Pharmacokinetics of PEGylated Gold Nanoparticles: In Vitro—In Vivo Correlation

Data suitable for assembling a physiologically-based pharmacokinetic (PBPK) model for nanoparticles (NPs) remain relatively scarce. Therefore, there is a trend in extrapolating the results of in vitro and in silico studies to in vivo nanoparticle hazard and risk assessment. To evaluate the reliability of such approach, a pharmacokinetic study was performed using the same polyethylene glycol-coated gold nanoparticles (PEG-AuNPs) in vitro and in vivo. As in vitro models, human cell lines TH1, A549, Hep G2, and 16HBE were employed. The in vivo PEG-AuNP biodistribution was assessed in rats. The internalization and exclusion of PEG-AuNPs in vitro were modeled as first-order rate processes with the partition coefficient describing the equilibrium distribution. The pharmacokinetic parameters were obtained by fitting the model to the in vitro data and subsequently used for PBPK simulation in vivo. Notable differences were observed in the internalized amount of Au in individual cell lines compared to the corresponding tissues in vivo, with the highest found for renal TH1 cells and kidneys. The main reason for these discrepancies is the absence of natural barriers in the in vitro conditions. Therefore, caution should be exercised when extrapolating in vitro data to predict the in vivo NP burden and response to exposure

Rapid identification of in vitro cell toxicity using an electrochemical membrane screening platform

This study compares the performance and output of an electrochemical phospholipid membrane platform against respective in vitro cell-based toxicity testing methods using three toxicants of different biological action (chlorpromazine (CPZ), colchicine (COL) and methyl methanesulphonate (MMS)). Human cell lines from seven different tissues (lung, liver, kidney, placenta, intestine, immune system) were used to validate this physicochemical testing system. For the cell-based systems, the effective concentration at 50 % cell death (EC₅₀) values are calculated. For the membrane sensor, a limit of detection (LoD) value was extracted as a quantitative parameter describing the minimum concentration of toxicant which significantly affects the structure of the phospholipid sensor membrane layer. LoD values were found to align well with the EC₅₀ values when acute cell viability was used as an end-point and showed a similar toxicity ranking of the tested toxicants. Using the colony forming efficiency (CFE) or DNA damage as end-point, a different order of toxicity ranking was observed. The results of this study showed that the electrochemical membrane sensor generates a parameter relating to biomembrane damage, which is the predominant factor in decreasing cell viability when in vitro models are acutely exposed to toxicants. These results lead the way to using electrochemical membrane-based sensors for rapid relevant preliminary toxicity screens

Potential use of deodorised water extracts: polyphenol-rich extract of Thymus pannonicus All. as a chemopreventive agent

Deodorised water extracts of aromatic plants are obtained as by-products of essential oil isolation and usually discarded as waste. However, phytochemical composition of these extracts encourages their further utilization as food additives or functional food ingredients. In this study we investigated phytochemical composition, antioxidant and in vivo antiproliferative activity of deodorised water extract of Thymus pannonicus All. (DWE). HPLC analysis revealed rosmarinic acid (RA) (71.11 +/- 1.54 mg/g) as the most abundant constituent of the extract, followed by salvianolic acid H (14.83 +/- 0.79 mg/g, calculated as RA). DWE exhibited pronounced antioxidant activity in vitro, in FRAP and DPPH tests (FRAP value: 7.41 mmol Fe/g and SC50: 3.80 mu g/g, respectively). Using the model of Ehrlich carcinoma cells in mice that were treated with DWE prior, at the time, and after tumour cells implantation, the tumour growth suppression and redox status of malignant cells (i.e., activities of antioxidant enzymes, level of glutathione and intensity of lipid peroxidation) were followed. DWE applied as pretreatment caused disturbance of antioxidant equilibrium as well as apoptosis/necrosis of up to 90% EAC cells. Results obtained in the present study revealed chemopreventive potential and possibility of T. pannonicus DWE usage. High content of RA and other phenolic compounds explains, at least in part, the observed effects

Safety and Effectiveness of UFE in Fibroids Larger than 10 cm

INTRODUCTION: Early literature suggested that the size of the uterus, the size of the dominant fibroid, and the amount of applied embolization particles would be the risk factors for major postprocedural complications, but recent publications have confuted these early results. The purpose of our study was to evaluate whether the size of the dominant fibroid would influence the complication rate and effectiveness in a large single-center cohort. PATIENTS AND METHODS: From 28 April 2008 until 31 December 2012, 303 patients had uterine artery embolization (UAE). 262 patients had small [largest diameter 10 cm (Group 2)] fibroid. UAE was performed from unilateral femoral access using 500-710 and 355-500 microm polyvinyl alcohol particles. Periprocedural and postprocedural complications and numerical analog quality-of-life scores (0-unbearable symptoms; 100-perfect quality of life) were listed and statistically analyzed. RESULTS: During the mean follow-up time [7.79 +/- 5.16 (SD) month], data on 275 patients (275/303 = 90.8 %) were available. Quality-of-life score was 33.3 +/- 23.5 and 33.5 +/- 24.1 before, whereas 85.6 +/- 16.0 and 81.5 +/- 23.5 after UAE in Group 1 and Group 2, respectively, (Mann-Whitney U test one-sided, p = 0.365). There were 4 myoma expulsions, 1 acute myomectomy, and 2 acute hysterectomies reported from Group 1, meanwhile 1 myoma expulsion, 1 acute myomectomy, and 2 acute hysterectomies were documented from Group 2 (NS differences). CONCLUSION: There was no significant difference in the effectiveness and in the number of minor and major complications between fibroids with 10 cm

Optimization of a Small Tropomyosin-Related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of Depression

Structure–activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is critical for agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-containing molecules and to elevate the agonistic effect of the lead compound, we initiated the lead optimization campaign by synthesizing various bioisosteric derivatives. Here we show that the optimized 2-methyl-8-(4'-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one derivative possesses enhanced TrkB stimulatory activity. Chronic oral administration of this compound significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compound possesses the improved features compared to the previous lead compound. Hence, this optimized compound may act as a promising lead candidate for in-depth drug development for treating various neurological disorders including depression