REMEMBERING THE FIRST LADY OF ALS

By Robert Ross
MDA Senior Vice President and Executive Director

It is with great sadness that I announce to the ALS caregiver community the untimely death of one of its outstanding leaders, Vicki Appel, wife of Dr. Stanley Appel, director of our MDA ALS Center at Baylor College of Medicine in Houston. Vicki died Oct. 24, at the age of 65, after a long illness.

I think of Vicki as the "first lady" of the ALS caregiver community, not only because she was always a helpmate to Stan, a splendid ALS researcher and clinician, but also because she was in her own right an expert in this challenging disorder. She was a source of strength to families attending the Baylor center, and, through her writings, to those affected by ALS everywhere.

In 1954, Vicki graduated from the University of Houston and Methodist Hospital School of Nursing with a bachelor's degree and preparation to be a registered nurse. She was to become a pioneer in a new generation of nurses who would change the face of the profession in the coming decades.

In 1968, Vicki started the Neurological-Neurosurgical Nurse Specialist Program at the Methodist Hospital, instructing the next generation of nurses in the application of sophisticated techniques in patient care. She headed this program until 1975.

In 1978, she became a certified neuroscience registered nurse, serving on the Board of Directors of the Association of Neuroscience Nurses from 1977 to 1981 and as its president in 1981 and 1982.

She joined the faculty of the Department of Neurology at Baylor College of Medicine as a research nurse instructor in 1978 and was promoted to assistant professor in 1994.

In 1982, Vicki used her considerable nursing and administrative skills to start the MDA ALS Clinic at Baylor, and she continued to coordinate this clinic (now one of 15 major MDA ALS centers) until this year. It's considered among the finest research and patient care facilities in the world.

Vicki was a tireless source of information and support for us at MDA as well as to her patients. She served as editor or author of several outstanding MDA publications and videos on such topics as nutrition and mobility in ALS, caring for a loved one with ALS, and living with ALS. Barbara Babbitt, a long-time friend of the Appels, is a former member of the MDA Gulf Coast Chapter Executive Committee and has spinal muscular atrophy. She remembers a long-ago visit to MDA's neuromuscular clinic at Baylor where Vicki Appel assisted in her care.

"One thing that I'll never forget," Babbitt says, "is the time when Vicki came in and said, 'Would you like to see your muscle biopsy?' She said, 'Let me show it to you.' It was a picture that looked like a mosaic, showing the good muscle cells, I guess, and I remember her pointing all this out to me. It was so nice; she explained everything." Babbitt began attending sessions at the ALS Clinic even though she had spinal muscular atrophy, another motor neuron disorder.

"When they started that ALS clinic, Vicki was always there," Babbitt recalls. "I noticed that she was such a sensitive caregiver to all the people with ALS. It's very difficult to see people progress through ALS. She had so much compassion. I remember her fixing things like pudding so everybody would have a little snack that they'd be able to eat. She was a very compassionate person, and she and Dr. Appel were a really great team."

All of us concerned about ALS have lost a very dear friend.

Contributions to support ALS research and services can be made to MDA in Mrs. Appel's memory.

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MYOTROPHIN DECISION STALLED AGAIN

The long-awaited decision by the Food and Drug Administration (FDA) on the drug Myotrophin for ALS was once again postponed on Nov. 11.

Myotrophin, a brand name held by drug companies Cephalon (West Chester, Pa.) and Chiron (Emeryville, Calif.) for insulin-like growth factor 1, was first brought before the FDA in June 1996. At that time, the agency allowed the drug to be used on an experimental basis.

In August 1996, the drug companies started an "expanded access" program for people to obtain Myotrophin by random selection. This program is still operating.

In May 1997, an advisory panel for the FDA again considered Cephalon and Chiron's application for Myotro-phin and rejected it by a 6-3 vote.

Following much protest and controversy in the ALS community, the FDA agreed to postpone a final decision about Myotrophin until Nov. 11. (Normally, the FDA makes a final decision about a drug shortly after an advisory panel of experts gives its verdict.) Many people with ALS protested that, even though the data about Myotrophin didn't clearly demonstrate that the drug is effective, they wanted the chance to take it anyway. Others with the disorder protested that the drug companies were trying to market an expensive, ineffective and possibly dangerous drug and using the ALS community to help their marketing effort.

Now, the decision has again been postponed. In the words of Cephalon spokeswoman Kori Beer, the FDA said it "wants to get more comfy with this data." Beer said Cephalon and the FDA came to a mutual decision to withdraw the application for Myotrophin and then resubmit it in order to restart the drug approval "clock," which had run out. Congress mandates time limits on drug approvals through the Prescription Drug User Fee Act, Beer said.

"Logistically," she said, "the way to do that [restart the clock] was to withdraw the application and then resubmit it, as crazy as that sounds." Beer said the agency has six months to again review the data, but she doesn't think they will take that long. "I would hope not, added Beer."

