Ivermectin Treatment; Does COVID-19 Attack Hemoglobin (Lecture 52)
Welcome to another MedCram COVID-19 update, and we’re approaching 1.5 million infections confirmed worldwide, and almost eighty-four thousand deaths. One thing I found that’s interesting is that the number of cases in this country is the top in the world, and the total tests that have been done in the world are also the highest in the United States at this point, and that did not used to be the case.
You know, a lot of people are asking “when is this going to end? when is it going to peak?”, and I think one of the best sites for that as we discussed in our update yesterday is covid19.healthdata.org, which looks at projections that have been updated and use a model developed at the University of Washington. The projection model is updated fairly often. There are some countries that are missing notably, Canada is not on this model for some reason.
But as we talked about before with the potential benefits of hydrotherapy and Finland, I wanted to take a look since they did have a modeling for those countries in the Nordic area. And so if we look at, for instance, we can see here that in Norway all of the beds well underneath the threshold that is needed. ICU beds actually exceed the threshold, so they may have an issue there with ICU beds in Norway. And then of course they have invasive ventilators. In terms of deaths per day in a country of about five and a half million people. We are looking at deaths per day currently at around 10 and to go up to as high as maybe even 25 based on this or if the model predicts the worst-case scenario up to 70 deaths per day.
If we go to Sweden, we can see there again. All beds seem to exceed the beds available ICU beds greatly seem to exceed the beds available, I have to see what happens in that situation in terms of deaths per day that is projected to be in 19 days. For instance, and we can see where we are right now. They’re predicting as high as over a hundred maybe even a hundred and twenty deaths per day to as high as 450, until it comes back down here before June. These of course are based on assumptions of isolation.
Now, let’s go to Finland.
All beds well below their ability to take care of them. They might have a little bit of a crunch there in terms of ICU beds and then down here in terms of deaths per day, might be peaking here at the end of April at about six or seven deaths per day, but could be as high as 26 to 27 deaths per day and that will be in about 16 days. In terms of the United States for those who are wondering it looks as though the peak is going to be around April 12 April 13 could be as high as 5,000 deaths per day, but we’ll have to see where we are and where we’re going with this and hopefully by June will see the numbers come down enough, if we continue isolation will be interesting to see by then if we are still doing isolation and what the effects of lifting isolation will be.
Okay. Let’s talk about Ivermectin. Ivermectin is like hydroxychloroquine in that it is an FDA-approved medication that already has a purpose for some other infection, but it’s looking like it might be helpful with covid-19. Ivermectin is usually used for parasites and it has been investigated in other viruses like West Nile Virus and influenza, but now researchers are looking at this for covid-19. To get a better understanding of how this Ivermectin actually works, we’ve got to go back to cellular biology. so this is the sell of course here. .We have the nucleus. We’ve got DNA here in the nucleus and we’ve got a protein here in the nuclear membrane that allows the messenger RNA to come out into the cytoplasm and allows it to be translated into protein. Well, the problem is that the virus when it comes in it also has its version of RNA and of course the ribosomes can’t tell the difference and so they start to translate the messenger RNA from the virus into viral proteins and these viral proteins can have problems they can have unintended consequences and these proteins can come in and go through these proteins that allow the viral proteins to go into the nucleus where they can cause problems. And that could lead to decreased immunity especially against this virus. And some scientists believe that this is actually what’s going on with the coronavirus.
Yes, there’s a specific Target for this transporting in or importing in and cleverly they call this protein the important protein. And there are several different versions of this. There’s an important alpha and there’s also an important beta-1. So otherwise, this is known as imp alpha and imp beta-1. And what Ivermectin does is Ivermectin shuts down this ability to transport in proteins–viral proteins in this case, into the nucleus, which diminishes the ability of the virus to cause harm to the cell. So this article that was published on the 3rd of April, 2020 goes into that data. And the version that I’m showing you here has a link in the description below and it is a journal pre-proof of publication and the summary of the article is although several clinical trials are now underway to test possible therapies. The worldwide response to the covid-19 outbreak has been largely limited to monitoring and containment. We report here that Ivermectin and FDA-approved anti-parasitic previously shown to have broad spectrum antiviral activity in vitro is an inhibitor of the causative virus SARS-CoV-2 with a single addition to the Vero hSLAM cells. Those are the type of cells that they used here in the test tube two hours post infection with SARS-CoV-2 to able to affect a five-thousand-fold reduction in viral RNA at 48 hours. That’s pretty short amount of time, and a large amount. Ivermectin therefore warrants further investigation for possible benefits in humans. And this of course is weighty, because this medication is already being used in humans and has been deemed to be safe enough to be used in humans. So, after giving the cells Ivermectin, they looked at day 0,1, 2 and 3 to see what the relative viral load of RNA was in terms of percent and you can see here over a couple of days. It drops one two, three, four five orders of magnitude in just a 48-hour period so that’s inside the cells the amount of virus inside the cells supernatant is referring to the solution outside the cells and here you can see over a couple of days. We have a one, two, three, four, almost five orders of magnitude drop in the amount of relative viral RNA.
