BLOOD TESTS TO CHECK LIVER URGED FOR THOSE ON RILUZOLE
Most Doctors, Drug Maker Long Aware of Liver Effects

The March 1999 issue of the Journal of Hepatology included an article titled "Acute Hepatitis After Riluzole Administration," which reported two cases of a type of liver inflammation from a hospital in Montpellier, France. In both patients, tests of liver function returned to normal after the drug, which is frequently prescribed for ALS, was discontinued.

The article, however, became a "shot heard 'round the world!" ALS Web sites and on-line publications quickly picked up the story, alarming readers with messages such as "Anyone taking riluzole should be aware of the following" and "ALS Medical Alert," followed by a summary of the French story.

In reality, Rhone-Poulenc Rorer, maker of riluzole (brand name Rilutek), and most doctors who prescribe it for people with ALS, have been aware of riluzole's potential to cause liver damage ever since the drug was first approved by the Food and Drug Administration in late 1995.

"What they did was summarize the article in the Journal of Hepatology, which was reporting on some past cases of liver problems with patients on Rilutek," said Sheryl Williams, senior manager of communications at RPR, of reports by ALS groups. Williams said one of the French patients had already been in RPR's clinical trial of riluzole and the other person's liver problem had been reported to the FDA as an "adverse event."

Williams said RPR is well aware of the drug's potential to cause liver damage and that this is reflected in the labeling for the drug, which all physicians should have. Labeling information, including all precautions, can be viewed on RPR's new ALS Web site at alsinfo.com. The newly developed Web site supplements information on RPR's main site, www.rp-rorer.com.

"We know that liver enzymes can become elevated with Rilutek," Williams said, and physicians should be monitoring their patients on a regular basis. "Anybody who's taking Rilutek and not getting regular liver enzyme tests needs to question the physician about that." (A rise in certain enzymes in the blood can indicate damage to liver cells.)

RPR recommends to doctors that a serum ALT level (a blood test of liver function) be checked every month during the first three months of treatment with Rilutek, then every three months during the remainder of the first year, and periodically after that. 

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MDA-ASSOCIATED DOCTORS RESPOND

Neurologist Lawrence Z. Stern, who directs MDA's clinic at University Medical Center in Tucson, Ariz., and serves as MDA's medical consultant, monitors his patients' liver enzymes with regular blood tests. "Problems are reversible if you catch them early," Stern says.

Robert Miller, a neurologist who directs the MDA/ALS Research Center at California Pacific Medical Center in San Francisco, says a slight elevation of liver enzymes in the blood can occur in people who have ALS whether they're taking riluzole or not. The enzymes actually come mostly from damaged muscles, he says, but can be misinterpreted as signs of hepatitis (inflammation of the liver) or pancreatitis (inflammation of the pancreas).

Taking riluzole may cause a further rise in the serum enzyme levels, Miller says, and this should be monitored.

"The slight elevation of liver function tests that I have seen always reverts to normal when the drug is stopped," he notes. He checks his patients' liver function monthly for the first three months and then at three-month intervals, following RPR's recommendations.

"This is the only way to detect the problem, if there is one," he says. In general, says Miller, "the safety of the drug is excellent."

Neurologist Jonathan Goldstein, director of the MDA/ALS Center at Yale University in New Haven, Conn., said, "Of all the patients I've treated with riluzole, I have seen zero complications." He says there are no warning signs that patients should watch for, but notes, "Your doctor should do the blood test." 

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AMGEN DROPS GDNF PROGRAM, CONTINUES BDNF STUDY

The pharmaceutical company Amgen has announced it will no longer pursue development of the experimental drug GDNF (glial-derived neurotrophic factor) for treatment of ALS or other neurodegenerative disorders.

"Our early-stage clinical trials, which delivered GDNF directly to the ventricles [cavities] of the brain, failed to demonstrate benefit to patients, and as a result, we have decided to discontinue our current development program," Jeanne Flynn, associate director of Professional Services at Amgen, said. The company tested GDNF in both ALS and Parkinson's disease, and found it didn't show benefit in patients with either disorder.

