Possible Role of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Recovery of Post-COVID-19 Anosmia
Zaki F Aref, Shamardan Ezz Eldin S Bazeed, Mohammed H Hassan, Abeer S Hassan, Ali A Ghweil, Mennatallah Ali Abdelrhman Sayed, Alaa Rashad, Haggagy Mansour, Aida A Abdelmaksoud
Infection and Drug Resistance, doi:10.2147/idr.s381715
Anosmia or hyposmia, with or without taste changes, are common symptoms that occur in SARS-CoV-2 infection and frequently persist as post-COVID-19 manifestations. This is the first trial to assess the potential value of using local ivermectin in the form of a mucoadhesive nanosuspension nasal spray to treat post-COVID-19 anosmia. Methods: It is a controlled, randomized trial. Participants were recruited from South Valley University Hospitals in Qena, Upper Egypt, from the ENT and Chest Diseases Departments and outpatient clinics. Patients with persistent post COVID-19 anosmia were randomly divided into two groups, the first group "ivermectin group" included 49 patients treated by ivermectin nanosuspension mucoadhesive nasal spray (two puffs per day). The second group included 47 patients "placebo group" who received saline nasal spray. Follow-up of anosmia [using Visual analogue scale (VAS)] in all patients for three months or appearance of any drug related side effects was done.
Results: The mean duration of pre-treatment post COVID-19 anosmia was 19.5± 5.8 days in the ivermectin group and 19.1± 5.9 days in the placebo group,p˃0.05. Regarding the median duration of anosmia recovery, the ivermectin group recovered from post COVID-19 anosmia in 13 days compared to 50 days in the placebo group, p˂ 0.001. Following the first week of ivermectin nanosuspension mucoadhesive nasal spray therapy, the ivermectin group had a significantly higher percentage of anosmia recovery (59.2%) than the placebo group (27.7%), p˂ 0.01, with no significant differences in recovery rates between the two groups at 1, 2, and 3 months of follow up, p˃0.05.
Conclusion: In the small number of patients treated, local Ivermectin exhibited no side effects. In persistent post-COVID-19 anosmia, it could be used for one week at the most as the treatment was extended to one, two and three months, with no difference in recovery compared to the placebo treatment. Trial Registration No: NCT04951362.
Consent for Publication Not applicable because the manuscript lacked the names, identifiers, or images of the patients.
Consent for Participation After thorough explanation of the study's objectives and procedures, informed written consent was obtained from each participant in the trial, or from relatives if the patients were less than 18 years old and those who supplied consent on their behalf were their parents or legal guardians.
Author Contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure The authors report no conflicts of interest in relation to this work.
Infection and Drug Resistance
Dovepress
References
Abdelmaksoud, Ghweil, Hassan, Olfactory Disturbances as Presenting Manifestation Among Egyptian Patients with COVID-19: possible Role of Zinc, Biol Trace Elem Res
Ahmed, Karim, Ross, A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, Int J Infect Dis,
doi:10.1016/j.ijid.2020.11.191Alshweiat, Csóka, Tömösi, Nasal delivery of nanosuspension-based mucoadhesive formulation with improved bioavailability of loratadine: preparation, characterization, and in vivo evaluation, Int J Pharm,
