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Friday, September 03, 2021 | Science

Ivermectin and COVID-19

Ivermectin has strong antiviral activity in vitro. It is neither a miracle drug nor a quack cure

P artly because the news media have started attacking ivermectin, many people have concluded that it must be highly effective—a miracle treatment against COVID. But there's a vast amount of misinformation on the Internet and in the press on this drug.

Ivermectin is not just, as the media claim, a horse deworming drug. Nor is ivermectin particularly toxic. It works against parasites by binding to and opening the GABA-gated chloride channels and glutamate-gated chloride channels in the motor synapses of nematodes, and in the muscle and nerves of insects and crustaceans. This causes influx of chloride ions, causing hyperpolarization, paralysis and death.

Humans, of course, also have GABA and glutamate gated chloride channels in the brain. However, ivermectin does not reach the brain effectively in adult humans because it is rapidly expelled from the brain by a protein called P-glycoprotein. Infants have lower levels of P-gp, so ivermectin is not recommended for children or for pregnant women, and it was classified as a Category C teratogen with repeated dosing, though there are few studies on this.

Ivermectin has a macrocyclic lactone structure similar to paclitaxel. It is actually a mixture of two compounds (80% 22,23-dihydroavermectin B1a and 20% 22,23-dihydroavermectin B1b).

It is thought that other drugs such as azithromycin and albendazole increase the concentration of ivermectin in the lung, where it needs to go to be effective against COVID-19. Vitamin C interferes with it and lowers its blood plasma concentration.

Safety and antiviral activity

Ivermectin has negligible adverse effects and is described in the literature as “extremely safe even at high doses.”

Ivermectin is a broad-spectrum antiviral. It works preferentially on RNA viruses and has in vitro activity against RNA viruses HIV-1, dengue virus, influenza, Venezuelan equine encephalitis virus, and West Nile virus. It has weaker activity against DNA viruses.

Dose-response curve of ivermectin

Dose-response curve of ivermectin (redrawn from Caly et al. [3])

There are many theories about its mechanism. One theory is it acts by binding to and inhibiting a protein called importin alpha/beta1, which is a protein that imports proteins from the cytoplasm, carrying them through the nuclear pore and into the nucleus. Even though SARS-CoV-2 replicates in the cytosol, its nucleocapsid protein still travels to the nucleus, where it interferes with the host cell's Type-I interferon antiviral response.[6,7] So, in the case of SARS-CoV-2, ivermectin's task would be to block the transport of the nucleocapsid protein to the nucleus and preserve the interferon response.

Some researchers claim that ivermectin inhibits RNA-dependent RNA polymerase [1], inhibiting virus replication. Another report [2] speculates that it could work as an ionophore, but provides no evidence and the chemistry proposed is not convincing. It's worth mentioning that hydroxychloroquine is also not believed to act therapeutically as an ionophore, despite popular claims to the contrary.

Another theory is that ivermectin binds to the carbohydrates on the spike protein and shields it from binding to the ACE2 receptor and CD147, the latter being a protein said to be responsible for COVID's vascular effects. Of course, it's possible that ivermectin could do all these things.

Does it work?

As with any drug, whether it works in patients is determined by its IC50, which is the concentration that inhibits its target by 50%. Ivermectin's IC50 is in the 1–4 μM range, which is considered low affinity.

Why is knowing the drug mechanism so important?

I've seen several clinical drug trials fail because the drug was rushed to the clinic before the clinician knew how the drug was supposed to work.

Unless you know what concentration to shoot for, deciding on the dosage and dosing schedule relies mainly on guesswork. Giving too much or too little can cause a study to fail for obvious reasons. But giving it too early, too late, or in conjunction with other treatments can also cause a useful drug to fail.

Aspirin is a good example. Aspirin irreversibly inhibits cyclooxygenase, an enzyme that creates a pain/inflammation molecule called PGE2. To inhibit platelet aggregation, you take several low doses over a long period. To cure a headache, you take a single larger dose during the headache. Doing it the other way around just creates problems.

Caly et al. [3] found that 2 μM ivermectin reduces SARS-CoV-2 level in cultured Vero-hSLAM cells by 5000×. There is thus general agreement that if this concentration could be achieved in lung tissue without producing toxicity, ivermectin would be effective against COVID-19. Whether that is possible is the main point of contention.

A typical oral dose for onchocerciasis is 150 μg/kg. For scabies the standard treatment is a single dose of 200 μg/kg. At this dose, ivermectin reaches a maximum concentration (Cmax) of 43 ng/ml [4]. This is equivalent to 0.05 μM, which is 60 times less than the concentration needed for antiviral activity (2600 ng/ml, or 3 μM). Even a dose of 120 mg produces only 247 ng/ml, which is still ten times too low for an effect.[5] To achieve an effective antiviral concentration, 12,000 μg/kg would be needed, which is uncom­fort­ably close to the LD50 dose of 24,000 μg/kg in monkeys. It's not beyond the realm of possi­bil­ity that ivermectin could work in vivo at lower concentrations than in cell culture. For instance, it might be metabolized in liver to a more potent derivative, though there's no evidence of this. It should also be noted that lung tissue concentrations are are likely to be much lower than the concentration in blood.

This puzzle about dosage has to be resolved before scientists can accept any positive clinical results. If some clinician claimed that ivermectin worked at concentrations too low for it to be effective, it would mean that something had likely gone wrong in the study.

Nonetheless, clinical trials are underway. The results so far are mixed. As with HCQ, there's been too much low quality research on ivermectin to know for sure. Even meta-analysis has not helped, as some studies claim a huge effect and others find no effect. It is unfair to claim that scientists are biased against ivermectin. In one meta-analysis, researchers found that the evidence so far is simply too unreliable to draw any conclusion.

What is really needed, and as Merck is doing, is for drug companies to use ivermectin as a starting point for drug development and increase its potency. Now that the FDA has shown it will approve just about anything, given enough outside pressure, it is a good day to be a drug company. Being a patient, as always, sucks.

1 Parvez MSA, Karim MA, Hasan M, Jaman J, Karim Z, Tahsin T, Hasan MN, Hosen MJ. Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach. Int J Biol Macromol. 2020 Nov 15;163:1787-1797. doi: 10.1016/j.ijbiomac.2020.09.098. PMID: 32950529; PMCID: PMC7495146.

2 Rizzo E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(7):1153-1156. doi:10.1007/s00210-020-01902-5

3 Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. PMID: 32251768; PMCID: PMC7129059.

4 Eberhard ML, Hightower AW, McNeeley DF, Lammie PJ. Long-term suppression of microfilaraemia following ivermectin treatment. Trans R Soc Trop Med Hyg. 1992;86:287–288.

5 Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42:1122–1133

6 Wulan WN, Heydet D, Walker EJ, Gahan ME, Ghildyal R. Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses. Front Microbiol. 2015 Jun 2;6:553. doi: 10.3389/fmicb.2015.00553. PMID: 26082769; PMCID: PMC4451415.

7 Li JY, Liao CH, Wang Q, Tan YJ, Luo R, Qiu Y, Ge XY. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res. 2020 Sep;286:198074. doi: 10.1016/j.virusres.2020.198074. PMID: 32589897; PMCID: PMC7309931.

sep 03 2021, 6:30 am. updated sep 04 2021, and sep 14 2021

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