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Review

Nasal delivery as a strategy for the prevention and treatment of COVID-19

ORCID Icon, ORCID Icon, , , ORCID Icon, ORCID Icon & ORCID Icon show all
Pages 1115-1130 | Received 10 Jun 2023, Accepted 22 Sep 2023, Published online: 10 Oct 2023

References

  • Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. New Engl J Med. 2020;382(8):727–733. doi: 10.1056/NEJMoa2001017
  • Kirtipal N, Bharadwaj S, Kang SG. From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses. Infect Genetics Evol. 2020;85:104502. doi: 10.1016/j.meegid.2020.104502
  • Lee BC, Lee BU. Minimum sizes of respiratory particles carrying SARS-CoV-2 and the possibility of aerosol generation. Int J Environ Res Public Health. 2020;17(19):6960. Int J Environ Res Pu. 2021;18:11738. doi: 10.3390/ijerph17196960
  • Sungnak W, Huang N, Bécavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681–687. doi: 10.1038/s41591-020-0868-6
  • Funk CD, Laferrière C, Ardakani A. A snapshot of the global race for vaccines targeting SARS-CoV-2 and the COVID-19 pandemic. Front Pharmacol. 2020;11:937. doi: 10.3389/fphar.2020.00937
  • Hou YJ, Okuda K, Edwards CE, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell. 2020;182(2):429–446.e14. doi: 10.1016/j.cell.2020.05.042
  • Chavda VP, Vora LK, Pandya AK, et al. Intranasal vaccines for SARS-CoV-2: from challenges to potential in COVID-19 management. Drug Discov Today. 2021;26(11):2619–2636. doi: 10.1016/j.drudis.2021.07.021
  • Kozlov M. Could a nose spray a day keep COVID away? Nature. 2022; doi: 10.1038/d41586-022-03341-z
  • Lam JKW, Cheung CCK, Chow MYT, et al. Transmucosal drug administration as an alternative route in palliative and end-of-life care during the COVID-19 pandemic. Adv Drug Deliv Rev. 2020;160:234–243. doi: 10.1016/j.addr.2020.10.018
  • Himi T, Takano K, Ogasawara N, et al. Mucosal immune barrier and antigen-Presenting system in human nasal epithelial cells. Adv Oto-Rhino-Laryng. 2011;72:28–30.
  • Thwala LN, Préat V, Csaba NS. Emerging delivery platforms for mucosal administration of biopharmaceuticals: a critical update on nasal, pulmonary and oral routes. Expert Opin Drug Deliv. 2017;14(1):23–36. doi: 10.1080/17425247.2016.1206074
  • Leal J, Smyth HDC, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery. Int J Pharm. 2017;532(1):555–572. doi: 10.1016/j.ijpharm.2017.09.018
  • Newby JM, Seim I, Lysy M, et al. Technological strategies to estimate and control diffusive passage times through the mucus barrier in mucosal drug delivery. Adv Drug Deliv Rev. 2018;124:64–81. doi: 10.1016/j.addr.2017.12.002
  • Marttin E, Schipper NGM, Verhoef JC, et al. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Deliv Rev. 1998;29(1–2):13–38. doi: 10.1016/S0169-409X(97)00059-8
  • Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Re. 2013;3(1):42–62. doi: 10.1007/s13346-012-0108-9
  • Nasal Preparations. European pharmacopoeia. 11.0. Strasburg: EDQM; 2022.
  • Bommer R. Drug delivery: nasal route. In: Swarbrick J, editor. Encyclopedia of pharmaceutical technology. (NY): Informa Healthcare; 2006. p. 1201–1208.
