Ivermectin is probably the most renowned antiparasitic molecule, due to its broad spectrum of activity and overall safety profile, which have made it a widely used drug in both veterinary and human medicine. It was discovered in the late 1970s thanks to a collaboration between the Kitasato Institute in Japan and Merck, Sharpe and Dohme research laboratories in the USA. At that time, Dr Satoshi Ōmura, a microbiologist at Kitasato Institute, in Minato, Tokyo, used to collect thousands of soil samples across Japan and screen them in vitro for their antimicrobial activity. More than 10,000 km away, his collaborator at Merck Research Labs, New Jersey, Dr William Campbell, would further test the most promising samples against parasitic worms from livestock. Eventually, one culture, obtained from a soil sample collected in the vicinity of a golf course in Kawana, Shizuoka Prefecture (approximately 80 miles southwest of Tokyo), displayed an outstanding potency. The bacterium isolated therein was a novel species, named as Streptomyces avermitilis. The characterised active ingredient was called “avermectin” to indicate the worm-free, ‘averminous’ conditions that it yielded. The compound was later on chemically modified into its ‘dihydro derivative’ “ivermectin” (i.e. “22,23-dihydroavermectin B”), so to enhance its activity and safety profile. Strikingly, despite numerous efforts, S. avermitilis remains the only source of avermectin known so far1, through which ivermectin is obtained ‘semi-synthetically’ [1-3].
Such a discovery warranted, more than thirty years later, the 2015 Nobel Prize in Physiology or Medicine, awarded, for one half, to Dr Ōmura and Dr Campbell, “for their discoveries concerning a novel therapy against infections caused by roundworm parasites” and, for the other half, to Dr Tu Youyou “for her discoveries concerning a novel therapy against Malaria” (i.e. artemisinin) .
Ivermectin was commercialised for the first time as a product for veterinary use in 1981, providing the world (and the market!) with the first example of an ‘endectocidal’ antiparasitic, able to control a wide range of internal and external parasites, including numerous genera of nematodes and arthropods. Veterinary uses, encompassing livestock and companion animals, include the control of endoparasites such as gastrointestinal nematodes and heartworms, and ectoparasites such as mites, boophilid ticks, lice and even hornflies. Ivermectin is also used in aquaculture to treat fish infestations by ectoparasitic copepods . By the late 1980s, ivermectin was the top-selling veterinary product in the world, with sales surpassing 1 billion USD/year for more than 20 years [1,3]. Ivermectin’s reputation of ‘wonder drug’ is however also attributable to its crucial role in improving human health and well-being especially in areas of the developing world, affected by neglected tropical diseases (NTDs). Uses for human medicine include indeed the control of “river blindness” (i.e. onchocerciasis), “elephantiasis” (i.e. lymphatic filariasis, LF), infections by certain soil-transmitted helminths (e.g. Ascaris lumbricoides and Strongyloides stercoralis) and scabies . In particular, ivermectin represents the mainstay of two global campaigns aiming at the elimination of onchocerciasis and LF, by the means of Mass Drug Administration (MDA), made possible through donations of the compound (produced under the brand name Mectizan®) by Merck & Co., Inc. (for LF, ivermectin is administered in combination with the anthelmintic albendazole, donated by GlaxoSmithKline, GSK) . Being essentially effective against juvenile rather than adult stages of the parasites, numerous years of MDA are needed in order to eliminate onchocerciasis or filariasis from a given territory. Initiated in 1987, the “Mectizan® Donation Program” reaches more than 300 million people/year, and has so far allowed for the treatment of more than 2.7 billion individuals. By doing so, four countries in the Americas (i.e. Colombia, Ecuador, Guatemala, and Mexico) have eliminated river blindness, and one country in Africa (i.e. Togo) has eliminated LF . Other African countries have also made great strides towards the elimination of the two diseases, although delays due to the ongoing COVID-19 pandemic need to be considered8. In addition to health-related outcomes, ivermectin-based MDAs have also generated tangible socio-economic benefits in treated communities [9,10]. Due to these extensive uses, with time, resistances against this drug and several other compounds from the same chemical class of macrocyclic lactones (MLs), have emerged in several parasites of veterinary and medical importance. This has triggered copious research efforts in pursuit of alternative efficacious options. While some valuable alternatives have been discovered over the years to control some gastrointestinal nematodes and external parasites in several livestock species, the broad-spectrum of activity of ivermectin and more in general MLs remains still to a great extent irreplaceable, especially for human use.
