Nanosponges: As a Dynamic Drug Delivery Approach for Targeted Delivery

Recent advancements in nanotechnology have resulted in improved medicine delivery to the target site. Nanosponges are three-dimensional drug delivery systems that are nanoscale in size and created by cross-linking polymers. The introduction of Nanosponges has been a significant step toward overcoming issues such as drug toxicity, low bioavailability, and predictable medication release. Using a new way of nanotechnology, nanosponges, which are porous with small sponges (below one microm) flowing throughout the body, have demonstrated excellent results in delivering drugs. As a result, they reach the target place, attach to the skin's surface, and slowly release the medicine. Nanosponges can be used to encapsulate a wide range of medicines, including both hydrophilic and lipophilic pharmaceuticals. The medication delivery method using nanosponges is one of the most promising fields in pharmacy. It can be used as a biocatalyst carrier for vaccines, antibodies, enzymes, and proteins to be released. The existing study enlightens on the preparation method, evaluation, and prospective application in a medication delivery system and also focuses on patents filed in the field of nanosponges.Copyright © 2023 The Authors.

Cyclodextrin-Derived Drug Delivery Systems in Respiratory Diseases

Respiratory diseases like chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, lung cancer, tuberculosis (TB), pneumonia, and, currently, respiratory infection due to novel Coronavirus (2019-nCoV) have been the major cause of concern these days and pose a serious challenge before the medical practitioners. Various types of dosage forms, surgeries, and radiotherapies are available as the major treatment options;however, these approaches are of limited use in the successful management of the above disorders and some seem very expensive. Conventional dosage form-based therapies have many disadvantages, including poor bioavailability, safety issues, poor site specificity, and drug resistance. In recent years, with the recent advancement in research and develop- ment, different novel drug delivery approaches have been aimed for comprehen- sive management of various types of respiratory diseases. Cyclodextrins (CDs) based formulations played a significant role in improving the treatment of respi- ratory diseases. It is utilized to improve the drug's physicochemical properties, however, some of its derivatives offer direct therapeutic efficacy. In this chapter, the derivates of CD, provided with their sources and physicochemical properties, are discussed with their applications in treating major lung diseases like COPD, chronic bronchitis, asthma, lung cancer, pulmonary fibrosis, pneumonia, etc. We have also aimed to showcase, based on the ongoing clinical trials, the recent translational potential of CD-based drug delivery systems used in the respiratory disease therapy. © The Author (s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.

Determination of the Effects of Prenatal Remdesivir Exposure on Placenta Morphology, Placental IgG Transfer, and Fetal Growth in a Humanized Mouse Model

Remdesivir (RDV) is an antiviral medication used most recently for the treatment of COVID-19. Although no adverse effects were observed on perinatal parameters in reproductive and development toxicology studies at doses up to four-fold clinical area under the curve (AUC) exposures, some researchers have reported that therapeutic levels of RDV may impair early embryogenesis, as observed by in vitro studies. In addition, the influence of prenatal RDV exposure on maternal IgG transfer in the placenta is still unknown. Administration of RDV in pregnant humanized mouse model (Tg32), which expresses the human Fc gamma receptor and transporter (FCGRT) gene, was used to further evaluate potential effects on IgG transfer and concurrent perinatal endpoints. Animals were dosed daily from gestational days (GDs) 10- 14 with 25 mg/kg RDV (GS-5734) via intravenous injection (n=3-5 per group). Concurrent vehicle control animals were dosed intravenously with 12% sulfobutyl ether- beta-cyclodextrin in water (pH3.5;NaOH/HCl). All animals were administered 2 mg/kg human IgG via intravenous injection on GD 14. Placentae and fetuses were collected from dams on GD 14, 15, 16, and 18 and evaluated using histopathology and qPCR for inflammation markers. No abnormal morphologies (necrosis/apoptosis) of placentae were observed between the concurrent control and RDVdosed groups. Additionally, no differences in maternal body weights were observed. There were no statistically significant differences in placenta weights. There were no statistically significant changes in pregnancy parameters (implantation sites and dead fetuses/litter) and fetal weights between the RDV-dosed group and concurrent controls at GD 14, 15, 16, and 18. No changes were observed in transcript levels of inflammation markers in the RDV-dosed group when compared to the concurrent control group. There was a slightly lower ratio of fetal IgG level to maternal IgG levels in the RDV-dosed group;however, no statistically significant differences were observed between the RDV-dosed group and concurrent controls on GD 14, 15, 16, and 18. Our results suggest that a daily dose of 25 mg/kg RDV on GDs 10-14 in humanized mice did not cause adverse effects on placenta and fetal development. (Funded by the Perinatal Health Center of Excellence: E0300201.).

