FDA Consumer magazine (September 1995) VOL. 29 No. 7 SEPTEMBER 1995 ------------------------------------------------------------------------ Features First Vaccine for Chickenpox Another childhood disease is beginning to be conquered through immunization as a chickenpox vaccine, approved by FDA earlier this year, becomes available. The Rise of Antibiotic-Resistant Infections Complacency, antibiotic overuse, and social factors all play a part in the growing problem of bacteria becoming resistant to certain antibiotics. Though some antibiotic resistance is inevitable, there are measures that can be taken to slow the process. On the Teen Scene: Food Label Makes Good Eating Easier Whether you're concerned with losing or gaining weight, eating the right amounts of protein, calcium or fat, or simply staying in good shape, you can make the new food label work for you. FDA Examining Computer Diagnosis Computer software is being used for more and more medical purposes, ranging from diagnosing exotic diseases to finding precancerous cells. FDA is looking at how best to regulate these programs when they function as medical devices. Medical Possibilities for Psychedelic Drugs LSD, mescaline, and some other drugs better known for their abuse potential are being carefully investigated for medical uses, such as treating drug addictions and relieving pain. ------------------------------------------------------------------------ Departments Updates The latest information on FDA-related issues, gathered from FDA Press Releases, Talk Papers, and other sources. Notebook A potpourri of items of interest gathered from the Federal Register and other sources. Investigators' Reports Selected cases illustrating regulatory and administrative actions--such as inspections, recalls, seizures, and court proceedings--by FDA's regional and district offices across the country Summaries of Court Actions Cases involving seizure, criminal and injunction proceedings. ------------------------------------------------------------------------ First Vaccine for Chickenpox by Isadora B. Stehlin The days when nearly everyone spent a week of their childhood with the itchy, miserable rash of chickenpox may be on the wane. Last March 17, the Food and Drug Administration licensed a new vaccine, Varivax (varicella virus vaccine live). Commonly known as the chickenpox vaccine, it will prevent the typical cases of itchy, uncomfortable, week-long rashes and mild fevers, and the rarer cases of serious illness caused by the virus. Although chickenpox is generally mild and not normally life-threatening, the Centers for Disease Control and Prevention estimates that there are 9,300 chickenpox-related hospitalizations and 50 to 100 deaths annually, mainly among young children. Before receiving approval from FDA, researchers tested Varivax in about 11,000 children and adults. Scientists predict that it will be 70 to 90 percent effective in preventing the disease. Of those who did get chickenpox after vaccination, almost all had a mild form of the disease. Adverse reactions to the vaccine were generally mild and included pain, rash, hardness, and swelling at the injection site, fever, and generalized rashes. Mary L. Kumar, M.D., chief of pediatric infectious diseases at MetroHealth Clinic in Cleveland, tested the vaccine on about 500 children and 200 adults in the Cleveland area. She says the vaccine trials were very easy to recruit for. "We actually had people calling us," Kumar explains, adding that there was not only great interest from parents who wanted to spare their children from the disease, but also from adults in health-care professions who were concerned about getting chickenpox themselves and about infecting susceptible patients. Will It Last? Throughout the development of the chickenpox vaccine, there has been concern about whether the vaccine would confer lifetime immunity or simply delay infection until adulthood. When adults get chickenpox, the cases are usually more severe and the risk of complications such as pneumonia greater. "Over the period of time it's been looked at carefully, which is about five years, we're not able to find evidence for substantial waning in immunity," says Philip Krause, M.D., senior research investigator in FDA's Center for Biologics Evaluation and Research. "It's complicated to determine how long immunity lasts, because right now people who are vaccinated are exposed to children who have [naturally acquired] chickenpox and they presumably are getting a booster effect from those repeated exposures." "Longer is more difficult to tell," says Krause. "The only way to sort that out is going to be to see what happens after the vaccine is introduced." At FDA's request, Merck will follow several thousand vaccinated children for 15 years to determine the long-term effects of the vaccine and possible need for a booster immunization. Shingles As with the question of immunity, more time is needed to answer another question about the vaccine--will it cause shingles in adulthood? Shingles is the second act of chickenpox. Once someone has had chickenpox, the virus doesn't die, it simply becomes dormant. It lingers in the body's nerve cells next to the spinal cord. Then, for reasons still not definitely known but possibly related to a weakened immune system, the virus reactivates and infects nerve fibers, causing severe pain, burning or itching. Because weakened immunity often accompanies aging, shingles usually occurs after age 50. Can the chickenpox vaccine, which is a weakened form of the live virus, cause shingles? "Nobody's sure what the effect will be," says Krause. "We really don't have the data to say what's going to happen in 20 to 30 years. Based on our knowledge of how the virus works and the data available so far, it doesn't appear that the rate of shingles cases in vaccinated individuals will be any greater than in the naturally infected population. There's some data in children who were immunocompromised that suggests that the vaccine may reduce the likelihood of shingles over the short term. But more data are required to determine the effect of the vaccine on shingles in healthy individuals over a lifetime." Just One or Two Shots A single injection of the vaccine is recommended for children ages 12 months to 12 years, while two injections four to eight weeks apart are recommended for adolescents and adults who have never had chickenpox. "We're not really sure why teens and adults don't get immunity with one shot," says Krause. "The immune response to a single shot if you're 13 or older is not nearly as good as it is if you're younger. But two shots provide immune responses comparable to what younger people get." For children, the vaccine has been shown to be safe and effective and can be administered at the same time as the measles, mumps and rubella vaccine. (The MMR vaccine is given at 15 months and again between 4 and 6 years or before junior high or middle school. See "Kids' Vaccinations Get a Little Easier," in the March 1994 FDA Consumer.) Public health officials hope that being able to give the chickenpox vaccine along with an already scheduled vaccine will encourage vaccination. Vaccine Development Varivax's development began with a sample of varicella (chickenpox) virus isolated from the blood of a 3-year-old Japanese boy in 1972. Japanese researcher Michiaki Takahashi, M.D., attenuated (weakened) the virus by growing it in different human and animal host cells. He then tested the weakened virus in children as a vaccine against chickenpox. His tests were successful, and in 1981, Merck obtained the rights to use the "Oka" strain (named after the 3-year-old boy) to develop its own vaccine. Merck began clinical trials of the vaccine for safety and effectiveness. But obtaining successful test results was only half the battle for Merck to bring the vaccine to market. Making enough vaccine to meet demand was the other. Unlike other weakened live viruses used for vaccines that spontaneously emerge from cultivated cells, varicella stays in the cell. "In the case of varicella, we have to collect the infected cells and then break them open," explains Barry D. Garfinkle, Ph.D., Merck's vice president for vaccine quality operations. "We do this using an ultrasonic device." The ultrasound creates heat and, in this case, creates problems. Although the varicella virus is extremely virulent in its natural environment inside the human host, once it's removed from the infected cells in the lab "varicella is very, very sensitive to elevated temperatures," says Garfinkle. "We have to use the right amount of [ultrasound] to get the virus freed but not so much that we damage the virus," says Garfinkle. "Getting those parameters correct took us a while." To this end, Merck built a new facility in West Point, Pa., where robots handle most of the vaccine production. Garfinkle explains that using robots allows for better control of the exacting ultrasound procedure. Merck submitted data on Varivax's safety and effectiveness to FDA in May 1993. In January 1994, FDA's Vaccines and Related Biological Products Advisory Committee concluded that the vaccine was safe and effective. But the committee advised FDA to address several questions before making a final decision, including how to address whether vaccinating children would shift the disease to adults and whether doctors could give Varivax at the same time as other vaccines. In January 1995, FDA presented to the committee clinical data from the manufacturer resolving those issues. Easy to Catch An estimated 3.7 million Americans get chickenpox each year, with more than 90 percent of cases in people younger than 15. Chickenpox is transmitted through fluid from broken blisters and through coughing or sneezing. A person is contagious for one or two days before the rash appears until all the lesions are dried, which usually takes four to five days. The average incubation period (the time between exposure to the virus and the onset of illness) is 10 to 21 days. Those at greatest risk for a serious case of chickenpox are people age 13 and older, and anyone with impaired immunity. Chickenpox can also be serious for fetuses and newborn babies. When a woman breaks out in chickenpox just before or after delivery, her baby may develop a severe form of the disease; as many as 5 percent of these babies die. Infection early in pregnancy may cause the fetus to develop limb abnormalities, scarring of internal organs, or damage to the central nervous system. In addition, "there are a fair number of complications that require hospitalization of otherwise healthy children," says Kumar. That was the case for Brittany Evans (not her real name). The only risk factor for the healthy two-and-half-year-old was her 5-year-old sister's routine bout with chickenpox two weeks before. "Frequently in a family, the second and third cases can be more severe," explains Kumar. Siblings generally spend more time with each other than with friends and schoolmates and this gives the virus the opportunity to infect siblings when it's most virulent. Brittany's chickenpox broke out on Friday, March 10. By the next Wednesday she was covered with blisters and running a fever of almost 105 degrees Fahrenheit. "She had [blisters] between her fingers so bad she couldn't get her fingers side by side," says her mother. "I couldn't rub my hand along her tummy and find a spot that didn't have a blister." Brittany was admitted to Shady Grove Hospital in Gaithersburg, Md., on March 17 (ironically, the same day the vaccine was licensed). She spent three days there to make sure she didn't become dangerously dehydrated from the high fever. Her body's own defenses finally overcame the virus, and she recovered. On April 10, the American Academy of Pediatrics recommended the vaccine for all healthy children between the ages of 12 months and 13 years who have not had chickenpox. For children between 12 and 18 months, the academy recommends giving the chickenpox vaccine at the same time as the first measles, mumps and rubella shot. Older children should be vaccinated at the earliest convenient time. While some doctors still question the need for vaccinating against a generally mild disease, Kumar agrees with the academy's recommendations because of the need to prevent unforeseen complications and hospitalizations. Brittany's mom isn't a medical expert, but she says, "I never want to go through this again. My husband and I are thinking about having another child, and I'll get the next one the vaccine, without a doubt." Isadora B. Stehlin is a staff writer for FDA Consumer. ------------------------------------------------------------------------ Treating Chickenpox Public health officials don't know yet how many children will be vaccinated since the chickenpox vaccine isn't required for school admission at this time. In otherwise healthy children and adults, the disease should be allowed to run its course. But that doesn't mean the symptoms should be ignored. Calamine lotion applied to the lesions may offer some relief from the infamous itch of the chickenpox rash. Soaking in a cornstarch, baking soda, or oatmeal bath may also do the trick. However, because any relief is at best temporary, doctors advise parents to cut children's nails very short, since scratching can lead to secondary skin infection by bacteria on the skin, such as staphylococcus ("staph") and permanent scarring. A daily bath with soap is also recommended to clean as much bacteria off the skin as possible. A non-aspirin pain reliever and fever reducer such as acetaminophen (Datril, Tempra, Tylenol, and others) can ease headaches, fever, or general malaise. Aspirin or any medication that contains aspirin or salicylates should never be used because of the risk of Reye syndrome, a rare but serious illness that typically strikes children and teenagers just as they appear to be recovering from the flu or chickenpox. If a doctor visit is necessary, pediatricians usually make special arrangements to see children who might have chickenpox to avoid exposing others. "They might see [those children] after hours or when the office isn't busy," says Mary L. Kumar, M.D., a pediatrician in Cleveland. Although diagnosis may be possible over the phone, "I like to take a look myself," she says. "Over the phone can be pretty accurate if other children in the family just had chickenpox. But there are many other rashes that can look somewhat like the varicella [chickenpox] rash, so I don't think it's easy over the phone to be certain." During the course of the infection, the doctor should be called if the patient's temperature goes above 102 degrees Fahrenheit (39 degrees Celsius) or any fever lasts longer than four days, or if areas of the rash become very red, warm, or tender, which may signal a bacterial infection requiring antibiotics. In February 1992, FDA approved the use of oral Zovirax (acyclovir) to treat chickenpox in otherwise healthy children. (FDA had already approved the drug to treat genital herpes and shingles.) When a patient receives oral Zovirax within 24 hours after the rash appears, the number of lesions are reduced, and average recovery time is shortened approximately one day. However, the American Academy