{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:38:18Z","timestamp":1792204698805,"version":"4.4.0"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: COVID-19 is an asymptomatic condition in 40% of cases, and most symptomatic patients present with mild\/moderate disease not requiring hospitalization or intensive care, especially during the Omicron wave, when the hospitalization rate was estimated to be 0.3%. The main port of entry for SARS-CoV-2 in the human body is the nasal cavity and the upper respiratory tract is affected since the early stages of the infection. Nasal irrigation or aerosol by isotonic or hypertonic saline solution is a traditional therapeutic approach for respiratory or nasal inflammation, also featured by prophylactic properties against upper respiratory infections. Methods: We conducted a prospective open-label controlled study to assess the superiority of an already existing medication (Tonimer Lab Panthexyl 800)\u2014a sterile hypertonic solution containing seawater, xylitol, panthenol and lactic acid\u2014to reduce the viral shedding time in patients affected by asymptomatic or mild COVID-19. COVID-19 patients (N = 108) were split into two groups: a treatment arm (50 participants receiving standard of care plus nasal spray 3 times\/day with Tonimer Lab Panthexyl 800) and a control arm (58 participants receiving standard of care but nasal spray with Tonimer Lab Panthexyl 800). The two groups, both testing initially positive for SARS-CoV-2 at real-time PCR (RT-PCR) on nasal swab, were followed up over time to assess the daily number of positive swab tests turning negative (study endpoint). Treatment effectiveness at various time lags since the first positive RT-PCR swab test was measured by rate of events in the experimental arm (EER) and in the control arm (CER), absolute risk increase (ARI) = (EER \u2212 CER), and number needed to treat (NNT) = (1\/ARI). To investigate the endpoint, we used logistic and Cox regression models, expressing the result as odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (95%CI), respectively. The symptoms recorded with a modified COVID-Q questionnaire at both diagnosis and first negative antigenic swab test were compared in each group (treated versus controls) by exact symmetry test. Results: During the first five days of treatment, COVID-19 patients treated with Tonimer Lab Panthexyl 800 were more likely to become negative two days before controls. According to NNT, four subjects had to be treated for five days to achieve the study endpoint in one individual. The negativization rate in patients treated with Tonimer Lab Panthexyl 800 was significantly higher than patients\u2019 treated with standard of care alone (OR = 7.39, 95%CI: 1.83\u201329.8; HR = 6.12, 95%CI: 1.76\u201321.32). There was no evidence of side effects. Conclusions: Nasal spray with Tonimer Lab Panthexyl 800 was effective against SARS-CoV-2, stopping viral shedding in the treatment arm two days before the control group. This treatment should be continued for at least five days after the first positive swab test for SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/pharmaceutics14112502","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T03:57:44Z","timestamp":1668743864000},"page":"2502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Early Negativization of SARS-CoV-2 Infection by Nasal Spray of Seawater plus Additives: The RENAISSANCE Open-Label Controlled Clinical Trial"],"prefix":"10.3390","volume":"14","author":[{"given":"Luca","family":"Cegolon","sequence":"first","affiliation":[{"name":"Department of Medical, Surgical & Health Sciences, University of Trieste, 34137 Trieste, Italy"},{"name":"Occupational Medicine Unit, University Health Agency Giuliano Isontina (ASUGI), 34148 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Mastrangelo","sequence":"additional","affiliation":[{"name":"University of Padua, 35122 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Emanuelli","sequence":"additional","affiliation":[{"name":"Otolaringology Unit, Ca\u2019 Foncello Hospital, Local Health Unit N.2 \u201cMarca Trevigiana\u201d, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Camerotto","sequence":"additional","affiliation":[{"name":"Section of Otolaringology, Department of Neurosciences, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Spinato","sequence":"additional","affiliation":[{"name":"Section of Otolaringology, Department of Neurosciences, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Frezza","sequence":"additional","affiliation":[{"name":"Otolaringology Unit, Ca\u2019 Foncello Hospital, Local Health Unit N.2 \u201cMarca Trevigiana\u201d, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"key":"ref_1","unstructured":"European Centre for Disease Prevention and Control (2022, October 04). Clinical Characteristics of COVID-19. Available online: https:\/\/www.ecdc.europa.eu\/en\/covid-19\/latest-evidence\/clinical."