After we are exposed to a known case of Covid like President Biden has been, the next phase is mostly careful observation for the development of symptoms. For better or worse I don’t know anyone who is quarantining, or even wearing a post-exposure mask for others anymore. So, is there something else Joe Biden might be able to do to reduce his chance of converting to Covid disease? Can First Lady Jill Biden reduce the duration of her illness and chance of transmission? I assume she is taking Paxlovid if eligible, and that should help.
But we don’t have a lot of other fancy tools to help reduce Covid transmission after exposure. A trial of Paxlovid in household members of a sick family member did not really work to prevent transmission. We all know about ventilation, masking, etc. But there is a nasal spray called Enovid that purports to be an effective and underutilized tool in the fight against Covid disease, transmission, and prevention. Does it work??
A somewhat overlooked study last year dropped the following headline:
And while this did flash across my radar last summer, I did not hear that much else about it. Did you? The FDA did not rush to approve nitric oxide nasal sprays, and so they are still not available in the U.S. Most of the medical experts, journals, and organizations that establish treatment guidelines did not jump on board. Why?
For some reason I’m getting a trickle of questions about nitric oxide nasal sprays like Enovid recently. It’s probably because cases are up, wearing a mask is more socially awkward than ever, and as Jon Snow warned winter is coming. And so I thought I should do a deep dive. It’s a typical rabbit hole. There’s not a lot of good analysis out there, so I had to grind it out from scratch for you. Sorry this is a long post!
Should we be ordering this stuff from Israel, Germany, India, or a handful of other countries where it has been approved? A lot of people are.
* Why it might work
Nitric oxide is a compound that is already found in the human body. It has several functions including promoting vasodilation and immune system regulation. It can also be toxic to viruses. Mechanisms include preventing viruses from entering cells by causing conformational changes to proteins like spike, and messing up protease enzymes viruses use to replicate. In bacteria and fungi nitric oxide can cause DNA damage and inhibition of DNA repair, as well as damage to lipid components of cell membranes. A safe dose of nitric oxide for human cells can still be lethal for viruses and bacteria.
Enovid also contains other ingredients which are not “active” but that may also serve as a mechanical coating, shielding cells from spike proteins trying to unlock their gates. This includes hydroxypropyl methylcellulose (HPMC), a thickening agent that is used in making hydrophilic films.
What were the results of the clinical trial?
I’m going to focus on the spray made by the company SaNOtize, and depending on which country you’re in, it may be called Enovid, VirX, or FabiSpray. Instead of writing Nitric Oxide Nasal Spray, I’ll use the term NONS from here on out.
The top line results of the published study sound really impressive.
About 300 patients started NONS or placebo within 3 days of symptoms onset. Patients had mild symptoms at the time of randomisation. Subjects used NONS or saline placebo, 2 sprays per nostril, 6 times a day, at least two to three hours apart while awake for a week.
Nitric oxide (NO) released from SaNOtize’s nasal spray formulation inactivated more than 99.9% of SARS-CoV-2 (COVID-19 isolates) to below the limit of detection, for all variants tested to date, within two minutes of contact.
Nitric oxide released by nasal spray reduced SARS-CoV-2 viral RNA load by more than 95% in infected participants within 24 hours of treatment, and by more than 99% in 48 to 72 hours in two randomized, double blinded controlled studies.
It was also shown to cut the time of positive (PCR) to negative by 50% in high-risk individuals
Patients using NONS for Covid treatment reported feeling better a median of 3 days sooner than those using placebo saline sprays.
I feel ready to buy some at this point, but let’s break these claims and numbers down.
Virus inactivation
Nitric oxide (NO) released from SaNOtize’s nasal spray formulation inactivated more than 99.9% of SARS-CoV-2 (COVID-19 isolates) to below the limit of detection, for all variants tested to date, within two minutes of contact.
This 99.9% was obtained from laboratory studies of NONS sprayed onto coronaviruses outside the body. Agents like bleach and ethyl alcohol probably have similar efficacy, but with great potential toxicity to human cells. This claim establishes that NONS will kill coronavirus in a lab.
