The RECOVERY trial, led by the University of Oxford, led to the finding that dexamethasone can decrease the COVID-19 mortality rate for those patients with severe SARS-CoV-2 infections necessitating assistance with breathing via ventilator or mechanical device. In fact, even POTUS was given the corticosteroid when he was diagnosed with COVID-19. However, a new study showcases some new risks associated with the drug. More specifically a discovery associated with how the body actually transports dexamethasone indicates that diabetes and other factors may actually reduce its potential lifesaving effectiveness. Based on the findings from a team of scientists from University of Virginia Medical School, the University of South Carolina and Poland, doctors may need to consider how they dose the drug for select groups of patients. The team’s findings indicate diabetes or low albumin levels may make it difficult for patients to achieve the benefits of dexamethasone.
Now a drug on many national COVID-19 medication guidelines thanks to the RECOVER trial, doctors now may consider who they administer this drug moving forward.
The team identified that diabetes actually is associated with high blood sugar levels which results in a modification of albumin and this in fact may alter the binding site for dexamethasone. In a recent University of Virginia Medical School press release its indicated that other drugs may also compete with dexamethasone for the limited space in serum albumin’s cargo holds. It turns out that low albumin levels in the blood are associated with reduction in cargo capacity.
Lead researcher Wladek Minor PhD of UVA’s Department of Molecular Physiology and Biological Physics described “At this point, we do not have a readily available treatment better than dexamethasone for severe COVID-19 cases, but, like COVID-19 itself, its effectiveness is somewhat unpredictable.” Dr. Minor continued “In order to provide a comprehensive picture, this research was conducted in collaboration among structural biologists, computer scientists and clinicians. So, every author of this paper had to step out of the box to combine medical data with structural biology results in order to suggest possible modifications of the treatment that could potentially save more human lives.”
Researcher Ivan Shabalin, PhD, the first author of a new paper outlining the findings, added: “Working on this interdisciplinary team and seeing how our research in fundamental science may save lives in the current pandemic felt extremely rewarding.”
Dexamethasone and COVID-19
For the first time, Minor and his colleagues have demonstrated exactly how serum albumin binds with dexamethasone so that the drug can be distributed through our bodies.
Serum albumin binds with dexamethasone the same way it binds with the hormone testosterone, suggesting that the two could compete with each other, the researchers report. More men die of COVID-19 than women, and low testosterone levels have already been associated with worse outcomes. The authors of the study hypothesized that high dexamethasone levels might affect testosterone transport by competing for the same drug site on albumin.
Serum albumin also uses the same binding dock to pick up several common nonsteroidal anti-inflammatory drugs, so doctors may need to consider the potential for competition in deciding COVID-19 treatment plans, the research suggests.
More Research Required to Understand
That said, it’s not as simple as increasing the dexamethasone dose for patients with diabetes or low serum albumin. Too much dexamethasone can be harmful or have unwanted side effects. More research is needed to determine the best dosing in various patient populations, particularly for people with diabetes or low albumin levels, the researchers say.
Real World Data in Wuhan
To better understand serum albumin’s role in COVID-19, the researchers analyzed data from 373 patients at a hospital in Wuhan, China, that treated many severe cases of the disease. The scientists found that patients who died had lower albumin levels than those who survived. Those who died also had higher levels of blood sugar. That aligned with the researchers’ conclusion that high blood sugar could affect serum albumin’s ability to carry its cargo.
“In order to provide rapid response to emerging biomedical challenges and threats like COVID-19, we need to analyze medical data in the context of other in-vitro and in-vivo results,” Minor said. “Five years ago, I wrote in Expert Opinion in Drug Discovery that, ‘The use of recent advancements in biochemical, spectroscopy and bioinformatics methods may revolutionize drug discovery, albeit only when these data are combined and analyzed with effective data management systems. Accurate and complete data management is crucial for developing experimental procedures that are robust and reproducible.’ This assessment is still valid, and, clearly, not enough progress has been made, because it is mistakenly not recognized as a grand challenge for biomedical sciences.”
“Until a vaccine or new drugs are widely available, we have to make the best use of the drugs we know can help fight COVID-19,” added team member Dariusz Brzezinski, PhD.
The researchers have published their findings in the scientific journal IUCrJ, and the research will be featured on the journal’s cover. The research team consisted of Shabalin, Mateusz P. Czub, Karolina A. Majorek, Brzezinski, Marek Grabowski, David R. Cooper, Mateusz Panasiuk, Maksymilian Chruszcz and Minor. Minor disclosed that he has participated in the development of software and data tools that were later commercialized and, some of which were used in the research. A full list of the authors’ disclosures is included in the paper.
The research drew on resources from Advanced Photon Source, a Department of Energy Office of Science User Facility at Argonne National Laboratory. The work was supported by the National Institutes of Health’s National Institute of General Medical Sciences, grants R01-GM132595 and U54-GM094662; the Polish National Agency for Academic Exchange, grant PPN/BEK/2018/1/00058/U/00001; the Polish National Science Center, grant 2020/01/0/NZ1/00134; a Robert R. Wagner Fellowship at UVA; and a COVID-19 Research Initiative grant from the Office of the Vice President for Research at the University of South Carolina.
Wladek Minor, PhD of University of Virginia, Department of Molecular Physiology and Biological Physics