Nanoparticles and molecular delivery system for nutraceuticals bioavailability

This contribution discusses methods for transferring exogenous materials and drugs, particularly, into biological tissues. The focus is on matrices such as micelles, vesicles, and oil-based dispersions as well as carbon nanotubes. An ensemble of physical forces takes a fundamental role in drug dispersion and includes van der Waals (vdW), steric (ST), double layer, (DL), osmotic (OS), etc. Combination of these forces is responsible for drug uptake in matrices and for their release in tissues. Uptake of exogenous either macro- or small molecules into cargo particles and their transfer to recipient cells is the result of complex processes, concomitant to drug partition among supramolecular aggregates and the bulk. Similar conclusions apply to drug release, mostly as to the kinetic features are concerned; therefore, adsorption of nutraceuticals and release within target organs are particularly relevant. These complex features can be accounted for on thermodynamic grounds and expressed as the combination of different forces. In what follows some details on the energies to be considered are outlined. These include terms controlling the fate of transfectants. We will consider first the forces responsible for the formation of such supramolecular entities on physicochemical grounds and the drug uptake; finally, we will review the actual possibility of transfecting cargo-mediated aggregates of nanoparticle/drug complexes to cells or tissues of interest and their bioactivity upon release within the cell matrix

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

International audienceAbstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 )