Brain penetration assessment in vivo: a reliable and simple method in anesthetized rats at steady state.

BACKGROUND: For CNS drugs, brain disposition is of critical importance during drug discovery. In vitro methods are used early followed by more predictive in vivo methods later on in the drug discovery process. Current in vivo methods are costly, have long turnover times or do not measure brain disposition at steady state. NEW METHOD: A new method to evaluate drug brain disposition in vivo was developed in anaesthetized rats. Seven reference compounds were administered as an initial IV bolus (loading dose) followed by IV infusion for 4.5 h in order to obtain a steady state plasma concentration before brain sampling. The loading dose was estimated from a preliminary single dose IV pharmacokinetic study and was found to successfully bring plasma concentrations to steady state for compounds exhibiting either mono- or bi-compartmental pharmacokinetics. RESULTS: Using this method, a steady state lasting at least 2h was obtained, thus making the in vivo method robust with respect to differences in the pharmacokinetics and/or blood-to-brain equilibration rate of the compounds tested. The method produced highly reproducible results, with substantial advantages in terms of cost, turnaround time and animal welfare. COMPARISON WITH EXISTING METHODS: The results agreed with those reported in other, more elaborate preclinical models and in humans, enabling brain disposition to be assessed in a simple, efficient and robust in vivo model for new chemical entities. CONCLUSIONS: Introducing the presented method in drug discovery allows brain disposition to be assessed earlier in the drug discovery pipeline and thus facilitate the selection of potent and penetrant CNS drugs.

1D graphene-like silicon systems: silicene nano-ribbons.

Through this review we can follow the various phases that have led to the discovery of the new allotrope form of silicon: silicene. This is a one-atom thick silicon sheet arranged in a honeycomb lattice, similar to graphene. For silicon, which usually is sp3 hybridized, it represents an unusual and rare structure. First, silicene was theoretically hypothesized and subsequently its structure calculated as a possible candidate for nano-ribbons of Si grown on the anisotropic Ag(110) surface. It was only later, when the physical and chemical properties of this peculiar form of silicon, demonstrating the presence of π and π* bands giving the so-called Dirac cones at the K corners of the Brillouin zone, the sp2-like nature of the valence orbitals of the Si-Si bonds and its strong resistance towards oxygen were reported, that the real existence of silicene became recognized in the scientific community. This review is essentially focused on the experimental work performed on 1D isolated silicene nano-ribbons and their 1D dense array grown on Ag(110) surfaces.

Burning match oxidation process of silicon nanowires screened at the atomic scale.

Silicon oxide nanowires hold great promise for functional nanoscale electronics. Here, we investigate the oxidation of straight, massively parallel, metallic Si nanowires. We show that the oxidation process starts at the Si NW terminations and develops like a burning match. While the spectroscopic signatures on the virgin, metallic part, are unaltered we identify four new oxidation states on the oxidized part, which show a gap opening, thus revealing the formation of a transverse internal nanojunction.

Growth of straight, atomically perfect, highly metallic silicon nanowires with chiral asymmetry.

In the quest of nano-objects for future electronics, silicon nanowires could possibly take over carbon nanotubes. Here we show the growth by self-organization of straight, massively parallel silicon nanowires having a width of 1.6 nm, which are atomically perfect and highly metallic conductors. Surprisingly, these silicon nanowires display a strong symmetry breaking across their widths with two chiral species that self-assemble in large left-handed and right-handed magnetic-like domains.

ELF non ionizing radiation changes the distribution of the inner chemical functional groups in human epithelial cell (HaCaT) culture.

Human skin cell culture (HaCaT) that has been exposed to an AC magnetic field undergoes detectable changes in its biochemical properties and shapes. Such changes were observed by infrared wavelength-selective scanning near-field optical microscopy with a resolution of 80-100 nm. We specifically investigated the changes in the distribution of the inner chemical functional groups and in the cell morphology induced by a 24 h exposure to a 1 mT (rms), 50 Hz sinusoidal magnetic field in a temperature regulated solenoid. These results further accentuate the crucial questions, raised by several recent studies, about the impact of low-frequency electromagnetic field on human cells.

Chemically resolved imaging of biological cells and thin films by infrared scanning near-field optical microscopy.

The infrared (IR) absorption of a biological system can potentially report on fundamentally important microchemical properties. For example, molecular IR profiles are known to change during increases in metabolic flux, protein phosphorylation, or proteolytic cleavage. However, practical implementation of intracellular IR imaging has been problematic because the diffraction limit of conventional infrared microscopy results in low spatial resolution. We have overcome this limitation by using an IR spectroscopic version of scanning near-field optical microscopy (SNOM), in conjunction with a tunable free-electron laser source. The results presented here clearly reveal different chemical constituents in thin films and biological cells. The space distribution of specific chemical species was obtained by taking SNOM images at IR wavelengths (lambda) corresponding to stretch absorption bands of common biochemical bonds, such as the amide bond. In our SNOM implementation, this chemical sensitivity is combined with a lateral resolution of 0.1 micro m ( approximately lambda/70), well below the diffraction limit of standard infrared microscopy. The potential applications of this approach touch virtually every aspect of the life sciences and medical research, as well as problems in materials science, chemistry, physics, and environmental research.