Amorphous Solid Dispersion of Niclosamide with Water-Soluble β-Cyclodextrins for Dissolution and Bioavailability Enhancement

Cyclodextrins (CDs) are cyclic oligosaccharides widely employed for the solubility enhancement of poorly water-soluble drugs. Niclosamide is a BCS class II drug for tapeworm infections and is currently under repurposing for various other indications, including COVID-19. Due to its low aqueous solubility, a high daily dose (2 g) is required for clinical efficacy. Herein, we investigate the potential of beta-cyclodextrin (β-CD) and its sulfobutylether and hydroxypropyl derivatives for the dissolution enhancement of niclosamide. The solid dispersions were prepared by kneading the drug and cyclodextrins together by adding solvent, water: methanol (1 : 1 v/v). Among various CDs studied, 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) in the 1: 2 molar ratio (SB-IC-N4 batch) shows the most significant improvement in water solubility of niclosamide (6.3 vs. 182 μg/ml), resulting in 2-fold improved in-vitro dissolution. The comparative oral pharmacokinetics in Wistar rats at 50 mg/kg produced 1.69-fold higher plasma exposure of niclosamide. The spectral characterization provided molecular insights into interactions of niclosamide with HP-β-CD. These results suggest that the dispersion of niclosamide with HP-β-CD aid in faster dissolution and better drug bioavailability. © 2023 Wiley-VCH GmbH.

ß-Cyclodextrins as affordable antivirals to treat coronavirus infection.

The SARS-CoV-2 pandemic made evident that there are only a few drugs against coronavirus. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety profile. Starting from a list of 116 drug candidates, we used molecular modelling tools to rank the 44 most promising inhibitors. Next, we tested their efficacy as antivirals against α and ß coronaviruses, such as the HCoV-229E and SARS-CoV-2 variants. Four drugs, OSW-1, U18666A, hydroxypropyl-ß-cyclodextrin (HßCD) and phytol, showed in vitro antiviral activity against HCoV-229E and SARS-CoV-2. The mechanism of action of these compounds was studied by transmission electron microscopy and by fusion assays measuring SARS-CoV-2 pseudoviral entry into target cells. Entry was inhibited by HßCD and U18666A, yet only HßCD inhibited SARS-CoV-2 replication in the pulmonary Calu-3 cells. Compared to the other cyclodextrins, ß-cyclodextrins were the most potent inhibitors, which interfered with viral fusion via cholesterol depletion. ß-cyclodextrins also prevented infection in a human nasal epithelium model ex vivo and had a prophylactic effect in the nasal epithelium of hamsters in vivo. All accumulated data point to ß-cyclodextrins as promising broad-spectrum antivirals against different SARS-CoV-2 variants and distant alphacoronaviruses. Given the wide use of ß-cyclodextrins for drug encapsulation and their high safety profile in humans, our results support their clinical testing as prophylactic antivirals.

Hydroxypropyl-ß-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells.

Vaccination has drastically decreased mortality due to coronavirus disease 19 (COVID-19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alternative strategies such as inhibition of virus entry by interference with angiotensin-I-converting enzyme 2 (ACE2) receptors could be warranted. Cyclodextrins (CDs) are cyclic oligosaccharides that are able to deplete cholesterol from membrane lipid rafts, causing ACE2 receptors to relocate to areas devoid of lipid rafts. To explore the possibility of reducing SARS-CoV-2 entry, we tested hydroxypropyl-ß-cyclodextrin (HPßCD) in a HEK293T-ACE2hi cell line stably overexpressing human ACE2 and Spike-pseudotyped SARS-CoV-2 lentiviral particles. We showed that HPßCD is not toxic to the cells at concentrations up to 5 mM, and that this concentration had no significant effect on cell cycle parameters in any experimental condition tested. Exposure of HEK293T-ACEhi cells to concentrations of HPßCD starting from 2.5 mM to 10 mM showed a concentration-dependent reduction of approximately 50% of the membrane cholesterol content. In addition, incubation of HEK293T-ACEhi cells with HIV-S-CoV-2 pseudotyped particles in the presence of increasing concentrations of HPßCD (from 0.1 to 10 mM) displayed a concentration-dependent effect on SARS-CoV-2 entry efficiency. Significant effects were detected at concentrations at least one order of magnitude lower than the lowest concentration showing toxic effects. These data indicate that HPßCD is a candidate for use as a SARS-CoV-2 prophylactic agent.

