Ivermectin - Wonder drug from Japan and Covid-19 Articles

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Andy CRUMP, Satoshi ŌMURA

Proc Jpn Acad Ser B Phys Biol Sci. 2011 Feb 10; 87(2): 13–28. doi: 10.2183/pjab.87.13

PMCID: 

PMC3043740

Article PubReader PDF–584KCitation

Abstract

Discovered in the late-1970s, the pioneering drug ivermectin, a dihydro derivative of avermectin—originating solely from a single microorganism isolated at the Kitasato Intitute, Tokyo, Japan from Japanese soil—has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found. This paper looks in depth at the events surrounding ivermectin’s passage from being a huge success in Animal Health into its widespread use in humans, a development which has led many to describe it as a “wonder” drug.

Keywords: avermectin, ivermectin, mode of action, onchocerciasis, lymphatic filariasis, drug resistance

Go to:

Introduction

There are few drugs that can seriously lay claim to the title of ‘Wonder drug’, penicillin and aspirin being two that have perhaps had greatest beneficial impact on the health and wellbeing of Mankind. 

But ivermectin can also be considered alongside those worthy contenders, based on its versatility, safety and the beneficial impact that it has had, and continues to have, worldwide—especially on hundreds of millions of the world’s poorest people. 

Several extensive reports, including reviews authored by us, have been published detailing the events behind the discovery, development and commercialization of the avermectins and ivermectin (22,23-dihydroavermectin B), as well as the donation of ivermectin and its use in combating Onchocerciasis and lymphatic filariasis.1–6) 

However, none have concentrated in detail on the interacting sequence of events involved in the passage of the drug into human use.

When it first appeared in the late-1970s, ivermectin, a derivative of avermectin (Fig. ​(Fig.1 )1 ) was a truly revolutionary drug, unprecedented in many ways. It was the world’s first endectocide, forerunner of a completely new class of antiparasitic agents, potently active against a wide range of internal and external nematodes and arthropods. 

In the early-1970s, a novel international Public Sector–Private Sector partnership was initiated by one of us (Ōmura, then head of the Antibiotics Research Group at Tokyo’s Kitasato Institute), forming a collaboration with the US-based Merck, Sharp and Dohme (MSD) pharmaceutical company.

Under the terms of the research agreement, researchers at the Kitasato Institute isolated organisms from soil samples and carried out preliminary in vitro evaluation of their bioactivity. Promising bioactive samples were then sent to the MSD laboratories for further in vivo testing where a potent and promising novel bioactivity was found, subsequently identified as being caused by a new compound, which was named ‘avermectin’.7) 

Despite decades of searching around the world, the Japanese microorganism remains the only source of avermectin ever found.1)

Originating from a single Japanese soil sample and the outcome of the innovative, international collaborative research partnership to find new antiparasitics, the extremely safe and more effective avermectin derivative, ivermectin, was initially introduced as a commercial product for Animal Health in 1981. 

It is effective against a wide range of parasites, including gastrointestinal roundworms, lungworms, mites, lice and hornflies.7–12) 

Ivermectin is also highly effective against ticks, for example, the ixodid tick Rhipicephalus (Boophilus) microplus, one of the most important cattle parasites in the tropics and subtropics, which causes enormous economic damage. Indicative of the impact, in Brazil, where some 80% of the bovine herd is infested, losses total about $2 billion annually.13) 

Today, ivermectin is being used to treat billions of livestock and pets around the world, helping to boost production of food and leather products, as well as keep billions of companion animals, particularly dogs and horses, healthy. 

The ‘Blockbuster’ drug in the Animal Health sector, meaning that it achieved annual sales in excess of over US$1 billion, maintained that status for over 20 years. It is so useful and adaptable that it is also being used off-label, sometimes, illegally, for example to treat fish lice in the aquaculture industry, where it can have a negative impact on non-target organisms. It also has extensive uses in agriculture.2)

Figure 1.

Molecular diagrams of avermectin and the di-hydro derivative, ivermectin.

Ivermectin proved to be even more of a ‘Wonder drug’ in human health, improving the nutrition, general health and wellbeing of billions of people worldwide ever since it was first used to treat Onchocerciasis in humans in 1988. 

