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Pharmaceutics Jun 2024The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis....
The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis. As a non-invasive therapeutic method, radiotherapy is utilized for tumor ablation. In this study, we aimed to improve the therapeutic impact of radiotherapy and trigger an immune response by formulating a benzothiazole sulfinate (BTS)-loaded fusion liposome (BFL) nanoplatform, which was then combined with radiotherapy for anti-cancer treatment. The platelet cell membrane, equipped with distinctive surface receptors, enables BFL to effectively target tumors while evading the immune system and adhering to tumor cells. This facilitates BFL's engulfment by cancer cells, subsequently releasing BTS within them. Following the release, the BTS produces sulfur dioxide (SO) for gas therapy, initiating the oxidation of intracellular glutathione (GSH). This process demonstrates efficacy in repairing damage post-radiotherapy, thereby achieving effective radiosensitization. It was revealed that an immune response was triggered following the enhanced radiosensitization facilitated by BFL. This approach facilitated the maturation of dendritic cell (DC) within lymph nodes, leading to an increase in the proportion of T cells in distant tumors. This resulted in significant eradication of primary tumors and inhibition of growth in distant tumors. In summary, the integration of personalized BFL with radiotherapy shows potential in enhancing both tumor immune response and the elimination of tumors, including metastasis.
PubMed: 38931953
DOI: 10.3390/pharmaceutics16060833 -
Pharmaceutics Jun 2024Progesterone (PROG) is a natural steroid hormone with low solubility and high permeability that belongs to biopharmaceutics classification system class II. In this...
Progesterone (PROG) is a natural steroid hormone with low solubility and high permeability that belongs to biopharmaceutics classification system class II. In this study, novel pharmaceutical cocrystals of PROG were successfully prepared by solvent evaporation or a liquid-assisted grinding process aimed at enhancing its solubility and bioavailability. The cocrystal formers selected based on crystal engineering principles were carboxylic acids, namely, 4-formylbenzeneboronic acid (BBA), isophthalic acid (IPA), and 3-nitrophthalic acid (NPA). The cocrystal structures were characterized using multiple techniques. Single-crystal X-ray diffraction results showed that the carbonyl group, acting as a hydrogen bond acceptor, was pivotal in the cocrystal network formation, with C-H···O interactions further stabilizing the crystals. The cocrystals exhibited improved solubility and dissolution profiles in vitro, with no significant changes in hygroscopicity. The parallel artificial membrane permeability assay (PAMPA) models indicated that the cocrystals retained PROG's high permeability. Pharmacokinetic studies in Sprague-Dawley rats revealed that all cocrystals increased PROG exposure, with AUC values for PROG-BBA, PROG-IPA, and PROG-NPA being 742.59, 1201.72 and 442.67 h·ng·mL, respectively. These values are substantially higher compared to free PROG, which had an AUC of 301.48 h·ng·mL. Notably, PROG-IPA provided the highest AUC improvement, indicating a significant enhancement in bioavailability. Collectively, the study concludes that the cocrystal approach is a valuable strategy for optimizing the physicochemical properties and oral bioavailability of PROG, with potential implications for the development of other poor water-soluble drugs.
PubMed: 38931937
DOI: 10.3390/pharmaceutics16060816 -
Pharmaceutics Jun 2024Novel antifungal drugs are urgently needed to treat candidiasis caused by the emerging fungal multidrug-resistant pathogen . In this study, the most cost-effective drug...
Novel antifungal drugs are urgently needed to treat candidiasis caused by the emerging fungal multidrug-resistant pathogen . In this study, the most cost-effective drug repurposing technology was adopted to identify an appropriate option among the 1615 clinically approved drugs with anti- activity. High-throughput virtual screening of 1,3-beta-glucanosyltransferase inhibitors was conducted, followed by an analysis of the stability of 1,3-beta-glucanosyltransferase drug complexes and 1,3-beta-glucanosyltransferase-dutasteride metabolite interactions and the confirmation of their activity in biofilm formation and planktonic growth. The analysis identified dutasteride, a drug with no prior antifungal indications, as a potential medication for anti- activity in seven clinical isolates from Saudi Arabian patients. Dutasteride was effective at inhibiting biofilm formation by while also causing a significant reduction in planktonic growth. Dutasteride treatment resulted in disruption of the cell membrane, the lysis of cells, and crushed surfaces on , and significant (-value = 0.0057) shrinkage in the length of was noted at 100,000×. In conclusion, the use of repurposed dutasteride with anti-. potential can enable rapid recovery in patients with difficult-to-treat candidiasis caused by and reduce the transmission of nosocomial infection.
