Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19
Corresponding Author
Hatem Elalfy
Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Correspondence Hatem Elalfy, Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Email: [email protected] and [email protected]
Search for more papers by this authorTarek Besheer
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAhmed El-Mesery
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAbdel-Hady El-Gilany
Department of Public Health and Preventive Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMahmoud Abdel-Aziz Soliman
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAhmed Alhawarey
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMohamed Alegezy
Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorTamer Elhadidy
Chest Department, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAsem A. Hewidy
Chest Medicine Department, Mansoura University, Mansoura, Egypt
Search for more papers by this authorHossam Zaghloul
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMustafa Ahmed Mohamed Neamatallah
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorDouaa Raafat
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorWafaa M. El-Emshaty
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorNermin Y. Abo El Kheir
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMahmoud El-Bendary
Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorCorresponding Author
Hatem Elalfy
Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Correspondence Hatem Elalfy, Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Email: [email protected] and [email protected]
Search for more papers by this authorTarek Besheer
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAhmed El-Mesery
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAbdel-Hady El-Gilany
Department of Public Health and Preventive Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMahmoud Abdel-Aziz Soliman
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAhmed Alhawarey
Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMohamed Alegezy
Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorTamer Elhadidy
Chest Department, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAsem A. Hewidy
Chest Medicine Department, Mansoura University, Mansoura, Egypt
Search for more papers by this authorHossam Zaghloul
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMustafa Ahmed Mohamed Neamatallah
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorDouaa Raafat
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorWafaa M. El-Emshaty
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorNermin Y. Abo El Kheir
Department of Clinical Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorMahmoud El-Bendary
Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
Search for more papers by this authorAbstract
This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Open Research
DATA AVAILABILITY STATEMENT
data can be requested from the hospital administration after approval from Institutional Review Board (IRB) due to ethical & confidentiality reasons.
REFERENCES
- 1Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382(8): 727-733.
- 2Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30(3): 269-271.
- 3Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020; 323(18): 1824-1836.
- 4Fox LM, Saravolatz LD. Nitazoxanide: a new thiazolide antiparasitic agent. Clin Infect Dis. 2005; 40(8): 1173-1180.
- 5Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014; 110: 94-103.
- 6Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016; 9(3): 227-230.
- 7Hong SK, Kim HJ, Song CS, Choi IS, Lee JB, Park SY. Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. Int Immunopharmacol. 2012; 13(1): 23-27.
- 8Cao J, Forrest JC, Zhang X. A screen of the NIH clinical collection small molecule library identifies potential anti-coronavirus drugs. Antiviral Res. 2015; 114: 1-10.
- 9Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci U S A. 2001; 98(12): 6895-6900.
- 10Graci JD, Cameron CE. Mechanisms of action of ribavirin against distinct viruses. Rev Med Virol. 2006; 16(1): 37-48.
- 11Hultgren C, Milich DR, Weiland O, Sallberg M. The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. J Gen Virol. 1998; 79(Pt 10): 2381-2391.
- 12Kobayashi T, Nakatsuka K, Shimizu M, et al. Ribavirin modulates the conversion of human CD4(+) CD25(-) T cell to CD4(+) CD25(+) FOXP3(+) T cell via suppressing interleukin-10-producing regulatory T cell. Immunology. 2012; 137(3): 259-270.
- 13Li Z, Ping Y, Yu Z, et al. Dynamic changes in CD45RA(-)Foxp3(high) regulatory T-cells in chronic hepatitis C patients during antiviral therapy. Int J Infect Dis. 2016; 45: 5-12.
- 14Tam RC, Pai B, Bard J, et al. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J Hepatol. 1999; 30(3): 376-382.
- 15Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis. 2014; 20: 42-46.
- 16Booth CM. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003; 289(21): 2801-2809.
- 17Chong YP, Song JY, Seo YB, et al. Antiviral treatment guidelines for Middle East respiratory syndrome. Infect Chemother. 2015; 47(3): 212-222.
- 18Habib AMG, Ali MAE, Zouaoui BR, Taha MAH, Mohammed BS, Saquib N. Clinical outcomes among hospital patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection. BMC Infect Dis. 2019; 19(1): 870.
- 19Khalid M, Al Rabiah F, Khan B, Al Mobeireek A, Butt TS, Al Mutairy E. Ribavirin and interferon-α2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases. Antivir Ther. 2015; 20(1): 87-91.
- 20Lee N, Hui D, Wu A, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003; 348(20): 1986-1994.
- 21Peiris J, Chu C, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003; 361(9371): 1767-1772.
- 22Poutanen SM, Low DE, Henry B, et al. Identification of severe acute respiratory syndrome in Canada. N Engl J Med. 2003; 348(20): 1995-2005.
