Duchenne primarily affects males and is usually diagnosed by age 4. While a variety of therapies can slow progression and extend life expectancy, the disease has no cure yet. Those born with Duchenne seldom live beyond their mid-20s.
In 2017, researchers learned that weekly doses of prednisone, a widely prescribed steroid, appear to provide better support for weakening muscles compared to daily doses while also reducing the significant side effects induced by daily intake.
More than 2.5 million Americans use prednisone and similar drugs to manage inflammation for conditions ranging from allergy treatment to preventing organ transplant rejection.
Confirming a clear time-based influence for the use of prednisone among Duchenne patients very likely will help improve outcomes for affected children, but it also raises questions about the time of day for other uses of the steroid.
“Our internal clock system is quite complex. Not only do we have our central circadian rhythm dictated by a special region in our brain, but all our tissues – for instance, muscle – have their internal molecular clock constantly ticking,” Quattrocelli says.
In mice, researchers found that once-weekly prednisone doses administered at the start of the light period (approximately 7 am) promoted muscle function.
The team observed that the treatment boosted nutrient utilization and strengthened mitochondrial bioenergetics in muscle. It also increased endurance and improved muscle mass and muscle force. However, these responses were lost when dosing occurred in the dark period.
With mice being primarily nocturnal, their circadian clocks vary considerably from humans, so the specific time of day that achieves the most beneficial effect would be different for humans than for mice.
However, researchers report that many of the time-based mechanisms involving muscle cell activity are conserved between mice and humans, which suggests that timing also will matter for treating people with muscle diseases.
If confirmed in future human studies, the findings suggest that precision drug timing may maximize the drug benefits while avoiding side effects that may be more likely when a drug is given at the wrong time of day.
That might help improve the efficacy of treatment and possibly quality of life for a range of muscle conditions, from muscular dystrophy to aging to metabolic stress.
This study focused exclusively on prednisone and muscle tissue. The time-based effectiveness of other synthetic glucocorticoids, such as dexamethasone and vamorolone (currently in trial for Duchenne muscular dystrophy (NCT03439670)) remains to be determined.
Aside from differing drug characteristics, various tissues have their internal clocks. So more research will be needed to determine if the day vs. night effects of prednisone also apply when treating conditions affecting other organ tissues.
Notably, most uses of prednisone are related to controlling inflammation, often in immune conditions rather than muscle diseases. Time of day studies for treating immune conditions have only just begun.
Besides the obvious difference that mice are nocturnal animals while humans are mainly diurnal, we must consider many factors that will inevitably affect chronopharmacology in our population.
For instance, people have far more complex patterns of eating, working, playing, and sleeping compared to mice. All these differences would need further exploration to translate mouse-based learning to human medical care.
Source: Medindia