Myotrophin is a laboratory-generated form of insulin-like growth factor 1, a naturally occurring substance in the human nervous system.

Myotrophin is still available through the expanded access program. The number to call is (800) 829-3054. Cephalon spokesman Jason Rubin said there are now about 450 people getting Myotrophin through this program.

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PEOPLE WITH ALS FEATURED ON MDA TELETHON

The Jerry Lewis MDA Labor Day Telethon, which aired from CBS Television City in Hollywood for 21½ hours from Aug. 31 through Sept. 1, presented a mix of entertainment and information, including a number of segments focused exclusively on families and individuals affected by ALS.

Tom Poston, the well-known comic actor from such popular programs as "Newhart," appeared in a special video profile with his wife, Kay, who has ALS. Kay was walking with a cane when she and Tom first appeared on the Telethon two years ago, but now she uses a wheelchair.

"She's very much loved," Tom said in the video. "I want people to know that, in spite of this terrible disease, it's possible to be a person with a very great spirit, because my wife is a champion."

After the video segment, the Postons joined Jerry Lewis live on the Telethon stage, and Kay expressed gratitude on behalf of herself and her husband to everyone who supports MDA's programs of research and services.

Another sequence provided an update on James Keller, the former baseball coach from Austin, Texas, who has had ALS since 1992. Keller recently received the kind of honor usually reserved for greats like Lou Gehrig; he had his No. 19 coaching jersey permanently retired in honor of his years of service to Concordia University.

Keller has compared his fight against ALS to a baseball game. "In baseball, there's no clock. It doesn't matter how far behind you get. As long as you don't give up, you've got a chance." Segments about Keller have appeared on the Telethon every year since 1993.

In 1994, Barry Goldberg, the corporate executive from Plano, Texas, who received a diagnosis of ALS in 1990, appeared on the Telethon and had a profound impact on talk show host Leeza Gibbons, who was interviewing him on the broadcast in her role as Telethon co-host.

Despite the fact that ALS had stolen his ability to walk and was compromising his speech and breathing, Goldberg's remarks displayed great courage, humor and tenacity. As a symbol of his positive attitude toward life, Goldberg presented Gibbons with an "Energizer Bunny," the toy rabbit of TV commercial fame known for its propensity to keep "going, and going, and going . . ."

To this day, Gibbons keeps the rabbit above her desk. "It's very inspirational to me," she says.

Although Goldberg himself was too ill too appear on the 1997 Telethon, Gibbons returned to the broadcast this year to make a special tribute to her friend. "Strong is the soul, and wise and beautiful," she said, quoting words of 19th-century poet Matthew Arnold, which she said could have been written specifically about Goldberg. She went on to say that she had faith that ALS would be defeated if people continued to support MDA research.

In memory of Janis Dorfman, the school teacher, wife and mother from Long Island, N.Y., who had ALS, the 1997 Telethon featured an encore airing of the video profile about her that appeared the previous year. Dorfman died of the disease in August of this year, only days before the 1997 broadcast.

The MDA Telethon is the only annual broadcasting event that has consistently educated and informed the public about ALS. Funds raised by the Telethon help support research and clinic services that benefit people with ALS and related neuromuscular disorders.

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FULLERENES MAY BE NEXT MAJOR ANTIOXIDANTS

Vitamin E may be moving over and making room for the newest, possibly most powerful antioxidants yet -- fullerenes. Named after architect Buckminster Fuller, known for his geodesic dome designs of the 1950s and 1960s, these molecules are hollow spheres made entirely of carbon molecules (see illustration). Not surprisingly, they're also called "buckyballs."

In the Aug. 19 issue of Proceedings of the National Academy of Sciences, researcher Laura Dugan of Washington University in St. Louis describes how two kinds of synthetic fullerene molecules can mop up toxic substances known as free radicals in laboratory dishes and in mice with ALS.

These new fullerenes were altered so that they became water-soluble, greatly increasing their effectiveness in cells.

The mice, which were bred to have a genetic form of ALS (by giving them mutated genes for the protein SOD1), were treated with fullerenes pumped into their abdomens beginning at the age of 2 months. The treated mice started showing ALS symptoms later than the untreated mice by about 10 days, lived longer by about nine days and did better on tests of function every week throughout the trial.

According to Dugan, mice with this genetic form of ALS usually develop disease symptoms at the age of about 110 days and then live, on average, only about another 12 days.

What Antioxidants Do

Antioxidants take the sting out of naturally produced chemicals known as free radicals. These substances are the byproducts of a number of normal biochemical reactions but are probably increased in many conditions in which cells are degenerating and safety checks fail.

A free radical is an atom that's looking for electrons (atomic components) and is ready and willing to steal one or more from other atoms or molecules. Electrons are charged particles that orbit the center of an atom. They like to travel in pairs, but some atoms naturally have unpaired electrons, or they lose or gain an electron after reacting with another substance.

