Assessing Dose-Exposure-Response Relationships of Miltefosine in Adults and Children using Physiologically-Based Pharmacokinetic Modeling Approach.

Miltefosine is the first and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with differences in exposure patterns and cure rates among different population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure-response relationship of miltefosine in in silico clinical trials and evaluate the differences in population groups, particularly children and adults. The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under different dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUC  > 535 µg⋅day/mL in the virtual population. It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no significant difference in the predicted dose-exposure-response of the miltefosine treatment for different simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment. The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the difference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials. [Abstract copyright: © 2023. The Author(s).

Establishing and validating a new source analysis method using phase

Electroencephalogram (EEG) measures the brain oscillatory activity non-invasively. The localization of deep brain generators of the electric fields is essential for understanding neuronal function in healthy humans and for damasking specific regions that cause abnormal activity in patients with neurological disorders. The aim of this study was to test whether the phase estimation from scalp data can be reliably used to identify the number of dipoles in source analyses. The steps performed included: i) modeling different phasic oscillatory signals using auto-regressive processes at a particular frequency, ii) simulation of two different noises, namely white and colored noise, having different signal-to-noise ratios, iii) simulation of dipoles at different areas in the brain and iv) estimation of the number of dipoles by calculating the phase differences of the simulated signals. Moreover we applied this method of source analysis on real data from temporal lobe epilepsy (TLE) patients. The analytical framework was successful in identifying the sources and their orientations in the simulated data and identified the epileptogenic area in the studied patients which was confirmed by pathological studies after TLE surgery

Plasmonic nanostars for SERS application

We report a reproducible plasmonic SERS device, composed of nanostars fabricated by means of electron beam lithography. Cresyl violet dye is used as a probing molecule, deposited on SERS device. Optical transmission measurements show a broad plasmonic resonance around 900 nm. SERS measurements were performed for this device using 633 nm and 830 nm excitation laser lines which are, respectively, far from and close to the plasmonic resonance band position. The estimated SERS enhancement is 1.7 104 and 5.9 104 with respect to the flat Au surface, when excited by 633 nm and 830 nm,respectively.</p

Design and top-down fabrication of metallic L-shape gap nanoantennas supporting plasmon-polariton modes

In this work the design, fabrication and optical characterization of a polarization-sensitive L-shape nanoantenna device are reported. Such configuration supports plasmon-polariton modes that are combinations of in-phase and out-of-phase single antenna long-axis surface plasma oscillations. In the former case charges distributions induce in the gap region an intense hot spot while in the latter one a “zero-field spot” occurs in a plasmonic mode which can be referred to a non-zero dipolar momentum

Fabrication and characterization of a nanoantenna-based Raman device for ultrasensitive spectroscopic applications

We report on the fabrication and spectroscopic characterization of a polarization-selective Raman sensor composed of an ordered array of planar nanoantennas. The device shows two distinct plasmon resonances associated with the main axes of the elongated nanostructures and is able to significantly enhance the Raman signal when the excitation wavelength matches one of these resonances