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lirget: Adverse Drug Reactions
lirget: Adverse Drug Reactions FDA Reporting Systetn Zeroes in On tReal World' Drug Use
In the last few issues of American Pharmacy, several articles have addressed the FDA drug approval process--how it works, its impact on pharmaceutical research, and the results in terms of important new drugs. Any drug submitted for approval undergoes rigorous testing, including clinical human trials . Most commonly occurring adverse reactions (say, those with an incidence of 0.510%) are spotted at that time-before the drug reaches the public. But what happens after a product is put on the market? Are its effects monitored? Is anyone watching out for long-term or less common reactions that can be detected only when the drug is used in much larger populations? How is the health of the American people being safeguarded? These questions address the issue of postmarketing drug surveillance -a concern that motivated the Pharmaceutical Manufacturers Association and Sen. Edward Kennedy (D-MA) to form the Joint Commission on Prescription Drug Use . The
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FDA's Judith K. Jones American Pharmaceutical Association is a financial supporter of the JCPDU, and two Commission representatives are APhA members. Through the years a number of professional groups and organizations (e.g., the Boston Collaborative Drug Surveillance Program, the American Medical Association, and the World Health Organization) have attempted to investigate specific facets of postmarketing drug use and adverse effects. The Food and Drug Administration has played a significant role in asking -and answering-the important questions. FDA's Jones--On Target Judith K. Jones, MD, PhD, should know the answers to all these questions. As director of the Division of Drug Experience in FDA's Bureau of Drugs, Jones is in charge of the adverse drug reaction (ADR) reporting program, established in 1961 parallel to the discontinued AMA Regis-
try of Adverse Reactions. Jones came to FDA via a circuitous route that took her from her birthplace in Coffeyville, KS, to Baylor University where she received her undergraduate and medical degrees, to Chicago for her internship, to the University of California for a residency, clinical pharmacology fellowship, and PhD in pharmacology and several years of private practice in internal medicine, and finally to Rockville, MD, and FDA's Parklawn Building. "My interest has always been in prescribing practice~what happens to drugs in the real world, " Jones said. To further that interest, she: • Taught clinical pharmacology to house staff and practicing physicians in the San Francisco Bay area; • Helped coordinate a hospital clinical pharmacy program for the University of the Pacific School of Pharmacy in Stockton, CA; • Consulted for the FDA GTC panel on hemorrhoidal drugs; • Headed the clinical pharmacology division at Presbyterian Hospital, Pacific Medical Center, in San Francisco; • Participated on various local committees, including the pharmacy and therapeutics committee at UCSF hospital; • Went into private medical p ractice, "partly because I felt that I should have the prescribing experience." A year ago, with this broad a nd many-faceted background in drug utilization, Jones took over the Division of Drug Experience (DOE). Since then, she has been overhauling and streamlining the system. Her activities include lecturing to professional associations, ' hospital groups, and students, a nd publishing articles to promote u nderstanding and increase interest in adverse reaction reports. In a recent briefing of American Pharmacy and APhA staff, Jones e xplained how the ADR reporting p ro- . gram operates and what pharmacists can do to improve it. Most of the information comes to
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ODE from any of five sources: • A spontaneous reaction reporting system; • Intensive drug monitoring studies; • Special epidemiological studies; • Review of current literature; • Communications with the World Health Organization and national drug monitoring centers. Jones's discussion focused on the first of these sources, the spontaneous reporting system. Using organizational charts, algorithms, and tables to reinforce her explanation, Jones described how the system works-and how pharmacists can make it work better. Reaction Reports
The spontaneous reporting system accounts for about 12,000 rep orts each year. Several elements contribute: manufacturers, who are required to file all adverse reactions w ith FDA's New Drug Evaluations Division; members of the medical community, whose efforts are volu ntary; and separate registries, which collect and evaluate patterns of occurrence. Just what is considered an ad. verse drug reaction? According to the FDA Code of Federal Regulations, an ,ADR is "any adverse experience associated with the use of the drug, whether or not considered drug-related," including "any side effect, injury, toxicity, or sensitivity reaction, or significant failure of expected pharmacological action." "Basically," Jones explained, "we're interested in reactions that are new, serious, or unusual and not mentioned in the labelingwhat we designate' A' reactions." "B" reactions are serious but are described in the labeling, and "c" reactions are less serious and are listed in the labeling. Manufacturers must report .A reactions within 15 days after notification by a detail person, patient, or health practitioner. These ADRs receive top priority treatment. B reactions get second priority, and Cs are simply fed into
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'My interest has always been in prescribing practice-what happens to drugs in the real world.'