Aqueous cannabidiol ß-cyclodextrin complexed polymeric micelle nasal spray to attenuate in vitro and ex vivo SARS-CoV-2-induced cytokine storms.

Cannabidiol (CBD) has a number of biological effects by acting on the cannabinoid receptors CB1 and CB2. CBD may be involved in anti-inflammatory processes via CB1 and CB2 receptors, resulting in a decrease of pro-inflammatory cytokines. However, CBD's poor aqueous solubility is a major issue in pharmaceutical applications. The aim of the present study was to develop and evaluate a CBD nasal spray solution. A water-soluble CBD was prepared by complexation with ß-cyclodextrin (ß-CD) at a stoichiometric ratio of 1:1 and forming polymeric micelles using poloxamer 407. The mixture was then lyophilized and characterized using FT-IR, DSC, and TGA. CBD-ß-CD complex-polymeric micelles were formulated for nasal spray drug delivery. The physicochemical properties of the CBD-ß-CD complex-polymeric micelle nasal spray solution (CBD-ß-CDPM-NS) were assessed. The results showed that the CBD content in the CBD-ß-CD complex polymeric micelle powder was 102.1 ± 0.5% labeled claim. The CBD-ß-CDPM-NS was a clear colorless isotonic solution. The particle size, zeta potential, pH value, and viscosity were 111.9 ± 0.7 nm, 0.8 ± 0.1 mV, 6.02 ± 0.02, and 12.04 ± 2.64 cP, respectively. This formulation was stable over six months at ambient temperature. The CBD from CBD-ß-CDPM-NS rapidly released to 100% within 1 min. Ex vivo permeation studies of CBD-ß-CDPM-NS through porcine nasal mucosa revealed a permeation rate of 4.8 µg/cm2/min, which indicated that CBD was effective in penetrating nasal epithelial cells. CBD-ß-CDPM-NS was tested for its efficacy and safety in terms of cytokine production from nasal immune cells and toxicity to nasal epithelial cells. The CBD-ß-CDPM-NS was not toxic to nasal epithelial at the concentration of CBD equivalent to 3.125-50 µg/mL. When the formulation was subjected to bioactivity testing against monocyte-like macrophage cells, it proved that the CBD-ß-CDPM-NS has the potential to inhibit inflammatory cytokines. CBD-ß-CDPM-NS demonstrated the formulation's ability to reduce the cytokine produced by S-RBD stimulation in ex vivo porcine nasal mucosa in both preventative and therapeutic modes.

Development of Diphenyl carbonate-Crosslinked Cyclodextrin Based Nanosponges for Oral Delivery of Baricitinib: Formulation, Characterization and Pharmacokinetic Studies.

Background: The aim of the present investigation is to prepare baricitinib (BAR)-loaded diphenyl carbonate (DPC) ß-cyclodextrin (ßCD) based nanosponges (NSs) to improve the oral bioavailability. Methods: BAR-loaded DPC-crosslinked ßCD NSs (B-DCNs) were prepared prepared by varying the molar ratio of ßCD: DPC (1:1.5 to 1:6). The developed B-DCNs loaded with BAR were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), % yield and percent entrapment efficiency (%EE). Results: Based on the above evaluations, BAR-loaded DPC ßCD NSs (B-CDN3) was optimized with mean size (345.8±4.7 nm), PDI (0.335±0.005), Yield (91.46±7.4%) and EE (79.1±1.6%). The optimized NSs (B-CDN3) was further confirmed by SEM, spectral analysis, BET analysis, in vitro release and pharmacokinetic studies. The optimized NSs (B-CDN3) showed 2.13 times enhancement in bioavailability in comparison to pure BAR suspension. Conclusion: It could be anticipated that NSs loaded with BAR as a promising tool for release and bioavailability for the treatment of rheumatic arthritis and Covid-19.

