Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Reactive Deep Eutectic Solvent for an Eco-Friendly Synthesis of Cellulose Carbamate.

The limited solubility of natural cellulose in water and common organic solvents hinders its diverse applications, despite being one of the most abundant and easily accessible biopolymers on Earth. Chemical derivatization, such as cellulose carbamate (CC), offers a pathway to enhance both solubility and industrial processability. In this study, CC was synthesized by exploiting a novel type IV deep eutectic solvent (DES) composed of erbium trichloride and urea. This DES was shown to be not only an environmentally friendly reaction medium/catalyst but also actively participated in the synthetic process as a reagent. The resultant cellulose carbamate samples were characterized through FT-IR and elemental analysis. A nitrogen content value of 1.59% was afforded determining a degree of substitution corresponding to a value of 0.19. One of the key scientific advancements lies in the preparation of cellulose carbamate using a straightforward and cost-effective method. This approach utilizes non-toxic compounds, aligning with the principles of green chemistry and contributing to sustainable development in cellulose derivative production.

Reactive deep eutectic solvents for EDC-mediated amide synthesis.

The sustainability of amide bond formation is an ever-present topic in the pharmaceutical industry, as it represents the common motif in many clinically approved drugs. Despite many procedures for accomplishing eco-friendly amide synthesis having been developed, this transformation still remains a contemporary challenge. Herein, we report a greener approach for amide synthesis by using Reactive Deep Eutectic Solvents (RDESs) acting as both the reaction medium and reactants. The procedure not only avoids the use of hazardous solvents but also provides operationally simple product recovery with high purity and efficiency, without chromatographic purification. This approach was efficiently applied to the synthesis of a key intermediate in the production of an active pharmaceutical ingredient like atenolol. The green metrics of the gram-scale procedure were compared to the conventional industrial strategy showing an advancement in the greening of amide synthesis.

Green Chemistry Principles for Nano- and Micro-Sized Hydrogel Synthesis.

The growing demand for drug carriers and green-technology-based tissue engineering materials has enabled the fabrication of different types of micro- and nano-assemblies. Hydrogels are a type of material that have been extensively investigated in recent decades. Their physical and chemical properties, such as hydrophilicity, resemblance to living systems, swelling ability and modifiability, make them suitable to be exploited for many pharmaceutical and bioengineering applications. This review deals with a brief account of green-manufactured hydrogels, their characteristics, preparations, importance in the field of green biomedical technology and their future perspectives. Only hydrogels based on biopolymers, and primarily on polysaccharides, are considered. Particular attention is given to the processes of extracting such biopolymers from natural sources and the various emerging problems for their processing, such as solubility. Hydrogels are catalogued according to the main biopolymer on which they are based and, for each type, the chemical reactions and the processes that enable their assembly are identified. The economic and environmental sustainability of these processes are commented on. The possibility of large-scale processing in the production of the investigated hydrogels are framed in the context of an economy aimed at waste reduction and resource recycling.

COVID-19 vaccination hesitancy in pregnant and breastfeeding women and strategies to increase vaccination compliance: a systematic review and meta-analysis.

INTRODUCTION: Pregnant and breastfeeding women are at an increased risk of severe illness from COVID-19. Despite this, low vaccination coverages are reported in this population sub-group. AREAS COVERED: The purpose of this study is to estimate the proportion of pregnant and breastfeeding women expressing hesitation to the COVID-19 vaccine worldwide. Forty-six studies were included, selected from scientific articles available in three scientific databases between 1 January 2020 and 6 February 2022. The vaccine hesitation rate among pregnant and breastfeeding women was 48.4% (95%CI=43.4-53.4%). In a sub analysis by study period, it was 40.0% (95%CI=31.6-46.6%) considering surveys administered in 2020, 58.0% (95%CI=48.9-66.9%) considering surveys administered in the first semester of 2021, and 38.1% (95%CI=25.9-51.2%) considering surveys administered in the second semester of 2021. The main reasons for vaccine hesitation were lack of information about vaccination, opinion that the vaccine is unsafe, and fear of adverse events. EXPERT OPINION: Available evidence in the literature has shown that fighting vaccine resistance is harsh and too slow as a process, considering the rapidity and unpredictability of a pandemic. Health education should be provided in order to improve the willingness of the community, especially for those with lower levels of education.

