key: cord-0943006-psvaduo7 authors: Jicsinszky, László; Martina, Katia; Cravotto, Giancarlo title: Cyclodextrins in the antiviral therapy date: 2021-05-20 journal: J Drug Deliv Sci Technol DOI: 10.1016/j.jddst.2021.102589 sha: e09b80c30a259985e71c4138f47dfcbc3146237b doc_id: 943006 cord_uid: psvaduo7 The main antiviral drug-cyclodextrin interactions, changes in physicochemical and physiological properties of the most commonly used virucides are summarized. The potential complexation of antiviral molecules against the SARS-Cov2 also pointed out the lack of detailed information in designing effective and general medicines against viral infections. The principal problem of the current molecules is the 3D structures of the currently active compounds. Improving the solubility or bioavailability of antiviral molecules is possible, however, there is no universal solution, and the complexation experiments dominantly use the already approved cyclodextrin derivatives. This review discusses the basic properties of the different cyclodextrin derivatives, their potential in antiviral formulations, and the prevention and treatment of viral infections. The biologically active new cyclodextrin derivatives are also discussed. Although the cavity is only less hydrophilic and less polar than hydroxyl rims, it can form 54 complexes with geometrically suitable hydrophilic or polar groups, too. CDs can capture 55 neutral molecules, various inorganic and organic salts, acids, or bases. The hollow structure 56 of CDs allows the formation of inclusion complexes, but a real inclusion can frequently exist 57 in crystalline structures only. In solutions, usually, the guest molecule freely moves in-and 58 outward the cavity since the complexation process is a dynamic equilibrium. The 59 composition and (apparent) complex stability constants -derived from the complex 60 equilibrium equation (Eq. 1) -characterize the inclusion complexes. Due to mathematical 61 limitations, the calculated complex stability constant is always apparent because the 62 calculations neglect the less abundant other complex compositions. 63 x CD + y Guest  CD x Guest y => K xy =[CD x Guest y ]/([CD free ] x [Guest free ] y ) Eq. 1 64 deeper and remove the reports on the analytical applications, the picture is even worse, not 115 only for the whole CD literature but also within these subgroups, as shown in Figure 3b . 116 Although some CD-lipid/membrane interaction has been known for a long time, the most 117 known is the cholesterol-CD interaction. The effect of CDs on these viral and cell 118 constituents is still unclear or not entirely understood. In the articles, pharmaceutical and medical applications play a leading role, and the 123 appearance of CDs in antiviral formulations is less pronounced. It is also true that many 124 accepted antiviral molecules are usually soluble in water, poorly absorbed from oral 125 formulations, or owing to their chemical structures like the nucleoside or nucleotide subunits, 126 less suitable guests for complexation with the most common/accepted CDs. Another 127 weakness is that some of the molecules are pro-drugs, and the parenteral administration is the 128 only available route. Although near one hundred accepted chemicals are available for 129 antiviral treatments, only less than half of these compounds have experimented with CDs. 148 Although the number of CD derivatives is continuously increasing, the number of 149 pharmacologically accepted molecules, either as active components or excipients, has not 150 changed much in the past decades. The presence of CDs in the GRAS list shows a similar 151 trend. A specially designed curare-type antagonist Sugammadex, (octakis(6-deoxy-6-S-(2-152 carboxy)ethylsulfanyl)-γ-cyclodextrin, Bridion®), and (2-hydroxy)propyl-β-and -γCD 153 (HPβCD and with restrictions HPγCD), and (4-sulfobutyl-βCD) are approved derivatives for 154 parenteral administration so far. The SB-and HP-CD derivatives are randomly (statistically) 155 substituted derivatives, i. e., not only the degree of substitution (DS, number of 156 substituents/CD ring) is an average value, but