An Excellent Pharmacology Study Published in Nature! Ditching Paxlovid?
I just read an excellent pharmacology paper published in Nature, and it’s about how a cheap old liver drug that could prevent COVID. I haven’t seen this study covered in mainstream media, and I don’t even see my YouTube colleagues covering it, so I am taking the first jab on this one. Let’s get started.
FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
https://www.nature.com/articles/s41586-022-05594-0
First, we are not here to talk about some of the other controversial alternative COVID therapy. (I want to tell you about a paper that is so thoroughly and nicely done to examine the hypothesis and validate the potential mechanism of how this cheap drug could be the key to preventing COVID,) using cell, animal, and human lungs and epidemiology data to prove their points.
This cheap drug is called Actigall, or ursodiol, commonly known as ursodeoxycholic acid. This is an off-patent drug approved to treat primary biliary cholangitis is a chronic disease in which the bile ducts in your liver are slowly destroyed.
This drug compound was initially found in bear bile but has been produced synthetically since the 1950s.
I am fascinated about the origin of this drug because, for hundreds of years, bear bile juice was used in Ancient China to treat various liver and gallbladder conditions. I remember growing up reading ancient time novels where martial artists would carry bear bile juice as an antidote.
Though I must emphasize that it is totally unethical to harvest bear bile juice for any reason in today’s world. That’s why we now made the ursodiol compound in the lab.
Back to the study. This study began with a good hypothesis. The authors knew that SARS-CoV-2 uses the ACE2 receptor on the cell surface to gain entry and open the doorway to infection. This mechanism is conserved and has not changed in all the variants since the original strain.
Vaccine-induced, infection-induced, and monoclonal antibodies work by binding to the spike proteins to prevent them from attaching to ACE2. But what if we could get rid of ACE2, or the door, so the virus wouldn’t be able to find a way in?
It turned out that a transcriptional factor known as the farnesoid X receptor (FXR) regulates the expression of ACE2 receptors. If there is a way to reduce FXR, then ACE2 expression should be reduced.
Luckily, we have an FDA-approved drug, ursodiol, that can decrease the level of FXR and, therefore, the level of ACE2 in cells.
Now the question is how did the researchers test to see if ursodiol can prevent viral infection by lowering the number of doors that allow viral entry?
First, they started with test tubes and cell experiments. They showed that when the cells were treated with ursodiol at a concentration similar to what humans achieve in their blood after standard dosing were less likely to be infected by the SARS-CoV-2. The dose is the key here. They used a realistic dose that is translatable to clinical use, not some random high dose that will never be able to achieve.
This graph stained the spike protein with red, and you can see that when FXR is inhibited by ursodiol, there is a lot less spike protein binding to the cells.
Not bad. But cells are not human. So they moved up the ladder to animal studies using mice and Syrian golden hamsters. They didn’t randomly choose these little furry animals. Mice and Syrian gold hamsters are quite easily infected by human COVID and have been used in many other COVID-related studies.
This is the animal experiment setup.
There were two groups. The uninfected mice red group was treated with the control vehicle; similarly, the uninfected mice in the blue group were treated with ursodiol. Then they put a COVID-infected mouse into each box. They saw that the mice treated with ursodiol were less likely to become infected, and they also had a lowered level of ACE2 in their nasal passages.
Pretty good! But mice are not little humans. So let’s move up the level again, human lung tissue. (a meme?)
The research team used perfused human lungs that had been declined for transplantation. These lungs were perfused with a special nutrient liquid to keep them alive and were also mechanically ventilated.
One lung was treated with ursodiol, and the other was a control.
They showed that ACE2 levels decreased in the ursodiol-treated lung. After sample tissues from both lungs were exposed to the virus, the lung tissue with ursodiol had lower levels of viral infection.
So far, everything has panned out and supported their hypothesis. A regular paper would have stopped here. But this one was published in the top-tier journal Nature, so there was more to the story.
They recruited eight human volunteers to take ursodiol for five days, and they saw ACE2 levels in the nasal passages went down over the course of treatment. They also reconfirmed their result using a proteomics database containing several hundred people who had received ursodiol for clinical reasons. Ursodiol-treated people had lower levels of ACE2.
Finally, they looked at an epidemiological dataset with information on over 1000 patients with liver disease who had contracted COVID-19. Thirty-one of them had been receiving ursodiol. After adjustment for baseline differences, those who received ursodiol were less likely to be hospitalized, require an ICU, or die.
Let’s take a break here. I am so impressed by this paper. This is how a pre-clinical drug repurposing study should be done. They started with a well-defined hypothesis and carefully tested it step by step. Every step provided evidence to reinforce the central theme. This study has really paved the way for clinical trials.
Now, let’s come back to the real world. Is that going to change how the officials’ COVID treatment and prevention recommendations anytime soon?
No. We are not in March 2020 anymore. Now there are stakeholders with commercial interests in treatments, such as Paxlovid. Considering the US government is paying Pfizer more than $500 per course of Paxlovid treatment. When Paxlovid goes to the private market in 2023, it’s likely to be two to three times more expensive without insurance. That’s a lot of money.
The truth is that a cheap generic drug like ursodiol will face tremendous pushback from big pharma.
We are pretty sure COVID is not going away, so it is not difficult to get patients to do large, randomized, placebo-controlled trials to study ursodiol’s effect in treating or preventing COVID. Hopefully, we will see that from academic researchers in the near future.
Basically, we will all have to live with COVID for a very long time, if not forever, so I firmly believe the more inexpensive, safe, and effective options we have, the better for everyone on Earth.