Here, they’re looking at the RNA dependent RNA polymerase Gene, which we talked about a number of weeks ago is the gene that’s coded for by the RNA in the virus. And that is also known as replicase which causes gene replication here. We can see that Ivermectin at specific concentrations completely knocks out that genome and here we see the medication Ivermectin inhibiting this imp-alpha and imp-beta-1 from allowing the coronavirus proteins from going into the nucleus. You see when they go into the nucleus the hypothesis is that there’s an enhanced infection and reduced antiviral response when Ivermectin binds imp Alpha and imp beta 1 it prevents it from binding to the coronavirus protein and importation through that nuclear membrane so that you have infection not enhanced and there is a robust antiviral response that occurs.
So This research is interesting because it does address the issue regarding immunity that we’ve discussed over the last couple of weeks and it also correlates with what I’ve personally seen in the hospital with patients arriving in the emergency room only to decompensate within the next 12 to 24 hours and die which tells me for some of these cases that the only way you’re going to be able to intervene is in those precious hours and days before decompensation this mechanism that we’re seeing here of reducing the immunity reducing the ability to mount an immune response is an important one.
So I’ve gotten a lot of comments recently about the topic of “does the virus cause an inability of the human globin molecule to bind oxygen?” and it seems as though a lot of those concerns are brought up in this article from ChemRXiv, which again is another preprint repository of non peer-reviewed articles not to say that that is bad in general, but just realize that these articles have not been peer-reviewed and the title of this is covid-19 attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit heme metabolism. They looked at the different structures to see what was conserved and they made 3D modeling and they tried to see where this virus could bind elsewhere in the human body and based on this. It seems to attack the One beta chain of hemoglobin and also the porphyrin ring so you need to be able to understand this before you can really evaluate what is going on in this article. So here we have the alveolus and the capillary where blood gas exchange occurs. And this is where you have oxygen that you breathe in the alveolus of course is the air sac where oxygen comes in and diffuses into the capillary into the bloodstream. So, oxygen is here and it is going to diffuse passively across this alveolar membrane into the bloodstream. So here we have plasma. The next thing that happens is that this oxygen is going to dissolve into the plasma and the way we measure that is with something called the partial pressure of oxygen the plasma does not hold a tremendous amount of oxygen it does diffuse and it does dissolve in the plasma, but by far and large the amount of oxygen that can be dissolved in the plasma is just way too small for our organs to really benefit from it. The main way that organs get enough oxygen is with this red blood cell that is filled with hemoglobin. Of course, each human globin molecule is a tetramer meaning for and it can hold four molecules of oxygen, and this really is where the ion? share of oxygen is carried in these bags of hemoglobin. Now hemoglobin also has with it heme that’s where the term hemoglobin comes from and also iron and it’s usually in its iron-2 plus state (Fe2+) as opposed to its iron three-plus state(Fe3+) and that’s what allows the oxygen to bind to it. But the red blood cell holds the Lion’s Share if you will of oxygen and what determines how saturated this hemoglobin molecule is in the red blood cell is determined by something called the hemoglobin binding curve. But you’ve got to understand that that hemoglobin binding curve is simply a function of the partial pressure of oxygen out here. So here we have saturation on the y-axis the partial pressure of oxygen on the x-axis instead of a straight line going up a linear line. Because of cooperativity in the hemoglobin molecule, we actually have something that looks more like this where as the PaO2 goes up. You actually have better and increased binding of oxygen.
Okay, so why do I go through all of this? Why does this even matter? Well, if covid-19 is affecting, as some indicate, the ability of hemoglobin to bind to oxygen, it’s preventing the oxygen from binding to hemoglobin. It’s stripping. I keep hearing this trippingly oxygen stripping the hemoglobin. The problem that we should have is in our saturation because that’s a function of the PaO2. We shouldn’t on the other hand have a problem with oxygen going through initially into the plasma and so there are two things that we can measure–we can measure the saturation. That’s the SpO2. That’s the thing that we measure on your finger. That’s the saturation on the Monitor and we can also measure the pao2. That’s the partial pressure of oxygen that dissolves. Obviously if we have a problem here in the red blood cell that should not necessarily cause a problem here at the membrane and we should see that we might have a normal PaO2 (partial pressure of oxygen), but we would have a low saturation. On the other hand, If this is truly an ARDS issue where there is inflammation and in fact instead of having a nice thin wall, we have a thick hazy wall where it’s very difficult for oxygen to diffuse. Then what we’ll see is a very low PaO2 and as a consequence to that, we will see a low saturation and as it turns out when I have taken care of patients with COVID-19 this is exactly what I am seeing. I’m seeing patients with a low PaO2 and a low saturation, not patients with a low saturation and a normal PaO2.