the numerous regioisomers are also present in 157 the accepted derivatives. This kind of structural diversity has posed grave challenges to drug 158 authorities and makes it difficult to register a new and more effective CD derivative. The 159 glucopyranoside units have three, somehow different reactive hydroxyl groups. In CDs, the 160 most reactive hydroxyl group is C(2)-OH. Although it is also true that the C(3)-OH groups 161 are practically as reactive as the C(2)-OH groups, owing to the truncated cone average shape 162 of the most common CDs, the C(3)-OHs sterically hindered that reduces their reactivity, 163 particularly in cases of bulkier reagents. In general, the sterically crowded, bulk reagents 164 prefer the primary hydroxyls. However, it is also true that as the molecular complexity or 165 symmetry increases, whether it is a cyclodextrin derivative with a well-defined structure or 166 another good solubility enhancing property, the production costs increase significantly. 167 While the formation of an inclusion complex may not only affect the distribution of drug 168 molecules, the interaction of HPβCD, unlike the SBβCD, with cellular components may even 169 be detrimental. In some cases, however, this effect may be beneficial. Because of their molecular dimensions, macrocycles are generally less suitable guest 314 molecules, but the substituents attached to them can interact with CDs. In such cases, CD-315 macrocycle complexes of various compositions may be formed, as is the case, e.g., among 316 the taxane derivatives [66]. However, a new, more effective formulation is rarely attractive 317 for the profit-oriented pharmaceutical industry because a new composition does not always 318 bring quick benefits and may discard earlier investments into the formulation developments. 319 The lipid fraction of a cell is usually the perfect guest for CDs, and changes in membrane 320 structure often cause cell death. Although this may be useful in antibacterial agents, it is less 321 prevalent in antiviral therapy because, unfortunately, viruses do not have a cell wall, which 322 reduces the direct virus-killing potential of CDs. Advantageously, when the lipid envelope 323 has a high cholesterol content, an antiviral effect is reported. 324 Although cyclodextrin-protein interaction can modify the secondary and tertiary structures 325 [67], these effects do not always lead to denaturation. Due to the dynamic equilibrium, the 326 regeneration of tertiary/quaternary protein structures is generally possible, as only a few 327 amino acids have an appropriate moiety for a stable inclusion [68] . Although it can be administered internally, the dominant application is a topical formulation 360 despite the low absorption rate. Aqueous solubility is moderate, and though conversion to the 361 sodium salt may increase it, the bioavailability of the ionized form remains low [89] . 362 The cyclodextrin complexation can considerably increase the solubility (1.3-2.7-fold) and 363 oral bioavailability (≈1.6-fold) [ Ganciclovir has been approved for medical use more than 30 years ago and administered both 390 oral and intravenous ways. The oral absorption is low, and some topical applications are also 391 known. The aqueous solubility is in the range of ≈0.4-0.9% range. CD complexation can 392 increase not only its solubility but the bioavailability, as well. Interaction with natural CDs 393 has been tested, and βand γCD showed some significant improvements in the physiological 394 properties by decreasing the LD50 value. The βCD can form a complex with ganciclovir only 395 [104]. Since the symmetrically methylated βCD, DIMEB (heptakis(2,6-di-O-methyl)-βCD) 396 can enhance transepithelial permeability, increase bioavailability, but this CD derivative is 397 actually out of play due to the limited availability of isomeric pure DIMEB and price. The Amantadine has been used selectively as an oral prophylactic agent against the influenza A 522 virus since the early 1960s. However, since the early 1980s, when the first publication 523 appeared about drug resistance, the incidence of resistance has been steadily increasing. 