Clinical, Biochemical and Molecular Evaluations of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Reducing Upper Respiratory Symptoms of Mild COVID-19

Zaki F Aref, Shamardan Ezz Eldin S Bazeed, Mohammed H Hassan, Abeer S Hassan, Alaa Rashad, Rehab G Hassan, Aida A Abdelmaksoud, Zaki F Aref, Shamardan Ezz Eldin S Bazeed, Mohammed H Hassan, Abeer S Hassan, Alaa Rashad, Rehab G Hassan, Aida A Abdelmaksoud

Abstract

Background: Ivermectin is an FDA-approved broad-spectrum anti-parasitic agent that has been shown to inhibit SARS-CoV-2 replication in vitro.

Objective: We aimed to assess the therapeutic efficacy of ivermectin mucoadhesive nanosuspension intranasal spray in treatment of patients with mild COVID-19.

Methods: This clinical trial included 114 patients diagnosed as mild COVID-19. Patients were divided randomly into two age and sex-matched groups; group A comprising 57 patients received ivermectin nanosuspension nasal spray twice daily plus the Egyptian protocol of treatment for mild COVID-19 and group B comprising 57 patients received the Egyptian protocol for mild COVID-19 only. Evaluation of the patients was performed depending on improvement of presenting manifestations, negativity of two consecutive pharyngeal swabs for the COVID-19 nucleic acid via rRT-PCR and assessments of hematological and biochemical parameters in the form of complete blood counts, C-reactive protein, serum ferritin and d-dimer which were performed at presentation and 7 days later.

Results: Of the included patients confirmed with mild COVID-19, 82 were males (71.9%) and 32 females (28.1%) with mean age 45.1 ± 18.9. In group A, 54 patients (94.7%) achieved 2 consecutive negative PCR nasopharyngeal swabs in comparison to 43 patients (75.4%) in group B with P = 0.004. The durations of fever, cough, dyspnea and anosmia were significantly shorter in group A than group B, without significant difference regarding the duration of gastrointestinal symptoms. Duration taken for nasopharyngeal swab to be negative was significantly shorter in group A than in group B (8.3± 2.8 days versus 12.9 ± 4.3 days; P = 0.0001).

Conclusion: Local use of ivermectin mucoadhesive nanosuspension nasal spray is safe and effective in treatment of patients with mild COVID-19 with rapid viral clearance and shortening the anosmia duration.

Clinicaltrialsgov identifier: NCT04716569; https://ichgcp.net/clinical-trials-registry/NCT04716569.

Keywords: COVID-19; biochemical and molecular; ivermectin nanosuspension; nasal spray.

Conflict of interest statement

No potential conflicts of interest between authors to be declare.

© 2021 Aref et al.

Figures

Figure 1
Figure 1
Flow chart of the study design.

