Bioavailability Study of an Innovative Orobuccal Formulation of Glutathione

Alteration of the ubiquitous thiol tripeptide glutathione (GSH) is involved in oxidative stress, which plays a role in ageing; consequently, GSH is closely related to this process characterized by progressive decline in the efficiency of physiological function and increased susceptibility to disease. When circulating GSH decreases, oral administration might be considered a therapeutic benefit. Unfortunately, due to the hydrolysis of the tripeptide by intestinal γ-glutamyltransferase, dietary glutathione is not a major determinant for its increase. Aim of this work was to evaluate improvement of GSH systemic availability testing, in vitro and in vivo, an optimized orobuccal fast-slow release formulation tablet containing pure stabilized GSH. In vitro evaluation of the penetration capability of the innovative GSH-release formulation showed that GSH was well absorbed by the reconstructed oral epithelium and its absorption has features of time-dependence. In addition, in vivo results, obtained from 15 healthy volunteers, were in favor of GSH level improvement in blood showing fast (after 30 and 60 minutes) absorption through oral mucosa. In conclusion, the intake of GSH formulated through optimized orobuccal fast-slow release tablets gave positive results in raising GSH blood concentration

Raman Spectroscopy Characterization of Multi-Functionalized Liposomes as Drug-Delivery Systems for Neurological Disorders

The characterization of nanoparticle-based drug-delivery systems represents a crucial step in achieving a comprehensive overview of their physical, chemical, and biological features and evaluating their efficacy and safety in biological systems. We propose Raman Spectroscopy (RS) for the characterization of liposomes (LPs) to be tested for the control of neuroinflammation and microglial dysfunctions in Glioblastoma multiforme and Alzheimer’s disease. Drug-loaded LPs were functionalized to cross the blood–brain barrier and to guarantee localized and controlled drug release. The Raman spectra of each LP component were used to evaluate their contribution in the LP Raman fingerprint. Raman data analysis made it possible to statistically discriminate LPs with different functionalization patterns, showing that each molecular component has an influence in the Raman spectrum of the final LP formulation. Moreover, CLS analysis on Raman data revealed a good level of synthetic reproducibility of the formulations and confirmed their stability within one month from their synthesis, demonstrating the ability of the technique to evaluate the efficacy of LP synthesis using small amount of sample. RS represents a valuable tool for a fast, sensitive and label free biochemical characterization of LPs that could be used for quality control of nanoparticle-based therapeutics

Dual Functionalized Liposomes for Selective Delivery of Poorly Soluble Drugs to Inflamed Brain Regions

Dual functionalized liposomes were developed to cross the blood–brain barrier (BBB) and to release their cargo in a pathological matrix metalloproteinase (MMP)-rich microenvironment. Liposomes were surface-functionalized with a modified peptide deriving from the receptor-binding domain of apolipoprotein E (mApoE), known to promote cargo delivery to the brain across the BBB in vitro and in vivo; and with an MMP-sensitive moiety for an MMP-triggered drug release. Different MMP-sensitive peptides were functionalized at both ends with hydrophobic stearate tails to yield MMP-sensitive lipopeptides (MSLPs), which were assembled into mApoE liposomes. The resulting bi-functional liposomes (i) displayed a −5 cm/min; (iii) when exposed to functional MMP2 or 9, efficiently released an encapsulated fluorescein dye; (iv) showed high biocompatibility when tested in neuronal cultures; and (v) when loaded with glibenclamide, a drug candidate with poor aqueous solubility, reduced the release of proinflammatory cytokines from activated microglial cells

Synthesis and Characterization of Novel Mono- and Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult

Acid-sensitive ion channels (ASICs) are sodium channels partially permeable to Ca2+ ions, listed among putative targets in central nervous system (CNS) diseases in which a pH modification occurs. We targeted novel compounds able to modulate ASIC1 and to reduce the progression of ischemic brain injury. We rationally designed and synthesized several diminazene-inspired diaryl mono- and bis-guanyl hydrazones. A correlation between their predicted docking affinities for the acidic pocket (AcP site) in chicken ASIC1 and their inhibition of homo- and heteromeric hASIC1 channels in HEK-293 cells was found. Their activity on murine ASIC1a currents and their selectivity vs mASIC2a were assessed in engineered CHO-K1 cells, highlighting a limited isoform selectivity. Neuroprotective effects were confirmed in vitro, on primary rat cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation, and in vivo, in ischemic mice. Early lead 3b, showing a good selectivity for hASIC1 in human neurons, was neuroprotective against focal ischemia induced in mice

Synthesis and Characterization of Novel Mono- and Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult

Acid-sensitive ion channels (ASICs) are sodium channels partially permeable to Ca2+ ions, listed among putative targets in central nervous system (CNS) diseases in which a pH modification occurs. We targeted novel compounds able to modulate ASIC1 and to reduce the progression of ischemic brain injury. We rationally designed and synthesized several diminazene-inspired diaryl mono- and bis-guanyl hydrazones. A correlation between their predicted docking affinities for the acidic pocket (AcP site) in chicken ASIC1 and their inhibition of homo- and heteromeric hASIC1 channels in HEK-293 cells was found. Their activity on murine ASIC1a currents and their selectivity vs mASIC2a were assessed in engineered CHO-K1 cells, highlighting a limited isoform selectivity. Neuroprotective effects were confirmed in vitro, on primary rat cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation, and in vivo, in ischemic mice. Early lead 3b, showing a good selectivity for hASIC1 in human neurons, was neuroprotective against focal ischemia induced in mice

Prevalence and features of delirium in older patients admitted to rehabilitation facilities: a multicenter study

Background: Delirium is thought to be common across various settings of care; however, still little research has been conducted in rehabilitation. Aim: We investigated the prevalence of delirium, its features and motor subtypes in older patients admitted to rehabilitation facilities during the three editions of the "Delirium Day project". Methods: We conducted a cross-sectional study in which 1237 older patients (age ≥ 65 years old) admitted to 50 Italian rehabilitation wards during the three editions of the "Delirium Day project" (2015 to 2017) were included. Delirium was evaluated through the 4AT and its motor subtype with the Delirium Motor Subtype Scale. Results: Delirium was detected in 226 patients (18%), and the most recurrent motor subtype was mixed (37%), followed by hypoactive (26%), hyperactive (21%) and non-motor one (16%). In a multivariate Poisson regression model with robust variance, factors associated with delirium were: disability in basic (PR 1.48, 95%CI: 1.17-1.9, p value 0.001) and instrumental activities of daily living (PR 1.58, 95%CI: 1.08-2.32, p value 0.018), dementia (PR 2.10, 95%CI: 1.62-2.73, p value < 0.0001), typical antipsychotics (PR 1.47, 95%CI: 1.10-1.95, p value 0.008), antidepressants other than selective serotonin reuptake inhibitors (PR 1.3, 95%CI: 1.02-1.66, p value 0.035), and physical restraints (PR 2.37, 95%CI: 1.68-3.36, p value < 0.0001). Conclusion: This multicenter study reports that 2 out 10 patients admitted to rehabilitations had delirium on the index day. Mixed delirium was the most prevalent subtype. Delirium was associated with unmodifiable (dementia, disability) and modifiable (physical restraints, medications) factors. Identification of these factors should prompt specific interventions aimed to prevent or mitigate delirium

Visual and Hearing Impairment Are Associated With Delirium in Hospitalized Patients: Results of a Multisite Prevalence Study

Sensory deficits are important risk factors for delirium but have been investigated in single-center studies and single clinical settings. This multicenter study aims to evaluate the association between hearing and visual impairment or bi-sensory impairment (visual and hearing impairment) and delirium