PubMed: 38931930
DOI: 10.3390/pharmaceutics16060810 -
Neuroprotective Activity of a Non-Covalent Imatinib+TP10 Conjugate in HT-22 Neuronal Cells In Vitro.Pharmaceutics Jun 2024This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson's disease. Through...
This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson's disease. Through the inhibition of c-Abl, which is a non-receptor tyrosine kinase and an indicator of oxidative stress, imatinib has shown promise in preclinical animal models of this disease. The poor distribution of imatinib within the brain tissue triggered experiments in which a conjugate was obtained by mixing the drug with TP10, which is known for exhibiting high translocation activity across the cell membrane. The conjugate was tested on the HT-22 cell line with respect to its impact on MPP-induced oxidative stress, apoptosis, necrosis, cytotoxicity, and mortality. Additionally, it was checked whether the conjugate activated the ABCB1 protein. The experiments indicated that imatinib+PEG+TP10 reduced the post-MPP oxidative stress, apoptosis, and mortality, and these effects were more prominent than those obtained after the exposition of the HT-22 cells to imatinib alone. Its cytotoxicity was similar to that of imatinib itself. In contrast to imatinib, the conjugate did not activate the ABCB1 protein. These favorable qualities of imatinib+PEG+TP10 make it a potential candidate for further in vivo research, which would confirm its neuroprotective action in PD-affected brains.
PubMed: 38931899
DOI: 10.3390/pharmaceutics16060778 -
Pharmaceutics Jun 2024Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended,...
BACKGROUND
Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU/mL. Owing to heparin's heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. The aim of this study was to build a pharmacokinetic model of heparin accounting for potential confounders, and derive an optimized dosing regimen for a given anti-Xa target.
METHODS
Adult patients undergoing VA-ECMO were included between January 2020 and June 2021. Anticoagulation was managed with an initial 100 IU/kg heparin loading dose followed by a continuous infusion targeting 0.2 to 0.7 IU/mL anti-Xa. The data were split into model development and model validation cohorts. Statistical analysis was performed using a nonlinear mixed effects modeling population approach. Model-based simulations were performed to develop an optimized dosing regimen targeting the desired anti-Xa.
RESULTS
A total of 74 patients were included, with 1703 anti-Xa observations. A single-compartment model best fitted the data. Interpatient variability for distribution volume was best explained by body weight, C-reactive protein and ECMO indication (post-cardiotomy shock or medical cardiogenic shock), and interpatient variability for elimination clearance was best explained by serum creatinine and C-reactive protein. Simulations using the optimized regimen according to these covariates showed accurate anti-Xa target attainment.
CONCLUSION
In adult patients on VA-ECMO, heparin's effect increased with serum creatinine and medical indication, whereas it decreased with body weight and systemic inflammation. We propose an optimized dosing regimen accounting for key covariates, capable of accurately predicting a given anti-Xa target.
PubMed: 38931891
DOI: 10.3390/pharmaceutics16060770 -
Pharmaceutics May 2024The treatment of skin and soft tissue infections (SSTIs) can be challenging due to bacterial resistance, particularly from strains like MRSA and biofilm formation....
The treatment of skin and soft tissue infections (SSTIs) can be challenging due to bacterial resistance, particularly from strains like MRSA and biofilm formation. However, combining conventional antibiotics with natural products shows promise in treating SSTIs. The objective of this study is to develop a nanoemulsion-based hydrogel containing extract and mupirocin and evaluate its potential for the treatment of SSTIs. The nanoemulsion was obtained by phase inversion and subsequently characterized. The antibacterial activity was evaluated in vitro against MRSA, including the synergism of the combination, changes in membrane permeability using flow cytometry, and the anti-biofilm effect. In addition, the irritative potential was evaluated by the HET-CAM assay. The combination exhibited synergistic antibacterial activity against and MRSA due to the extract enhancing membrane permeability. The hydrogel demonstrated suitable physicochemical properties, inhibited biofilm formation, and exhibited low irritation. The formulation was nanometric (176.0 ± 1.656 nm) and monodisperse (polydispersity index 0.286 ± 0.011). It exhibited a controlled release profile at 48 h and high encapsulation efficacy (94.29 ± 4.54% for quercitrin and 94.20 ± 5.44% for mupirocin). Therefore, these findings suggest that the hydrogel developed could be a safe and effective option for treating SSTIs.
