On April 22, I reported on the first large series of post-mortem analyses that suggested blood clots within the small arteries of the lungs may be at the root of the COVID-19 hypoxemia (low blood oxygen). Since then, New York City doctors have reported strokes occurring in COVID-19 patients under the age of 50, including one as young as 33. This is consistent with the disease causing blood clots, which are the major cause of stroke in Western countries.
In my first article, I warned against jumping to over-the-counter anti-inflammatory drugs to prevent blood clotting, as it is conceivable they could promote viral growth:
It is important not to jump to conclusions here and use drugs with anti-clotting activity, such as NSAIDs, to treat COVID-19 before we have more data. Such drugs can alter levels of PGE2, a substance that is involved in blood clotting, but which also can promote or inhibit viral growth, depending on the virus.
Yesterday, a new preprint* was released suggesting that naproxen, an NSAID often marketed as Aleve, actually inhibits viral growth.
Important: Since this update discusses medications, I want to put special emphasis on the fact that I am not a medical doctor and am not offering medical advice. I am here to provide education and analysis of the research. I have a more detailed disclaimer at the bottom.
Background to the New Paper
Naproxen has previously been shown to inhibit replication of influenza A both in isolated cells and in live mice.
This might be partly a result of its inhibition of cyclooxygenase, which produces PGE2, a substance that can sometimes promote viral growth. However, it also binds to the N protein, which makes up the protein coating around the genetic material of the virus and plays a number of roles in infection, including antagonizing the interferon response and facilitating the copying of the genetic material to allow replication. Naproxen binding to the N protein strongly inhibits the copying of the genetic material, and, as a consequence, viral replication.
The N protein of each virus is different, and we cannot assume that its effect on the influenza N protein will translate to an effect on the N protein of SARS-CoV-2, the coronavirus that causes COVID-19.
The Results
However, in this new study, computer modeling suggested that naproxen binds to the N protein of SARS-CoV-2 even better than it binds to that of influenza A.
Then they tested the effect on viral replication in human cells that line the nose and the bronchus. Bronchi are part of the lungs and constitute the air passages that connect the lungs to the windpipe.
Strangely, naproxen strongly inhibited viral replication in the bronchial cells, but not the nasal cells. 90 and 300 micromoles per liter (uM), a measure of the concentration of the drug, inhibited viral replication in the bronchial cells by about 75%. Neither concentration had a statistically significant effect on viral replication in nasal cells, but the replication was about 10% higher at 90 uM and a few percent lower at 300 uM.
The virus replicates more quickly in the lower respiratory tract (bronchus) than the upper respiratory tract (nose), so it may be the case that the effect of naproxen was easier to show in the bronchial cells because of a more severe level of infection. Alternatively, there could be differences in the cellular response of the nasal cells and the bronchial cells.
Is This Likely to Hold Up in Live Humans?
Could naproxen have antiviral effects in humans?
In the bronchial cells, the IC50, the concentration required for 50% inhibition of viral replication, was 46.07 uM.
Two 220 mg naproxen sodium tablets taken together lead to a maximal plasma concentration of 65.88 micrograms per milliliter, which, using this calculator, is 286.12 uM. This is much higher than the IC50 and much higher than the concentration required for maximal effect (which was the ~75% decrease in viral replication seen with both 90 and 300 uM).
The half-life of naproxen is 12-17 hours. Generally, taking a dose once every half life will result in an average plasma concentration that is roughly double the single dose on its own. This suggests that 220 mg naproxen sodium taken twice a day would be the best way to maintain plasma concentrations close to 300 uM.
While this does not make it certain that naproxen would inhibit viral replication in humans, it makes it very promising. Randomized controlled trials would be needed to test the effect.
What About Blood Clotting?
Naproxen inhibits cyclooxygenase-1 (COX-1) in platelets, which is necessary for clotting. This can be measured with a platelet function assay that passes blood through a membrane with small holes. The time the platelets take to close the holes is measured, and is called the “closure time.” In humans, 250 mg taken twice a day increases the closure time by 42%.
Is Naproxen Safe?
Naproxen has a long list of potential side effects. I am particularly concerned about the potential of frequent use of NSAIDs to cause food intolerances and autoimmune issues (because of this, this, this, and this). Obviously anything that has anti-clotting effects could risk excessive blood thinning in some people. Please discuss any use of this or any other medication with your doctor to determine whether there is anything in your clinical history that would make it unsafe. With that said, naproxen has a history of widespread use as an over-the-counter medication and has a safety profile consistent with over-the-counter medications.
How This Changes My Position on NSAIDs
As I quoted myself at the beginning of this update, my initial position was to warrant caution against NSAIDs, since their inhibition of COX enzymes and PGE2 production can inhibit the growth of some viruses and promote the growth of others.
This new research removes my concern specifically for naproxen. It did not promote viral growth in nasal cells, and it strongly inhibited viral growth in bronchial cells.
However, this study did not investigate the role of COX and PGE2 in this finding. Therefore, we do not know if it translates to other NSAIDs, which all share that mechanism of COX inhibition. In particular, the binding of naproxen to the N protein might be involved in the antiviral effect, and we do not know if any other NSAIDs bind to the N protein in the same way.
Therefore, I remain cautious of other NSAIDs but consider naproxen relieved of this concern.
The Bottom Line
Naproxen has not been shown to be beneficial for COVID-19, and randomized controlled trials would be needed to show that it is effective.
However, taken at standard over-the-counter doses, it strongly inhibits replication of the virus in bronchial cells, and it has anti-clotting effects on platelets. Given that clotting may underly the hypoxemia and the rare but deeply concerning incidence of stroke in young people, these anti-clotting effects may help prevent a case from becoming severe or fatal.
Over-the-counter medications are not zero-risk medications, but if something with a risk profile suitable to use for a headache or a menstrual cramp also has the potential to prevent COVID-19 from becoming severe or fatal, many people may choose to use it.
Personally, because I am concerned about the side effects of frequent use, I would only use it short-term during an illness and would not use it preventatively.
Stay safe,
Chris
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Disclaimer
I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.