ß-Cyclodextrin Polymer-Based Fluorescence Enhancement Strategy via Host-Guest Interaction for Sensitive Assay of SARS-CoV-2.

Nucleocapsid protein (N protein) is an appropriate target for early determination of viral antigen-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have found that ß-cyclodextrin polymer (ß-CDP) has shown a significant fluorescence enhancement effect for fluorophore pyrene via host-guest interaction. Herein, we developed a sensitive and selective N protein-sensing method that combined the host-guest interaction fluorescence enhancement strategy with high recognition of aptamer. The DNA aptamer of N protein modified with pyrene at its 3' terminal was designed as the sensing probe. The added exonuclease I (Exo I) could digest the probe, and the obtained free pyrene as a guest could easily enter into the hydrophobic cavity of host ß-CDP, thus inducing outstanding luminescent enhancement. While in the presence of N protein, the probe could combine with it to form a complex owing to the high affinity between the aptamer and the target, which prevented the digestion of Exo I. The steric hindrance of the complex prevented pyrene from entering the cavity of ß-CDP, resulting in a tiny fluorescence change. N protein has been selectively analyzed with a low detection limit (11.27 nM) through the detection of the fluorescence intensity. Moreover, the sensing of spiked N protein from human serum and throat swabs samples of three volunteers has been achieved. These results indicated that our proposed method has broad application prospects for early diagnosis of coronavirus disease 2019.

Veklury® (remdesivir) formulations inhibit initial membrane-coupled events of SARS-CoV-2 infection due to their sulfobutylether-ß-cyclodextrin content.

BACKGROUND AND PURPOSE: Despite its contradictory clinical performance, remdesivir (Veklury®) has a pivotal role in COVID-19 therapy. Possible contributions of the vehicle, sulfobutylether-ß-cyclodextrin (SBECD) to Veklury® effects have been overlooked. The powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane-coupled events of SARS-CoV-2 infection focusing on the cholesterol depletion-mediated role of SBECD. EXPERIMENTAL APPROACH: Using time-correlated flow cytometry and quantitative three-dimensional confocal microscopy, we studied early molecular events of SARS-CoV-2-host cell membrane interactions. KEY RESULTS: Veklury® and different cholesterol-depleting cyclodextrins (CDs) reduced binding of the spike receptor-binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan-Hu-1, Delta and Omicron variants. Correlations of these effects with cholesterol-dependent changes in membrane structure and decreased lipid raft-dependent ACE2-TMPRSS2 interaction establish that SBECD is not simply a vehicle but also an effector along with remdesivir due to its cholesterol-depleting potential. Veklury® solution inhibited RBD binding more efficiently due to its twice higher SBECD content. The CD-induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression, indicating that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low. CONCLUSION AND IMPLICATIONS: Our findings call for the differentiation of Veklury® formulations in meta-analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant cyclodextrin (CD) therapy, even at higher doses, in COVID-19.

Electrospun Cyclodextrin/Poly(L-lactic acid) Nanofibers for Efficient Air Filter: Their PM and VOC Removal Efficiency and Triboelectric Outputs.

In this work, PLLA and CD/PLLA nanofibers were fabricated using electrospinning and utilized as a particulate matter (PM) and volatile organic compounds (VOCs) filter. The electrospun PLLA and CD/PLLA were characterized with various techniques, including SEM, BET, FTIR, XRD, XPS, WCA, DSC, tensile strength testing, PM and VOCs removal efficiency, and triboelectric performance. The results demonstrated that the best air filter was 2.5 wt%CD/PLLA, which performed the highest filtration efficiencies of 96.84 ± 1.51% and 99.38 ± 0.43% for capturing PM2.5 and PM10, respectively. Its PM2.5 removal efficiency was 16% higher than that of pure PLLA, which were contributed by their higher surface area and porosity. These 2.5 wt%CD/PLLA nanofibers also exhibited the highest and the fastest VOC entrapment. For triboelectric outputs, the 2.5 wt%CD/PLLA-based triboelectric nanogenerator provided the highest electrical outputs as 245 V and 84.70 µA. These give rise to a three-fold enhancement of electrical outputs. These results indicated that the 2.5 wt%CD/PLLA can improve surface charge density that could capture more PM via electrostatic interaction under surrounding vibration. Therefore, this study suggested that 2.5 wt%CD/PLLA is a good candidate for a multifunction nanofibrous air filter that offers efficient PM and VOC removal.