of Pediatrics does not recommend the use of oral Zovirax in otherwise healthy children. The academy says the medication's relief of chickenpox symptoms is minimal, it's extremely difficult to start it during the first 24 hours, and there is a potential for unforeseen dangers when treating large numbers of children who are at low risk of developing complications. The academy recommends use of oral Zovirax only in people at high risk for severe chickenpox or complications, including: * healthy nonpregnant teenagers and adults * children over 1 year who have chronic skin or lung disorders, or who must take aspirin daily for conditions such as arthritis * children taking corticosteroids for conditions such as asthma. A biological product that actually prevents infection is available for people at high risk. But the product, varicella-zoster immune globulin, or VZIG (doctors pronounce it "vee-zig"), must be administered within 96 hours of exposure, long before symptoms appear. And it serves little purpose to the otherwise healthy population because VZIG gives only temporary protection. VZIG is prepared from the plasma of normal blood donors who have high levels of antibodies to the varicella virus, which causes chickenpox. It confers a "passive" immunization that lasts only about three months. The Centers for Disease Control and Prevention recommend VZIG for the following * high-risk individuals who have no immunity to chickenpox: * immunocompromised children and adults * newborns whose mothers came down with chickenpox five days before to two days after delivery * premature infants exposed after birth. VZIG may be recommended for mothers who are exposed during the first trimester. However, taking VZIG at this time only benefits the mother's health. There is no indication that VZIG can prevent the birth defects associated with the chickenpox virus. Those at highest risk for complications are not candidates for the chickenpox vaccine. (Healthy teenagers and adults, who are considered at high risk for chickenpox complications simply because of their age, can get the vaccine.) "People who have compromised immune systems are more likely to get worse reactions to the vaccine because it is a live virus," says FDA's Philip R. Krause, M.D. "The hope is that if enough healthy children get the vaccine there will be less natural chickenpox floating around and [high-risk] people will not be exposed." --I.B.S. ------------------------------------------------------------------------ The Rise of Antibiotic-Resistant Infections by Ricki Lewis, Ph.D. When penicillin became widely available during the second world war, it was a medical miracle, rapidly vanquishing the biggest wartime killer--infected wounds. Discovered initially by a French medical student, Ernest Duchesne, in 1896, and then rediscovered by Scottish physician Alexander Fleming in 1928, the product of the soil mold Penicillium crippled many types of disease-causing bacteria. But just four years after drug companies began mass-producing penicillin in 1943, microbes began appearing that could resist it. The first bug to battle penicillin was Staphylococcus aureus. This bacterium is often a harmless passenger in the human body, but it can cause illness, such as pneumonia or toxic shock syndrome, when it overgrows or produces a toxin. In 1967, another type of penicillin-resistant pneumonia, caused by Streptococcus pneumoniae and called pneumococcus, surfaced in a remote village in Papua New Guinea. At about the same time, American military personnel in southeast Asia were acquiring penicillin-resistant gonorrhea from prostitutes. By 1976, when the soldiers had come home, they brought the new strain of gonorrhea with them, and physicians had to find new drugs to treat it. In 1983, a hospital-acquired intestinal infection caused by the bacterium Enterococcus faecium joined the list of bugs that outwit penicillin. Antibiotic resistance spreads fast. Between 1979 and 1987, for example, only 0.02 percent of pneumococcus strains infecting a large number of patients surveyed by the national Centers for Disease Control and Prevention were penicillin-resistant. CDC's survey included 13 hospitals in 12 states. Today, 6.6 percent of pneumococcus strains are resistant, according to a report in the June 15, 1994, Journal of the American Medical Association by Robert F. Breiman, M.D., and colleagues at CDC. The agency also reports that in 1992, 13,300 hospital patients died of bacterial infections that were resistant to antibiotic treatment. Why has this happened? "There was complacency in the 1980s. The perception was that we had licked the bacterial infection problem. Drug companies weren't working on new agents. They were concentrating on other areas, such as viral infections," says Michael Blum, M.D., medical officer in the Food and Drug Administration's division of anti-infective drug products. "In the meantime, resistance increased to a number of commonly used antibiotics, possibly related to overuse of antibiotics. In the 1990s, we've come to a point for certain infections that we don't have agents available." According to a report in the April 28, 1994, New England Journal of Medicine, researchers have identified bacteria in patient samples that resist all currently available antibiotic drugs. Survival of the Fittest The increased prevalence of antibiotic resistance is an outcome of evolution. Any population of organisms, bacteria included, naturally includes variants with unusual traits--in this case, the ability to withstand an antibiotic's attack on a microbe. When a person takes an antibiotic, the drug kills the defenseless bacteria, leaving behind--or "selecting," in biological terms--those that can resist it. These renegade bacteria then multiply, increasing their numbers a millionfold in a day, becoming the predominant microorganism. The antibiotic does not technically cause the resistance, but allows it to happen by creating a situation where an already existing variant can flourish. "Whenever antibiotics are used, there is selective pressure for resistance to occur. It builds upon itself. More and more organisms develop resistance to more and more drugs," says Joe Cranston, Ph.D., director of the department of drug policy and standards at the American Medical Association in Chicago. A patient can develop a drug-resistant infection either by contracting a resistant bug to begin with, or by having a resistant microbe emerge in the body once antibiotic treatment begins. Drug-resistant infections increase risk of death, and are often associated with prolonged hospital stays, and sometimes complications. These might necessitate removing part of a ravaged lung, or replacing a damaged heart valve. Bacterial Weaponry Disease-causing microbes thwart antibiotics by interfering with their mechanism of action. For example, penicillin kills bacteria by attaching to their cell walls, then destroying a key part of the wall. The wall falls apart, and the bacterium dies. Resistant microbes, however, either alter their cell walls so penicillin can't bind or produce enzymes that dismantle the antibiotic. In another scenario, erythromycin attacks ribosomes, structures within a cell that enable it to make proteins. Resistant bacteria have slightly altered ribosomes to which the drug cannot bind. The ribosomal route is also how bacteria become resistant to the antibiotics tetracycline, streptomycin and gentamicin. How Antibiotic Resistance Happens Antibiotic resistance results from gene action. Bacteria acquire genes conferring resistance in any of three ways. In spontaneous DNA mutation, bacterial DNA (genetic material) may mutate (change) spontaneously (indicated by starburst). Drug-resistant tuberculosis arises this way. n a form of microbial sex called transformation, one bacterium may take up DNA from another bacterium. Pencillin-resistant gonorrhea results from transformation. Most frightening, however, is resistance acquired from a small circle of DNA called a plasmid, that can flit from one type of bacterium to another. A single plasmid can provide a slew of different resistances. In 1968, 12,500 people in Guatemala died in an epidemic of Shigella diarrhea. The microbe harbored a plasmid carrying resistances to four antibiotics! A Vicious Cycle: More Infections and Antibiotic Overuse Though bacterial antibiotic resistance is a natural phenomenon, societal factors also contribute to the problem. These factors include increased infection transmission, coupled with inappropriate antibiotic use. More people are contracting infections. Sinusitis among adults is on the rise, as are ear infections in children. A report by CDC's Linda F. McCaig and James M. Hughes, M.D., in the Jan. 18, 1995, Journal of the American Medical Association, tracks antibiotic use in treating common illnesses. The report cites nearly 6 million antibiotic prescriptions for sinusitis in 1985, and nearly 13 million in 1992. Similarly, for middle ear infections, the numbers are 15 million prescriptions in 1985, and 23.6 million in 1992. Causes for the increase in reported infections are diverse. Some studies correlate the doubling in doctor's office visits for ear infections for preschoolers between 1975 and 1990 to increased use of day-care facilities. Homelessness contributes to the spread of infection. Ironically, advances in modern medicine have made more people predisposed to infection. People on chemotherapy and transplant recipients taking drugs to suppress their immune function are at greater risk of infection. "There are the number of immunocompromised patients, who wouldn't have survived in earlier times," says Cranston. "Radical procedures produce patients who are in difficult shape in the hospital, and are prone to nosocomial [hospital-acquired] infections. Also, the general aging of patients who live longer, get sicker, and die slower contributes to the problem," he adds. Though some people clearly need to be treated with antibiotics, many experts are concerned about the inappropriate use of these powerful drugs. "Many consumers have an expectation that when they're ill, antibiotics are the answer. They put pressure on the physician to prescribe them. Most of the time the illness is viral, and antibiotics are not the answer. This large burden of antibiotics is certainly selecting resistant bacteria," says Blum. Another much-publicized concern is use of antibiotics in livestock, where the drugs are used in well animals to prevent disease, and the animals are later slaughtered for food. "If an animal gets a bacterial infection, growth is slowed and it doesn't put on weight as fast," says Joe Madden, Ph.D., strategic manager of microbiology at FDA's Center for Food Safety and Applied Nutrition. In addition, antibiotics are sometimes administered at low levels in feed for long durations to increase the rate of weight gain and improve the efficiency of converting animal feed to units of animal production. FDA's Center for Veterinary Medicine limits the amount of antibiotic residue in poultry and other meats, and the U.S. Department of Agriculture monitors meats for drug residues. According to Margaret Miller, Ph.D., deputy division director at the Center for Veterinary Medicine, the residue limits for antimicrobial animal drugs are set low enough to ensure that the residues themselves do not select resistant bacteria in (human) gut flora. FDA is investigating whether bacteria resistant to quinolone antibiotics can emerge in food animals and cause disease in humans. Although thorough cooking sharply reduces the likelihood of antibiotic-resistant bacteria surviving in a meat meal to infect a human, it could happen. Pathogens resistant to drugs other than fluoroquinolones have sporadically been reported to survive in a meat meal to infect a human. In 1983, for example, 18 people in four midwestern states developed multi-drug-resistant Salmonella food poisoning after eating beef from cows fed antibiotics. Eleven of the people were hospitalized, and one died. A study conducted by Alain Cometta, M.D., and his colleagues at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and reported in the April 28, 1994, New England Journal of Medicine, showed that increase in antibiotic resistance parallels increase in antibiotic use in humans. They examined a large group of cancer patients given antibiotics called fluoroquinolones to prevent infection. The patients' white blood cell counts were very low as a result of their cancer treatment, leaving them open to infection. Between 1983 and 1993, the percentage of such patients receiving antibiotics rose from 1.4 to 45. During those years, the researchers isolated Escherichia coli bacteria annually from the patients, and tested the microbes for resistance to five types of fluoroquinolones. Between 1983 and 1990, all 92 E. coli strains tested were easily killed by the antibiotics. But from 1991 to 1993, 11 of 40 tested strains (28 percent) were resistant to all five drugs. Towards Solving the Problem Antibiotic resistance is inevitable, say scientists, but there are measures we can take to slow it. Efforts are under way on several fronts--improving infection control, developing new antibiotics, and using drugs more appropriately. Barbara E. Murray, M.D., of the University of Texas Medical School at Houston writes in the April 28, 1994, New England Journal of Medicine that simple improvements in public health measures can go a long way towards preventing infection. Such approaches include more frequent hand washing by health-care workers, quick identification and isolation of patients with drug-resistant infections, and improving sewage systems and water purity in developing nations. Drug manufacturers are once again becoming interested in developing new antibiotics. These efforts have been spurred both by the appearance of new bacterial illnesses, such as Lyme disease and Legionnaire's disease, and resurgences of old foes, such as tuberculosis, due to drug resistance. FDA is doing all it can to speed development and availability of new antibiotic drugs. "We can't identify new agents--that's the job of the pharmaceutical industry. But once they have identified a promising new drug for resistant infections, what we can do is to meet with the company very early and help design the development plan and clinical trials," says Blum. In addition, drugs in development can be used for patients with multi-drug-resistant infections on an "emergency IND (compassionate use)" basis, if the physician requests this of FDA, Blum adds. This is done for people with AIDS or cancer, for example. No one really has a good idea of the extent of antibiotic resistance, because it hasn't been monitored in a coordinated fashion. "Each hospital monitors its own resistance, but there is no good national system to test for antibiotic resistance," says Blum. This may soon change. CDC is encouraging local health officials to track resistance data, and the World Health Organization has initiated a global computer database for physicians to report outbreaks of drug-resistant bacterial infections. Experts agree that antibiotics should be restricted to patients who can truly benefit from them--that is, people with bacterial infections. Already