ARTICLE IN BRIEF
- ✓ In a small placebo-controlled trial, the beta-2 agonist albuterol improved lean body mass in boys with DMD, but there were no significant improvements in manual muscle tests and other measures of physical functioning.
In a small trial, short-term treatment with albuterol increased lean body mass, decreased fat mass, and improved physical function in boys with Duchenne muscular dystrophy (DMD). Investigators found no significant change in the range of motion or strength of specific muscle groups, however, according to a study published in the Jan. 8 issue of Neurology.
Experts agreed that further studies may be warranted and that neurologists should remain cautious when interpreting results.
DMD is characterized by a loss of skeletal muscle, progressive weakness, and cardiomyopathy; most boys with the X-linked DMD lose the ability to walk between ages 10 and 12.
Lead investigator Melissa J. Spencer, PhD, associate professor of neurology at the David Geffen School of Medicine at the University of California-Los Angeles, said the findings suggest that albuterol, a beta-2 adrenegic agonist and an FDA-approved drug for asthma, might also help retain muscle tissue in boys with DMD. The percentage of body fat in boys with DMD increases with age, and the percentages of lean body mass and physical function decline.
The investigators were interested in albuterol because other beta-2 agonists as a class had improved strength and function of healthy and diseased muscle in animal studies and human trials. In a pilot trial of nine patients with DMD or its less severe form, Becker muscular dystrophy (BMD), muscle strength increased significantly in those who took albuterol, according to a November 2004 study in Neurology.
The current trial included 14 ambulatory boys with DMD, ages 6 to 11; two had BMD. The boys were not eligible for the trial if they had used corticosteroids, or any other drug to treat DMD or BMD within three months prior to the study; had used any beta adrenergic antagonists; or had cardiovascular disease.
The boys were randomized to an experimental group or placebo, completing two 12-week treatment cycles separated by a 12-week washout period. They took three pills daily of 4 mg extended-release albuterol, for a total of 12 mg each day.
Lean body mass — measured by a DEXA scan — was significantly higher at 4 percent and fat mass was significantly lower at 2 percent for 12 of the 14 boys following albuterol treatment, and the time it took to run or walk 30 feet improved significantly. However, there were no significant differences between experimental and placebo groups on manual muscle or range of motion tests. In addition, in a questionnaire, parents reported that they did not perceive differences in their child's function between the drug and placebo periods.
Seven of the 14 participants opted to take albuterol after the trial and returned for follow-up assessment at three months; four of those seven participants also returned for evaluation at six months. At follow-up, however, there were slight declines in the scores for muscle tests and knee joint movements, and they were slower on the timed tests of physical functioning.
Investigators offered several explanations for why muscle strength was not sustained. The standard tests used to measure muscle strength or movement may not detect small changes in strength in individual muscle groups, they said. Also, children with DMD get fatigued and their performance on tests may vary. Because there is a lot of variability in a particular subject from day to day, the standard of error is very high, Dr. Spencer said.
In addition, she noted that the albuterol formulations for the pilot study (Proventil Repetabs) and current study (Volmax) were different — and so the different mechanisms of drug release could have affected the drug concentrations in the blood.
Wendy M. King, a physical therapist and clinical assistant professor of neurology at the Ohio State University Neuromuscular Disease Center in Columbus, agreed that the different albuterol formulations could have accounted for differences in results between the pilot and current study. She also noted that “only 60- to 70-percent or so of lean body mass measured by DEXA analyses represents skeletal muscle… An increase in muscle may not translate into an increase in muscle strength if the increase included non-muscular tissues or a true increase in muscle simply was of insufficient magnitude to translate into improved strength.”
She added that the “number of patients in both the pilot study and this trial were extremely small, and it is hard to draw any firm conclusions from the data.”
Other limitations besides a small sample size include its short time-frame and a wide age range (six to 11 years), experts observed. “There is an enormous difference in strength ability between 6- and 11-year-old boys with DMD, and older boys may have been too weak to show a significant change and thus dampened the results for all,” King told Neurology Today.
King suggested that future trials include only younger boys and possibly combine albuterol with other anabolic agents or with corticosteroids. “New generation” beta-2 agonists, such as formoterol, have a long duration of action and elicit hypertrophy, but they do not increase fatigue, she said. Changing the dosing regimen to allow “pulsing” of the drug would be another potential method, King added.
Valerie A. Cwik, MD, the medical director and vice president of research at the Muscular Dystrophy Association in Tucson, AZ, added: “The authors do not describe the power calculations for this study, so it may have been underpowered to detect a small change in strength.” She continued, “If further studies on beta-2 agonists are considered, it is important that the studies be designed and powered to answer, definitively, whether or not beta-2 agonists are of benefit in DMD.”
Paula R. Clemens, MD, associate professor of neurology at the University of Pittsburgh School of Medicine in Pittsburgh, PA, said that future trials should include longer treatment periods, different dosages, and consider adjunctive corticosteroids. “The possibility of efficacy was shown and the medication was relatively well tolerated,” she said. But, she noted that “only a few continued taking the drug in the open-label phase, suggesting that either the patients thought it wasn't worth it or that there were some occult adverse effects.”
George Karpati, MD, the I.W. Killam Chair of Neurology at McGill University, said: “This is a relatively nontoxic drug that shows some promise in increasing lean muscle mass and decreasing fat even after medium term oral administration. However, it is certainly not a cure and it is unclear if there will be actual functional benefit on the long term without side effects.”
Dr. Karpati said that the reasons for the lack of improved force generation should be investigated. “The possible reasons cited by the authors are not plausible,” he said. “The cause of improved speed of certain timed movements is also peculiar and it may not be due a muscular effect but some action on neurally based motor unit activation pattern. That could be investigated.”
While Dr. Spencer is now focusing on mouse models and doing pre-clinical studies to identify novel targets for DMD, she said that she and her UCLA colleagues are well positioned to test any promising drugs and plan to do future clinical trials.
“I hope that with better beta agonists (such as salbutamol) and appropriate cardiac monitoring, a drug will be identified to be used as supportive, muscle building therapy for other more-potent agents or as part of a drug cocktail.”
MORE ABOUT DMD
Duchenne muscular dystrophy (DMD) is the most common of the four forms of muscular dystrophy that begin in childhood. It is also the most common of the muscular dystrophies overall, accounting for about 50 percent of all cases, according to the NINDS.
DMD results from an absence of the muscle protein dystrophin, which plays a role in maintaining stability of the muscle membrane. Approximately one in 3,500 boys is affected.
Typical drug treatment includes corticosteroids such as prednisone and deflazacort, but these drugs often have multiple side effects such as adverse behavioral effects, weight gain, decreased bone density, hypertension, and growth inhibition. Children with DMD usually succumb to severe respiratory or cardiac problems in their teens or early 20s, while those with the less severe form, Becker muscular dystrophy, can survive into late adult years.