524 Although its importance as an antiviral agent is gradually diminishing, it is early to bury it 525 because it inhibits the virus's genetic material release. In combination with other virucidals, it 526 can control the spreading of similar viruses. 527 As a salt, it is highly soluble in water and forms a stable complex with βCD, which has 528 apparent complex stability constant in the range of 10 4 M -1 . [ [148] were also tested., but the last one is not a cyclic glucuronic acid variant of βCD, but a 531 The rich sulfur content is suitable for CD complexation, and the use of HPCD increased in 551 topical administration not only its aqueous solubility (up to near 1 %) but bioavailability (≈3-552 fold), too [71] . 553 Thioguanine is developed as an antimetabolite administered in oral formulations against 555 various leukemias and has many side effects [154] . Its aqueous solubility near-neutral pH is 556 low (<0.1%), but alkaline solutions can ionize it, and the solubility increases dramatically. 557 The antiviral properties of 6-thioguanine against rotaviruses have recently been discovered 558 Generic favipiravir is an RNA polymerase inhibitor used mainly in Asian countries to treat 608 more severe flu cases. One publication discussed in detail the mechanism of its effect, finding 609 lethal mutagenesis of SARS-Cov2, though the published results did not yet provide 610 convincing evidence for efficacy, primarily due to inadequately followed study protocols. 611 However, favipiravir was more effective against Covid-19 than the combination of lopinavir 612 and ritonavir [176, 177] . 613 Favipiravir is poorly soluble in PBS (≈0.01%), and its effective dose is relatively high (600-614 1600 mg/day). A serious drawback, in the best case, the 1:1 complexation of βCD would 615 require a minimum of ≈4.3-13.5 g/day CD orally. Although large tablets could resolve these 616 amounts only, the βCD intake would be well above the EMA recommendation of ≈0.5-1 617 g/day. The more tolerated other CDs oral intake can be higher, 1-10 g per day, but their 618 molecular weights are even higher than the βCD. So far, no favipiravir/CD complexes are 619 reported in the literature, although the molecular structure suggests only low stability 620 constant or little improvement in aqueous solubility. 621 Remdesivir targets the inhibition of an enzyme that is necessary for the genetic material copy 623 of a virus, and it was among the first targets of drug reconsiderations against the symptoms of 624 Covid-19. Remdesivir is still the subject of studies to assess its effectiveness [178] [179] [180] [181] [182] . 625 Although it is allowed to use in Japan, and both FDA and EMA have also permitted its 626 therapeutic use within the USA and EU in less severe infections, some conditions of use and 627 biological effects are still unclear. 628 Low aqueous solubility at neutral or slightly acidic pHs is its serious drawback of 629 parenterally administered remdesivir. To increase the solubility, SBβCD is used, which, 630 while having much worse complexing properties than HPβCD, makes its anionic property 631 suitable for the solubility enhancement of an ionizable molecule at a tolerable pH. SBβCD 632 has fewer side effects than HPβCD, though the drug/CD weight ratio is worse. The current 633 formulation contains, in the dissolvable powder contains near 3% remdesivir, and about half 634 of this in the liquid infusion formulation [183] . Increasing the drug/CD ratio is more than a 635 wish. In some formulations, using organic co-solvents and/or ultrasound-assisted dissolution 636 can result in better solubilization of remdesivir by SBβCD [184] . The sulfobutyl group is a 637 relatively strong acid, almost entirely neutralized by sodium ions in the commercial product. 