Research Roundup updates as of January 2005
The pharmaceutical company Maas Biolab, of Albuquerque, N.M., and Lund, Sweden, has received Orphan Drug designation from the U.S. Food and Drug Administration to develop cyclosporine specifically for ALS.
Cyclosporine is an immunosuppressant drug that already has FDA approval to prevent rejection of transplanted organs and to treat rheumatoid arthritis and psoriasis.
In ALS, investigators have found, its main mechanism is likely to be protection of the mitochondria, the energy-producing units of cells. Unfortunately, cyclosporine doesn’t cross membranes that lie between the bloodstream and nervous system (the blood-brain barrier), which has until now limited its potential benefits.
In the 1980s, oral cyclosporine was tested in people with ALS, but it showed only modest benefit for some of the participants. Researchers have found since then that the drug extends survival in ALS-affected mice bred with an especially permeable blood-brain barrier and in mice given the drug directly into the brain.
If cyclosporine could be delivered by a more direct route to the nervous system, it might be effective in humans without causing unwanted immunologic effects, investigators have speculated.
The Maas product is designed to be put into the fluid surrounding the spinal cord via a pump implanted under the abdominal skin.
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Ceftriaxone helps mice
The antibiotic drug ceftriaxone, scheduled to be tested in a multicenter clinical trial in ALS this year, has shown significant benefits in mice with a genetic form of the disease.
Researchers at Johns Hopkins University in Baltimore and Columbia University in New York reported their findings in the Jan. 6 issue of Nature. The team included Jeffrey Rothstein, who directs the MDA/ALS Center at Hopkins.
Rothstein and others say they believe ceftriaxone increases production of a glutamate transporter, a natural but potentially toxic substance that removes glutamate from the vicinity of nerve cells after it has transmitted a signal.
When mice genetically destined to develop ALS were given ceftriaxone injections starting at 12 weeks, they showed significantly better strength and higher body weight than did animals treated with a salt solution, and the effect lasted for four to six weeks. They also lived an average of 10 days longer than the mice treated with the salt solution.
When 10-week-old mice received ceftriaxone for two weeks, they had significantly more muscle-controlling nerve cells than the non-ceftriaxone group, and their spinal cords had higher transporter levels.
Ceftriaxone has to be given intravenously to penetrate the nervous system.
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Modafinil may help with staying awake
The drug modafinil (Provigil), which has Food and Drug Administration approval for the treatment of certain sleep disorders, may help with the daytime sleepiness in ALS.
Physicians Greg Carter and Michael Weiss, co-directors of the MDA/ALS Center at the University of Washington-Seattle, and colleagues, studied 15 people with ALS-related fatigue.
The participants were asked about their sleep habits and fatigue before and after taking 200 or 400 milligrams a day of modafinil for two weeks.
The results, which are published in the January-February issue of the American Journal of Hospice & Palliative Medicine, showed that modafinil was well tolerated and that all the measured factors showed improvement.
The investigators suggest that a morning dose of 200 milligrams may be the best regimen.
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Novartis drug fails ALS test
Novartis Pharmaceuticals has announced that its experimental ALS drug, TCH346, has failed to show any difference from a placebo (inert substance) on measures of disease progression or survival.
In a phase 2, multinational trial that included 591 people with ALS, the compound didn’t live up to expectations.
During the six-month study, participants took one of four different doses of TCH346 or a placebo. No obvious adverse effects occurred in the trial.
Novartis recommends that patients currently on TCH346 contact their study centers immediately for advice on discontinuing the drug.
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Researchers associate enzyme with ALS
Researchers from Massachusetts General Hospital in Boston, and University College and King’s College in London, report an elevated activity level of an enzyme known as reverse transcriptase in the blood serum of ALS patients.
The investigators, who included Robert Brown, director of the MDA/ALS Center at Massachusetts General, and Merit Cudkowicz, who has related MDA support, analyzed the serum of 30 ALS patients without any family history of the disease. They then compared the ALS serum to serum from 14 blood relatives of the patients, 16 of their spouses and 28 people who were neither relatives nor spouses.
Activity from reverse transcriptase (RT), an enzyme that certain viruses use to replicate themselves, was noted in 47 percent of those with ALS, 13 percent of their spouses, and 18 percent of non-spouse, unrelated participants. Unexpectedly, 43 percent of the ALS patients’ blood relatives showed RT activity.
The researchers, who published these findings in the Feb. 8 issue of Neurology, say the RT activity in the patients and their relatives is more likely caused by inherited retroviruses present in their shared DNA, rather than by a new virus, which would likely be shared by spouses.
Inherited, dormant retroviruses are common, they say, and they’re occasionally activated by a variety of factors.
The authors say there is some "biologic plausibility" to the suggestion that activation of retroviruses in humans might have a role in ALS, although that role is unclear.
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Physical activity affects ALS onset but not risk
A Dutch study of 219 people with ALS and 254 people without ALS has revealed that physical activity, even if it’s extreme, doesn’t increase the risk of developing the disease. However, those whose leisure-time physical activity level was high showed ALS symptoms sooner than those whose activity level was low.
Subjects who reported high leisure-time physical activities during the 10 years prior to disease onset developed ALS an average of three years sooner than the low-activity group.
Subjects with high scores on leisure-time physical activity before the age of 25 developed ALS an average of seven years earlier.
The investigators, at University Medical Center in Utrecht, the Netherlands, published their findings in the Jan. 25 issue of Neurology.
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