a computer for future reference. Since 1968 the FDA has .received more than 168,000 spontaneous reports, all of which are stored on computer. "That's over 1,000 entries for many drugs," Jones pointed out. At first, FDA used a report form containing 25 elements. The form (FD 1639) is still used by pharmaceutical manufacturers and hospitals, but practitioners found it cumbersome. When a new short form was developed in 1973, voluntary reporting increased markedly. The short form (FD 1639a) contains only 13 elements and also has the advantage of a self-mailing, prestamped format. It is attached periodically to the FDA Bulletin, which is received by more than 1,000,000 health practitioners. Report Procedure
Let's follow a report from the time it arrives in Jones' office. First, the report is examined by one of .the six members of the medical review staff (consisting of four pharmacists and two physicians) specializing in the
appropriate area that corresponds to New Drug Evaluation divisions in the Bureau of Drugs: cardiorenal, metabolic and endocrine, neuropharmacological, anti-infective, surgical-dental, or oncological. As a result of this review the reaction is classified A, B, or C, and a copy of the report may be forwarded to a related government office with parallel interest-for example, the Bureau of Biologics or the National Institute on Occupational Safety and Health. "Suppose a report says that the patient had nausea, vomiting, and black spots on the fingers and became comatose, and was taking five different drugs," said Jones. "As you can see, some of these problems are rather difficult to sort out, particularly since the number of reports we need to establish causality with a specific drug is determined on an individual basis, depending on how the criteria are met. We've been attempting to formalize our evaluation procedures and eliminate arbitrary judgments as much as possible." A step-by-step procedures manual is in draft stage. Jones hopes that it will help health professionals in developing their own methods of ad verse reaction reporting.
Health practitioners can report adverse reactions on form FD 1639a, a self-mailer from FDA.
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The second phase, which is carried out almost simultaneously with the first one, is to assess the suspected degree of cause-and-effect relationship. Reactions are classified as definite, probable, possible, or remote, according to several criteria: • Whether there is a reasonable temporal relationship between use of the drug and the reaction; • Whether the patient improved after stopping the drug (dechal .. lenge); • Whether the reaction reappeared on repeated exposure to the drug (rechallenge); • Whether the reaction could be reasonably explained by the known characteristics of the patient's physical state or disease. Finally, the need for follow-up informa tion is determined. Reactions are reviewed on a weekly basis. If a report has been classified A or notable B (for example, a fatal reaction), Jones and her staff try to corroborate it from their stored ADR computer summary and other sources such as published literature and contracted studies (e.g., the Boston Collaborative Drug Surveillance Program). The DOE reviewers also meet regularly with medical reviewers in the New Drug Evaluation Division to discuss these reports. If the report is indeed significant, an Alert" is
sent to the Bureau of Drugs, the World Health Organization (WHO), and contractors studying adverse reactions. In some cases this action results in labeling changes and other regulatory decisions. Examples of changes made in the last six months include: • Warnings on Norpace (disopyramide phosphate, an antiarrythmic cardiac depressant) concerning congestive heart failure and hypoglycemia; • Indications of cimetidine..Coumadin (warfarin) and Diabinese (chlorpropamide )-warfarin interactions. The original reporters also benefit from their contributions. As of this year, a feedback mechanism has gone into effect whereby all indivi-
dual reporters receive a list of all definite and probable suspected ADRs for the drug in question. The mechanism is expected to be flPplied soon for manufacturers. (Through the Freedom of Information Act, anyone can request a copy of the summary of adverse reactions that ODE stores on microfilm. The reports, minus all personal identification, are provided at cost.) A nonquantitative computer printout of all reactions reported to drugs where there were at least three definite or probable associations is distributed within the FDA, as well as to WHO and national centers. In time, it will be available from the National Technical -Information Service, a federal information clearinghouse in Springfield, VA.
Jones (second from left) and DDE pharmacists (left to right) Michael Dreis, Dianne Kennedy, Carolyn Brophy, Kay Pearson, Mary Forbes, and Kevin Gallagher discuss adverse reactions at weekly review meetings. "Pharmacy is a critical part of our division," says Jones.
