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Pharmaceuticals

Can Pepcid treat COVID-19?

With clinical trials ongoing, doctors try to unravel how famotidine could be working to fight the disease caused by SARS-CoV-2

by Bethany Halford
June 15, 2020 | APPEARED IN VOLUME 98, ISSUE 25

 

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Credit: Bethany Halford/C&EN
Doctors are investigating whether the popular heartburn drug Pepcid, sold generically as famotidine, can treat COVID-19.

Doctors and scientists are studying many existing drugs with the hope of finding therapies they can repurpose to fight COVID-19. Some of these, like Gilead Sciences’ remdesivir, directly go after the virus SARS-CoV-2, which causes the disease. Others, like Incyte’s ruxolitinib, aim to dampen the overactive immune response that characterizes later stages of disease in COVID-19.

And then there are the oddballs. Take famotidine, the active ingredient in the over-the-counter heartburn drug Pepcid. The histamine-H2-receptor antagonist works by preventing stomach acid production. That it would have any activity in an infectious disease is a bit of a head-scratcher.

Doctors first became interested in famotidine after hearing reports that people in China who took the drug for heartburn were surviving COVID-19, while other people who essentially had the same risk factors but were taking different heartburn drugs like cimetidine or omeprazole (sold in the US as Tagamet and Prilosec, respectively) were dying from the disease. Perhaps famotidine was somehow bolstering these patients and improving their chances for survival.

In early April, doctors began a clinical trial at New York’s Northwell hospitals to test that theory. They reasoned that even if evidence for famotidine’s effectiveness was largely anecdotal, the drug has been around since the 1980s and has a good safety profile. If it worked, it would be a fast and cheap way to ease the symptoms of COVID-19.

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They decided to use high doses of intravenous famotidine. Their goal was to enroll 1,200 people with moderate to severe COVID-19 and see if those that got famotidine were less likely to die or require a ventilator. Then, in late April, the first news report about the trial appeared in Science. Boxes of Pepcid began to fly off of pharmacy shelves as people sought out any potential remedy during the pandemic.

Shortly afterward, on May 8, a team, led by Columbia University doctors Daniel Freedberg and Julian Abrams, posted a study on the preprint server medRxiv that compared the outcomes of people with COVID-19 who were prescribed famotidine within 24 hours of being admitted to the hospital to those who didn’t get the heartburn drug. They looked at the records of more than 1,600 patients at Columbia University Irving Medical Center between late February and mid-April. Of those, 84 patients received 10–40 mg of intravenous famotidine daily over the course of about 6 days.

The patients who got famotidine fared better. According to the study, they were far less likely to die or require a ventilator—a twofold decrease in risk—than those not receiving the drug. The results were published in the peer-reviewed journal Gastroenterology later in May (2020, DOI: 10.1053/j.gastro.2020.05.053).

“This is merely an association, and these findings should not be interpreted to mean that famotidine improves outcomes in patients hospitalized with COVID-19,” the team says in a statement. “It is also not clear why those patients who received famotidine had improved outcomes.”

For clarity on famotidine’s effectiveness, the team recommends awaiting the outcome of the trial going on at Northwell hospitals. “Hopefully the results from this trial will determine whether famotidine is efficacious for the treatment of COVID-19,” the team says in its statement.

Meanwhile, in early June, the journal Gut published a small case series of 10 people who developed COVID-19 and reported taking famotidine during their illness (2020, DOI: 10.1136/gutjnl-2020-321852). These people were not sick enough to go to the hospital, but their symptoms, such as cough and shortness of breath, improved within a day or two of taking the heartburn drug. It’s a small study, and the researchers acknowledge that it’s not enough to establish there’s any real benefit from taking famotidine for people who have COVID-19. Those authors recommend a clinical trial with famotidine be carried out with patients with milder disease in addition to the trial going on at Northwell hospitals.

I think there’s going to be some intriguing science trying to draw a connection between the activity—if it is proven to have that in patients—and how it’s actually working in the context of SARS-CoV-2 infection.
Matthew D. Hall, acting director of biology and group leader, Early Translation Branch, at NIH’s National Center for Advancing Translational Sciences

But the Northwell trial has slowed for two reasons, says Joseph Conigliaro, the physician who is leading it. Cases of COVID-19 in New York have declined, making it challenging to reach the enrollment requirements for the study.

And shifting treatment approaches have further complicated efforts. When the trial began, COVID-19 patients in New York were getting the antimalarial hydroxychloroquine as part of their treatment regimen. So the study was designed to compare patients receiving hydroxychloroquine and famotidine with patients receiving hydroxychloroquine and a placebo. But that standard treatment regimen has changed, and hydroxychloroquine is no longer given routinely. As a consequence, the researchers are looking to modify the study’s protocol, Conigliaro says.