this is being done in the hospital setting, where the routine use of antibiotics to prevent infection in certain surgical patients is being reexamined. "We have known since way back in the antibiotic era that these drugs have been used inappropriately in surgical prophylaxis [preventing infections in surgical patients]. But there is more success [in limiting antibiotic use] in hospital settings, where guidelines are established, than in the more typical outpatient settings," says Cranston. Murray points out an example of antibiotic prophylaxis in the outpatient setting--children with recurrent ear infections given extended antibiotic prescriptions to prevent future infections. (See "Protecting Little Pitchers' Ears" in the December 1994 FDA Consumer.) Another problem with antibiotic use is that patients often stop taking the drug too soon, because symptoms improve. However, this merely encourages resistant microbes to proliferate. The infection returns a few weeks later, and this time a different drug must be used to treat it. Targeting TB Stephen Weis and colleagues at the University of North Texas Health Science Center in Fort Worth reported in the April 28, 1994, New England Journal of Medicine on research they conducted in Tarrant County, Texas, that vividly illustrates how helping patients to take the full course of their medication can actually lower resistance rates. The subject--tuberculosis. TB is an infection that has experienced spectacular ups and downs. Drugs were developed to treat it, complacency set in that it was beaten, and the disease resurged because patients stopped their medication too soon and infected others. Today, one in seven new TB cases is resistant to the two drugs most commonly used to treat it (isoniazid and rifampin), and 5 percent of these patients die. In the Texas study, 407 patients from 1980 to 1986 were allowed to take their medication on their own. From 1986 until the end of 1992, 581 patients were closely followed, with nurses observing them take their pills. By the end of the study, the relapse rate--which reflects antibiotic resistance--fell from 20.9 to 5.5 percent. This trend is especially significant, the researchers note, because it occurred as risk factors for spreading TB--including AIDS, intravenous drug use, and homelessness--were increasing. The conclusion: Resistance can be slowed if patients take medications correctly. Narrowing the Spectrum Appropriate prescribing also means that physicians use "narrow spectrum" antibiotics--those that target only a few bacterial types--whenever possible, so that resistances can be restricted. The only national survey of antibiotic prescribing practices of office physicians, conducted by the National Center for Health Statistics, finds that the number of prescriptions has not risen appreciably from 1980 to 1992, but there has been a shift to using costlier, broader spectrum agents. This prescribing trend heightens the resistance problem, write McCaig and Hughes, because more diverse bacteria are being exposed to antibiotics. One way FDA can help physicians choose narrower spectrum antibiotics is to ensure that labeling keeps up with evolving bacterial resistances. Blum hopes that the surveillance information on emerging antibiotic resistances from CDC will enable FDA to require that product labels be updated with the most current surveillance information. Many of us have come to take antibiotics for granted. A child develops strep throat or an ear infection, and soon a bottle of "pink medicine" makes everything better. An adult suffers a sinus headache, and antibiotic pills quickly control it. But infections can and do still kill. Because of a complex combination of factors, serious infections may be on the rise. While awaiting the next "wonder drug," we must appreciate, and use correctly, the ones that we already have. ------------------------------------------------------------------------ Big Difference If this bacterium could be shown four times bigger, it would be the right relative size to the virus beneath it. (Both are microscopic and are shown many times larger than life.) Although bacteria are single-celled organisms, viruses are far simpler, consisting of one type of biochemical (a nucleic acid, such as DNA or RNA) wrapped in another (protein). Most biologists do not consider viruses to be living things, but instead, infectious particles. Antibiotic drugs attack bacteria, not viruses. ------------------------------------------------------------------------ The Greatest Fear--Vancomycin Resistance When microbes began resisting penicillin, medical researchers fought back with chemical cousins, such as methicillin and oxacillin. By 1953, the antibiotic armamentarium included chloramphenicol, neomycin, terramycin, tetracycline, and cephalosporins. But today, researchers fear that we may be nearing an end to the seemingly endless flow of antimicrobial drugs. At the center of current concern is the antibiotic vancomycin, which for many infections is literally the drug of "last resort," says Michael Blum, M.D., medical officer in FDA's division of anti-infective drug products. Some hospital-acquired staph infections are resistant to all antibiotics except vancomycin. Now vancomycin resistance has turned up in another common hospital bug, enterococcus. And since bacteria swap resistance genes like teenagers swap T-shirts, it is only a matter of time, many microbiologists believe, until vancomycin-resistant staph infections appear. "Staph aureus may pick up vancomycin resistance from enterococci, which are found in the normal human gut," says Madden. And the speed with which vancomycin resistance has spread through enterococci has prompted researchers to use the word "crisis" when discussing the possibility of vancomycin-resistant staph. Vancomycin-resistant enterococci were first reported in England and France in 1987, and appeared in one New York City hospital in 1989. By 1991, 38 hospitals in the United States reported the bug. By 1993, 14 percent of patients with enterococcus in intensive-care units in some hospitals had vancomycin-resistant strains, a 20-fold increase from 1987. A frightening report came in 1992, when a British researcher observed a transfer of a vancomycin-resistant gene from enterococcus to Staph aureus in the laboratory. Alarmed, the researcher immediately destroyed the bacteria. Ricki Lewis is a geneticist and textbook author. ------------------------------------------------------------------------ On the Teen Scene: Food Label Makes Good Eating Easier by Paula Kurtzweil Tortilla chips. Chocolate pudding. Frozen yogurt. Allison Gilliam, 16, of Gaithersburg, Md., points out some of her favorite foods at her neighborhood grocery store. Sliced turkey. Dried fruit. The list of items goes on. They're all delicious, and you might never guess that they're also all low in or without fat. Even the chocolate pudding! It says so right on the food label, and Gilliam, a high-school junior, spots the information right away. A front-label fat claim draws her to the product, and she finds the Nutrition Facts panel on the side or back of the package with more complete information. Gilliam uses the food label to help her control her fat intake. "I used to be fat," she says. "I lost 45 pounds." She knows dietary fat is the most concentrated source of calories (9 calories per gram versus 4 calories per gram for carbohydrate and protein), so she checks the label to see how much fat a food contains. If the fat content is over 5 grams per serving, she considers buying something else instead. Like Gilliam, you can make the food label work for you--whether your concern is losing weight, gaining weight, eating enough protein, eating less fat, or simply staying in the good shape you're in. New Label The food label was revamped in 1994, thanks to regulations from the Food and Drug Administration and the U.S. Department of Agriculture. As a result, you get: * easy-to-read nutrition information required on almost every packaged food * %Daily Values, which show how a serving of food fits into a total day's diet * serving sizes that are closer to the amounts most people actually eat than previous labeling * nutrition claims that mean the same on every product * voluntary information for the most commonly eaten fresh fruits and vegetables, and raw fish and cuts of meat. This information may appear on posters or in brochures in the same area as the food. Get the Facts The main draw is the "Nutrition Facts" panel, which gives information about nutrients people are most concerned about today. For example, the panel gives the lowdown on fat, saturated fat, and cholesterol because of their link to heart disease. (See "On the Teen Scene: Good News About Good Nutrition" in the April 1992 FDA Consumer.) You may find particularly useful information about nutrients that teenagers especially need. For instance, girls, who often eat fewer calories than boys, sometimes don't get enough calcium and iron, so they can use the label to help them choose foods that give a good supply of those nutrients. Girls also have special needs for these nutrients: Consumption of milk and other products containing calcium in teen years may help prevent osteoporosis later in life; extra iron is sometimes needed to replace what's lost during menstruation. Almost everyone wants to know about calorie content. For sports-minded teens, getting enough calories may be the concern, while those who tend to be overweight may want to reduce their calorie intake. The food label can help because it almost always will list the calories in a serving of food. %Daily Values The amount of nutrients in a food is given in one or two ways: in grams (or milligrams) or as a percentage of the Daily Value, a new label reference tool. The %Daily Value shows how a serving of food fits in with current recommendations for a healthful daily diet. These reference numbers--called Daily Values--are based on the government's Dietary Guidelines; for example, one guideline recommends restricting fat intake to 30 percent or less of calorie intake. The government has set 2,000 calories a day as the basis for calculating %Daily Values. Of course, not everyone eats this amount. Teen-age girls often average 2,200 calories a day, while some teen-age boys may eat 2,500 or more calories a day. Whatever your calorie intake, you still can use the %Daily Values on the label to get a general idea of how a serving of food fits into the total daily diet. The goal is to eat about 100 percent of the Daily Value for each nutrient each day. For nutrients that may be related to health problems--such as fat, saturated fat, and sodium--100 percent should be the upper limit. For other nutrients that are often needed to maintain good health and which may be in short supply--such as fiber and calcium--the goal is to eat at least 100 percent. A good rule of thumb: If the %Daily Value listed on the panel is 5 or less, the food contributes a small amount of that nutrient to the diet. Nutrient Claims Just as Gilliam does for low-fat products, you can easily spot foods offering the kind of nutritional benefits you want by looking for claims on the package. (See accompanying article.) The government has set strict definitions for 11 "core" terms: * free * reduced * lean * less * light * extra lean * low * fewer * high * more * good source These terms can be used only if the food meets certain criteria, so when you see them, you can believe them. Health Claims Another type of claim, the health claim, also can alert you to nutritious foods. FDA has approved eight claims. They show a link between: * calcium and a lower risk of osteoporosis. The claim must state that regular exercise and a healthy diet with enough calcium helps teen and young adult white and Asian women maintain good bone health and may reduce their high risk of osteoporosis later in life. * fat and a greater risk of cancer * saturated fat and cholesterol and a greater risk of heart disease * fiber-containing grain products, fruits and vegetables and a reduced risk of cancer * fruits, vegetables and grain products that contain fiber and a reduced risk of heart disease * sodium and a greater risk of high blood pressure * fruits and vegetables and a reduced risk of cancer * folic acid and a decreased risk of neural tube defects in fetuses. Neural tube malformations are serious birth defects that cause disability or death. (See "FDA Proposes Folic Acid Fortification," in the May 1994 FDA Consumer.) Look for the Info The food label won't tell you what foods to eat--that's your decision--but it will help you find foods with the kinds of nutritional benefits you want. Also, many fast-food places voluntarily offer nutrition information about their foods. The information is often available on request. Many of these restaurants now offer low-fat choices, including lettuce salads and low-fat entrees. So, like 15-year-old Gilliam, you, too, may soon find yourself eating a whole new way. In Gilliam's case, that's a low-fat diet that includes such foods as baked tortilla chips, fat-free pudding, nonfat frozen yogurt, and skim milk. After all, said Gilliam, "It's second nature to me now." Paula Kurtzweil is a member of FDA's public affairs staff. ------------------------------------------------------------------------ What Some Claims Mean high-protein: at least 10 grams (g) high-quality protein per serving good source of calcium: at least 100 milligrams (mg) calcium per serving more iron: at least 1.8 mg more iron per serving than reference food. (Label will say 10 percent more of the Daily Value for iron.) fat-free: less than 0.5 g fat per serving low-fat: 3 g or less fat per serving. (If the serving size is 30 g or less or 2 tablespoons or less, 3 g or less fat per 50 g of the food.) reduced or fewer calories: at least 25 percent fewer calories per serving than the reference food sugar-free: less than 0.5 g sugar per serving light (two meanings): * one-third fewer calories or half the fat of the reference food. (If 50 percent or more of the food's calories are from fat, the fat must be reduced by 50 percent.) * a "low-calorie," "low-fat" food whose sodium content has been reduced by 50 percent of the reference food ------------------------------------------------------------------------ For Teachers A 50-page food label education program for 10th- through 12th-grade students is available for $5 a copy. The New Food Label: There's Something in It for Everybody was developed by FDA and the International Food Information Council Foundation to help students learn how to use the food label to choose healthy foods. It covers a range of food labeling topics--from product dating to Nutrition Facts. It consists of five lesson plans with learner outcomes, learning strategies, handouts, charts and worksheets, and suggested activities. To order, send check or money order payable to the International Food Information Council Foundation to IFIC Foundation, 1100 Connecticut Ave., N.W., Suite 430, Washington, DC 20036. State number of copies desired at $5 each. (D.C. residents add 6 percent sales tax.) FDA Examining Computer Diagnosis by Robert A. Hamilton When Paul A. Mongerson of Marathon, Fla., had