The data-driven approach of supervised learning methods has limited applicability in solving dipole inversion in Quantitative Susceptibility Mapping (QSM) with varying scan parameters across different objects. To address this generalization issue in supervised QSM methods, we propose a novel training-free model-based unsupervised method called MoDIP (Model-based Deep Image Prior). MoDIP comprises a small, untrained network and a Data Fidelity Optimization (DFO) module. The network converges to an interim state, acting as an implicit prior for image regularization, while the optimization process enforces the physical model of QSM dipole inversion. Experimental results demonstrate MoDIP\'s excellent generalizability in solving QSM dipole inversion across different scan parameters. It exhibits robustness against pathological brain QSM, achieving over 32 % accuracy improvement than supervised deep learning methods. It is also 33 % more computationally efficient and runs 4 times faster than conventional DIP-based approaches, enabling 3D high-resolution image reconstruction in under 4.5 min.

This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A microsomal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the concentrations of blonanserin and its metabolite. Compared with wild type CYP34A, the relative clearance of blonanserin by CYP3A4.29 significantly increased to 251.3%, while it decreased notably with CYP3A4.4, 5, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 23, 24, 28, 31, 33, and 34, ranging from 6.09% to 63.34%. Among 153 tested drugs, nimodipine, felodipine, and amlodipine were found to potently inhibit the metabolism of blonanserin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half-maximal inhibitory concentration and enzymatic kinetics assay demonstrated that the metabolism of blonanserin was noncompetitively inhibited by nimodipine in rat liver microsomes and was inhibited in a mixed manner by felodipine and amlodipine in both rat liver microsomes and human liver microsomes. When nimodipine and felodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-∞), and C max of blonanserin increased. When amlodipine and blonanserin were combined, the C max of blonanserin C increased remarkably. The vast majority of CYP3A4 variants have a low ability to catalyze blonanserin. With combined administration of nimodipine, felodipine, and amlodipine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin. SIGNIFICANCE STATEMENT: The enzyme kinetics of novel CYP3A4 enzymes for metabolizing blonanserin were investigated. Clearance of blonanserin by CYP3A4.4, 5, 7-10, 12-14, 16-18, 23-24, 28, 31, 33, and 34 decreased notably, but increased with CYP3A4.29. Additionally, we established a drug interaction spectrum for blonanserin, in which nimodipine, felodipine, and amlodipine kinetics exhibited mixed inhibition. Moreover, their inhibitory potencies decreased with CYP3A4.4 and 5 compared to CYP3A4.1. This study provides essential data for personalized clinical use of blonanserin.

This study aimed to explore the role and mechanism of felodipine in lung cancer therapy. Murine subcutaneous lung squamous cancer (LUSC) models constructed by KLN-205 cells were utilized to assess the effect of felodipine monotherapy and in combination with the programmed cell death protein 1 antibody (PD1ab) and cytotoxic T lymphocyte-associated antigen-4 (CTLA4ab). Immunohistochemistry analysis was subsequently applied to detect the number of CD8+ T cells and Ki67+ cells. Lastly, a series of in vitro and in vivo experiments were performed to evaluate the effects of felodipine on human LUSC cells and explore the preliminary mechanism underlying felodipine inhibition. The results revealed that felodipine monotherapy exerted a significant inhibitory effect on LUSC growth and synergistic antitumoral activity with PD1ab and CTLA4ab. Meanwhile, immunohistochemistry analysis displayed that felodipine promoted CD8+ T-cell infiltration and downregulated Ki67 expression in tumor cells. Moreover, in vitro and in vivo experiments utilizing human LUSC cells determined that felodipine impaired the proliferative and migratory abilities of cancer cells. In addition, TCGA data analysis uncovered that nuclear factor of activated T cell (NFAT1) expression was positively correlated with overall survival and disease-free survival. Finally, the cell counting kit-8 assay signaled that felodipine might suppress tumor growth by modulating NFAT1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this \"two-cell\" (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.

