ARE THERE MEDICATIONS TO TREAT DMD?

Many medications and dietary supplements have been tried over the years as treatments for DMD. These include amino acids (building blocks of proteins), calcium blockers, growth hormone, growth hormone blockers, protease inhibitors, coenzyme Q, catabolic and anabolic steroids, immunosuppressants, vitamins, zinc and many others.

Some of these have shown promise and are still being investigated. But so far, there is only one group of drugs -- the catabolic steroids -- that have been shown to have a significant benefit in DMD, and they, unfortunately, also have a serious downside.

Prednisone and Its Relatives (Catabolic Steroids)

In many clinical trials since the 1970s, prednisone (Orasone, Deltasone and other brand names) and its close cousins prednisolone (Prelone, others) and deflazacort (Calcort, not marketed in the United States) have been shown to slow the loss of muscle function in DMD or even to increase strength in this disease.

(Note: Prednisone and related compounds are known as catabolic steroids, corticosteroids or glucocorticoids, depending on the context. Catabolic refers to their metabolic effects; the word refers to the breakdown of tissue, or catabolism. Cortico refers to where these compounds are made in the body, which is in the cortex [outer covering] of the adrenal glands. Gluco refers to their interactions with the sugar glucose.)

The positive effects have been noteworthy. Prednisone seems to allow a boy to walk longer than he would otherwise have been expected to. Some doctors say walking can be prolonged for two to four years, although most studies don't bear that out as an average figure. Occasional reports of a child who seems to have "recovered" from his DMD or is still walking at age 17 are unconfirmed.

Prednisone and its relatives are synthetic forms of the natural substance hydrocortisone, made by the body's adrenal glands. In the natural condition, hydrocortisone helps with the body's stress response. In general, it breaks down body tissue to liberate glucose (sugar) for immediate energy, stops or slows inflammation in the body (probably to help mobilize energy to meet an immediate danger), raises blood pressure and causes fluid retention.

The mechanism of action of prednisone isn't well understood, but it's being studied. In other diseases where prednisone is used, it fights inflammation by suppressing parts of the immune system. It may be suppressing inflammation in DMD also (there is some inflammation around the degenerating muscles in this condition), but the situation here is less clear than in other diseases.

There are other theories about why prednisone seems to help in Duchenne. It might, for example, cause a greater than usual amount of a protein to be made in muscle, and that as-yet-unidentified protein might be affecting muscle fiber survival.

But prednisone also has an extraordinary number of potentially damaging systemic effects, which can be severe over a prolonged period. If high levels of hydrocortisone existed in the body for months or years, many things would occur. The extra sugar circulating in the blood would cause a kind of diabetes and extra fat deposits. The slowed inflammatory responses would impair wound healing and infection fighting. The raised blood pressure and increased fluid retention would cause a strain on several systems. The effects on the brain might cause psychosis. The lenses of the eye would develop cataracts.

The synthetic forms of the catabolic steroid hydrocortisone were designed to have fewer side effects than the natural form, but they have many of these same side effects to some degree.

People who take prednisone or its relatives at high doses for several months or more experience significant weight gain, loss of bone and (paradoxically) muscle tissue, thinning of the skin, raised blood pressure and blood sugar, and many other problems, among them often significant psychological distress.

While prednisone often does prolong muscle strength and respiratory function (to varying degrees in different boys), these results should be weighed against the down- side. For example, the boy can gain so much weight that his mobility is actually impaired, rather than enhanced, even if he is slightly stronger (and his parents may not be able to lift him anymore). Obesity can severely impair respiratory function as well and can make it hard to use certain kinds of devices designed to assist ventilation. Obesity can also negatively affect his self-esteem.

Osteoporosis, a thinning of the bones, is another frequent complication of prednisone. Falls are common when the boy with DMD loses the muscle strength to correct his balance but is nevertheless still walking. Prednisone markedly increases the likelihood that such falls will lead to serious bone fractures, with forced loss of mobility and the possibility of erasing any gain in muscle strength brought about by the drug.

Calcium supplements are sometimes used with prednisone in an attempt to offset osteoporosis. Recent research suggests that combining calcium with a bone-stabilizing drug, such as etidronate (Didronel), may slow the course of prednisone-caused osteoporosis.

Not to be overlooked are the psychic effects of prednisone. "You just can't think on that drug," one young man commented. Difficulty thinking, sleeping and controlling behavior are common with prednisone, and severe depressions can occur. To a boy with Duchenne, especially an adolescent, the life of the mind is terribly important. Some young men may feel that the ability to think, read, interact with people and mobilize coping skills is more important than an extra few months or even years of walking.

Many American doctors prescribe prednisone for boys with DMD, some even suggesting that it should be used for all patients over the age of 5. However, many don't prescribe it, for all the reasons noted above. In Europe, it's far less popular. In the late 1990s, the consensus of the European Neuromuscular Centre, a group of experts in neuromuscular diseases that advises the European muscular dystrophy associations, was that prednisone should only be used as part of a clinical trial and not prescribed as a routine treatment for DMD.

Parents who are pleased with prednisone emphasize the importance of careful monitoring for side effects. They often take such precautions as controlling their sons' diets to prevent excess weight gain or requesting antidepressant medications.

