Search

Objectives: This study aims to characterize the population pharmacokinetics of polymyxin B in lung transplant recipients and optimize its dosage regimens. Patients and methods: This prospective study involved carbapenem-resistant organisms-infected patients treated with polymyxin B. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological efficacy, nephrotoxicity, and hyperpigmentation were assessed. Monte Carlo simulation was performed to calculate the probability of target attainment in patients with normal or decreased renal function. Results: A total of 34 hospitalized adult patients were included. 29 (85.29%) patients were considered of clinical cure or improvement; 14 (41.18%) patients had successful bacteria elimination at the end of the treatment. Meanwhile, 5 (14.71%) patients developed polymyxin B-induced nephrotoxicity; 19 (55.88%) patients developed skin hyperpigmentation. A total of 164 concentrations with a range of 0.56-11.66 mg/L were obtained for pharmacokinetic modeling. The pharmacokinetic characteristic of polymyxin B was well described by a 1-compartment model with linear elimination, and only creatinine clearance was identified as a covariate on the clearance of polymyxin B. Monte Carlo simulations indicated an adjusted dosage regimen might be needed in patients with renal insufficiency and the currently recommended dose regimens by the label sheet of polymyxin B may likely generate a subtherapeutic exposure for MIC = 2 mg/L. Conclusion: Renal function has a significant effect on the clearance of polymyxin B in lung transplant recipients, and an adjustment of dosage was needed in patients with renal impairments. [ABSTRACT FROM AUTHOR]

Rapid growth of residual tumors can occur as a result of their recurrence and progression. The present study aimed to investigate the expression of hypoxia inducible factor-2 subunit a (HIF-2a), vascular endothelial growth factor A (VEGFA), erythropoietin-producing hepatocellular A2 (EphA2) and angiogenesis in residual hepatocellular carcinoma (HCC), following treatment with high-intensity focused ultrasound (HIFU) ablation, in order to investigate the association between protein expression and tumor recurrence and growth. Athymic BALB/c (nu/nu) mice were subcutaneously inoculated with the HCC cell line HepG2, in order to create xenograft tumors. Approximately 30 days post-inoculation, eight mice were treated with HIFU, whereas eight mice received no treatment and acted as the control group. Residual tumor tissues were obtained from the experimental groups after one month. Levels of HIF-2a, VEGFA, EphA2 and cluster of differentiation 31 (CD31) expression was measured by immunohistochemical staining. CD31-positive vascular endothelial cells were counted to calculate microvascular density (MVD), and western blot analysis was performed to determine levels of HIF-2a, VEGFA, and EphA2 protein. It was found that the expression levels of HIF-2a, VEGFA, EphA2, and MVD proteins in residual HCC tissues were significantly higher than in the control group tissues (P<0.05). Tumor MVD was strongly correlated with VEGFA (R=0.957, P<0.01) and EphA2 (R=0.993, P<0.01) protein expression levels. Furthermore, there was a significant positive correlation between HIF-2a and EphA2 expression (R=0.991, P<0.01). The correlation between VEGFA and EphA2 expression was also positive (R=0.985, P<0.01). These data suggest that overexpression of HIF-2a, VEGFA and EphA2 is related to angiogenesis in residual HCC following HIFU ablation, potentially via their association with key mediators of recurrence. [ABSTRACT FROM AUTHOR]

Normal hepatocytes express connexin32 (Cx32), which forms gap junctions at cell-cell contact areas. The aim of the present study was to investigate whether Cx32 mediates the cell death-inducing effects of ultrasound microbubbles carrying the herpes simplex virus thymidine kinase (HSV-TK) suicide gene against hepatocellular carcinoma cells in vitro and in vivo. HepG2 cells were exposed to different concentrations of trans-retinoic acid (ATRA) in culture, to evaluate the intrinsic antitumor effect of ATRA. Detailed in-vitro and in-vivo investigations on the antitumor effects of ATRA via Cx32 mediation were performed, and the possible underlying mechanisms of action of the compound were then examined. The gene expression of HSV-TK transfected by ultrasound wave irradiation in the HepG2 cells was quantified using reverse transcription-quantitative polymerase chain reaction analysis. The effects on cell death were assessed using an MTT assay. The protein expression levels of Cx32 in ATRA-untreated or ATRA-treated tissues were quantified by immunohistochemical analysis and Western blot assays. The HSV-TK gene was successfully transfected into the HepG2 cell using ultrasound wave irradiation, and was stably expressed. Compared with the other groups, the HSV-TK gene group treated with ATRA exhibited an increased number of apoptotic cells (P<0.05) and improved tumor suppression (P<0.05). ATRA significantly increased the expression of Cx32 in the hepatoma tissues (P<0.01). The present study demonstrated that ATRA elevated the protein expression of Cx32 and enhanced the bystander effect of the HSV-TK/GCV suicide gene therapy system, which may provide a potential strategy for hepatocellular carcinoma treatment. [ABSTRACT FROM AUTHOR]

Polymeric micelles with a branched poly (ethylene imine) shell and a reductive ferrocene core were prepared via self-assembly of ferrocene modified branched poly (ethylene imine) (BPEI-Fc). The well-controlled polymeric micelles with a reductive core were used as templates to prepare core–shell-structured silver nanoparticles (AgNPs) in aqueous solution. The as-prepared nanoparticles were characterized by UV–Vis spectrophotometer, transmission electron microscope (TEM), selected-area electron diffraction (SAED), thermogravimetry analyzer (TGA), and dynamic light scattering (DLS). The AgNPs of 39 ± 9 nm with a 39-nm BPEI layer were obtained. It is demonstrated that ferrocene, which is a neutral, chemically stable, and nontoxic molecule, plays a dual role as the hydrophobe and as the electron donating group. Moreover, the formation of these particles was monitored in situ by UV–Vis spectrophotometer. It is found that the growth of AgNPs through reductive templates is much slower than that reduced by NaBH4. Meanwhile, the size distribution of AgNPs becomes narrower during the reaction. BPEI-covered AgNPs (Ag@BPEI) are stable up to 3 months and carry amino groups, which can further be bioconjugated. These core–shell-structured nanoparticles may enable them to be used for wide applications in aqueous solution. [ABSTRACT FROM AUTHOR]