- 23Hung IFN, Lung KC, Tso EYK, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020; 395(10238): 1695-1704.
- 24Zeng YM, Xu XL, He XQ, et al. Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha, and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate novel coronavirus disease 2019: study protocol. Chin Med J. 2020; 133(9): 1132-1134.
- 25Campbell WC, Benz GW. Ivermectin: a review of efficacy and safety. J Vet Pharmacol Ther. 1984; 7(1): 1-16.
- 26Crump A, Ōmura S. Ivermectin, 'wonder drug' from Japan: the human use perspective. Proc Jpn Acad Ser B. 2011; 87(2): 13-28.
- 27Lv C, Liu W, Wang B, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. 2018; 159: 55-62.
- 28Wang X, Lv C, Ji X, Wang B, Qiu L, Yang Z. Ivermectin treatment inhibits the replication of porcine circovirus 2 (PCV2) in vitro and mitigates the impact of viral infection in piglets. Virus Res. 2019; 263: 80-86.
- 29Raza S, Shahin F, Zhai W, et al. Ivermectin inhibits bovine herpesvirus 1 DNA polymerase nuclear import and interferes with viral replication. Microorganisms. 2020; 8(3): 409.
- 30Lundberg 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.
- 31Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020; 178:104787.
- 32Overbeck S, Rink L, Haase H. Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases. Arch Immunol Ther Exp. 2008; 56(1): 15-30.
- 33Kumar A, Kubota Y, Chernov M, Kasuya H. Potential role of zinc supplementation in prophylaxis and treatment of COVID-19. Med Hypotheses. 2020; 144:109848-109848.
- 34Rahman MT, Idid SZ. Can Zn be a critical element in COVID-19 treatment? Biol Trace Elem Res. 2020; 199: 1-9.
- 35 Clinical management of COVID-19 interim guidance. May 2020. https://www.who.int/publications/i/item/clinical-management-of-covid-19
- 36Yousefi B, Valizadeh S, Ghaffari H, Vahedi A, Karbalaei M, Eslami M. A global treatments for coronaviruses including COVID-19. J Cell Physiol. 2020; 235(12): 9133-9142.
- 37Zhong H, Wang Y, Zhang Z-L, et al. Efficacy and safety of current therapeutic options for COVID-19—lessons to be learnt from SARS and MERS epidemic: a systematic review and meta-analysis. Pharmacol Res. 2020; 157:104872.
- 38Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; 395(10236): 1569-1578.
- 39Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30(3): 269-271.
- 40Kelleni MT. Nitazoxanide/azithromycin combination for COVID-19: a suggested new protocol for early management. Pharmacol Res. 2020; 157:104874.
- 41Mahmoud DB, Shitu Z, Mostafa A. Drug repurposing of nitazoxanide: can it be an effective therapy for COVID-19? J Genet Eng Biotechnol. 2020; 18(1): 35-35.
10.1186/s43141-020-00055-5 Google Scholar
- 42Chaccour C, Hammann F, Rabinovich NR. Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety. Malar J. 2017; 16(1): 161.
- 43Guzzo CA, Furtek CI, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002; 42(10): 1122-1133.
- 44Yamasmith E. Efficacy and Safety of Ivermectin against dengue Infection: a phase III, randomized, double-blind, placebo-controlled trial. The 34th Annual Meeting of the Royal College of Physicians of Thailand- ‘Internal Medicine and One Health’: Chonburi, Thailand. Registry. 2018. https://clinicaltrials.gov/ct2/show/NCT02045069. Accessed November 4, 2020.
- 45te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLOS Pathog. 2010; 6(11):e1001176.
- 46Bae SN, Lee KH, Kim JH, Lee SJ, Park LO. Zinc induces apoptosis on cervical carcinoma cells by p53-dependent and -independent pathway. Biochem Biophys Res Commun. 2017; 484(1): 218-223.
- 47Simonart T, de Maertelaer V. Systemic treatments for cutaneous warts: a systematic review. J Dermatolog Treat. 2012; 23(1): 72-77.
- 48Bhutta ZA, Bird SM, Black RE, et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr. 2000; 72(6): 1516-1522.
- 49Asdamongkol N, Phanachet P, Sungkanuparph S. Low plasma zinc levels and immunological responses to zinc supplementation in HIV-infected patients with immunological discordance after antiretroviral therapy. Jpn J Infect Dis. 2013; 66(6): 469-474.
- 50Pal A, Squitti R, Picozza M, et al. Zinc and COVID-19: basis of current clinical trials. Biol Trace Elem Res. 2020: 1-11.
