ARTICLE IN BRIEF
A single dose of a drug approved for erectile dysfunction reduced exercise-induced muscle ischemia in 10 patients with Becker muscular dystrophy. Experts say the findings are promising but more testing is needed to ensure the drug is safe in children with the disorder.
Tadalafil (Cialis), a drug approved to treat erectile dysfunction, reduced exercise-induced muscle ischemia in patients with Becker muscular dystrophy (BMD), according to a paper in the Nov. 28, 2012, Science Translational Medicine. While the study examined the effect of only a single dose of the drug, there are reasons to believe it may work over the longer term as well. It is currently unknown what, if any, contribution ischemia makes to the pathogenesis of BMD, but the results of the study immediately offer a means to determine that contribution, and provide the rationale for further clinical trials in both BMD and Duchenne muscular dystrophy.
BMD is caused by gene mutations that shorten the dystrophin protein, removing some of the so-called “spectrin” repeats in the middle of the molecule. One function of these spectrin units is to bind neuronal nitric oxide synthase mu (nNOS-mu) and target it to the muscle sarcolemma. It has been clear for a number of years that the amount of properly localized nNOS-mu is dramatically reduced in BMD patients.
nNOS-mu creates and releases nitric oxide (NO), a locally acting signaling molecule with a variety of functions. In the muscle, NO is created during exercise, and crosses the sarcolemma to the microvessels in the vicinity. Once there, it increases cyclic GMP (guanosine monophosphate), which ultimately inhibits local alpha-adrenergic vasoconstriction, thus maintaining blood flow to a muscle that is contracting.
Cyclic GMP is broken down by phosphodiesterase, and tadalafil is an inhibitor of phosphodiesterase 5A (PDE5A), the most important form in muscle. Previous work in mouse models of Duchenne muscular dystrophy showed that other PDE5A inhibitors improved some aspects of the disease. That led Ronald G. Victor, MD, and colleagues to test whether tadalafil — the most muscle-specific of available agents —might benefit BMD patients. Dr. Victor is professor of medicine at the David Geffen School of Medicine of the University of California, Los Angeles, and is director of the Cedars-Sinai Center for Hypertension.
From the initial studies in animals, Dr. Victor said, “we thought the nNOS was almost all gone. The key is almost — there is still some residual nNOS, otherwise it wouldn't work,” because some NO is required to increase cyclic GMP concentrations.
To test the ability of tadalafil to prevent ischemia, Dr. Victor had to find a reproducible way of causing it. The most common activity in daily life that triggers vasoconstriction is standing up, which activates the alpha-adrenergic system to reduce blood flow to the skeletal muscles, in order to maintain blood pressure. But rather than replicate that in the lab, Dr. Victor chose to reduce the air pressure on the lower body of his subjects, which reliably shifts about half a unit of blood from the heart in to the lower body, simulating orthostatic stress and causing vasoconstriction.
He measured oxygenation of the forearm muscles using near-infrared spectroscopy under four conditions: while the muscle was relaxed and the lower body was under normal air pressure; relaxed and under low pressure; active and under normal pressure; and active and under low pressure.
In normal subjects and in 10 patients with BMD, oxygenation decreased in relaxed muscle when pressure was lowered. But in normal subjects, when the muscle was exercised even lightly, low pressure did not induce deoxygenation. In nine of the 10 BMD patients, on the other hand, low pressure led to deoxygenation even while the patient was exercising, inducing functional ischemia. One patient had essentially normal responses, and a muscle biopsy indicated that he retained some sarcolemmal nNOS. “This is one end of the Becker spectrum,” Dr. Victor said.
Then Dr. Victor tested a single dose of 20 mg tadalafil in the BMD patients in a randomized, placebo-controlled crossover design. That dose is the same as that used for erectile dysfunction, and half of what is used for pulmonary hypertension, for which tadalafil is also approved.
Under the influence of the drug, most patients' ability to keep their exercising muscles oxygenated in the face of low pressure was essentially normalized. “What was reassuring to me is that the effect was really consistent” among those patients, Dr. Victor said.
In the one patient who had normal responses to the experimental conditions, there was no additional improvement from tadalafil. In another patient, tadalafil had no effect, despite significant exercise-induced ischemia and a confirmed high serum concentration of the drug. His lack of response remains unexplained.
There was no effect on blood pressure, and no patient experienced side effects, including spontaneous erection, flushing, or visual disturbance. The study did not include strength testing, but an increase in strength was unexpected, since weakness arises not from acute ischemia, but from long-term muscle degeneration.
There are no data yet on the duration of effect from a single dose, but the elimination half-life of the drug is 17 hours, suggesting it may be able to produce an extended benefit. There is also no experience yet with multiple dosing, “but that's next,” Dr. Victor said. “I am optimistic the effects will persist.” He noted that in the long clinical experience with tadalafil, including daily use, there is no evidence for development of tolerance.
Next, Dr. Victor said, he hopes to test whether the treatment is also valuable in Duchenne muscular dystrophy, and whether there is a benefit in BMD in cardiac muscle, which is most severely affected in the disease.
“We need to do some long, large clinical trials to see if this translates into a clinically meaningful benefit that will improve quality of life. The promise of a clinical impact is very exciting,” he said.
He also hopes to begin to address the question of whether reducing ischemia has an effect on disease progression. His working hypothesis is that muscle degeneration occurs both from contractile injury and from the repeated ischemic insults of daily living, “but we need to do additional studies to address that. We don't yet know what portion of Becker disability can be attributed to this mislocalization of nNOS. That's the sixty-four thousand dollar question.”
QUESTION ABOUT OVERALL PATHOLOGY
“I think it looks very promising,” commented James Tidball, PhD, professor of physiology and director of the Duchenne Muscular Dystrophy Research Center at the University of California, Los Angeles, who was not part of the study. “The big question that is still out there is how important this defect is to the overall pathology, but this will provide a chance to test it. That it in itself will be a big advance.”
He cautioned that until more testing is done, it would be unwise for patients with either Becker or Duchenne muscular dystrophy to use tadalafil or other PDE5A inhibitors off label. “Patients are asking about it, especially families with Duchenne. But we need to make sure it is safe for pediatric populations. It needs to be tested carefully” before considering more widespread use, he said.
The study was funded by the Muscular Dystrophy Association and the NIH National Center for Advancing Translational Sciences.