doi:10.1016/j.ijpharm.2020.119166Aref, Bazeed, Hassan, Clinical, Biochemical and Molecular Evaluations of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Reducing Upper Respiratory Symptoms of Mild COVID-19, Int J Nanomedicine,
doi:10.2147/IJN.S313093Canga, Prieto, Liébana, Martínez, Vega et al., The pharmacokinetics and interactions of ivermectin in humans--a mini-review, AAPS J,
doi:10.1208/s12248-007-9000-9Carfì, Bernabei, Landi, Gemelli, Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19, JAMA,
doi:10.1001/jama.2020.12603Cazzolla, Lovero, Muzio, Taste and Smell Disorders in COVID-19 Patients: role of Interleukin-6, ACS Chem. Neurosci
Ci, Li, Yu, Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway, Fundam Clin Pharmacol,
doi:10.1111/j.1472-8206.2009.00684.xEl-Mahdy, Hassan, El-Badry, El-Gindy, Performance of curcumin in nanosized carriers niosomes and ethosomes as potential anti-inflammatory delivery system for topical application, Bull Pharm Sci Assiut,
doi:10.21608/bfsa.2020.93599Fodoulian, Tuberosa, Rossier, SARS-CoV-2 Receptors and Entry Genes Are Expressed in the Human Olfactory Neuroepithelium and Brain, iScience,
doi:10.1016/j.isci.2020.101839Gane, Kelly, Hopkins, Isolated sudden onset anosmia in COVID-19 infection. A novel syndrome?, Rhinology,
doi:10.4193/Rhin20.114Götz, Magar, Dornfeld, Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import, Sci Rep,
doi:10.1038/srep23138Hamming, Timens, Bulthuis, Lely, Navis et al., Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis, J Pathol,
doi:10.1002/path.1570Hung, Chim, Chan, Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome, Clin Chem,
doi:10.1373/clinchem.2003.025437Junior, Cardoso, Giufrida, De Souza, Cardozo-Filho, Production and computational fluid dynamics-based modeling of PMMA nanoparticles impregnated with ivermectin by a supercritical antisolvent process, J CO2 Util,
doi:10.1016/j.jcou.2019.08.025Ketkar, Yang, Wormser, Wang, Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system, Diagn Microbiol Infect Dis,
doi:10.1016/j.diagmicrobio.2019.03.012Kow, Merchant, Mustafa, Hasan, The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis, Pharmacol Rep,
doi:10.1007/s43440-021-00245-zLozada-Nur, Chainani-Wu, Fortuna, Sroussi, Dysgeusia in COVID-19: possible Mechanisms and Implications, Oral Surg Oral Med Oral Pathol Oral Radiol,
doi:10.1016/j.oooo.2020.06.016López-Medina, López, Hurtado, Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: a Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2021.3071Maraie, Almajidi, Application of nanoemulsion technology for preparation and evaluation of intranasal mucoadhesive nano-in-situ gel for ondansetron HCl, J Glob Pharm Technol
Mastrangelo, Pezzullo, Burghgraeve, Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug, J Antimicrob Chemother,
doi:10.1093/jac/dks147Prajapati, Shahrvini, Macdonald, Association of subjective olfactory dysfunction and 12-item odor identification testing in ambulatory COVID-19 patients, Int Forum Allergy Rhinol,
doi:10.1002/alr.22688Saindane, Pagar, Vavia, Nanosuspension based in situ gelling nasal spray of carvedilol: development, in vitro and in vivo characterization, AAPS PharmSciTech,