1/
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The short FDA forms account for appoximately 20% of ADR reports, Jones says. In addition, DDE reviews more than 100 medical journals each month and assembles an abstract summary for distribution to the Bureau of Drugs, WHO, and more than 20 national ADR centers throughout the world. The summaries also are published regularly. Jones is currently developing a computer file of literature. What else is this mountain of reports used for besides corroboration of other ADRs? Jones enumerated some of the many applications: • Analysis by DDE's drug use analysis branch of trends in drug use and misuse to identify populations at risk; • Hypotheses for drug epidemiology studies; • Profile of drug actions; • Risk assessment and benefit risk analysis (a combined activity of the ADR, epidemiology, and drug use analysis branches). Pharmacists' Vital Role Jones outlined several areas in which pharmacist participation can be particularly useful. "For example, drug information centers are important, and both hospital and community pharmacists can serve as conduits for reporting adverse reactions and educating the medical community about them. Pharmacists often help other health professionals in deciding whether a drug really contributed to a specific clinical event." Another way in which pharmacists can provide input is through hospital pharmacy and therapeutics committees. The Joint Commission on Accreditation of Hospitals is promoting the idea that every hospital should have an adverse reaction reporting program. * "We get hundreds of letters from
'Both hospital and community pharmacists can serve as conduits for reporting adverse reactions and educating the medical community about t~em.'
P&T committees asking how to go about it," said Jones. She recently published an article presenting some of the options-which, incidentally, don't always relate to FDA objectives. "Each hospital has to develop its own goals in such a program," sa'i d Jones. "Some facilities may prefer to concentrate on quality of care and preventable ADRs such as insulin reactions. Others may want to focus on the rare birds that come along once a year. Ideally, of course, you'd like to look at both kinds." Here, too, pharmacists-especially those with strong clinical training --can be primary movers. Jones is advising on a project with the Veterans Administration where pharmacists will act in a surveillance capacity to review adverse reactions. "There is considerable interest in developing a number of methods of monitoring both inpatient and outpatient use 'of drugs," she said. Since hospital and long-term care
facility pharmacists perform most drug utilization reviews, Jones feels that these people are the logical choice for developing a comprehensive national hospital drug utilization system. But there are still a number of logistical problems that pharmacists could help solve, and DDE would like to enlist their aid . "Opportunities exist within the division for short-term training and/ or experience," said Jones. "For example, there are some special fellowship and part-time employment opportunities for 700 hours or less for interested pharmacists. We've had COSTEP pharmacists in the division for a number of years. In fact, one of our evaluators is a former COSTEP pharmacist. . It's a good way for professionals inpharmacy to get an overview of what happens in the FDA." To Jones it is clear that pharmacists are in a unique position to monitor drug use. By using their frequent contact with physicians, colleagues, and other members of the medical community they can have easy access to suspected new, rare, and unpublished adverse reactions. "But," Jones emphasized, "the system can function only when we have nationwide participation. With pharmacists' participation we will have one of the most valuable tools for understanding drugs as they are actually used in practice." -JSW
• A booklet put out by the FDA Bureau of Drugs, "Adverse
Drug Reaction Reporting-Guidelines for Hospital Reporting Programs," is available. To receive a copy, or for additional information on any aspect of the adverse reaction reporting program, write: Bureau of Drugs, HFD-21O, Food and Drug Administration , 5600 Fishers Lane, Rockville, MD 20857.
American Pharmacy VoI.NS19, No,9, August 1979/497
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Biochemical Individuality And the Case fur Supplemental Vitamins
and megadosing are organizations such as the FQod and Drug Administration and the American Medical Association. Proponents include many renowned researchers, among them Linus Pauling. The FDA's position is clearly stated: 1 "So-called average or normal eaters probably never need supplemental vitamins. Anyone who eats 'all over the store,' meaning a reasonably varied diet, should normally never need supplemental vitamins." . The AMA is just as firm:2 "All recommended nutrient intakes considered essential to maintenance of health in normal individuals can be provided by a balanced diet of commercial foods including fortified items." Herbere,4 carries this viewpoint to its conclusion. He takes the position, as he says all medical texts do, that most diseases have little to do with diet, that most people are not poorly nourished, and that processing and storage do not remove large amounts of nutritive value from food. To maintain a positive . state of health, all one needs to eat is a moderate amount of food from the four basic categories-meats, dairy products, legumes and cereals, and fruits and vegetables. These amounts will supply vitamins equal to the recommended daily dietary allowance (RDA). Any excess is a waste. Biochemical Individuality
By WARREN D. KUMLER America today is becoming more and more conscious of nutrition. Knowing that many ,loods arrive in our grocery stores stripped of their
Warren D. Kumler, PhD, is professor of chemistry and pharmaceutical chemistry emeritus at the University of California School of Pharmacy, San Francisco, CA 94143. Dr. Kumler reports that he became interested in vitamins and nutrition several years ago when he was able to correct his poor dark adaptation by taking vitamin A supplements.