When an electron-hungry atom goes searching for electrons to steal, it can start a chain reaction. If it takes an electron from a nearby substance, that substance then has to get one from another substance, and so forth. In this way, cell membranes can become leaky, DNA can be damaged, vital proteins can be destroyed, and cells can die.

Giving up an electron is called "oxidation," and antioxidants intervene in oxidation reactions. Some antioxidants can safely lend electrons to free radicals without becoming toxic themselves (although they sometimes have to be detoxified later in a second step). Others catalyze (make possible) a chemical reaction that changes the free radicals into safer substances while they themselves are unchanged.

Fullerenes are in the first group. Their surfaces are made of carbon atoms, each of which has room for four electrons. They attract free radicals like sponges; in one report, 34 free radicals were attached to one fullerene.

Oxidation Part of Picture

Oxidation, sometimes termed "oxidative stress," is probably involved in nerve cell degeneration in ALS, although it may be secondary to other stresses in these cells. One way oxidative stress may occur in nerve cells is through overstimulation by so-called excitatory neurotransmitters, the chemical "on switches" that tell nerve cells to do something.

When they reach motor neurons, excitatory neurotransmitters tell them to send a signal to the next neuron, the end result being muscle movement.

The FDA-approved ALS drug riluzole (Rilutek) works by decreasing the amount of glutamate reaching nerve cells. In so doing, it probably indirectly decreases oxidative stress.

Gabapentin (Neurontin), another glutamate inhibitor, is now being tested in ALS (see Drug Trials in San Francisco), and relieving oxidative stress may likewise be one of its indirect actions.

Some people have a genetic form of ALS that's caused by a mutation in the gene for SOD1. SOD1 is itself an antioxidant protein under normal circumstances. But, when the SOD1 is flawed, it takes on toxic characteristics that may actually lead to more free radical production, rather than less.

Vitamin E has been shown to delay both onset and progression of ALS, but not to prolong survival in mice bred with genes for abnormal SOD1. In the same study, which is in the February 1996 issue of Annals of Neurology, gabapentin and riluzole prolonged survival of the mice.

The fullerene study also used mice with mutated SOD1 genes. In these mice, fullerenes delayed the onset of ALS symptoms, slowed disease progression and prolonged survival.

"I find these compounds (fullerenes) highly interesting," said MDA grantee Heather Durham, a neurobiologist at Montreal Neurological Institute. She was particularly intrigued by one type of fullerene made by Dugan that is soluble in both water and lipid, the main component in cell membranes.

MDA grantee M. Flint Beal of Boston's Massachusetts General Hospital has co-authored a book on oxidative stress and free radicals. He commented, "The fullerene data provide further evidence linking oxidative mechanisms to ALS pathogenesis [causation]. These compounds may prove to be useful, but they require further development. In the meantime, several pharmaceutical companies are developing other improved antioxidants that may be useful for ALS treatment."

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DRUG TRIALS IN SAN FRANCISCO

California Pacific Medical Center in San Francisco reminds people that it's still recruiting for two ALS drug trials.

Gabapentin (Neurontin) Trial

One trial is with the drug gabapentin (Neurontin), a partial glutamate blocker. Glutamate is a central nervous system chemical that may have toxic effects in ALS. The trial is double-blind and placebo-controlled and will last nine months. Participants who complete the study will be guaranteed free gabapentin for six months after the trial has ended.

Patients are not restricted to those living in the San Francisco area, but they must agree to come to California Pacific Medical Center monthly.

• definite, probable or possible ALS
• no more than three years' duration of ALS symptoms
• forced vital capacity (respiratory function test) greater than 60 percent of normal

Call Giovanna Kushner at (415) 923-3604 for details.

SR 57746A Trial

The other trial at Cal Pacific will test the drug SR 57746A (known as the "Sanofi drug" because it's made by Sanofi, a French drug company). This drug is an oral compound that seems to stimulate production of neurotrophic factors, natural substances that promote survival of nerve cells.

The trial is double-blind and placebo-controlled and will last 18 months. There are two arms to the study. One allows participants to take riluzole (Rilutek), and the other is for people who have not used riluzole in the previous 12 weeks. Participants will have the option of enrolling in an open-label (non-blinded), long-term safety study at the completion of the trial. There is no cost to participants or third-party payors.

There are no restrictions on residency, but participants must come to Cal Pacific for monthly visits.

• definite or probable ALS
• forced vital capacity (respiratory function test) greater than 60 percent of normal
• no more than five years' duration of ALS symptoms
• ability to swallow; no feeding tubes permitted prior to starting drug

Call Giovanna Kushner in San Francisco at (415) 923-3604 for details.

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The Association welcomes gifts for ALS research honoring significant occasions of achievement. These gifts may be made in tribute to special people or to mark such events as anniversaries, birthdays, weddings, graduations or retirements.

THE ALS NEWSLETTER
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