Inhomogeneity is a key factor that significantly influences the dissolution behavior of amorphous solid dispersion (ASD). However, the underlying mechanisms of the effects of inhomogeneous phase on the dissolution characteristics as well as the bioavailability of ASDs are still unclear. In this study, two types of felodipine/PVPVA based ASDs with 30 wt % drug loading but different homogeneity were prepared: homogeneous \"30 wt % ASD\" prepared by spray drying, as well as inhomogeneous \"30 wt % PM\" prepared by physically mixing the sprayed dried 70 wt % ASD with PVPVA. We aimed to investigate (1) drug-polymer interaction mechanism and \"apparent\" interaction strength within the two ASDs and (2) dissolution mechanism as well as in vivo performance of the two ASDs. DSC thermogram revealing a single Tg in 30 wt % ASD confirmed its homogeneous phase. 1H NMR, FT-IR, and DVS studies collectively proved that strong hydrogen bonding interactions formed between felodipine and PVPVA in ASDs. Moreover, homogeneous \"30 wt % ASD\" has more numbers of interacting drug-polymer pairs, and thus exhibits stronger \"apparent\" interaction strength comparing with that of inhomogeneous \"30 wt % PM\". Unexpectedly,in the in vitro dissolution studies, inhomogeneous \"30 wt % PM\" showed much faster dissolution and also generated drug concentration ∼4.4 times higher than that of homogeneous \"30 wt % ASD\". However, drug precipitate recrystallized much slower in homogeneous \"30 wt % ASD\", presumably because much more polymer coprecipitated with amorphous drug in this system, which helps inhibiting drug crystallization. Surprisingly, homogeneous \"30 wt % ASD\" showed a significantly higher bioavailability in the in vivo pharmacokinetic studies, with the maximum plasma concentrations (Cmax) and the area under the curve (AUC) values of about 2.7 and 2.3 times higher than those of inhomogeneous \"30 wt % PM\". The above findings indicated that the amorphous state of drug precipitate contributes significantly to increase bioavailability of ASDs, while traditional in vitro dissolution studies, for instance, if we only compare the dissolved drug in solution or the capability of an ASD to generate supersaturation, are inadequate to predict in vivo performance of ASDs. In conclusion, the phase behavior of ASDs directly impact the formation of drug-polymer interaction, which controls not only drug supersaturation in solution but also drug crystallization in precipitate, and ultimately affect the in vivo performance of ASDs.

This study aimed to analyze the effect of felodipine combined with enalapril in the treatment of patients with essential hypertension and coronary artery disease. Also, the effect of these medicines was evaluated on the peripheral blood Salusin-β, Apelin levels, and PON1 gene expression. For this purpose, 110 patients with essential hypertension combined with coronary heart disease, admitted to the hospital from January 2019 to January 2021, were selected and randomly divided into two groups. The control group was given felodipine treatment alone, and the study group was treated with combined application of felodipine and enalapril. The treatment effect, peripheral blood Salusin-β, Apelin, PON1 gene expression, and the safety of medication were compared between the two groups. The results showed that the post-treatment systolic blood pressure in the study group was 119.77 ± 5.23 mm Hg and diastolic blood pressure was 86.84 ± 5.42 mm Hg, both of which were significantly lower than those in the control group (127.81 ± 6.92 mm Hg and 95.13 ± 6.08 mm Hg), with statistically significant differences (p<0.05). The effective rates of the study group and the control group were 92.73% and 74.54% respectively, with statistically significant differences (P<0.05). The post-treatment peripheral blood Salusin-βlevel in the study group was 3.77±0.53mmol/L, and Apelin was 1.94±0.58μg/L, with statistically significant differences compared to the control group (P<0.05). The PON1 gene expression in the study group was higher than those in the control group after treatment (P<0.05). Also, the results showed that there was no statistical difference in adverse reactions between the two groups (P>0.05). According to these results, the combination of felodipine and enalapril in patients with essential hypertension combined with coronary artery disease can effectively lower the patients\' blood pressure and improve their peripheral blood Salusin-β, Apelin levels, and PON1 gene expression, thus enhancing the patients\' therapeutic effect with few adverse effects and high safety.