It proved ideal in many ways, being highly effective and broad-spectrum, safe, well tolerated and could be easily administered (a single, annual oral dose). It is used to treat a variety of internal nematode infections, including Onchocerciasis, Strongyloidiasis, Ascariasis, cutaneous larva migrans, filariases, Gnathostomiasis and Trichuriasis, as well as for oral treatment of ectoparasitic infections, such as Pediculosis (lice infestation) and scabies (mite infestation).14) 

Ivermectin is the essential mainstay of two global disease elimination campaigns that should soon rid the world of two of its most disfiguring and devastating diseases, Onchocerciasis and Lymphatic filariasis, which blight the lives of billions of the poor and disadvantaged throughout the tropics. 

It is likely that, throughout the next decade, well over 200 million people will be taking the drug annually or semi-annually, via innovative globally-coordinated Mass Drug Administration (MDA) programmes. 

Indeed, the discovery, development and deployment of ivermectin, produced by an unprecedented partnership between the Private Sector pharmaceutical multinational Merck & Co. Inc., and the Public Sector Kitasato Institute in Tokyo, aided by an extraordinary coalition of multidisciplinary international partners and disease-affected communities, has been recognized by many experts and observers as one of the greatest medical accomplishments of the 20th century.15) 

In referring to the international efforts to tackle Onchocerciasis in which ivermectin is now the sole control tool, the UNESCO World Science Report concluded, “the progress that has been made in combating the disease represents one of the most triumphant public health campaigns ever waged in the developing world”.16)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043740/

Similar articles in PubMed

• Ivermectin: 25 years and still going strong.[Int J Antimicrob Agents. 2008]
• Ivermectin: panacea for resource-poor communities?[Trends Parasitol. 2014]
• Ivermectin 20 years on: maturation of a wonder drug.[Trends Parasitol. 2005]
• Ivermectin: uses and impact 20 years on.[Curr Opin Infect Dis. 2006]
• History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents.[Curr Pharm Biotechnol. 2012]
• 
  

<< Previous Page 1 of 2 Next >>

Is Cited by the Following 40 Articles in this Archive:

The broad spectrum host-directed agent ivermectin as an antiviral for SARS-CoV-2 ?

David A. Jans, Kylie M. Wagstaff

Biochem Biophys Res Commun. 2020 Oct 21 doi: 10.1016/j.bbrc.2020.10.042 [Epub ahead of print]

PMCID: 

PMC7577703

Article PubReader PDF–786KCitation

Anti-SARS-CoV Natural Products With the Potential to Inhibit SARS-CoV-2 (COVID-19)

Surjeet Verma, Danielle Twilley, Tenille Esmear, Carel B. Oosthuizen, Anna-Mari Reid, Marizé Nel, Namrita Lall

Front Pharmacol. 2020; 11: 561334. Published online 2020 Sep 25. doi: 10.3389/fphar.2020.561334

PMCID: 

PMC7546787

Article PubReader PDF–1.7MCitation

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

David A. Jans, Kylie M. Wagstaff

Cells. 2020 Sep; 9(9): 2100. Published online 2020 Sep 15. doi: 10.3390/cells9092100

PMCID: 

PMC7564151

Article PubReader PDF–913KCitation

Avermectin Derivatives, Pharmacokinetics, Therapeutic and Toxic Dosages, Mechanism of Action, and Their Biological Effects

Gaber El-Saber Batiha, Ali Alqahtani, Omotayo B. Ilesanmi, Abdullah A. Saati, Amany El-Mleeh, Helal F. Hetta, Amany Magdy Beshbishy

Pharmaceuticals (Basel) 2020 Aug; 13(8): 196. Published online 2020 Aug 17. doi: 10.3390/ph13080196

PMCID: 

PMC7464486

Article PubReader PDF–2.5MCitation

Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen

Fatemeh Heidary, Reza Gharebaghi

J Antibiot (Tokyo) 2020 Jun 12 : 1–10. doi: 10.1038/s41429-020-0336-z [Epub ahead of print]

PMCID: 