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essential nutrients, people are going "back to basics"-baking their own bread with unbleached whole grain flour, growing their own fruits and vegetables-in an effort to obtain the vitamins and minerals they need to stay healthy. Some, however, have opted to supplement natural sources with vitamin supplements-many take them in amounts far exceeding the recommended daily allowance (megadoses). Advocates and opponents heatedly debate the relative risks and benefits of vitamin therapy. Speaking against supplemental vitamins
On the other side of the vitamin argument are experts such as Roger J. Williams, PhD, former pr~sident of the Anterican Chemical Society. He finds that biochemical individuality in the same species of animals, including humans, varies sometimes tens and hundreds of times. 5 Since the RDAs were set at about a 50% increase over the minimum daily requirement-that is, the minimum amount of any particular vitamin necessary to prevent the occurrence of the disease associated with the vitamin deficiency-it is appa- ( rent that these amounts are not suf-
ficien Will zyme duals to fif comp certa essar quan be su neces Some • A psori took retur disco again • A eyes reme of ab • S patie ribofl • A durin by 25 , acid d • C ferer" thenic daily) min w The norma tain v enoug these to cor likely norma mins.
Vitam
Let' mins. do no constr body. formin maint provid norma level o Alth do not
American Pharmacy Vol.NS19, No.9, August 1979/498 American P
= ficient to account for such variances. Williams's documentation 5 ,6 of enzyme deficiencies in normal individuals, which varied from threefold to fiftyfold, indicates strongly that comparable increased quantities of certain vitamins also would be necessary for maximum effect. Such quantities could not be expected to be supplied by food and thus would necessitate the use of supplements. Some of his case studies: • A skin condition diagnosed as psoriasis cleared when the patient took 25,000 units of vitamin A daily, returned when the vitamin A was discontinued, then disapppeared again after therapy was resumed; • A woman's inability to use her eyes for continuous reading was remedied completely by daily intake of about 10 mg of thiamine; • Sensitivity to glare in another patient was abolished by 15 mg of riboflavin daily; • Allergy symptoms apparent during desert travel were improved by 25 mg or more of pantothenic , acid daily; • Constipation in a "lifelong sufferer" disappeared with pantothenic acid therapy (about 25 mg daily) but returned when the vitamin was discontinued. These people evidently had abnormally high requirements for certain vitamins. They were fortunate enough to find out that they had these requirements and so were able to correct their disorder. It is highly likely that many people have abnormal requirements for some vitamins.
are not the fuel that is metabolized in the body to produce energythey do function in a sense as energy catalysts. If the vitamins are not present in sufficient amounts, metabolic reactions will proceed ineffectively or not at all. The FDA argument is analogous to saying that if an automobile engine is not producing sufficient power because of dirty spark plugs, there is no point in cleaning them, because spark plugs do not provide energy. Vitamins have a number of functions beyond those for which they were originally designated. For example, vitamin C, originally used to prevent scurvy, is involved in building hydroxyproline and hydroxylysine into collagen6 and acts as a reducing agent and free radical scavenger. For these additional functions the necessary intake is
many times the few milligrams daily needed to prevent scurvy. Today's "refined" foods often do not provide adequate amounts of vitamins and minerals. The milling process to produce white flour removes 22 known essential nutrients from the wheat, including 90% of the vitamin E; flour is labeled "enriched" when four of these nutrients are returned, namely, thiamine, riboflavin, niacin, and iron. The refining of sugar to produce 99.9% sucrose removes virtually all of the vitamins and minerals necessary for its metabolism. Most vegetable oils now are heated to 200-250° in processing, which removes lecithin, essential fatty acids, and vitamins A and E. Cooked and reheated potatoes contain only one tenth the amount of vitamin C as the raw product. 7
Vitamins and Nutrition Let's look at the functions of vitamins. FDA says:1 "They (vitamins) do not provide energy, nor do they construct or build any part of the body. They are needed for transforming foods into energy and body maintenance .... Vitamins will not provide extra pep, vitality beyond normal expectations, or an unusual level of well-being." Although it is true that vitamins do not provide direct energy-they
--
American Pharmacy VoI.NS19, No.9, August 1979/499