Tenofovir antiviral drug solubility enhancement with ß-cyclodextrin inclusion complex and in silico study of potential inhibitor against SARS-CoV-2 main protease (Mpro).

Tenofovir (TFR) is an antiviral drug commonly used to fight against viral diseases infection due to its good potency and high genetic barrier to drug resistance. In physiological conditions, TFR is less water soluble, more unstable, and less permeable, limiting its effective therapeutic applications. In addition to their use in treating the Coronavirus disease 2019 (COVID-19), cyclodextrins (CDs) are also being used as a molecule to develop therapies for other diseases due to its enhance solubility and stability. This study is designed to synthesize and characterization of ß-CD:TFR inclusion complex and its interaction against SARS-CoV-2 (MPro) protein (PDB ID;7cam). Several techniques were used to characterize the prepared ß-CD:TFR inclusion complex, including UV-Visible, FT-IR, XRD, SEM, TGA, and DSC, which provided appropriate evidence to confirm the formation. A 1:1 stoichiometry was determined for ß-CD:TFR inclusion complex in aqueous medium from UV-Visible absorption spectra by using the Benesi-Hildebrand method. Phase solubility studies proposed that ß-CD enhanced the excellent solubility of TFR and the stability constant was obtained at 863 ± 32 M-1. Moreover, the molecular docking confirmed the experimental results demonstrated the most desirable mode of TFR encapsulated into the ß-CD nanocavity via hydrophobic interactions and possible hydrogen bonds. Moreover, TFR was validated in the ß-CD:TFR inclusion complex as potential inhibitors against SARS-CoV-2 main protease (Mpro) receptors by using in silico methods. The enhanced solubility, stability, and antiviral activity against SARS-CoV-2 (MPro) suggest that ß-CD:TFR inclusion complexes can be further used as feasible water-insoluble antiviral drug carriers in viral disease infection.

Surfactant-Impregnated MOF-Coated Fabric for Antimicrobial Applications.

Since the onset of the SARS-CoV-2 pandemic, the world has witnessed over 617 million confirmed cases and more than 6.54 million confirmed deaths, but the actual totals are likely much higher. The virus has mutated at a significantly faster rate than initially projected, and positive cases continue to surge with the emergence of ever more transmissible variants. According to the CDC, and at the time of this manuscript submission, more than 77% of all current US cases are a result of the B.5 (omicron). The continued emergence of highly transmissible variants makes clear the need for more effective methods of mitigating disease spread. Herein, we have developed an antimicrobial fabric capable of destroying a myriad of microbes including betacoronaviruses. We have demonstrated the capability of this highly porous and nontoxic metal organic framework (MOF), γ-CD-MOF-1, to serve as a host for varied-length benzalkonium chlorides (BACs; active ingredient in Lysol). Molecular docking simulations predicted a binding affinity of up to -4.12 kcal·mol-1, which is comparable to that of other reported guest molecules for this MOF. Similar Raman spectra and powder X-ray diffraction patterns between the unloaded and loaded MOFs, accompanied by a decrease in the Brunauer-Emmett-Teller surface area from 616.20 and 155.55 m2 g-1 respectively, corroborate the suggested potential for pore occupation with BAC. The MOF was grown on polypropylene fabric, exposed to a BAC-loading bath, washed to remove excess BAC from the external surface, and evaluated for its microbicidal activity against various bacterial and viral classes. Significant antimicrobial character was observed against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, bacteriophage, and betacoronavirus. This study shows that a common mask material (polypropylene) can be coated with BAC-loaded γ-CD-MOF-1 while maintaining the guest molecule's antimicrobial effects.

A New Synergistic Strategy for Virus and Bacteria Eradication: Towards Universal Disinfectants.

In response to the COVID-19 and monkeypox outbreaks, we present the development of a universal disinfectant to avoid the spread of infectious viral diseases through contact with contaminated surfaces. The sanitizer, based on didecyldimethylammonium chloride (DDAC), N,N-bis(3-aminopropyl)dodecylamine (APDA) and γ-cyclodextrin (γ-CD), shows synergistic effects against non-enveloped viruses (poliovirus type 1 and murine norovirus) according to the EN 14476 standard (≥99.99% reduction of virus titer). When a disinfectant product is effective against them, it can be considered that it will be effective against all types of viruses, including enveloped viruses. Consequently, "general virucidal activity" can be claimed. Moreover, we have extended this synergistic action to bacteria (P. aeruginosa, EN 13727). Based on physicochemical investigations, we have proposed two independent mechanisms of action against bacteria and non-enveloped viruses, operating at sub- and super-micellar concentrations, respectively. This synergistic mixture could then be highly helpful as a universal disinfectant to avoid the spread of infectious viral or bacterial diseases in community settings, including COVID-19 and monkeypox (caused by enveloped viruses).