PMC7290143

Article PubReader PDF–639KCitation

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19

Khan Sharun, Kuldeep Dhama, Shailesh Kumar Patel, Mamta Pathak, Ruchi Tiwari, Bhoj Raj Singh, Ranjit Sah, D. Katterine Bonilla-Aldana, Alfonso J. Rodriguez-Morales, Hakan Leblebicioglu

Ann Clin Microbiol Antimicrob. 2020; 19: 23. Published online 2020 May 30. doi: 10.1186/s12941-020-00368-w

PMCID: 

PMC7261036

Article PubReader PDF–1.2MCitation

Identification of new drug treatments to combat COVID19: A signature-based approach using iLINCS

Sinead M O’Donovan, Hunter Eby, Nicholas D Henkel, Justin Creeden, Ali Imami, Sophie Asah, Xiaolu Zhang, Xiaojun Wu, Rawan Alnafisah, R. Travis Taylor, James Reigle, Alexander Thorman, Behrouz Shamsaei, Jarek Meller, Robert E McCullumsmith

Version 1. Res Sq. Preprint. 2020 Apr 30. doi: 10.21203/rs.3.rs-25643/v1

PMCID: 

PMC7336712

Abstract Article PDF–730KCitation

Ivermectin and COVID-19: A report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses

Mike Bray, Craig Rayner, François Noël, David Jans, Kylie Wagstaff

Antiviral Res. 2020 Jun; 178: 104805. Published online 2020 Apr 21. doi: 10.1016/j.antiviral.2020.104805

PMCID: 

PMC7172803

Article PubReader PDF–666KCitation

The Benefit of a Single Oral Dose of Ivermectin in Humans: The Adverse Effects on Cimex lectularius L. Populations and Fecundity

Johnathan M Sheele, Gale Ridge, Xiaolin Li, Danie Schlatzer, Elizabeth Lesser

Cureus. 2019 Nov; 11(11): e6098. Published online 2019 Nov 8. doi: 10.7759/cureus.6098

PMCID: 

PMC6901371

Article PubReader PDF–543KCitation

Combined effect of the entomopathogenic fungus Metarhizium robertsii and avermectins on the survival and immune response of Aedes aegypti larvae

Yuriy A. Noskov, Olga V. Polenogova, Olga N. Yaroslavtseva, Olga E. Belevich, Yuriy A. Yurchenko, Ekaterina A. Chertkova, Natalya A. Kryukova, Vadim Yu Kryukov, Viktor V. Glupov

PeerJ. 2019; 7: e7931. Published online 2019 Oct 25. doi: 10.7717/peerj.7931

PMCID: 

PMC6816395

Article PubReader PDF–5.6MCitation

Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform

Maria Zachari, Sigurdur R. Gudmundsson, Ziyue Li, Maria Manifava, Ronak Shah, Matthew Smith, James Stronge, Eleftherios Karanasios, Caterina Piunti, Chieko Kishi-Itakura, Helena Vihinen, Eija Jokitalo, Jun-Lin Guan, Folma Buss, Andrew M. Smith, Simon A. Walker, Eeva-Liisa Eskelinen, Nicholas T. Ktistakis

Dev Cell. 2019 Sep 9; 50(5): 627–643.e5. doi: 10.1016/j.devcel.2019.06.016

Correction in: 

Dev Cell. 2020 Oct 26; 55(2): 251.

PMCID: 

PMC6739445

Article PubReaderCitation

Reducing malaria burden and accelerating elimination with long-lasting systemic insecticides: a modelling study of three potential use cases

Prashanth Selvaraj, Joshua Suresh, Edward A. Wenger, Caitlin A. Bever, Jaline Gerardin

Malar J. 2019; 18: 307. Published online 2019 Sep 5. doi: 10.1186/s12936-019-2942-4

PMCID: 

PMC6727392

Article PubReader PDF–1.4MCitation

Ivermectin Impairs the Development of Sexual and Asexual Stages of Plasmodium falciparum In Vitro

Lais Pessanha de Carvalho, Thaisa Lucas Sandri, Edésio José Tenório de Melo, Rolf Fendel, Peter G. Kremsner, Benjamin Mordmüller, Jana Held

Antimicrob Agents Chemother. 2019 Aug; 63(8): e00085-19. Prepublished online 2019 May 20. Published online 2019 Jul 25. doi: 10.1128/AAC.00085-19