doi:10.1208/s12249-012-9896-yVaira, Salzano, Fois, Piombino, Riu, Potential pathogenesis of ageusia and anosmia in COVID-19 patients, Int Forum Allergy Rhinol,
doi:10.1002/alr.22593Vallejos, Zoni, Bangher, Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial, BMC Infect Dis,
doi:10.1186/s12879-021-06348-5Van Riel, Verdijk, Kuiken, The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system, J Pathol,
doi:10.1002/path.4461Ventre, Rozières, Lenief, Topical ivermectin improves allergic skin inflammation, Allergy,
doi:10.1111/all.13118Whittaker, Anson, Harky, Neurological Manifestations of COVID-19: a systematic review and current update, Acta Neurol Scand,
doi:10.1111/ane.13266Xia, Quan, Piao, Preparation of stable nitrendipine nanosuspensions using the precipitation-ultrasonication method for enhancement of dissolution and oral bioavailability, Eur J Pharm Sci,
doi:10.1016/j.ejps.2010.04.006Yildiz, Yildiz, Kuzu, Günebakan, Bucak et al., 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,
doi:10.1007/s12070-021-02749-9Zhang, Song, Xiong, Inhibitory effects of ivermectin on nitric oxide and prostaglandin E2 production in LPS-stimulated RAW 264.7 macrophages, Int Immunopharmacol,
doi:10.1016/j.intimp.2008.12.016{ 'indexed': {'date-parts': [[2022, 9, 20]], 'date-time': '2022-09-20T05:34:45Z', 'timestamp': 1663652085692},
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'given': 'Zaki F',
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'given': 'Shamardan Ezz Eldin S',
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'affiliation': []},
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'member': '301',
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'reference': [ { 'key': 'ref1',
'unstructured': 'World Health Organization. Coronavirus disease (COVID-2019) situation '
'reports; 2020. Available from: '
'https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/. '
'Accessed April 9, 2020.'},
{ 'key': 'ref2',
'unstructured': 'Centers for Disease Control and Prevention. Coronavirus disease 2019 '
'(COVID-19): cases in U.S; 2020. Available from: '
'https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html. '
'Accessed April 9, 2020.'},
{ 'key': 'ref3',
'doi-asserted-by': 'publisher',
'first-page': '14',
'DOI': '10.1111/ane.13266',
'volume': '142',
'author': 'Whittaker',
'year': '2020',
'journal-title': 'Acta Neurol Scand'},
{ 'key': 'ref4',
'doi-asserted-by': 'publisher',
'first-page': '1014',
'DOI': '10.1016/S0140-6736(20)30633-4',
'volume': '395',
'author': 'Weiss',
'year': '2020',
'journal-title': 'Lancet'},
{ 'key': 'ref5',
'doi-asserted-by': 'publisher',
'first-page': '344',
'DOI': '10.1016/j.oooo.2020.06.016',
'volume': '130',
'author': 'Lozada-Nur',
'year': '2020',
'journal-title': 'Oral Surg Oral Med Oral Pathol Oral Radiol'},
{ 'key': 'ref6',
'doi-asserted-by': 'publisher',
'first-page': '299',
'DOI': '10.4193/Rhin20.114',
'volume': '58',
'author': 'Gane',
'year': '2020',
'journal-title': 'Rhinology'},
{ 'key': 'ref7',
'doi-asserted-by': 'publisher',
'first-page': '603',
'DOI': '10.1001/jama.2020.12603',
'volume': '324',
'author': 'Carfì',
'year': '2020',
'journal-title': 'JAMA'},
{ 'key': 'ref8',
'doi-asserted-by': 'publisher',
'first-page': '1103',
'DOI': '10.1002/alr.22593',
'volume': '10',
'author': 'Vaira',
'year': '2020',
'journal-title': 'Int Forum Allergy Rhinol'},
{ 'key': 'ref9',
'doi-asserted-by': 'publisher',
