Healthcare Systems across Europe and the US: The Managed Entry Agreements Experience.

This systematic study aims at analyzing the differences between the approach of the European healthcare systems to the pharmaceutical market and the American one. This paper highlights the opportunities and the limitations given by the application of managed entry agreements (MEAs) in European countries as opposed to the American market, which does not regulate pharmaceutical prices. Data were collected from the Organisation for Economic Co-operation and Development (OECD), the European Medicines Agency, and the national healthcare agencies of US and European countries. A literature review was undertaken in PubMed, Scopus, MEDLINE, and Google for a period ten years (2010-2019). The period 2020-2021 was considered to compare health expenditure before and after the SARS-CoV-2 pandemic. Scarce information from national agencies has been given in terms of MEAs related to the COVID-19 pandemic. The comparison between the United States approach and the European one shows the importance of a market access regulation to reduce the cost of therapies, increasing the efficiency of national healthcare systems and the advantages in terms of quality and accessibility to the final users: patients. Nevertheless, it seems that the golden age of MEAs for Europe was during the examined period. Except for Italy, countries will move to other forms of reimbursements to obtain higher benefits, reducing the costs of an inefficient implementation and outcomes in the medium term.

Preparation, Characterization, and Biological Evaluation of a Hydrophilic Peptide Loaded on PEG-PLGA Nanoparticles.

The encapsulation of peptides and proteins in nanosystems has been extensively investigated for masking unfavorable biopharmaceutical properties, including short half-life and poor permeation through biological membranes. Therefore, the aim of this work was to encapsulate a small antimicrobial hydrophilic peptide (H-Ser-Pro-Trp-Thr-NH2, FS10) in PEG-PLGA (polyethylene glycol-poly lactic acid-co-glycolic acid) nanoparticles (Nps) and thereby overcome the common limitations of hydrophilic drugs, which because they facilitate water absorption suffer from rapid degradation. FS10 is structurally related to the well-known RNAIII inhibiting peptide (RIP) and inhibits S. aureus biofilm formation. Various parameters, including different method (double emulsion and nanoprecipitation), pH of the aqueous phase and polymeric composition, were investigated to load FS10 into PEG-PLGA nanoparticles. The combination of different strategies resulted in an encapsulation efficiency of around 25% for both the double emulsion and the nanoprecipitation method. It was found that the most influential parameters were the pH­which tailors the peptides charge­and the polymeric composition. FS10-PEG-PLGA nanoparticles, obtained under optimized parameters, showed size lower than 180 nm with zeta potential values ranging from −11 to −21 mV. In vitro release studies showed that the Nps had an initial burst release of 48−63%, followed by a continuous drug release up to 21 h, probably caused by the porous character of the Nps. Furthermore, transmission electron microscopy (TEM) analysis revealed particles with a spherical morphology and size of around 100 nm. Antimicrobial assay showed that the minimum inhibitory concentration (MIC) of the FS10-loaded Nps, against S. aureus strains, was lower (>128 µg/mL) than that of the free FS10 (>256 µg/mL). The main goal of this work was to develop polymeric drug delivery systems aiming at protecting the peptide from a fast degradation, thus improving its accumulation in the target site and increasing the drug-bacterial membrane interactions.

Boron-based hybrids as novel scaffolds for the development of drugs with neuroprotective properties.

Novel boron-based compounds (BBCs) were synthesized and evaluated as potential candidates for the development of novel drugs against Alzheimer's disease (AD). The neuroprotective profile of novel BBCs was evaluated using Aß1-42-treated-SH-SY5Y cells while their antioxidant activity was evaluated by total antioxidant capacity (TAC) and total oxidative status (TOS) assays. Results showed that BLA (a novel boron-based hybrid containing an antioxidant portion) inhibited cell death induced by Aß1-42-exposure in differentiated SH-SY5Y cells, resulting in an increase in cell viability by 25-33% (MTT assay) and by 63-71% (LDH assay) in a concentration range of 25-100 µM. Antioxidant assays demonstrated a good capability of BLA to counteract the oxidative status. Moreover, BLA possessed a significant ability to inhibit acetylcholinesterase (AChE) (22.96% at 50 µM), an enzyme whose enzymatic activity is increased in AD patients. In the present work, absorption and distribution properties of boron-based hybrids were predicted using Pre-ADMET software. In vitro preliminary results suggested that boron-based hybrids could be new structural scaffolds for the development of novel drugs for the management of AD.

