotaxime in comparison with their effect on lymphatic tissue drainage

Introduction. The lymphatic system plays a key role in spreading pathogens, including those causing intraabdominal infections. An urgent task of pharmacology is to create methods for the targeted delivery of antibiotics to lymphatic vessels and intestinal tissues. One approach is to use agents acting as endolymphatic conductors to achieve a high drug concentration in the lymphatic system. Aim. To evaluate the effect of various drugs on the concentration of cefotaxime, a third-generation antibiotic, in blood and intestinal tissues, as well as on lymphatic drainage in experiments on mice. Materials and methods. We investigated the effect of hyaluronidase (HLRD), bovgialuronidase azoximer (BovGLRD+Az), terrilitin (TRL), papaya milky juice (PMJ ), sodium heparin (HepS ), aprotinin (APRT), azoximer bromide (AzBrom), furosemide (FRSD) and sodium deoxyribonucleate (DRN) on the removal time of lymphotropic dye from mouse mesentery and the cefotaxime concentration in blood plasma and intestinal tissues by high-performance liquid chromatography. Results. HLRD reduced the time of dye removal from the mesentery by 26.2%, BovGLRD+Az – by 33.5%, TRL – by 36%, PMS – by 23.1%, HepS – by 30.1%, APRT – by 34.6%. The differences in lymphostimulating activity between these drugs were not statistically significant. AzBrom and FRSD increased the dye removal time by 8.3% and 6%, respectively; the DRN had no effect. HLRD, BovGLRD, TRL, PMJ, HepS and APRT increased the CF concentration in blood and intestinal tissues 1.5 and 24 hours after injection, in contrast to the single injection of antibiotic. AzBrom increased the CF concentration only after 1.5 hours. FRSD increased the antibiotic concentration in intestinal tissues but not in blood plasma. The DRN did not affect the studied indicators. Conclusion. Lymphostimulating drugs HLRD, BovGLRD, TRL, PMJ, HepS and APRT effectively direct the antibiotic to the lymphatic system and can be used for lymphotropic therapy.

Enhancing mitochondrial functions in neuroinflammatory mouse model using isoflavones-loaded nanoparticles: A potential approach for Alzheimer's disease treatment

A significant reduction in mitochondrial functions, coupled with increased oxidative stress, is believed to trigger the histological changes associated with the Alzheimer's disease (AD). Daidzein (DEZ) and Daidzin (DZ), natural isoflavones, exhibit anti-oxidant properties and enhance mitochondrial biogenesis. However, their low solubility presents challenges for drug circulation and adversely affecting their bioavailability. Novel drug-delivery modalities capable of overcoming these limitations and facilitating brain delivery could enhance therapeutic outcomes. In this work, Tween 80-coated PLGA-NPs and chitosan-coated PLGA-NPs (CS-PLGA-NPs) loaded with DEZ and DZ were evaluated for their ability to enhance cognition in a neuroinflammatory mouse model. The hydrodynamic diameter and zeta potential were measured to be 62 ± 13 nm and −16.8 ±1 mV for PLGA-NPs and to 159 ± 5 nm and +31 ± 5 mV for CS-PLGA-NPs. Biodistribution studies revealed accumulation of both PLGA-NPs and CS-PLGA-NPs in the brain following intravenous administration to animals with neuroinflammation induced by lipopolysaccharides (LPS). Administration of drug-loaded NPs improved cognitive functions compared to untreated animals, in contrast to unloaded NPs or free DEZ and DZ. Animals treated with DEZ-CS-PLGA-NPs and DZ-CS-PLGA-NPs showed significant reductions in superoxide dismutase levels compared to those receiving LPS, suggesting a role in mitigating oxidative stress. When compared to animals receiving LPS, concentrations of Amyloid-β were markedly reduced and complex I activity and ATP levels were significantly increased in animals receiving drug-loaded NPs, unloaded NPs and free drugs, indicating enhanced mitochondrial functions. For drug delivery, CS-PLGA-NPs outperformed PLGA-NPs due sustained drug-release resulting in higher drug concentrations in the brain.

Intranasal Administration of Bedaquiline-Loaded Fucosylated Liposomes Provides Anti-Tubercular Activity while Reducing the Potential for Systemic Side Effects.

