How Can Deep Eutectic Systems Promote Greener Processes in Medicinal Chemistry and Drug Discovery?

Chemists in the medicinal chemistry field are constantly searching for alternatives towards more sustainable and eco-friendly processes for the design and synthesis of drug candidates. The pharmaceutical industry is one of the most polluting industries, having a high E-factor, which is driving the adoption of more sustainable processes not only for new drug candidates, but also in the production of well-established active pharmaceutical ingredients. Deep eutectic systems (DESs) have emerged as a greener alternative to ionic liquids, and their potential to substitute traditional organic solvents in drug discovery has raised interest among scientists. With the use of DESs as alternative solvents, the processes become more attractive in terms of eco-friendliness and recyclability. Furthermore, they might be more effective through making the process simpler, faster, and with maximum efficiency. This review will be focused on the role and application of deep eutectic systems in drug discovery, using biocatalytic processes and traditional organic chemical reactions, as new environmentally benign alternative solvents. Furthermore, herein we also show that DESs, if used in the pharmaceutical industry, may have a significant effect on lowering production costs and decreasing the impact of this industry on the quality of the environment.

Postpandemic Rebound in Noninvasive Group a Streptococcal Disease is not Synchronous with Winter RSV and Influenza Epidemics.

An increase in invasive group A Streptococcus infections was reported in 2022, associated with intense respiratory virus circulation. We describe a marked increase of noninvasive group A Streptococcus infections. Although the rise coincided with epidemics of respiratory syncytial virus and influenza, it continued after detection of these viruses fell to low levels, suggesting that other factors have contributed to this epidemiologic change.

International Pediatric COVID-19 Severity Over the Course of the Pandemic.

Importance: Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear. Objective: To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children. Design, Setting, and Participants: Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded. Exposures: SARS-CoV-2 hospitalization during the stipulated time frame. Main Outcomes and Measures: The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy. Results: Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children. Conclusions and Relevance: This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.

Using Natural Deep Eutectic Systems as Alternative Media for Ocular Applications.

The major goal of this work was to study the potential of natural deep eutectic systems (NADES) as new media for ocular formulations. In formulating eye drops, it is important to increase the retention time of the drug on the surface of eye; hence, due to their high viscosity, NADES may be interesting candidates for formulation. Different systems composed of combinations of sugars, polyols, amino acids, and choline derivatives were prepared and then characterized in terms of rheological and physicochemical properties. Our results showed that 5-10% (w/v) aqueous solutions of NADES have a good profile in terms of viscosity (0.8 to 1.2 mPa.s), osmolarity (412 to 1883 mOsmol), and pH (7.4) for their incorporation of ocular drops. Additionally, contact angle and refractive index were determined. Acetazolamide (ACZ), a highly insoluble drug used to treat glaucoma, was used as proof-of-concept. Herein, we show that NADES can increase the solubility of ACZ in aqueous solutions by at least up to 3 times, making it useful for the formulation of ACZ into ocular drops and thereby enabling more efficient treatment. The cytotoxicity assays demonstrated that NADES are biocompatible up to 5% (w/v) in aqueous media, promoting cell viability (above 80%) when compared to the control after 24 h incubation in ARPE-19 cells. Furthermore, when ACZ is dissolved in aqueous solutions of NADES, the cytotoxicity is not affected in this range of concentrations. Although further studies are necessary to design an optimal formulation incorporating NADES, this study shows that these eutectics can be powerful tools in the formulation of ocular drugs.

Use of natural deep eutectic systems as new cryoprotectant agents in the vitrification of mammalian cells.

In this work we present the potential of Natural Deep Eutectic Systems (NADES) as new vitrification media for the cryopreservation of mammalian cells. Several NADES composed of natural metabolites were prepared and tested as CPAs in two cell lines, L929 and HacaT cells. After the harvesting, cells were mixed with the eutectic systems, and frozen directly into liquid nitrogen to achieve a vitreous state. Then, the cells were thawed and it was observed that NADES were able to exert a significant cryoprotective effect in L929 cells, when compared with DMSO or in the absence of a CPA. For HacaT cells, only a eutectic system showed a slightly improvement in cell survival, while DMSO caused complete cell death. Moreover, the thermal behaviour of the best systems was studied for further understanding the protective properties of NADES as CPAs, and have shown a significant difference in terms of Tm and Tc when compared with DMSO and water. Additionally, the results obtained showed that NADES can be maintained in the growth media after the thawing step, without compromising cell viability. In summary, we have shown the great potential of NADES to be used as CPAs for the cryopreservation of different cell types, using the vitrification method.