  • Hellfritzsch M, Scherließ R. Mucosal vaccination via the respiratory tract. Pharmaceutics. 2019;11(8):375. doi: 10.3390/pharmaceutics11080375
  • Salade L, Wauthoz N, Goole J, et al. How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods. Int J Pharm. 2019;561:47–65. doi: 10.1016/j.ijpharm.2019.02.026
  • Moffa A, Costantino A, Rinaldi V, et al. Nasal delivery devices: a comparative study on cadaver model. Biomed Res Int. 2019;2019:4602651. doi: 10.1155/2019/4602651
  • Tai J, Han M, Lee D, et al. Different methods and formulations of drugs and vaccines for nasal administration. Pharmaceutics. 2022;14(5):1073. doi: 10.3390/pharmaceutics14051073
  • Scherließ R. Nasal formulations for drug administration and characterization of nasal preparations in drug delivery. Ther Deliv. 2020;11(3):183–191. doi: 10.4155/tde-2019-0086
  • CHMP. Guideline on the pharmaceutical quality of inhalation and nasal products. EMEA; 2006. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-quality-inhalation-nasal-products_en.pdf
  • Tiozzo Fasiolo LT, Manniello MD, Tratta E, et al. Opportunity and challenges of nasal powders: drug formulation and delivery. Eur J Pharm Sci. 2018;113:2–17. doi: 10.1016/j.ejps.2017.09.027
  • Shrewsbury SB. The upper nasal space: option for systemic drug delivery, mucosal vaccines and “nose-to-brain”. Pharmaceutics. 2023;15(6):1720. doi: 10.3390/pharmaceutics15061720
  • Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med. 2005;11(S4):S45–S53. doi: 10.1038/nm1213
  • Neutra MR, Kozlowski PA. Mucosal vaccines: the promise and the challenge. Nat Rev Immunol. 2006;6(2):148–158. doi: 10.1038/nri1777
  • Janeway CA, Travers P, Walport M, et al. The mucosal immune system. Immunobiology: the immune system in Health and disease. 5th ed. (NY): Garland Science; 2001. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27169/.
  • Ainai A, Riet E, Ito R, et al. Human immune responses elicited by an intranasal inactivated H5 influenza vaccine. Microbiol Immunol. 2020;64(4):313–325. doi: 10.1111/1348-0421.12775
  • Davis SS. Nasal vaccines. Adv Drug Deliv Rev. 2001;51(1–3):21–42. doi: 10.1016/S0169-409X(01)00162-4
  • Csaba N, Garcia-Fuentes M, Alonso MJ. Nanoparticles for nasal vaccination. Adv Drug Deliv Rev. 2009;61(2):140–157. doi: 10.1016/j.addr.2008.09.005
  • Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. New Engl J Med. 2007;356(7):685–696. doi: 10.1056/NEJMoa065368
  • Carter NJ, Curran MP. Live attenuated influenza vaccine (FluMist®; Fluenz™). Drugs. 2011;71(12):1591–1622. doi: 10.2165/11206860-000000000-00000
  • Topol EJ, Iwasaki A. Operation nasal vaccine—lightning speed to counter COVID-19. Sci Immunol. 2022;7(74). doi: 10.1126/sciimmunol.add9947
  • Tang J, Zeng C, Cox TM, et al. Respiratory mucosal immunity against SARS-CoV-2 following mRNA vaccination. Sci Immunol. 2022;7(76):eadd4853. doi: 10.1126/sciimmunol.add4853
  • Lycke N. Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol. 2012;12(8):592–605. doi: 10.1038/nri3251
  • Xu H, Cai L, Hufnagel S, et al. Intranasal vaccine: factors to consider in research and development. Int J Pharm. 2021;609:121180. doi: 10.1016/j.ijpharm.2021.121180
  • Mutsch M, Zhou W, Rhodes P, et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. New Engl J Med. 2004;350(9):896–903. doi: 10.1056/NEJMoa030595
  • Shim E, Brown ST, DePasse J, et al. Cost effectiveness of influenza vaccine for U.S. Children live attenuated and inactivated influenza vaccine. Am J Prev Med. 2016;51(3):309–317. doi: 10.1016/j.amepre.2016.02.027
  • Alu A, Chen L, Lei H, et al. Intranasal COVID-19 vaccines: from bench to bed. EBioMedicine. 2022;76:103841. doi: 10.1016/j.ebiom.2022.103841
  • King RG, Silva-Sanchez A, Peel JN, et al. Single-dose intranasal administration of AdCOVID elicits systemic and mucosal immunity against SARS-CoV-2 and fully protects mice from lethal challenge. Vaccines. 2021;9(8):881. doi: 10.3390/vaccines9080881
