Time-resolved characterization of the mechanisms of toxicity induced by silica and amino-modified polystyrene on alveolar-like macrophages.

Macrophages play a major role in the removal of foreign materials, including nano-sized materials, such as nanomedicines and other nanoparticles, which they accumulate very efficiently. Because of this, it is recognized that for a safe development of nanotechnologies and nanomedicine, it is essential to investigate potential effects induced by nano-sized materials on macrophages. To this aim, in this work, a recently established model of primary murine alveolar-like macrophages was used to investigate macrophage responses to two well-known nanoparticle models: 50 nm amino-modified polystyrene, known to induce cell death via lysosomal damage and apoptosis in different cell types, and 50 nm silica nanoparticles, which are generally considered non-toxic. Then, a time-resolved study was performed to characterize in detail the response of the macrophages following exposure to the two nanoparticles. As expected, exposure to the amino-modified polystyrene led to cell death, but surprisingly no lysosomal swelling or apoptosis were detected. On the contrary, a peculiar mitochondrial membrane hyperpolarization was observed, accompanied by endoplasmic reticulum stress (ER stress), increased cellular reactive oxygen species (ROS) and changes of metabolic activity, ultimately leading to cell death. Strong toxic responses were observed also after exposure to silica, which included mitochondrial ROS production, mitochondrial depolarization and cell death by apoptosis. Overall, these results showed that exposure to the two nanoparticles led to a very different series of intracellular events, suggesting that the macrophages responded differently to the two nanoparticle models. Similar time-resolved studies are required to characterize the response of macrophages to nanoparticles, as a key parameter in nanosafety assessment.

Darunavir Population Pharmacokinetic Model Based on HIV Outpatient Data.

BACKGROUND: Darunavir is a second-generation protease inhibitor and is registered for the treatment of HIV-1 infection. The aim of this study was to develop and validate a darunavir population pharmacokinetic model based on data from daily practice. METHODS: Data sets were obtained from 2 hospitals: ASST Fatebenefratelli Sacco University Hospital, Italy (hospital A), and University Medical Center Groningen, the Netherlands (hospital B). A pharmacokinetic model was developed using data from the largest data set using the iterative two-stage Bayesian procedure within the MWPharm software package. External validation was conducted using data from the smaller data set with Passing-Bablok regression and Bland-Altman analyses. RESULTS: In total, data from 198 patients from hospital A and 170 patients from hospital B were eligible for inclusion. A 1-compartment model with first-order absorption and elimination resulted in the best model. The Passing-Bablok analysis demonstrated a linear correlation between measured concentration and predicted concentration with r = 0.97 (P < 0.05). The predicted values correlated well with the measured values as determined by a Bland-Altman analysis and were overestimated by a mean value of 0.12 mg/L (range 0.23-0.94 mg/L). A total of 98.2% of the predicted values were within the limits of agreement. CONCLUSIONS: A robust population pharmacokinetic model was developed, which can support therapeutic drug monitoring of darunavir in daily outpatient settings.