In more recent times, ivermectin has started being evaluated for its capacity to control malaria by reducing the fitness of mosquitoes that feed on treated humans or livestock (e.g. cattle) [11-13]. Results obtained so far have shown good potential, although ivermectin alone may not suffice to eradicate malaria from endemic areas . Interestingly, other effects beyond parasiticidal activity have also been documented, including regulation of glucose and cholesterol concentration in diabetic mice, suppression of malignant cell proliferation in various cancers3, inhibition of replication of RNA viruses such as Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, Chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome and even human immunodeficiency virus type 1 . The anti-viral efficacy of the drug may be due to some of the intracellular events it causes (i.e. inhibition of the importin α/β receptor, which is responsible for transmitting viral proteins into the host cell nucleus) . Recently, ivermectin has also been evaluated for the control of COVID-19 infection, showing to be able to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)’s in vitro replication14. A number of clinical trials and observational studies have been carried out in this respect, with some concluding that ivermectin may help towards an earlier clearance of SARS-CoV-2 . Caution is however needed when faced with these findings, given the limitations of these studies, including small sample sizes, potentially high (thus unsafe) dosing regimens and use of concomitant medications, amongst others. Accordingly, the European Medicine Agency (EMA) and the US Food and Drug Administration (FDA) have recently advised against the use of ivermectin for the prevention or treatment of COVID-19 [17, 18].
On the whole, while established or spreading resistances in some nematodes and acarians may be hindering its future use for certain indications, the valuable contribution made by ivermectin to the history of humankind, first and foremost as an anti-parasitic drug, is still in the making. Forty years later, the discovery of ivermectin can be regarded as a ‘revolutionary’ event in the field of Global Health not only for its unprecedent findings and the beneficial effects it has brought to humanity thus far, but also for the innovative framework within which it occurred at that time: a public-private partnership. With time, this type of initiatives, of which the Japanese government is a strong backer , have proven to be an instrumental, besides necessary, tool in the global fight against NTDs. Because yes, parasites matter…and so do antiparasitic drugs.
This post was taken from the second issue of the feature ‘Because Parasites Matter – Stories of parasitism in a globalised world’, published on the April 2021 Newsletter of the World Association for the Advancement of Veterinary Parasitology (WAAVP).
1. Ōmura S & Crump A. The life and times of ivermectin - a success story. Nat Rev Microbiol. 2004; 2: 984–989
2. Crump A & Ōmura S. Ivermectin, ‘Wonder drug’ from Japan: the human use perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011; 87: 13–28
3. Laing R et al. Ivermectin – Old Drug, New Tricks? Trends Parasitol. 2017; 33: 463–472
5. Horsberg TE. Avermectin use in aquaculture. Curr Pharm Biotechnol. 2012; 13: 1095–102
6. Sarukhan A Ivermectin: From Soil to Worms, and Beyond. Barcelona Institute for Global Health. Blog; 21.11.2019
8. Hamley JID et al. What does the COVID-19 pandemic mean for the next decade of onchocerciasis control and elimination? Trans R Soc Trop Med Hyg. 2021; 115: 269–280
9. Turner HC et al. Economic evaluations of onchocerciasis interventions: a systematic review and research needs. Trop Med Int Health. 2019; 24: 788-816
11. Ōmura S & Crump A. Ivermectin and malaria control. Malar J. 2017; 16: 172
13. Slater HC. Ivermectin as a novel complementary malaria control tool to reduce incidence and prevalence: a modelling study. Lancet Infect Dis. 2020; 20: 498–508
14. Heidary F & Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot (Tokyo). 2020; 73: 593–602
15. Yang SNY et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antivir Res. 2020; 177: 104760
16. Ahmed S et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2021; 103: 214–216
19. Lorusso V. Japan’s involvement in Africa’s development – the story so far and future perspectives. 2019; https://www.africajapan.org/post/japan-s-involvement-in-africa-s-development-the-story-so-far-and-future-perspectives