638 The solubility enhancement of this CD derivative is more related to some non-ionized 639 sulfobutyl groups than to the formation of inclusion complexes. These protonated sulfonic 640 acid groups provide a strongly acidic microenvironment for remdesivir. The substituents 641 mainly locate on the secondary hydroxyl edge of βCD, which not only widens the cavity but 642 may promote the ionization of remdesivir due to the high density of negatively charged 643 groups. A recent publication that appeared during the revision process made attempts to 644 demonstrate some lipophilic interaction between remdesivir both the cyclodextrin and the 645 sulfobutyl side chain, furthermore, NMR and molecular modeling make the interaction of 646 ionizable groups also possible [185] . The NMR studies suggest a more realistic ensemble of 647 the guest than as figured on a drug development forum in the mid of 2020 [186] . 648 Although the salt formation can be more expressed than inclusion formation, finally, it is 649 entirely irrelevant for the current formulation. A significantly increased drug content and 650 enhanced efficacy in patients in the early stages of Covid-19 may accelerate recovery from 651 the disease, decrease the side effects of high SBβCD dose, reduce the hospital burden and 652 patient suffering. 653 Dexamethasone is a corticosteroid immunomodulator introduced to medical treatments in the 655 early 1960s. Many ways, including oral formulations, are available to treat the patients. This 656 drug is on the NIH recommendation list [187] after it was found effective in reducing 657 mortality rates in critical stages in Covid-19. Although its wide application in antiviral 658 therapy is still under study, the available data suggest its beneficial effect on infected patients 659 [188, 189] . Currently, a single daily dose of medication appears to be sufficient, as it 660 successfully increases patient survival in either injectable or tablet form, and this long-lived 661 molecule is one of the inexpensive treatments. 662 Although the aqueous solubility is low (<0.01%), its bioavailability is over 80%. From the 663 beginning of its life-cycle, numerous reviews deal with its interactions with various CDs and 664 CD derivatives [190] [191] [192] . 665 The CDs can increase the aqueous solubility of dexamethasone and the residence time in the 666 body. Many times topical applications can provide faster absorption and better 667 bioavailability, too [193] [194] [195] [196] [197] . 668 6.5 (Hydroxy)chloroquine 669 Hydroxychloroquine and chloroquine are oral anti-malarial drugs worldwide that have also 670 been used since the middle of the last century and to treat rheumatoid arthritis and porphyria, 671 as well. Its use in Covid-19 treatments [198, 199] Although ivermectin is principally intended for use in animals, there are also some human 687 formulations [209, 210] . Although the replication of SARS-Cov2 was successfully inhibited 688 in vitro [211] , after a short period of study, NIH does not recommend it against SARS-Cov2. 689 The high dose and many side effects have put it into a non-recommended status [212] . Fenofibrate is used to lower blood lipids, but since this type of statins has shown a less 702 significant reduction in the risk of heart disease or death, its popularity has dropped. Its 703 prolonged use causes some hepatotoxic effects, too. The mechanism of action of SARS-Cov2 704 suggests that Covid-19 leads to lipid deposits in the lung. This effect increases the severity of 705 the infection. Although this drug is safe, further comprehensive studies are needed to prove 706 its effectiveness against the new coronavirus, as there is currently no direct evidence that 707 Covid-19 is beneficial for patients. 708 The aqueous solubility (<0.01%) and oral bioavailability of fenofibrate are very low, but 709 some nanoparticle formulations can improve these properties. Although there are attempts to use CD derivatives as antiviral agents, a real therapeutic 786 utilization is far below the horizon. It is much more due to their complicated and expensive 787 synthesis [242] , industrial production difficulties, and eventually their inadequate in vivo 788 properties. Among the authorized CD derivatives, the anti-HIV properties of HPβCD had 789 been a promising candidate in contagion prevention but the initial enthusiasm soon followed 790 by a long silence [65, 243] . 