PubMed: 38931824
DOI: 10.3390/pharmaceutics16060700 -
Sensors (Basel, Switzerland) Jun 2024As a noninvasive neuromodulation technique, transcranial magnetic stimulation (TMS) has important applications both in the exploration of mental disorder causes and the...
As a noninvasive neuromodulation technique, transcranial magnetic stimulation (TMS) has important applications both in the exploration of mental disorder causes and the treatment of mental disorders. During the stimulation, the TMS system generates the intracranial time-varying induced E-field (E-field), which alters the membrane potential of neurons and subsequently exerts neural regulatory effects. The temporal waveform of the induced E-fields is directly related to the stimulation effect. To meet the needs of scientific research on diversified stimulation waveforms and flexible adjustable stimulation parameters, a novel efficient pulse magnetic stimulation circuit (the EPMS circuit) design based on asymmetric cascaded multilevel technology is proposed in this paper. Based on the transient analysis of the discharge circuit, this circuit makes it possible to convert the physical quantity (the intracranial induced E-field) that needs to be measured after magnetic stimulation into easily analyzable electrical signals (the discharge voltage at both ends of the stimulation coil in the TMS circuit). This EPMS circuit can not only realize monophasic and biphasic cosine-shaped intracranial induced E-fields, which are widely used in the market, but also realize three types of new intracranial induced E-field stimulation waveform with optional amplitude and adjustable pulse width, including monophasic near-rectangular, biphasic near-rectangular and monophasic/biphasic ladder-shaped stimulation waveform, which breaks through the limitation of the stimulation waveform of traditional TMS systems. Among the new waveforms produced by the EPMS circuit, further research was conducted on the dynamic response characteristics of neurons under the stimulation of the biphasic four-level waveform (the BFL waveform) with controllable parameters. The relationship between TMS circuit parameters (discharge voltage level and duration) and corresponding neural response characteristics (neuron membrane potential change and neuronal polarizability ratio) was explained from a microscopic perspective. Accordingly, the biological physical quantities (neuronal membrane potential) that are difficult to measure can be transformed into easily analyzable electrical signals (the discharge voltage level and duration). Results showed that compared with monophasic and biphasic cosine induced E-fields with the same energy loss, the neuron polarization ratio is decreased by 54.5% and 87.5%, respectively, under the stimulation of BFL waveform, which could effectively enhance the neuromodulation effect and improve the stimulation selectivity.
Topics: Transcranial Magnetic Stimulation; Humans; Neurons; Animals; Equipment Design
PubMed: 38931623
DOI: 10.3390/s24123839 -
Pharmaceuticals (Basel, Switzerland) May 2024Mesenchymal stem cells (MSCs) have emerged as a promising approach for drug delivery strategies because of their unique properties. These strategies include stem cell... (Review)
Review
Mesenchymal stem cells (MSCs) have emerged as a promising approach for drug delivery strategies because of their unique properties. These strategies include stem cell membrane-coated nanoparticles, stem cell-derived extracellular vesicles, immunomodulatory effects, stem cell-laden scaffolds, and scaffold-free stem cell sheets. MSCs offer advantages such as low immunogenicity, homing ability, and tumor tropism, making them ideal for targeted drug delivery systems. Stem cell-derived extracellular vesicles have gained attention for their immune properties and tumor-homing abilities, presenting a potential solution for drug delivery challenges. The relationship between MSC-based drug delivery and the self-renewal and differentiation capabilities of MSCs lies in the potential of engineered MSCs to serve as effective carriers for therapeutic agents while maintaining their intrinsic properties. MSCs exhibit potent immunosuppressive functions in MSC-based drug delivery strategies. Stem cell-derived EVs have low immunogenicity and strong therapeutic potential for tissue repair and regeneration. Scaffold-free stem cell sheets represent a cutting-edge approach in regenerative medicine, offering a versatile platform for tissue engineering and regeneration across different medical specialties. MSCs have shown great potential for clinical applications in regenerative medicine because of their ability to differentiate into various cell types, secrete bioactive factors, and modulate immune responses. Researchers are exploring these innovative approaches to enhance drug delivery efficiency and effectiveness in treating various diseases.
