A Wonder Drug in the Arsenal against COVID - 19: Medication Evidence from Ivermectin
Journal of Advances in Medicine and Medical Research,
Page 30-37
DOI:
10.9734/jammr/2020/v32i1030512
Abstract
Ivermectin, an FDA approved broad-spectrum anti-parasitic agent has been recently reported to show an inhibitory activity against SARS-CoV-2 in an in-vitro study. This antiviral response has rendered it as a potential drug to be repurposed for COVID-19. Previously, ivermectin had showed inhibitory activity against RNA viruses in-vitro and DNA viruses in-vitro and in-vivo respectively. Much of its characterization has been related to SARS-CoV wherein viral proteins interacting with IMPα/β1 (Importins) were proposed to enhance the viral infectivity. These documentations serve as a ray of hope for considering ivermectin in treating COVID-19 due to its suggested nuclear transport inhibitory mechanism. Importantly, these recent findings warrant detailed investigations for understanding its benefit in terms of efficacy and safety in COVID-19 patients. This review article throws light on the current consensus in this regard.
Keywords:
- COVID-19
- SARS-CoV-2
- SARS-CoV
- ivermectin
How to Cite
Kumar, B. S., Jeyaraman, M., Jain, R., & Anudeep, T. C. (2020). A Wonder Drug in the Arsenal against COVID - 19: Medication Evidence from Ivermectin. Journal of Advances in Medicine and Medical Research, 32(10), 30-37. https://doi.org/10.9734/jammr/2020/v32i1030512
References
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Ōmura S. Ivermectin: 25 years and still going strong. Int. J. Antimicrob. Agents. 2008;31:91–98.
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA - approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. J Antiviral. 2020;104787.
Slisco A. Anti-parasite drug used since 1980s may help stop coronavirus, new study says. Newsweek; 4th April; 2020.
Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA; 2020.
Menez C, Sutra JF, Prichard R, Lespine A. Relative neurotoxicity of ivermectin and moxidectin in Mdr1ab (-/-) mice and effects on mammalian GABA(A) channel activity. PLoS Negl Trop Dis. 2012;6:e1883.
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1–12.
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19–associated acute hemorrhagic necrotizing encephalo-pathy: CT and MRI features. RSNA Radiology; 2020.
Chandler RE. Serious neurological adverse events after ivermectin-do they occur beyond the indication of onchocerciasis? Am J Trop Med Hyg. 2018;98:382–388.
Panahi Y, Poursaleh Z, Goldust M. The efficacy of topical and oral ivermectin in the treatment of human scabies. Annals of Parasitology. 2015;61(1):11–16.
World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization; 2019.
Yates DM, Wolstenholme AJ. An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis. International Journal for Parasitology. 2004;34(9):1075–81.
Borst P, Schinkel AH. What have we learnt thus far from mice with disrupted P-glycoprotein genes? European Journal of Cancer. 1996;32A(6):985–90.
Turner SA, Maclean JD, Fleckenstein L, Greenaway C. Parenteral administration of ivermectin in a patient with disseminated strongyloidiasis. Am J Trop Med Hyg 2005; 73:911–914.
Campbell WC, Benz GW. Ivermectin: A review of efficacy and safety. J. Vet. Pharmacol. Ther. 1984;7:1–16.
Satoshi Omura, Andy Crump. Ivermectin: Panacea for resource-poor communities? Trends in Parasitology. 2014;30(9):445-455.
Taylor HR, Pacque M, Munoz B, Greene BM. Impact of mass treatment of onchocerciasis with ivermectin on the transmission of infection. Science. 1990; 250(4977):116-118.
Dora Buonfrate, Joaquin Salas-Coronas, José Muñoz, Begoña Trevino Maruri, Paola Rodari, Francesco Castelli. Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): A multicentre, open-label, phase 3, randomised controlled superiority trial. The Lancet Infectious Diseases. 2019;19(11):1181-1190.