Liposomal formulations of antibiotics for inhalation offer the potential for the delivery of high drug doses, controlled drug release kinetics in the lung, and an excellent safety profile. In this study, we evaluated the in vivo performance of a liposomal formulation for the poorly soluble, antituberculosis agent, bedaquiline. Bedaquiline was encapsulated within monodisperse liposomes of ∼70 nm at a relatively high drug concentration (∼3.6 mg/mL). Formulations with or without fucose residues, which bind to C-type lectin receptors and mediate a preferential binding to macrophage mannose receptor, were prepared, and efficacy was assessed in an in vivo C3HeB/FeJ mouse model of tuberculosis infection (H37Rv strain). Seven intranasal instillations of 5 mg/kg bedaquiline formulations administered every second day resulted in a significant reduction in lung burden (∼0.4-0.6 Δlog10 CFU), although no differences between fucosylated and nonfucosylated formulations were observed. A pharmacokinetic study in healthy, noninfected Balb/c mice demonstrated that intranasal administration of a single dose of 2.5 mg/kg bedaquiline liposomal formulation (fucosylated) improved the lung bioavailability 6-fold compared to intravenous administration of the same formulation at the same dose. Importantly, intranasal administration reduced systemic concentrations of the primary metabolite, N-desmethyl-bedaquiline (M2), compared with both intravenous and oral administration. This is a clinically relevant finding as the M2 metabolite is associated with a higher risk of QT-prolongation in predisposed patients. The results clearly demonstrate that a bedaquiline liposomal inhalation suspension may show enhanced antitubercular activity in the lung while reducing systemic side effects, thus meriting further nonclinical investigation.

Antibiotic killing of drug-induced bacteriostatic cells.

There is a long-standing belief that bacteriostatic drugs are inherently antagonistic to the action of bactericidal antibiotics. This belief is primarily due to the fact that the action of most bactericidal antibiotics requires the target bacteria to be growing. Since bacteriostatic drugs stop the growth of treated bacteria, these drugs would necessarily work against one another. We have recently shown that bacteria treated with high concentrations of bacteriostatic drugs retain some metabolic activity, dividing on average once per day. We seek to determine if this low level of growth is sufficient to allow for bactericidal antibiotics of different classes to still kill after bacteria are treated with bacteriostatic drugs. We first treated Escherichia coli and Staphylococcus aureus with two different bacteriostatic drugs, followed by one of three bactericidal drugs of three different classes. The density of these bacteria was tracked over six days to determine the amount of killing that occurred. Our results question this long-standing belief by demonstrating conditions where sequential treatment with a bacteriostatic then bactericidal antibiotic is as or more effective than treatment with a bactericidal drug alone. These results raise the need to investigate the pharmacodynamics of the joint action of bacteriostatic and bactericidal antibiotics in vitro and in vivo.

Emergence of community behaviors in the gut microbiota upon drug treatment

Pharmaceuticals can directly inhibit the growth of gut bacteria, but the degree to which such interactions manifest in complex community settings is an open question. Here, we compared the effects of 30 drugs on a 32-species synthetic community with their effects on each community member in isolation. While most individual drug-species interactions remained the same in the community context, communal behaviors emerged in 26% of all tested cases. Cross-protection during which drug-sensitive species were protected in community was 6 times more frequent than cross-sensitization, the converse phenomenon. Cross-protection decreased and cross-sensitization increased at higher drug concentrations, suggesting that the resilience of microbial communities can collapse when perturbations get stronger. By metabolically profiling drug-treated communities, we showed that both drug biotransformation and bioaccumulation contribute mechanistically to communal protection. As a proof of principle, we molecularly dissected a prominent case: species expressing specific nitroreductases degraded niclosamide, thereby protecting both themselves and sensitive community members.

Organo magadiites for diclofenac adsorption: influence of the surfactant chain.

