A study conducted in 10 boys with Duchenne muscular dystrophy (DMD) has found that blood flow to exercising muscles is deficient and that treatment with either tadalafil (Cialis) or sildenafil (Viagra) normalizes this blood flow, at least in the short term (after one dose of either drug).
Tadalafil and sildenafil, both PDE5 inhibitors, are approved by the U.S. Food and Drug Administration (FDA) to treat erectile dysfunction.
Michael Nelson at Cedars-Sinai Medical Center in Los Angeles, and colleagues, published the new PDE5 inhibitor findings online May 7, 2014, in Neurology.
In their paper, the authors say that the present study reports three major new findings: there is insufficient blood flow to exercising muscles in children with DMD, even when they are taking other medications that might be expected to combat this problem; tadalafil alleviates this blood-flow deficiency in proportion to the dose given; and sildenafil replicates the effect of tadalafil, strongly supporting PDE5 inhibition as the mechanism by which these drugs work.
"These results add to the body of knowledge that inadequate blood flow to exercising muscle is part of the problem in Duchenne and Becker muscular dystrophies," said neurologist Valerie Cwik, MDA's chief medical and scientific officer. "Drugs like sildenafil and tadalafil have been shown to improve blood flow in these muscular dystrophies. However, many questions remain unanswered, including whether these drugs can preserve muscle strength and function. We look forward to learning the results from the larger trials in both disorders."
Eli Lilly, maker of Cialis, is supporting a large-scale, phase 3 trial of tadalafil versus a placebo in DMD that is open to new participants.
MDA support for related research
Ronald Victor, a physician specializing in cardiovascular disorders at Cedars-Sinai Medical Center in Los Angeles, and the senior author on the newly reported study, has received MDA support for closely related research on blood flow in men with Becker muscular dystrophy (BMD). Both DMD and BMD are caused by mutations in the gene for the muscle protein dystrophin, and patients with either disorder have been found to have insufficient increases in blood flow to contracting muscles.
In 2012, Victor and colleagues, with MDA support, found that tadalafil alleviates the muscle blood-flow deficiency in men with BMD.
A larger study of tadalafil in men with BMD is ongoing but closed to new participants.
About the pilot study of tadalafil, sildenafil in DMD
Nelson and his research team first studied 10 boys with DMD who were asked to perform handgrip exercise and undergo various tests of blood flow and other functions, and compared them to 10 boys who were the same age but didn't have DMD.
The researchers found that signals from the nervous system that increase blood flow in exercising muscles in boys without DMD do not appear to do the same in boys with DMD.
In the next stage of the study, boys with DMD received single doses of sildenafil or tadalafil, followed by two weeks without either drug, and then a single dose of whichever medication they had not received the first time.
All participants were receiving corticosteroid drugs — either prednisone or deflazacort — and five were also receiving the heart medications lisinopril or losartan, given to postpone or prevent the development of cardiac abnormalities.
Participants received 0.5 milligrams per kilogram of body weight of sildenafil or tadalafil as a first dose and then 1 milligram per kilogram of the drug not yet taken as the second dose, after the two-week "washout" period.
Measurements of blood flow were taken an hour after sildenafil was given and three hours after tadalafil was given, to match the expected peak blood levels of these drugs.
Tadalafil restored muscle blood flow in boys with DMD in proportion to the dose given, with higher doses correlated with greater blood flow. In six of the participants, the investigators confirmed these results with sildenafil.
Both drugs appeared safe and well-tolerated. Facial flushing occurred in all participants with both doses of either PDE5 inhibitor. Blood pressure was not affected by either drug. Two participants experienced prolonged erections, but these were not painful or dangerous and resolved without treatment.
"We do not know whether the improved blood flow regulation will be sustained with chronic administration [of PDE65 inhibitors]," the study authors write. They also note, "This proof-of-concept study does not address the crucial question of whether restoring normal blood flow regulation will preserve dystrophic skeletal muscle and slow disease progression."
However, they note that the data from this and other studies "have informed the design of a pivotal, multicenter clinical trial to determine whether chronic daily tadalafil can preserve muscle function in boys with DMD."
To participate in the large-scale trial of tadalafil in DMD
For more information about participating in the phase 3, large-scale, 48-week trial of tadalafil in DMD, contact Eli Lilly at (877) 285-4559 or (317) 615-4559, Monday through Friday from 9 a.m. to 5 p.m. Eastern time. To learn more, read A Study of Tadalafil for Duchenne Muscular Dystrophy (a list of study sites is posted) and Trial of Tadalafil in DMD Open to Participants.