Nose-to-brain delivery of antiviral drugs: A way to overcome their active efflux?

Although several viruses can easily infect the central nervous system (CNS), antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs). These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1), multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5), and breast cancer resistance protein (ABCG2 or BCRP). Inhibitors of AETs may be considered, but their co-administration causes serious unwanted effects. Nasal administration of antiviral drugs is therefore proposed in order to overcome the aforementioned problems, but innovative devices, formulations (thermoreversible gels, polymeric micro- and nano-particles, solid lipid microparticles, nanoemulsions), absorption enhancers (chitosan, papaverine), and mucoadhesive agents (chitosan, polyvinilpyrrolidone) are required in order to selectively target the antiviral drugs and, possibly, the AET inhibitors in the CNS. Moreover, several prodrugs of antiretroviral agents can inhibit or elude the AET systems, appearing as interesting substrates for innovative nasal formulations able to target anti-Human Immunodeficiency Virus (HIV) agents into macrophages of the CNS, which are one of the most important HIV Sanctuaries of the body

Numerical and Experimental Dynamic Analysis of IC Engine Test Beds Equipped with Highly Flexible Couplings

Driveline components connected to internal combustion engines can be critically loaded by dynamic forces due to motion irregularity. In particular, flexible couplings used in engine test rig are usually subjected to high levels of torsional oscillations and time-varying torque. This could lead to premature failure of the test rig. In this work an effective methodology for the estimation of the dynamic behavior of highly flexible couplings in real operational conditions is presented in order to prevent unwanted halts. The methodology addresses a combination of numerical models and experimental measurements. In particular, two mathematical models of the engine test rig were developed: a torsional lumped-parameter model for the estimation of the torsional dynamic behavior in operative conditions and a finite element model for the estimation of the natural frequencies of the coupling. The experimental campaign addressed torsional vibration measurements in order to characterize the driveline dynamic behavior as well as validate the models. The measurements were achieved by a coder-based technique using optical sensors and zebra tapes. Eventually, the validated models were used to evaluate the effect of design modifications of the coupling elements in terms of natural frequencies (torsional and bending), torsional vibration amplitude, and power loss in the couplings

Effects of Microencapsulated Ferulic Acid or Its Prodrug Methyl Ferulate on Neuroinflammation Induced by Muramyl Dipeptide

Ferulic acid (Fer) is known for its antioxidant and anti-inflammatory activities, which are possibly useful against neurodegenerative diseases. Despite the ability of Fer to permeate the brain, its fast elimination from the body does not allow its therapeutic use to be optimized. The present study proposes the preparation and characterization of tristearin- or stearic acid-based solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. The microparticles were produced by conventional hot emulsion techniques. The synthesis of the methyl ester of Fer (Fer-Me) allowed its encapsulation in the SLMs to increase. Fer-Me was hydrolyzed to Fer in rat whole blood and liver homogenate, evidencing its prodrug behavior. Furthermore, Fer-Me displayed antioxidant and anti-inflammatory properties. The amount of encapsulated Fer-Me was 0.719 +/- 0.005% or 1.507 +/- 0.014% in tristearin or stearic acid SLMs, respectively. The tristearin SLMs were able to control the prodrug release, while the stearic acid SLMs induced a significant increase of its dissolution rate in water. Jointly, the present results suggest that the tristearin SLMs loaded with Fer-Me could be a potential formulation against peripheral neuropathic pain; conversely, the stearic acid SLMs could be useful for Fer-Me uptake in the brain after nasal administration of the formulation

Responses of peripheral blood mononucleated cells from non-celiac gluten sensitive patients to various cereal sources

Non-celiac gluten sensitivity (NCGS) is still an undefined syndrome whose triggering mechanisms remain unsettled. This study aimed to clarify how cultured peripheral blood mononucleated cells (PBMC) obtained from NCGS patients responded to contact with wheat proteins. Results demonstrated that wheat protein induced an overactivation of the proinflammatory chemokine CXCL10 in PBMC from NCGS patients, and that the overactivation level depends on the cereal source from which proteins are obtained. CXCL10 is able to decrease the transepithelial resistance of monolayers of normal colonocytes (NCM 460) by diminishing the mRNA expression of cadherin-1 (CDH1) and tight junction protein 2 (TJP2), two primary components of the tight junction strands. Thus, CXCL10 overactivation is one of the mechanisms triggered by wheat proteins in PBMC obtained from NCGS patients. This mechanism is activated to a greater extent by proteins from modern with respect to those extracted from ancient wheat genotypes

Strong reduction of the off-momentum halo in crystal assisted collimation of the SPS beam

A study of crystal assisted collimation has been continued at the CERN SPS for different energies of stored beams using 120 GeV/. c and 270 GeV/. c protons and Pb ions with 270 GeV/. c per charge. A bent silicon crystal used as a primary collimator deflected halo particles using channeling and directing them into the tungsten absorber. A strong correlation of the beam losses in the crystal and off-momentum halo intensity measured in the first high dispersion (HD) area downstream was observed. In channeling conditions, the beam loss rate induced by inelastic interactions of particles with nuclei is significantly reduced in comparison with the non-oriented crystal. A maximal reduction of beam losses in the crystal larger than 20 was observed with 270 GeV/. c protons. The off-momentum halo intensity measured in the HD area was also strongly reduced in channeling conditions. The reduction coefficient was larger than 7 for the case of Pb ions. A strong loss reduction was also detected in regions of the SPS ring far from the collimation area. It was shown by simulations that the miscut angle between the crystal surface and its crystallographic planes doubled the beam losses in the aligned crystal.peer-reviewe

Comparative results on collimation of the SPS beam of protons and Pb ions with bent crystals

New experiments on crystal assisted collimation have been carried out at the CERN SPS with stored beams of 120 GeV/. c protons and Pb ions. Bent silicon crystals of 2 mm long with about 170 μrad bend angle and a small residual torsion were used as primary collimators. In channeling conditions, the beam loss rate induced by inelastic interactions of particles with the crystal nuclei is minimal. The loss reduction was about 6 for protons and about 3 for Pb ions. Lower reduction value for Pb ions can be explained by their considerably larger ionization losses in the crystal. In one of the crystals, the measured fraction of the Pb ion beam halo deflected in channeling conditions was 74%, a value very close to that for protons. The intensity of the off-momentum halo leaking out from the collimation station was measured in the first high dispersion area downstream. The particle population in the shadow of the secondary collimator-absorber was considerably smaller in channeling conditions than for amorphous orientations of the crystal. The corresponding reduction was in the range of 2-5 for both protons and Pb ions.peer-reviewe

Observation of parametric X-rays produced by 400 GeV/c protons in bent crystals

Spectral maxima of parametric X-ray radiation (PXR) produced by 400 GeV/c protons in bent silicon crystals aligned with the beam have been observed in an experiment at the H8 external beam of the CERN SPS. The total yield of PXR photons was about 10-6 per proton. Agreement between calculations and the experimental data shows that the PXR kinematic theory is valid for bent crystals with sufficiently small curvature as used in the experiment. The intensity of PXR emitted from halo protons in a bent crystal used as a primary collimator in a circular accelerator may be considered as a possible tool to control its crystal structure, which is slowly damaged because of irradiation. The intensity distribution of PXR peaks depends on the crystal thickness intersected by the beam, which changes for different orientations of a crystal collimator. This dependence may be used to control crystal collimator alignment by analyzing PXR spectra produced by halo protons.peer-reviewe