Drug Res (Stuttg) 2020; 70(08): 337-340
DOI: 10.1055/a-1185-8913
Opinion Paper

The Battle against COVID 19 Pandemic: What we Need to Know Before we “Test Fire” Ivermectin

Kushal Banerjee
1   Post graduate trainee, Department of Pharmacology, Medical College and Hospital Kolkata, Kolkata, West Bengal, India
,
Manab Nandy
2   Professor, Department of Pharmacology, Medical College and Hospital Kolkata, Kolkata, West Bengal, India
,
Chanchal Kumar Dalai
3   Associate Professor, Department of Pharmacology, The West Bengal University of Health Sciences, College of Medicine and JNM Hospital, Kalyani, West Bengal, India
,
Shah Newaz Ahmed
4   Demonstrator, Department of Pharmacology, The West Bengal University of Health Sciences, College of Medicine and JNM Hospital, Kalyani, West Bengal, India
› Institutsangaben

Abstract

The world is faced with the dire challenge of finding an effective treatment against the rampaging COVID 19 pandemic. Amidst the crisis, reports of in vitro inhibitory activity of ivermectin, an approved anthelmintic, against the causative SARSCoV2 virus, have generated lot of optimism. In this article, we have fished and compiled the needed information on the drug, that will help readers and prospective investigators in having a quick overview. Though the primordial biological action of the drug is allosteric modulation of helminthic ion channel receptor, its in vitro activity against both RNA and DNA viruses is known for almost a decade. In the past two years, efficacy study in animal models of pseudorabies and zika virus was found to be favourable and unfavourable respectively. Only one clinical study evaluated the drug in dengue virus infection without any clinical efficacy. However, the proposed mechanism of drug action, by inhibiting the importin family of nucleus-cytoplasmic transporters along with favourable pharmacokinetics, warrants exploration of its role in COVID 19 through safely conducted clinical trials. Being an available and affordable drug, enlisted in WHO List of Essential Medicine, and a long track record of clinical safety, the drug is already in clinical trials the world over. As the pandemic continues to ravage human civilisation with unabated intensity, the world eagerly waits for a ray of hope emanating from the outcome of the ongoing trials with ivermectin as well as other drugs.



Publikationsverlauf

Eingereicht: 05. Juni 2020

Angenommen: 21. Mai 2020

Artikel online veröffentlicht:
19. Juni 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 
  • References

  • 1 Cascella M, Rajnik M, Cuomo A et al. Features, Evaluation and Treatment Coronavirus (COVID-19) [Internet]. In: StatPearls. Treasure Island (FL): StatPearls Publishing 2020; [cited 2020 Apr 22]. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/ http://www.ncbi.nlm.nih.gov/books/NBK554776/
  • 2 Alpern JD, Gertner E. Off-Label Therapies for COVID-19-Are We All In This Together? Clin Pharmacol Ther 2020 Apr 20. doi: 10.1002/ cpt.1862. Epub ahead of print. PMID: 32311763.
  • 3 Caly L, Druce JD, Catton MG. et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020; 178: 104787
  • 4 Markowska A, Kaysiewicz J, Markowska J. et al. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. Bioorg Med Chem Lett. 2019; 29: 1549-54
  • 5 Zemkova H, Tvrdonova V, Bhattacharya A et al. Allosteric modulation of ligand gated ion channels by ivermectin. Physiol Res 2014; 63 Suppl 1S: 215–224
  • 6 Macrocyclic Lactone - an overview | ScienceDirect Topics [Internet]. [cited 2020 May 2]; Available from https://www.sciencedirect.com/topics/chemistry/macrocyclic-lactone
  • 7 Damle B, Vourvahis M, Wang E et al. Clinical pharmacology perspectives on the antiviral activity of azithromycin and use in COVID-19. Clin Pharmacol Ther 2020 Apr 17:10.1002/cpt.1857. doi: 10.1002/ cpt.1857. Epub ahead of print. PMID: 32302411
  • 8 Chen I-S, Kubo Y.. Ivermectin and its target molecules: Shared and unique modulation mechanisms of ion channels and receptors by ivermectin. J Physiol 2018; 596: 1833-45
  • 9 Liu J, Zhang K, Cheng L. et al. Progress in understanding the molecular mechanisms underlying the antitumour effects of Ivermectin. Drug Des Devel Ther 2020; 14: 285-96
  • 10 Wagstaff KM, Sivakumaran H, Heaton SM. et al. 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: 851-6
  • 11 Yang SNY, Atkinson SC, Wang C. et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res 2020; 177: 104760
  • 12 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: 662-72
  • 13 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: 1-15
  • 14 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: 1884-94
  • 15 Lv 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
  • 16 Tay MYF, Fraser JE, Chan WKK. 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
  • 17 Wulan W.N., Heydet D., Walker E.J.. et al. Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses. Frontiers in microbiology 2015; 6: 553
  • 18 Ketkar H, Yang L, Wormser GP. et al. Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system. Diagn Microbiol Infect Dis 2019; 95: 38-40
  • 19 Xu T-L, Han Y, Liu W. et al. Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus. PLoS Negl Trop Dis 2018; 12: e0006934
  • 20 Crump A.. Ivermectin: enigmatic multifaceted “wonder” drug continues to surprise and exceed expectations. J Antibiot (Tokyo) 2017; 70: 495-505
  • 21 Buonaguro FM, Puzanov I, Ascierto PA. Anti-IL6R role in treatment of COVID-19-related ARDS. J Transl Med 2020; 18: 165
  • 22 Chaccour C, Hammann F, Ramón-García S et al. Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in Times of Urgency. Am J Trop Med Hyg. 2020;102: 1156–1157
  • 23 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: 42-6
  • 24 Muñoz J, Ballester MR, Antonijoan RM. et al. Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers. PLoS Negl Trop Dis 2018; 12: e0006020
  • 25 Lespine A, Dupuy J, Alvinerie M. et al. Interaction of macrocyclic lactones with the multidrug transporters: the bases of the pharmacokinetics of lipid-like drugs. Curr Drug Metab 2009; 10: 272-88
  • 26 Guzzo 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: 1122-33
  • 27 Lifschitz A, Virkel G, Sallovitz J. et al. Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle. Vet Parasitol 2000; 87: 327-38
  • 28 Lespine A, Alvinerie M, Sutra J-F. et al. Influence of the route of administration on efficacy and tissue distribution of ivermectin in goat. Vet Parasitol 2005; 128: 251-60
  • 29 Berthe A, Fronteau C, Le Fur É. et al. Medication reconciliation: a tool to prevent adverse drug events in geriatrics medicine. Geriatr Psychol Neuropsychiatr Vieil 2017; 15: 19-24
  • 30 WHO | WHO Model Lists of Essential Medicines [Internet]. [cited 2020 May 4]; Available from https://www.who.int/medicines/publications/essentialmedicines/en/
  • 31 Search of: ivermectin | COVID - List Results - ClinicalTrials.gov [Internet]. [cited 2020 May 4]; Available from https://clinicaltrials.gov/ct2/results?cond=COVID&term=ivermectin&cntry=&state=&city=&dist