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Vitamin requirements are also known to increase from smoking, air pollution, some drugs, bacterial and viral infections, surgery, worry, burns, aging, and other factors. 8 The human species is one of the few animals known that do not manufacture their own vitamin C. Some idea of how much vitamin C human beings require could be obtained by studying how much is produced daily by animals that synthesize vitamin C and then extrapolating on the basis of body weight. J When this estimation was made with the rat as a standard of comparison, the results for humans were 2-4 g without stress and 15 g under moderate stress. In other animals the equivalent rate is about 10 g per day for 154 pounds body ~eight. These amounts are about 160 times the RDA of 60 mg for humans--an indication that the current RDA for this vitamin is far too low. This theory may help explain why some people are more prone to bacterial and viral infections--their natural defense mechanisms are lowered by inadequate intake of essential nutrients. Williams says, "That malnutrition-unbalanced or inadequate nutrition-at the cellular level should be thought of as a major cause of human disease, seems crystal clear to me. It is the inevitable conclusion to be drawn from facts produced by decades of 'biochemical research.' I
Benefits vs. Risks What benefits are likely from relatively large doses of some vitamins, and how do they stack up against the possible toxic effects and the cost? Let's look at the risks first . Just how harmful are vitamin intakes tha t exceed several times the RD As? A list of the possibilities has been developed but without much evidence at what level the assumed harmful effects may occur. However, specific studies have documented these findings: • Overdoses of vitamin A are known to cause nausea, irritability,
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hair loss, and headaches, but daily doses of 100,000 IV have been administered to adults for months without ill effect. 7 "All reported cases (of hypervitaminosis A) in children have been associated with chronic ingestion of 50,000-500,000 units per day."lO From the above, it is evident that doses for adults up to 20,000-30,000 IV daily should be safe, and this is the amount recommended in "The Book of Vitamin Therapy." • With vitamin 0, evidence indicates that a level of 100,000-150,000 IV daily for several months must be reached before harm in adults can resul t. Although the RD A is 400 IV, doses of 800-1,200 IV would appear safe by many factors . • The B vitamins have all been reported to be relatively nontoxic. • In the case of vitamin E, the Food and Nutrition Board notes: "Toxicity symptoms have not been reported even at intakes of 800 IV per kilogram of body weight daily for five months.,,7 For a 154-pound person this amounts to a daily intake of 56,000 IV, 18,000 times the RDA. However, vitamin E is known to improve the efficiency of the heart, raise the blood pressure, and
increase the imbalance between the two sides ~of the heart. Thus it should be used with caution by hypertensive and rheumatic fever patients. • A number of side effects have been reported for megadoses of vitamin C: 3 rebound scurvy has occurred in· offspring of mothers and in others who suddenly stopped megadose therapy; certain ethnic groups, including some Sephardic Jews, Orientals, and American Blacks, who have congenital gIticose-6-phosphate dehydrogenase deficiency may develop hemolytic anemia; some people develop diarrhea; the uric acid level may be raised; gout may be precipitated in predisposed individuals; and glucose and daily blood-in-stool tests may show false positive results. It has also been contended that 0. 5 g of vitamin C daily in a hospital diet will destroy a substantial part of the vitamin B12 in the diet. This statement, however, has been disputed, and the results attributed tq the use of an unreliable method of analysis. A high intake of vitamin C was reported to cause abortions; however, this finding is based on only one paper, and when the authors were asked whether any test for pregnancy was carried out, no reply was received. II Nobelist Linus Pauling, a strong vitamin C advocate, has given detailed consideration to all these side effects and reports that in almost all cases, large doses can be taken without any harmful side effects. 1 1 This contention is substantiated by the report of Hoffer,I2 who has used daily megadoses of 3-30 g of vitamin C in more than 1,000 patients since 1953 without one case of .miscarriage, kidney stone formation, excessive hydration, or any other serious toxicity. KIenner has given patients 10 g of vitamin C daily for more than 30 years without any serious toxic effects. 13.14 Thus the reports on toxicity of most vitamins indicate that, except for vitamin E in individuals with rheumatic heart and specific indi-
American Pharmacy VoI.NS19, No.9, August 1979/500