GDNF is a natural substance that has shown promise in protecting neurons from destruction under certain conditions in laboratory animals.

Amgen began clinical trials of GDNF in ALS patients in 1997 at six centers, using an unusual drug delivery system that pumped the drug directly into the brain's open areas, or ventricles.

Flynn said Amgen is continuing to develop BDNF (brain-derived neurotrophic factor), which is in clinical trials for ALS, and is working on another class of drugs known as neuroimmunophilins, which have not yet reached the clinical trial stage.

For updated information, call Amgen at (800) 772-6436 or check Amgen's Web site at www.amgen.com. 

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RESEARCHERS REPORT MUTANT SOD1 PROTEIN INACTIVATES GLUTAMATE TRANSPORTERS

New research from MDA grantees Matthias Hediger of Brigham and Women's Hospital and Robert Brown of Massachusetts General Hospital, both in Boston, has established the first direct link between oxidative stress and problems with glutamate transport in the SOD1-linked familial form of ALS. The researchers' work appears in the May issue of Nature Neuroscience.

The finding is important because it helps explain the relationship between two different cellular problems -- abnormal glutamate transport and excess free radical production -- that are known to occur in both sporadic ALS and SOD1-linked familial ALS.

(The rare SOD1-linked form of the disease is caused by defects in the gene that codes for a protein called superoxide dismutase 1, and is hereditary. Some 75 to 80 percent of people with ALS have the sporadic form, of which the cause is unknown. It occurs without a family history of the disease.)

Researchers have long suspected that nerve cell death in sporadic ALS may be caused by a problem known as glutamate excitotoxicity. Glutamate is a small chemical found in the central nervous system that serves as a messenger to bridge the physical gap, called the synaptic cleft, between two nerve cells, or neurons.

When neurons signal to one another, glutamate is released from one neuron into the synaptic cleft, where it can bind to receptors on the next neuron. Normally, after a signal passes between neurons, cells called astrocytes "vacuum up" the leftover glutamate with special proteins on their surfaces known as glutamate transporters.

Glutamate excitotoxicity occurs when the neurons are exposed to glutamate for too long or in too large quantities and become overstimulated. This overstimulation can lead to a chain reaction of events that are destructive to nerve cells, resulting in the paralysis that occurs in ALS.

Early studies suggested that extra glutamate could be a problem in sporadic ALS. This is the logic behind the drug riluzole, taken by people with ALS, which works to reduce the amount of glutamate released during cell signaling.

Normal Glutamate Regulation When nerve cells signal to one another, glutamate is released from one nerve cell ending into the synaptic cleft. Receptors on the second nerve cell ending bind to the glutamate and "excite" the second nerve cell. Extra glutamate is soaked up by astrocytes through glutamate transporters.	Glutamate Regulation in SOD1-Linked ALS In SOD1-linked ALS, researchers suspect that the mutant SOD1 protein generates free radicals that, in turn, inactivate the glutamate transporters on astrocytes. Glutamate collects in the synaptic cleft and the second nerve cell becomes fatally overexcited. This phenomenon is known as glutamate excitotoxicity.

In 1998, MDA grantee Jeffrey D. Rothstein of Johns Hopkins University in Baltimore added credence to this theory with his report that some people with sporadic ALS may not be making the glutamate transporter properly, and thus clearing glutamate too slowly from the spaces between their nerve cells.

It's less clear what role abnormal glutamate transport may play in the SOD1-linked form of familial ALS. A large body of evidence suggests that SOD1-linked ALS is caused by free radical damage due to abnormal activities of the mutant SOD1 protein (free radicals are highly reactive charged ions that can damage components of cells). Hediger wondered if the free radical damage, known as oxidative stress, was affecting glutamate transport in SOD1-linked ALS.

"There was some evidence suggesting that glutamate transport is impaired in the SOD1-linked form of the disease," Hediger says, "but it wasn't known if oxidative stress is causally linked to impaired transport."

Now Hediger and Brown have found that the mutant SOD1 can directly inactivate a specific type of glutamate transporter.

"Our results establish a link between exposure to oxidative damage and the ability of the body to mop up glutamate," Hediger says.