The presence of drugs in aquatic environments has been considered a global challenge and several remediation technologies have been proposed, including adsorption. In this study, new diclofenac adsorbents were obtained from the reaction of sodium magadiite (Na-Mag) with surfactants dodecylpyridinium chloride hydrate (C12pyCl) and hexadecylpyridinium chloride monohydrate (C16pyCl)), 1-hexadecyltrimethylammonium bromide (C16Br), and dodecyltrimethylammonium bromide (C12Br). The synthesis was carried out in the microwave at 50°C for 5min using surfactant amounts of 100% and 200% in relation to the cation exchange capacity of Na-Mag. The elemental analysis indicated that surfactants with a longer organic chain were more incorporated into Na-Mag, whose values were 1.42 and 1.32mmolg-1 for C16pyMag200% and C16Mag200%, respectively. X-ray diffraction results suggested formation of intercalated products with basal space in the range of 2.81-4.00nm. Diclofenac was quickly adsorbed on all organophilic magadiites, at an equilibrium time of 1min. Drug capacity adsorption was influenced by the arrangement and packing density of organic cations, the basal distance, and the organic contents of the samples at high drug concentrations. Alkylpyridinium magadiites exhibited maximum adsorption capacities higher than alkylammonium magadiites, of 96.4, 100.7, 131.7, and 166.1mgg-1 for C12pyMag100%, C12pyMag200%, C16pyMag100%, and C16pyMag200%, respectively, at pH 6.0 and 30°C. Diclofenac removal by samples was not affected by the presence of ibuprofen, which was also removed from binary system by organophilic magadiites reaching removal of 76.5% and 86.9% by C16pyMag100% and C16pyMag200%, respectively. Regeneration studies demonstrated a drug removal percentage of 83-92% for C16pyMag and C16Mag after three cycles of adsorption.

Integrating Vascular Phenotypic and Proteomic Analysis in an Open Microfluidic Platform.

This research introduces a vascular phenotypic and proteomic analysis (VPT) platform designed to perform high-throughput experiments on vascular development. The VPT platform utilizes an open-channel configuration that facilitates angiogenesis by precise alignment of endothelial cells, allowing for a 3D morphological examination and protein analysis. We study the effects of antiangiogenic agents─bevacizumab, ramucirumab, cabozantinib, regorafenib, wortmannin, chloroquine, and paclitaxel─on cytoskeletal integrity and angiogenic sprouting, observing an approximately 50% reduction in sprouting at higher drug concentrations. Precise LC-MS/MS analyses reveal global protein expression changes in response to four of these drugs, providing insights into the signaling pathways related to the cell cycle, cytoskeleton, cellular senescence, and angiogenesis. Our findings emphasize the intricate relationship between cytoskeletal alterations and angiogenic responses, underlining the significance of integrating morphological and proteomic data for a comprehensive understanding of angiogenesis. The VPT platform not only advances our understanding of drug impacts on vascular biology but also offers a versatile tool for analyzing proteome and morphological features across various models beyond blood vessels.

Hygrophilla Auriculata Extract Loaded Microemulsion gel for treatment of skin cancer

Globally, skin cancer is the most common type of cancer and is on the rise. It is broadly divided into Melanoma and Non-melanoma skin cancer, or Keratinocyte carcinoma, which are malignancies produced from melanocytes and epidermal cells, respectively. One of the most deadly malignant illnesses, cancer can spread to other tissues and organs and exhibit unchecked and aberrant cell division. Therefore, achieving a safe formulation for the treatment of skin cancer is important. The aim of this research is to formulate the Hygrophila Auriculata Flower extract Loaded Microemulsion Gel with small droplet size, high drug concentration, and high stability for skin application. A magnetic stirrer was used to create the Hygrophila Auriculata Flower extract Loaded Microemulsion, which was examined for morphology, clarity, dilution, zeta potential, particle size, stability, and chromatography. The cytotoxicity study of the formulation was performed in A431 cells and compared with a marketed formulation. The smallest particle size of the emulsion droplets improves the bioavailability of the drug, playing a vital role in skin penetration and effectiveness against skin cancer. Hence, the study predicts that the Hygrophila Auriculata Flower extract Loaded Microemulsion Gel could be effective for the treatment of skin cancer in the future.

