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Doctors Test Therapy for a Brain Malady

Doctors Test Therapy for a Brain Malady

August 14, 2001 New York Times by Sandra Blakeslee Two patients with forms of Creutzfeldt-Jakob disease, one of which was contracted from eating infected beef, have been treated at a San Francisco hospital with an obsolete malaria drug that doctors hope will alleviate the fatal brain malady.

The drug, quinacrine, was widely used during World War II to treat malarial infections of the brain, but was replaced by newer drugs. When researchers found in a random screening process that the drug killed mouse cells infected with the agent that causes mad cow disease, they decided to test it quickly in people. A clinical trial is scheduled to begin in the fall.

But, "before our trial was ready, two patients arrived on our doorstep," said Dr. Bruce Miller, a neurologist at the School of Medicine at the University of California at San Francisco who will head the trial.

"It put a lot of pressure on us to do the right thing," Dr. Miller said. "We felt we could not turn them away and so gave the drug in compassionate use." Compassionate use is the practice of giving an unapproved drug or one meant for a different disease to treat a dying patient in the hope that the drug may have some effect.

"It is way too early to make any claims that the drug is working," Dr. Miller said. "One person has gotten worse and about the other we just don't know. We are far from a cure. We are all hoping the drug will have some efficacy, but our eyes are wide open. It could absolutely not work."

But over the weekend, the father of one patient, 20-year-old Rachel Forber of Merseyside, in northwest England, told a London tabloid that after 19 days of treatment his daughter was able to walk unaided, use a knife and fork, and complete coordination tests she had previously found impossible. The tabloid reported that Ms. Forber was given the diagnosis in June and told she had a year to live, and that she had become disabled and needed a wheelchair.

Efforts by The New York Times to contact the family were unsuccessful. The San Francisco researchers declined to reveal specifics about the patients, citing their confidentiality. The researchers identified the other patient taking the drug as an older American and said only that both patients had returned home, where they would continue taking the drug.

Details of how the new use for the old drug was discovered are published in today's issue of The Proceedings of the National Academy of Sciences. The malaria drug and another drug, chlorpromazine, which has been used for decades to treat schizophrenia, appear to be effective against all forms of Creutzfeldt-Jakob disease.

When the disease is contracted from eating meat from infected cows, as has occurred in Britain and other parts of Europe, it is called variant Creutzfeldt-Jakob disease. On average, patients survive 14 months after the disease is diagnosed. Of the 106 people known to have contracted variant Creutzfeldt- Jakob disease since 1995, fewer than 10 are still alive. No cases of variant Creutzfeldt-Jakob disease have been identified in the United States.

About 300 Americans each year die from other types of the disease: a type called sporadic Creutzfeldt-Jakob disease or, more rarely, a hereditary form caused by a genetic defect.

Doctors believe that the diseases develop when a normal protein found on the the surface of cells somehow misfolds into an abnormal shape. The misshapen protein, called an infectious prion, causes other healthy proteins to misfold in a chain reaction. Infected cells eventually die, leaving lethal holes in brain tissue.

Under the leadership of Dr. Stanley B. Prusiner, who won a Nobel Prize in 1997 for his work on prion diseases, a team of researchers at the University of California at San Francisco has been trying to design new drugs to disable misfolded proteins. That research is progressing well, said Dr. Fred Cohen, a neurologist on the team. But because the drugs are new, it will take at least five years to obtain approval for use in patients.

Meanwhile, another team member, Dr. Carsten Korth, decided seven months ago to look for existing drugs that might treat the disease, which has begun killing children in Britain.

"One thing any drug would have to do is cross the blood-brain barrier," he said, referring to the fact that many drugs which circulate in the bloodstream cannot get into the brain. "My idea was to try all drugs that cross this barrier in a cell model."

This involved putting known, approved drugs into dishes containing mouse cells infected with abnormal prions.

Thirteen classes of compounds cross the blood-brain barrier, Dr. Korth said. Only one class was efficient against prions. It has the shape of three linked rings with a chain of amino acids hanging off the middle ring.

Dr. Korth then tried dozens of drugs that belong to this structural class of compounds and found two that killed prion-infected cells. Quinacrine is an old drug that was once widely used to treat malaria and is still used to treat giardiasis, a common parasitic infection. Chlorpromazine is used to treat schizophrenia and other acute psychotic diseases. Even though they are structurally similar, both drugs work on different targets in the brain and do not cross react, Dr. Korth said.

To confirm that the mouse cells were cleared of prions, the researchers stopped treatment to see what would happen. Prion infection did not reappear for three weeks, the interval used to define a cure in this kind of laboratory experiment.

Because these two drugs have been used for decades for other conditions, they can be tried immediately on Creutzfeldt-Jakob disease patients. However, both can have serious side effects. In higher doses, quinacrine's side effects include damage to the heart, liver, intestines and central nervous system. The drug has been used in developing countries to sterilize women by producing inflammation of the fallopian tubes. High doses of chlorpromazine can cause permanent shaking in muscles throughout the body.

No longer protected by patents, both are cheap and easy to make. They may not be perfect, Dr. Cohen said, but if the drugs work even slightly in people, researchers can go to the chemistry lab and make improved compounds

"This disease has a grapevine that is amazing," Dr. Miller said. Dr. Korth's results were only recognized six weeks ago. "We're not really sure how the patients' families found out and got here so quickly," he said. Both patients are being given quinacrine.

The clinical trial, which has been approved by the Food and Drug Administration, should start enrolling patients next month, Dr. Miller said. They will come to the university's hospital for a two-week stay to get various doses of quinacrine alone or quinacrine plus chlorpromazine. They will then continue taking the drug therapy as outpatients for up to six months.

While chlorpromazine crosses more easily into the brain, quinacrine is 10 times more effective at killing infected cells, Dr. Miller said. The study will try to find the best dosage for each drug and how much gets into the brain.

The drugs will be termed successful if patients survive significantly longer than they normally would and are able to function, Dr. Miller said. It is not known whether they will suffer from permanent brain damage from the disease or whether people who are in earlier, asymptomatic stages of Creutzfeldt-Jakob disease can benefit from the drugs.

British scientists will participate in the clinical trial, Dr. Miller said. They are designing studies at a London clinic devoted to the care of patients with variant Creutzfeldt-Jakob disease.

http://www.nytimes.com/2001/08/14/health/anatomy/14PRIO.html?ex=998822041&ei=1&en=db73e0348df955f8


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