PMCID: 

PMC6658753

Article PubReader PDF–1.1MCitation

Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer

Patrycja Nowak-Sliwinska, Leonardo Scapozza, Ariel Ruiz i Altaba

Biochim Biophys Acta Rev Cancer. 2019 Apr; 1871(2): 434–454. doi: 10.1016/j.bbcan.2019.04.005

PMCID: 

PMC6528778

Article PubReaderCitation

Oral activity of the antimalarial endoperoxide 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Leishmania donovani complex

Kofi Dadzie Kwofie, Kai Sato, Chizu Sanjoba, Akina Hino, Rieko Shimogawara, Michael Amoa-Bosompem, Irene Ayi, Daniel A. Boakye, Abraham K. Anang, Kyung-Soo Chang, Mitsuko Ohashi, Hye-Sook Kim, Nobuo Ohta, Yoshitsugu Matsumoto, Shiroh Iwanaga

PLoS Negl Trop Dis. 2019 Mar; 13(3): e0007235. Published online 2019 Mar 25. doi: 10.1371/journal.pntd.0007235

PMCID: 

PMC6433226

Article PubReader PDF–1.2MCitation

New indications for topical ivermectin 1% cream: a case series study

Wioletta Barańska-Rybak, Elżbieta Kowalska-Olędzka

Postepy Dermatol Alergol. 2019 Feb; 36(1): 58–62. Published online 2019 Feb 22. doi: 10.5114/ada.2019.82825

PMCID: 

PMC6409879

Article PubReader PDF–163KCitation

Use of Ivermectin in Neurocysticercosis: A Case Report

Mohammed S. Samannodi, Andrew Zhao, Rodrigo Hasbun

Am J Case Rep. 2018; 19: 1378–1381. Published online 2018 Nov 20. doi: 10.12659/AJCR.911269

PMCID: 

PMC6253560

Article PubReader PDF–702KCitation

Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus

Tie-Long Xu, Yin Han, Wei Liu, Xing-Ya Pang, Bin Zheng, Yi Zhang, Xiao-Nong Zhou

PLoS Negl Trop Dis. 2018 Nov; 12(11): e0006934. Published online 2018 Nov 19. doi: 10.1371/journal.pntd.0006934

PMCID: 

PMC6277121

Article PubReader PDF–1.1MCitation

Ivermectin Promotes Peripheral Nerve Regeneration during Wound Healing

Dana M. Cairns, Jodie E. Giordano, Sylvia Conte, Michael Levin, David L. Kaplan

ACS Omega. 2018 Oct 31; 3(10): 12392–12402. Published online 2018 Oct 1. doi: 10.1021/acsomega.8b01451

PMCID: 

PMC6210064

Article PubReader PDF–7.2MCitation

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

Balázs Csóka, Zoltán H. Németh, Ildikó Szabó, Daryl L. Davies, Zoltán V. Varga, János Pálóczi, Simonetta Falzoni, Francesco Di Virgilio, Rieko Muramatsu, Toshihide Yamashita, Pál Pacher, György Haskó

JCI Insight. 2018 Jun 7; 3(11): e99431. Published online 2018 Jun 7. doi: 10.1172/jci.insight.99431

PMCID: 

PMC5997389

Article PubReader PDF–1.3MCitation

Differential susceptibilities of Anopheles albimanus and Anopheles stephensi mosquitoes to ivermectin

Staci M. Dreyer, Kelsey J. Morin, Jefferson A. Vaughan

Malar J. 2018; 17: 148. Published online 2018 Apr 3. doi: 10.1186/s12936-018-2296-3

PMCID: 

PMC5883420

Article PubReader PDF–978KCitation

Evolution of epilepsy prevalence and incidence in a Tanzanian area endemic for onchocerciasis and the potential impact of community-directed treatment with ivermectin: a cross-sectional study and comparison over 28 years

Helena Greter, Bruno Mmbando, Williams Makunde, Mohamed Mnacho, William Matuja, Advocatus Kakorozya, Patrick Suykerbuyk, Robert Colebunders

BMJ Open. 2018; 8(3): e017188. Published online 2018 Mar 31. doi: 10.1136/bmjopen-2017-017188

PMCID: 

PMC5884367

Article PubReader PDF–823KCitation

PRECLINICAL EVALUATION OF AVERMECTINS AS NOVEL THERAPEUTIC AGENTS FOR ALCOHOL USE DISORDERS

Sheraz Khoja, Nhat Huynh, Alicia M.P. Warnecke, Liana Asatryan, Michael W. Jakowec, Daryl L. Davies

Psychopharmacology (Berl) Author manuscript; available in PMC 2019 Jun 1.