Multifunctional Membranes Based on ß-Glucans and Chitosan Useful in Wound Treatment.

In this work, bio-based membranes prepared using a crosslinked ß-glucans-chitosan dispersed in the chitosan matrix useful in promoting wound healing were studied for the first-time. Wound healing is a process that includes sequential steps designed to restore the structure and function of damaged cells and tissue. To minimize damage and the risk of infection during the healing process and to promote restoration of the integrity of damaged tissue, the wound should be dressed. Generally, according to their function in the wound, dressings are classified on the basis of type of material and physical form. The substances used to make a dressing are generally natural polymers such as hydrocolloids, alginates, polyurethane, collagen, chitosan, pectin and hyaluronic acid. The combination of polymeric substances, with antibacterial and antioxidant properties, could be exploited in the biomedical field for the development of biocompatible materials able to act as a barrier between the wound and the external environment, protecting the site from bacterial contamination and promoting healing. To this aim, bio-based membranes were prepared by the phase inversion induced by solvent evaporation, using the crosslinked ß-glucans-chitosan obtained by esterification reactions as a functional additive in the chitosan membrane. The reaction intermediates and the final products were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) while the morphological properties of membranes were analyzed using electronic scanning microscopy (SEM). The chemical bonding between chitosan and ß-glucans allowed for the obtainment of a better dispersion of the combined new material into the membrane's matrix and as a consequence, an enhanced antibacterial property evaluated through in vitro tests, with respect to the starting materials.

Deep Eutectic Solvents for Improving the Solubilization and Delivery of Dapsone.

Owing to a growing awareness toward environmental impact, the use of safer and eco-friendly solvents like deep eutectic solvents (DESs), has recently undergone important growth in the pharmaceutical field, with regard to their application as non-aqueous liquid administration vehicles, since they do not carry the same risks of toxicity and handling as traditional organic solvents. Major attention has been given to the development of advantageous transdermal drug delivery systems, because of their ease of use and better acceptability. Here, we report the use of two different DESs, based on choline chloride, used as hydrogen bond acceptor (HBA), and ascorbic acid or propylene glycol, used as hydrogen bond donors (HBDs), able to enhance the solubility and the topical delivery of dapsone, representing a class IV drug. The interactions between the DESs' components and the drug were studied by performing DSC, FT-IR, and NMR analysis of the eutectic systems and the pure drug, confirming the establishment of H-bonds between the drug and the DESs' components. Diffusion and permeability studies, carried out in a Franz cell, showed an increase in permeability, highlighting the great potential of DESs as dissolution and permeation enhancers in the development of novel and more effective drug delivery systems in topical administration.

Novel Nanoparticles Based on N,O-Carboxymethyl Chitosan-Dopamine Amide Conjugate for Nose-to-Brain Delivery.

A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson's disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying therapy. Although several bio-nanomaterials have been evaluated for encapsulation of neurotransmitter dopamine (DA) or dopaminergic drugs in order to restore the DA content in parkinsonian patients, the premature leakage of the therapeutic agent limits this approach. To tackle this drawback, we undertook a study where the active was linked to the polymeric backbone by a covalent bond. Thus, novel nanoparticles (NPs) based on N,O-Carboxymethylchitosan-DA amide conjugate (N,O-CMCS-DA) were prepared by the nanoprecipitation method and characterized from a technological view point, cytotoxicity and uptake by Olfactory Ensheating Cells (OECs). Thermogravimetric analysis showed high chemical stability of N,O-CMCS-DA NPs and X-ray photoelectron spectroscopy evidenced the presence of amide linkages on the NPs surface. MTT test indicated their cytocompatibility with OECs, while cytofluorimetry and fluorescent microscopy revealed the internalization of labelled N,O-CMCS-DA NPs by OECs, that was increased by the presence of mucin. Altogether, these findings seem promising for further development of N,O-CMCS-DA NPs for nose-to-brain delivery application in PD.

Green solvents for the formation of amide linkages.

