welcome to impact factor, your weekly commentary on new medical research. At Yale Medical School he is Dr. F. Perry Wilson.
As soon as the pandemic began, the search began for drugs that could stave off infection, or at least the worst consequences of infection.
It’s cheap to make, secure, easy to distribute, and ideally already available. The search had a fairy-tale quest-like quality: a society poisoned by COVID will find an antidote somewhere else if we look hard enough.
you know the story There have been some pretty dramatic failures: Hydroxychloroquine, IvermectinThere have been some successes like . Dexamethasone.
I’m not here today to tell you that the antidote has been found.but i want to tell youpaper It lays out the discussion of potential COVID precautions so thoroughly and rigorously, unlike so many that have come before it, that this little drug, ursodeoxycholic acid (UDCA) — You may know it as Actigal. A rare form of liver disease — he could actually help prevent COVID infection.
How would you argue that an existing drug (UDCA in this case) could help prevent or treat COVID? Original Ivermectin StudyThis basically put a bundle of cells and virus into a tube filled with antiparasitic drugs at varying concentrations. this paper Appeared in Nature Please provide multiple supporting evidence. I will explain step by step.
All good science begins with a biologically plausible hypothesis. In this case, the authors realized that SARS-CoV-2, in all its variants, requires the presence of her ACE2 receptor on the cell surface for binding.
That’s the gateway to infection. Vaccines and antibodies block the key to this door, the spike protein and its receptor-binding domain. But what if you could get rid of the door entirely?
The authors first showed that ACE2 expression is regulated by a specific transcription factor known as the farnesoid X receptor (FXR). Therefore, reducing FXR binding should reduce ACE2 expression.
With luck, UDCA (Actigal) reduces FXR levels and decreases ACE2 expression in cells.
all right. Now that we have drugs that reduce ACE2, we know that viruses need ACE2 to infect cells. Does UDCA prevent viral infections?
Starting with test tubes, they showed that cells were less likely to become infected with SARS-CoV-2 in the presence of UDCA at concentrations similar to those achieved in humans in the blood after standard administration. . The red stain here is the spike protein. It is found to be significantly lower in cells exposed to UDCA.
So far, so good. But test tubes are not people. So they moved on to rats and Syrian golden hamsters. These cute companions are highly sensitive to her COVID in humans and have been model organisms in countless studies.
Mice and hamsters treated with UDCA in the presence of COVID-infected littermates were less likely to become infected themselves compared to untreated mice. Mice and hamsters have shown low levels of ACE2 in their nasal cavities.
Of course, rats are not humans either. So the researchers didn’t stop there.
To investigate the effects of UDCA on human tissue, they utilized perfused human lungs that had been rejected for transplantation. Lungs were perfused with a special fluid and mechanically ventilated to maintain survival. One lung was exposed to her UDCA and the other served as a control. The authors were able to show that his ACE2 levels were reduced in exposed lungs. And, importantly, when tissue samples from both lungs were exposed to SARS-CoV-2, UDCA-exposed lung tissue had lower levels of viral infection.
They didn’t stop there.
Eight volunteers were recruited to take UDCA for five days. Her ACE2 levels in the nasal cavity decreased over the course of treatment. They confirmed the results obtained from a proteomics dataset of hundreds of people who underwent her UDCA for clinical reasons. Treated individuals had lower ACE2 levels.
Finally, they examined epidemiological effects. They examined a dataset containing information on more than 1000 of her patients with liver disease who were infected with COVID-19. 31 of them had received her UDCA. Even after adjusting for baseline differences, those who underwent UDCA were less likely to be hospitalized, less likely to require ICU, or to die.
ok, let’s stop there. Reading this study, I was able to think that Yes! This is how you create evidence that you have a drug that might work – at the cautious stage.
But be careful. Does this study show that taking Actigall prevented her from getting COVID? It is not meant to cure COVID as well. But I bring it up because the rigor of this study is in contrast to something that generated great enthusiasm early in the pandemic and only let us down in randomized trials. Or if a drug to treat has existed all along, this is how we will find it. What’s the next step? Test in a randomized trial.
At Medscape, I’m Perry Wilson.
F. Perry Wilson, M.D., MSCE, is Associate Professor of Medicine and Director of the Clinical and Translational Research Accelerator at Yale University. His science communication work can be found in the Huffington Post, NPR, and his Medscape.he tweets @fperrywilson and his new book, how drugs work and when they don’t, is currently available for pre-order.