The discovery was made when Hediger laboratory member Davide Trotti examined the activity of human glutamate transporters and mutant SOD1 proteins in frog egg cells, which are large and can be injected easily with foreign DNA. Trotti found that egg cells making the glutamate transporter were able to take up glutamate, but egg cells making both the glutamate transporter and the mutant SOD1 had problems with glutamate uptake. The researchers also found that the effect of the mutant SOD1 on the glutamate transporter could be nullified if strong antioxidant chemicals were delivered to the cells.

These results suggest that problems with glutamate transport in some people with sporadic ALS may be caused by oxidative damage, even though they have normal SOD1. The findings also reinforce the logic behind the use of antioxidants and riluzole in slowing the course of sporadic ALS. Further research is needed to uncover the causes of oxidative stress in people with sporadic ALS. 

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STUDY OF ALS GENETIC FACTORS STILL NEEDS PARTICIPANTS

A study of genetic "susceptibility factors" (see The ALS Newsletter, vol. 4, no. 1, February 1999) in sporadic ALS continues to require participants.

The study is being conducted at Northwestern University in Chicago under the direction of neurologist Teepu Siddique. The NWU Neurogenetics Laboratory will examine whether there are predisposing genetic factors involved in the development of sporadic ALS (ALS without a family history).

The researchers need families in which only one person has ALS. They need blood samples from the person with ALS and from other family members, such as parents or a sibling.

The study needs a minimum of 300 sets of patients and parents; so far, 115 have been collected. The study also needs at least 300 patient-sibling sets; so far, 198 have been collected.

There is no immediate benefit expected from participating in the study, but it's hoped that the results will help determine underlying causes for sporadic ALS and eventually lead to treatments.

Any charges associated with the research will be compensated.

For further information, call research nurse Nailah Siddique at Northwestern University at (312) 503-2712 or send e-mail to nsiddique@nwu.edu. Or, contact genetic counselor Mara Gaudette at (312) 503-0154 or mgaudette@nwu.edu. 

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READING RESOURCES FOR PEOPLE WITH DISABILITIES

The Library of Congress has a free reading program for anyone who is unable to read standard printed materials because of a visual or physical disability.

Cassettes and records can be borrowed by mail from approximately 140 cooperating libraries by anyone who is medically certified as being unable to hold a book. Special playback equipment can also be borrowed.

For more on this program, write to National Library Service for the Blind and Physically Handicapped, Library of Congress, Washington, DC 20542; call (202) 707-5100 or (800) 424-8567; or visit lcweb.loc.gov/nls on the Internet.

A nonprofit organization called Recording for the Blind and Dyslexic has a 77,000-volume lending library of audio and electronic books for people who can't read standard print because of a visual, perceptual or physical disability. Membership and annual fees apply. Contact RFB&D, 20 Roszel Road, Princeton, NJ 08540; (609) 452-0606 or (800) 221-4792; www.rfbd.org. 

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UTAH ARTIST WITH ALS REPRESENTED IN MDA COLLECTION

Harry Taylor received his master of fine arts degree from the Art Institute of Chicago and worked for over 30 years as an art director at a publishing company in Ogden, Utah.

Taylor, who's now 80, retired in 1985 and devoted himself to creating a wide range of fine artworks, including oils, watercolors, drawings and etchings. His latest enthusiasm is for woodcuts.

After his retirement, he visited Venice, Italy, to soak up the influences of classic art. While there, Taylor began to experience unexpected falls while navigating the city's marble steps. The problem forced his return to the States, where he received a diagnosis of ALS.

Taylor, who now uses a wheelchair, once enjoyed camping and fishing and other activities but now pours all of his energy into art.

His ALS progression has been relatively slow, and Taylor has been able to adopt different techniques to continue creating his art, including the use of special carving tools and drills such as a Japanese motorized chisel.

Although Taylor creates the blocks himself, he has an assistant to create the prints, which are sometimes multicolored.

"I don't feel I fall into any school of art," Taylor has said. "I work for myself and not the public."

Nevertheless, Taylor's work has met with considerable public success, having appeared in several dozen exhibitions throughout the United States and overseas. Last year he received a Utah Governor's Award for outstanding contribution to the arts.