The formation of the amide bond is among the most commonly performed transformations in the pharmaceutical industry and the wider chemical industry. The current methods for its installation in organic compounds frequently rely on the use of large amounts of organic solvents, mainly N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), and dichloromethane (DCM), which have been associated with adverse environmental and health concerns over the last decades. This fact led academia and industry to make significant efforts toward the development of synthetic routes with the aim to avoid, reduce or replace the use of hazardous solvents. The present review fits into this framework and discusses the literature existing over the past ten years on strategies for reducing and replacing hazardous solvents, focusing on the use of biobased and neoteric solvents, such as ionic liquids and deep eutectic solvents (ILs and DESs, respectively), and on the reaction media that proved to be greener alternatives for amide bond formation.

The relationship between maternal-fetus attachment and perceived parental bonds in pregnant women: Considering a possible mediating role of psychological distress.

Maternal-Fetal Attachment (MFA) delineates the emotional, cognitive, and behavioral aspects that mothers develop toward the unborn baby during pregnancy. The literature indicates that optimal attachment in pregnancy represents a protective factor for the mother-child attachment bond after birth and child development outcomes. To date, there are few studies that have investigated associated factors of MFA. This study sets out to explore the association between perceived parental bonds and maternal-fetal bonding in pregnant women, accounting for factors such as psychological distress, socio-demographic and obstetric characteristics. Methods: In this cross-sectional study, 1,177 pregnant women answered the Parental Bonding Instrument, the Maternal-Fetal Attachment Scale, State-Trait Anxiety Inventory (STAI-Y), and Beck-Depression Inventory (BDI-II). Results: We found out that perceived maternal and paternal care had significant direct effects on maternal-infant bonding during the pregnancy period when controlling for some confounders, including gestational age and mother age among others. Such maternal and paternal perceived care effects were not mediated by levels of psychological distress, which in turn resulted to be a "borderline" significant predictor of prenatal attachment. Interestingly, the gestational age and the mother age emerged to have a significant and synergic nonlinear effect, suggesting the influence on the MFAS of the gestational age depends on the values of the mother age, and likewise, the effect of mother age on MFAS depends on the gestational week. Conclusion: This study expands our knowledge of the intergenerational transmission of attachment pointing out the effects of a woman's perceived bond in relation to her parental figures during the development of the prenatal attachment process. Findings also suggests that parenting support interventions may have benefits that are realized across generations.

Gel-Based Materials for Ophthalmic Drug Delivery.

The most common route of administration of ophthalmic drugs is the topical route because it is convenient, non-invasive, and accessible to all patients. Unfortunately, drugs administered topically are not able to reach effective concentrations. Moreover, their bioavailability must be improved to decrease the frequency of administrations and their side effects, and to increase their therapeutic efficiency. For this purpose, in recent decades, particular attention has been given to the possibility of developing prolonged-release forms that are able to increase the precorneal residence time and decrease the loss of the drug due to tearing. Among these forms, gel-based materials have been studied as an ideal delivery system because they are an extremely versatile class with numerous prospective applications in ophthalmology. These materials are used in gel eye drops, in situ gelling formulations, intravitreal injections, and therapeutic contact lenses. This review is intended to describe gel-based materials and their main applications in ophthalmology.

Effects of maternal psychological distress and perception of COVID-19 on prenatal attachment in a large sample of Italian pregnant women.

BACKGROUND: Evidence concerning the impact of COVID-19-related stress exposure on prenatal attachment in pregnant women is unknown. In this study we sought to assess the effect of psychological distress and risk perception of COVID-19 on prenatal attachment in a Italian sample of pregnant women. METHODS: 1179 pregnant women completed an anonymous online survey and self-report questionnaires measuring socio-demographic and obstetric characteristics, psychological distress (STAI Form Y-1-2 and BDI-II), prenatal attachment (PAI) and risk perception of COVID-19. Data were collected from March 2020 to April 2020 referring to the national lockdown period. RESULTS: After adjusting for the socio-demographic and obstetric factors in the multivariable analysis, we found out the state anxiety was shown to be a significant predictor (p < 0001) of prenatal attachment. Moreover, the COVID-19-risk perception positively moderate the relationship between trait anxiety and prenatal attachment (p=0008), indicating that when COVID-19-risk perception is high, the effects of trait anxiety on prenatal attachment is attenuated. The synergistic effect between STAI Form Y-1 and COVID-19-risk perception index on PAI is partially mediated by STAI Form Y-2 score. CONCLUSIONS: Findings from this study showed that state anxiety related to COVID-19 outbreak in pregnant women may affect the prenatal attachment process of the expectant mother negatively. However, an adequate and functional perception of COVID-19 could enhance prenatal attachment. These results underline the importance of monitoring the prenatal attachment process and the mother's mental health during pandemics, to safeguard maternal and infant mental health.