So, if we go back to the conclusions of this article, it talks about the molecular docking technology where they are looking at the three-dimensional structure of some of these proteins that they’re able to determine, based on the genetics that are evaluated. They go on to say viral proteins would attack the heme portion of the hemoglobin molecule and cause dissociation of iron from the porphyrin and then this would cause less hemoglobin to carry oxygen and carbon dioxide. If this were the case, in my humble opinion terms of clinical manifestations, I would expect initially for the partial pressure of oxygen that is the oxygen dissolved in the plasma to not be affected but only the saturation potentially or even the amount of oxygen delivery to the peripheral tissues that would cause an increase in lactic acidosis, and I’m not seeing at least in the patients that I am seeing an elevated lactic acid frequently the authors here then go on to say that this inability to carry oxygen and release carbon dioxide would cause the lungs to have extreme intense inflammation. It says here due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images.
Now, it’s interesting that they say that, because the more classical interpretation of that is it is the inflammatory action to the virus in those epithelial cells that is causing the ground glass opacification, and not the inability to exchange carbon dioxide and oxygen frequently.
So, this is what we found in terms of the hemoglobin issue. I think a bigger issue one that we’re going to tackle and upcoming update is the question of strategy of ventilation and that’s been a big one in the news terms of doctor Gatineau Knee in Italy and his publication normally these patients with viral pneumonia have low compliance and that is what we typically see in ARDS. There’s some data coming out of Italy that’s talking about high compliance and patients just with hypoxemia, you know, maybe we haven’t seen enough patients with covid-19 or I haven’t seen enough patients with covid-19, but the patients that I am seeing clinically in the hospital are behaving like ARDS patients. Of course, that doesn’t mean that there aren’t those that are not and it may be that there are so many patients that are behaving so differently that we don’t know if we’re going to get a good handle on this anytime soon and we’ll have something more few coming up on the next update and speaking of different clinical presentations. I found this article in the New York Times very interesting, showing that some coronavirus patients are actually coming in with confusion signs and symptoms of stroke and even seizures in other words,they are presenting like encephalitis.
Here’s a patient and in early March in Florida have lost the ability to speak. Patient had jerky movements in his legs and appeared to be having a seizure and when they suspected covid-19 the results came back positive. Here’s another patient in her late 50s with covid-19, was confused, complained of a headache. She could tell the Physicians her name, but little else became less responsive over time. The brain scan showed abnormal swelling and inflammation in several regions with smaller areas where some cells that actually died, and this is known as necrotizing encephalopathy. It’s a rare complication of influenza and other viral infections. But I think because there are so many people coming down with this viral infection, we’re starting to see some of these rare cases more commonly. And then finally I want to talk about this article that was in The Washington Post titled “New Zealand isn’t just flattening the curve. It’s squashing it”. This is the New Zealand prime minister, and she’s talking about what’s going on in New Zealand, they’ve decided to do four weeks of isolation and they’ve been pretty strict about that–even restricting swimming at the beach and hunting in the bushland, as these are considered non-essential activities, despite the fact that they are doing a lot more testing. The number of new cases are shrinking dramatically over there and they are getting a reprieve on the Coronavirus.
And I have to admit when I look at their cases on worldometer, I’m pretty impressed. They have tested over 46,000 people. The total number of cases in the country is only 1200 and the total deaths is one, and only four in critical condition in the entire country.
But there has been a sense of collective purpose. The police phone line for non-emergencies has been overwhelmed with people calling to “dob in” as we say here “reporting others they think are breaching the rules”. The response has been notably a political, the centre-right national party has clearly made a decision not to criticize the government’s response. And in fact to help it .these efforts appear to be paying off. After peaking at 89 on April 2nd the number of new cases down to 67 on Monday and 54 on Tuesday. The vast majority of cases can be linked to international travel making contact tracing relatively easy. And that one person that died was an elderly woman with existing health problems.
Of course one wonders how long that can keep up New Zealand of course is a small island nation and to keep the virus at bay, you would have to make sure that anyone coming into the country is quarantine for two weeks at least or if they’re not you have to wait for the entire pandemic to be over. So where does that leave the United States where that line goes is really up to us, collectively as a nation. We will put the links to this and other sites that we have discussed in the description below. Thanks for joining us.
Questions that may be asked
- Now that Ivermectin has been proved effective for inhibiting SARS-CoV-2, how long does it take for us to see it in clinical trials?
- How is it possible for countries like New Zealand to have such a low level of mortality, as compared to those states with powerful medical resources like the state of NY?
- What is the relationship between PaO2 and SpO2 in COVID19 patients?
- Please explain in detail what ground- glass-like lung images are.