Drug-polymer interactions are of great importance in amorphous solid dispersion (ASD) formulation for both dissolution performance and physical stability considerations. In this work, three felodipine ASD systems with drug loading ranging from 5 to 20% were prepared using PVP, PVP-VA, or HPMC-AS as the polymer matrix. The amorphization and homogeneity were confirmed by differential scanning calorimetry and powder X-ray diffraction. The intrinsic dissolution behavior of these ASDs was studied in 0.05 M HCl and phosphate-buffered saline (PBS) (pH 6.5). In 0.05 M HCl, PVP-VA ASDs with low drug loading (<15%) showed rapid dissolution accompanied with nano-species generation, while in the PVP system, rapid dissolution and nano-species generation were observed only when drug loading was less than 10%, and HPMC-AS ASDs always released slowly with no nano-species formation. In PBS, PVP-VA ASDs with drug loading less than 10% showed rapid dissolution accompanied with nano-species generation, while for PVP ASDs, rapid dissolution and nano-species generation were observed only when drug loading was 5%. However, 20% drug loading HPMC-AS ASDs exhibited rapid dissolution of felodipine and nano-species generation. When the drug loading was above the transition point of PVP-VA ASDs and PVP ASDs, the release rate was significantly lowered, and no nano-species was generated. To understand this phenomenon, drug-polymer interactions were studied using the melting point depression method and the Flory-Huggins model fitting. The Flory-Huggins interaction parameters (χ) for felodipine/HPMC-AS, felodipine/PVP, and felodipine/PVP-VA were determined to be 0.62 ± 0.07, -0.55 ± 0.20, and -1.02 ± 0.21, respectively, indicating the existence of the strongest attractive molecular interaction between felodipine and PVP-VA, followed by felodipine/PVP, but not in felodipine/HPMC-AS. Furthermore, dynamic vapor sorption further revealed that the molecular interactions between felodipine and PVP or PVP-VA were resistant to water. We concluded that water-resistant drug-polymer interactions in felodipine/polymer systems were responsible for the formation of nano-species, which further facilitated the rapid initial drug dissolution.

In this work, a CdTe quantum dot-based fluorescent probe was synthesized to determine felodipine (FEL). The synthesis conditions, structure, and interaction conditions with FEL of CdTe quantum dots were analysed by fluorescence spectrophotometry, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), UV-visible spectroscopy, and TEM. The CdTe QD concentration was 2.0 × 10-4 mol/L. The amount of quantum dots controlled in the experiment was 0.8 mL. The controlled feeding ratio of N (Cd2+):N (Te2-):N (TGA) was 2:1:4, the heating temperature was 140 °C, the heating time was 60 min, and the pH of the QD precursor was adjusted to 11 for subsequent experiments. The UV-visible spectrum showed that the emission wavelength of CdTe quantum dots at 545 nm was the strongest and symmetric. The particle size of the synthesized quantum dots was approximately 5 nm. In the interaction of CdTe quantum dots with FEL, the FEL dosage was 1.0 mL, the optimal pH value of Tris-HCl buffer was 8.2, the amount of buffer was 1.5 mL, and the reaction time was 20 min. The standard curve of FEL was determined under the optimal synthesis conditions of CdTe quantum dots and reaction of CdTe quantum dots with FEL. The linear equation was Y = 3.9448x + 50.068, the correlation coefficient R2 was 0.9986, and the linear range was 5 × 10-6-1.1 × 10-4 mol/L. A CdTe quantum dot-based fluorescent probe was successfully constructed and could be used to determine the FEL tablet content.

Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters.

Relationship between the stability of fat nano-emulsions and the incorporated drug at the molecular level are rarely known. Herein, fat nano-emulsions containing dihydropyridine drugs were prepared and the microstructure of their palisade layers were investigated.The prepared 1.0 mg/mL nimodipine nano-emulsion was found to contain 65.50% drug in the palisade layer. The increasing drug concentration led to a decrease-increase-decrease trend in centrifugal stability constant, particle size and proton nuclear magnetic resonance (1H NMR) signal intensity of the lecithin trimethyl ammonium group in the nimodipine and felodipine nano-emulsions. The 1H NMR spectra of test solutions including nano-emulsions suggest that increasing drugs penetrated into the palisade layer, resulting in the lecithin arrangement from loose to tight, and then from monolayer to bilayer. Nimodipine and felodipine nano-emulsions showed two valley values at concentrations of 0.15 and 0.75 mg/mL, and 0.30 and 0.90 mg/mL respectively, which indicated that the nano-emulsion has two more stable states corresponding to the tightly arranged mono- and bi-palisade layer. These two concentrations are positively correlated with lipophilicity of nimodipine and felodipine. Further, nimodipine liposomes were prepared to validate the effect of drugs on the arrangement of lecithin in the palisade layer. 1H NMR characterizations of the liposomes showed a similar profile to that of nano-emulsions. These results demonstrated that the increasing drug concentration could cause a rearrangement of lecithin in the palisade layer, thus affecting emulsion stability.