Valorization of Tomato Waste as a Source of Carotenoids.

Fast-accumulating scientific evidence from many studies has revealed that fruits and vegetables are the main source of bioactive compounds; in most cases, wastes and byproducts generated by the food processing industry present similar or a higher content of antioxidant compounds. In recent years, the ever-growing amount of agricultural and food wastes has raised serious concerns from an environmental point of view. Therefore, there is an increasing interest in finding new ways for their processing toward safely upgrading these wastes for recovering high-value-added products with a sustainable approach. Among food waste, the abundance of bioactive compounds in byproducts derived from tomato suggests possibility of utilizing them as a low-cost source of antioxidants as functional ingredients. This contribution gives an overview of latest studies on the extraction methods of carotenoids from tomato waste, along with an evaluation of their antioxidant activity, as well as their industrial applications.

Bleeding events in COVID-19: the other side of the coin?

We present three cases of patients affected by severe SARS-CoV-2-related pneumonia treated with a low molecular weight heparin for prevention or treatment of pulmonary embolism, who presented a major bleed, in particular an ileopsoas haematoma that caused severe anaemia; in one case it was fatal. In the recent outbreak of novel coronavirus infection, significantly abnormal coagulation parameters in SARS-CoV-2 infection occur very often, but complications in the opposite direction such as bleeding diathesis are very rare. In these cases, there are different levels of gravity: for one patient the major bleed required the anticoagulant therapy to be stopped until bleeding stabilized, one patient needed interventional radiology and one patient died.

Nose-to-brain delivery: A comparative study between carboxymethyl chitosan based conjugates of dopamine.

Herein, the synthesis of a novel polymeric conjugate N,O-CMCS-Dopamine (DA) based on an amide linkage is reported. The performances of this conjugate were compared with those of an analogous N,O-CMCS-DA ester conjugate previously studied (Cassano et al., 2020) to gain insight into their potential utility for Parkinson's disease treatment. The new amide conjugate was synthesized by standard carbodiimide coupling procedure and characterized by FT-IR, 1H NMR spectroscopies and thermal analysis (Differential Scanning Calorimetry). In vitro mucoadhesive studies in simulated nasal fluid (SNF) evidenced high adhesive effect of both ester and amide conjugates. Results demonstrated that the amide conjugate exerted an important role to prevent DA spontaneous autoxidation both under stressed conditions and physiological mimicking ones. MTT test indicated cytocompatibility of the amide conjugate with Olfactory Ensheating Cells (OECs), which were shown by cytofluorimetry to internalize efficiently the conjugate. Overall, among the two conjugates herein studied, the N,O-CMCS-DA amide conjugate seems a promising candidate for improving the delivery of DA by nose-to-brain administration.

In vitro anti-proliferative and anti-bacterial properties of new C7 benzoate derivatives of pinocembrin.

In the present work, the in vitro anti-proliferative and anti-bacterial activities of three semi-synthetic benzoate pinocembrin derivatives, isolated from the aerial parts of Glycyrrhiza glabra L., were investigated. As occurs in most natural compounds, the bioavailability of pinocembrin is very poor, therefore it should be improved by chemical strategies aimed to prolong its shelf life and, consequently, its activity. On this basis, three benzoate derivatives of pinocembrin (a1-a3) were synthesised and assayed in order to ascertain their biological value. Among them, compound a1 showed the highest anti-proliferative activity on a wide panel of cancer cell lines, as well as low toxic effects on non-malignant breast cells. The calculated IC50 values in HeLa and SKBR3 cells were 8.5 and 12.7 µM, respectively. Briefly, a1 treatment increased ROS levels, induced mitochondrial membrane damage leading to necrotic death of HeLa cells. Moreover, a1 displayed a promising anti-bacterial activity.