severe abdominal pains in 1980, a battery of tests showed he had an elevated blood level of the enzyme lipase, which could indicate cancer of the pancreas. Though the diagnosis was not confirmed by other tests, his doctor recommended surgery. "I'm an engineer by training, so I made up a matrix, charting my symptoms and test results, the possible diseases that could cause my symptoms, and what other symptoms would be present with those diseases," Mongerson recalls. "My conclusion was that I could not have cancer of the pancreas, and the fifth doctor I consulted, at Mt. Sinai in New York, agreed with me." Eventually the pain disappeared, and he was found to have a condition known as pseudolipase, which results in abnormally high readings for the enzyme in tests. Mongerson said he thinks he might have bruised his pancreas while working around the house. "I said at that time, 'what I did is just what a computer would do.' Medicine has gone about as far as it can without computers. There's a limit to how much the mind can retain, even with the degree of specialization that we've seen in medicine," Mongerson said. "The field of knowledge is so big the human mind is incapable of grasping it all--but a computer could help." So Mongerson formed a foundation that provided financial assistance to physicians working to develop computer diagnosis systems. Today, medical diagnostic software puts entire medical libraries a mouse-click away. The Food and Drug Administration already regulates some diagnostic software, and as the number of programs expands, so does FDA's review. Anthony Voytovich, M.D., chief of staff at John Dempsey Hospital in Connecticut, who has worked with computerized diagnosis programs for more than a decade, said it's important to keep their function in perspective. "These programs are kind of like those Nordic Track machines. You can't put a machine like that in your bedroom and suddenly look like a million bucks; it's going to take a lot of sweat," Voytovich said. "When these programs were first put out there, a lot of people thought they would replace the physician, but they can't do that anymore than a high-speed drill will replace the dentist. They're a tool--a very effective tool that makes the physician's job much easier, but a tool nonetheless." Diagnostic software is enjoying increasingly wider use each year. Computers are helping in the general practitioner's office, where they can identify even exotic diseases the physician has never seen. In the laboratory, they might help find a precancerous cell from a pap smear or a lump in breast tissue. The programs are particularly good at prompting physicians with possibilities they might not otherwise envision. G. Octo Barnett, M.D., of Harvard Medical School's Laboratory of Computer Science, who developed the diagnostic software DXplain (2,200 diseases and 5,000 symptoms in its knowledge base), told of a physician in Texas seeing an adolescent boy with a skin rash and high fever. The computer suggested Rocky Mountain spotted fever, which the physician had not considered. He learned the boy had been hiking in Colorado recently, and subsequent tests confirmed the diagnosis. Jerome P. Kassirer, M.D., editor of the New England Journal of Medicine, wrote in an editorial June 23, 1994, about the use of a computer program in the case of an 18-year-old man who had symptoms of a heart attack. The software also suggested cocaine abuse, which had not been considered, but which could have been a cause. A study at the University of California San Diego Medical Center, focusing on emergency room patients experiencing chest pain, found computers accurately diagnosed 97 percent of heart attacks, compared with 78 percent for physicians. Closer Look FDA is now taking a closer look at medical diagnostic programs. Harvey Rudolph, Ph.D., acting deputy director of the Office of Science and Technology in the Center for Devices and Radiological Health, said FDA's policy has been that as long as the programs provided for "competent human intervention," they would not be actively regulated. "In effect, the stand-alone diagnostic software programs used by physicians are considered decision support systems, and are exempt from regulation," Rudolph said. "The programs are based on well-known, well-established data, and the person using the software is expected to be competent to interpret the results." FDA has always regulated computer software that modifies data entered by a user to control a medical device, or modifies data from a medical device to present it to a user. This includes, for instance, software that scans biopsied cells for signs of cancer. But as the use of computers in diagnosis grows, the line between the different types of software blurs. Currently, FDA has applications on file for premarket approval of programs that would, for instance, help in reading diagnostic images such as mammograms. Later this year, FDA plans to publish a Federal Register notice about its proposed policy for assessing and regulating various software, said Jurriaan Strobos, M.D., who is also an attorney and heads the policy research staff in FDA's Office of Policy. Possible Criteria Strobos suggested several criteria for determining whether software has the potential to adversely affect human health. Among them: * Is the software intended for critical use, such as pointing out imminent danger in an intensive care unit, or for a less crucial purpose, such as to store diagnostic images such as CT scans? * Is the user aware of the limitations of the program, and whether any of its recommendations depart from conventional medical practice? * How specific is the software to a particular patient? Does it provide general information on a condition, or does it manipulate specific data from a specific patient to develop a specific treatment plan? * How quickly do the software's recommendations need to be implemented? For instance, with an electrocardiogram program, will it recommend defibrillation at the appropriate time, or will it merely point out that a particular rhythm should be checked for abnormalities? And, as Strobos pointed out, software is constantly being upgraded and improved, and customized. Such revisions need to be checked for their impact on the safety and effectiveness of the device. "The [evaluation] process should not end when the software leaves the laboratory," Strobos said. "Postmarketing controls, as part of a life-cycle approach to software design, are important and should not be overlooked in developing a new system of agency review." Rapid Recent Developments Diagnostic programs have been around since the 1950s. The early programs were not used widely because they were unreliable, ran on bulky mainframes, and required a doctor to double as a data processing clerk. But in the last decade, engineers have put together more accurate and convenient programs. Hardware has shrunk to the size of a desktop, while computer memory has vastly expanded. Modems or network cables can easily link them together. In most stand-alone diagnostic systems the physician enters the symptoms, test results, and medical history into the program, which then suggests a list of possible diagnoses. Some even provide a probability--in a person with severe, recurring headaches, for instance, the computer might say there is a 97 percent probability that the patient has sinusitis, but only a 6 percent probability of a brain tumor. The programs can also help by highlighting some of the more likely diagnoses. "If I see someone with a given set of symptoms, I can usually think of 20 or 30 things that it could be, off the top of my head," Voytovich said. A decision support system "helps me to narrow it down to a few possible diagnoses." So far, the results of the programs have been mixed. A study by Eta S. Berner, Ph.D., of the University of Alabama, and colleagues from around the country, published in the New England Journal of Medicine, rated four of the most popular computer programs for medical diagnosis. The ratings were based on their ability to diagnose 105 cases chosen by a panel of experts, including some so complex they would not often be seen by the average physician. The study found the programs correctly diagnosed the conditions between 50 and 75 percent of the time, depending on the complexity of the case, particularly whether more than a single disease was present. Berner, a specialist in medical education, said that evaluation of the programs must also consider the doctor's rate of accuracy. "If the physician is making an accurate diagnosis only 30 percent of the time, these programs would be better than a doctor," Berner said. "The consumer expects the doctor to be right 90 percent of the time, and that these programs will help." Increased Complexity As the knowledge base expands, the systems become more complex, requiring ever larger amounts of memory. To help overcome that problem, PKC Corp. in Vermont, has begun marketing "Problem Knowledge Couplers," diagnostic software sold in modules that target a specific area. Under current FDA policy the software is not regulated. The PKC system prompts the physician with on-screen questions until it roots out the possible causes of the symptoms, then directs the physician to couplers, or software packages, that cover the appropriate disciplines. So far, PKC has developed 50 couplers, covering areas as diverse as hypertension, lung cancer, obesity, and male erectile problems. A "triage" coupler is used to help physicians determine whether a patient who calls with a problem needs to go to the emergency room, at an average cost of $230, or just make an appointment to come to the office. Doctor Still Needed The programs' limitations preclude them from replacing the physician. Barnett, who developed DXplain, contended that only the physician can comprehend the "gestalt" of the disease, or diseases, producing the symptoms. If a patient has only one disease, DXplain would stand a good chance of coming up with the correct diagnosis, Barnett said. "If they come in with two or three different diseases, though, it gets beyond the competence of any of the expert systems." In those cases, a physician's intuition, years of experience, and ability to make leaps of logic are the patient's best hope for unraveling the underlying diseases. Nor can the computer consider the patient's personality, stresses, and other factors, or judge how those might interplay. And, Barnett said, only physicians can quantify the disease, taking into account the myriad factors to determine its course in a particular patient. Is the pain radiating down the left arm from angina? Is it late- or early-stage disease? How severe is it? Will it get worse? Still, Barnett and others agree, diagnostic software can prompt consideration of diseases a physician might never have seen or remembered described since medical school. Computers are particularly effective for calculations needed for diagnosis. Susan Madden, a spokeswoman for Western Psychological Services in Los Angeles, said computers are commonly used in psychological assessments, to determine, for example, the potential of a patient for suicide, depression and anxiety, or substance abuse. "The clinician using one of these programs doesn't have to calculate the scores or write an interpretive report on their own," Madden said. "It frees them up to do more clinical work." Help for Technicians More recently, computer diagnosis has been used to supplement the skills of medical technicians. For instance, a technologist reviewing pap smears is expected to recognize a few abnormalities out of 100,000 cells--the equivalent of finding a couple of typographical errors in a large novel. A good technician might look at 90 slides a day. Estimates are that as many as many as 5 in 100 of the slides contain abnormalities that are missed, according to an article on the pap test in the Feb. 3, l989, issue of the Journal of the American Medical Association. But Papnet, a computer program under a premarket review by FDA, developed by Neuromedical Systems Inc. in Suffern, N.Y., can screen one slide every five minutes, and work round the clock if necessary. The computer program identifies the 1,000 most suspect cells under magnification, then does a secondary screening where it stores magnified colored images of the 128 most suspect cells. A technologist can review them later and determine which require a pathologist's review. A retrospective study by a team at Johns Hopkins University found Papnet identified suspect cells on slides from women whose undetected abnormalities had later gone on to develop lesions. "It has the potential to detect abnormalities much earlier," said Laurie J. Mango, M.D., medical director and vice president at Neuromedical Services. "The most accurate pap smear will always be one that's read in two independent ways. In that sense, this will always be a complementary screen. But this is also a task that's particularly suited to computers because it's so repetitive." The company is also investigating whether the program can be modified to screen cell samples from the respiratory tract and esophagus. Other programs are being developed to digitize the information from mammograms and detect abnormalities. Stephen Feig, M.D., of Thomas Jefferson University Hospital in Philadelphia, said digital enhancement was found to increase a radiologist's detection of abnormalities on mammograms, from 85 to 92 percent in one study, and from 81 to 90 percent in another. "It's not going to substitute for a radiologist, because no computer yet comes close to the human brain in terms of judgment, so determining whether something is benign or malignant is beyond its capabilities. But it might be of great value to a radiologist in that it would bring attention to potential abnormalities that he or she might not appreciate on a mammogram," Feig said. "Of course, it might also pick up abnormalities that are not there, but a radiologist could quickly rule them out." Systems Integration There is also an effort under way to integrate different computer systems. For instance, some electrocardiograms now come with a computer analysis attached to the printout, which notes some things the physician might want to consider based on the test results. Jerome H. Grossman, M.D., chairman of the New England Medical Center in Boston, said the programs can also be used to reduce unnecessary treatment or tests. Grossman, who is also chairman of the Federal Reserve Bank of Boston, said he has seen major changes in the way banks do business, to drive down costs by reducing duplication of services, or services too costly to justify. "Health care is in the final stages of a similar transformation," Grossman said. "There is a real market for efficiency and value in health care. We have a marketplace that never existed before." And, he predicted, there will be a continual sophistication of the software, integrating all the different information systems so that information on a patient's medical record is automatically considered by the diagnostic software, and the outcome of treatment, good or bad, is automatically fed back into the system to guide future decisions. In the meantime, there are gradual