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Cyclodextrins in peptide and protein delivery Copper(II)-complex Directed Regioselective Mono-p-toluenesulfonylation of 1114 Cyclomaltoheptaose at a Primary Hydroxyl Group Position: An NMR and Molecular 1115 Dynamics-aided Design Construction of 6-thioguanine and 6-mercaptopurine carriers based on β-cyclodextrins 1119 and gold nanoparticles Bioavailability and 1122 anticataract effects of a topical ocular drug delivery system containing disulfiram and 1123 hydroxypropyl-β-cyclodextrin on selenite-treated rats Development of Stabilizing Formulations of a Trivalent Inactivated Poliovirus 1127 Vaccine in a Dried State for Delivery in the Nanopatch™ Microprojection Array Protein stabilization by cyclodextrins in the liquid 1130 and dried state Emergency Use Authorization (EUA) for an Unapproved Product 1133 Fact Sheet for Healthcare Providers Administering Vaccine (vaccination 1135 Providers) Revision Toward Single Molecule Dna Sequencing: Direct 1137 Identification of Ribonucleoside and Deoxyribonucleoside 5'-monophosphates by 1138 Using an Engineered Protein Nanopore Equipped with a Molecular Adapter Continuous base 1141 identification for single-molecule nanopore DNA sequencing Potential therapeutic application of 1144 dendrimer/cyclodextrin conjugates with targeting ligands as advanced carriers for 1145 gene and oligonucleotide drugs Cell transfection 1148 with polycationic cyclodextrin vectors Characterisation 1151 of cationic amphiphilic cyclodextrins for neuronal delivery of siRNA: Effect of 1152 reversing primary and secondary face modifications Cyclodextrin-peptide conjugates for sequence specific DNA binding Multiple and time-scheduled in situ DNA delivery mediated by beta-1159 cyclodextrin embedded in a polyelectrolyte multilayer Synthesis and Characterization of Rabies irus Glycoprotein-tagged 1163 Amphiphilic Cyclodextrins for Sirna Delivery in Human Glioblastoma Cells: In Vitro 1164 Click-Modified Cyclodextrins as Nonviral Vectors for Neuronal 1167 siRNA Delivery Amphiphilic cationic cyclodextrins as non-viral vectors for gene and siRNA delivery Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-1173 beta-cyclodextrin History of Cyclodextrin Nanosponges Cyclodextrin 1179 nanoassemblies: a promising tool for drug delivery PTO-02 Dissolution Enhancement of Celecoxib by Complexation with 1183 Biological In Vitro Models for Absorption by Non-Oral Routes. Reference Module in 1187 Biowaiver 1191 Monographs for Immediate Release Solid Oral Dosage Forms: Aciclovir Ocular 1194 Tolerability and In ivo Bioavailability of Poly Drug delivery function of 1198 carboxymethyl-β-cyclodextrin modified upconversion nanoparticles for adamantine 1199 phthalocyanine and their NIR-triggered cancer treatment Acyclovir-loaded sulfobutyl ether-β-cyclodextrin decorated chitosan 1203 nanodroplets for the local treatment of HSV-2 infections Cyclodextrins as "smart" components of polymer nanoparticles Preparation and in vitro evaluation of the antiviral activity of the Acyclovir 1209 complex of a β-cyclodextrinoly(amidoamine) copolymer Chapter 10 -Microemulsion as drug and gene delivery 1212 vehicle: an inside story Acyclovir Cream for Treatment of Herpes Simplex Labialis: 1217 Results of Two Randomized, Double-Blind, Vehicle-Controlled Supramolecular Interactions between beta-Cyclodextrin and the 1222 Nucleobase Derivatives of Ferrocene Thermodynamic modelling of solubility and 1231 preferential solvation for ribavirin (II) in co-solvent mixtures of (methanol, n-1232 propanol, acetonitrile or 1,4-dioxane) + water Intracellular trafficking and therapeutic 1236 outcome of multiwalled carbon nanotubes modified with cyclodextrins and 1237 polyethylenimine Effect of the 1240 complexation with cyclodextrins on the in vitro antiviral activity of ganciclovir against 1241 Human Cytomegalovirus Multi-functional nanocomplex 1244 codelivery of Trp2 and R837 to activate melanoma-specific immunity Improved antiviral activity in vitro of ribavirin against measles virus after 1248 complexation with cyclodextrins Physicochemical Study of Ribavirin Complexes with alpha-, beta-and