Karthikeyan K. Treatment of scabies: newer perspectives. Postgrad. Med. J. 2005;81:7–11.
Chosidow O, Giraudeau B, et al. Oral ivermectin versus malathion lotion for difficult-to-treat head lice. N. Engl. J. Med. 2010;362:896–905.
Nontasut P, Bussaratid V, Chullawichit S, Charoensook N, Visetsuk K. Comparison of ivermectin and albendazole treatment for gnathostomiasis. Southeast Asian J. Trop. Med. Public Health. 2009;31:374–377.
Shinohara EH, Martini MZ, de oliveira neto hg, Takahashi A. Oral myiasis treated with ivermectin: case report. Braz. Dent. J. 2004;15:79–81.
Bregani ER, Rovellini A, Mbaïdoum N, Magnini MG, et al. Comparison of different anthelminthic drug regimens against Mansonella perstans filariasis. Trans. R. Soc. Trop. Med. Hyg. 2006;100: 458–463.
Basyoni MM, El-Sabaa AA. Therapeutic potential of myrrh and ivermectin against experimental Trichinella spiralis infection in mice. Korean J. Parasitol. 2013;51:297–304.
Belizario, VY, Amarillo ME, de Leon WU, de los Reyes AE, Bugayong MG, Macatangay BJ. A comparison of the efficacy of single doses of albendazole, ivermectin, and diethylcarbamazine alone or in combinations against Ascaris and Trichuris spp. Bull. World Health Organ. 2003;81:35–42.
Wimmersberger D, Coulibaly JT, Schulz JD, Puchkow M, Huwyler J, N'Gbesso Y, et al. Efficacy and safety of ivermectin against Trichuris trichiura in preschool-aged and school-aged children: A randomized controlled dose-finding trial. Clin Infect Dis. 2018.28;67(8):1247-1255.
Panchal M, Rawat K, Kumar G, Kibria KM, Singh S, Kalamuddin MD, et al. Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP. Cell Death Dis. 2014;5:e994.
Udensi UK, Fagbenro-Beyioku AF. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. J. Vector Borne Dis. 2012;49:143–150.
Kadir MA, Aswad HS, Al-Samarai AM, Al-Mula GA. Comparison between the efficacy of ivermectin and other drugs in treatment of cutaneous leishmaniasis. Iraqi J. Vet. Sci. 2009;23(II):175–180.
Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J. 2012;443(3):851–856.
Mastrangelo E, Pezzullo M, De Burghgraeve T, Kaptein S, Pastorino B, Dallmeier K, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: New prospects for an old drug. J. Antimcrob. Chemother. 2012;67:1884–1894.
Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5: protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res. 2013;99:301–306.
Carocci M, Hinshaw SM, Rodgers MA, Villareal VA, Burri DJ, Pilankatta R, et al. The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrobial Agents and Chemotherapy. 2015;59:85-95.
Varghese FS, Kaukinen P, Gläsker S, Bespalov M, Hanski L, Wennerberg K, et al. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Research. 2016;126:117–24.
Sidra Azeem, Muhammad Ashraf, Muhammad Adil Rasheed, Aftab Ahmad Anjum, Rabia Hameed. Evaluation of cytotoxicity and antiviral activity of ivermectin against newcastle disease virus. Pak J Pharm Sci. 2015;28(2):597-602.
Pettengil MA, Lam VW, Ollawa I, Marques-da-Silva C, Ojcius DM. Ivermectin inhibits growth of Chlamydia trachomatis in epithelial cells. PLoS ONE. 2012;7, e48456.
Lim L, Catherine Vilchèze, Carol Ng, William R. Jacobs, Santiago Ramón-García, Charles J. Thompson. Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob. Agents Chemother. 2013;57:1040–1046.