Semi-synthesis as a tool for broadening the health applications of bioactive olive secoiridoids: a critical review.

Covering: 2005 up to 2020Olive bioactive secoiridoids are recognized as natural antioxidants with multiple beneficial effects on human health. Nevertheless, the study of their biological activity has also disclosed some critical aspects associated with their application. Firstly, only a few of them can be extracted in large amounts from their natural matrix, namely olive leaves, drupes, oil and olive mill wastewater. Secondly, their application as preventive agents and drugs is limited by their low membrane permeability. Thirdly, the study of their biological fate after administration is complicated by the absence of pure analytical standards. Accordingly, efficient synthetic methods to obtain natural and non-natural bioactive phenol derivatives have been developed. Among them, semi-synthetic protocols represent efficient and economical alternatives to total synthesis, combining efficient extraction protocols with efficient catalytic conversions to achieve reasonable amounts of active molecules. The aim of this review is to summarize the semi-synthetic protocols published in the last fifteen years, covering 2005 up to 2020, which can produce natural olive bioactive phenols scarcely available by extractive procedures, and new biophenol derivatives with enhanced biological activity. Moreover, the semi-synthetic protocols to produce olive bioactive phenol derivatives as analytical standards are also discussed. A critical analysis of the advantages offered by semi-synthesis compared to classical extraction methods or total synthesis protocols is also performed.

Psychosocial precursors of the correct sanitation and sanitization of the patient unit in the hospital setting.

BACKGROUND AND AIM OF THE WORK: Worrying data indicate the urgency of strongly limiting Healthcare-Associated Infections (HAI). Therefore, according to the Theory of Planned Behavior, the psychosocial precursors of correct sanitation and sanitization were assessed. METHODS: An Italian sample of hospital health workers (nurses, healthcare assistants, cleaners; N=250), replied to a validated questionnaire measuring: a) knowledge of HAI; b) favorable attitude towards the correct sanitation and sanitization procedure; c) perception that the management and colleagues give importance to the government of infectious risk; d) perception of being able to implement risk management behaviors; e) perception of having received proper training for the prevention of HAI. RESULTS: The results show many mistakes about knowledge, the perception of insufficient specific training, and not always favorable attitude towards sanitation and sanitization practices. Workers also perceive that they can act the required behaviors and that the management of infectious risk represents a value in the group they belong to, but they believe that the management does not offer sufficient support. CONCLUSIONS: The improvement of the factors considered (knowledge, personal attitudes, actions of management and colleagues, perception of being able to implement the required behaviors) is affected by proper training. This is one of the aspects on which management should invest more.

Production of Plant-Derived Oleuropein Aglycone by a Combined Membrane Process and Evaluation of Its Breast Anticancer Properties.

Natural products and herbal therapies represent a thriving field of research, but methods for the production of plant-derived compounds with a significative biological activity by synthetic methods are required. Conventional commercial production by chemical synthesis or solvent extraction is not yet sustainable and economical because toxic solvents are used, the process involves many steps, and there is generally a low amount of the product produced, which is often mixed with other or similar by-products. For this reason, alternative, sustainable, greener, and more efficient processes are required. Membrane processes are recognized worldwide as green technologies since they promote waste minimization, material diversity, efficient separation, energy saving, process intensification, and integration. This article describes the production, characterization, and utilization of bioactive compounds derived from renewable waste material (olive leaves) as drug candidates in breast cancer (BC) treatment. In particular, an integrated membrane process [composed by a membrane bioreactor (MBR) and a membrane emulsification (ME) system] was developed to produce a purified non-commercially available phytotherapic compound: the oleuropein aglycone (OLA). This method achieves a 93% conversion of the substrate (oleuropein) and enables the extraction of the compound of interest with 90% efficiency in sustainable conditions. The bioderived compound exercised pro-apoptotic and antiproliferative activities against MDA-MB-231 and Tamoxifen-resistant MCF-7 (MCF-7/TR) cells, suggesting it as a potential agent for the treatment of breast cancer including hormonal resistance therapies.