  • Altimmune. Altimmune announces update on AdCOVID(tm) Phase 1 clinical trial. 2021; Available from: https://ir.altimmune.com/news-releases/news-release-details/altimmune-announces-update-adcovidtm-phase-1-clinical-trial
  • van Doremalen N, Purushotham JN, Schulz JE, et al. Intranasal ChAdOx1 nCoV-19/azd1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models. Sci Transl Med. 2021;13(607):eabh0755. doi: 10.1126/scitranslmed.abh0755
  • Madhavan M, Ritchie AJ, Aboagye J, et al. Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: an open-label partially-randomised ascending dose phase I trial. EBioMedicine. 2022;85:104298. doi: 10.1016/j.ebiom.2022.104298
  • WHO. COVID-19 vaccine tracker and landscape. 2023. Available from: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
  • Zhu F, Zhuang C, Chu K, et al. Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Respir Med. 2022;10(8):749–760. doi: 10.1016/S2213-2600(22)00131-X
  • Pilapitiya D, Wheatley AK, Tan H-X. Mucosal vaccines for SARS-CoV-2: triumph of hope over experience. EBioMedicine. 2023;92:104585. doi: 10.1016/j.ebiom.2023.104585
  • Sunagar R, Prasad SD, Ella R, et al. Preclinical evaluation of safety and immunogenicity of a primary series intranasal COVID-19 vaccine candidate (BBV154) and humoral immunogenicity evaluation of a heterologous prime-boost strategy with COVAXIN (BBV152). Front Immunol. 2022;13:1063679. doi: 10.3389/fimmu.2022.1063679
  • Singh C, Verma S, Reddy P, et al. Phase III pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID-19 vaccine (Covaxin®). NPJ Vaccines. 2023;8(1):125. doi: 10.1038/s41541-023-00717-8
  • Singh C, Verma S, Reddy P, et al. Immunogenicity and Tolerability of BBV154 (iNCOVACC®), an Intranasal SARS-CoV-2 Vaccine, Compared with Intramuscular Covaxin® in Healthy Adults: A Randomised, Open-Label, Phase 3 Clinical Trial. 2023. doi: 10.2139/ssrn.4342771
  • Codagenix. Codagenix initiates dosing in Phase 3 efficacy trial of intranasal COVID-19 vaccine as part of WHO-Sponsored solidarity trial vaccines. 2022; Available from: https://codagenix.com/codagenix-initiates-dosing-in-phase-3-efficacy-trial-of-intranasal-covid-19-vaccine-as-part-of-who-sponsored-solidarity-trial-vaccines/
  • Dodaran MS, Banihashemi SR, Es-Haghi A, et al. Immunogenicity and safety of a combined intramuscular/intranasal Recombinant Spike protein COVID-19 vaccine (RCP) in healthy adults aged 18 to 55 years old: a randomized, Double-blind, placebo-controlled, Phase I trial. Vaccines. 2023;11(2):455. doi: 10.3390/vaccines11020455
  • Waltz E. China and India approve nasal COVID vaccines — are they a game changer? Nature. 2022;609(7927):450–450. doi: 10.1038/d41586-022-02851-0
  • Guillen G, Limonta M, Muzio V, et al. Cuban vaccines Abdala and Mambisa Aagainst COVID-19. Int J Infect Dis. 2023;130:S9–S10. doi: 10.1016/j.ijid.2023.04.027
  • Stobart CC, Rostad CA, Ke Z, et al. A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation. Nat Commun. 2016;7(1):13916. doi: 10.1038/ncomms13916
  • Lam JH, Shivhare D, Chia TW, et al. Artificial cell membrane polymersome-based intranasal beta Spike formulation as a second generation covid-19 vaccine. ACS Nano. 2022;16(10):16757–16775. doi: 10.1021/acsnano.2c06350
  • Adler JM, Vidal RM, Voß A, et al. A non-transmissible live attenuated SARS-CoV-2 vaccine. Mol Ther. 2023;31(8):2391–2407. doi: 10.1016/j.ymthe.2023.05.004
  • Nouailles G, Adler JM, Pennitz P, et al. Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Nat Microbiol. 2023;8(5):860–874. doi: 10.1038/s41564-023-01352-8
  • European Vaccine Initiative. NOSEVAC, a new European collaboration to develop nasal vaccines. 2023; Available from: https://www.euvaccine.eu/post/nosevac-a-new-european-collaboration-to-develop-nasal-vaccines