Fabrication and Characterization of Andrographolide-loaded Microsponges to Enhance Oral Bioavailability of Drug against Colon Cancer Using HT29 Cells

Background: The current research aimed to determine ways to improve the bioavailability of andrographolide (AGP) for use in colon cancer treatment by developing and evaluating microsponges loaded with the drug. Methods: Utilising the quasi-emulsion solvent diffusion approach, microsponges containing AGP were synthesised. A total of ten formulations were prepared using different concentrations of drug, polymer and other excipients. Particle size, shape, and differential scanning calorimetry (DSC) were used to characterise the microsponges that were created. To find out the rate at which the microsponges would expel their contents, researchers measured their release dynamics. In vitro anticancer activity of formulation was determined using HT29 cells Results: Results showed that the percentage yield of the formulations ranged from 10.85-41.03%. The highest drug concentration was achieved in formulation F8 with a particle size of 33.7 nm. SEM analysis demonstrated that the particles were round and possessed a rough and porous surface. Increasing the ratio of ethyl cellulose to AGP reduces surface roughness. The microsponge's DSC difractogram reveals prominent peaks at 18°, 24°, and 38° (2 θ) with reduced intensity, suggesting that the microsponges' crystalline character has diminished. In vitro drug release study showed 93.85% release upto 12 hours. Mathematical models showed normal release of the formulations with “n” values greater than 0.90 of all the formulations. Formulation F8 decreased the HT-29 cells' ability to survive. The percentage of cell cytotoxicity was 75.54 at 100μg/ml. Since AGP microsponges had a detrimental effect on the survival of colorectal cancer cells. Conclusion: It can be concluded from the study that prepared formulations possess anticancer properties against cancerous cells and can be used as an alternative anticancer drug.

Antifungal activity of Cinnamaldehyde derivatives against fluconazole-resistant Candida albicans

BackgroundCandida albicans is an opportunistic pathogen commonly found in human mucous membranes. In light of the escalating challenge posed by antibiotic resistance of C. albicans strains worldwide, it is an urgently necessary to explore alternative therapeutic options. ObjectiveThis study aims to assess the efficacy of two Cinnamaldehyde derivatives, 2-Cl Cinnamaldehyde (2-Cl CA) and 4-Cl Cinnamaldehyde (4-Cl CA), against C. albicans through both in vitro experiments and in vivo murine models and to evaluate their potential as new drug candidates for treating C. albicans. Methods and resultsThe minimum inhibitory concentrations (MICs) of Cinnamaldehyde 2-Cl and 4-Cl benzene ring derivatives against C. albicans were 25 μg/mL. Time-killing experiments revealed that both Cinnamaldehyde derivatives exhibited fungicidal activity against C. albicans at concentrations of 5 MIC and 10 MIC. In the checkerboard experiment, 4-Cl CA did not show any antagonistic effect when combined with first-line antifungal drugs. Instead, it exhibited additive effects in combination with nystatin. Both 2-Cl and 4-Cl CA demonstrated inhibitory activity against C. albicans biofilm formation, especially at 8 MIC and 16 MIC concentrations. In C. albicans biofilm eradication experiments, although high drug concentrations of 2-Cl and 4-Cl CA were unable to eradicate the biofilm completely, they were still effective in killing C. albicans cells within the biofilm. Moreover, sub-inhibitory concentrations of 4-Cl CA (ranging from 5 to 20 μg/mL) significantly inhibited cell aggregation and hyphal formation. Furthermore, 4-Cl CA effectively inhibited intracellular C. albicans infection in macrophages. Lastly, the effectiveness of 4-Cl CA was evaluated in a mouse model of hematogenous disseminated candidiasis caused by C. albicans, which revealed that 4-Cl CA significantly reduced fungal burden and improved mouse survival compared to the untreated controls. ConclusionThe 4-Cl CA exhibited inhibitory effects against C. albicans through both in vivo and in vitro models, demonstrating its therapeutic potential as a promising new drug candidate for treating drug-resistant candidiasis albicans.

Controlled Transdermal Delivery of Dexamethasone for Pain Management via Photochemically 3D-Printed Bioresorbable Microneedle Arrays.