References

    1. El-Sayed, A., Kamel, M. Coronaviruses in humans and animals: the role of bats in viral evolution. Environ Sci Pollut Res. 2021;28:19589–19600. doi:10.1007/s11356-021-12553-1
    1. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, et al. The pharmacokinetics and interactions of ivermectin in humans–a mini-review. AAPS J. 2008;10(1):42–46. doi:10.1208/s12248-007-9000-9
    1. Götz V, Magar L, Dornfeld D, et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016;6:23138. doi:10.1038/srep23138
    1. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851–856. doi:10.1042/BJ20120150
    1. Siddiqui AJ, Jahan S, Ashraf SA, et al. Current status and strategic possibilities on potential use of combinational drug therapy against COVID-19 caused by SARS-CoV-2. J Biomol Struct Dyn. 2020;1–14. doi:10.1080/07391102.2020.1802345
    1. Siddiqui AJ, Danciu C, Ashraf SA, et al. Plants-derived biomolecules as potent antiviral phytomedicines: new insights on ethnobotanical evidences against coronaviruses. Plants. 2020;9(9):1244. doi:10.3390/plants9091244
    1. Surti M, Patel M, Adnan M, et al. Ilimaquinone (marine sponge metabolite) as a novel inhibitor of SARS-CoV-2 key target proteins in comparison with suggested COVID-19 drugs: designing, docking and molecular dynamics simulation study. RSC Adv. 2020;10(62):37707–37720. doi:10.1039/D0RA06379G
    1. Alzahrani FA, Saadeldin IM, Ahmad A, et al. The potential use of mesenchymal stem cells and their derived exosomes as immunomodulatory agents for COVID-19 patients. Stem Cells Int. 2020;2020:8835986. doi:10.1155/2020/8835986
    1. Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA. An AlphaScreen®-based assay for high-throughput screening for specific inhibitors of nuclear import. J Biomol Screen. 2011;16(2):192–200. doi:10.1177/1087057110390360
    1. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved]drug ivermectin inhibits the replication of SARS-CoV-2 invitro. Antiviral Res. 2020;178:104787. doi:10.1016/j.antiviral.2020.104787
    1. Ketkar H, Yang L, Wormser GP, Wang P. Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system. Diagn Microbiol Infect Dis. 2019;95(1):38–40. doi:10.1016/j.diagmicrobio.2019.03.012
    1. Alshweiat A, Csóka I, Tömösi F, et al. Nasal delivery of nanosuspension-based mucoadhesive formulation with improved bioavailability of loratadine: preparation, characterization, and in vivo evaluation. Int J Pharm. 2020;579:119166. doi:10.1016/j.ijpharm.2020.119166
    1. Alshweiat A, Ambrus R, Csoka I. Intranasal nanoparticulate systems as alternative route of drug delivery. Curr Med Chem. 2019;26(35):6459–6492. doi:10.2174/0929867326666190827151741
    1. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In Vivo. 2020;34(5):3023–3026. doi:10.21873/invivo.12134
    1. Rodriguez-Morales AJ, Gallego V, Escalera-Antezana JP, et al. COVID-19 in Latin America: the implications of the first confirmed case in Brazil. Travel Med Infect Dis. 2020;35:101613. doi:10.1016/j.tmaid.2020.101613
    1. Rodriguez-Morales AJ, Sánchez-Duque JA, Hernández-Botero S, et al. Preparación y control dela enfermedad por coronavirus 2019 (COVID-19) en América Latina. Acta Medica Peruana. 2020;37(1):3–7. doi:10.35663/amp.2020.371.909
    1. Gallego V, Nishiura H, Sah R, Rodriguez-Morales AJ. The COVID-19 outbreak and implications for the Tokyo 2020 Summer Olympic Games. Travel Med Infect Dis. 2020;2020:101604. doi:10.1016/j.tmaid.2020.101604
    1. Abdelmaksoud AA, Ghweil AA, Hassan MH, et al. Olfactory disturbances as presenting manifestation among egyptian patients with COVID-19: possible role of zinc. Biol Trace Elem Res. 2021:1–8. doi:10.1007/s12011-020-02546-5
    1. Wang YY, Jin YH, Ren XQ, et al. Updating the diagnostic criteria of COVID-19 “suspected case” and “confirmed case” is necessary. Mil Med Res. 2020;7(1):1–3. doi:10.1186/s40779-020-00245-9
    1. Li L, Li R, Wu Z, et al. Therapeutic strategies for critically ill patients with COVID-19. Ann Intensive Care. 2020;10(1):45. doi:10.1186/s13613-020-00661-z