Rowland RR, Chauhan V, Fang Y, Pekosz A, Kerrigan M, Burton MD, et al. Intracellular localization of the severe acute respiratory syndrome coronavirus nucleocapsid protein: Absence of nucleolar accumulation during infection and after expression as a recombinant protein in vero cells. J. Virol. 2005;79(17):11507–11512.
Timani KA, Liao Q, Ye L, Zeng Y, Liu J, Zheng Y, et al. Nuclear/nucleolar localization properties of C-terminal nucleocapsid protein of SARS coronavirus. Virus Res. 2005;114(1–2):23–34.
Wulan WN, Heydet D, Walker EJ, Gahan ME, Ghildyal R. Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses. Front. Microbiol. 2015;6:553.
Wurm T, Chen H, Hodgson T, Britton P, Brooks G, Hiscox JA. Localization to the nucleolus is a common feature of coronavirus nucleoproteins, and the protein may disrupt host cell division. J. Virol. 2001;75(19):9345–9356.
Frieman M, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 2007; 81(18):9812–9824.
Şimşek Yavuz S, Ünal S. Antiviral treatment of COVID-19. Turkish Journal of Medical Sciences. 2020;50(SI-1):611–619.
TWiV 599: Coronavirus update - we need a plan. This Week in Virology. Retrieved; April 21, 2020.
Do Not Use Ivermectin for Animals as Treatment for COVID-19 in Humans. U.S. Food and Drug Administration (FDA); April 10, 2020.
RM_270-2020-MINSA. Republica Del Peru Ministerio De Salud; May 8, 2020. Retrieved May 8, 2020.
Gotz V, Linda Magar, Dominik Dornfeld, Sebastian Giese, Anne Pohlmann, Dirk Höper, et al. Influenza A viruses escape from MxA restriction at the expense of effcient nuclear vRNP import. Sci. Rep. 2016;6:23138.
Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan equine encephalitis virus replication. Antivir. Res. 2013;100(3):662–672.
Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA. An alpha screen (R)-based assay for high-throughput screening for specific inhibitors of nuclear import. J. Biomol. Screen. 2011;16(2):192–200.
Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antivir. Res. 2020:104760.
Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antivir. Res. 2018;159:55–62.
Hiscox JA, Wurm T, Wilson L, Britton P, Cavanagh D, Brooks G. The coronavirus infectious bronchitis virus nucleoprotein localizes to the nucleolus. J. Virol. 2001; 75(1):506–512.
Yamasmith E, et al. Effcacy and safety of ivermectin against dengue infection: A phase III, randomized, double-blind, placebo-controlled trial. In: He 34th Annual Meeting the royal College of physicians of Thailand. Internal Medicine and One Health, Chonburi, Thailand; 2018.
ClinicalTrials.gov. Avaialble:https://www.clinicaltrials.gov
[Cited: 16th May, 2020].
Ōmura S. Ivermectin: 25 years and still going strong. Int. J. Antimicrob. Agents. 2008;31:91–98.
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA - approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. J Antiviral. 2020;104787.
Slisco A. Anti-parasite drug used since 1980s may help stop coronavirus, new study says. Newsweek; 4th April; 2020.
Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA; 2020.
Menez C, Sutra JF, Prichard R, Lespine A. Relative neurotoxicity of ivermectin and moxidectin in Mdr1ab (-/-) mice and effects on mammalian GABA(A) channel activity. PLoS Negl Trop Dis. 2012;6:e1883.
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1–12.
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19–associated acute hemorrhagic necrotizing encephalo-pathy: CT and MRI features. RSNA Radiology; 2020.
Chandler RE. Serious neurological adverse events after ivermectin-do they occur beyond the indication of onchocerciasis? Am J Trop Med Hyg. 2018;98:382–388.
Panahi Y, Poursaleh Z, Goldust M. The efficacy of topical and oral ivermectin in the treatment of human scabies. Annals of Parasitology. 2015;61(1):11–16.
World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization; 2019.
Yates DM, Wolstenholme AJ. An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis. International Journal for Parasitology. 2004;34(9):1075–81.
