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Pentamidine may have antidementia payoff.

A drug now taken by most AIDS patients to prevent pneumonia may have the added benefit of protecting against the mind-warping symptoms of AIDS dementia, according to results from a preliminary study.

The test-tube study -- performed by pharmacologists Ian J. Reynolds and Elias Aizenman of the University of Pittsburgh School of Medicine -- suggests that the widely used drug pentamidine can help prevent brain cells from succumbing to the deadly effects of HIV, the virus that causes AIDS. Physicians currently administer pentamidine to nearly every AIDS patient, both as treatment and as a preventive for Pneumocystis carinii pneumonia, a potentially fatal lung infection that commonly strikes people with AIDS. However, the study's authors and neurologists who treat AIDS patients caution that they must perform further tests to prove or disprove pentamidine's antidementia effects.

According to the American Academy of Neurology, roughly 60 percent of AIDS patients develop some symptoms of AIDS dementia, which range from forgetfulness and confusion to irrational or childlike behavior. Although the AIDS drug AZT (zidovudine) has shown some benefit against AIDS dementia, there is currently no effective treatment for the disorder.

Reynolds and Aizenman stumbled upon evidence that pentamidine might protect against AIDS dementia while searching for drugs that block the N-methyl-D-aspartate (NMDA) receptor on nerve cells. The recently isolated receptor, named for its ability to bind to the lab-made chemical NMDA, triggers nerve-cell death when overexcited by NMDA or by glutamate, a chemical released by brain cells after a stroke or other head injury (SN: 11/23/91, p.333). Many drug companies and academic laboratories are now developing "NMDA antagonists" to block this common mechanism of nerve-cell destruction.

Several groups of neuroscientists now believe the NMDA receptor plays a role in AIDS dementia. Although the exact cause of the disorder remains unknown, many studies have ruled out direct killing by HIV. Some neurologists surmise that HIV destroys nerve cells indirectly by prompting the overproduction of a brain chemical called quinolinic acid, which can cause toxic effects at high levels (SN: 3/7/92, p.151). Others support another indirect mechanism, in whic gp120-the outer protein of HIV -- interfaces with a brain protein called VIP. Some nerve cells need VIP to send electrical signals to one another (SN: 5/18/91, p.311).

In the March JOURNAL OF NEUROSCIENCE, Reynolds and Aizenman report that pentamidine outstripped another NMDA-blocking drug in binding to the NMDA receptors of fetal rat brain cells grown in the laboratory. Moreover, pentamidine protected the nerve cells from death in the presence of an otherwise lethal concentration of NMDA. The researchers cite a previous study in which investigators who performed autopsies on the brains of AIDS patients found pentamidine levels comparable to those used in the Pittsburgh experiment.

Reynolds says he and Aizenman intend to investigate pentamidine's antidementia effects by collaborating with neurologists who study AIDS dementia. "Presumably, what we would see is that patients who had taken pentamidine would have less dementia," he says.

One such neurologist, Bruce A. Cohen at Northwestern University in Evanston, Ill., terms Reynolds and Aizenman's study "potentially interesting, but at this point speculative." Cohen points out that most AIDS patients develop dementia despite pentamidine treatment, although he concedes that the inhaled form in which pentamidine is usually given might not reach the brain as readily as an injection of the drug. Richard Price, a neurologist at the University of Minnesota in Minneapolis, also cautions that injected pentamidine can cause seizures in some people.
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Author:Ezzell, Carol
Publication:Science News
Date:Mar 28, 1992
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