PubMed: 38931374
DOI: 10.3390/ph17060707 -
Pharmaceuticals (Basel, Switzerland) May 2024This study aimed to extract bioactive proteins and protein hydrolysates from larvae and assess their potential application in cosmetics as well as their irritation...
This study aimed to extract bioactive proteins and protein hydrolysates from larvae and assess their potential application in cosmetics as well as their irritation properties. The larvae were defatted and extracted using various mediums, including DI water, along with 0.5 M aqueous solutions of sodium hydroxide, ascorbic acid, citric acid, and hydrochloric acid. Subsequently, the crude proteins were hydrolyzed using the Alcalase enzyme. All extracts underwent testing for antioxidant activities via the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) and Griess assays. Anti-aging properties were evaluated in terms of anti-collagenase and anti-hyaluronidase effects. Irritation potential was assessed using the hen's egg chorioallantoic membrane (HET-CAM) test. The results revealed that the sodium hydroxide extraction showed promising outcomes in terms of yield, protein content, and effectiveness in inhibiting hyaluronidase, with the highest inhibition at 78.1 ± 1.5%, comparable to that of oleanolic acid. Conversely, crude protein extracted with ascorbic acid and its hydrolysate showed notable antioxidant and collagenase-inhibitory activities. Remarkably, their anti-collagenase effects were comparable to those of ascorbic acid and lysine. Additionally, it demonstrated safety upon testing with the CAM. In conclusion, the findings provided valuable insights into the utilization of larval proteins as active ingredients with a wide range of cosmeceutical applications, particularly due to their antioxidant, anti-aging, and low irritation properties, which hold significant promise for anti-skin wrinkles.
PubMed: 38931346
DOI: 10.3390/ph17060679 -
Pharmaceuticals (Basel, Switzerland) May 2024Liver cancer ranks among the most prevalent malignancies globally and stands as a leading cause of cancer-related mortality. Numerous isothiazolone derivatives and...
Liver cancer ranks among the most prevalent malignancies globally and stands as a leading cause of cancer-related mortality. Numerous isothiazolone derivatives and analogues have been synthesized and investigated for their potential as anticancer agents; however, limited data exist regarding their efficacy against liver cancer. In the present study, two nitrophenyl-isothiazolones, the 5-benzoyl-2-(4-nitrophenyl)isothiazol-3(2H)-one (IsoA) and the 2-(4-nitrophenyl)isothiazol-3(2H)-one (IsoB), were preliminarily investigated for their cytotoxicity against hepatoma human (Huh7) cells as a liver cancer model and Immortalized Human Hepatocytes (IHHs) as a model of non-cancerous hepatocytes. IsoB, derived from IsoA after removal of the benzoyl moiety, demonstrated the highest cytotoxic effect against Huh7 cells with CC values of 19.3 μΜ at 24 h, 16.4 μΜ at 48 h, and 16.2 μΜ at 72 h of incubation, respectively. IsoB also exhibited selective toxicity against the liver cancerous Huh7 cells compared to IHH cells, reinforcing its role as a potent and selective anticancer agent. Remarkably, the cytotoxicity of IsoB was higher when compared with the standard chemotherapeutical agent 5-fluorouracil (5-FU), which also failed to exhibit higher toxicity against the liver cancerous cell lines. Moreover, IsoB-treated Huh7 cells presented a noteworthy reduction in mitochondrial membrane potential (ΔΨm) after 48 and 72 h, while mitochondrial superoxide levels showed an increase after 24 h of incubation. The molecular mechanism of the IsoB cytotoxic effect was also investigated using RT-qPCR, revealing an apoptosis-mediated cell death along with tumor suppressor TP53 overexpression and key-oncogene MYCN downregulation.
PubMed: 38931341
DOI: 10.3390/ph17060673