I've been trying to understand the ivermectin controversy (especially in view of NIH's recent [partial] change of heart). Based on one of the more recent papers (Jans & Wagstaff) which proposes ivermectin as an antiviral, there are 70+ clinical trials of ivermectin for Covid-19 ongoing.

But what strikes me as odd is that besides a few in vitro research papers mentioned, there's almost a complete dearth of mentions/citations of animal models where ivermectin was successfully used as an antiviral. Contrast this with almost any antiviral for which there are dozens of such animal studies, e.g. for a nearly random example see oseltamivir in this WHO review. So, for ivermectin, as an antiviral, it seems a jump straight from "the test tube" to people.... which seem very unusual, especially since Jans & Wagstaff acknowledge that dosing something as an antiviral is not trivial.

As in many other disciplines, one of the biggest challenges in antiviral research is to transition from laboratory experiments to preclinical/clinical studies, with the question of dosing in the case of ivermectin for viral infectious indications contentious [...]. It is important, firstly, to stress the obvious in this context: that the antiviral activities of ivermectin documented in Table 2 have been derived from laboratory experiments that largely involve high, generally non-physiological, multiplicities of infection, and cell monolayer cultures, often of cell lines such as Vero cells (African green monkey kidney cells impaired in interferon α/β production) that are not clinically relevant.

(In addition, jwatch mentions the same dosing aspect but citing more clear critiques/concerns from three different papers.)

And then Jans & Wagstaff mention (just) one animal trial:

preclinical studies in a lethal Pseudorabies (PRV) mouse challenge model showed that dosing (0.2 mg/kg) 12 h post-infection protected 50% of mice, which could be increased to 60% through administration of ivermectin at the time of infection.

But maybe this paper is just not revealing the full breadth of animal studies for ivermectin as an antiviral, even though there are a lot more of them?

  • What is a reliable animal model for covid19? How is animal studies have been done on other covid19 therapeutic candiates? I don't think it's fair to not compare it to other covid19 treatment candidates. – Blue Various Feb 15 at 20:07
  • @BlueVarious: there are plenty of animal models for Covid-19. And yeah Covid vaccines have been tested that way too. And continue to be. – Fizz Feb 15 at 21:18
  • @BlueVarious: Besides, the theory is that ivermectin is a broad spectrum anti-viral due to its mechanism of action (at least the one advanced by Jans & Wagstaff); the more direct mechanism envisaged by other don't seem to even have in vitro studies done. – Fizz Feb 15 at 21:18
  • Thanks for the reply. Thanks for the info on the animal studies regarding the vaccine. But I think it's unfair not to compare it with the same antiviral agents. There seem to be many different antiviral candidates, what about them? covid19treatmentguidelines.nih.gov/antiviral-therapy – Blue Various Feb 19 at 14:39
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    The report seems to cite several studies in mouse and hamster models (see PP.5-6) covid19criticalcare.com/wp-content/uploads/2020/11/… – Blue Various Feb 21 at 22:18

First, we should focus on "ivermectin plus covid19 or a virus that mimics covid19. For now, the FDA recognizes ivermectin as an antiviral drug. Therefore, the comparison should be "antiviral drug + covid19 or covid19-mimicking virus".

The FLCCC may have a bit of a bias because they are enthusiastic proponents of ivermectin, but their report has the following description;

Arevalo et al investigated in a murine model infected with a type 2 family RNA coronavirus similar to SARS-CoV-2, (mouse hepatitis virus), the response to 500 mcg/kg of ivermectin vs. placebo (Arevalo et al., 2020). The study included 40 infected mice, with 20 treated with ivermectin, 20 with phosphate buffered saline, and then 16 uninfected control mice that were also given phosphate buffered saline. At day 5, all the mice were euthanized to obtain tissues for examination and viral load assessment. The 20 non-ivermectin treated infected mice all showed severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while in the ivermectin treated mice a much lower viral load was measured (23,192 AU; p<0.05), with only few livers in the ivermectin treated mice showing histopathological damage such that the differences between the livers from the uninfected control mice were not statistically significant.

Dias De Melo and colleagues recently posted the results of a study they did with golden hamsters that were intranasally inoculated with SARS-CoV-2 virus, and at the time of the infection, the animals also received a single subcutaneous injection of ivermectin at a dose of 0.4mg/kg on day 1 (de Melo et al., 2020). Control animals received only the physiologic solution. They found the following among the ivermectin treated hamsters; a dramatic reduction in anosmia (33.3% vs 83.3%, p=.03) which was also sex-dependent in that the male hamsters exhibited a reduction in clinical score while the treated female hamsters failed to show any sign of anosmia. They also found significant reductions in cytokine concentrations in the nasal turbinate’s and lungs of the treated animals despite the lack of apparent differences in viral titers

Based on this statement, the following two papers seem to fit our purpose. However, it should be noted that these are preprints.

Arevalo et al has following description;

However, experimental conditions with SARS-CoV2 are not easily available in research laboratories due to biosecurity reasons, thus having in vivo preclinical data is not always easy.

Isn't this description the answer to your question? If it is clinical research, there is no need to contain infected animals in a laboratory. It must be quite difficult to control a virus that is considered more dangerous than the flu. Also, in the case of influenza, the pharmaceutical companies are probably planning and conducting trials over a long period of time. In contrast, MSD does not seem to be active in the coronary indication of ivermectin.

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