Predictability in Contemporary Medicine.

Medical practice is increasingly coming under the guidance of statistical-mathematical models that are, undoubtedly, valuable tools but are also only a partial representation of reality. Indeed, given that statistics may be more or less adequate, a model is still a subjective interpretation of the researcher and is also influenced by the historical context in which it operates. From this opinion, I will provide a short historical excursus that retraces the advent of probabilistic medicine as a long process that has a beginning that should be sought in the discovery of the complexity of disease. By supporting the belonging of this evolution to the scientific domain it is also acknowledged that the underlying model can be imperfect or fallible and, therefore, confutable as any product of science. Indeed, it seems non-trivial here to recover these concepts, especially today where clinical decisions are entrusted to practical guidelines, which are a hybrid product resulting from the aggregation of multiple perspectives, including the probabilistic approach, to disease. Finally, before the advent of precision medicine, by limiting the use of guidelines to the original consultative context, an aged approach is supported, namely, a relationship with the individual patient.

PHoral: Effects of carnosine supplementation on quantity/quality of oral salivae in healthy volunteer and in subjects affected by common oral pathologies.

BACKGROUND: Diseases of the oral cavity (OC) with an infectious trigger such as caries and periodontal disease are extremely common in the general population and can also have effects at the cardiovascular level. The oral salivary flow, with its buffering capacity, is able to regulate the pH of the OC and, therefore, significantly contribute to the ecological balance of the microenvironment in which the oral microbiome (OM) develops. On the other side, when the quality/quantity of salivary flow is altered it is supposed the disruption of this balance with the potential increase in oral pathogens and triggered diseases. Among the endogenous substances able to exert a significant effect on the salivary flow and its characteristics, carnosine (Car), a dipeptide originally isolated in skeletal muscle, represents, thanks to the known buffering properties, a promising principle. METHODS: We aimed this protocol to evaluate the quantitative/qualitative characteristics of the salivary flow in healthy volunteer subjects (n = 20) and in subjects suffering from common OC pathologies (n = 40), before and after 7 days of supplementation with SaliflussTM (Metis Healthcare srl, Milan, Italy), a Class I medical device on the market as 400 mg mucoadhesive oral tablets that has Car as the main ingredient. DISCUSSION: Combining the characteristics of saliva with the OM and comparing them with OC pathologies, we expect to clarify their reciprocal relationship and, using quantitative proteomics techniques, to help clarify the mechanism of action of Car.

Calixarene-based artificial ionophores for chloride transport across natural liposomal bilayer: Synthesis, structure-function relationships, and computational study.

An amphiphilic calix[6]arene, alone or complexed with an axle to form a pseudo-rotaxane, has been embedded into liposomes prepared from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the permeability of the membrane-doped liposomes towards Cl- ions has been evaluated by using lucigenin as the fluorescent probe. The pseudo-rotaxane promotes transmembrane transport of Cl- ions more than calix[6]arene does. Surprisingly, the quenching of lucigenin was very fast for liposomes doped with the positively charged axle alone. Molecular dynamics (MD) simulations and quantum-chemical calculations were also carried out for providing a semi-quantitative support to the experimental results.

Anticancer effects of novel NSAIDs derivatives on cultured human glioblastoma cells.

