Mechanism and Application of Ivermectin in Antiviral Therapy

What is Ivermectin?

Ivermectin is a broad-spectrum antiparasitic medication which has been used for several parasitic infections. Developed first in the 1970s, it was praised for treating parasitic disease, such as river blindness (onchocerciasis), lymphatic filariasis and scabies. It's part of a group of drugs called avermectins, made from the bacterium Streptomyces avermitilis. During the years, ivermectin proved to be effective in other parasitic diseases and even in veterinary medicine in treating animals with parasitic infections.

Ivermectin was originally used to treat parasitic infections, but its use in other fields, such as antiviral treatment – has expanded over the past few years. Medicinal scientists studied ivermectin for its role in viral infection, particularly in emerging illnesses such as COVID-19. That enthusiasm for ivermectin's antiviral activity has led to controversy and research into how it works and does so effectively against a variety of viruses.

Fig.1 The molecular structure of avermectin. (Heidary, Fatemeh, and Reza Gharebaghi., 2020)

Table.1 Ivermectin related products at BOC Sciences.

Ivermectin Mechanism of Action

The way Ivermectin acts is largely a matter of interrupting the activity of parasites. When acting as an antiparasitic agent, ivermectin binds to channels of ions in the nervous and muscle cells of parasites. The parasite's nervous system requires these ion channels (glutamate-gated chloride channels). When ivermectin attaches to these channels, the chloride ions flow into the cells, hyperpolarizing and paralyzing the parasite. The parasite then freezes up, before it's killed by the host's immune system.

But ivermectin's potential antiviral effect is slightly different from its antiparasitic effects. It turns out that ivermectin can also bind to virus components, modulating how viruses replicate and cohere. This is ivermectin's antiviral activity, interacting with proteins on host cells involved in virus replication. In particular, ivermectin has been found to attach to importin /1, a protein complex that helps viral proteins to get into the nuclear environment. Thru the blocking of this process, ivermectin blocks the virus from reproducing in host cells. It seems to do this so the virus won't take over the host cell's machinery to copy its genome and form new viral particles.

Not only does ivermectin exert a direct antiviral effect, it also suppresses the host's immune system. And it's also been proven anti-inflammatory, perhaps alleviating the cytokine storm and inflammation seen in viral infections. These effects, and the fact that ivermectin inhibits replication of viruses, makes it a candidate for antiviral treatment, though there's still more to learn about its potential. 

How Ivermectin Works?

Ivermectin works through a multi-faceted approach, acting on both the virus and the host cell to limit viral replication and reduce the severity of infection. Its primary mechanism involves the inhibition of viral replication by interfering with the transport of viral proteins into the host cell nucleus. By blocking the import of viral proteins, ivermectin essentially prevents the virus from establishing a successful infection within the host.

Additionally, ivermectin has been shown to affect host cell signaling pathways. It can inhibit the activation of certain proteins that are involved in the inflammatory response. This is particularly relevant in the context of viral infections like SARS-CoV, where an overactive immune response, such as a cytokine storm, can lead to tissue damage and increased disease severity. By modulating immune responses, ivermectin helps mitigate excessive inflammation, which can worsen the clinical outcomes of viral infections.

Research has also indicated that ivermectin may affect the viral envelope and inhibit the fusion of the virus with host cell membranes. This is an important step in the viral life cycle, as it allows the virus to enter the host cell and begin replicating. By preventing fusion, ivermectin can stop the virus from entering host cells in the first place, thus halting the infection before it has a chance to spread.

What is Ivermectin Used For?