Doctors haven't reached consensus on when to start prednisone or, perhaps more important, when to stop it. The prednisone decision is a tough one. Make it with caution and care.

Anabolic Steroids

In a general sense, anabolic steroids build tissue, while catabolic steroids break down tissue. The male hormone testosterone is the body's main anabolic steroid in males, and oxandrolone (Oxandrin) is a synthetic hormone related to this natural compound that has shown some promise in treating DMD.

As of 1998, the evidence for oxandrolone comes from a small pilot study in which this drug increased strength in boys with Duchenne. A larger study is now under way.

If oxandrolone or other anabolic steroids fulfill their early promise, they could become important in the treatment of DMD.

Their main side effects relate to their natural actions, mainly masculinizing effects such as hair growth and a deeper voice. Since DMD is a disorder of boys, these effects will probably not be considered devastating. In the short run, anabolic steroids promote growth in children. However, in the long run, they can stunt growth, because they cause premature closure of the growth plates in the long bones.

The serious side effects seen when athletes use anabolic steroids probably result from high dosages without adequate monitoring. Nevertheless, liver damage, a serious side effect, can occur with some of these drugs even when they're used under a doctor's supervision.

Anabolic steroids aren't expected to influence the course of the disease to any great degree. It's hoped that they will "tip the balance" toward less muscle breakdown and more muscle survival, thereby slowing the course of the disease. But until a drug or other treatment can actually compensate for the crucial missing protein -- dystrophin -- the muscle probably can't survive and work the way a normal muscle does.

Calcium Blockers

Another type of drug that's had some attention in DMD is the calcium blocker. In muscles lacking dystrophin, the membrane of the muscle fiber (cell) becomes permeable; that is, it lets in things it normally wouldn't let in and leaks out things it normally would keep inside.

Calcium, always present in the fluid surrounding cells, can be a deadly substance if it gets into the cell in an unregulated manner. That's why many types of cells, including muscle cells, have special "gates" for calcium. These are known as calcium channels, and they open and close to regulate the flow of calcium from the outside to the inside of the cells.

There are drugs that can block these calcium channels, and some have been tried in DMD. Unfortunately, calcium is probably leaking into the muscle fibers of boys with DMD because there are tears in the membrane, so blocking the calcium channels may be like sticking a finger in a dike that has arm-size holes in it.

Some names of calcium channel blocking drugs are verapramil (Calan, Isoptin), diltiazem (Cardizem) and nifedipine (Adalat, Procardia). The antibiotic gentamicin (Garamycin, Jenamicin), which also blocks calcium channels, has been recently tried and found not effective in a pilot study.

Dantrolene (Dantrium) is another type of calcium-blocking drug. Instead of blocking calcium channels on the outside of the cell, it blocks the release of calcium from storage areas inside the cell. Although useful in other disorders, dantrolene hasn't been found helpful in DMD.

Do not stop your child from taking in calcium, in the form of milk or any other dietary product or supplement. In fact, if he's taking prednisone, calcium supplements may be prescribed for him. The calcium taken in orally doesn't change the concentration of calcium in the blood or the fluid surrounding cells (related to the blood calcium level). These concentrations are tightly regulated by the body so that they remain constant under all conditions. If a person doesn't take in enough calcium, the body will take it from the bones to bring the blood calcium level back to normal. This leaching of bone-stored calcium can lead to osteoporosis and fractures.

Immunosuppressants

DMD is caused by a genetic defect that results in the loss of a key muscle protein and isn't thought of as an immunologic disorder. However, researchers have theorized that there may be some immunologic problem in Duchenne. Whenever tissues degenerate in the body, the immune system gets involved to some extent in "cleaning up" the debris. Sometimes, this cleanup effort, though necessary, tips the balance toward an autoimmune, or "self-immune," response, either inflammation or an even more complete immunologic attack on some of the body's own tissues.

In DMD, where muscle fibers are breaking down and exposing their usually enclosed contents to the immune system's surveillance, it has seemed likely that the immune system might be a culprit in some of the final stages of muscle destruction.

After the benefits of prednisone were noted, researchers decided to study the drug azathioprine (Imuran), an immunosuppressant used in many diseases. Unfortunately, the drug didn't show any benefit in Duchenne.

Another drug that's been studied is cyclosporine (Sandimmune). A small study in 1993 suggested this drug might increase strength in boys with DMD, but later investigation failed to confirm this early result.

Immunosuppressants are dangerous drugs. They all interfere with the body's ability to fight off routine infections. Chicken pox could be particularly dangerous. Many have other serious side effects, including increasing the risk of cancer.

Most doctors believe their use in Duchenne at this time doesn't seem worth the risks.

Beta Receptor Agonists

A class of drugs known as beta receptor agonists may become part of the treatment of DMD in the future. These drugs are anabolic, but they're not steroids. An example is albuterol (Proventil, Ventolin), which is now on the market for the treatment of asthma and is being studied for the treatment of a non-Duchenne type of muscular dystrophy.

An accelerated heart rate is a frequent side effect of albuterol that concerns some doctors, especially since DMD usually involves heart problems.

Some experts believe future treatment plans will involve combinations of anabolic drugs. As noted, anabolic agents may help tip the balance away from continuous muscle destruction, but they're unlikely to be a cure.

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