Until the results of the study are in, Conigliaro can’t say whether famotidine works. “As a physician, I can’t tell people ‘go out and buy famotidine, and if you start getting an inkling of anything start taking it,’ ” he says. Even though the drug has long been considered safe, it’s unclear how to guide people to take it in terms of dose and disease stage. “We need to wait for the results of our trial,” he says.

Scientists are meanwhile trying to figure out why a heartburn medicine might also fight COVID-19. Using computational methods, a group in China used SARS-CoV-2 genes to predict the structures of viral proteins. The group then computationally screened existing drugs to see which could potentially act on those protein targets. Their study suggests that famotidine could inhibit the virus’s 3-chymotrypsin-like protease, which plays a role when the coronavirus makes copies of itself while inside the host (Acta Pharm. Sin. B 2020, DOI: 10.1016/j.apsb.2020.02.008).

Similarly, computational chemists at the scientific software company Molecular Forecaster virtually docked a library of 2,700 existing drugs and nutraceuticals to see which fit into a model of the papain-like protease, another key protein in SARS-CoV-2 replication. They were collaborating with scientists working for a US Department of Defense project called DOMANE. Famotidine was one of a few drugs that appeared to interact with the protease in the computational studies, says Robert Malone, a physician and consultant who is on the DOMANE team.

But other evidence derails those computational studies. Matthew D. Hall, acting director of biology and group leader, Early Translation Branch, at the National Center for Advancing Translational Sciences (NCATS), part of the US National Institutes of Health, points out that his group did studies in cells that show famotidine doesn’t have any ability to fight SARS-CoV-2. “In a direct antiviral assay, we don’t see any activity for any of the compounds in this class,” he says.

As a drug-repurposing candidate, Hall says, famotidine is attractive because it’s safe, affordable, and accessible. But making further conclusions about its usefulness in COVID-19 will require clinical trial data. If those trials show promise, Hall says, “I think there’s going to be some intriguing science trying to draw a connection between [clinical] activity and how it’s actually working in the context of SARS-CoV-2 infection. Understanding the primary mechanism may also drive long-term development of new therapeutics that are more potent.”

Malone has been working with a team of scientists to get a better understanding of just how famotidine might be working. Results of his team’s study, which have not yet been peer reviewed, appeared on a preprint server on May 23 (Research Square 2020, DOI: 10.21203/rs.3.rs-30934/v1).

Like the NCATS work, the team’s tests showed that famotidine has no effect on SARS-CoV-2’s papain-like protease, nor does it kill the virus. Instead, Malone and colleagues think the drug is working through its usual target—histamine H2 receptors. Famotidine treats heartburn by blocking H2 receptors, which when activated by histamine stimulate cells in the stomach to secrete acid.

As a physician, I can’t tell people ‘go out and buy famotidine and if you start getting an inkling of anything start taking it.’
Joseph Conigliaro, chief, General Internal Medicine, Northwell Health

But H2 receptors aren’t just in the stomach—they’re all over the body. Malone and colleagues argue that COVID-19 is disrupting mast cells, which release histamine and other signaling molecules in response to an inflammatory or allergic reaction. These cells can be found at the boundary between tissue and an external environment. They’re on the skin and line the gut and lungs. Malone reasons that mast cells could be responsible for the overactive immune response, often described as the cytokine storm, which does damage to patients with severe cases of COVID-19. By blocking the histamine that mast cells release, famotidine can dampen some of that response.

If famotidine is effective in COVID-19, why isn’t the other commonly used H2 blocker, cimetidine? The answer, Malone claims, comes down to pharmacokinetics: famotidine makes it into the bloodstream more readily than cimetidine.

Adrian M. Piliponsky, an immunologist at Seattle Children’s Research Institute who studies mast cells, says that it’s possible mast cells are playing a role in the inflammatory response to COVID-19. He notes that mast cells play a role in infections with other viruses. He thinks the idea proposed by Malone and colleagues merits further study, and he’s interested in seeing the results of the clinical trial.

Malone also would like to see a comprehensive trial of famotidine in people who are in the early stages of COVID-19. But he doesn’t think the drug alone will resolve the world’s COVID-19 pandemic. “We’re committed to trying to create an outpatient cocktail of drugs that will significantly reduce morbidity and mortality for COVID-19 and have it ready for deployment in the fall,” he says.

In the meantime, doctors are urging caution for people who might see these early results and rush out to stock up on Pepcid. Carl J. Lavie, medical director of cardiac rehabilitation and prevention at the John Ochsner Heart and Vascular Institute, recently cowrote a letter to the editor of Mayo Clinic Proceedings encouraging doctors to wait for the clinical trial results.