    1. Zhang J, Wang X, Jia X, et al. Risk factors for disease severity, unimprovement, and mortality in COVID-19 patients in Wuhan, China. Clin Microbiol Infect. 2020;26(6):767–772. doi:10.1016/j.cmi.2020.04.012
    1. Ministry of Health and Population. Egyptian national guidelines for COVID-19. 2020. Available online: . Accessed December1, 2020.
    1. Xia D, Quan P, Piao H, et al. Preparation of stable nitrendipine nanosuspensions using the precipitation–ultrasonication method for enhancement of dissolution and oral bioavailability. Eur J Pharm Sci. 2010;40(4):325–334. doi:10.1016/j.ejps.2010.04.006
    1. Hegazy AA, Hegazy RA. COVID-19: virology, pathogenesis and potential therapeutics. Afro-Egypt J Infect Endem Dis. 2020;10(2):93–99. doi:10.21608/AEJI.2020.93432
    1. Mastrangelo E, Pezzullo M, De Burghgraeve T, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012;67(8):1884–1894. doi:10.1093/jac/dks147
    1. Lundberg L, Pinkham C, Baer A, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce venezuelan equine encephalitis virus replication. Antiviral Res. 2013;100(3):662–672. doi:10.1016/j.antiviral.2013.10.004
    1. Azeem S, Ashraf M, Rasheed MA, Anjum AA, Hameed R. Evaluation of cytotoxicity and antiviral activity of ivermectin against newcastle disease virus. Pak J Pharm Sci. 2015;28(2):597–602.
    1. Jabeen T, Khader MA, Jabeen S. A review on the antiparasitic drug ivermectin for various viral infections and possibilities of using it for novel severe acute respiratory syndrome coronavirus 2: new hope to treat coronavirus disease-2019. Asian J Pharm Clin Res. 2020;13:21–27. doi:10.22159/ajpcr.2020.v13i8.38357
    1. Ghweil AA, Hassan MH, Khodeary A, et al. Characteristics, outcomes and indicators of severity for COVID- 19 among sample of ESNA Quarantine Hospital’s Patients, Egypt: a retrospective study. Infect Drug Resist. 2020;13:2375–2383. doi:10.2147/IDR.S263489
    1. Liu K, Chen Y, Lin R, Han K. Clinical features of COVID-19 in elderly patients: a comparison with young and middle-aged patients. J Infect. 2020. doi:10.1016/j.jinf.2020.03.005
    1. Mahase E. Covid-19: death rate is 0.66% and increases with age, study estimates. BMJ. 2020;369:m1327. doi:10.1136/bmj.m1327
    1. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91–95. doi:10.1016/j.ijid.2020.03.017
    1. Kumar S, Singh R, Kumari N, et al. Current understanding of the influence of environmental factors on SARS-CoV-2 transmission, persistence, and infectivity. Environ Sci Pollut Res Int. 2021;28(6):6267–6288. doi:10.1007/s11356-020-12165-1
    1. Aly MH, Rahman SS, Ahmed WA, et al. Indicators of critical illness and predictors of mortality in COVID-19 patients. Infect Drug Resist. 2020;13:1995–2000. doi:10.2147/IDR.S261159
    1. Marhl M, Grubelnik V, Magdič M, Markovič R. Diabetes and metabolic syndrome as risk factors for COVID-19. Diabetes Metab Syndr. 2020;14(4):671–677. doi:10.1016/j.dsx.2020.05.013
    1. Singh AK, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations. Diabetes Metab Syndr. 2020;14(4):303–310. doi:10.1016/j.dsx.2020.04.004
    1. Shouman WM, Hegazy AA, Nafae RM, et al. Use of ivermectin as a potential chemoprophylaxis for COVID-19 in Egypt: a randomised clinical trial. J Clin Diagn Res. 2021. doi:10.7860/JCDR/2020/46795.0000
    1. Alam MT, Murshed R, Bhiuyan E, Saber S, Alam R, Robin R. A case series of 100 COVID-19 positive patients treated with combination of ivermectin and doxycycline. J Bangladesh Coll Phys Surg. 2020;38:10–15. doi:10.3329/jbcps.v38i0.47512
    1. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ivermectin in COVID nineteen study. Chest. 2021;159(1):85–92. doi:10.1016/j.chest.2020.10.009
    1. Saindane NS, Pagar KP, Vavia PR. Nanosuspension based in situ gelling nasal spray of carvedilol: development, in vitro and in vivo characterization. Aaps Pharmscitech. 2013;14(1):189–199. doi:10.1208/s12249-012-9896-y
    1. 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

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj