San Francisco Chronicle - Monday May 15, 1989
David Perlman, Chronicle Science Editor

Test-tube experiments applying the drug in combination with AZT indicate that in relatively large doses the heart drug can boost AZT's ability to fight the AIDS virus as much as tenfold, according to Dr. John N. Weinstein, a physician and immunologist at the National Cancer Institute in Bethesda.

Although no date has been set for the first human tests of the new drug combination, the findings by Weinstein's team have already been reviewed by a committee on AIDS clinical drug development at the National Institute of Arthritis and Infectious Diseases, where Dr. Anthony Fauci, the institute's chief, directs the major nationwide trials of new AIDS drugs.

CLINICAL TRIALS

Plans are being developed for the first clinical trials of the drug combination.

Weinstein and his international team of research colleagues are reporting their experimental results today in the Proceedings of the National Academy of Sciences.

The drug they have been testing for more than a year is known to heart surgeons as dipyridamol. It has been in use so long that its patents have long since expired and about 30 different pharmaceutical companies manufacture it. Its common trade name is Persantine.

In an interview here yesterday, Weinstein cautioned that although his test-tube experiments have shown encouraging effects in potentiating the action of AZT and in reducing its toxic effects in one of the immune system's cell types tested, too little is yet known about the heart drug's mechanism of action in AIDS to predict whether the same results will occur when it is tried in human beings in combination with AZT.

Even though dipyridamol is easily available, Weinstein warned, AIDS patients who are now using AZT should not try combining the drugs on their own, as its action is so complex that it is impossible to predict from the laboratory experiments just how the combination will behave in actual use. It is even possible, he said, that in human AIDS patients the heart drug may reduce the effectiveness of AZT or increase its toxic effects.

HEART SURGERY DRUG

The drug called dipyridamol has long been used after coronary bypass surgery and during operations to replace faulty heart valves because it helps prevent dangerous clots from forming in blood vessels. It is also used to expand arteries so that blood can flow through them more freely.

This unique use use of the heart drug in AIDS was in a sense an accidental finding. Weinstein and Dr. Janos Szebeni, a visiting scientist from Hungary, introduced the drug into their experiments as they were seeking methods for targeting various compounds against cells infected by the AIDS virus. They noticed that the compound could increase the effectiveness of AZT when the two drugs were combined, and that the heart drug also curbed the side effects of AZT in one of the cell types they were examining.

The experiments in the cancer institute's theoretical immunology laboratory have also shown that in addition to its action with AZT, the heart drug also increases the effectiveness of another AIDS compound called dideoxycytidine, or DDC, which is now undergoing accelerated clinical trials alone.

Some people with AIDS now alternate the use of AZT and DDC, changing drugs when the toxic effects of each become too severe. Although it is an extremely useful anti-viral drug, it can destroy white blood cells and is so toxic to bone marrow that it can cause anemia. DDC also has its own toxic side effects - primarily causing a nervous system condition called peripheral neuropathy.

Dipyridamol, the heart drug, did not increase the toxicity of AZT when it was tested in bone marrow cells donated by healthy volunteers, Weinstein said.

HELP FOR ATTACK ON HIV

He and his colleagues found that the heart drug increases the ability of both AZT and DDC to prevent the human immunodeficiency virus that causes AIDS from reproducing inside specific elements of the immune system called macrophages and T cells.

Macrophages, often known as scavenger cells, engulf and destroy invading organisms such as viruses and bacteria. They are a major reservoir of HIV, where the virus can often lurk for a long time without destroying those cells. T-4 cells, a major factor in preserving a well-functioning immune system, are killed quickly when the AIDS virus invades them.

According to Weinstein's newly published report, a series of tests using AZT in combination with various doses of dipyridamol showed that AZT's ability to inhibit the reproduction of the AIDS virus was increased by five to 10 times, depending on the dose level of the heart drug.

POSSIBLE USES

If the same results are found after careful early clinical trials, the possibility exists that dipyridamol might be used either to increase the anti-viral power of drugs such as AZT and DDC, or to decrease the dose levels of the anti-virals so their ability to kill viruses remains but their hazards are minimized.

Although AZT is now in wide use against AIDS, and DDC is undergoing its clinical trials, hundreds of analogues of those two compounds are being explored, Weinstein noted in an interview here. Similarly, there are many possible biochemical analogues of dipyridamol that might also prove effective in potentiating the anti-viral drugs. All these avenues remain to be explored as possible pathways to still other new drug combinations in the fight against AIDS, Weinstein said.

Among his colleagues in this new research are Dr. Sharon Wahl of the laboratory of microbiology and immunology at the National Institute of Dental Health, Dr. Suzanne Gartner and Dr. Mikulas Popovic of the National Cancer Institute's laboratory of tumor cell biology, and Dr. Robert L. Fine of Duke University.

Always watch for outdated information. This article first appeared in 1989. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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