gamma-1252 Evaluation by Q-1255 RTPCR of the efficacy of ribavirin complexed with beta-cyclodextrin against measles 1256 virus in a mouse encephalitis model In 1259 vivo antiviral activity of ribavirin/alpha-cyclodextrin complex: Evaluation on 1260 experimental measles virus encephalitis in mice Effective ribavirin 1263 concentration in mice brain using cyclodextrin as a drug carrier: Evaluation in a 1264 measles encephalitis model Antiviral activity against the hepatitis C virus (HCV) of 1-indanone 1268 thiosemicarbazones and their inclusion complexes with hydroxypropyl-β-cyclodextrin 2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir 1273 from a nanofluidic implant for HIV pre-exposure prophylaxis In vitro profiling of the vaginal permeation 1276 potential of anti-HIV microbicides and the influence of formulation excipients Its chemical stability and 1280 cyclodextrin complexation in aqueous media Formulation development for a 1284 zidovudine chemical delivery system 1. Parenteral dosage forms Formulation development for a zidovudine chemical 1288 delivery system 2. Towards oral and non-parenteral dosage forms Diversity of β-cyclodextrin-based nanosponges for 1291 transformation of actives Hyaluronic Acid-Based Biocompatible Supramolecular Assembly for Sustained Release of Antiretroviral Drug A non-covalent "click chemistry" strategy to efficiently 1298 coat highly porous MOF nanoparticles with a stable polymeric shell Analogue-based Drug Discovery Physical and Chemical Stability of Gemcitabine 1303 Gemcitabine anticancer activity enhancement 1307 by water soluble celecoxib/sulfobutyl ether-beta-cyclodextrin inclusion complex Positively charged cyclodextrins 1311 as effective molecular transporters of active phosphorylated forms of gemcitabine into 1312 cancer cells Binding of Nucleotides and 1314 Nucleosides to Per(6-guanidino-6-deoxy)cyclodextrins in Solution Gemcitabine, a broad-1317 spectrum antiviral drug, suppresses enterovirus infections through innate immunity 1318 induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion Drug 1321 repurposing of pyrimidine analogs as potent antiviral compounds against human enterovirus A71 infection with potential clinical applications Gemcitabine and Nucleos(t)ide Synthesis Inhibitors Are 1325 Broad-Spectrum Antiviral Drugs that Activate Innate Immunity Antiviral activity of gemcitabine against human rhinovirus 1329 in vitro and in vivo Cyclodextrin as a magic switch in covalent and non-covalent 1332 anticancer drug release systems WHO model list of essential medicines: 21st list Enhanced Oral Bioavailability of 1338 Efavirenz by Solid Lipid Nanoparticles:In VitroDrug Release and Pharmacokinetics 1339 Studies Preparation and characterization 1341 of Efavirenz nanosuspension with the application of enhanced solubility and 1342 dissolution rate Cyclodextrin-Efavirenz Complexes 1345 Investigated by Solid State and Solubility Studies Host-guest interaction study 1348 of Efavirenz with hydroxypropyl-β-cyclodextrin and l-arginine by computational 1349 simulation studies: Preparation and characterization of supramolecular complexes Multicomponent systems with cyclodextrins and hydrophilic polymers for the delivery 1354 of Efavirenz Novel Inclusion Complexs of Oseltamivir 1357 Phosphate with ß-Cyclodextrin: Physico-Chemical Characterization Co-1361 administration of darunavir and a new pharmacokinetic booster: Formulation 1362 strategies and evaluation in dogs Pyromellitic dianhydride crosslinked soluble 1366 cyclodextrin polymers: Synthesis, lopinavir release from sub-micron sized particles 1367 and anti-HIV-1 activity Cyclodextrin 1371 solubilization and complexation of antiretroviral drug lopinavir: In silico prediction; 1372 effects of derivatization, molar ratio and preparation method Enhancement of solubility and dissolution 1375 rate of ritonavir by β cyclodextrin and solutol HS 15 -A factorial study Van den Mooter, The fate of ritonavir in the presence of darunavir Early identification 1380 of availability issues for poorly water-soluble microbicide candidates in biorelevant 1381 media: A case study with saquinavir