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A plant flavonoid found in capers and green tea is being eyed by some as a potential adjunct therapy for patients with COVID-19, but whether quercetin will stand the test of rigorous trials remains unclear.

Proponents of the supplement say it could be one part of a treatment regimen along with interventions like remdesivir or convalescent plasma, and that its over-the-counter availability and relatively good safety profile serve as advantages.

Skeptics see it as yet another small molecule in which researchers have overinvested hope. Long-time drug discoverer , PhD, said small molecule drugs like quercetin are known as "frequent hitters," because the molecular targets quercetin has been shown to interact with are so varied, numerous, and impotent that it makes it difficult to find meaningful associations.

With the disappointment of much-hyped hydroxychloroquine still fresh, clinicians may be hearing more about quercetin -- so 番茄社区app took a deep dive into the science behind the supplement.

Antiviral, Antioxidant Mechanisms

Quercetin has long been evaluated for its against cancers, heart disease, and cells that release histamines.

The agent promotes SIRT2, which then inhibits the NLRP3 inflammasome assembly involved with COVID-19 infection, said Samuel F. Yanuck, DC, of the Program on Integrative Medicine at the University of North Carolina Chapel Hill School of Medicine, who co-authored a on the subject. It also plays a role in facilitating zinc transportation across lipid membranes, Yanuck said.

"It's not a bizarre or experimental substance and given it has these potential important biological roles, I think it's worth being considered as part of an overall strategy," Yanuck told 番茄社区app, adding that quercetin would need to be one part of a multifactorial treatment regimen.

In cell cultures, quercetin has been shown to prevent viral entry and reduce the cytopathic effects of many viruses, including rhinovirus and poliovirus. In a rodents administered quercetin before being exposed to a lethal load of Ebola virus survived.

COVID-19 has been associated with high levels of interleukin-6, depleted levels of interferons, and a cytokine storm that damages the body and is related to respiratory failure, said Ruben Colunga Biancatelli, MD, of Old Dominion University in Norfolk, Virginia, and first author of a paper on quercetin and vitamin C as a potential therapy for treating SARS-CoV-2 in .

Using this rationale, researchers are postulating that vitamin C should be administered with quercetin because it can recycle oxidized quercetin, producing a synergistic effect and enhancing quercetin's antiviral capability, Biancatelli added.

After the 2003 SARS-CoV-1 coronavirus outbreak, researchers in China found quercetin and other small molecules interfering with its ability to infect host cells.

Human Studies

The signal from the SARS-CoV-1 study led researcher Hasan Önal, MD, and co-authors to conduct an open-label examining quercetin's role in COVID-19. In the trial, 95 patients with COVID-19 are receiving a 1,000-mg active treatment dose and 113 healthcare workers are receiving a 500-mg dose as prophylaxis. In both treatment arms, quercetin is administered with vitamin C and bromelain, a supplement extracted from pineapples that is used for burns or inflammation.

As of March, no COVID-19 cases were recorded among healthcare workers taking prophylactic quercetin and no deaths were observed among patients with COVID-19 on quercetin treatment, Önal told 番茄社区app in an email. However, there is no active comparator or placebo group in the trial and patients on quercetin self-selected the treatment, Önal added.

Önal's team also drew on a lone hospital practice guidance from Eastern Virginia Medical School in Norfolk, Virginia, written by Paul E. Marik, MD, chief of pulmonary and critical care medicine there. Marik included quercetin in the for prophylaxis and mild to moderate cases. He co-authored the paper on quercetin and vitamin C as a potential COVID-19 therapy.

"It's based on good, basic science and there are some really interesting papers postulating it's benefit, but unfortunately we don't have any [clinical] data," Marik told 番茄社区app. "If you have something that is potentially beneficial, safe, and cheap, what do you have to lose?"

Given the antiviral activity that has been demonstrated in preclinical data, it would be reasonable to prescribe quercetin in the context of a properly designed clinical trial for treating COVID-19, commented David M. Aronoff, MD, of Vanderbilt University in Nashville, Tennessee.

However, Aronoff told 番茄社区app in an email that "it should be subjected to rigorous clinical study and not recommended for use outside of clinical trials."

Warner C. Greene, MD, PhD, of the Gladstone Institutes and the University of California San Francisco, agreed that before widely administering quercetin to patients with COVID-19, it should be tested in a well-controlled clinical trial.

Although Greene told 番茄社区app in an email that quercetin can also act as a free radical scavenger with antioxidant effects, he said he was "not overly optimistic about quercetin as a potent antiviral for SARS-CoV-2 in patients."

The Next HCQ?

Lowe compared the recent attention quercetin is receiving to the early popularity of hydroxychloroquine, which showed promise in preclinical studies and was endorsed by President Donald Trump. Ultimately, hydroxychloroquine was shown to have no survival benefit and in fact trended toward an increased risk of death among COVID-19 patients.

"Twenty years from now, when we're remembering these COVID days, there are still going to be people with websites talking about how hydroxychloroquine could have saved someone if they had only done X, Y, and Z," Lowe said. "I don't think we are going to see any amazing therapies like this popping up."

In an email to 番茄社区app, Mark Cushman, PharmD, PhD, of Purdue University College of Pharmacy in West Lafayette, Indiana, said the analogy to hydroxychloroquine was "not unrealistic" as both agents are proposed to have similar mechanisms and inhibit the virus from entering cells.

"Quercetin is not a good candidate for drug development because it is metabolically unstable and it lacks potency in in vitro experiments," Cushman wrote. "The next step would be to demonstrate anti-SARS-CoV-2 activity in an animal model, but that would not likely lead to promising results because of the two factors listed in the previous sentence."

Lowe agreed, noting that the pharmacokinetics of quercetin show it "disappears in human dosing like a snowflake hitting a pancake griddle."

"If it just weakly hits some stuff enough for some academics to publish a paper where they list quercetin as one of the things that interacts with protein X, that does not mean it rises to the level of something that is pharmacokinetically interesting," Lowe told 番茄社区app. "You can find all these targets associated with various diseases and you can see it's a hit for this or that, but none of those rise to the level of actual interest."

Önal's trial in Turkey is slated to be completed this month, he said. Michel Chrétien, MD, and Majambu Mbikay, of the Montreal Clinical Research Institute in Canada, told CBC Radio in late February that they were awaiting approval for a . As of June, they had not yet registered any studies on ClinicalTrials.gov.

Neither Chrétien nor Mbikay responded to a request for comment from 番茄社区app, but in the interview with CBC Radio, Chrétien cautioned against giving "false hope" for the treatment.

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