Kyle: Dr. Seheult, working in the ICU, I know you've been following any potential treatment for COVID-19 very closely throughout the pandemic, and you've featured a number of potentially promising treatments in your COVID-19 update videos. And I want to ask your thoughts on this idea that, you know, viable treatments currently exist or viable options exist if one were to get COVID-19 or even potentially to prevent them from getting COVID-19, and therefore they don't need the vaccine because they can just treat it effectively if they get it. What are your thoughts on that?

Dr. Seheult: Yeah. So that's a very interesting philosophy. I follow the philosophy of the Swiss cheese model. Let me explain what that is a little bit. Imagine you've got a block of Swiss cheese, and you've sliced it up all throughout. And if you were to pull out one of those slices, you would see that there may be some Swiss cheese holes in there, and each slice would have the holes in different places. Maybe some slices would have more holes than other slices. Maybe some slices would have very little holes. Maybe others have a lot of holes. But the bottom line is, is that the more slices of Swiss cheese you put in there, the less likely you're going to be able to find a hole that's going to get through all of those slices. And that's kind of the general principle here that we see with the Swiss cheese model of making sure that we have the best protection we have to avoid the outcomes that we don't want to have. Let me put it in a different perspective. In the operating room, we want to make sure that we have no post-operative infections, and we have a lot of layers that we put into that. For instance, the surgeon wears a mask. They sterilize the instruments. They put a solution, a sterilizing solution over the area of the skin that they're going to make the incision. I mean, this goes on and on, positive pressure ventilation in the room, a scrub nurse, adjusting the humidity in the room just right, adjusting the temperature in the room just right. So we don't say that because sterilizing the equipment works, then therefore the mask doesn't work, or say the fact that we have to put sterilization solution on the skin that therefore we don't have to humidify the room. That's foreign to medical thinking. I mean, if we even think about it in the general practice, right, we do crash tests on vehicles, not because we don't think seat belts work. We don't put airbags into vehicles because we don't think crashed...I mean, what we're doing is we're doing multiple layers because the more layers we have, the better protection we're going to have in the end to avoid the undesired outcome at the end. So, to hear this about saying that people are getting vaccinated, but because we're making everyone wear masks, that must mean that the vaccines don't work. Completely, I'm lost on that. That's not the way we think in medicine. We try to avoid these things. And so the Swiss cheese model is how we think about this.

So one of the things that's come up is the idea of ivermectin. Ivermectin is this medication that was initially studied. This came out in June of 2020. And what they found was that in high enough concentrations in vitro in a test tube, when they went to something called 5 micromolar concentration, they were able to completely shut down and reduce by about 5,000-fold the ability of the SARS-CoV-2 virus to reproduce. And so obviously, there was a lot of excitement because perhaps we might be able to use a repurposed medication like ivermectin, which has been around for years and is used as an anti-parasitic or anthelmintic medication, especially in South America and Africa. Perhaps this could be used to treat COVID-19. And so this paper, which was an in vitro paper looking at 5 micromolar concentration that was required to shut down, was one of the things that were looked at. The problem was is that when you look at the actual dosing of ivermectin in a human being, you only get about 0.28 micromolar. So that's a number of orders of magnitude, if you will, reduced than the concentration that you would need to have in the cell to get that. And so this paper here that was published in the "British Journal of Clinical Pharmacology" said that "The free plasma concentration of ivermectin would need to be 250 times lower," was actually 250 times lower than the concentration required to reduce viral replication of SARS-CoV-2 in vitro. And so that was one of the things. But again, this is all in vitro, and so we look at actual randomized controlled data and meta-analyses. And there was a meta-analysis that came out in June of 2021 titled "Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis to Inform Clinical Guidelines." And what they did was they looked at a number of different studies, up to 25 different studies that were...some of them were randomized, some of them were not as well randomized. Some of them had bias. And they analyzed all of those things, and they came up with the conclusion that there was moderate certainty of evidence that there was a reduction in death compared with no ivermectin. But the rest of the conclusions had a very low certainty evidence. Now, this meta-analysis included a randomized controlled trial that was later retracted because there was basically fraud going on in the study. Although that hasn't been fully investigated yet, but it seems as though there were some problems in that study. The authors of the meta-analysis say that it wouldn't have changed the overall conclusion, but you can kind of see that there are some questions. And a lot of these studies were done in patients that were in basically outside of the United States. And why would that be an issue? If you think about this, ivermectin is a medication that kills off parasites. And if you look at some of the data, for instance, in Egypt, and in the Middle East, South America, the amount of clinically silent parasitic infections in the population approaches in some studies 50% to 60%. So you can imagine, if you take these patients who then come down with COVID-19, put them in the hospital, and apply to them large doses of dexamethasone, which is an immunosuppressant, it's possible...we don't know for sure, but it's possible that some of these parasitic infections may be coming less silent and becoming activated with the suppression of the immune system. And so it makes sense that in those types of situations, that adding ivermectin may be beneficial, not because it's helping out COVID-19 specifically, but because it's suppressing these concomitant infections that are going on. That is a potential possibility.

And so, if you're asking about whether or not ivermectin should be used in the United States, what you really need is randomized controlled trials in the United States, looking at the United States population. And right now I'm happy to say that there are a number of studies that are undergoing, not only in the United States, specifically at Temple University in Philadelphia, but also there's a trial data that's looking at McMaster University and also in Brazil called the Together Trial. And what they've done is they've actually made this platform where they can rapidly assess the efficacy of repurposed medication. So things like hydroxychloroquine was looked at. That didn't find any improvements, so they stopped that study. They looked at lopinavir-ritonavir, and they stopped that study because there wasn't improvement. They stopped the metformin study because there wasn't improvement. But there are two medications that they're currently looking at. They're looking at the ivermectin single dose to see if that is causing any improvements. They've now gone to three doses to see whether or not they are. There is some evidence that they're seeing some signal that may be appropriate, but the one that they're noticing actually has an even better signal that they're studying more is fluvoxamine, which is an antidepressant medication. It has some claims that it may be an anti-inflammatory medication, antioxidant. The point is, is that we should be looking at these medications. It should be done in a randomized controlled trial under a specific study platform, and we shouldn't be writing these things off. So, the question is, is whether or not we should be requiring the high level of evidence that we normally would have in a pandemic or not. And I think that's a reasonable question to have. But these things do need to be studied. They do need to be looked at. But realize, at the end of the day, this is just one slice in the large slices of cheese. We can't all depend on that one slice because every slice has holes in it, and the more slices we have, the better. And so as part of my philosophy, if there is something that works, great, that's a slice, but it doesn't mean that we don't do the other things that are important because nothing is 100%.