Chapter 23 - Nasal and pulmonary routes of drug delivery

Nasal and pulmonary drug delivery are attractive routes for the administration of a growing number of drugs for topical and systemic treatment as well as for prevention by vaccines. This is of particular interest for drugs with poor bioavailability, as the gastrointestinal passage and hepatic first pass effect can be avoided. The development of drugs, vehicles, and devices made substantial progress. The drug delivery research is focused on transmucosal absorption enhancers such as surfactants, enzyme inhibitors, biopolymers, tight junction modulators, cyclodextrins, and gelling systems and on nasal and pulmonary carrier systems like nanoparticles, microspheres, nano- or microemulsions, and liposomes. Many approaches are still in early development and need further investigation. The trend for devices is going to nasal dry powder inhalers and smart pulmonary nebulizers. A new research area includes inhalable vaccines, biological drugs, and coronavirus treatments.

Remdesivir administration for Japanese COVID-19 patients undergoing maintenance hemodialysis: a retrospective observation with six case reports.

Background: The mortality rate of novel coronaviral disease (COVID-19) patients undergoing dialysis is considerably higher than that of patients with normal kidney function. As of August 2021, only remdesivir has been approved in Japan as an antiviral drug for the treatment of COVID-19. However, in cases of kidney failure, remdesivir administration should be considered only if the therapeutic benefits outweigh the risks because of concern about the accumulation of its solubilizing excipient sulfobutylether-beta-cyclodextrin and subsequent renal tubular injury or liver injury. Recently, reports from overseas indicating the safety of the use of remdesivir for COVID-19 patients on dialysis have been gathered. Case presentation: From June 2021, in our hospital, we started the administration of remdesivir to patients with moderate cases of COVID-19 undergoing hemodialysis, with careful consideration of the dosage and timing. Since then, six out of seven COVID-19 patients on hemodialysis who had received remdesivir have completely recovered. In a patient who died, the initial dose of remdesivir was administered after the case developed into severe COVID-19. All six patients who were able to start receiving remdesivir immediately at the stage of moderate COVID-19 recovered and were discharged without the need for mechanical ventilation. While, two out of four patients before May 2021 who had not been administered remdesivir at admission became severe, transferred to another tertiary hospital, and died. During and after remdesivir administration, no increase in serum transaminase to five times or more of the normal upper limit was observed in any of the cases. There were no other adverse drug reactions, such as infusion reaction, gastrointestinal symptoms, or anemia. Conclusions: We were able to administer remdesivir to six Japanese patients with moderate COVID-19 on hemodialysis safely. It is expected that the safe use of remdesivir will bring an increase in treatment options for moderate cases of COVID-19 in dialysis patients as well as subsequent improvement in treatment outcomes. However, to confirm the efficacy and safety of such use, further careful observation in more cases is required.

Cyclodextrins as promising therapeutics against cholesterol overload

Dysregulation of cholesterol homeostasis and concomitant cellular cholesterol accumulation substantially contribute to the pathophysiological mechanisms of a great variety of diseases. This generates an emerging need to develop drugs that can selectively decrease cellular cholesterol levels while having favorable pharmacokinetic and biodistribution profiles without significant adverse effects. Cyclodextrins, which are cyclic oligosaccharides capable of complexing cholesterol and other lipids, represent novel promising therapeutic agents, since they meet all of these requirements. Furthermore, cyclodextrins have been shown to effectively manipulate cholesterol levels and trafficking in in vitro and animal experiments and even clinical trials. In this review, we summarize the beneficial effects of cyclodextrins in several diseases focusing on the fact that besides their direct interaction with cholesterol, these compounds are proposed to activate alternative signaling pathways that ultimately result in decreased cellular cholesterol levels. © 2022 Elsevier Inc. All rights reserved.