viduals with rare diseases, most adults can take all vitamins in amounts several times the ROA without any toxic side effects. Another consideration in evaluating the effects of vitamin therapy is whether na tural vitamins carry more risk than synthetic ones. Vitamins are chemical compounds that have the same structure and properties whether produced in nature or in a laboratory or factory. But natural vitamins are far more costly than their synthetic analogs. Morel over, natural products may contain impurities that result in deleterious effects. Cases in point are lead poisoning from herbal health pills and powdered bone. 15 So far, no clear evidence has been presented that any impurities in natural vitamins have beneficial effects. The benefits likely to accrue from megadose vitamin therapy are: • Better health from better resistance to disease (vitamins A, C, E, and possibly others); • Better metabolism; • More energy; • A possible slowing down of the aging process from the free radical scavenger effect of vitamins C and
E; • Possible improved circulation from vitamin E. Plen tiful amounts of vitamin 0, calcium, and magnesium are likely to reduce the chances of developing osteoporosis, arthritis, and other problems with bones and joints with which many people suffer in later years, particularly women. Supplemental doses of vitamin E have been shown to be beneficial 16 in cases of hemolytic anemia in premature infants, in treating malabsorption of fats and oils in postgastrectomy patients, and in patients with cystic fibrosis, liver cirrhosis, obstructive jaundice, and pancreatic insufficiency. In double-blind studies, vitamin E relieved intermittent claudication or calf pain when walking. Any approach to supplemental vitamins and megavitamin therapy would appear to call for expert pro-
American Pharmacy VoI.NS19, No.9, August 1979/501
fessional consultation to confirm that there is indeed a vitamin deficiency. If what is meant by a deficiency is a condition where symptoms such as pellegra, scurvy, beriberi, rickets, and night blindness are evident, then one's physician should recognize them. However, we are concerned here with deficiencies which are present long before these extreme manifestations are apparent. 6 Furthermore, we should be concerned with optimum vitamin dosages, not just those that prevent the aforementioned five condi tions. The Best Approach In view of the wide range and universal presence of biochemical individuality, it is likely that virtually everyone has need for, and would benefit from, supplemental vitamins. The methods of determining each individual's optimum requirements for each vitamin are not now readily available. However, with advances in biochemistry and computerized techniques, such analyses hopefully will be available and affordable some time in the future. Until that time, a considered approach would be for people to take large but safe doses of each vitamin and mineral, one at a time, for several weeks, along with the ROAs of the other vitamins and minerals, and to see whether their well-being improved. In this way they could determine for which vitamins and minerals they had an abnormal requirement. However, this procedure requires powers of observation and a diligence that most people do not possess. My approach is to take large but safe doses of all of the vitamins and adequate doses of minerals. I have stated previously what can be logically considered large but safe doses of vitamins based on the doses at which toxicity is reported. In the tables are listed the amounts of vitamins and minerals which I take. The foundation of my supplementation is the Vitamin and Mineral Insurance Formula recommended and
developed by Dr. Roger Williams. To this are added additional amounts of vitamins A, 0, E, C, B1 , B2 , B6 , B12 , biotin, folic acid, and the minerals calcium, magnesium, and zinc. Although much of the intake of these supplements might be wasted, the improvement in health should justify the few extra cents per day (as little as 27 cents) as money well spent. The cost of this supplementation is given in Table 2. 0 References 1. G .E. Damon, FDA COliSII mer, May 1974. 2. C.E. Butterworth in " Psychodietetics, " E. Cheraskin, W .M . Ringsdorf Jr ., Eds ., Bantam Books, New York, NY (1977) p . 157. 3. V.D . Herbert, COlltemp. Nlltr ., 2 (10) , Oct. 1977. 4. " The Health Robbers," S. Barrett and G . Knight. Eds ., George F. Stickley Co ., Philadelphia , PA, 1976. 5. R.J. Williams, " Biochemical Individuality," Wiley, New York, NY, 1963. 6. "Physician's Handbook of Nutritional Science," R.J. Williams, Charles C Thomas, Springfield, IL, 1975. 7. H . Rosenburg and A.N . Feldzamer, "The Book of Vitamin Therapy," Berkeley Publishing Corp., New York, NY, 1974. 8. I. Stone, "The Healing Factor: Vitamin C against Disease," Grosset & Dunlap, New York, NY, 1972, p .5l. 9. R.J. Williams, "Nutrition against Disease," Bantam, New York, NY, 1973. 10. "A Pharmacological Basis of Therapeutics," 5th ed ., L.S . Goodman and A. Gilman, Eds., Macmillan , New York, NY, 1977. 11 . L. Pauling, "Vitamin C, the Common Cold and the Flu," W .H . Freeman & Co., San Francisco, CA, 1976. 12. A. Hoffer, N .EnKl.J.Med. , 285, 635 (1971). 13. F.R. Klenner, J.lllt .Acad.Prev.Med ., L 15 (1974). 14. F.R. Klenner, J.Appl .Nlltr . 23 , 61 (1971). 15. W .H. Crosby, J.Am .Med . Assoc., 238, 1544 (1977) . 16. M .B. Sporn, Nutr.Rev ., 35. 57 (1977).
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In the last few issues of American Pharmacy, several articles have addressed the FDA drug approval process--how it works, its impact on pharmaceutical research, and the results in terms of important new drugs. Any drug submitted for approval undergoes rigorous testing, including clinical human trials . Most commonly occurring adverse reactions (say, those with an incidence of 0.510%) are spotted at that time-before the drug reaches the public. But what happens after a product is put on the market? Are its effects monitored? Is anyone watching out for long-term or less common reactions that can be detected only when the drug is used in much larger populations? How is the health of the American people being safeguarded? These questions address the issue of postmarketing drug surveillance -a concern that motivated the Pharmaceutical Manufacturers Association and Sen. Edward Kennedy (D-MA) to form the Joint Commission on Prescription Drug Use . The
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FDA's Judith K. Jones American Pharmaceutical Association is a financial supporter of the JCPDU, and two Commission representatives are APhA members. Through the years a number of professional groups and organizations (e.g., the Boston Collaborative Drug Surveillance Program, the American Medical Association, and the World Health Organization) have attempted to investigate specific facets of postmarketing drug use and adverse effects. The Food and Drug Administration has played a significant role in asking -and answering-the important questions. FDA's Jones--On Target Judith K. Jones, MD, PhD, should know the answers to all these questions. As director of the Division of Drug Experience in FDA's Bureau of Drugs, Jones is in charge of the adverse drug reaction (ADR) reporting program, established in 1961 parallel to the discontinued AMA Regis-
try of Adverse Reactions. Jones came to FDA via a circuitous route that took her from her birthplace in Coffeyville, KS, to Baylor University where she received her undergraduate and medical degrees, to Chicago for her internship, to the University of California for a residency, clinical pharmacology fellowship, and PhD in pharmacology and several years of private practice in internal medicine, and finally to Rockville, MD, and FDA's Parklawn Building. "My interest has always been in prescribing practice~what happens to drugs in the real world, " Jones said. To further that interest, she: • Taught clinical pharmacology to house staff and practicing physicians in the San Francisco Bay area; • Helped coordinate a hospital clinical pharmacy program for the University of the Pacific School of Pharmacy in Stockton, CA; • Consulted for the FDA GTC panel on hemorrhoidal drugs; • Headed the clinical pharmacology division at Presbyterian Hospital, Pacific Medical Center, in San Francisco; • Participated on various local committees, including the pharmacy and therapeutics committee at UCSF hospital; • Went into private medical p ractice, "partly because I felt that I should have the prescribing experience." A year ago, with this broad a nd many-faceted background in drug utilization, Jones took over the Division of Drug Experience (DOE). Since then, she has been overhauling and streamlining the system. Her activities include lecturing to professional associations, ' hospital groups, and students, a nd publishing articles to promote u nderstanding and increase interest in adverse reaction reports. In a recent briefing of American Pharmacy and APhA staff, Jones e xplained how the ADR reporting p ro- . gram operates and what pharmacists can do to improve it. Most of the information comes to
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ODE from any of five sources: • A spontaneous reaction reporting system; • Intensive drug monitoring studies; • Special epidemiological studies; • Review of current literature; • Communications with the World Health Organization and national drug monitoring centers. Jones's discussion focused on the first of these sources, the spontaneous reporting system. Using organizational charts, algorithms, and tables to reinforce her explanation, Jones described how the system works-and how pharmacists can make it work better. Reaction Reports
The spontaneous reporting system accounts for about 12,000 rep orts each year. Several elements contribute: manufacturers, who are required to file all adverse reactions w ith FDA's New Drug Evaluations Division; members of the medical community, whose efforts are volu ntary; and separate registries, which collect and evaluate patterns of occurrence. Just what is considered an ad. verse drug reaction? According to the FDA Code of Federal Regulations, an ,ADR is "any adverse experience associated with the use of the drug, whether or not considered drug-related," including "any side effect, injury, toxicity, or sensitivity reaction, or significant failure of expected pharmacological action." "Basically," Jones explained, "we're interested in reactions that are new, serious, or unusual and not mentioned in the labelingwhat we designate' A' reactions." "B" reactions are serious but are described in the labeling, and "c" reactions are less serious and are listed in the labeling. Manufacturers must report .A reactions within 15 days after notification by a detail person, patient, or health practitioner. These ADRs receive top priority treatment. B reactions get second priority, and Cs are simply fed into
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'My interest has always been in prescribing practice-what happens to drugs in the real world.'