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41579-022-00713-0","article-title":"SARS-CoV-2 pathogenesis","volume":"20","author":"Lamers","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1056\/NEJMc2001737","article-title":"SARS-CoV-2 Viral load in upper respiratory specimens of infected patients","volume":"382","author":"Zou","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/CM9.0000000000001892","article-title":"Reinfection rates among patients previously infected by SARS-CoV-2: Systematic review and meta-analysis","volume":"135","author":"Mao","year":"2022","journal-title":"Chin. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100572","DOI":"10.1016\/j.lanwpc.2022.100572","article-title":"SARS-CoV-2 in Malaysia: A surge of reinfection during the predominantly Omicron period","volume":"26","author":"Yang","year":"2022","journal-title":"Lancet Reg. Health\u2014Western Pac."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chatterjee, U., Chakraborty, A., Naskar, S., Saha, B., Bandyapadhyay, B., and Shee, S. (2021). Efficacy of Normal Saline Nasal Spray and Gargle on SARS-CoV-2 for Prevention of COVID-19 Pneumonia, Research Square.","DOI":"10.21203\/rs.3.rs-153598\/v2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113605","DOI":"10.1016\/j.ijheh.2020.113605","article-title":"Nasal disinfection for the prevention and control of COVID-19: A scoping review on potential chemo-preventive agents","volume":"230","author":"Cegolon","year":"2020","journal-title":"Int. J. Hyg. Environ. Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113520","DOI":"10.1016\/j.ijheh.2020.113520","article-title":"Investigating hypothiocyanite against SARS-CoV-2","volume":"227","author":"Cegolon","year":"2020","journal-title":"Int. J. Hyg. Environ. Health"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cegolon, L., Mirandola, M., Salaris, C., Salvati, M.V., Mastrangelo, G., and Salata, C. (2021). Hypothiocyanite and Hypothiocyanite\/Lactoferrin Mixture Exhibit Virucidal Activity In Vitro against SARS-CoV-2. Pathogens, 10.","DOI":"10.3390\/pathogens10020233"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"010332","DOI":"10.7189\/jogh.10.010332","article-title":"Hypertonic saline nasal irrigation and gar-gling should be considered as a treatment option for COVID-19","volume":"10","author":"Ramalingam","year":"2020","journal-title":"J. Glob. Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/s41598-018-37703-3","article-title":"A pilot, open labelled, randomized con-trolled trial of hypertonic saline nasal irrigation and gargling for the common cold","volume":"9","author":"Ramalingam","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1177\/1945892418773566","article-title":"Hypertonic saline versus isotonic saline nasal irrigation: Systematic review and meta-analysis","volume":"32","author":"Kanjanawasee","year":"2018","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"\u0160tanfel, D., Kalogjera, L., Ryazantsev, S.V., Hla\u010da, K., Radtsig, E.Y., Teimuraz, R., and Hraba\u010d, P. (2022). The role of seawater and saline solutions in treatment of upper respiratory conditions. Mar. Drugs, 20.","DOI":"10.20944\/preprints202202.0313.v3"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1001\/jamaoto.2020.1622","article-title":"Benefits and safety of nasal saline irrigations in a pandemic\u2014Washing COVID-19 away","volume":"146","author":"Farrell","year":"2020","journal-title":"JAMA Otolaryngol.\u2013Head Neck Surg."