The drug tadalafil (Cialis, Adcirca), which dilates blood vessels and is approved to treat erectile dysfunction and pulmonary hypertension, has been found to improve blood flow to exercising forearm muscles in people with Becker muscular dystrophy (BMD). Enhancing blood flow may reduce damage related to muscle contraction, although this has not yet been established.
Cardiologist and MDA research grantee Ronald Victor at Cedars-Sinai Medical Center in Los Angeles, with colleagues there and at other institutions, reported the findings Nov. 28, 2012, in Science Translational Medicine. (Subscribers can download the paper in its entirety.)
"Previous studies in laboratory mice suggested that drugs such as tadalafil could restore proper blood flow, but this is the first study showing that the drug may offer a therapeutic strategy in humans," said Victor, who directs the Cedars-Sinai Hypertension Center of Excellence, is associate director of the Cedars-Sinai Heart Institute, and holds the Burns and Allen Chair in Cardiology Research.
BMD and the related disorder Duchenne muscular dystrophy (DMD) both result from a deficiency of the dystrophin protein at the muscle-fiber membrane.
It's been recognized since the late 1980s that a complete lack of dystrophin (associated with DMD) or the presence of smaller-than-normal dystrophin protein (associated with BMD) renders the membrane fragile and the muscle fibers vulnerable to injury and destruction.
More recently, it’s been learned that dystrophin deficiency at the muscle-fiber membrane causes additional adverse effects, including reduced blood flow to exercising muscles.
If certain parts of the dystrophin protein are missing, an enzyme called neuronal nitric oxide synthase, or nNOS, isn't properly anchored to the membrane, and instead floats free in the fiber's interior. Without properly located nNOS and adequate amounts of the nitric oxide it helps synthesize, blood flow to exercising muscles is altered.
Normally, nitric oxide secreted in active muscle fibers overrides signals from the nervous system that constrict (narrow) blood vessels. But, when nNOS is mislocated and nitric oxide is deficient — as is often the case in BMD and DMD — the ability to override these vessel-constricting signals is impaired, with the result that blood flow to exercising muscles is impeded.
In the last few years, laboratory experiments have suggested that drugs like tadalafil may be able to restore blood flow to exercising muscles even when nNOS is mislocated and nitric oxide is deficient. Tadalafil and the related drug sildenafil (Viagra, Revatio) are PDE5 inhibitors, prolonging the effects of nitric oxide.
Victor and colleagues studied 10 men ages 18 to 55 with BMD who were able to walk and had normal heart function.
First, they compared them to seven men without BMD who were matched for age and other characteristics. Not surprisingly, they found the men with BMD had lower grip strength in both arms than did the controls.
They then measured blood flow to the forearm of the BMD-affected group and the control group during handgrip exercise, while applying negative pressure to the lower body. The negative pressure was applied to trigger signals from the nervous system that constrict blood vessels.
In the men without BMD, blood flow to the exercising forearm was maintained, despite the signals from the nervous system. In the men with BMD, however, it was markedly decreased, supporting the researchers' hypothesis that dystrophin deficiency can impair the body's usual ability to override vessel-constricting signals during exercise.
The researchers also hypothesize, although this was not established, that this diminution in blood flow in BMD or DMD could be harmful to the muscles, hastening disease progression.
After a single dose of tadalafil, nine of the 10 men with BMD showed completely restored blood flow to the exercising forearm, despite continued application of negative pressure to the lower body. The reason for the lack of response to tadalafil by one study participant isn't clear.
Nine out of 10 participants did not show restored blood flow after receiving a placebo. However, one person did. Interestingly, when the researchers analyzed his dystrophin mutation, they found it was one that was likely to allow for normal localization of nNOS to the muscle-fiber membrane.
There were no adverse events or side effects from the tadalafil.
Update (March 29, 2013): This news item was updated to reflect that recruitment for the Revatio in heart disease trial has been suspended.
The researchers are encouraged by the results, although they say larger and longer studies will be necessary before tadalafil or similar drugs can be recommended to people with BMD.
For one thing, they say, they excluded patients with heart failure, which biased their sample toward people with BMD from certain types of dystrophin mutations. They don't know whether tadalafil would be equally effective for patients with various dystrophin mutations.
They say they also don't know whether the positive effects of tadalafil on blood flow to exercising muscles would be sustained over time, although they note that patients who take the drug for erectile dysfunction or pulmonary hypertension experience sustained effects.
They also say they don't know whether tadalafil or other PDE5 inhibitors can slow disease progression or improve strength in BMD or DMD, although they suspect that, at least for people with certain dystrophin mutations, they may reduce ongoing muscle damage.
A longer, multicenter trial is being planned. For trials of tadalafil and the related sildenafil in BMD and DMD that are open now, see:
To learn more about tadalafil in BMD, read:
About Clinical Trials
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To learn more, see Learn About Clinical Studies and Being a Co-Adventurer, which is about neuromuscular disease clinical trials. To see a continuously updated database of clinical trials, go to ClinicalTrials.gov.