He tells C&EN that it’s premature to recommend famotidine just for COVID-19, but he adds, “I also think that it is benign, so it would seem very reasonable to use for upper GI symptoms now” before giving other heartburn drugs like omeprazole.

CORRECTION

This story was updated on June 16, 2020, to correctly characterize famotidine as a histamine-H2-receptor antagonist, not an agonist.

CORRECTION

This story was updated on June 22, 2020, to correctly identify the group that did a virtual docking study. It was chemists at Molecular Forecaster, not DOMANE.

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Comments
sdlmd (June 16, 2020 2:12 PM)
The hinted effectiveness against SARS-COV-2 of so many seemingly unrelated pharmaceuticals, from famotidine to hydroxychloroquine to BCG vaccine is fascinating, illustrating only how much remains unknown about the biology of this virus and our pathophysiologic response to it. And of course the release of even that hint has been enough to wipe every drugstore's shelves clean of famotidine for weeks now, which has caused potential trouble for people who rely on it to control gastroesophageal reflux and heartburn, especially since ranitidine was just pulled from shelves a few months ago, leaving only cimetidine, proton pump inhibitors and various buffer preparations as the only available treatment.

We must hope that President Trump doesn't mention famotidine, because if he does, the media will immediately condemn its unapproved use and trumpet the numerous (but extraordinarily rare) side effects, and Governors Whitmer and Cuomo will threaten to prosecute physicians who recommend it.
Liam (June 24, 2020 8:10 PM)
Totally agree with the insight shared on your first paragraph, but the second paragraph was unnecessary. This article was about the potential effectiveness of Famotidine to treat Covid-19 and trials being done. No one cares about personal political views.
Dan Kennedy (June 28, 2020 12:21 PM)
hydroxychloroquine has killed so many of our veterans in hospitals because Drs were forced to give it to them. Someday we will have a total of this affected.
Paul (September 5, 2020 5:11 PM)
Dan,
The HCQ that "killed" Veterans, were because the dosing was way, way, way, too high.
Jerry (June 29, 2020 5:00 PM)
I think Trump has moved on SDLMD. You know he has the attention of a 12yo ADHD so I don't think he'll be mentioning anything about COVID. As far as he's concerned, testing is why our numbers are going up but COVID is going to disappear soon.
Robert Taylor (August 6, 2020 6:18 AM)
Jerry, the virus will no longer be a major public health issue on November 4, 2020. I guarantee it.
heidi (June 16, 2020 7:35 PM)
i am a sickly person. i get bad respiratory infections/bronchitis twice a year on top of sinus infections, ear infections. Its never ending. All my life from age 13 to 49. a year ago i stated taking famotodine at night once a day for my acid reflux. have not been sick at all the past year outside of 1 mild cold. First time in my life.
Kay (June 30, 2020 5:50 AM)
Interesting! I have seen a couple doctors online recommend to take one a day pepcid as a preventative. I just began doing so.
Joe (June 25, 2020 5:24 PM)
Famotidine is a novel antiviral to fight COVID-19 in a unique way. It speeds up oxygen-carbon dioxide exchanges near alveoli toward the oxygen side. The carbon dioxide is downloaded faster than usual and hence more carriers in the blood are available to transport oxygen within the lung. It should be good for patients with mild to moderate symptoms as reported.
Jeff (June 26, 2020 5:59 PM)
I admit, I am one of the people who immediately went out and bought enough famotidine for my family as soon as I heard about it. We have it sitting in our cabinet waiting until we get infected. This virus is frightening and any ray of hope, we grab at it. The latest thing seems to be NAC and Glutathione. We're taking that twice a day before we get infected.
Kay (June 30, 2020 5:48 AM)
I did too! Smart move! I've also started taking generic pepcid one aday as a preventative. I've seen a few Drs online recommend it along with vitamin D. The price has gone back down as well. Cloth masks filter only 3% of particles and I can't breathe well in them, after just one hour I'm pretty dizzy! Doing vitamin D and pepcid instead. I'm alone in life and have PTSD, I don't care if I die I just don't want to be out of work for two weeks.
Mari (June 27, 2020 2:13 PM)
The same with ibuprofen the is a intiflamatory medicine the helps with the virus.
Dermot Fitzpatrick (June 28, 2020 6:53 PM)