Several epidemiologic, clinical and experimental reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) could have a potential as anticancer agents. The aim of this study was the evaluation of cytotoxic potential in human glioblastoma cells of novel synthesized NSAID derivatives, obtained by linking, through a spacer, α-lipoic acid (ALA) to anti-inflammatory drugs, such as naproxen (AL-3, 11 and 17), flurbiprofen (AL-6, 13 and 19) and ibuprofen (AL-9, 15 and 21). The effects on the level of gene expression were also determined using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. According to our results, NSAID derivatives exhibited concentration dependent cytotoxic effects on U87-MG cell line when compared with the control group. Moreover, treatment of the most active compounds (AL-3, AL-6 and AL-9) caused upregulation of tumor suppressor gene PTEN and downregulation of some oncogenes such as AKT1, RAF1 and EGFR. In conclusion, our results revealed that AL-3, AL-6 and AL-9 could be suitable candidates for further investigation to develop new pharmacological strategies for the prevention of cancer.

History repeating. The plague of 1630 in Milan and the COVID-19 pandemia.

In western democracies, individual behaviour will be crucial to control the spread of COVID-19, as well as government actions [1] that unfortunately, except China, South Korea and Italy, followed by others,  seems to be generally unconvinced and, speculatively, late. Indeed human history has been marked by epidemics/pandemics which have affected, more or less, large geographical areas [2]. Italy, as well as the rest of Europe, has often been affected by these phenomena and, Lombardy, due to his position, was, as today by COVID-19, severely stroked in Italy that is, after China, the second most affected country [3]. This is also linked to the position of Lombardy and its capital, Milan, but this is beyond this brief comment. There are several differences between the past plagues and the actual COVID-19 pandemic and these must be sought in the increased ability to transmit diseases at-distance through the mobility of humans and goods [4], and in the catastrophic consequences of the breakdown of ecosystems, as told, a few years ago, by David Quammen in the book Spillover [5].

Umbelliprenin as a novel component of the phytochemical pool from Artemisia spp.

Plants belonging to Artemisia spp. are known to biosynthesize a wide panel of 3,3-dimethylallyl- and sesquiterpenyl- substituted coumarins. In this short communication we applied a novel extraction methodology based on the use of subcritical butane under a counter-current mode to further characterize the presence of selected biologically active oxyprenylated phenylpropanoids, namely coumarins and ferulic acid derivatives, in extracts deriving from aerial parts of Artemisia vulgaris L. (commonly known as "common mugwort") (Asteraceae). In the mean time, we assessed the efficiency of the above mentioned extractive methodology with other routes like maceration and ultrasounds and microwaves-based methods using absolute EtOH as the solvents. UHPLC analysis coupled to UV/Vis detection revealed that, among the 5 pure chemical standard assayed, only umbelliprenin (7-farnesyloxycoumarin) was recorded, while boropinic acid, 4'-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene were not detected. The best extractive yield (0.18 %) was obtained after extaction with subcritical butane. The presence of umbelliprenin in Artemisia plant species has been reported herein for the first time. This coumarin may represent the biosynthetic precursors of sesquiterpenyloxycoumarins with more complex structures typically found in this genus.

Novel anti-Alzheimer phenol-lipoyl hybrids: Synthesis, physico-chemical characterization, and biological evaluation.

To date, drugs that hit a single target are inadequate for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. The development of multitarget ligands, able to interact with the different pathways involved in the progession of these disorders, represents a great challenge for medicinal chemists. In this context, we report here the synthesis and biological evaluation of phenol-lipoyl hybrids (SV1-13), obtained via a linking strategy, to take advantage of the synergistic effect due to the antioxidant portions and anti-amyloid properties of the single constituents present in the hybrid molecule. Biological results showed that SV5 and SV10 possessed the best protective activity against Aß1-42 induced neurotoxicity in differentiated SH-SY5Y cells. SV9 and SV10 showed remarkable antioxidant properties due to their ability to counteract the damage caused by H2O2 in SHSY-5Y-treated cells. Hovewer, SV5, showing moderate antioxidant and good neuroprotective activities, resulted the best candidate for further experiments since it also resulted stable both simulated and plasma fluids.