University Of Virginia Study Warns That Dexamethasone May Not Be Beneficial For COVID-19 Patients Who Are Diabetic Or Have Low Albumin Levels
: A new study led by researchers from University of Virginia-U.S. along with scientist from Polish Academy of Sciences-Poland, Poznan University of Technology-Poland, Medical University of Bialystok-Poland and University of South Carolina-U.S. has discovered a about how the human body transports dexamethasone, a drug that can increase the survival chances of patients with severe COVID-19, with findings showing that diabetes and other factors may reduce its potentially lifesaving effectiveness.
The study findings alert doctors and clinicians to rethink how they dose the drug for certain groups of patients.
Dexamethasone has been shown to cut deaths by approximately 30% for COVID-19 patients who were on ventilators and by 20% for those who were receiving oxygen therapy but were not on ventilators. Dexamethasone is a corticosteroid that exhibits potent anti-inflammatory and immunosuppressant effects. Dexamethasone suppresses the immune system by binding to the glucocorticoid receptor, which up-regulates the expression of anti-inflammatory proteins and down-regulates the expression of pro-inflammatory proteins.The reduced inflammation provides some relief for patients whose lungs have been devastated by the overactive immune response that accompanies severe cases of COVID-19, but shows no benefit for patients who do not require respiratory support . Along with anti-inflammatory action, steroids can also reduce airway spasm and obstruction in patients who have asthma or chronic obstructive pulmonary disease: groups of patients that are at especially high risk. In the RECOVERY trial, the therapeutic effect of dexamethasone appeared to depend on `using the right dose, at the right time, in the right patient'. A meta-analysis of seven randomized clinical trials that evaluated the efficacy of corticosteroids did not find evidence that a higher dose of corticosteroids was associated with a greater benefit than a lower dose of corticosteroids. In this study, the study team proposed that there may be another important factor which might influence the effectiveness of dexamethasone and should be investigated ie its vascular transport.
The research findings are published in the International Union of Crystallography (IUCr) Journal. https://journals.iucr.org/m/issues/2020/06/00/be5285/index.html
The study team has determined how a protein in our blood called serum albumin picks up dexamethasone and takes it where it is needed.
Dexamethasone is primarily delivered throughout the body by serum albumin; about 77% of dexamethasone in the blood is bound to plasma proteins, mostly to serum albumin Serum albumin has a typical blood concentration of 35–55 g l−1 (600 µM) and constitutes up to 55% of the total plasma protein. During its month-long lifetime, an albumin molecule makes nearly 15 000 trips around the body, facilitating the vascular transport of hormones, metals, fatty acids and drugs. The extensive drug-binding capacity of albumin is enabled by its high concentration and by the presence of at least ten distinct drug-binding sites on the molecule. Preferred binding sites on albumin are known for only 32 drugs, including ibuprofen, warfarin, cetirizine, naproxen, diazepam, eto
dolac and halothane. The free fraction of dexamethasone in blood and its distribution over time can be affected by several factors, including a decreased albumin plasma level, drugs competing for the same binding sites and albumin glycation.
It should be noted that low serum albumin levels are already considered a major risk factor for severe COVID-19, as is diabetes.
The study suggests diabetes or low albumin levels may make it difficult for patients to get the benefits of dexamethasone, a corticosteroid that calms the hyperactive immune response that can lead to death in severe COVID-19.
It has been found that diabetes is associated with high blood sugar levels, which results in a modification of albumin that may alter the binding site for dexamethasone. Other drugs may also compete with dexamethasone for the limited space in serum albumin's cargo holds. Albumin's cargo capacity is also naturally decreased when there is a low albumin level in the blood.
Currently 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.
So as to provide a comprehensive picture, the study was conducted in collaboration among structural biologists, computer scientists and clinicians.
Dr Wladek Minor, PhD, Study Lead Author, Department of Molecular Physiology and Biological Physics, University of Virginia told Thailand Medical News, “Every co-researcher in this study 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."
Co-researcher Dr Ivan Shabalin, PhD, the first author of a new paper outlining the findings said,"Working on this interdisciplinary team and seeing how our research in fundamental science may save lives in the current pandemic felt extremely rewarding."
Dr Minor and his colleagues for the first time have demonstrated exactly how serum albumin binds with dexamethasone so that the drug can be distributed through our bodies.
It was found that 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 study team hypothesized that high dexamethasone levels might affect testosterone transport by competing for the same drug site on albumin.
It was also found that 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.
To further complicate things, 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.
The study team says that more research is needed to determine the best dosing in various patient populations, particularly for people with diabetes or low albumin levels.
In order 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 study team found that patients who died had lower albumin levels than those who survived.
Interestingly 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.
The study team reports the molecular structure of albumin in complex with dexamethasone, provide new insights into the mechanism of its transport, and analyze serum albumin and glucose levels in publicly available clinical data. The team hypothesizes that compromised vascular transport of dexamethasone may limit its effectiveness in COVID-19 therapy, and propose that adjusted dexamethasone regimens should be further investigated.
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