  • Moakes RJA, Davies SP, Stamataki Z, et al. Formulation of a Composite nasal spray Enabling Enhanced surface Coverage and prophylaxis of SARS‐COV‐2. Adv Mater. 2021;33(26):2008304. doi: 10.1002/adma.202008304
  • Ludwig M, Enzenhofer E, Schneider S, et al. Efficacy of a carrageenan nasal spray in patients with common cold: a randomized controlled trial. Respir Res. 2013;14(1):124. doi: 10.1186/1465-9921-14-124
  • Eccles R, Winther B, Johnston SL, et al. Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial. Respir Res. 2015;16(1):121. doi: 10.1186/s12931-015-0281-8
  • Bentley K, Stanton RJ. Hydroxypropyl methylcellulose-based nasal sprays effectively inhibit in vitro SARS-CoV-2 infection and spread. Viruses. 2021;13(12):2345. doi: 10.3390/v13122345
  • Necas J, Bartosikova L. Carrageenan: a review. Vet Med (Praha). 2013;58:187–205. doi: 10.17221/6758-VETMED
  • Girond S, Crance JM, Cuyck-Gandre HV, et al. Antiviral activity of carrageenan on hepatitis a virus replication in cell culture. Res Virol. 1991;142(4):261–270. doi: 10.1016/0923-2516(91)90011-Q
  • Marchetti M, Pisani S, Pietropaolo V, et al. Inhibition of herpes simplex virus infection by negatively charged and neutral carbohydrate polymers. J Chemother. 1995;7(2):90–96. doi: 10.1179/joc.1995.7.2.90
  • Carlucci MJ, Scolaro LA, Damonte EB. Inhibitory action of natural carrageenans on herpes simplex virus infection of mouse astrocytes. Chemotherapy. 1999;45(6):429–436. doi: 10.1159/000007236
  • Cáceres PJ, Carlucci MJ, Damonte EB, et al. Carrageenans from chilean samples of stenogramme interrupta (phyllophoraceae): structural analysis and biological activity. Phytochemistry. 2000;53(1):81–86. doi: 10.1016/S0031-9422(99)00461-6
  • Zacharopoulos VR, Phillips DM. Vaginal formulations of carrageenan protect mice from herpes simplex virus infection. Clin Diagn Lab Immunol. 1997;4(4):465–468. doi: 10.1128/cdli.4.4.465-468.1997
  • Stiles J, Guptill-Yoran L, Moore GE, et al. Effects of λ-carrageenan on in vitro replication of feline herpesvirus and on Experimentally Induced Herpetic Conjunctivitis in cats. Invest Ophthalmol Vis Sci. 2008;49(4):1496. doi: 10.1167/iovs.07-1245
  • Buck CB, Thompson CD, Roberts JN, et al. Carrageenan is a potent inhibitor of papillomavirus infection. PLOS Pathog. 2006;2(7):e69. doi: 10.1371/journal.ppat.0020069
  • Grassauer A, Weinmuellner R, Meier C, et al. Iota-carrageenan is a potent inhibitor of rhinovirus infection. Virol J. 2008;5(1):107. doi: 10.1186/1743-422X-5-107
  • Morokutti-Kurz M, Fröba M, Graf P, et al. Iota-carrageenan neutralizes SARS-CoV-2 and inhibits viral replication in vitro. Plos One. 2021;16(2):e0237480. doi: 10.1371/journal.pone.0237480
  • Schütz D, Conzelmann C, Fois G, et al. Carrageenan-containing over-the-counter nasal and oral sprays inhibit SARS-CoV-2 infection of airway epithelial cultures. Am J Physiol Lung Cell Mol Physiol. 2021;320(5):L750–L756. doi: 10.1152/ajplung.00552.2020
  • Figueroa JM, Lombardo ME, Dogliotti A, et al. Efficacy of a nasal spray containing iota-carrageenan in the postexposure prophylaxis of COVID-19 in hospital personnel dedicated to patients care with COVID-19 disease. Int J Gen Med. 2021;14:6277–6286. doi: 10.2147/IJGM.S328486
  • McCarthy TD, Karellas P, Henderson SA, et al. Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention. Mol Pharm. 2005;2(4):312–318. doi: 10.1021/mp050023q
  • Tyssen D, Henderson SA, Johnson A, et al. Structure activity relationship of dendrimer microbicides with dual action antiviral activity. Plos One. 2010;5(8):e12309. doi: 10.1371/journal.pone.0012309
  • Castellarnau A, Heery GP, Seta A, et al. Astodrimer sodium antiviral nasal spray for reducing respiratory infections is safe and well tolerated in a randomized controlled trial. Sci Rep. 2022;12(1):10210. doi: 10.1038/s41598-022-14601-3
  • Rupp R, Rosenthal SL, Stanberry LR. VivaGel (SPL7013 gel): a candidate dendrimer–microbicide for the prevention of HIV and HSV infection. Int J Nanomed. 2007;2:561–566.