Enhanced oral 1384 absorption of saquinavir with Methyl-Beta-Cyclodextrin -Preparation and in vitro and 1385 in vivo evaluation Committee for medicinal products for human use (CHMP)Agenda for the 1388 meeting on 19-22 The Use of Supersaturation for the Vaginal Application of Microbicides: A 1391 Case Study with Dapivirine Stability Constants of the Inclusion Complexes of 1394 β-Cyclodextrin with Various Adamantane Derivatives. A UV-Vis Study The Effect of 1397 Intravenous Sulfobutylether Adamantane-Containing Compounds Intranasal dolutegravir sodium loaded 1404 nanoparticles of hydroxypropyl-beta-cyclodextrin for brain delivery in Neuro-AIDS Enhancement of Solubility of Rilpivirine by 1407 Inclusion Complexation with Cyclodextrins Enhancement of oral 1410 bioavailability of anti-HIV drug rilpivirine HCl through nanosponge formulation Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via 1417 different modes The purine path to chemotherapy Pan, 6-Thioguanine inhibits rotavirus 1423 replication through suppression of Rac1 GDP/GTP cycling Huibregtse, 6-Thioguanine blocks SARS-CoV-2 1427 replication by inhibition of PLpro protease activities Sperimentate su culture pure di bacilli del carbonchio demonstrarano 1430 notevole potere antisettica Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus 1433 erythematosus in mice Combination delivery of TGFβ inhibitor and IL-2 by 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management -prospects and limitations Cetylpyridinium Chloride (CPC) Exhibits Rapid Activity Against Influenza Viruses in vitro and in vivo Cetylpyridinium 1483 chloride blocks herpes simplex virus replication in gingival fibroblasts Cetylpyridinium chloride as a tool against COVID-19 Brief Report: 1489 The Virucidal Efficacy of Oral Rinse Components Against SARS-CoV-2 In Vitro Potential 1493 Role of Oral Rinses Targeting the Viral Lipid Envelope in SARS-CoV-2 Infection Mechanisms of interaction of Cetylpyridinium chloride 1497 with Staphylococcus aureus in the presence of β-cyclodextrin Experimental Treatment 1502 with Favipiravir for COVID-19: An Open-Label Control Study, Engineering-London 1503 Adults Hospitalized with Severe Covid-19, New Engl Remdesivir -An Important First Step Remdesivir for the Treatment of Covid-19 -Final Report, New 1522 Engl Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 Remdesivir for the Treatment of Covid-19 -1530 Preliminary Report Remdesivir for 1533 treatment of COVID-19; an updated systematic review and meta-analysis Sulfobutylether-beta-cyclodextrin-enabled antiviral remdesivir: 1541 characterization of electrospun-and lyophilized formulations FORMULATION FORUM -Application of 1544 Captisol® Technology to Enable the Formulation of Remdesivir in Treating COVID-1545 Dexamethasone in hospitalised patients with COVID-1551 19: addressing uncertainties Corticosteroids for COVID-19: the search for an optimum 1554 duration of therapy Cyclodextrins in Parenteral Formulations 1559 Technological evolution of cyclodextrins in the pharmaceutical field Cyclodextrins as versatile 1562 building blocks for regenerative medicine Cyclodextrins in transdermal and rectal delivery Cyclodextrin-based controlled drug release system Cyclodextrins in ophthalmic drug delivery Cyclodextrins in targeting: Application to 1571 nanoparticles The role of solid nanoparticle technology in the parenteral delivery of 1574 poorly water-soluble drugs Chloroquine phosphate has shown apparent 1577 efficacy in treatment of COVID-19 associated pneumonia in clinical studies Of chloroquine and COVID-19 Misguided Use of Hydroxychloroquine for COVID-19 Hydroxychloroquine 1584 Alternatives for Chronic Disease: Response to a Growing Shortage Amid the Global 1585 COVID-19 Pandemic Hydroxychloroquine in the prevention of COVID-19 mortality FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 1590 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. 