},{"key":"ref_15","first-page":"004","article-title":"Nasal Irrigation in the COVID-19 Era","volume":"13","author":"Georgiou","year":"2021","journal-title":"IJCMCR"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15761\/TiM.1000249","article-title":"Hypertonic saline nasal irrigation and gargling as an inexpensive practical adjunctive weapon to combat asymptomatic SARS-CoV-2 infections. A case reports","volume":"20","author":"Rosati","year":"2020","journal-title":"Trends Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1002\/alr.22703","article-title":"Interim analysis of an open-label randomized controlled trial evaluating nasal irrigations in non-hospitalized patients with COVID-19","volume":"10","author":"Kimura","year":"2020","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yildiz, E., Koca, Y.S., Kuzu, S., G\u00fcnebakan, \u00c7., Bucak, A., and Kahveci, O.K. (2021). Comparison of the Healing Effect of Nasal Saline Irrigation with Triamcinolone Acetonide Versus Nasal Saline Irrigation alone in COVID-19 Related Olfactory Dysfunction: A Randomized Controlled Study. Indian J. Otolaryngol. Head Neck Surg., 1\u20136.","DOI":"10.1007\/s12070-021-02749-9"},{"key":"ref_19","first-page":"683","article-title":"Smell recovery in patients with COVID-19: An experience with nebulized nasal treatment","volume":"35","author":"Varricchio","year":"2021","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_20","first-page":"1155","article-title":"Viral shedding in symptomatic patients with mild COVID-19: An experience with nebulized nasal treatment","volume":"35","author":"Varricchio","year":"2021","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_21","first-page":"1151","article-title":"Hypertonic saline with xylitol and hyaluronate may shorten the viral shedding duration in asymptomatic COVID-19 positive subjects: A pilot study","volume":"35","author":"Ciprandi","year":"2021","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jhin.2021.10.019","article-title":"Virucidal activity of nasal sprays against severe acute respiratory syndrome coronavirus-2","volume":"120","author":"Meister","year":"2022","journal-title":"J. Hosp. Infect."},{"key":"ref_23","unstructured":"(2022, August 16). NCT05458336. A Non-Randomized Controlled Clinical Trial on the Use of Saline Nasal Irrigations to Eradicate Localized Nasal Infection by SARS-CoV-2, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05458336."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"652842","DOI":"10.3389\/fpubh.2021.652842","article-title":"Characteristics of Viral Shedding Time in SARS-CoV-2 Infections: A systematic review and meta-analysis","volume":"9","author":"Yan","year":"2021","journal-title":"Front. Public Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e14829","DOI":"10.1111\/ijcp.14829","article-title":"COVID-Q: Validation of the first COVID-19 questionnaire based on patient-rated symptom gravity","volume":"75","author":"Spinato","year":"2021","journal-title":"Int. J. Clin. Pract."},{"key":"ref_26","unstructured":"University of British Columbia Clinical Significance Calculator, University of British Columbia. Available online: https:\/\/www.elcomprimido.com\/FARHSD\/DOC_CD_Curso_Palma_2006\/calculadoras\/UBC%20Clinical%20Significance%20Calculator.htm."},{"key":"ref_27","unstructured":"Peace, K.E. (1990). Intention to treat in clinical trials. Statistical Issues in Drug Research and Development, Marcel Dekker."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1186\/s13063-018-2989-5","article-title":"Statistical analysis plan of a randomized controlled trial to compare a restrictive strategy to usual care for the effectiveness of cholecystectomy (SECURE trial)","volume":"19","author":"Wennmacker","year":"2018","journal-title":"Trials"},{"key":"ref_29","unstructured":"United Stated Environmental Protection Agency (USEPA) (2022, November 07). About List N: Disinfectants for Corona-Virus (COVID-19), Available online: https:\/\/www.epa.gov\/coronavirus\/about-list-n-disinfectants-coronavirus-covid-19-0."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1007\/s00228-021-03102-3","article-title":"Essentials in saline pharmacology for nasal or respiratory hygiene in times of COVID-19","volume":"77","author":"Huijghebaert","year":"2021","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1021\/acsptsci.1c00080","article-title":"Inhibition of severe acute respiratory syndrome coronavirus 2 replication by hypertonic saline solution in lung and kidney epithelial cells","volume":"4","author":"Machado","year":"2021","journal-title":"ACS Pharmacol. Trans. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3181\/00379727-106-26352","article-title":"Effect of several inorganic salts on the infectivity of Mengo virus","volume":"106","author":"Speir","year":"1961","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1038\/ncomms6081","article-title":"Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension","volume":"5","author":"Kasahara","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Akgun, E., Tuzuner, M.B., Sahin, B., Kilercik, M., Kulah, C., Cakiroglu, H.N., Serteser, M., Unsal, I., and Baykal, A.T. (2020). Proteins associated with neutrophil degranulation are upregulated in nasopharyngeal swabs from SARS-CoV-2 patients. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240012"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1090\/S0002-9904-1967-11798-1","article-title":"Differentiable dynamical systems","volume":"73","author":"Smale","year":"1967","journal-title":"Bull. Am. Math. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1177\/154405910808701003","article-title":"Inorganic chemistry of defensive peroxidases in the human oral cavity","volume":"87","author":"Ashby","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1128\/iai.51.1.49-53.1986","article-title":"Antimicrobial factors in whole saliva of human infants","volume":"51","author":"Tenovuo","year":"1986","journal-title":"Infect. Immun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s11046-017-0175-z","article-title":"N-chlorotaurine, a promising future candidate for topical therapy of fungal infections","volume":"n183","author":"Nagl","year":"2018","journal-title":"Mycopathologia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8","DOI":"10.21037\/ajo-21-45","article-title":"Xylitol nasal preparations in sinonasal disease: A literature review and meta-analysis","volume":"5","author":"Hui","year":"2022","journal-title":"Aust. J. Otolaryngol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1080\/09546634.2017.1325310","article-title":"Topical use of dexpanthenol: A 70th anniversary article","volume":"28","author":"Proksch","year":"2017","journal-title":"J. Dermatol. Treat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1007\/s00405-021-06644-5","article-title":"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","volume":"278","author":"Giarratana","year":"2021","journal-title":"Arch. Otorhinolaryngol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/S1473-3099(20)30232-2","article-title":"Viral dynamics in mild and severe cases of COVID-19","volume":"20","author":"Liu","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1136\/pgmj.2006.054767","article-title":"Acute rhinosinusitis in adults: An update on current management","volume":"83","author":"Masood","year":"2007","journal-title":"Postgrad. Med. J."},{"key":"ref_44","unstructured":"(2022, August 14). NHS England Updated UK Health Security Agency (UKHSA) Guidance\u2013Isolation. Available online: https:\/\/www.england.nhs.uk\/coronavirus\/documents\/updated-uk-health-security-agency-ukhsa-guidance-isolation\/#Self%20isolation%20for%20NHS%20staff."},{"key":"ref_45","unstructured":"European Centre for Disease Prevention and Control (ECDC) (2022, August 14). Guidance on Quarantine of Close Contacts to COVID-19 Cases and Isolation of COVID-19 Cases, in the Current Epidemiological Situation, 7 January 2022. Available online: https:\/\/www.ecdc.europa.eu\/en\/covid-19\/prevention-and-control\/quarantine-and-isolation."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Cegolon, L., Ronchese, F., Ricci, F., Negro, C., and Larese-Filon, F. (2022). SARS-CoV-2 Infection in Health Care Workers of Trieste (North-Eastern Italy), 1 October 2020\u20137 February 2022: Occupational Risk and the Impact of the Omicron Variant. Viruses, 14.","DOI":"10.3390\/v14081663"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Jin, Y., Yang, H., Ji, W., Wu, W., Chen, S., Zhang, W., and Duan, G. (2020). Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses, 12.","DOI":"10.3390\/v12040372"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/11\/2502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:20:54Z","timestamp":1760145654000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/11\/2502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,18]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["pharmaceutics14112502"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14112502","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,18]]}}}