PHARMACOLOGICAL MANAGEMENT

PHARMACEUTICALS THAT MAY IMPROVE FUNCTION OR PROLONG LIFE

Major pharmacologic advances have occurred over the past decade. Although a comprehensive discussion of clinical trials is beyond the scope of this article, some of the major advances are noted. Given the severity and rapid progression of the disease, ALS has received the most attention in terms of pharmaceuticals aimed at prolonging life.

Riluzole is a neuroprotective agent that appears to inhibit glutaminergic neurotransmission in the spinal cord. Riluzole is the

first agent approved by the Food and Drug Administration (FDA) for use in ALS patients. Although it is only modestly effective at improving life expectancy in patients with ALS,

Riluzole is nonetheless a major advancement. Various neurotrophic growth factors also appear quite promising, particularly insulin-derived growth factor, commercially known as Myotrophin.

Data suggest that cannabidiol, a naturally occurring nonpsychotropic cannabinoid, has a potential role as a therapeutic agent for the neurodegenerative disorders produced by excessive cellular oxidation, such as ALS.

This compound is chemically classified as a terpene, similar to tamoxifen, which also has been shown to prolong cell survival in a mouse model of ALS. This suggests a similar mechanism of action, although this remains to be delineated.

DMD, also a severe disease, has received a fair degree of study. Although not FDA-approved for this use, prednisone, at 1 mg/kg/d, given to boys aged 4-8 years with DMD, has been shown to prolong the time of ambulation and should at least be considered for use in this disease.

Major adverse effects of prednisone include weight gain, osteoporosis, and mood lability. Deflazacort has similar beneficial effects and may have slightly fewer adverse effects than prednisone; however, deflazacort is not currently available in the United States.

Several randomized, crossover, double-blind, placebo-controlled pilot studies of extended release albuterol have been performed in patients with dystrophinopathies (DMD, BMD) and FSHD. Outcomes

involved isometric knee extensor testing, flexor strength testing, and manual muscle testing.

The results showed some small evidence of benefit in patients with the dystrophinopathies, but not with FSHD. Therefore, a 12-week treatment with extended-release albuterol may increase strength in patients with dystrophinopathies, but, clearly, larger double-blind randomized studies are necessary to confirm these results.

Some literature shows that the protein creatine monohydrate is modestly beneficial for transient improvement of strength in patients with DMDs. Initial studies of creatine in ALS showed no effect, which was disappointing since creatine was tremendously beneficial in the mouse model of ALS.

Human trials of a timed-release form of creatine are ongoing in patients with ALS. A study showed that 200-400 mg of modafinil taken daily provided some relief from fatigue in patients with ALS. Further study is warranted before conclusive recommendations can be made.

Phase III trials are currently underway with recombinant human acid alpha-glucosidase enzyme replacement therapy (ERT) to treat patients with late-onset Pompe disease.