refinements of existing software programs, and each year they become a little better at helping physicians figure out what is wrong with each patient who comes through the door. Robert A. Hamilton is a writer in Franklin, Conn. ------------------------------------------------------------------------ Medical Possibilities for Psychedelic Drugs by Paula Kurtzweil Scientists at the Orenda Institute in Baltimore are taking a novel approach to treating drug addiction: They plan to give patients LSD. That's lysergic acid diethylamide, or "acid" for short, one of several psychedelic drugs that were placed under the U.S. Controlled Substances Act in 1970. They're Schedule I drugs, which means they're considered to have a high potential for abuse, present an unacceptable safety risk, and have no acceptable medical use. However, in recent years, the Food and Drug Administration has sought ways to allow human studies to test LSD and other Schedule I psychedelic drugs to see if they have any medical usefulness. The National Institute on Drug Abuse funds some of these studies. In the Baltimore study, scientists are examining LSD as a possible treatment for addiction to heroin, opium, alcohol, and sedative hypnotics. University of Miami researchers are studying the psychedelic drug ibogaine to treat cocaine addiction. Other scientists are focusing their psychedelic research on learning more about the human brain, discovering antidotes to drug overdoses, and relieving pain in cancer patients. It's still too early to say whether the drugs have medicinal uses or not, according to government scientists. "These are all very small studies, mostly with fewer than 10 patients," said Curtis Wright, M.D., a medical officer with the addiction medicine staff in FDA's Center for Drug Evaluation and Research. "It's far too early to tell whether these drugs work or not or provide any therapeutic benefit." Drugs of Abuse The drugs are known more for their abuse potential. They include, in addition to LSD and ibogaine, mescaline, MDMA (3-4-methylenedioxymethamphetamine--commonly called "Ecstasy"), DMT (dimethyltryptamine--known on the street as "Businessman's Special"), PCP ("Angel Dust"), N,N-diethyltryptamine (DET), psilocybin, psilocin, and alpha-ethyltryptamine (alpha-ET--also known on the street as "Trip" and "ET"). Some of the drugs occur naturally, such as ibogaine, which comes from the root of a rain forest shrub. Others, such as MDMA, are synthesized, mostly illegally, in clandestine laboratories. As a group, the drugs are often referred to as psychedelic (meaning mind-altering) or hallucinogenic because they cause people to have hallucinations; that is, to imagine they see and hear things. Each drug has its own unique properties, though. "There are differences, big pharmacological and psychopharmacological differences," said Frank Vocci, Ph.D., deputy director for the medications development branch of the National Institute on Drug Abuse (NIDA). "The drugs are alike only in that they share a common ability to alter perceptions or result in some type of hallucinatory experience." Street users call these experiences "trips," which can be extremely pleasant or highly unpleasant and frightening. Hallucinogens' Hazards The drugs can cause other adverse reactions, too. LSD, for example, can dilate pupils; increase body temperature, heart rate, blood pressure, and sweating; and cause loss of appetite, sleeplessness, dry mouth, and tremors. Also, many LSD users experience flashbacks, spontaneous recurrences of certain aspects of the person's "trip" (without the user having taken the drug again). Long-term LSD users may develop psychoses, such as schizophrenia and severe depression. MDMA users also may suffer from psychological difficulties, including confusion, depression, sleep problems, drug craving, severe anxiety, and paranoia--during and sometimes weeks after taking the drug. Physical symptoms of MDMA use include muscle tension, nausea, blurred vision, rapid eye movements, faintness, chills or sweating, and increased heart rate and blood pressure--a special risk for people with heart disease. Overuse of some pyschedelic drugs is associated with death. The pyschedelic drug alpha-ET, which was sold legally under the trade name Monase in the early 1960s for depression, was taken off the market after only one year because three illnesses and four deaths in patients taking the drug were documented. The drug was associated with a significant decrease in certain body cells. Ibogaine as well has been linked to at least three deaths overseas. "We have to realize that there are problems with these drugs," said Michael Klein, Ph.D., a senior interdisciplinary scientist on FDA's pilot drug evaluation staff. "We don't want to make it sound as though these drugs offer exciting possibilities, when we really don't know for sure. Each drug has to be weighed on its own merits." Hallucinogen History Scientific interest in these drugs is not new. Information about the effects of ibogaine, which West Africans use as a stimulant and aphrodisiac and in religious rituals, began appearing in the medical literature in the early 1900s. Mescaline, from the peyote cactus and used in Native American religious rituals, was studied in the 1920s. LSD, perhaps the most popular of the psychedelic drugs, was first synthesized in 1938. It is made from lysergic acid, which is found in ergot, a fungus that grows on rye and other grains and has been known throughout history as a source of various types of medications. Its psychedelic effects were discovered in 1943. During the 20 years following World War II, LSD was used to study brain chemistry and to determine its effects in patients with schizophrenia and other mental disorders. It also was studied for use in conjunction with psychotherapy--with, for example, alcoholics and cancer patients. Due to concern about possible unpredictable side effects and abuse, LSD research came to a virtual halt by the mid-1970s. Unsupervised use of these drugs by millions of young adults in the 1960s made use and abuse of psychedelic drugs a major public health concern. According to FDA's Klein, the Controlled Substances Act was an attempt to control the use of these drugs so that they would be used only for scientific reasons. "The purpose of the act was not to hinder or stop research," he said, "but to ensure that as the research proceeded, proper controls were in place to prevent abuse and misuse of the drugs." However, by the 1970s, psychedelic drugs were not only viewed as a public health problem but also carried a social implication. Psychedelic drugs were associated with "hippies," a counterculture of mostly young people who felt alienated from the mainstream American society and grew, in part, out of the anti-Vietnam war sentiment of the time. "There seemed to be an increasing hysteria about hallucinogenic drugs in the 1960s that essentially shut down the research," NIDA's Vocci said. "It became socially unacceptable to do this kind of work." Promising Potential Early research suggested medical promise for psychedelic drugs. According to a 1992 report by Richard Yensen, Ph.D., and Donna Dryer, M.D., director and medical director at the Orenda Institute, a 1960s' study of 135 alcoholics found that six months after treatment with LSD, 53 percent of a high-dose group reported abstinence compared with 33 percent of a low-dose group. Alcoholics receiving conventional therapy had a 12 percent improvement rate. In a study of 31 cancer patients suffering from anxiety, depression and uncontrollable pain, 71 percent showed improvement in their physical and emotional status after each LSD session. According to Yensen, researchers also observed that many cancer patients receiving LSD reported that their desire for addictive pain medicines, such as morphine, had diminished or vanished, along with the pain. An article in the winter 1995 edition of MAPS, published by the Multidisciplinary Association for Psychedelic Studies, reports success with another hallucinogen, ibogaine, in the treatment of chemical dependencies. The article's author, Howard Lotsof, founder of NDA International Inc.--a private organization based in Staten Island, N.Y., that treats drug addicts overseas--discusses several treatment successes, including a medical doctor whose addiction to a pain medication vanished after receiving four doses of ibogaine. Lotsof reported in the article that "29 of 35 patients successfully treated with ibogaine had numerous unsuccessful experiences with other treatment modalities." Lotsof's studies are not sanctioned by FDA, and he is not authorized to treat patients in the United States. Members of FDA's pilot drug evaluation staff advise caution in interpreting the results of these early studies and observations. "We have to wonder: What was the quality of the drugs?" FDA's Klein said. "What other factors were involved? Were the doses adhered to? What was the outcome measured? These are the kinds of questions we need to go back and look at objectively." Research Renewed The current round of research activity got under way in the late 1980s, bolstered in large part by advances in the understanding of brain chemistry. FDA has granted IND status to several psychedelic drugs in recent years. The IND status means the drugs have been studied in the laboratory for their major physical and chemical properties and tested in laboratory animals for their pharmacologic and toxic effects. In granting IND status, FDA carefully monitors study protocols to ensure that they meet FDA's safety and scientific standards. "The studies have to be safe and conducted under controlled conditions," Klein said. "Otherwise, the research may offer questionable or, at best, minimal returns." Because the drugs are controlled substances, scientists must apply to the Drug Enforcement Administration for a Schedule I permit in conjunction with filing an IND application with FDA. And, to receive IND approval, researchers must document that they have a suitable drug source whose manufacturing capabilities meet the agency's good manufacturing procedures. That presents a challenge because few reputable U.S. drug manufacturers make these drugs. To get high-quality drugs, psychedelic researchers rely on European manufacturers, hospital pharmacies, and university chemistry labs. Recruiting subjects can be a challenge, too, because in many cases, experienced psychedelic users are preferred, and their identities need to be protected for most studies. "They're less likely to panic," said Rick Strassman, M.D., associate professor of psychiatry at the University of New Mexico. "It can happen that people get frightened." For that reason, in these studies, subjects are closely monitored in the clinical setting by one or more health professionals. Drugs, such as Valium (diazepam), are on hand to reduce the effects of bad reactions. The researchers foresee various uses for their research. At the University of New Mexico, where scientists are studying the effects of DMT and psilocybin in humans, lead investigator Strassman believes his work may enable scientists to develop treatments for drug overdoses. "People on the street take these drugs," he said. "If we determine how these drugs work, perhaps we would be able to treat those who come into the emergency room because of a bad trip or panic reaction." Other scientists say psychedelic research may serve as a way to learn more about the human brain. Writing in a 1994 National Institute on Drug Abuse report, Stephen Sz‡ra, M.D., D.Sc., former chief of the institute's biomedical research branch, said, "Recent advances in the neurosciences and cognitive sciences have created opportunities for using hallucinogens as tools in attacking the supreme mystery: How does the brain work?" NIDA's Vocci believes that this time around, scientists may have a better chance to find the answer to this and other psychedelic research questions. "The investigators are very serious, dedicated professionals," he said. "They're truly interested in trying to evaluate what these drugs can do." Paula Kurtzweil is a member of FDA's public affairs staff. ------------------------------------------------------------------------ Updates FDA on the Web Electronic FDA information is available on the Internet's World Wide Web. FDA's "home page," a graphic menu, offers information on foods, human drugs, toxicology, FDA news, and other topics. The menu includes FDA Consumer articles, press releases, backgrounders, talk papers, industry guidance, new product approvals, and budget and scientific information. Eventually, it will include links to all areas of FDA and will replace FDA's Electronic Bulletin Board. The Internet address of FDA's home page is http://www.fda.gov/. For more information, phone FDA's Office of Information Resources Management at (301) 443-7549; E-mail: vcamp@bangate.fda.gov. Children's Motrin Goes OTC A doctor's prescription will no longer be needed for a children's form of Motrin (ibuprofen). FDA approved Children's Motrin Oral Suspension in June. Available in pediatric strength by prescription since 1989, it is the first nonsteroidal anti-inflammatory drug approved for pediatric, over-the-counter (OTC) use. It is approved to reduce fever and relieve minor aches and pain due to colds, flu, sore throat, headaches, and toothaches in children ages 2 to 11. Doses are based on age and weight. The labeling advises parents: * not to give the drug to a child for more than three days without a doctor's approval * to call a doctor if the child doesn't improve within 24 hours after the first dose or appears to worsen * not to give the drug to a child allergic to aspirin or a child dehydrated due to continued vomiting, diarrhea, or lack of fluid intake. Last March, an FDA advisory committee of outside experts recommended that the agency approve Children's Motrin as a nonprescription medication. The committee's decision came after presentations by the sponsor and FDA reviewers, including results from a safety study in more than 80,000 children. Children's Motrin is one of the first OTC drugs to carry new, more consumer-friendly labeling. It will be distributed by Johnson & Johnson's McNeil Consumer Products unit of Fort Washington, Pa. Tagamet Cleared for OTC Sales An over-the-counter version of the prescription ulcer medicine Tagamet (cimetidine) has received FDA clearance for use as a heartburn remedy. Tagamet HB, cleared for OTC sales June 19, is the second such drug this year to switch to OTC status. Pepcid AC Acid Controller (famotidine) was the first, on April 28. Both drugs treat heartburn by reducing the amount of stomach acid produced. Antacids, also available over the counter to treat heartburn, work by neutralizing stomach acid. (See "Taming Tummy Turmoil" in the June 1995 FDA Consumer.) Tagamet HB will be sold in 100-milligram tablets to relieve symptoms of occasional heartburn, acid indigestion, and "sour stomach" in people age 12 or older. The labeling advises consumers to: * consult their doctors before taking Tagamet HB if they are taking theophylline (for asthma), warfarin (for blood-thinning), or phenytoin (for seizures) * take no more than 400 mg over 24 hours * take the