Not surprisingly, in the Northern Hemisphere, colds reach their peak in winter: There is prevalence of colds in Sheffield, England, during the 1960s. In the tropics colds occur most frequently during the rainy season. The Caribbean island of Trinidad for example, has no winter, and colds are at their worst there in June and July.
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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.
The cost of the interferon used in the Common Cold Unit experiment—administered as a nasal spray—was nearly $3,000 per subject tested. Promising though the test results were for progress against colds, Merigan and others experimenting with interferon turned their attention to the substance’s value in combating chronic and life-threatening diseases associated with the immune system such as chronic hepatitis, rabies and cancer.
Cold sufferers, however, need not give up on interferon, for a great deal is being done to get around its scarcity and lower its cost. Three strategies are in the experimental stage. It may be possible to find artificial substances that mimic the effects of interferon. When scientists learn more about the nature of a cell’s interferon receptors and the internal mechanisms that take direction from them, they may be able to create a compound that, like interferon, will switch on a healthy cell’s receptors and make it produce antiviral proteins. Or the antiviral proteins themselves may be synthesized or imitated.
More productive has been a second approach: the creation of agents known as interferon inducers. They are substances that stimulate the body to make extra amounts of its own interferon—but in the absence of infection. Several such inducers have been found as a result of a deeper understanding of the natural actions of the immune system.
The cell’s natural production of interferon, it turns out, is stimulated by the internal components of a virus, the nucleic-acid compounds that make up the virus’s heredity- controlling ribonucleic and deoxyribonucleic acids—RNA and DNA. In the late 1960s scientists at the Merck Institute for Therapeutic Research in West Point, Pennsylvania, synthesized an RNA-like molecule that proved to be a very potent inducer of interferon production in the test tube, and in animals and humans as well. However, this synthetic, which they named poly 1:C, turned out to have some dangerous side effects. So, unfortunately, did several other synthetics with similar powers.
Another promising strategy for making the body produce interferon also involves inducers, but in compounds derived from natural rather than synthetic sources. These so-called biological inducers act like viruses in stimulating interferon production but lack viruses’ virulence and contagion. One is endotoxin, a substance in bacterial cell walls that has been found to stimulate interferon production in many types of animal cells. Endotoxin also is poisonous, but some less harmful bacterial product artificially seeded in the respiratory tract of a human cold sufferer could set off a release of booster doses of interferon and antiviral proteins. Similar promise as a biological inducer is shown by the mycoplasmas, cells that resemble—but are smaller than—bacteria.
But the likeliest route to cheap and plentiful interferon seems to lie on the frontiers of genetic engineering in the controversial field known as recombinant DNA technology, or gene splicing. It offers a way to make pure human interferon in vats, milking the priceless elixir from specially bred bacteria, This goal was achieved experimentally in 1979, when a group of scientists led by Dr. Charles Weissmann, Professor of Molecular Biology at the University of Zurich, succeeded in synthesizing human interferon outside the body, using something other than human cells.
The scientists isolated the group of nucleic acids—the gene—in human DNA that is responsible for producing interferon in the human body. In a delicate process of biological cut-and-paste, they then spliced this portion of human DNA into the DNA molecule of Escherichia co/i, a common species of bacteria found in the intestines. The subtly modified Escherichia co/i grows readily in culture mediums, its recombined DNA molecule producing a protein essentially like human interferon. Though differing somewhat in molecular make-up from interferon, the laboratory product possesses many of the genetic original’s antiviral characteristics.
Even in its imperfect state, gene-spliced interferon seems to have a number of major advantages over its current natural and induced counterparts. Once in production, it will be a good deal less expensive than interferon extracted from human blood (Escherichia co/i is cheap labor). It is also safer than induced interferon, because no foreign catalyst comes into play. And it can be manufactured on what amounts to an industrial assembly line, in large quantities.