During 1999, a Taylor woodcut titled "I Hate Ants" will be on display in San Francisco and Amsterdam, Holland, as part of an exhibit sponsored by the California Society of Printmakers.

Last year, Taylor donated two of his multicolored woodcuts to become permanent displays in the MDA Art Collection, a distinguished gallery of artwork created solely by adults and children affected by neuromuscular diseases. The Collection has traveled extensively since its establishment in 1992 but maintains its permanent home in the corridors of MDA's national headquarters in Tucson, Ariz.

One of the two Taylor works in the Collection, "Tucson," offers a nighttime view of downtown buildings in the Southwestern city. The other, "Flip Flop," is more abstract in nature and presents a geometric design.

For more information about artworks created by people with ALS and related neuromuscular disorders, write to the MDA Art Collection, 3300 East Sunrise Drive, Tucson, AZ 85718-3208, or e-mail to communityprograms@mdausa.org. 

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USE CAUTION WITH CREATINE
Fluids, Care With Dose Advised

This March, MDA grantee M. Flint Beal at Cornell University Medical Center in New York announced a startling discovery: The over-the-counter dietary supplement creatine prolonged the life of mice with a form of ALS for an average of 26 days.

Since the announcement, people with ALS around the world have been buying creatine and taking it, but they and their doctors have wondered, "How much is safe? How much is effective?" A few reports in medical journals suggest some people may sustain kidney damage from taking oral creatine supplements.

MDA-associated physicians are reluctant to recommend a drug that hasn't yet been tested in humans with ALS, but they recognize that many people are going to take the substance before tests are done. (MDA is planning to test the drug as soon as a clinical trial can be organized.)

Commercial creatine preparations and package directions for taking them vary. The instructions for one brand, FSI Nutrition, tell people to take 5 grams four times a day for five days and then begin a "maintenance phase" of 5 grams every morning. But instructions like these are aimed at athletes and healthy people who want to have more energy or build muscle.

"There is no known dosing for people with a medical disease," says neurologist Jonathan M. Goldstein, who directs the MDA/ALS Center at Yale University in New Haven, Conn., because formal studies that would identify side effects and correct dosages haven't been performed.

"It should not be, 'the more, the better.' People should not think, 'If a little bit of creatine helps, maybe if I take more, I'll do better.'"

Goldstein recommends that people with ALS consult with their family physicians and neurologists before taking creatine. He tells his ALS patients to take 2 grams of creatine twice a day. However, he says, "That's based on nothing, really. It's based on something we discussed at one meeting, once. It's not really a standard of care." He says the doses arrived at during the meeting were extrapolated from animal data.

Goldstein notes that people with subnormal kidney function or those who are dehydrated are at high risk of problems from creatine. "I tell them they have to stay hydrated," he says. (Hydration is maintained by taking in adequate amounts of fluid.)

Neurologist Lawrence Z. Stern, MDA's medical consultant and director of the MDA clinic at University Medical Center in Tucson, Ariz., recommends creatine for his ALS patients, but cautions them about side effects such as diarrhea, if they take too much.

Stern prescribes 1 gram of creatine three times a day for his ALS patients. "They should be able to tolerate this dose if their kidney function is normal," Stern says.

Robert G. Miller, director of the MDA/ALS Center at California Pacific Medical Center in San Francisco, says he's "on the fence" about creatine until a clinical trial shows it actually helps in ALS. Without more data, he's not sure whether there are dangers in taking creatine.

Miller, like other doctors who treat ALS, says he knows many physicians do advocate taking creatine. "Most people recommend 3 to 5 grams per day," he says, "but we don't know what dose is best." 

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CALIFORNIA MAN LEAVES GIFT TO FIGHT ALS

A Santa Ana, Calif., businessman has benefited MDA's ALS program through an annuity plan.

Ernest Peterson Jr., who received an ALS diagnosis in 1994, had made arrangements that upon his death MDA should be the beneficiary of a substantial financial gift from the annuity plan in his name. He passed away this year.

In keeping with his wishes, the gift will be directed to support MDA's efforts to conquer ALS through comprehensive programs of research and clinical services.