Supercritical CO2 Assisted Impregnation of Ibuprofen on Medium-Chain-Length Polyhydroxyalkanoates (mcl-PHA).

In this work, we propose the utilization of scCO2 to impregnate ibuprofen into the mcl-PHA matrix produced by Pseudomonas chlororaphis subs. aurantiaca (DSM 19603). The biopolymer has adhesive properties, is biocompatible and has a melting temperature of 45 °C. Several conditions, namely, pressure (15 and 20 MPa) and impregnation time (30 min, 1 h and 3 h) were tested. The highest ibuprofen content (90.8 ± 6.5 mg of ibuprofen/gPHA) was obtained at 20 MPa and 40 °C, for 1 h, with an impregnation rate of 89 mg/(g·h). The processed mcl-PHA samples suffered a plasticization, as shown by the decrease of 6.5 °C in the Tg, at 20 MPa. The polymer's crystallinity was also affected concomitantly with the matrices' ibuprofen content. For all the impregnation conditions tested the release of ibuprofen from the biopolymer followed a type II release profile. This study has demonstrated that the mcl-PHA produced by P. chlororaphis has a great potential for the development of novel topical drug delivery systems.

Natural deep eutectic systems, an emerging class of cryoprotectant agents.

This work aimed at evaluating the potential of using natural deep eutectic systems (NADES) as cryoprotectant agents (CPAs). Several combinations between natural primary metabolites that have been identified in animals that live in extreme cold climates were prepared. All systems showed very little cytoxicity towards L929 cells at concentrations high as 1-2 M. Moreover, this cell line was highly tolerant to 10% (w/v) of NADES when compared to Me2SO. To test NADES as CPAs, two cell lines were used, L929 and HacaT cells. After freeze/thawing cycle, it was possible to observe that for L929 cells, NADES presented similar behaviour to Me2SO. For Hacat cell line a significant improvement on post-thawing recovery was observed. Moreover, the results presented herein showed that NADES do not need to be removed from the freezing media after thawing the cells, which is a great advantage of these materials. Additionally, we have shown that NADES can act as CPA when cells are frozen at -20 °C. In overall, the results demonstrate the high potential of NADES to be used in cryobiology as alternative CPAs.

Reproductive success of assisted reproductive technology in couples with chromosomal abnormalities.

PURPOSE: Infertility is estimated to affect 15% of couples, having chromosome abnormalities an important role in its etiology. The main objective of this work was to access the reproductive success of ART in infertile couples with chromosomal abnormalities comparing to a control group with normal karyotype. METHODS: A 7-year retrospective karyotype analysis of infertile couples was done. Data regarding type of infertility, couples' ages, ART performed, and their reproductive success were obtained. Adjusted odds ratio (OR) were used to estimate magnitude of association between the reproductive success and the different groups. RESULTS: We found a prevalence of 7.83% of chromosome abnormalities in our population (233 couples out of 2989). Chromosomal anomalies were found in 82 men (34.75%) and 154 women (65.25%), with low-grade mosaicism being the most prevalent (50.85%), followed by autosomal translocations (17.37%) and sex chromosomes abnormalities (13.56%). Only 2359 couples were treated with ART. There was a non-significant lower reproductive success rate in the cases (OR = 0.899, p = 0.530) with IVF providing the higher success rate. In general, female carriers of chromosome anomalies had a higher success rate, although not significant. CONCLUSION: Although the differences regarding success rate between groups were not found statistically significant, we still advocate that cytogenetic analysis should be performed routinely in all infertile couples namely before ART. This might help deciding the best treatment options including Preimplantation Genetic Testing for aneuploidies or structural rearrangements and minimize the risk of transmission of anomalies to the offspring.