Ivermectin's primary clinical use has been in treating parasitic infections. It is widely used to treat conditions such as:

1. Onchocerciasis (River Blindness): Ivermectin has been effective in treating river blindness, a disease caused by Onchocerca volvulus, a parasitic worm. The drug helps eliminate the microfilariae (larvae) of the parasite, which are responsible for the disease's symptoms.
2. Lymphatic Filariasis: Ivermectin is also used in the treatment of lymphatic filariasis, a condition caused by parasitic worms that affect the lymphatic system. The drug helps to eliminate the microfilariae of these worms.
3. Scabies: Ivermectin is used to treat scabies, a skin condition caused by an infestation of the Sarcoptes scabiei mite. The drug targets the mites and eliminates them from the skin.
4. Strongyloidiasis: This is an infection caused by the parasitic roundworm Strongyloides stercoralis. Ivermectin is used to treat this condition by killing the parasites in the intestines.
5. Other Parasitic Infections: Ivermectin is also used for other parasitic conditions, such as head lice, intestinal worms, and various ectoparasites.

In recent years, however, ivermectin has gained attention for its potential use against viral infections. Research has focused on its ability to inhibit the replication of several viruses, making it a candidate for treatment in viral diseases such as COVID-19 and the flu.

Ivermectin for COVID

The use of ivermectin for COVID-19 has been one of the most controversial and heavily debated topics in the field of antiviral therapy. Early studies and laboratory experiments suggested that ivermectin could inhibit the replication of SARS-CoV-2, the virus responsible for COVID-19. These findings sparked global interest, particularly in the context of the ongoing pandemic and the urgent need for effective treatments.

Initial in vitro studies demonstrated that ivermectin could reduce the viral load of SARS-CoV-2 by preventing the virus from entering host cells and interfering with viral replication. However, these studies were conducted in laboratory settings with doses much higher than those typically used in humans, raising questions about the practical applicability of ivermectin as a treatment for COVID-19.

Subsequent clinical studies have produced mixed results. Some studies reported that ivermectin could reduce the severity and duration of COVID-19 symptoms, while others found no significant benefit. The World Health Organization (WHO) and the U.S. Food and Drug Administration (FDA) have both issued statements urging caution, recommending that ivermectin should not be used for COVID-19 outside of clinical trials. The safety and efficacy of ivermectin for treating COVID-19 have not been conclusively established, and more rigorous clinical trials are needed to determine its true potential.

Table.2 SARS-CoV related products at BOC Sciences.

Ivermectin for Flu

In addition to its use for parasitic infections, ivermectin has been investigated for its potential effectiveness against other viral infections, including influenza. Influenza viruses, like SARS-CoV-2, rely on host cell machinery to replicate and spread throughout the body. Studies have shown that ivermectin can inhibit the replication of influenza viruses in vitro, suggesting that it may have potential as a treatment for the flu.

Similar to its action against SARS-CoV-2, ivermectin's antiviral effect on the flu virus appears to be related to its ability to disrupt the nuclear import of viral proteins, preventing the virus from replicating inside host cells. Additionally, ivermectin may help modulate the host's immune response, reducing inflammation and potentially alleviating some of the symptoms associated with influenza.

However, while early studies are promising, more research is needed to determine whether ivermectin is an effective and safe treatment for the flu. Current antiviral treatments for influenza, such as oseltamivir (Tamiflu), are more widely accepted and have demonstrated proven efficacy in clinical settings.

Table.3 Influenza virus related products at BOC Sciences.

Summary

Ivermectin is a well-established antiparasitic drug with broad-spectrum activity against a range of parasitic infections. Its potential application in antiviral therapy, particularly for conditions like COVID-19 and influenza, has generated significant interest in recent years. The mechanisms by which ivermectin exerts its antiviral effects involve disrupting viral replication, inhibiting viral entry, and modulating the host's immune response. While early laboratory studies have shown promise, the clinical evidence for its effectiveness against viral infections remains mixed.

The use of ivermectin as a treatment option remains controversial, with mixed results from clinical trials and concerns regarding its safety and efficacy. Ongoing research and well-controlled clinical trials are needed to fully understand the role ivermectin can play in antiviral therapy.

References

• Laing, Roz, et al., Ivermectin–old drug, new tricks? Trends in parasitology 33.6 (2017): 463-472.
• Heidary, Fatemeh, and Reza Gharebaghi. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. The Journal of antibiotics 73.9 (2020): 593-602.

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