Borst P, Schinkel AH. What have we learnt thus far from mice with disrupted P-glycoprotein genes? European Journal of Cancer. 1996;32A(6):985–90.
Turner SA, Maclean JD, Fleckenstein L, Greenaway C. Parenteral administration of ivermectin in a patient with disseminated strongyloidiasis. Am J Trop Med Hyg 2005; 73:911–914.
Campbell WC, Benz GW. Ivermectin: A review of efficacy and safety. J. Vet. Pharmacol. Ther. 1984;7:1–16.
Satoshi Omura, Andy Crump. Ivermectin: Panacea for resource-poor communities? Trends in Parasitology. 2014;30(9):445-455.
Taylor HR, Pacque M, Munoz B, Greene BM. Impact of mass treatment of onchocerciasis with ivermectin on the transmission of infection. Science. 1990; 250(4977):116-118.
Dora Buonfrate, Joaquin Salas-Coronas, José Muñoz, Begoña Trevino Maruri, Paola Rodari, Francesco Castelli. Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): A multicentre, open-label, phase 3, randomised controlled superiority trial. The Lancet Infectious Diseases. 2019;19(11):1181-1190.
Karthikeyan K. Treatment of scabies: newer perspectives. Postgrad. Med. J. 2005;81:7–11.
Chosidow O, Giraudeau B, et al. Oral ivermectin versus malathion lotion for difficult-to-treat head lice. N. Engl. J. Med. 2010;362:896–905.
Nontasut P, Bussaratid V, Chullawichit S, Charoensook N, Visetsuk K. Comparison of ivermectin and albendazole treatment for gnathostomiasis. Southeast Asian J. Trop. Med. Public Health. 2009;31:374–377.
Shinohara EH, Martini MZ, de oliveira neto hg, Takahashi A. Oral myiasis treated with ivermectin: case report. Braz. Dent. J. 2004;15:79–81.
Bregani ER, Rovellini A, Mbaïdoum N, Magnini MG, et al. Comparison of different anthelminthic drug regimens against Mansonella perstans filariasis. Trans. R. Soc. Trop. Med. Hyg. 2006;100: 458–463.
Basyoni MM, El-Sabaa AA. Therapeutic potential of myrrh and ivermectin against experimental Trichinella spiralis infection in mice. Korean J. Parasitol. 2013;51:297–304.
Belizario, VY, Amarillo ME, de Leon WU, de los Reyes AE, Bugayong MG, Macatangay BJ. A comparison of the efficacy of single doses of albendazole, ivermectin, and diethylcarbamazine alone or in combinations against Ascaris and Trichuris spp. Bull. World Health Organ. 2003;81:35–42.
Wimmersberger D, Coulibaly JT, Schulz JD, Puchkow M, Huwyler J, N'Gbesso Y, et al. Efficacy and safety of ivermectin against Trichuris trichiura in preschool-aged and school-aged children: A randomized controlled dose-finding trial. Clin Infect Dis. 2018.28;67(8):1247-1255.
Panchal M, Rawat K, Kumar G, Kibria KM, Singh S, Kalamuddin MD, et al. Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP. Cell Death Dis. 2014;5:e994.
Udensi UK, Fagbenro-Beyioku AF. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. J. Vector Borne Dis. 2012;49:143–150.
Kadir MA, Aswad HS, Al-Samarai AM, Al-Mula GA. Comparison between the efficacy of ivermectin and other drugs in treatment of cutaneous leishmaniasis. Iraqi J. Vet. Sci. 2009;23(II):175–180.
Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J. 2012;443(3):851–856.
Mastrangelo E, Pezzullo M, De Burghgraeve T, Kaptein S, Pastorino B, Dallmeier K, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: New prospects for an old drug. J. Antimcrob. Chemother. 2012;67:1884–1894.
Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5: protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res. 2013;99:301–306.