Microneedle array patches (MAPs) are extensively studied for transdermal drug delivery. Additive manufacturing enables precise control over MAP customization and rapid fabrication. However, the scope of 3D-printable, bioresorbable materials is limited. Dexamethasone (DXM) is widely used to manage inflammation and pain, but its application is limited by systemic side effects. Thus, it is crucial to achieve high local drug concentrations while maintaining low serum levels. Here, poly(propylene fumarate-co-propylene succinate) oligomers are fabricated into DXM-loaded, bioresorbable MAPs via continuous liquid interface production 3D printing. Thiol-ene click chemistry yields MAPs with tailorable mechanical and degradation properties. DXM-loaded MAPs exhibit controlled elution of drug in vitro. Transdermal application of DXM-loaded MAPs in a murine tibial fracture model leads to substantial relief of postoperative pain. Pharmacokinetic analysis shows that MAP administration is able to control pain at a significantly lower dose than intravenous administration. This work expands the material properties of 3D-printed poly(propylene fumarate-co-propylene succinate) copolyesters and their use in drug delivery applications.

Illuminating the fight against breast cancer: Preparation and visualized photothermal therapy of hyaluronic acid coated ZIF-8 loading with indocyanine green and cryptotanshinone for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by higher recurrence rate and mortality. Thermally-mediated ablation via photothermal therapy (PTT) demonstrates considerable promise for the eradication of breast cancer. Nonetheless, the efficacy of PTT is impeded by the thermal tolerance of tumor cells, which is attributed to the augmented expression of heat shock proteins (HSPs). These proteins, which function as ATP-dependent molecular chaperones, confer protection to cancer cells against the cytotoxic heat generated during PTT. Glycolysis is an important way for breast cancer cells to produce ATP, which can promote the occurrence and development of lung metastasis of breast cancer. Therefore, inhibiting glycolysis may diminish the expression of HSPs, curtail the growth of breast cancer, and prevent its metastasis. Glycolytic metabolism plays a pivotal role in the ATP biosynthesis within breast cancer cells, facilitating the progression and dissemination of pulmonary metastases. Consequently, targeting glycolysis presents a strategic approach to HSP expression, the proliferation of breast cancer, and impede its metastatic spread. Herein, we designed an indocyanine green (ICG) and cryptotanshinone (CTS) loaded hyaluronic acid (HA) coated Zeolitic Imidazolate Framework-8 (ZIF-8) drug delivery system. The drug delivery system had excellent photothermal properties, which could reach temperature sufficient for photothermal ablation of tumor cells. (ICG + CTS)@HA-ZIF-8 also showed pH-responsive drug release, enhancing the sustained release of ICG and CTS to extend their systemic circulation duration. Moreover, the HA modification of ZIF-8 served to augment its targeting capabilities both in vitro and in vivo, leveraging the enhanced permeation and retention (EPR) effect, as well as active tumor targeting via the CD44 receptor pathway, resulting in a higher drug concentration and a better therapeutic effect in tumor. (ICG + CTS)@HA-ZIF-8 could downregulate the expression of glycolysis-related protein pyruvate kinase-M2 (PKM2), thereby inhibiting the glycolysis process, further suppressing tumor cell energy metabolism, downregulating the expression of HSPs, overcoming tumor cell heat resistance, and improving PTT effect. It exhibited a notable suppressive impact on both the proliferation and migration of breast cancer cells, potentially offering innovative insights for the visualized PTT in breast cancer treatment.

Antiretroviral therapy adherence among peripartum women with HIV in Kenya: an explanatory mixed methods study using dry blood spot measures and narrative interviews

ABSTRACT Adherence to antiretroviral therapy (ART) remains sub-optimal among pregnant and postpartum women with HIV (PPWH) in high HIV prevalence low resource settings with few effective behavioral interventions. A large body of qualitative literature has established general barriers and facilitators to ART adherence in PPWH at various levels (individual, interpersonal, structural). However, research exploring the underlying behavioral mechanisms of ART adherence in PPWH with objectively verified adherence biomarkers is extremely limited. We conducted 24 in-depth interviews with postpartum women in western Kenya who had linked ART drug concentrations obtained from three dried blood spot samples across the peripartum period. Among PPWH with a low drug concentration (n = 13) compared to those with continuously high drug concentrations (n = 11), distinct themes emerged related to HIV status disclosure, social support, interactions with the health system, and health beliefs. By combining ART biomarkers with patient reported challenges, there is the potential for real-time interventions to support sustained ART adherence among PPWH and improve maternal and infant health outcomes.