1591 Does not affect FDA-approved uses for malaria, lupus, and rheumatoid arthritis Formation & specification of 1596 host-guest inclusion complexes of an anti-malarial drug inside into cyclic 1597 oligosaccharides for enhancing bioavailability Characterisation and solubility studies of Quinine 1600 sulphate and Hydroxychloroquine sulphate inclusion complexes with α -cyclodextrin Potentiometric sensors based on 1603 hydroxychloroquine-phosphotungstate ion-pair and β-cyclodextrin ionophore for 1604 improved determination of hydroxychloroquine sulfate Azithromycin for severe COVID-19 Formulation of azithromycin and 1609 chloroquine phosphate FDT by enhancing their solubility using cyclodextrins 1610 complex Wonder drug" from apan: the human use 1612 perspective Ivermectin: enigmatic multifaceted "wonder" drug continues to surprise 1614 and exceed expectations The FDA-approved drug 1616 ivermectin inhibits the replication of SARS-CoV-2 in vitro COVID-19 Treatment Guidelines: Ivermectin 1619 The Pharmacokinetics and Interactions of Ivermectin in Humans-A Mini-review Chapter 10 -Getting under the skin: Cyclodextrin inclusion for the 1625 controlled delivery of active substances to the dermis FDA EMA advises against use of ivermectin for the prevention or treatment of 1632 COVID-19 outside randomised clinical trials Methyl-beta-cyclodextrin Treatment on Secretion Profile of Interferon-beta and 1638 Zonula Occuludin-1 Architecture in Madin-Darby Canine Kidney Cell Monolayers Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host 1645 protein eEF1A Inhibitory effect of glycyrrhizin on the in vitro infectivity and cytopathic activity of 1648 the human immunodeficiency virus Antiviral activity of glycyrrhizin against varicella-zoster virus in 1651 vitro Enhancing innate immunity against virus in times of COVID-19: Trying to untangle 1656 facts from fictions Prospect of biobased antiviral face 1660 mask to limit the coronavirus outbreak The 1663 direct evidence and mechanism of traditional Chinese medicine treatment of COVID-1664 19 Water soluble biocompatible vesicles based on 1674 polysaccharides and oligosaccharides inclusion complexes for carotenoid delivery Effect of 18β-glycyrrhetinic acid and hydroxypropyl γcyclodextrin complex 1679 on indomethacin-induced small intestinal injury in mice Synthesis and 1682 structure-activity relationship studies of water-soluble β-cyclodextrin-glycyrrhetinic 1683 acid conjugates as potential anti-influenza virus agents Izquierdo-Useros, Identification of 1688 Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug 1689 Repurposing Screen Plitidepsin Cellular Binding and Rac1/JNK 1692 Pathway Activation Depend on Membrane Cholesterol Content Amiodarone and Bepridil Inhibit Anthrax 1696 Toxin Entry into Host Cells A screen of 1701 approved drugs and molecular probes identifies therapeutics with anti-Ebola virus 1702 activity Thapsigargin Is a Broad-Spectrum 1707 Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial 1708 Virus and Influenza A Virus Methyl-beta-cyclodextrin modulates thapsigargin-induced store-1711 dependent Ca2+ entry in macrophages COVID-19 Vaccines 1714 (Revisited) and Oral-Mucosal Vector System as a Potential Vaccine Platform, Nato Cyclic 1717 Oligosaccharides as Active Drugs, an Updated Review Blocking anthrax lethal toxin at the protective antigen channel by using structure-1721 inspired drug design Clostridium perfringens epsilon toxin by β-cyclodextrin derivatives Design, synthesis and biological 1727 evaluation of water-soluble per-O-methylated cyclodextrin-C60 conjugates as anti-1728 influenza virus agents Sulfated Polysaccharides Extracted from Sea Algae as 1733 Antiviral activity of the bicyclam 1737 derivative JM3100 against drug-resistant strains of human immunodeficiency virus 1738 type 1 Garc a-Carmona Applications of cyclodextrins in food science. A review Supramolecular cyclodextrin complex: 1743 Diversity, safety, and applications in ocular therapeutics Latest developments in the application of 1746 cyclodextrin host-guest complexes in beverage technology processes A Comprehensive Review on Cyclodextrin-Based Carriers for 1749 Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and 1753 young adults with Niemann-Pick disease type C1: a case report analysis Lung toxicity of 1756 hydroxypropyl-β-cyclodextrin infusion