Good Drug, Bad Drug, Same Drug

In hindsight, drugs seem to dominate the 1960s. The ones that leap to mind first may be illegal substances like marijuana and LSD, but the most infamous was perfectly legal. It was a pharmaceutical called thalidomide.

If that name generates no pangs in your memory bank, you're too young to have been paying attention to the news media in the early '60s. Thalidomide then was a popular sedative in Europe and Japan, where it was often prescribed for pregnant women because it eased symptoms of morning sickness. In this country, the ponderous processes of the U.S. Food and Drug Administration had moved the drug along in the approval process only as far as clinical trials when it became obvious that thalidomide was horribly dangerous. Taken early in pregnancy, the drug stopped limb growth in human embryos. Nearly 10,000 so-called "thalidomide babies" were born with malformed or virtually nonexistent legs and arms. Thalidomide was taken off the market, and became a nightmarish example of medicine gone awry.

Both lawyers and medical researchers had cause to amass all records of thalidomide and its effects. Some 25 years after the event, immunologist Gilla Kaplan found among those records a benign side effect of thalidomide possibly relevant to her research. This side effect had been found in 1964, when a person suffering from leprosy observed that thalidomide eased symptoms apparently caused by the bacteria-killing drugs necessary to stem the disease.

Those symptoms, if not as bad as leprosy itself, can be painful and debilitating. Effective therapies against leprosy can cause high fevers, arthritis, skin lesions, and severe loss of appetite and weight. Thalidomide curbed those problems---it is the only use for which it is approved anywhere---but no one could understand how it produced that desirable effect. Kaplan reasoned that deciphering how thalidomide worked would help her to deduce what caused the symptoms attending the therapy.

According to a report in the September-October 1993 issue of American Scientist, Kaplan and her colleagues at Rockefeller University may have found even more than they expected. Thalidomide turns out to inhibit the body's production of a specific protein important in the workings of the immune system. This protein, tumor necrosis factor alpha or TNF-a, helps turn on some kinds of cells so they can attack invading organisms, such as bacteria and parasites, or misbehaving cells, such as tumors. Apparently, however, the systems of people battling chronic infections such as leprosy can crank out too much TNF-a. Kaplan's team found very high levels of TNF-a in leprosy patients who experienced the problems. The levels dropped when they took thalidomide, and the symptoms went away.

And that made Kaplan think of other diseases exhibiting the same set of problems. The most conspicuous among those illnesses nowadays is AIDS; patients nearing the end of their battle with Acquired Immune Deficiency Syndrome often have painful skin ulcers, severe weight loss, and fevers. She tested thalidomide in test-tube cultures of human cells often attacked by the AIDS-causing virus.

The drug inhibited TNF-a production in both monocytes and lymphoid cells, two types of immune system cells known to be targets for the virus. Furthermore, in tests run on monocytes actually infected by the virus, thalidomide suppressed viral reproduction by almost 80 percent.

Please note that thalidomide is not being touted as the cure for AIDS. There is no known cure for AIDS. But thalidomide may well join the arsenal of drugs useful in alleviating AIDS symptoms and in extending the enjoyable years of life for people who have the disease. To test that hopeful possibility, Kaplan's group will be monitoring a small clinical trial for human subjects during the next few months.

But no one's forgotten thalidomide's troubles. Women of childbearing age are to be excluded from the trial.