The owner of Ernie's Pool Service, Peterson learned he had ALS at age 56. He sought help from MDA and became registered at the Association's office in Orange, Calif.

"We're deeply grateful when compassionate individuals like Ernest Peterson make arrangements to leave legacies to help others who are fighting ALS," said MDA Senior Vice President and Executive Director Robert Ross.

Anyone interested in finding out more about how to help in MDA's war on ALS through gift and estate planning should call Fred Stecker in MDA's Planned Giving Department at (800) 572-1717 or e-mail to plannedgiving@mdausa.org. 

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FAITH AND FAMILY KEEP SPIRITS HIGH

Those who know Garfield Hodges say, wherever he goes, people just seem to be drawn to him. That's how it was for the nearly 20 years he worked for 7 UP and that's how it is in the nursing home where he now lives.

"Someone from the staff told me I made a lot of people happy here," says Hodges of the Oak Manor Nursing Home staff in Booneville, Ark. "I guess they need someone to talk to and I'm it."

Hodges, 56, received an ALS diagnosis in 1994. In October 1998, he moved into the nursing home so his 80-year-old mother, Fern, wouldn't have to continue caring for him as his health declined.

In 1998 he received MDA's Personal Achievement Award for Arkansas in recognition of his frequent visits with the sick, including those with neuromuscular diseases, at home, in hospitals and in rehabilitation centers. People who know Hodges say he "pushed, prodded and pulled" those who needed encouragement.

Last year, when Pat MacHenry and her husband, Earl, moved to Fort Smith, where Hodges lived, he was one of the first friends they made. He met Pat, who has facioscapulohumeral (FSH) muscular dystrophy, at an MDA support group meeting, and frequently visited her and her husband.

"He always made me feel better," Pat MacHenry says. "He always had such a positive attitude. No matter how tired I was, when he left I always felt rejuvenated."

Hodges' energetic voice reflects a strong will and an enthusiasm for life. He greets everyone with determination.

"I'm going to beat this," Hodges states firmly of his ALS. "I'm going to walk again." Throughout his life, Hodges has been a religious man. "My strong faith in the church and God keeps me going," Hodges says. "And having family stick by you."

Hodges' four children visit or speak with him regularly, as does his mother. Garfield III, 31, drives an 18-wheel truck and lives in Mississippi. Brian, 30, a police officer, and Hodges' twin daughters, Michele and Daniele, 22, live in Arkansas. The daughters work for the same pharmacy.

Their father is known as a "goodwill ambassador" for his church from his work with the church's Little League and girls' softball teams. Hodges is deeply involved in the church and Sunday school classes, where his fellow 50-plus-year-olds meet to talk, discuss problems and build close friendships. For Hodges' birthday in December, his classmates surprised him at the nursing home with a cake and a party.

Earl MacHenry has taken Hodges to local high school football games, a sport Hodges knows well. He was a high school football star known for his sense of humor and caring.

"A lot of people know Garfield and when we go to the games, word gets around," MacHenry says. "People say, 'Hey, Garfield's here' and they come over to see him."

Hodges also was a star player for 7 UP, says Bob Shelby, the former marketing manager, now retired.

"I hired Garfield. He was a great employee. He worked so hard and so fast, he was so energetic," Shelby says.

Shelby describes Hodges' dedication to charities even before his illness. When the company built displays for MDA fund-raising promotions, Hodges was always on hand to help. Hodges would say, "Anything I could do to help MDA," Shelby recalls. 7 UP is a national MDA sponsor.

"And that was before he ever dreamed that he would need it," Shelby says.

After Shelby retired, Hodges would drive his van to visit him at his home. Hodges couldn't get in and out easily so the two would talk at the van.

"We'd talk for three hours," Shelby recalls.

When Hodges appears on the local broadcast of the Jerry Lewis MDA Telethon, Shelby says, he draws many donations.

"He's so sincere," Shelby says. "People just start calling in after they see him. He means so much to us that when he gets to feeling down, you want to get up and do something with MDA." 

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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
Muscular Dystrophy Association
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Tucson, Arizona 85718-3208

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