Carocci M, Hinshaw SM, Rodgers MA, Villareal VA, Burri DJ, Pilankatta R, et al. The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrobial Agents and Chemotherapy. 2015;59:85-95.
Varghese FS, Kaukinen P, Gläsker S, Bespalov M, Hanski L, Wennerberg K, et al. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Research. 2016;126:117–24.
Sidra Azeem, Muhammad Ashraf, Muhammad Adil Rasheed, Aftab Ahmad Anjum, Rabia Hameed. Evaluation of cytotoxicity and antiviral activity of ivermectin against newcastle disease virus. Pak J Pharm Sci. 2015;28(2):597-602.
Pettengil MA, Lam VW, Ollawa I, Marques-da-Silva C, Ojcius DM. Ivermectin inhibits growth of Chlamydia trachomatis in epithelial cells. PLoS ONE. 2012;7, e48456.
Lim L, Catherine Vilchèze, Carol Ng, William R. Jacobs, Santiago Ramón-García, Charles J. Thompson. Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob. Agents Chemother. 2013;57:1040–1046.
Rowland RR, Chauhan V, Fang Y, Pekosz A, Kerrigan M, Burton MD, et al. Intracellular localization of the severe acute respiratory syndrome coronavirus nucleocapsid protein: Absence of nucleolar accumulation during infection and after expression as a recombinant protein in vero cells. J. Virol. 2005;79(17):11507–11512.
Timani KA, Liao Q, Ye L, Zeng Y, Liu J, Zheng Y, et al. Nuclear/nucleolar localization properties of C-terminal nucleocapsid protein of SARS coronavirus. Virus Res. 2005;114(1–2):23–34.
Wulan WN, Heydet D, Walker EJ, Gahan ME, Ghildyal R. Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses. Front. Microbiol. 2015;6:553.
Wurm T, Chen H, Hodgson T, Britton P, Brooks G, Hiscox JA. Localization to the nucleolus is a common feature of coronavirus nucleoproteins, and the protein may disrupt host cell division. J. Virol. 2001;75(19):9345–9356.
Frieman M, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 2007; 81(18):9812–9824.
Şimşek Yavuz S, Ünal S. Antiviral treatment of COVID-19. Turkish Journal of Medical Sciences. 2020;50(SI-1):611–619.
TWiV 599: Coronavirus update - we need a plan. This Week in Virology. Retrieved; April 21, 2020.
Do Not Use Ivermectin for Animals as Treatment for COVID-19 in Humans. U.S. Food and Drug Administration (FDA); April 10, 2020.
RM_270-2020-MINSA. Republica Del Peru Ministerio De Salud; May 8, 2020. Retrieved May 8, 2020.
Gotz V, Linda Magar, Dominik Dornfeld, Sebastian Giese, Anne Pohlmann, Dirk Höper, et al. Influenza A viruses escape from MxA restriction at the expense of effcient nuclear vRNP import. Sci. Rep. 2016;6:23138.
Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan equine encephalitis virus replication. Antivir. Res. 2013;100(3):662–672.
Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA. An alpha screen (R)-based assay for high-throughput screening for specific inhibitors of nuclear import. J. Biomol. Screen. 2011;16(2):192–200.
Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antivir. Res. 2020:104760.
Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antivir. Res. 2018;159:55–62.
Hiscox JA, Wurm T, Wilson L, Britton P, Cavanagh D, Brooks G. The coronavirus infectious bronchitis virus nucleoprotein localizes to the nucleolus. J. Virol. 2001; 75(1):506–512.
Yamasmith E, et al. Effcacy and safety of ivermectin against dengue infection: A phase III, randomized, double-blind, placebo-controlled trial. In: He 34th Annual Meeting the royal College of physicians of Thailand. Internal Medicine and One Health, Chonburi, Thailand; 2018.
ClinicalTrials.gov. Avaialble:https://www.clinicaltrials.gov
[Cited: 16th May, 2020].
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