drug no longer than two weeks at maximum dose without consulting a doctor * see a doctor if they have swallowing difficulty or persistent abdominal pain, because these symptoms could indicate a more serious problem. Consumers seeking information about drug interactions or having other questions about Tagamet HB can call SmithKline Beecham Consumer Affairs at (1-800) 482-4394. The product will be distributed by SmithKline Beecham PLC, of Philadelphia. New OTC Labels New FDA prototypes of easier-to-read labels for over-the-counter drugs reflect the agency's continuing interest in making labeling more consumer friendly. The prototypes deliver information clearly and concisely by using bullets rather than paragraphs, and highlighting active ingredients, uses, directions, and warnings. Much like the "Nutrition Facts" food labels FDA introduced in 1994, the OTC drug label prototypes provide a standard format, so consumers can readily find information in the same location. FDA already is applying its new format concept to drugs switching from prescription to OTC use, such as the new Children's Motrin Oral Suspension (ibuprofen) and Pepcid AC Acid Controller (famotidine). Manufacturers of some other OTC drugs are voluntarily moving to the new format. FDA encourages this trend and expects to publish a proposal for a more useful OTC drug label in the Federal Register. The agency released its prototypes at a Nonprescription Drug Advisory Committee meeting last fall to stimulate discussion and provide a model for more useful OTC drug labeling. In January, FDA cosponsored a public workshop with the Drug Information Association on how to communicate OTC drug information to consumers more effectively through labeling. Experts in many disciplines explored consumer, industry, government, and academic research perspectives on the topic. FDA will continue to meet with those interested in providing high-quality, consistent information about OTC medicines. Bone Loss Test Approved The first commercial test to detect bone loss was recently cleared by FDA. The test indicates when people may be losing bone, which may put them at a higher risk for osteoporosis, a condition in which bones become easily breakable. The test may not be used to diagnose osteoporosis. Osteomark, made by Ostex International Inc., of Seattle, became available in clinical labs across the country last May. It measures the levels of a broken-down bone fragment called NTx that has been shown in laboratory and patient tests to be a reliable marker of bone loss. When bone loss occurs more quickly than bone formation, bone mass decreases, leading to osteoporosis. "By helping to identify patients suffering from rapid bone loss ... physicians can administer preventive therapy and ultimately lessen the need for costly hospital care following a fracture," said Charles Chesnut, M.D., director of the Osteoporosis Research Center at the University of Washington and chairman of Ostex's Scientific Advisory Board. According to the National Osteoporosis Foundation, osteoporosis affects more than 25 million Americans, 80 percent of whom are women. Forty percent of all women will have at least one spinal fracture by the time they reach 80, and one-third of all men will be affected by the disease by 75. (For more on osteoporosis, see "Osteoporosis Treatment Advances" in the April 1991 FDA Consumer.) Investigational Drugs Available Two investigational drugs--one for HIV infection and the other for Lou Gehrig's disease--have joined the growing list of treatments FDA is making available while they're under study to patients with serious illness. In a lottery system, saquinavir is available in an open-label study to 2,280 persons infected with HIV, the virus that causes AIDS. The drug is being distributed under the trade name Invirase by its manufacturer, Hoffmann-La Roche Inc. of Nutley, N.J. It is a protease inhibitor, a new class of anti-AIDS drugs that block an enzyme necessary for HIV replication in the body. Saquinavir is the first protease inhibitor available outside controlled clinical trials. None have been approved for marketing. Patients who have not benefited from existing anti-HIV therapy and who are not currently enrolled in saquinavir trials are eligible to be registered for the open label study by their physicians by calling (1-800) 332-2144. FDA has granted riluzole, an investigational drug, Treatment IND (investigational new drug) status, making it available to certain patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. Patients with ALS suffer progressive muscle weakness and paralysis. There is no cure, including riluzole. A study has shown significant improvement in survival rates in patients on the drug during the first year of treatment. By two years, however, there has been no difference in survival between patients taking riluzole and those taking a placebo. Riluzole is distributed by Rhône-Poulenc Rorer Inc. of Collegeville, Pa., under the trade name Rilutek. Telectronics Takes Time Out To Correct Problems Telectronics Pacing Systems agreed to stop its U.S. distribution of all pacemakers and pacemaker leads made at two of its facilities while it corrects manufacturing problems. In a consent decree signed by Telectronics (also called TPLC, Inc.) and its president, the firm agreed to bring its Englewood, Colo., and Miami Lakes, Fla., facilities into compliance with current good manufacturing practice regulations, FDA announced May 23. Recent FDA inspections found that Telectronics' practices were inadequate in these areas: * testing and inspecting * investigating device failures, both before and after products were distributed * reviewing and investigating complaints. FDA identified many of these same problems during 1993 and 1994 inspections, but Telectronics did not correct them. Since then, because of similar problems, FDA has prohibited importing products from the firm's Australian and French facilities. Telectronics agreed to have its corrections certified by an outside consultant, and then to demonstrate to FDA that corrective action was taken. Outside audit inspections will be conducted at least twice a year for three years to ensure the facilities continue to meet the agency's regulations. Last fall, certain implanted Telectronics pacemaker atrial "J" lead wires were reported to fracture in some patients. Telectronics alerted doctors and their patients with the implants to this problem. Unused leads were recalled. (See "Possible Defects in Pacemaker Leads" in the Updates section of the April 1995 FDA Consumer.) High-Quality Mammography Women can locate high-quality mammography facilities in their area by calling the Cancer Information Service toll-free at (1-800) 4-CANCER (1-800-422-6237) Monday through Friday from 9 a.m. to 8 p.m. Eastern time. The service, also available in Spanish and for the hearing impaired, lists all facilities that FDA has certified as capable of providing quality mammograms. The Mammography Quality Standards Act of 1992 requires all mammography facilities to be accredited by an accrediting body approved by FDA; be certified by FDA as meeting uniform, high-quality standards; and display the certificate prominently. The law applies to practically all facilities in the country, whether in a hospital, doctor's office, mobile van, or military base. (Exceptions are Veterans Administration facilities, which have similar standards of their own.) As of June 1995, nearly 9,300 of approximately 10,300 facilities had been fully certified by FDA, and 940 more had been provisionally certified while undergoing accreditation review. For certification, each facility must: * have adequately trained and experienced radiologic technologists who perform mammography, physicians who interpret mammograms, and medical physicists who survey equipment * have an effective quality control program and record-keeping system * have a system to track mammograms revealing potential problems and to obtain biopsy results * be inspected annually by FDA-trained inspectors to ensure safe and effective mammography. FDA Revises Blood Donor Criteria To Exclude Prisoners Blood and plasma centers were recently advised by FDA not to accept as donors current and certain recent prison inmates as blood donors. Excluded for 12 months following their last date of incarceration are those jailed longer than 72 consecutive hours during the previous year. FDA's Center for Biologics Evaluation and Research made the recommendation last June 8 after reviewing a series of reports by the U.S. Department of Justice, the national Centers for Disease Control and Prevention, and others. The reports found that a significant proportion of inmates are likely to have engaged in high-risk behavior--such as illegal intravenous drug use--before incarceration. This finding correlates with a high rate of infection among inmates and incoming prisoners with bloodborne transmissible agents, such as HIV and hepatitis viruses. Other risk factors for these disease agents, such as tattooing and high-risk sexual activity, have also been reported for inmates. Obtaining blood and plasma donations from inmates, never a widespread practice in the United States, has declined in recent years and now occurs at only a handful of institutions. People who wish copies of the recommendation may request document Number 4015 from the Center for Biologics Evaluation and Research at (301) 594-1800, the CBER Fax Information System at (301) 594-1939, or by return E-mail by sending a message to mem06895@a1.cber.fda.gov. Precautions Advised for Blood Supply An Ad Hoc Advisory Committee on Creutzfeldt-Jakob disease (CJD) has been established by FDA to advise the agency on the appropriate disposition of blood and plasma products made from donations by individuals subsequently diagnosed with the disease. CJD is a rare, invariably fatal, degenerative disease of the central nervous system. The panel of 15 outside experts met for the first time June 22 and advised FDA, as a precaution, to remove from the market blood and plasma products donated by people subsequently diagnosed with CJD. It is not known whether CJD can be transmitted by transfusion of blood products. No cases have been reported. However, CJD has been transmitted by transplantation of corneas and dura mater (a brain-associated membrane), injections of human pituitary-derived growth hormone, and reuse of electroencephalogram electrodes used on CJD patients. The risk of transmitting CJD by transfusion is considered extremely small, if it exists at all. After hearing from people with hemophilia and others, the panel voted to recommend that the blood and plasma products from people with CJD not be used. The committee's recommendation is not binding on FDA, but the agency will consider it carefully when deciding what action to take. At press time in July, no decision had been made. Over the past 12 years, seven cases of CJD have been confirmed in people who previously gave blood. In each case, blood centers voluntarily withdrew the unused blood products. FDA has authorized the ad hoc committee to deliberate for one year. 5 Free Reprints Five free FDA Consumer reprints are available: * Mercury in Fish: Cause for Concern? (FDA) 95-2285 * Labeling Rules for Young Children's Food (FDA) 95-2292 * An FDA Guide to Nonprescription Pain Relievers (FDA) 95-3213 * Making It Easier to Read Prescriptions (FDA) 95-3217 * Progress in Blood Supply Safety (FDA) 95-9013. To order single copies, write to FDA, HFE-88, Rockville, MD 20857. To order two to 100 copies, write to FDA, HFI-40, at the same address, or fax your order to (301) 443-9057. Include the publication number. ------------------------------------------------------------------------ Notebook The Notebook: a potpourri of items of interest gathered from FDA news releases, other news sources, and the Federal Register (designated FR, with date of publication). The Federal Register is available in many public libraries. Orphan products development grants for fiscal year 1996 are available from FDA. The agency intends to make $12 million available for clinical trials of products to treat diseases and conditions that affect fewer than 200,000 Americans. Deadlines for grant applications are Oct. 16, 1995, and Jan. 16, 1996. Application forms are available from Robert L. Robins, Grants Management Officer, Grants and Agreements Management Branch (HFA-250), Rockville, MD 20857; telephone (301) 443-6170. (FR June 22) Nutrition labeling information provided by retailers for raw fruits, vegetables and fish is available in an FDA report. "Food and Drug Administration Nutrition Labeling Information Study, Raw Fruits/Vegetables and Raw Fish" summarizes data on actions taken by retailers to provide information on those products. For a free copy, send two self-addressed adhesive labels and a request for docket number 93N-0156 to Dockets Management Branch (HFA-305), FDA, Rockville, MD 20857. (FR May 5) Compliance policy guidance, including regulatory action guidance, is available in a new, bound manual. "FDA Compliance Policy Guides" contains 500 individual guides, 227 of which have been revised or updated. The manual, which costs $61 plus $6 handling, may be ordered from the National Technical Information Service, U.S. Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161; telephone (703) 487-4650. Request NTIS order number PB95-915499. (FR June 20) An artificial sweetener, acesulfame potassium, was found safe for use in alcoholic beverages and approved by FDA last May 3, according to an agency final rule. (FR May 3) Tea standards for 1995 became effective last May 1, according to an FDA final rule. The agency's Board of Tea Experts, under the Tea Importation Act, set the standards for black and green tea, Formosa and Canton oolong, scented black tea, and spiced tea. The act prohibits importation of tea that is inferior to the annual standard. (FR June 7) New nutrition standards for the National School Lunch and School Breakfast Programs were set in a U.S. Department of Agriculture final rule effective last July 13. The rule requires that by school year 1996-1997, school lunches and breakfasts comply with the recommendations of the Dietary Guidelines for Americans. The rule sets specific minimum standards for key nutrients and calories in school meals. (FR June 13) Vitamin E supplements may lower the incidence of coronary heart disease because of the vitamin's ability to reduce coronary artery lesion progression, according to a Journal of the American Medical Association (JAMA) article. Researchers found that men between 40 and 59 who took 100 international units or more of vitamin E per day showed significantly less artery lesion progression than did men who took less than 100 IU of vitamin E per day. (JAMA June 20) ------------------------------------------------------------------------ Investigators' Reports Drug Trafficker Jailed by Paula Kurtzweil A 52-year-old California man is serving a 16-month sentence at Federal Prison Camp, Boron, Calif., for helping to sell and distribute an illegal drug touted for weight control, bodybuilding, and insomnia. Frank Richards Zenker, also known as Frank Richards, formerly of Villa Park, Calif., now of Laguna Beach, Calif., was sentenced Oct. 27, 1994, for conspiring to illegally distribute gamma hydroxybutyrate, or GHB. His co-worker, Lance Crews Griffin, 46, was sentenced March 28, 1994, to two years, nine months. GHB is legally allowed as an investigational new drug for treatment of narcolepsy, a rare sleeping sickness. Illegally, it has been promoted for strength training, muscle building, weight loss, and as a replacement for L-tryptophan, a food supplement used as a sleep aid FDA ordered removed from the market in 1989, after it was linked to a rare blood disorder. GHB also is used illegally as a hallucinogen. GHB can cause severe stomach pain, low blood pressure, irregular heartbeat, vomiting, dizziness, seizures, respiratory arrest, liver failure, and coma. Health authorities have received reports of illnesses in at least 30 people in California, Florida and Georgia since 1991. Under the name Omniopathy Products, Zenker and Griffin sold GHB in bulk powder and capsule form, bottled and falsely labeled as another illegal product, glutathione, from a fictitious company named RTL Labs of Oakland, Calif. They distributed the product throughout the United States and abroad. FDA learned about the men's illegal activities through "Operation Big Mouth," a massive effort by FDA, the U.S. Customs Service, the U.S. Attorney's Office, and other government agencies to identify and prosecute illicit drug traffickers. It was so named because defendants cooperated with authorities by admitting guilt and identifying other drug traffickers. Cooperating defendants also helped FDA make undercover purchases of illegal drugs. Armed with information about Omniopathy, in March 1991, FDA investigators went to the business address at a residence in Villa Park, Calif., where they spoke to Griffin. (This address was later identified as also being Zenker's residence.) Griffin identified himself as company owner and said he founded the company--a pharmaceutical distributorship--in 1988. He said he had more than 800 customers and the company made about $350,000 a year. He also told investigators he stopped selling GHB in 1991, after FDA issued a warning about the drug. FDA learned that Zenker worked for Omniopathy part time and was one of six employees. None of the employees was a licensed pharmacist and none had FDA approval to receive, make or distribute drugs. In August 1991, FDA investigators tracked the business to a new site in Santa Ana, Calif. Searching through trash at the new location, investigators found invoices and other documents showing Omniopathy was selling GHB. One invoice included the typed statement "Dr. Thatcher, the Oxy-Sleep is the product that we had discussed before (GHB, relabeled), an outstanding product for sleep plus for its growth hormone properties." In January 1992, an undercover FDA investigator called Omniopathy's toll-free number and talked to a person who identified himself as Frank Richards. They discussed the company's "Oxy-Sleep." According to the investigator, Richards said the product's active ingredient was gamma hydroxybutyrate, which he acknowledged was "off the market." The investigator ordered and received various dosage forms of Oxy-Sleep. FDA analyses showed the product contained GHB. In other undercover telephone calls, FDA ordered, received and tested additional supplies of Oxy-Sleep, which also tested positive for GHB. In February 1992, investigators, armed with a warrant, searched the premises in Santa Ana. Among items seized were: * numerous computers containing invoices for drug products dated from 1989 through 1992 * promotional materials for Omniopathy products * letters and documents on adverse reactions people had to Omniopathy products * numerous drug injectables, powders and capsules worth an estimated $500,000, according to Omniopathy's price list. FDA analysis showed the drugs were GHB. During the search, investigators extracted from computer data information about the Villa Park site, which led FDA to obtain a second search warrant for that site. There, investigators found 645 kilograms of GHB and various other illegal drugs. In interviews with Omniopathy employees and business associates, FDA learned that Griffin bought GHB and placed it in unlabeled bottles and jars stored at Zenker's Villa Park residence. Griffin then had labels made and had an unindicted co-conspirator of his and Zenker's put the labels on the bottles and jars. The labels identified the product as Oxy-Sleep and falsely stated that the active ingredient was the illegal drug glutathione. Also, the labels did not give adequate directions for use and warnings. From his home, Zenker helped fill and ship GHB orders via the U.S. Postal Service and from assorted private mail drops. In June 1992, a grand jury for the U.S. District Court for the Central District of California handed down a six-count indictment against Zenker and Griffin. Because of health problems, Zenker was tried separately from Griffin in June 1994, at which time the jury found Zenker guilty of all counts. In addition to prison, Zenker was sentenced to two years' probation. He is eligible for parole in 1996. Paula Kurtzweil is a member of FDA's public affairs staff. ------------------------------------------------------------------------ FDA Says No to "Premature" Videos Combine modern technology with instant gratification, and it was bound to happen--a video production of little Susie or Sammy even before their actual debut into the world. Recently, companies with names like Womb With a View and Peek-A-Boo Baby have sprung up, offering expectant moms and dads ultrasound images of baby still in the womb. But FDA says these "keepsake videos," taken for purely entertainment purposes with no medical need or prescription, are an unapproved use of ultrasound equipment. As of February 1995, the agency had warned seven companies to stop making the videos or face possible seizure, injunction, or other regulatory action. The Texas State Health Department took action against another three firms. By May, five companies had stopped operating, and FDA was monitoring compliance at several others. Ultrasound imaging is a common diagnostic medical procedure. It uses high-frequency sound waves that generate echoes when they bounce off tissues. The echoes are conveyed to a computer, which translates them into images of the target tissue or organ. "Obstetricians use ultrasound imaging to check the size, location, number, or age of fetuses, the presence of some types of birth defects, and fetal movement, breathing and heartbeat," says Tom Jakub, chief of the diagnostic devices branch in FDA's Center for Devices and Radiological Health's Office of Compliance. "Ultrasound is generally considered safe when properly used for medical reasons, and often the doctor will give parents a still photo from these tests." But laboratory studies show that ultrasound can produce physical effects in tissue, such as jarring vibrations and rise in temperature. Although there is no evidence that this can harm the fetus, public health experts agree that casual exposure to ultrasound, especially during pregnancy, should be avoided. "Viewed in this light, there's no justification for exposing the fetus to ultrasound when no medical benefit is expected," Jakub says. "Furthermore, FDA believes that ultrasound imaging for medical purposes should be done with as low an output of acoustic radiation as possible to get a good image. Keepsake video companies sometimes may use the ultrasound machine for as long as an hour to get a video of the fetus." FDA first learned about keepsake video operations from consumers in Texas in the early spring of 1994. The Texas Department of Health and FDA's Dallas district office jointly inspected three firms--Baby Images, Inc., in Houston, Peek-A-Boo, Inc., in Plano, and Womb With a View in Dallas. The Center for Devices and Radiological Health then initiated investigations of similar firms in other parts of the country. In August 1994, FDA wrote of its concerns to 10 health professional organizations and the National Electrical Manufacturers Association, saying, "Persons who promote, sell or lease ultrasound equipment for making 'keepsake' fetal videos should know that we view this as an unapproved use of a medical device, and that we are prepared to take regulatory action against those who engage in such misuse of medical equipment." The agency asked the organizations to have their members discourage patients from having ultrasound procedures for nonmedical reasons and to notify FDA of any keepsake video operations in their communities. FDA inspections uncovered numerous companies offering a wide variety of ultrasound packages. Romper Womb in Indianapolis, for example, advertised a "Peek-A-Boo Package," priced at $65, consisting of a 10-minute video "for which you may bring a tape or CD to be included as background music." For $90, clients could choose the "Pink or Blue Package," a 15-minute video, also with background music. "See the world within the womb from the perspective of your new baby(s). In this fifteen minutes, we will try and provide you with genitalia visualization," the ad said. The firm's "Winter Special Package" for $150 provided parents 30 minutes of video divided into two 15-minute sessions or three 10-minute sessions. Also included was "your selection of a customized coffee mug starring your baby or a $50.00 savings bond." And for the "ultimate" package, Romper Womb suggested the "Baby Shower Super Show Package," which "can be shown to all the well-wishers at the baby's shower. You can have your shower here or we can come to a different site where we can show you a 'Womb With a View' that will truly be baby's shower." The cost "varies." As of May 1995, Wee Imaging, Inc., in Spartanburg, S.C., If They Could See Me Now in Tallahassee, Fla., Peek-A-Boo, Inc., in Plano, Texas, Peek-A-Boo Baby, in Weatherby Lake, Mo., and Womb With a View in Dallas had gone out of business. The FDA district offices are continuing to monitor other firms to ensure they are in compliance. --Marian Segal ------------------------------------------------------------------------ Unapproved Devices Seized An Ohio judge recently ordered the destruction of 61 Relaxman Synchro-energizers--gadgets consisting of glasses, headphones, and a control box producing sound and flashing light patterns. The manufacturer had promoted and distributed the device as a solution to myriad health problems, without supporting documentation of their safety and effectiveness and without complying with FDA medical device regulations. On Feb. 23, 1995, Judge Ann Aldrich, of the U.S. District Court for the Northern District of Ohio, ordered the destruction of the unapproved medical devices, manufactured by Meta Brain/Mind Biomedical Research Foundation, Cleveland, Ohio, and worth approximately $30,000. FDA's investigation of Meta Brain began Sept. 1, 1992, when the agency's San Francisco district office received a consumer complaint that a Synchro-energizer device caused a seizure in a 21-year-old woman. The woman, who had never had a seizure before, had used the device as part of a work-related stress reduction seminar. A physician who examined the woman afterwards confirmed that she had had a seizure. In response to the complaint, beginning on Nov. 9, FDA investigators Stephen J. Kilker and Donald F. Fernholz, from the agency's Brunswick, Ohio, resident post, inspected Meta Brain. During the inspection, the investigators learned that the firm's owner, Krystina J. Rymsky, had not submitted a premarket approval application to FDA for the Relaxman and had not registered the firm with the agency. The investigators explained to Rymsky that because of these violations, FDA could initiate legal action against the goods, the firm, and the responsible individuals. Rymsky said she would register the company and file premarket approval notifications. However, she never followed through. During the inspection, the investigators collected labeling and promotional materials for the Relaxman. Jerilyn Glass, M.D., a neurologist with FDA's Center for Devices and Radiological Health, reviewed the materials and found numerous health claims for the device, including control of pain, habits and addictions, and improved digestion and sexual function. According to the promotional literature, the Relaxman achieved these beneficial effects by changing electrical brainwave activity. A search of the scientific literature through FDA's Medical Library revealed that no well-designed studies or investigations had been published in peer-reviewed scientific journals to demonstrate the safety or effectiveness of the Relaxman device for these purposes. In addition, the promotional literature did not adequately warn about the danger of seizure. A statement in the device's user guide did warn that people with "any history whatsoever [of] epilepsy or brain seizures" should not use the device "except under the direct supervision and/or order of [a] licensed M.D., Ph.D., or other qualified health care professional." However, Glass says, the warning was inadequate, because it did not warn that all users, even those with no prior history of seizure or epilepsy, could be at risk. On Dec. 11, 1992, Evelyn D. Forney, a compliance officer with FDA's Cincinnati district office, recommended to the agency's Center for Devices and Radiological Health that all Relaxman devices in Meta Brain's possession be seized. The center agreed, but asked that the district verify that the firm was still selling the device. On May 11, 1993, FDA investigator Frederick M. Lochner called Meta Brain and requested information about the Relaxman. He received promotional materials similar to the ones collected during the November inspection. On July 28, 1993, at FDA's request, a seizure complaint was filed in the U.S. District Court for the Northern District of Ohio. The complaint charged that the devices: * had no approved application for premarket approval and were not exempt from this requirement * had not been listed with FDA as required, and no premarket notification was provided to FDA * had false or misleading labeling * did not have adequate directions for use * were a danger to health when used as recommended in the labeling * lacked adequate warnings concerning potential health hazards. The devices were seized on Aug. 3, 1993. Rymsky filed a response to the seizure admitting that the seized goods were devices, but generally denying the other allegations in the complaint. On Nov. 22, 1994, the Justice Department, on FDA's behalf, filed a motion for summary judgment requesting the devices be condemned as adulterated and misbranded and be forfeited to the United States. The motion also requested that Rymsky pay all costs and fees as required by law. Rymsky did not respond, and on Feb. 23, 1995, the court granted the government's motion. At press time the devices were in possession of the U.S. marshals, awaiting destruction. --Isadora B. Stehlin ------------------------------------------------------------------------ FDA Permits Illinois Firm To Sell Reconditioned Food A year and a half after an estimated $1Êmillion worth of insect-infested food products were seized, an Elk Grove, Ill., firm