Reduction of coronaviruses (viral load) in actual patients
Nitric oxide released by nasal spray reduced SARS-CoV-2 viral RNA load by more than 95% in infected participants within 24 hours of treatment, and by more than 99% in 48 to 72 hours in two randomized, double blinded controlled studies.
This clinical result is astonishing at first, but if you dig into the actual study, you find briefly mentioned key words that confirm this reduction in viral load is based only on samples collected from nasal swabs. Therefore, the 95% and 99% viral load reductions are occurring just in the front of the nose. As we’ve learned, this coronavirus infects pretty much every organ system and tissue in the body, moving way past the nose and into our nervous, gastrointestinal, pulmonary, and cardiovascular systems for example.
Moreover, these percentages are based on counting viruses in log base 10. I did a quick math refresher last night. I’m a family doctor not a biostatistics whiz, so take this with a grain of salt, and if you’re mathematically smarter than me please do advise… but here’s what I got by crunching the study numbers:
Viral load on day zero in the NONS treatment group was 10 to the 6.96 power = 9,120,108 horrible viruses per milliliter
⏲️ Viral load at 24 hours after treatment was 10 to the 5.86 power = 724,435 horrible viruses per milliliter. This is about a 95% reduction.
⏲️ Viral load at 48 hours after treatment was 10 to the 5.09 power = 123,026 horrible viruses per milliliter. This is about a 99% reduction.
Nice! Still a lot of viruses going on, but we’ll take it. So what about the placebo group that just shot saline up their noses six times a day for a week?
Viral load on day zero was 10 to the 7.16 power = 14,454,397 horrible viruses per ml. This is actually a much greater starting point than the treatment group. The authors state this was “comparable.”
⏲️ Viral load 24 hours after saline was 10 to the 6.71 power = 5,128,613 horrible viruses per ml. This is about a 65% reduction.
⏲️ Viral load 48 hours after saline was 10 to the 5.98 power = 954,992 horrible viruses per ml. This is about a 93% reduction.
So we can see that the NONS group definitely cleared nasal viruses better, but the saline group was not so shabby either.
Now here is where I’ll just have to trust the higher-level mathematical skills of the researchers as they conclude that the NONS group achieved a 6.6 fold better reduction in nasal virus compared to the saline group on day 1, and a 7.4 fold better reduction on day 2, adjusting for the different viral load starting points.
It should also be noted that a study in India reported that NONS shortened the time from infection to PCR negative status by 3 days. This was not a quantitative result but was instead qualitative (just positive or negative).
So what does a drop in nasal viral load mean?
[This post was originally published on a Substack newsletter I write called Examined. I present vital and overlooked ideas your family doctor might share if only we had more time. New subscribers are always welcome, and I am happy to repost this article today for any interested DailyKos community members with the paywall removed 🙂
Does dropping the viral load in the nose faster make you feel better?
According to this study, yes, to some degree. The authors claim: “Patients using NONS for Covid treatment reported feeling better a median of 3 days sooner than those using placebo saline sprays.”
But here’s a graph from the study to the right. The red bars represent the percentage of people improving with NONS, and the other bars are on placebo. Feel free to just get the gist of it… does not seems vastly different by day 8, right? And by day 18 even more convergence.
Hospitalizations and death?
The study was too small, and no patients in either group died or were hospitalized. The study population skewed young and healthy, see below.
Did using NONS reduce Covid transmission?
In this study there was a trend towards a sick patient using NONS and perhaps some protection of close contacts. The methods and details of how this was analyzed are opaque though, and statistical analysis was not published. We just have this second graph to the right showing mildly higher rates of Covid transmission to contacts of those using just saline. Once again details were sparse.
Does using NONS preventatively help reduce the risk of contracting Covid?