Covid 19 could be a gastrointestinal virus. It is potentially triggering the release of histamines in the gut either for the mast cell, bacteria in the gut or a combination of the two. The longer it takes to clear the virus the more the build up of histamines until it reaches toxic levels. Excess histamines enter the lungs causing contraction of the lungs and inflammation. This inflammation continues until the blood oxygen levels start to drop which in turn triggers hypoxia whereby the mast cells in the lungs release more histamines. This increases the histamine level further creating more inflammation and a cycle of hypoxia occurs. The histamines also in the bloodstream cause blood clots and fribinolysis while triggering the H1 and H2 receptors causing increased blood flow and blood pressure leading to heart attacks and strokes. Histamine in the brain disrupts the neural functioning and histamines cause damage to the liver and kidneys. The Famotidine in large dose blocks the histamine in the gut. This reduction in histamine reduces inflammation in the lungs allowing oxygen levels to rise, this in turn reduces the hypoxia also reducing histamine levels and reduces the risk to the other related complications. Famotidine is 20 times more potent a antihistime blocker than cimetidine. So a relatively lower dosage is more effective. This drug in combination with high dose vitiman d, a mast cell Stabaliser could be an affective treatment.
Art C. (July 9, 2020 10:42 PM)
My wife has tested positive for Covid 19.. I been taking Pepcid AC for awhile now way before my wife got sick.. Since she tester positive I still sleep next to her, kiss her and I have yet to get major symptoms of Covid. I only got a head ache for a day or so and a scratchy throat for 2 days. I think the famotidine has helped me from getting the sick. I still continue to take it on a daily bases for my heartburn issue.
ken osborn (July 12, 2020 11:17 PM)
the connection between histamine over production and severity of Covid-19 infection makes mechanistic sense. Combined with even small studies this to me is a basis for making a reasonable risk decision (as opposed to a scientific decision) about whether or not to take Famotidine. On a preventive basis I would not take it as it could interfere with digestion (proteases like low pH). But if I had early symptoms of Covid-19 I would be taking it.
Richard Danno (July 15, 2020 4:11 AM)
The anecdotal information available about famotidine is sufficient to convince me that it should be used for outpatient treatment immediately upon developing symptoms of Covid-19 and it may very well work for prophylaxis. I can vouch from personal experience with my wife’s onset of a Shingles rash on her lateral trunk, that Tagamet (cimetidine) will stop the herpes zoster infection in its tracks if given within the first three or four days of onset. The proper dose is 200 mg. three times a day and 400 mg. at bedtime. For ten days. She had no side effects. I suppose famotidine would do the same, but the anecdotal reports I read at the time only mentioned cimetidine.
Elizabeth Sackel (July 15, 2020 7:39 PM)
There is also a study investigating both famotidine (H2 blocker) and cetirizine (H1 blocker Zyrtec) to work together. I agree that famotidine is a drug that's been around for a long time and I take it as directed on the package. If I feel symptoms, plan to increase the dose. I know people who 'recovered' form Covid but are still struggling for months with scarred lungs after only mild infection symptoms. Felt good at first and then the exhaustion hit. I like to think prophylactic.
Thomas Dehel (July 17, 2020 7:06 PM)
The use of famotidine to fight a Covid -19 infection seems to have a biological mechanism and observations of benefit enough to convince me to use it if I catch Covid. I don’t understand why there isn’t a massive national take-it-at home trial for those with positive Covid-19 test results. As is known, famotidine is safe, inexpensive and readily available (Sams Club near me has many cases). Would some doctor please step up and save thousands of lives and countless suffering?
Richard Danno (July 18, 2020 9:00 PM)
When cimetidine, a H2 receptor blocker like famotidine , was used to reverse and eliminate my wife’s Shingles rash, the mechanism of action wasn’t its effect on mast cells but rather the inhibition of virus replication. Hydroxychloroquine when first touted was shown to or alleged to have cleared the COVID virus in six days. I hope famotidine has similar efficacy for COVID when taken at the first sign of symptoms.
Alice (July 26, 2020 5:43 PM)
Thanks for the detailed review! I agree with Malone and would like to see a comprehensive trial of famotidine in people who are in the early stages of COVID-19. I think that famotidine can help only in combination with other treatment. I've also read an interesting post about the latest research conducted by Israeli scientists: they believe that simple medical cannabis can be used as one of the means of COVID-19 treatment. Indeed, certain constituent components of cannabis may help to treat COVID-19, adding to the many therapeutic benefits of medical marijuana. Look if interested https://affordablecertification.com/blog/israeli-researchers-study-cannabis-as-possible-covid-19-treatment/

Tom (September 8, 2020 5:22 AM)
Recent computational studies completed by the Oak Ridge (TN) supercomputer on hundreds of thousands of Covid-19 patients/pathology and outcomes is revealing a Bradykinin (peptide) Storm hypothesis. This article from June was prescient!
Tom Christenbury (September 8, 2020 5:37 AM)
Here's the link...
https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63
It would seem that under the Bradykinin Storm Hypothesis- Famotidine, Vitamin D (preferably via sunlight), and a Z-Pac, may be our best 1st line of defense....

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