Published in final edited form as: Psychopharmacology (Berl). 2018 Jun; 235(6): 1697–1709. Published online 2018 Mar 2. doi: 10.1007/s00213-018-4869-9

PMCID: 

PMC5949264

Article PubReader PDF–554KCitation

Absence of Loa loa Microfilaremia among Newly Arrived Congolese Refugees in Texas

Jessica Montour, Deborah Lee, Cathy Snider, Emily S. Jentes, William Stauffer

Am J Trop Med Hyg. 2017 Dec 6; 97(6): 1833–1835. Published online 2017 Sep 5. doi: 10.4269/ajtmh.17-0337

PMCID: 

PMC5805057

Article PubReader PDF–60KCitation

Ivermectin-treated cattle reduces blood digestion, egg production and survival of a free-living population of Anopheles arabiensis under semi-field condition in south-eastern Tanzania

Issa N. Lyimo, Stella T. Kessy, Kasian F. Mbina, Ally A. Daraja, Ladslaus L. Mnyone

Malar J. 2017; 16: 239. Published online 2017 Jun 6. doi: 10.1186/s12936-017-1885-x

PMCID: 

PMC5461717

Article PubReader PDF–1.3MCitation

A BRIEF REVIEW ON THE MODE OF ACTION OF ANTINEMATODAL DRUGS

Melanie Abongwa, Richard J Martin, Alan P Robertson

Acta Vet (Beogr) Author manuscript; available in PMC 2018 Feb 5.

Published in final edited form as: Acta Vet (Beogr). 2017 Jun; 67(2): 137–152. Published online 2017 Jun 26. doi: 10.1515/acve-2017-0013

PMCID: 

PMC5798647

Article PubReader PDF–2.2MCitation

Mutational Analysis at Intersubunit Interfaces of an Anionic Glutamate Receptor Reveals a Key Interaction Important for Channel Gating by Ivermectin

Nurit Degani-Katzav, Revital Gortler, Marina Weissman, Yoav Paas

Front Mol Neurosci. 2017; 10: 92. Published online 2017 Apr 6. doi: 10.3389/fnmol.2017.00092

PMCID: 

PMC5382172

Article PubReader PDF–3.0MCitation

Trapping of ivermectin by a pentameric ligand-gated ion channel upon open-to-closed isomerization

Nurit Degani-Katzav, Moshe Klein, Moran Har-Even, Revital Gortler, Ruthi Tobi, Yoav Paas

Sci Rep. 2017; 7: 42481. Published online 2017 Feb 20. doi: 10.1038/srep42481

PMCID: 

PMC5317004

Article PubReader PDF–2.2MCitation

Honoring antiparasitics: The 2015 Nobel Prize in Physiology or Medicine

Wei-June Chen

Biomed J. 2016 Apr; 39(2): 93–97. Published online 2016 Jun 6. doi: 10.1016/j.bj.2016.04.002

PMCID: 

PMC6139675

Article PubReader PDF–366KCitation

Does Increasing Treatment Frequency Address Suboptimal Responses to Ivermectin for the Control and Elimination of River Blindness?

Kwadwo K. Frempong, Martin Walker, Robert A. Cheke, Edward Jenner Tetevi, Ernest Tawiah Gyan, Ebenezer O. Owusu, Michael D. Wilson, Daniel A. Boakye, Mark J. Taylor, Nana-Kwadwo Biritwum, Mike Osei-Atweneboana, María-Gloria Basáñez

Clin Infect Dis. 2016 Jun 1; 62(11): 1338–1347. Published online 2016 Mar 21. doi: 10.1093/cid/ciw144

PMCID: 

PMC4872292

Article PubReader PDF–949KCitation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043740/citedby/