  • Romanowski EG, Yates KA, Paull JRA, et al. Topical astodrimer sodium, a non-toxic polyanionic dendrimer, demonstrates antiviral activity in an experimental ocular adenovirus infection model. Molecules. 2021;26(11):3419. doi: 10.3390/molecules26113419
  • Paull JRA, Luscombe CA, Castellarnau A, et al. Protective effects of astodrimer sodium 1% nasal spray formulation against SARS-CoV-2 nasal challenge in K18-hACE2 mice. Viruses. 2021;13(8):1656. doi: 10.3390/v13081656
  • O’Loughlin J, Millwood IY, McDonald HM, et al. Safety, tolerability, and pharmacokinetics of SPL7013 gel (VivaGel®): a dose ranging, Phase I study. Sex Transm Dis. 2010;37(2):100–104. doi: 10.1097/OLQ.0b013e3181bc0aac
  • McGowan I, Gomez K, Bruder K, et al. Phase 1 randomized trial of the vaginal safety and acceptability of SPL7013 gel (VivaGel) in sexually active young women (MTN-004). AIDS. 2011;25(8):1057–1064. doi: 10.1097/QAD.0b013e328346bd3e
  • Paull JRA, Heery GP, Bobardt MD, et al. Virucidal and antiviral activity of astodrimer sodium against SARS-CoV-2 in vitro. Antivir Res. 2021;191:105089. doi: 10.1016/j.antiviral.2021.105089
  • Eisenhour DD, Brown RK. Bentonite and its impact on modern life. Elements. 2009;5(2):83–88. doi: 10.2113/gselements.5.2.83
  • Park J-H, Shin H-J, Kim MH, et al. Application of montmorillonite in bentonite as a pharmaceutical excipient in drug delivery systems. J Pharm Invest. 2016;46(4):363–375. doi: 10.1007/s40005-016-0258-8
  • Clark KJ, Sarr AB, Grant PG, et al. In vitro studies on the use of clay, clay minerals and charcoal to adsorb bovine rotavirus and bovine coronavirus. Vet Microbiol. 1998;63(2–4):137–146. doi: 10.1016/S0378-1135(98)00241-7
  • Fais F, Juskeviciene R, Francardo V, et al. Drug-free nasal spray as a barrier against SARS-CoV-2 and its Delta variant: In Vitro study of safety and efficacy in human nasal airway epithelia. Int J Mol Sci. 2022;23(7):4062. doi: 10.3390/ijms23074062
  • Cheng Y-S. Mechanisms of pharmaceutical aerosol deposition in the respiratory tract. AAPS Pharm Sci Tech. 2014;15(3):630–640. doi: 10.1208/s12249-014-0092-0
  • Herrera D, Serrano J, Roldán S, et al. Is the oral cavity relevant in SARS-CoV-2 pandemic? Clin Oral Invest. 2020;24(8):2925–2930. doi: 10.1007/s00784-020-03413-2
  • Huang N, Pérez P, Kato T, et al. SARS-CoV-2 infection of the oral cavity and saliva. Nat Med. 2021;27(5):892–903. doi: 10.1038/s41591-021-01296-8
  • Papineni RS, Rosenthal FS. The size distribution of droplets in the exhaled breath of healthy human subjects. J Aerosol Med. 1997;10(2):105–116. doi: 10.1089/jam.1997.10.105
  • Chavda VP, Baviskar KP, Vaghela DA, et al. Nasal sprays for treating COVID-19: a scientific note. Pharmacol Rep. 2023;75(2):249–265. doi: 10.1007/s43440-023-00463-7
  • Popov TA, Emberlin J, Josling P, et al. In vitro and in vivo evaluation of the efficacy and safety of powder hydroxypropylmethylcellulose as nasal mucosal barrier. Med Devices (Auckl). 2020;13:107–113. doi: 10.2147/MDER.S236104
  • Shmuel K, Dalia M, Tair L, et al. Low pH Hypromellose (Taffix) nasal powder spray could reduce SARS-CoV-2 infection rate post mass-gathering event at a highly endemic community: an observational prospective open label user survey. Expert Rev Anti-Infective Ther. 2021;19(10):1325–1330. doi: 10.1080/14787210.2021.1908127
  • Hull D, Rennie P, Noronha A, et al. Effects of creating a non-specific, virus-hostile environment in the nasopharynx on symptoms and duration of common cold. Acta Otorhinolaryngol Ital. 2007;27(2):73–77.
  • Mann BJ. TaffiX® nasal powder forms an effective barrier against SARS-CoV-2. Biomed J Sci Technical Res. 2021;33(3). doi: 10.26717/BJSTR.2021.33.005405
  • Ng YL, Salim CK, Chu JJH. Drug repurposing for COVID-19: approaches, challenges and promising candidates. Pharmacol Therapeut. 2021;228:107930. doi: 10.1016/j.pharmthera.2021.107930
  • Brüssow H. Clinical trials with antiviral drugs against COVID -19: some progress and many shattered hopes. Environ Microbiol. 2021;23(11):6364–6376. doi: 10.1111/1462-2920.15769
  • Aherfi S, Pradines B, Devaux C, et al. Drug repurposing against SARS-CoV-1, SARS-CoV-2 and MERS-CoV. Future Microbiol. 2021;16(17):1341–1370. doi: 10.2217/fmb-2021-0019
  • Consortium WHO Solidarity Trial. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO solidarity randomised trial and updated meta-analyses. Lancet. 2022;399:1941–1953.
  • Group RC, Horby PW, Mafham M, et al. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396(10259):1345–1352. doi: 10.1016/S0140-6736(20)32013-4
  • Lamers MM, Haagmans BL. SARS-CoV-2 pathogenesis. Nat Rev Microbiol. 2022;20(5):270–284. doi: 10.1038/s41579-022-00713-0
  • Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Therapeut. 2020;209:107512. doi: 10.1016/j.pharmthera.2020.107512
  • Sajadian SA, Ardestani NS, Esfandiari N, et al. Solubility of favipiravir (as an anti-COVID-19) in supercritical carbon dioxide: an experimental analysis and thermodynamic modeling. J Supercrit Fluids. 2022;183:105539. doi: 10.1016/j.supflu.2022.105539
  • Djekic L. Novel mucoadhesive polymers for nasal drug delivery. In: Pathak Y Yadav H editors. In Nasal drug delivery formulations, developments, challenges, and solutions. Cham:Springer. 2023; p. 189–234. doi: 10.1007/978-3-031-23112-4_11
  • Washington N, Steele RJC, Jackson SJ, et al. Determination of baseline human nasal pH and the effect of intranasally administered buffers. Int J Pharm. 2000;198(2):139–146. doi: 10.1016/S0378-5173(99)00442-1
  • Alcantara KP, Nalinratana N, Chutiwitoonchai N, et al. Enhanced nasal deposition and anti-coronavirus effect of favipiravir-loaded mucoadhesive chitosan–alginate nanoparticles. Pharmaceutics. 2022;14(12):2680. doi: 10.3390/pharmaceutics14122680
  • Gattani V, Dawre S. Development of favipiravir loaded PLGA nanoparticles entrapped in in-situ gel for treatment of covid-19 via nasal route. J Drug Deliv Sci Tec. 2023;79:104082. doi: 10.1016/j.jddst.2022.104082
  • Grundeis F, Ansems K, Dahms K, et al. Remdesivir for the treatment of COVID‐19. Cochrane Database Syst Rev. 2023;2023(1):CD014962. doi: 10.1002/14651858.CD014962.pub2
  • Tsai Y, Wu J, Liu T, et al. Clinical effectiveness of oral antiviral agents in older patients with COVID‐19 based on real‐world data. J Med Virol. 2023;95(6):e28869. doi: 10.1002/jmv.28869
  • Chung S, Peters JM, Detyniecki K, et al. The nose has it: opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters. Epilepsy Behav Reports. 2023;21:100581. doi: 10.1016/j.ebr.2022.100581
  • Timani KA, Liao Q, Ye L, et al. Nuclear/Nucleolar localization properties of C-terminal nucleocapsid protein of SARS coronavirus. Virus Res. 2005;114(1–2):23–34. doi: 10.1016/j.virusres.2005.05.007
  • Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res. 2020;178:104787. doi: 10.1016/j.antiviral.2020.104787
  • NIH. Ivermectin | COVID-19 treatment guidelines. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/miscellaneous-drugs/ivermectin/
  • Arshad U, Pertinez H, Box H, et al. Prioritization of anti‐SARS‐Cov‐2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther. 2020;108(4):775–790. doi: 10.1002/cpt.1909
  • Errecalde J, Lifschitz A, Vecchioli G, et al. Safety and pharmacokinetic assessments of a novel ivermectin nasal spray formulation in a pig model. J Pharm Sci. 2021;110(6):2501–2507. doi: 10.1016/j.xphs.2021.01.017
  • Aref ZF, Bazeed SEES, Hassan MH, et al. Clinical, biochemical and molecular evaluations of ivermectin mucoadhesive nanosuspension nasal spray in reducing upper respiratory symptoms of mild COVID-19. Int J Nanomed. 2021;16:4063–4072. doi: 10.2147/IJN.S313093
  • Aref ZF, Bazeed SEES, Hassan MH, et al. Possible role of ivermectin mucoadhesive nanosuspension nasal spray in recovery of post-COVID-19 anosmia. Infect Drug Resist. 2022;15:5483–5494. doi: 10.2147/IDR.S381715
  • Reznikov LR, Norris MH, Vashisht R, et al. Identification of antiviral antihistamines for COVID-19 repurposing. Biochem Bioph Res Commun. 2021;538:173–179. doi: 10.1016/j.bbrc.2020.11.095
  • Konrat R, Papp H, Kimpel J, et al. The Anti-Histamine Azelastine, identified by computational drug repurposing, inhibits infection by major variants of SARS-CoV-2 in cell cultures and reconstituted human nasal tissue. Front Pharmacol. 2022;13:861295. doi: 10.3389/fphar.2022.861295
  • Klussmann JP, Grosheva M, Meiser P, et al. Early intervention with azelastine nasal spray may reduce viral load in SARS-CoV-2 infected patients. Sci Rep-UK. 2023;13(1):6839. doi: 10.1038/s41598-023-32546-z
  • Westover J, Ferrer G, Vazquez H, et al. In vitro virucidal effect of intranasally delivered chlorpheniramine maleate compound against severe acute respiratory syndrome coronavirus 2. Cureus. 2020;12:e10501. doi: 10.7759/cureus.10501
  • Xu W, Xia S, Pu J, et al. The antihistamine drugs carbinoxamine maleate and chlorpheniramine maleate exhibit potent antiviral activity against a broad spectrum of influenza viruses. Front Microbiol. 2018;9:2643. doi: 10.3389/fmicb.2018.02643
  • Sanchez-Gonzalez M, Westover J, Rizvi S, et al. Intranasal chlorpheniramine maleate for the treatment of COVID-19: translational and clinical evidence. Med Res Arch. 2022;10(3):10. doi: 10.18103/mra.v10i3.2752
  • Go CC, Pandav K, Sanchez-Gonzalez MA, et al. Potential role of xylitol plus grapefruit seed extract nasal spray solution in COVID-19: case series. Cureus. 2020;12:e11315. doi: 10.7759/cureus.11315
  • Cannon ML, Westover JB, Bleher R, et al. In vitro analysis of the anti-viral potential of nasal spray constituents against SARS-CoV-2. bio Rxiv. 2020.408575. doi: 10.1101/2020.12.02.408575
  • Nguyen AA, Habiballah SB, Platt CD, et al. Immunoglobulins in the treatment of COVID-19 infection: proceed with caution! Clin Immunol. 2020;216:108459. doi: 10.1016/j.clim.2020.108459
  • Ku Z, Xie X, Hinton PR, et al. Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants. Nature. 2021;595(7869):718–723. doi: 10.1038/s41586-021-03673-2
  • Seow HC, Cai J-P, Pan HW, et al. Neutralisation of SARS-CoV-2 by monoclonal antibody through dual targeting powder formulation. J Control Release. 2023;358:128–141. doi: 10.1016/j.jconrel.2023.04.029
  • Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: Current state of the science. Immunity. 2020;52(6):910–941. doi: 10.1016/j.immuni.2020.05.002
  • Ochi H, Abraham M, Ishikawa H, et al. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25−LAP+ T cells. Nat Med. 2006;12(6):627–635. doi: 10.1038/nm1408
