Interferon And Anmantadine
Interferon has received so much international celebrity that significant developments in another kind of cure for respiratory infection—synthetic chemical compounds that would kill viruses the way antibiotics kill bacteria—have gone almost unnoticed. None is yet effective against colds, but one such chemical, given the generic name amantadine hydrochloride and the trade name Symmetrel by its makers, E. I. du Pont de Nemours & Co., not only has gone through the long stages of laboratory experiment and clinical testing, but has actually reached the market as a prescription drug for influenza A. Amantadine is a molecule with an unusually symmetrical shape, resembling a diamond. Through mechanisms not yet identified, amantadine keeps the influenza-A virus from initiating new growth in the respiratory tract. Whether taken as a preventive before the onset of flu symptoms or as a treatment afterward, it quickly goes to work either blocking penetration of the virus into healthy cells or inhibiting some early phase of viral replication in those cells.
Amantadine ‘s journey from the test tube to the drugstore shows the obstacles that must be overcome by any new drug but particularly by one designed for respiratory infections. Amantadine emerged from the standard drug-company technique of screening promising compounds to find one or two that showed potential against a chosen target—in this case respiratory viruses. Then the researchers synthesized related compounds and tried them. One, amantadine, proved highly effective against influenza A. It then underwent years of trials in animals to see what desirable and undesirable effects it produced and to set preliminary dosage levels that could be applied to humans. At that point, Du Pont secured government permission to test it on humans as what the U.S. Food and Drug Administration calls an investigational new drug.
In 1963 a University of Illinois team headed by Dr. George Gee Jackson, one of the leading figures in respiratory-disease research, demonstrated that amantadine produced up to a 70 per cent reduction in clinical illness from influenza A. After several more years of testing the drug for safety and efficacy, Du Pont applied for permission to market it.
Because knowledge of the idiosyncratic nature of influenza viruses is so hazy, only a limited license for amantadine’s use was granted. The drug could be sold to treat but one strain of flu, Asian H2N2, the strain used in tests and prevalent in the general population in the early 1 960s. Then, shortly after the license was issued in 1966, an event occurred that was to give the rapidly advancing amantadine a serious setback. The existing influenza-A strain went through a major shift—a new strain called A/Hong Kong/68 (H3N2) swept the world.
Without satisfying official requirements for further clinical trials involving the Hong Kong strain but with laboratory evidence on its side, Du Pont urged doctors to use amantadine as a preventive against the new influenza-A strain. This action proved a major legal and tactical error, for the company was ordered to retract its statements in a letter sent to every physician in the United States. As far as flu sufferers were concerned, no antiviral drug was available in 1969.
Amantadine simultaneously ran into trouble with some medical authorities, who believed that viruses, being natural parasites of humans, were so intimately involved with the life processes of human cells that they could not be selectively destroyed or inhibited by any drug, amantadine included. To attack the virus, these critics asserted, was to attack the cell, with consequences of a potentially very serious nature.
In the face of worsening publicity and legal obstacles, amantadine might have been withdrawn from production in the United States, even though Du Pont had already spent millions of dollars in carrying it from invention to this stalemate. But an 11 th-hour discovery that amantadine had another, quite unrelated, use kept it on the market. A woman suffering from the degenerative nervous disorder called Parkinson ‘s disease was told by her doctor to take amantadine as a flu preventive—and found to her astonishment that the Parkinsonian tremors and loss of movement were markedly alleviated. Doctors traced the serendipitous effects to amantadine, and it came into widespread use for this ailment over the next several years. As a result, many lingering questions as to its possible toxicity were favorably answered.
As had been claimed all along, amantadine turned out to be extremely selective—it attacked only viruses, and cell function was not tampered with. Its side effects were chiefly mild transitory changes in the function of the central nervous system —lightheadedness, nervousness, difficulty in concentration, insomnia or, contrarily, drowsiness—that occurred in some 7 per cent of users. Such side effects were similar to those sometimes associated with common over-the-counter antihistamines or decongestants.
Reassured by these findings and by reports from Europe, particularly from the Soviet Union, of amantadine’s value in treating a number of influenza-A strains, the United States formally licensed amantadine ‘s broader use in 1976. Today, amantadine is recommended for prevention of influenza A (but not for influenza B or any other respiratory virus). It also can be used to treat an existing influenza-A infection—particularly within the first 48 hours after symptoms appear— but with less efficacy than as a preventive.
Amantadine is not suggested as an equal alternative to vaccination. To protect yourself against influenza, you are still advised to follow your physician’s judgment on whether or not you fall into one of the risk groups and should receive a shot. Rather, amantadine is best used along with other strategies for controlling flu, particularly during epidemics.
Amantadine can protect individuals while they develop maximum immunity following vaccination. Amantadine is also the only alternative for individuals who for some reason cannot tolerate flu vaccines—for example, people who are allergic to eggs, in which the vaccines are grown. It may also be an effective reinforcer of immunity for those who have been vaccinated but fall into the high-risk category—hospital patients, the chronically ill, and people in semiclosed communities, particularly members of that double-jeopardy group, the elderly in old-age homes.
Where prevention is the goal, the recommended adult dosage of amantadine is 100 milligrams twice a day for 30 to 60 days, the usual span of a local flu epidemic, or for the two weeks or so required for a vaccination to take full effect. Therapeutic dosages are also 100 milligrams twice a day, beginning, if possible, within 48 hours after the onset of symptoms and continuing for up to two days after the last sign of illness disappears, usually about a week later. While amantadine as a therapeutic cannot abruptly terminate the infection, it does have some effect in reducing the severity of symptoms, possibly reducing in turn the likelihood of those secondary complications, such as pneumonia, that add so greatly to flu’s potential dangers. Amantadine also seems to bring about a significant reduction in the amount of flu virus a carrier sheds, an effect that helps contain the infection once it gets within the precincts of the family.
Now that amantadine has successfully blazed a trail, many more antiviral drugs seem certain to follow. Rimantadine, closely related to amantadine but lacking some of its side effects, is currently under study in the United States and is already being used against influenza A in the Soviet Union, where much research on it has been done. Other compounds having antiviral effects on the herpes simplex virus (which causes cold sores and may be associated with some cancers) have shown promising results in early testing. And at Texas A&M University, student volunteers suffering from flu were given a new experimental drug called ribavirin. According to the study director, Dr. Vernon Knight of the Baylor College of Medicine, ribavirin seemed to alleviate the symptoms of the flu sufferers and showed no toxic effects.
Virtually every large pharmaceutical company in the world has some portion of its research budget invested in the high-stakes race to find a drug to combat cold and flu viruses. For the moment, chicken soup may still be the drug of choice, but more effective help is on the way.
