Three antihistamine medications have been found in preliminary tests to inhibit infection of cells by the coronavirus that causes COVID-19, UF researchers report.

Their findings, based on laboratory tests of cells and a detailed analysis of nearly a quarter-million California patients’ medical records, were published Dec. 3 in the journal Biochemical and Biophysical Research Communications. The data may support the launch of a randomized, controlled clinical trial to determine whether the specific antihistamines can treat or even prevent COVID-19 in humans, the researchers said.

Last year, Leah Reznikov, Ph.D., an assistant professor of physiological sciences in the UF College of Veterinary Medicine and the study’s principal investigator, began collaborating with David A. Ostrov, Ph.D., an immunologist and associate professor in the UF College of Medicine’s department of pathology, immunology and laboratory medicine. They and other colleagues set out to identify approved drugs that can interfere with the way the SARS-CoV-2 virus binds to cells. Blocking that connection essentially locks a cellular doorway that inhibits the virus’s transmission to the respiratory system.

“We discovered epidemiological data showing that the usage of specific drugs was associated with a reduced likelihood of testing positive for SARS-CoV-2, the virus that causes COVID-19. We then found that these specific drugs exhibited direct antiviral activity against SARS-CoV-2 in the lab,” Ostrov said.

While there is an association between the medications and infection rates, the researchers stressed there is much more to be learned and no cause and effect has been formally established.

To establish their findings, the collaborators focused on angiotensin-converting enzyme-2, or ACE2, a “gateway” protein the virus uses to invade human cells. Working with a colleague at the University of California San Francisco, they analyzed medical records of nearly a quarter million California patients. People age 61 and older who had used certain antihistamines were less likely to test positive for the SARS-CoV-2 virus than those who did not take the medications, the researchers found.

Next, the researchers tested this group of antihistamines for their ability to inhibit the coronavirus in a combination of human and primate cells. Three of the drugs — hydroxyzine, diphenhydramine and azelastine — showed direct, statistically significant antiviral effects on the SARS-CoV-2 virus.

Hydroxyzine, sold as Atarax, and the nasal spray azelastine are prescription medications while diphenhydramine is sold over-the-counter as Benadryl, a treatment for cold and allergy symptoms.

Clinical trials will be necessary to establish the drugs’ effectiveness in prevention, early treatment and as a secondary therapy for severe COVID-19.

Although the findings are intriguing, Reznikov and Ostrov note there is still much to be learned about the mechanisms of how antihistamines interact with the SARS-CoV-2 virus.

Research funding was provided by the UF Clinical and Translational Science Institute, the University of California San Francisco Clinical & Translational Science Institute, the National Institutes of Health and the Center for Data Driven Insight and Innovation at University of California Health.

Q: Could you tell us how you and your lab became interested in conducting the studies you embarked on, around the time the pandemic hit in the spring of 2020?

A: We had a study published right when the pandemic was gaining significant attention in the United States, in the middle of March. In that study, my lab identified a drug that decreased airway obstruction.  That drug happened to have an off-target effect on ACE2, meaning it could bind to ACE2 and change its activity.  That was sort of an ‘aha’ moment for me because we were just learning that ACE2 was the receptor for SARS-CoV-2. That lead me to think that maybe the drug we studied or similar drugs could bind to ACE2 and block SARS-CoV-2 from entering cells. Sort of like a competitive antagonist.

Q: What excites you most about this work?

A: The possibility that our findings might positively impact humans is the most exciting part of our work. With newer evidence demonstrating that a variety of species can now contract SARS-CoV-2, it is also possible our findings can positively influence veterinary medicine.

Q: There’s been so much coverage of the COVID-19 vaccines lately. Could you describe how and why the studies being conducted by your lab supplement the work these new vaccines will be doing to prevent infection when it comes to the fight against COVID-19?

A: The vaccines are game changers. It’s difficult to predict the actual impact that our work will have without a proper clinical trial performed.  If a clinical trial was conducted and it demonstrated that certain antihistamines were associated with prevention or decreased severity of SARS-CoV-2, then it is possible that antihistamines could be widely distributed to help control SARS-CoV-2 while vaccine distribution and administration ramped up.  It is also possible that if antihistamines were shown to be beneficial in a clinical trial, they could be administered widely to other locations/countries that do not readily have access to vaccines or healthcare.

Q: I know the many collaborations have been key to your success. Anything you would like to say about that?

I think collaborating with people is one of the best parts of science.  Bringing distinct skill sets together to make a strong team and have everything fall into place is really rewarding. I continue to work with several individuals that were part of our original team.  We are expanding the collaboration to work with additional people both within the UF College of Veterinary Medicine and the UF College of Medicine.

A: Any more news on the status of a possible clinical trial as a next step in your work?

We have initiated discussions and reached out to several funding agencies. There have been recommendations from UF COM physicians about best ways to move forward, so we are doing as advised.

Q: Anything else you might offer as a personal anecdote or story that reflects your passion for this area of study and the promise of your research?

A: We’ve received dozens of emails from general public providing anecdotal stories about their experience using antihistamines and testing negative for SARS-CoV-2, when they believe they should have tested positive.  As a point of reference, these individuals were already taking antihistamines for health conditions that antihistamines are prescribed for.  Hearing these stories from people all across the country, and even some from around the globe, gives me hope that our findings really will make an impact.