'first-page': '101839',
'DOI': '10.1016/j.isci.2020.101839',
'volume': '23',
'author': 'Fodoulian',
'year': '2020',
'journal-title': 'iScience'},
{ 'key': 'ref10',
'doi-asserted-by': 'publisher',
'first-page': '277',
'DOI': '10.1002/path.4461',
'volume': '235',
'author': 'van Riel',
'year': '2015',
'journal-title': 'J Pathol'},
{ 'key': 'ref11',
'first-page': '2774',
'volume': '11',
'author': 'Cazzolla',
'year': '2020',
'journal-title': 'Neurosci'},
{ 'key': 'ref12',
'doi-asserted-by': 'publisher',
'first-page': '4457',
'DOI': '10.1158/0008-5472.CAN-15-2887',
'volume': '76',
'author': 'Dou',
'year': '2016',
'journal-title': 'Cancer Res'},
{ 'key': 'ref13',
'doi-asserted-by': 'publisher',
'first-page': '354',
'DOI': '10.1016/j.intimp.2008.12.016',
'volume': '9',
'author': 'Zhang',
'year': '2009',
'journal-title': 'Int Immunopharmacol'},
{ 'key': 'ref14',
'doi-asserted-by': 'publisher',
'first-page': '449',
'DOI': '10.1111/j.1472-8206.2009.00684.x',
'volume': '23',
'author': 'Ci',
'year': '2009',
'journal-title': 'Fundam Clin Pharmacol'},
{ 'key': 'ref15',
'doi-asserted-by': 'publisher',
'first-page': '1212',
'DOI': '10.1111/all.13118',
'volume': '72',
'author': 'Ventre',
'year': '2017',
'journal-title': 'Allergy'},
{ 'key': 'ref16',
'first-page': '1',
'volume': '3',
'author': 'Abdelmaksoud',
'year': '2021',
'journal-title': 'Biol Trace Elem Res'},
{ 'key': 'ref17',
'doi-asserted-by': 'publisher',
'first-page': '42',
'DOI': '10.1208/s12248-007-9000-9',
'volume': '10',
'author': 'González Canga',
'year': '2008',
'journal-title': 'AAPS J'},
{ 'key': 'ref18',
'doi-asserted-by': 'publisher',
'first-page': '1884',
'DOI': '10.1093/jac/dks147',
'volume': '67',
'author': 'Mastrangelo',
'year': '2012',
'journal-title': 'J Antimicrob Chemother'},
{ 'key': 'ref19',
'doi-asserted-by': 'publisher',
'first-page': '23138',
'DOI': '10.1038/srep23138',
'volume': '6',
'author': 'Götz',
'year': '2016',
'journal-title': 'Sci Rep'},
{ 'key': 'ref20',
'doi-asserted-by': 'publisher',
'first-page': '104787',
'DOI': '10.1016/j.antiviral.2020.104787',
'volume': '178',
'author': 'Caly',
'year': '2020',
'journal-title': 'Antiviral Res'},
{ 'key': 'ref21',
'doi-asserted-by': 'publisher',
'first-page': '38',
'DOI': '10.1016/j.diagmicrobio.2019.03.012',
'volume': '95',
'author': 'Ketkar',
'year': '2019',
'journal-title': 'Diagn Microbiol Infect Dis'},
{ 'key': 'ref22',
'doi-asserted-by': 'publisher',
'first-page': '119166',
'DOI': '10.1016/j.ijpharm.2020.119166',
'volume': '579',
'author': 'Alshweiat',
'year': '2020',
'journal-title': 'Int J Pharm'},
{ 'key': 'ref23',
'doi-asserted-by': 'publisher',
'first-page': '6459',
'DOI': '10.2174/0929867326666190827151741',
'volume': '26',
'author': 'Alshweiat',
'year': '2019',
'journal-title': 'Curr Med Chem'},
{ 'key': 'ref24',
'doi-asserted-by': 'publisher',
'first-page': '4063',
'DOI': '10.2147/IJN.S313093',
'volume': '16',
'author': 'Aref',
'year': '2021',
'journal-title': 'Int J Nanomedicine'},
{ 'key': 'ref25',
'doi-asserted-by': 'publisher',
'first-page': 'CD011995',
'DOI': '10.1002/14651858.CD011995.pub2',
'volume': '4',
'author': 'Chong',
'year': '2016',
'journal-title': 'Cochrane Database Syst Rev'},
{ 'key': 'ref26',
'doi-asserted-by': 'publisher',
'first-page': '1',
'author': 'Yildiz',
'year': '2021',
'journal-title': 'Indian J Otolaryngol Head Neck Surg',
'DOI': '10.1007/s12070-021-02749-9'},
