Tadalafil Relieves Ischemia in Becker Muscular Dystrophy

Ricki Lewis, PhD

November 28, 2012

The drug tadalafil (Cialis, Lilly), already approved to treat erectile dysfunction and pulmonary hypertension, also corrects abnormal blood flow in exercised forearms of men with Becker muscular dystrophy (BMD).

A proof-of-concept pilot study showing that treatment with tadalafil alleviated functional muscle ischemia and restored normal blood flow regulation in the muscles of a small number of men with BMD is published in the November 28 issue of Science Translational Medicine.

"Patients with Becker and Duchenne muscular dystrophy have no specific treatment, so patients are hungry for some hope. But it's important to evaluate this drug scientifically, in a blinded fashion," Ronald G. Victor, MD, director of the Cedars-Sinai Center for Hypertension, Burns and Allen Chair in Cardiology Research at the Cedars-Sinai Heart Institute, Los Angeles, California, and leader of the research team, told Medscape Medical News.

"I am concerned that patients with muscular dystrophy might ask their doctors to prescribe tadalafil based on our study," Dr. Victor said. "We haven't yet shown a sustained effect over time." However, the investigators hypothesize that using the drug to reduce muscle injury might slow the course of BMD.

Override Failure of Vasodilation?

BMD and the more prevalent and more severe Duchenne muscular dystrophy (DMD) are X-linked disorders that affect the cytoskeletal protein dystrophin. Patients with BMD live a normal lifespan but develop progressive muscle wasting, and many develop cardiomyopathy.

Elizabeth A. Martin, PhD, from Cedars-Sinai Medical Center, and colleagues hypothesized that tadalafil might override failure of exercised skeletal muscle to vasodilate, which men with BMD experience as muscle fatigue and injury. Their work follows up on experiments done by others with the mdx mouse model of BMD/DMD that indicated the drug might exert this effect.

Dystrophin provides scaffolding that anchors other proteins in the sarcolemma. These include a muscle-specific splice variant of the neuronal isoform of nitric oxide synthase (nNOSμ) that prevents muscle damage and fatigue from exercise.

Normally during exercise, an adaptive response called functional sympatholysis counters local α-adrenergic vasoconstriction, perfusing the working skeletal muscle. In DMD and BMD, residual nNOSμ may be localized in the cytosol rather than the sarcolemma. The researchers hypothesized that the drug might mobilize this supply.

Both tadalafil and sildenafil (Viagra, Pfizer) inhibit phosphodiesterase 5, which breaks down cyclic guanosine 3'5'-monophosphate (cGMP), the downstream target of nitric oxide in vascular smooth muscle. The drugs prolong the half-life of cGMP, compensating for insufficient or mislocated nNOSμ.

The researchers conducted 2 experiments for this report. First, a case-control study compared 10 patients with BMD who had disease severity similar to that of 7 healthy controls matched for age, body mass index, blood pressure, heart rate, and left ventricular ejection fraction. Patients with heart disease were excluded.

Participants performed a light rhythmic handgrip exercise using a dynamometer and were exposed to lower body negative pressure (LBNP), a technique to stress the cardiovascular system. For this, the lower body was enclosed in a negative-pressure chamber, simulating mild orthostatic stress that induces a reflex increase in sympathetic vasoconstriction. The researchers used near-infrared spectroscopy to measure decrease in forearm muscle oxygenated hemoglobin (Hb) and myoglobin (Mb).

At rest, case-patients and controls had the same forearm muscle oxygenation. Under LBNP with forearm movement, decrease in oxygenation was attenuated in controls but not in patients with BMD, demonstrating muscle ischemia in the disease.

Double-Blind Trial

Next, in a double-blinded randomized placebo-controlled crossover trial, each of these patients took one oral 20-mg dose of tadalafil or placebo, followed by a 2-week washout period, and then took the opposite pill. One of the original 10 patients was excluded because his unusual mutation still allowed targeting of nNOSμ to the sarcolemma.

The researchers then assessed sympatholysis after each treatment. They found that tadalafil restored normal sympatholysis in 8 of 9 patients with BMD. The researchers don't know why the ninth patient didn't respond.

Specifically, the drug attenuated muscle oxygenation by 52% ± 12% (change in HbO2 + MbO2, –17% ± 2% at rest vs –9% ± 2% during handgrip; P < .01) under LBNP conditions in patients with BMD. No adverse effects occurred.

The study demonstrates that binding of nNOSμ to the sarcolemma is critical to sympathetic vasoconstriction during exercise, the researchers conclude, with practical implications.

"A key question is will the findings translate into a clinically meaningful outcome? Will the drug slow the course of the disease? That's what we're working on next," said Dr. Victor.

The findings may also extend to "a broader patient population," which might include individuals with limb-girdle muscular dystrophy or early amyotrophic lateral sclerosis, Dr. Victor added.

Limitations of the study include lack of BMD controls in the case-control study; exclusion of patients with cardiomyopathy, which might have selected for certain mutations; assessing only a single dose; and measuring response only in the forearm.

Asked for comment on these findings by Medscape Medical News, Sanjay Bidichandani, MBBS, PhD, vice president–research for the Muscular Dystrophy Association, said the study "further supports the use of FDA [Food and Drug Administration]-approved PDE5A inhibitors like tadalafil and sildenafil as therapeutic agents in BMD.

"These results are encouraging, and demonstrate a clear need for larger trials to evaluate clinically meaningful effects on muscle strength and disease progression in BMD," Dr. Bidichandani said.

The authors and commentator have disclosed no relevant financial relationships.

Sci Transl Med. 2012;4:162ra155. Abstract