This marvelous broad-spectrum protective mechanism, researchers have found, begins to work within several hours after the initial viral invasion. The amount of interferon produced is usually insufficient to block all of the viruses before infection takes some toll in damaged and destroyed cells. But the substance is critical in slowing viral spread, thereby buying the body time to mount its other defenses—eater cells, killer T cells and so on—in a combined effort to terminate infection.
The effectiveness of interferon against colds was demonstrated in 1973 by Dr. Thomas Merigan of Stanford University and a group of researchers at Britain’s Common Cold Unit. They tested it on groups of volunteers who were deliberately exposed to the common rhino type of cold virus. Five of the 16 subjects who received no interferon showed significant symptoms of infection following exposure to cold viruses; none of the 16 volunteers receiving interferon showed any symptoms.
This landmark experiment showed for the first time that interferon applied artificially could block viral reproduction and spread in a human respiratory infection. It was also the first demonstration in history of successful local antiviral treatment for a respiratory infection.
Other similar studies of interferon’s power as a cold preventive were begun in 1979 with very small samples of students at the Baylor College of Medicine and Texas A&M University (page 147). In these tests the interferon was administered nasally through an apparatus that produced an aerosol mist. (A control group of volunteers was administered a salt-water aerosol.) The incidence of colds was reduced by almost half in the subjects given interferon.
Interferon, unfortunately, is not only scarce but different in every creature. Unlike antibodies, which can be taken from animals to make human vaccines, interferon from most animals has virtually no effect in humans. Thus, over the initial years of experimentation with this substance, researchers were obliged to depend upon extracts collected with great difficulty from human blood supplies. It takes some 90,000 pints of blood—as much as is donated in Seattle, Washington, in an entire year—to produce 10,000 pints of the crude material from which .014 ounce of interferon can be refined. And because the method of extraction is technically difficult, the supplying of interferon to researchers has been expensive and slow.
By giving volunteers doses of the vitamin that have been made harmlessly radioactive, they can trace the radioactivity and follow vitamin C as it moves through the body, thereby establishing the patterns of bodily processing, storage, uptake by the blood, and elimination. These patterns become the basis for establishing healthful vitamin C levels in an overall set of dietary standards, the recommended dietary allowances promulgated by government health authorities. In the United States these standards are based on measurements of the daily quantity sufficient to prevent scurvy, to replenish amounts chemically processed by the body in 24 hours, and to maintain an adequate reserve against the unlikely circumstance of an extended lapse in normal vitamin C intake.
The recommendations vary slightly from country to country, primarily because different countries use slightly different criteria for measurement. In West Germany, for example, the daily recommendation for adults is 75 milligrams in “food as purchased.” The United Kingdom stipulates a minimum—30 milligrams per day for adults. In Denmark, Finland, East Germany, Japan and Czechoslovakia, the recommendations for adults are 45, 30, 70, 50 and 50 milligrams per day, respectively.
In the United States the suggested amount, called a recommended dietary allowance, or RDA, for healthy teenagers and adults is 60 milligrams, for young children 45 milligrams, for infants 35 milligrams. Pregnant women, particularly those in the second and third trimesters, need an extra 20 milligrams a day. Nursing mothers need as much as 40 additional milligrams daily, virtually all of which is passed on to the suckling infant, Labels on processed foods generally express vitamin content as a percentage of the RDA contained.
Anyone eating a moderately well-balanced diet will more than meet the RDA for vitamin C. A single eight-ounce glass of fresh, canned or frozen orange juice, for example, provides approximately 120 milligrams of vitamin C, 20 per cent more than the RDA for nursing mothers and twice as much as the average adult needs. In addition to citrus fruits, fresh fruits of many sorts are rich in vitamin C, as are such fresh vegetables as broccoli, brussels sprouts, turnips, and red and green peppers. (Albert Szent-Gyorgyi delightedly noted that the vitamin he discovered was richly provided by the distinctive seasoning of his native Hungary: paprika.)