{ 'key': 'ref27',
'doi-asserted-by': 'publisher',
'first-page': '1209',
'DOI': '10.1002/alr.22688',
'volume': '10',
'author': 'Prajapati',
'year': '2020',
'journal-title': 'Int Forum Allergy Rhinol'},
{ 'key': 'ref28',
'doi-asserted-by': 'publisher',
'first-page': '47',
'DOI': '10.1016/j.jcou.2019.08.025',
'volume': '35',
'author': 'Junior',
'year': '2020',
'journal-title': 'J CO2 Util'},
{ 'key': 'ref29',
'doi-asserted-by': 'publisher',
'first-page': '325',
'DOI': '10.1016/j.ejps.2010.04.006',
'volume': '40',
'author': 'Xia',
'year': '2010',
'journal-title': 'Eur J Pharm Sci'},
{ 'key': 'ref30',
'doi-asserted-by': 'publisher',
'first-page': '105',
'DOI': '10.21608/bfsa.2020.93599',
'volume': '43',
'author': 'El-Mahdy',
'year': '2020',
'journal-title': 'Bull Pharm Sci Assiut'},
{ 'key': 'ref31',
'doi-asserted-by': 'publisher',
'first-page': '1426',
'DOI': '10.1001/jama.2021.3071',
'volume': '325',
'author': 'López-Medina',
'year': '2021',
'journal-title': 'JAMA'},
{ 'key': 'ref32',
'doi-asserted-by': 'publisher',
'first-page': '635',
'DOI': '10.1186/s12879-021-06348-5',
'volume': '21',
'author': 'Vallejos',
'year': '2021',
'journal-title': 'BMC Infect Dis'},
{ 'key': 'ref33',
'doi-asserted-by': 'publisher',
'first-page': '214',
'DOI': '10.1016/j.ijid.2020.11.191',
'volume': '103',
'author': 'Ahmed',
'year': '2021',
'journal-title': 'Int J Infect Dis'},
{ 'key': 'ref34',
'doi-asserted-by': 'publisher',
'first-page': '1473',
'DOI': '10.1007/s43440-021-00245-z',
'volume': '73',
'author': 'Kow',
'year': '2021',
'journal-title': 'Pharmacol Rep'},
{ 'key': 'ref35',
'doi-asserted-by': 'publisher',
'first-page': '423',
'DOI': '10.1093/chemse/bjaa040',
'volume': '45',
'author': 'Han',
'year': '2020',
'journal-title': 'Chem Senses'},
{ 'key': 'ref36',
'doi-asserted-by': 'publisher',
'first-page': '502',
'DOI': '10.1016/0042-6822(92)90220-J',
'volume': '191',
'author': 'Stewart',
'year': '1992',
'journal-title': 'Virology'},
{ 'key': 'ref37',
'doi-asserted-by': 'publisher',
'first-page': '8913',
'DOI': '10.1128/JVI.74.19.8913-8921.2000',
'volume': '74',
'author': 'Arbour',
'year': '2000',
'journal-title': 'J Virol'},
{ 'key': 'ref38',
'doi-asserted-by': 'publisher',
'first-page': '2108',
'DOI': '10.1373/clinchem.2003.025437',
'volume': '49',
'author': 'Hung',
'year': '2003',
'journal-title': 'Clin Chem'},
{ 'key': 'ref39',
'doi-asserted-by': 'publisher',
'first-page': '415',
'DOI': '10.1084/jem.20050828',
'volume': '202',
'author': 'Gu',
'year': '2005',
'journal-title': 'J Exp Med'},
{ 'key': 'ref40',
'doi-asserted-by': 'publisher',
'first-page': '631',
'DOI': '10.1002/path.1570',
'volume': '203',
'author': 'Hamming',
'year': '2004',
'journal-title': 'J Pathol'},
{ 'key': 'ref41',
'unstructured': 'ClinicalTrials.gov. Provided by the U.S. National Library of Medicine. '
'Available from: '
'https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=ivermectin&cntry=&state=&city=&dist=. '
'Accessed August 28, 2020.'},
{ 'key': 'ref42',
'first-page': '431',
'volume': '10',
'author': 'Maraie',
'year': '2018',
'journal-title': 'J Glob Pharm Technol'},
{ 'key': 'ref43',
'doi-asserted-by': 'publisher',
'first-page': '189',
'DOI': '10.1208/s12249-012-9896-y',
'volume': '14',
'author': 'Saindane',
'year': '2013',
'journal-title': 'AAPS PharmSciTech'}],
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