In a mouse model, weekly doses of prednisone to enhance muscle function were significantly more effective when given at specific times-ScienceDaily.

Duchenne muscular dystrophy mainly affects men and is usually diagnosed by the age of four. Various treatments can slow the progression and prolong life expectancy, but the disease has not yet been cured. People born with Duchenne muscular dystrophy rarely live beyond their mid-twenties.

In 2017, researchers found that a weekly dose of the widely prescribed steroid prednisone better supports muscle weakness compared to a daily dose, while being caused by daily intake. I learned that it seems to reduce serious side effects. Currently, new studies report that the time of delivery of the drug may be important for the effectiveness of such treatments.

Detailed findings based on the mouse model were published online on February 18, 2022. Science Advances.. Dr. Mattia Quattrocelli, a researcher at the Cincinnati Children’s Cardiovascular Institute, is the corresponding author of this study. Co-authors include Dr. Daniel Levine, Dr. Clarapeak, Dr. Joseph Bass, and Lab Team Members of Dr. Elizabeth McNally, Ph.D., researchers at Cincinnati Childrens and Northwestern University. Was included.

The findings represent another advance in the growing field of time pharmacology, examining how drugs work in sync with or inconsistently with our body’s circadian rhythms. Many important discoveries in this area have been guided by Cincinnati Children’s experts. Cincinnati Childrens recently launched the only clinic in the country specializing in pediatric circadian sleep disorders.

Confirming a clear time-based effect on prednisone use in patients with Duchenne muscular dystrophy is very likely to help improve outcomes in affected children, but with other use of steroids. It also raises questions about time. More than 2.5 million Americans use prednisone-like medicines to control inflammation in conditions ranging from allergy treatment to prevention of organ transplant rejection.

“Our internal clock system is very complex. Not only does it have a central circadian rhythm determined by a special area of ​​the brain, but every tissue (eg muscle) has its own ever-changing interior. There is a molecular clock. ” “We are beginning to learn more about the importance of drug dosing timing to tissue effects.”

“This study focused on the interaction of muscle clocks with drug-activating molecules, but how these findings extend beyond the specific uses of prednison we studied. It takes quite a lot of research to determine, “he says.

Potential tool for precision dosing

In mice, researchers found that weekly prednisone administration at the beginning of the light period (around 7 am) promotes muscle function. The team observed that this treatment promoted nutrient utilization and enhanced the bioenergy of muscle mitochondria. It also increased endurance and improved muscle mass and strength. However, these reactions were lost when the medication was given in the dark.

Circadian clocks are quite different from humans because mice are primarily nocturnal. Therefore, the specific time to achieve the most beneficial effect differs between humans and mice. However, Quattrocelli et al. Report that many of the time-based mechanisms associated with muscle cell activity are conserved between mice and humans. This suggests that timing is also important in the treatment of people with muscle disorders.

When confirmed in future human studies, findings suggest that accurate drug timing may maximize the benefits of the drug while avoiding the side effects that are likely to occur if the drug is given at the wrong time. It suggests that there is. It may help improve the effectiveness of treatment and possibly quality of life for a variety of muscle conditions, from muscular dystrophy to aging and metabolic stress.

Further research needed to investigate the impact

This study focused only on prednisone and muscle tissue. The time-based efficacy of other synthetic glucocorticoids, such as dexamethasone and bamorolone (currently under trial for Duchenne muscular dystrophy (NCT03439670)), has not yet been determined.

Another pilot clinical trial is underway at Northwestern University (NCT04054375) that uses prednisone in forms other than Duchenne muscular dystrophy once a week. This study adapts the time of drug intake based on the new findings reported here.

Patients were instructed to take the drug in the evening (between 7 and 9 pm) after the last meal in the first attempt to reflect the positive findings found in the mice. “The results of the trial are still pending and we hope to help improve our time pharmacological approach to muscular dystrophy and other symptoms,” said Quattrocelli.

Apart from different drug properties, different tissues have their own internal clocks. Therefore, further research is needed to determine if the day and night effects of prednisone also apply when treating conditions that affect other organ tissues. In particular, most uses of prednisone are associated with the control of inflammation and are often immune rather than muscular disease. Time zone research for treating immune status is still in its infancy.

“Every tissue in our body has an internal clock, and in this study we use the internal clock of the muscle to interact with time-specific drug administration and enhance the positive effects of the drug on energy and function. We are reporting the fact that we can do it. Research is needed to accurately translate these findings into humans, “says Quattrocelli. “In addition to the obvious difference that mice are nocturnal animals and humans are predominantly diurnal, we need to consider many factors that inevitably affect the time pharmacology of our population. For example, people have much more complex diet, work, play, and sleep patterns compared to mice. All these differences are further to transform mouse-based learning into human medicine. I need to investigate. “

About this study

Funding sources for this work included the Councilor’s Award from the National Institutes of Health (AR052646, HL061322, DK121875, HL158531), the Cincinnati Children’s Awards, and the Cardiovascular Institute Translation Grant. Quattrocelli and McNally are also listed as inventors of related patent applications filed by Northwestern University.