Versatile Applications of Nanosponges in Biomedical Field: A Glimpse on SARS-CoV-2 Management.

Nanotechnology has a versatile use in the field of disease therapy, targeted drug delivery, biosensing, and environmental protection. The cross-linked nanosponges are one of the types of nanostructures that provide huge application in the biomedical field. They are available up to the fourth generation and can act as a payload for both kinds of hydrophilic and hydrophobic drugs. There are different methods available for the synthesis of these nanosponges as well as loading the drugs inside them. A variety of approved drugs based on nanosponges are already in the market including drugs for cancer. Other applications include the uses of nanosponges as topical agent, in improving solubility, as protein carrier, in chemical sensors, in wastewater remediation, and in agriculture. The present review discusses in detail about different applications of nanosponges and also mentions about the recent SARS-CoV-2 management using nanosponges.

Structural Investigation of Hesperetin-7-O-Glucoside Inclusion Complex with ß-Cyclodextrin: A Spectroscopic Assessment.

Flavonoids are biologically active natural products of great interest for their potential applications in functional foods and pharmaceuticals. A hesperetin-7-O-glucoside inclusion complex with ß-cyclodextrin (HEPT7G/ßCD; SunActive® HCD) was formulated via the controlled enzymatic hydrolysis of hesperidin with naringinase enzyme. The conversion rate was nearly 98%, estimated using high-performance liquid chromatography analysis. The objective of this study was to investigate the stability, solubility, and spectroscopic features of the HEPT7G/ßCD inclusion complex using Fourier-transform infrared (FTIR), Raman, ultraviolet-visible absorption (UV-vis), 1H- and 13C- nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), liquid chromatography/mass spectroscopy (LC-MS), scanning electron microscopy (SEM), and powdered X-ray diffraction (PXRD) spectroscopic techniques including zeta potential, Job's plot, and phase solubility measurements. The effects of complexation on the profiles of supramolecular interactions in analytic features, especially the chemical shifts of ß-CD protons in the presence of the HEPT7G moiety, were evaluated. The stoichiometric ratio, stability, and solubility constants (binding affinity) describe the extent of complexation of a soluble complex in 1:1 stoichiometry that exhibits a greater affinity and fits better into the ß-CD inner cavity. The NMR spectroscopy results identified two different configurations of the HEPT7G moiety and revealed that the HEPT7G/ßCD inclusion complex has both -2S and -2R stereoisomers of hesperetin-7-O-glucoside possibly in the -2S/-2R epimeric ratio of 1/1.43 (i.e., -2S: 41.1% and -2R: 58.9%). The study indicated that encapsulation of the HEPT7G moiety in ß-CD is complete inclusion, wherein both ends of HEPT7G are included in the ß-CD inner hydrophobic cavity. The results showed that the water solubility and thermal stability of HEPT7G were apparently increased in the inclusion complex with ß-CD. This could potentially lead to increased bioavailability of HEPT7G and enhanced health benefits of this flavonoid.

Epigallocatechin Gallate Stabilized by Cyclodextrin Inactivates Influenza Virus and Human Coronavirus 229E.

Natural products are attractive antiviral agents because they are environment-friendly and mostly harmless. Epigallocatechin gallate (EGCg), a type of catechin, is a well-known natural antiviral agent that can inhibit various viruses. However, EGCg easily oxidizes and loses its physiological activity. Although this problem can be overcome by combining EGCg with cyclodextrin (CD-EGCg), which makes it stable in water at high concentrations, the antiviral effect of this compound remains unclear. Here, we show that in Madin-Darby canine kidney (MDCK) and MRC-5 cells, CD-EGCg is cytotoxic for 50% of cells at 85.61 and 65.34 ppm, respectively. Furthermore, CD-EGCg mainly shows its antiviral effect during the adsorption step for all four influenza virus strains (median effect concentration (EC50) was 0.93 to 2.78 ppm). Its antiviral effect post-adsorption is less intense, and no inhibitory effect is observed on influenza viruses pre-adsorption. Moreover, human coronavirus 229E (HCoV-229E) was inhibited at the adsorption step in short contact (EC50 = 2.5 ppm) and long contact conditions (EC50 = 0.5 ppm) by mixing CD-EGCg with HCoV-229E. These results suggest that CD-EGCg effectively inhibits various viruses that require an adsorption step, and is an effective tool for preventing infection.