received permission from FDA to sell approximately 880,000 pounds of reconditioned products. Another 33,000 pounds of food, valued at about $1Êper pound, could not be salvaged and was destroyed. House of Spices finished reconditioning its rice, lentils, mung beans, spices, and other foods last May 5. The firm paid $10,400 for FDA's supervision of the reconditioning. FDA Chicago district investigators inspected the firm's warehouse Oct. 13 to 19, 1993, after the State of Illinois embargoed 916,000 pounds of foods packed in cloth, paper and cardboard containers. "We found flying Indian meal moths all over the place, as well as other grain-type insects such as cowpea weevils and cigarette beetles," said district compliance officer Paul Boehmer. Because the entire warehouse was infested with insects, at FDA's request, the U.S. Attorney's Office filed a civil suit Oct. 22 in the U.S. District Court for the Northern District of Illinois, Eastern Division, seeking forfeiture and destruction of all insect-susceptible products stored there. The same day, the U.S. marshal seized the products. For the next three months, House of Spices' attorneys and FDA officials negotiated a consent decree that the firm's manager, Kaushik Shah, signed Jan. 10, 1994. The firm agreed to recondition the products it could and destroy all others, fumigate the warehouse, and maintain sanitary conditions. On Feb. 8, FDA again inspected the firm's warehouse. Investigators found the warehouse clean with no evidence of insect activity. House of Spices "fumigated its warehouse, killing all flying insects, and vacuumed everything else," Boehmer said, but added that FDA was still concerned about insects, larvae, eggs, excreta, and other contaminants that remained inside the bagged products. "The bagged products looked good on the outside, but we had to make sure it was clean inside," he said. Over the next five months, House of Spices' attorneys submitted various reconditioning plans to FDA, but they were inadequate. On July 11, 1994, the agency accepted a detailed phase I reconditioning plan for all of the firm's paper-packaged products. During the phase I reconditioning, FDA conducted a follow-up inspection from Aug. 29 to Sept. 7. Investigators again found live and dead insects on the exterior of bags in several lots. The firm again fumigated and proceeded with its phase II plan--screening to separate insect filth from the food products--which FDA had accepted on Nov. 9. The reconditioning operation was completed on May 5. --Kevin L. Ropp ------------------------------------------------------------------------ Summaries of Court Actions Summaries of Court Actions are given pursuant to Section 705 of the Federal Food, Drug, and Cosmetic Act. Summaries of Court Actions report cases involving seizure proceedings, criminal proceedings, and injunction proceedings. Seizure proceedings are civil actions taken against goods alleged to be in violation, and criminal and injunction proceedings are against firms or individuals charged to be responsible for violations. The cases generally involve foods, drugs, devices, or cosmetics alleged to be adulterated or misbranded or otherwise violative of the law when introduced into and while in interstate commerce. Summaries of Court Actions are prepared by Food and Drug Division, Office of the General Counsel, HHS, and are published by direction of the Secretary of Health and Human Services. SEIZURE ACTIONS Food/Contamination, Spoilage, Insanitary Handling PRODUCT: Claw Crabmeat, at Crawfordsville, Fla. (N.D.Fla.); Civil No. 94-40130/WS. CHARGED 4-7-94: While held for sale after shipment in interstate commerce at Barwick Crab Company, in Crawfordsville, Fla., the article was adulterated in that it contained Listeria monocytogenes--402(a)(1). The article consisted in part of animal hair, and it contained the bacteria Escherichia coli--402(a)(3) and 402(a)(4). The article also consisted of decomposed crab meat, and it was prepared, packed and held under insanitary conditions--402(a)(3) and 402(a)(4). DISPOSITION: Default--article was buried at a landfill. (F.D.C. No. 66931; S. No. 94-682-795; S.J. No. 1) PRODUCT: Haddock Fillets, frozen, at Colonie, N.Y. (N.D.N.Y.); Civil No. 1:93-CV-1184 TJM/RWS. CHARGED 9-13-93: While held for sale after shipment in interstate commerce at Golub Corporation Frozen Food Warehouse in Colonie, N.Y., the articles were adulterated in that pollock in part was substituted for haddock--402(b)(2). The articles' labeling was misleading in that it suggested that the only fish in the article was haddock--403(a)(1); and the articles offered the pollock for sale under the name of haddock--403(b). DISPOSITION: A consent decree of condemnation and constructive destruction ordered the articles delivered to a charitable institution. (F.D.C. No. 66781; S. No. 93-579-297; S.J. No. 2) PRODUCT: Stellated Sturgeon in tomato sauce, carp in tomato sauce, and other low-acid canned foods, at Brooklyn, N.Y. (E.D.N.Y.); Civil No. CV-94-3488. CHARGED 7-22-94: While held for sale after shipment in interstate commerce at Western Star Foods Distributors, Inc., in Brooklyn, N.Y., the articles were adulterated in that they were prepared and packed under conditions whereby they might have been rendered injurious to health--402(a)(4); and the articles were misbranded in that the stellated sturgeon was in package form and failed to bear a label containing the name and place of business of the manufacturer, packer or distributor--403(e)(1). The label of the carp stated the name and place of business of the manufacturer, packer or distributor in a foreign language--403(f); and the articles were fabricated from two or more ingredients and their labels failed to bear the common or usual name of each such ingredient--403(i)(2). DISPOSITION: The articles were destroyed. (F.D.C. No. 66986; S. No. 94-691-601; S.J. No. 3) PRODUCT: Tuna Loins, Yellow Fin, at Pensacola, Fla. (N.D.Fla.); Civil No. 94-30091/LAC. CHARGED 3-28-94: While held for sale after shipment in interstate commerce at ATL Cold Storage Company in Pensacola, Fla., the articles were adulterated in that they contained decomposed seafood--402(a)(3). DISPOSITION: An order of forfeiture ordered the articles destroyed. (F.D.C. No. 66942; S. No. 94-447-479; S.J. No. 4) PRODUCT: Tuna Loins, Yellow Fin, at Seattle, Wash. (W.D.Wash.); Civil No. C94-316. CHARGED 3-3-94: While held for sale after shipment in interstate commerce at City Ice and Cold Storage Company in Seattle, Wash., the articles were adulterated in that they contained a poisonous substance, histamine--402(a)(1); and the articles consisted in part of decomposed fish--402(a)(3). DISPOSITION: A consent decree of condemnation, forfeiture and destruction ordered the articles destroyed. The articles were buried by the U.S. marshal at a landfill. (F.D.C. No. 66936; S. No. 94-630-112; S.J. No. 5) Drugs/Human Use PRODUCT: Hydrocortisone, maximum strength, at East Rutherford, N.J. (D.N.J.); Civil No. 93-3340(HLS). CHARGED 7-28-95: While held at Ambix Laboratories in East Rutherford, N.J., the article was adulterated in that the methods used in, and the facilities and controls used for its manufacture, processing and holding did not conform to current good manufacturing practice requirements--501(a)(2)(B). DISPOSITION: A consent decree of permanent injunction ordered the destruction of the article. (F.D.C. No. 66733; S. No. 93-707-651; S.J. No. 6) PRODUCT: Oxygen USP, at Lake Worth, Fla. (S.D.Fla.); Civil No. 94-08695-CIV-Moreno. CHARGED 12-1-94: While held for sale after shipment of one or more of its components in interstate commerce at Coastal Surgical in Lake Worth, Fla., the article was adulterated in that the methods used in, and the facilities and controls used for, its manufacture, processing, packaging, and holding did not conform to current good manufacturing practice requirements--501(a)(2)(B); and the adulterated article was introduced into interstate commerce--301(a). DISPOSITION: The oxygen vessel was emptied and returned to the owner. (F.D.C. No. 67028; S. No. 94-682-963; S.J. No. 7) PRODUCT: Oxygen USP, at Pittsburgh, Pa. (W.D.Pa.); Civil No. 93-0951. CHARGED 6-15-93: While held for sale after shipment of one or more of its components in interstate commerce at United Health Care Services, Inc. in Pittsburgh, Pa., the article was adulterated in that the methods used in, and the facilities and controls used for, its manufacture, processing, packing, and holding did not conform to and were not operated and administered in conformity with current good manufacturing practice requirements--501(a)(2)(B). The article was misbranded in that the individual home units failed to bear labeling containing a statement of the net quantity of contents--502(b)(2); and the oxygen was manufactured, prepared and processed in an unregistered establishment--502(o). DISPOSITION: A consent decree of permanent injunction was filed, and costs were paid by the claimant. (F.D.C. No. 66715; S. No. 93-607-687; S.J. No. 8) PRODUCT: Oxygen USP, at Rice Lake, Wis. (W.D.Wis.); Civil No. 94-C-666-S. CHARGED 9-7-94: While held for sale at Home Medical Products and Services in Rice Lake, Wis., the article was adulterated in that the methods used in, and the facilities and controls used for its manufacture and processing did not conform to and were not operated and administered in conformity with current good manufacturing practice requirements--501(a)(2)(B). DISPOSITION: The article was reconditioned by the firm. (F.D.C. No. 67006; S. No. 94-719-025; S.J. No. 9) PRODUCT: Simethicone Tablets, at St. Louis, Mo. (E.D.Mo.); Civil No. 4:94CV2126 CEJ. CHARGED 10-31-94: While held for sale after shipment in interstate commerce at GATX Logistics, Inc., in St. Louis, Mo., the articles were adulterated in that the methods used in, and the facilities and controls used for its manufacture, processing, packing, and holding did not conform with current good manufacturing practice requirements--501(a)(2)(B). DISPOSITION: A default decree of condemnation ordered the articles destroyed. (F.D.C. No. 66987; S. No. 94-673-935; S.J. No. 10) Drugs/Veterinary PRODUCT: Cyan-5 Way Wormer, at Raleigh, N.C. (E.D.N.C.); Civil Action No. 5:94-CV-46-F3. CHARGED 1-28-94: While held for sale after shipment of one or more of its components in interstate commerce at National Hog Medicine Company in Raleigh, N.C., the article was adulterated in that it was an unapproved "new animal drug"--501(a)(5), 201(w)(1), 512(b). The article was misbranded in that the labeling did not accurately state the quantity of its contents, and the labeling failed to bear the caution statement for veterinary prescription drugs--502(b)(2) and 502(c). The article was offered for sale to lay persons without the benefit of a vet/client/patient relationship, and its labeling did not bear adequate directions for its intended use--502(f)(1). DISPOSITION: Default--article destroyed. (F.D.C. No. 66800; S. No. 93-505-983; S.J. No. 11) Medical Devices PRODUCT: Lymphtech Neon-Argon Photon Particle Beam Generator, at Toledo, Ohio (N.D.Ohio); Civil No. 3:93CV7466. CHARGED 8-23-93: While held at Lymphtech N.A. in Toledo, Ohio, the article was adulterated in that it was a Class III device that did not have an application for premarket approval--501(f)(1)(B). The article was misbranded in that the labeling failed to bear adequate directions for use, and it was not manufactured in a registered establishment--502(f)(1) and 502(o). DISPOSITION: A consent decree of condemnation was filed, and the generator was destroyed. (F.D.C. No. 66707; S. No. 93-670-824; S.J. No. 12) CRIMINAL ACTIONS DEFENDANT: James Michael Anthony, M.D., at Memphis, Tenn. (M.D.Tenn.); Criminal No. 93-20029-H. CHARGED 2-16-93: Count 1: The defendant unlawfully exchanged the drug sample Ansaid with the drug Rocephin, which was not intended for sale, for the purpose of using Ansaid to promote the sale of Rocephin--503(c)(1) and 301(t). Counts 2-3: The defendant intentionally obtained possession of the controlled substance Histussin by fraud--403(a)(3) of the Controlled Substances Act. DISPOSITION: Guilty plea; ordered to pay a $150 special assessment. (F.D.C. No. 66585; S.J. No. 13) DEFENDANTS: Highland Laboratory and Kenneth Scott, at Mt. Angel, Ore. (D.Or.); Criminal No. 93-10-IFR. CHARGED 1-19-93: Counts 1-2: The defendant, Kenneth Scott, refused to permit an inspection by FDA of finished and unfinished materials, containers, and labeling of the drug Co-Q10 at a facility where the drug was produced, packed, and held for shipment in interstate commerce--301(f) and 303(a)(2). Counts 3-4: The corporate defendant, Highland Laboratory, distributed unapproved new drugs with false statements regarding their usage--301(d) and 303(a)(1). DISPOSITION: Guilty pleas. Defendant Scott was ordered to pay a $5,000 fine and a special assessment of $50 for both counts; he was sentenced to five years' probation and six months of home confinement. Highland Laboratory was sentenced to three years' probation and ordered to comply with a consent decree of permanent injunction. (F.D.C. No. Nos. 66571 and IG-18; S. No. 9-89-07301-3; S.J. No. 14) INJUNCTION ACTIONS DEFENDANTS: Simed Corporation, and Peter W. Cheung, at Bothell, Wash. (W.D.Wash.); Civil No. C-94-973. CHARGED 6-38-94: This case was converted from a seizure to an injunction. The defendants manufactured and distributed pulse oximeters with accessories. While held at SiMed Corporation in Bothell, Wash., the devices were adulterated in that they were Class III devices that did not have an application for premarket approval--501(f)(1)(B); and the devices were misbranded in that certain information had not been provided to FDA --502(o). The defendants were advised that the devices required filing for premarket notification; however, the defendants continued to produce and distribute the devices without filing with FDA the required application. DISPOSITION: A complaint of permanent injunction was filed. The devices were brought into compliance. (F.D.C. No. 66691; S. No. 93-668-433; S.J. No. 15) DEFENDANTS: Craven Crab Company, Inc., Gaston B. Fulcher Jr., and J. Brent Fulcher, at New Bern, N.C. (E.D.N.C.); Civil No. 4-94-CV-9H2. CHARGED 1-13-94: The defendants introduced adulterated crab meat into interstate commerce--301(a). The crab meat was adulterated in that it contained Listeria monocytogenes, and the crab meat was prepared, packed or held in insanitary conditions whereby it might have become contaminated with filth rendering it injurious to health--402(a)(1) and 402(a)(4). DISPOSITION: A consent decree of permanent injunction was filed. Later, the defendants were found guilty of criminal contempt after violating the consent decree. Defendants Gaston B. Fulcher Jr. and J. Brent Fulcher were ordered to pay a $5,000 fine and to pay FDA $6,491 for inspection costs. J. Brent Fulcher was also sentenced to six months' probation, during which he must spend two weekends confined in a county correction facility. The Craven Crab Company, Inc., was ordered to pay a $10,000 fine. (Inj. No. 1337; S. No. 93-696-494; S.J. No. 16) ------------------------------------------------------------------------ FDA Consumer magazine (September 1995)