Supersolubilization and Amorphization of a Weakly Acidic Drug, Flurbiprofen, by applying Acid-Base supersolubilization (ABS) principle

Improvement in drug solubility is a major challenge for developing pharmaceutical products. It was demonstrated earlier that aqueous solubilities of weakly basic drugs could be increased greatly by interaction with weak acids that would not form salts with the drugs, and the highly concentrated solutions thus produced converted to amorphous solids upon drying. The technique was called acid-base supersolubilization (ABS). The current investigation explored whether the ABS principle could also be applied to weakly acidic drugs. By taking flurbiprofen (pKa 4.09; free acid solubility 0.011 mg/mL) as the model weakly acidic drug and tromethamine, lysine, meglumine, and NaOH as bases, it was studied which of the bases would result in ABS. While in the presence of NaOH and tromethamine, flurbiprofen converted to salts having aqueous solubility of 11–19 mg/mL, the solubility increased to > 399 mg/mL with lysine and > 358 mg/mL with meglumine, producing supersolubilization. However, crystallization of lysine salt was observed with time, followed by some decrease in solubility after reaching maximum solubility with lysine. In contrast, the supersolubilization was maintained with meglumine, and no crystallization of meglumine salt was observed. Upon drying, flurbiprofen-meglumine solutions produced amorphous materials that dissolved rapidly and produced high drug concentrations in aqueous media. Thus, the ABS principle also applies to acidic drugs depending on the weak base used.

Magic Touch sirolimus-coated balloon: animal and clinical evidence of a coronary sirolimus drug-coated balloon.

The Magic Touch sirolimus-coated balloon (SCB) was recently introduced in Europe and features robust clinical technology different from other devices on the market. This device is able to deliver a sufficient sirolimus dose to the target segment to reduce neointimal proliferation with very little exposure downstream and no apparent adverse effects at sustained high drug concentrations. The SCB represents a promising novelty within the drug-coated balloon arena due to its mid-term efficacy and safety in the treatment of coronary artery disease, especially in de novo and small-vessel coronary lesions. The purpose of this article is to provide an up-to-date overview of the currently available animal and clinical trial results, as well as to highlight ongoing trials on the Magic Touch SCB.

Contemporary directions in the therapy of sensory hearing loss

&lt;b&gt;Introduction:&lt;/b&gt; More than 5% of the world’s population experience hearing impairment. The most common form is presbycusis (age-related hearing loss; ARHL). It affects almost one in three people over the age of 65. The hair cells of the cochlea play an important role in the process of sound registration. Genetic mutations, aging and environmental factors can cause damage that contributes to the hearing loss.&lt;b&gt;Methods and results:&lt;/b&gt; The currently explored research directions include drug treatments, gene therapies, and stem cell therapies. To date, no significant differences in the therapeutic effect depending on the route of corticosteroid administration have been demonstrated in patients with moderate to severe hearing loss. New dexamethasone-containing hydrogel formulations, as well as lipid formulations, thermosensitive polymers, and nanoparticles, have been developed to achieve high drug concentrations in the inner ear structures. Otoprotective effects of antioxidants or substances that modify the toxic effects of e.g. cisplatin, are also being studied. Attempts at auditory cells’ regeneration seem promising in hearing loss research. Substances that regulate the central mechanisms of the Notch and Wnt pathways are being explored to this end. The genetic determinants of presbycusis suggest that interference at the level of specific genes may be a promising option for the treatment of this condition. With the CRISPR/Cas9 technology, the functions of inner ear genes can be effectively studied by disrupting normal gene alleles. The CRISPR/Cas9 complexes developed to target specific genes are delivered using cationic lipids, proteins, and viral vectors. They are then transported through the round window membrane by diffusion, without the need to surgically disrupt the inner ear. The potential of using antisense oligonucleotides to treat hereditary deafness caused by hair cell degeneration has also been established. Another research direction is related to stem cells being used for the development of in vitro 3D models of the human inner ear. Studies are also pursued to identify the mechanisms underlying the formation of cochlear organoids from pluripotent cells as well as determine the critical time points and events for cochlear sensory epithelial development and targeted hair cell differentiation.&lt;b&gt;Conclusions:&lt;/b&gt; In summary, significant progress has been made over the past decade in the search for novel therapies for sensory hearing loss. This line of research remains an ambitious and important area for further exploration.