It would be great if taking a couple sprays of NONS before heading into a higher risk situation might help us avoid catching a case of Covid. No studies have assessed this. But there was another related study in Thailand run by the Enovid manufacturers. It looked at using NONS right after possible exposure. It was a retrospective study of low quality, but that being said there was some possible benefit for NONS reducing transmission. I’ll copy and paste the meat of the study, but the whole thing is here:
The (Thai University) plan called for opening two new quarantine buildings with one for confirmed COVID-19 positive students and another for “high-risk contacts” who were exposed to COVID-19 positive individuals. A high-risk contact (HRC) person was defined as a student who self-reported being in direct contact with a confirmed positive COVID-19 person for more than 5 minutes without wearing a mask, usually when both were either eating or sleeping together in the same room….
The investigators performed a retrospective data analysis on 1039 students who reported that they were in contact with a confirmed COVID-19 student… They were housed in either one of the new quarantine buildings or in their own accommodations. Upon data review, 199 students were excluded due to having had low-risk of exposure, while 215 students were excluded due to a positive antigen test for COVID-19 within the first 24 hours…
The study demonstrated a statistically significant difference at the p<0.0001 level in infection rate of 6.40% in the (NONS) group versus 25.59% in the group that did not use NONS.”
So maybe there is some benefit to starting NONS right after exposure, but once again this study was not of very good quality. The researchers admit as much but did secure additional money based on this Thai study, and a larger, randomized, placebo-controlled Phase 3 trial is currently underway.
Other limitations and bones to pick
Ok, back to the main trial. I just want to comment on a few disappointing aspects for me.
The trial had only about 300 participants.
The researchers tout NONS as effective for high-risk patients. Granted, 53% of the participants were unvaccinated, but they also defined “high risk patients” as those over age 45 yo. Usually we think of 65 and up.
Only 27% of the “high risk” participants were actually over age 45, the rest were younger. Furthermore, 88% of the patients had no co-morbid medical problems. So the population studied was young and healthy compared to what one might see in a typical primary care workday, although they were less vaccinated.
I also found it a bit disingenuous when the authors compared viral load reductions with NONS to oral Paxlovid (around 90%) and other FDA approved antiviral therapies. Although Paxlovid also proved its 90% reduction as measured by nasal swabs, we can safely assume that since it is taken orally, 3 pills three times per day, it is able to lower viral loads in most parts of the whole body.
Finally, I don’t love the preservative used in Enovid. Benzalkonium chloride has been shown to harm the nasal ciliary apparatus and potentially hamper immune function to some degree in the nasal passages.
Why isn’t Enovid/NONS approved in the U.S.?
Canada and the United States have yet to approve this product. The FDA informed the manufacturer SaNOtize that it must prove a reduction in hospitalizations and deaths for approval. A simple reduction in viral load will not suffice. I do wonder if a better designed study proving a decrease in transmission, either before or shortly after exposure, would suffice?
Takeaway
NONS/Enovid has been shown to reduce viral load in the nose when taken early, 2 sprays in each nostril, 6 times per day. Viral load also goes down naturally, but at a pace 6-7 times lower over the first day or two. Systemic viral load reduction outside the nose has not been studied, but it is safe to assume that the virus is still replicating in multiple organ systems. Symptoms may improve a little faster, perhaps because many symptoms are nasopharyngeal, or there is just one big factory slowed down in the nose. Positive rapid antigen tests may convert to negative sooner, and this might correlate with potential for decreased transmission. But this is speculative. A low authority, retrospective study in Thai university students exposed to Covid showed the potential for a decreased rate of subsequent illness, but this needs to be confirmed with that better ongoing study. It would seem that the most promising use of NONS might be to add another layer of protection heading into a communicable situation… but the data is not there, just the mechanisms that might help. Enovid does provide a barrier of sorts, and nitric oxide has plausible antiviral properties. If it were available in the U.S. I might use it as an added layer of protection in high-risk situations, but I would assume that it is definitely inferior to good ventilation and a well-fitting N95 mask. In terms of treatment of Covid, it can also be assumed that systemic antivirals like Paxlovid and remdesivir not only clean up the nasal passages but inhibit coronavirus replication in the rest of the body. That’s why they are FDA-approved and have been conclusively shown to reduce risks of severe disease, hospitalization, death, and long Covid.
If you were Joe or Jill Biden and had access to this medication, would you take it?
Are you among the people who have already ordered it from abroad, or thinking of doing so?