Even cooked vegetables and fruits—whether fresh, frozen or canned—will supply significant amounts of vitamin C if they are heated briefly, at moderate temperatures and for immediate consumption. Frozen and canned vegetables and fruits, if picked at peak maturity and properly processed with little delay, may actually retain more vitamin C than fresh counterparts that have been stored poorly or for long periods.
Although health authorities around the world are in general if not perfect agreement on optimum amounts of vitamin C, Linus Pauling has disputed the consensus, contending that the present RDAs are too low to help the body fight colds. The obvious way to find out if he is right is to test his thesis: Give experimental groups large doses of the vitamin and see if they catch fewer colds than other people. This has been done, The results are controversial, as such tests are maddeningly subject to error. The challenge is to design a study so flawless that even the most biased opponent can repeat it with his own staff and subjects and get the same results.
The more that researchers learn about the complexities of colds, the harder it is for them to create such unchallengeable tests. If one group of volunteers gets measured doses of vitamin C and a second, control, group takes doses of a substance known to be innocuous—a placebo—the two groups must be virtually identical in age distribution, male- female ratio, general state of health, past experience of colds, general diet, smoking habits, stress levels, family composition and work environment.
As the test proceeds, the dropout rates of the two groups must remain substantially the same. The sample size and the duration of the test must be great enough to rule out chance variations that have nothing to do with the effect of the vitamin or the placebo.
For example, if the group includes hundreds of individuals, the impact of one person’s cold on the total test results will be far less likely to tilt scores one way or the other than the impact of such an event in a group of just 10 people. Another essential for a reputable test is a safeguard against psychologically induced error, for medical experimenters and their subjects are very vulnerable to self-deception. Subjects and test administrators alike must be kept completely in the dark about who is and who is not receiving the active drug. This technique, known as a double-blind study, is never more necessary than in investigating colds and flu.
Evaluation of respiratory infections depends on slippery data—the subjective views of the sufferer and the investigator, who must record what are at best inexact and unquantifiable symptoms. For some test subjects, the psychosomatic effect of knowing they are getting vitamin C rather than a placebo will be enough to make them feel better.
Similarly, subjects who learn that they have only a placebo to ward off infection may in some way become more susceptible to sickness or at least tend subconsciously to give more importance to the symptoms they do experience. The test administrator, who may well begin his research with an unacknowledged bias for or against the test substance, may subconsciously permit that bias to get in the way of a fair evaluation, too.
In a classic double-blind test a system of coded numbers, known only to a third party, matches volunteers and medications, keeping everyone on an equally infirm footing. Further, great care is taken to make the placebo and the medication similar in size, color and taste, so that no one involved has any basis for identifying the substance until after the results are tabulated. One experiment with vitamin C ran into problems because -of a simple error that was discovered only after the experiment ended: The researchers tested the sharply acid vitamin against a bland-tasting placebo. When they later asked the subjects if they were able to guess which they had been administered, several said they were. (Those subjects were eliminated from the results, which, thus corrected, indicated no special value for the vitamin.)
Finally, a proper test should include a reasonable certainty of compliance on the part of subjects. Many “open” tests depend on unsupervised volunteers, who have to remember to take a prescribed dose two or three times a day, week after week, and to keep accurate records of their experiences. More reliable on this score are trials administered in a “closed” situation such as a school, a prison or a common place of employment, where supervisory personnel can oversee the administration of substances, the general diet and the reporting of illness. However, a closed environment introduces errors of its own. The special nature of the situation raises doubts about the relevance of participants’ reactions to those of the general population.
The complexities of modem drug testing and the potential for misinterpretation that lurks in all tests make it clear that seeing should not always be believing when it comes tojudging the efficacy of vitamin C. Persuasive though Aunt Millie’s unfailing success with vitamin C or mustard plaster may be, her miracles could derive from any number of circum stances, including hyperactive cilia, a super immune system or a natural bent for looking on the bright side, none of which owe anything to vitamins or the bracing sting of mustard.