  • Wu HY, Maron R, Tukpah A-M, et al. Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. J Immunol. 2010;185(6):3401–3407. doi: 10.4049/jimmunol.1000836
  • Moreira TG, Matos KTF, Paula GSD, et al. Nasal administration of anti-CD3 monoclonal antibody (foralumab) reduces lung inflammation and blood inflammatory biomarkers in mild to moderate COVID-19 patients: a pilot study. Front Immunol. 2021;12:709861. doi: 10.3389/fimmu.2021.709861
  • Cao L, Zhang L, Zhang X, et al. Types of interferons and their expression in plant systems. J Interf Cytokine Res. 2022;42(2):62–71. doi: 10.1089/jir.2021.0148
  • Zhou Q, Chen V, Shannon CP, et al. Interferon-α2b treatment for COVID-19. Front Immunol. 2020;11:1061. doi: 10.3389/fimmu.2020.01061
  • Zhou Q, MacArthur MR, He X, et al. Interferon-α2b treatment for COVID-19 is associated with improvements in lung abnormalities. Viruses. 2020;13(1):44. doi: 10.3390/v13010044
  • Zhou J, Chen X, Lu Y, et al. Interferon-α-2b nasal spray for treating SARS-CoV-2 Omicron variant-infected children. J Clin Immunol. 2023;43(5):862–864. doi: 10.1007/s10875-023-01452-4
  • Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001;2(10):907–916. doi: 10.1038/ni1001-907
  • Akerstrom S, Mousavi-Jazi M, Klingstrom J, et al. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005;79(3):1966–1969. doi: 10.1128/JVI.79.3.1966-1969.2005
  • Åkerström S, Gunalan V, Keng CT, et al. Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected. Virology. 2009;395(1):1–9. doi: 10.1016/j.virol.2009.09.007
  • Winchester S, John S, Jabbar K, et al. Clinical efficacy of nitric oxide nasal spray (NONS) for the treatment of mild COVID-19 infection. J Infection. 2021;83(2):237–279. doi: 10.1016/j.jinf.2021.05.009
  • Tandon M, Wu W, Moore K, et al. SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: a randomized trial. Lancet Reg Health Southeast Asia. 2022;3:100036. doi: 10.1016/j.lansea.2022.100036
  • Tada R, Yamazaki H, Nagai Y, et al. Intranasal administration of sodium nitroprusside augments antigen-specific mucosal and systemic antibody production in mice. Int Immunopharmacol. 2023;119:110262. doi: 10.1016/j.intimp.2023.110262
  • Boecker D, Zhang Z, Breves R, et al. Antimicrobial efficacy, mode of action and in vivo use of hypochlorous acid (HOCl) for prevention or therapeutic support of infections. GMS Hyg Infect Control. 2023;18:Doc07. doi: 10.3205/dgkh000433
  • Giarratana N, Rajan B, Kamala K, et al. A sprayable acid-oxidizing solution containing hypochlorous acid (AOS2020) efficiently and safely inactivates SARS-Cov-2: a new potential solution for upper respiratory tract hygiene. Eur Arch Oto-Rhino-L. 2021;278(8):3099–3103. doi: 10.1007/s00405-021-06644-5
  • Panatto D, Orsi A, Bruzzone B, et al. Efficacy of the Sentinox spray in reducing viral load in mild COVID-19 and its virucidal activity against other respiratory viruses: results of a randomized controlled trial and an in vitro study. Viruses. 2022;14(5):1033. doi: 10.3390/v14051033
  • Lapuente D, Fuchs J, Willar J, et al. Protective mucosal immunity against SARS-CoV-2 after heterologous systemic prime-mucosal boost immunization. Nat Commun. 2021;12(1):6871. doi: 10.1038/s41467-021-27063-4
  • Hoffmann M, Hofmann-Winkler H, Smith JC, et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBio Medicine. 2021;65:103225. doi: 10.1016/j.ebiom.2021.103255
  • Breining P, Frølund AL, Højen JF, et al. Camostat mesylate against SARS-CoV-2 and COVID-19-Rationale, dosing and safety. Basic Clin Pharmacol Toxicol. 2021;128(2):204–212. doi: 10.1111/bcpt.13533