Questions and Answers about Ivermectin and COVID-19


After April 3rd, the day Caly et al. published their in vitro results about ivermectin and SARS-CoV-2, the research world and the general public was pulled into two extreme and opposite views about this topic. One group called for an early kill of the drug for its use against COVID-19, because the effective concentrations reported by Caly et al. were too high to be achieved in vivo and therefore any effort invested in pursuing this would be a waste and generate a false sense of hope. The other group, following a rightful sense of urgency, launched into promoting widespread use, even without appropriate evidence of efficacy and, more importantly, of safety for this specific use. Both extremes are equally wrong. Here we provide answers to common questions on this topic and show the involvement of ISGlobal researchers in finding answers to some of them.

Questions and Answers about Ivermectin and COVID-19

What is ivermectin? Ivermectin is an anti-parasitic drug developed during the 1970s as a partnership between the Kitasato Institute in Japan and Merck & Co. The project was led by Satoshi Omura and William Campbell on each side respectively. Given its broad spectrum against internal and external parasites that improved animal health and boosted productivity, ivermectin quickly became a blockbuster drug in the veterinary field. During the 1970s, the world was waging a war against river blindness, also known as onchocerciasis, a disease caused by the Onchocerca volvulus parasite in rural areas that crippled whole communities. Some success had already been achieved thanks to the involvement of the World Bank. But once ivermectin was commercialized, it was noticed that Onchocerca cervicalis, the agent of onchocerciasis in horses, practically disappeared in areas where the new drug was used. The burden of onchocerciasis: children leading blind adults in Africa. [Image: Otis Historical Archives National Museum of Health & Medicine] This lead to accelerated efforts to test ivermectin in humans that ended with the approval of the French regulatory authorities in the early 1980s and was followed by the unprecedented decision by Merck & Co. to donate as much ivermectin as needed, for as long as needed to eradicate river blindness. This gave birth to the Mectizan donation program. This program has distributed more than 3 billion treatments over the last 30 years and contributed to save countless lives throughout this period. The program was later expanded to include Lymphatic filariasis, another debilitating disease caused by filarial worms. Elephantiasis of leg due to filariasis, in Luzon, Philippines. Omura and Campbell were awarded the Nobel prize for physiology or medicine in 2015 for this discovery, an honour shared with Tu Youyou, the Chinese researcher responsible for the discovery of the antimalarial artemisinin. More information on the story and the uses of ivermectin, here. What is ivermectin used for in humans? Here we describe some of the approved uses around the world. 1. In the US, ivermectin is marketed at doses of up to 200 mcg/kg once a year for the following indications:

  • a. Strongyloides stercoralis, an intestinal parasite capable of causing severe systemic disease.

A two-year-old girl with disseminated strongyloidiasis cured with ivermectin (A) before, (B) faecal sample, (C) sputum sample and (D) six weeks after treatment. [Image from Chaccour and Del Pozo, NEJM, 2012]

  • b. Onchocerciasis or river blindness

2. In Europe, ivermectin is also marketed against Lymphatic filariasis and scabies at single doses of up to 400 mcg/kg. 3. In Australia, 3 or more-200 mcg/kg doses within a month are recommended for the treatment of severe crusted scabies. One promising line of work in which ISGlobal researchers have been deeply involved is the use of ivermectin at population level to kill mosquitoes and reduce malaria transmission Any other proven or potential uses? Although not marketed for these indications, ivermectin has partial efficacy against other common intestinal parasites in humans such as Ascaris lumbricoides and Trichuris trichura. It is also sometimes used out of label against ectoparasites like head lice and Tunga penetrans among many other internal or external parasites. One promising line of work in which ISGlobal researchers have been deeply involved is the use of ivermectin at population level to kill mosquitoes that feed on treated humans or animals and reduce malaria transmission. Is ivermectin safe? When used for the current indications, at the currently approved doses, ivermectin is a very safe drug. To date, more than three billion treatments have been distributed in the context of the Mectizan Donation Program alone with an excellent safety profile. Most adverse reactions are mild, transitory and associated with parasite death rather than with the drug itself. Ivermectin targets the glutamate-gated chlorine channels that are only present in invertebrates. Mammals only express a similar channel that could cross react with ivermectin (the GABA-gated chlorine channels), but these are only expressed in the central nervous system and are protected by the blood brain barrier, a system of pumps that keeps potential toxics outside our nervous system. In spite of that, Rebecca Chandlerdescribed a series of 28 cases with severe neurological adverse reactions after ivermectin treatment outside onchocerciasis endemic areas. When used for the current indications, at the currently approved doses, ivermectin is a very safe drug In individuals infected with a high burden (>30.000 mf/ml) of the parasite known as Loa loa, ivermectin treatment can lead to severe encephalopathy and death. This has prevented the administration of ivermectin in several countries of central Africa, where the recent test-and-not-treat strategy may allow for the use of the drug. There is no robust evidence to support the use of ivermectin in children under 15 kg of weight. There is no evidence to support the use of ivermectin during pregnancy. Is ivermectin safe at higher doses than approved? Guzzo et al. conducted a study with escalating doses of ivermectin in which some volunteers safely received doses of up to 2,000 mcg/kg, i.e. ten times the approved dose for onchocerciasis. Although not described by Guzzo, persons receiving ivermectin at doses of 800 mcg/kg or above in other studies have sometimes described transient visual disturbances. Smit et al. safely administered 600 mcg/kg daily for three days. Does ivermectin have anti-viral properties? Yes. Ivermectin has been proven to inhibit the replication of several RNA viruses such as:

  • Dengue

  • Zika

  • Yellow fever

  • West Nile

  • Chikungunya

  • Venezuelan equine encephalitis

  • Semliki Forest virus

  • Sindbis virus

  • Porcine reproductive and respiratory syndrome virus , and recently

  • SARS-CoV-2

Could ivermectin have a role in the treatment or prevention of COVID-19? Perhaps, but the answer is not straightforward. The in vitro experiments by Caly et al. were done by adding ivermectin into a cellular culture infected with the virus on a petri dish. The concentrations shown to reduce the viral replication by 50% and 99% in these experiments were 2.8 and 5 microMolar respectively. To put this into perspective, the maximum concentration achieved in the blood after a single oral dose of 200 mcg/kg (the usual dose for river blindness) is of 40 ng/ml. 2.8 microMolar is the equivalent of 2,450 ng/ml, i.e. 60-fold higher than the maximum concentration after usual doses or 10-fold the maximum concentration observed in the high-dose Guzzo study. Then why bother researching this? COVID-19 is a public health emergency of international concern and there is no specific treatment for it. This fact, together with the excellent safety profile of ivermectin combine to warrant research on its potential use. Additionally, extrapolating directly from a Petri dish into a live organism is not correct. Several factors may contribute to make ivermectin efficacious in vivo at lower doses than those described by Caly et al, here are some of them:

Credited to Carlos Chaccour


 



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