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Published On January 25, 2021

BASIC RESEARCH

Fighting COVID-19 with the Body’s Clock

The fledgling field of chronotherapy—timing drugs to a patient’s circadian rhythms—may yet come to the aid of those at risk from the virus.

Even as the COVID-19 vaccines roll out, current cases of the disease remain on the rise. Better ways to treat the infected are still sorely needed, and that holds especially true for countries where resources are limited and vaccinations are likely to move more slowly. So it is with interest that many are considering a resource as free as the rising and setting of the sun.

Human circadian patterns, chemical changes in the body linked to the time of day, have been mapped to changes in a number of the body’s systems. A relatively new research specialty looks at how those circadian rhythms might be harnessed to boost the effectiveness of many pharmaceuticals. The cancer drug fluorouracil, for instance, appears to work better when given at night, while oxaliplatin, another chemotherapy agent, works best in the afternoon.

What role might timing medication play in the treatment of COVID-19? Most of the attention has focused on the immune response. In one of the worst complications of the infection, lung damage can cause the immune system to go into overdrive, leading to a storm of chemical responses. Anti-inflammatory drugs can blunt that damage but may also compromise the body’s efforts to hunt down and destroy the virus.

It now appears that one class of anti-inflammatory drugs—glucocorticoids—may have varying effects depending on when during the day they’re taken, says Christoph Scheiermann, associate professor at the University of Geneva, whose lab focuses on circadian rhythms of immune response. “We know that delivering these kinds of drugs at a time when immune pathways are active has a stronger effect on reducing the inflammatory response,” Scheiermann says.

The specifics, however, are harder to pin down. John Hogenesch, a genome and circadian biologist at Cincinnati Children’s Hospital Medical Center, has been looking at those immune pathways—which include not only cells but enzymes, transporters and other molecules—to find a way to make immunotherapy delivery more precise and effective. “If you have a short-acting drug, and you give it at the wrong time, you may miss interacting with its target altogether,” he says.

Hogenesch’s group has reviewed 106 clinical trials that timed the administration of 70 drugs, for asthma, arthritis, hypertension, cancer and other conditions. In 75% of the trials, timed administration was linked to better outcomes, safety profiles or both.

In treating COVID-19, anti-inflammatory drugs would ideally kick in at a time that makes the most of the body’s natural responses: a time when the good, virus-targeting parts of the system are less active and potentially harmful immune cells are more of a threat.  That might be the afternoon, according to a recent review article authored in part by Harry Karmouty-Quintana, assistant professor of biochemistry and molecular biology at The University of Texas Health Science Center at Houston – McGovern Medical School.

But the unique attributes of COVID-19 complicate that approach. Being connected to a ventilator or undergoing other late-stage treatments for the virus can dramatically throw off circadian rhythm, says Karmouty-Quintana. The COVID-19 virus itself may target molecules and pathways involved in those rhythms, making it even harder to tell where a patient is in the circadian cycle. And people of advanced age—who account for a disproportionate number of severe cases—are also more likely to have sleep disorders, themselves a kind of circadian disruption.

Moreover, body clocks, in general, tend to vary from person to person. Some people naturally have irregular or misaligned sleep cycles, and others—such as those employed in shift work or experiencing jet lag—might have dysregulated circadian rhythms.

Cytokine levels in the blood can be measured to pinpoint where in the circadian cycle a particular patient might be. But such testing is mostly confined to research settings, says Karmouty-Quintana, and would need to be vastly scaled up to make it feasible for clinical use.

As researchers puzzle out these problems in treatment, there might be more immediate applications on the vaccine front, Hogenesch says. Previous research suggests flu vaccines given in the morning offer more protection than those administered in the afternoon. Evidence also suggests the hormone melatonin—which plays a key role in regulating the body’s sleep-wake cycles—may be able to boost COVID-19 vaccine efficacy.

Though Hogenesch and his colleagues tried to connect with vaccine makers during the development of COVID-19 vaccines, no current trials are factoring in timed administration or melatonin. “Everyone is trying to collect data very quickly,” he says. “Adding additional restrictions makes these trials more complicated.”

Such approaches could be investigated in reseach for later generations of vaccines, however. If adding a clock to the administration protocol for vaccines proved effective, it could be a low-cost, efficient way to get more out of current tools to prevent COVID-19.

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