a computer for future reference. Since 1968 the FDA has .received more than 168,000 spontaneous reports, all of which are stored on computer. "That's over 1,000 entries for many drugs," Jones pointed out. At first, FDA used a report form containing 25 elements. The form (FD 1639) is still used by pharmaceutical manufacturers and hospitals, but practitioners found it cumbersome. When a new short form was developed in 1973, voluntary reporting increased markedly. The short form (FD 1639a) contains only 13 elements and also has the advantage of a self-mailing, prestamped format. It is attached periodically to the FDA Bulletin, which is received by more than 1,000,000 health practitioners. Report Procedure
Let's follow a report from the time it arrives in Jones' office. First, the report is examined by one of .the six members of the medical review staff (consisting of four pharmacists and two physicians) specializing in the
appropriate area that corresponds to New Drug Evaluation divisions in the Bureau of Drugs: cardiorenal, metabolic and endocrine, neuropharmacological, anti-infective, surgical-dental, or oncological. As a result of this review the reaction is classified A, B, or C, and a copy of the report may be forwarded to a related government office with parallel interest-for example, the Bureau of Biologics or the National Institute on Occupational Safety and Health. "Suppose a report says that the patient had nausea, vomiting, and black spots on the fingers and became comatose, and was taking five different drugs," said Jones. "As you can see, some of these problems are rather difficult to sort out, particularly since the number of reports we need to establish causality with a specific drug is determined on an individual basis, depending on how the criteria are met. We've been attempting to formalize our evaluation procedures and eliminate arbitrary judgments as much as possible." A step-by-step procedures manual is in draft stage. Jones hopes that it will help health professionals in developing their own methods of ad verse reaction reporting.
Health practitioners can report adverse reactions on form FD 1639a, a self-mailer from FDA.
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The second phase, which is carried out almost simultaneously with the first one, is to assess the suspected degree of cause-and-effect relationship. Reactions are classified as definite, probable, possible, or remote, according to several criteria: • Whether there is a reasonable temporal relationship between use of the drug and the reaction; • Whether the patient improved after stopping the drug (dechal .. lenge); • Whether the reaction reappeared on repeated exposure to the drug (rechallenge); • Whether the reaction could be reasonably explained by the known characteristics of the patient's physical state or disease. Finally, the need for follow-up informa tion is determined. Reactions are reviewed on a weekly basis. If a report has been classified A or notable B (for example, a fatal reaction), Jones and her staff try to corroborate it from their stored ADR computer summary and other sources such as published literature and contracted studies (e.g., the Boston Collaborative Drug Surveillance Program). The DOE reviewers also meet regularly with medical reviewers in the New Drug Evaluation Division to discuss these reports. If the report is indeed significant, an Alert" is
sent to the Bureau of Drugs, the World Health Organization (WHO), and contractors studying adverse reactions. In some cases this action results in labeling changes and other regulatory decisions. Examples of changes made in the last six months include: • Warnings on Norpace (disopyramide phosphate, an antiarrythmic cardiac depressant) concerning congestive heart failure and hypoglycemia; • Indications of cimetidine..Coumadin (warfarin) and Diabinese (chlorpropamide )-warfarin interactions. The original reporters also benefit from their contributions. As of this year, a feedback mechanism has gone into effect whereby all indivi-
dual reporters receive a list of all definite and probable suspected ADRs for the drug in question. The mechanism is expected to be flPplied soon for manufacturers. (Through the Freedom of Information Act, anyone can request a copy of the summary of adverse reactions that ODE stores on microfilm. The reports, minus all personal identification, are provided at cost.) A nonquantitative computer printout of all reactions reported to drugs where there were at least three definite or probable associations is distributed within the FDA, as well as to WHO and national centers. In time, it will be available from the National Technical -Information Service, a federal information clearinghouse in Springfield, VA.
Jones (second from left) and DDE pharmacists (left to right) Michael Dreis, Dianne Kennedy, Carolyn Brophy, Kay Pearson, Mary Forbes, and Kevin Gallagher discuss adverse reactions at weekly review meetings. "Pharmacy is a critical part of our division," says Jones.
1/
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The short FDA forms account for appoximately 20% of ADR reports, Jones says. In addition, DDE reviews more than 100 medical journals each month and assembles an abstract summary for distribution to the Bureau of Drugs, WHO, and more than 20 national ADR centers throughout the world. The summaries also are published regularly. Jones is currently developing a computer file of literature. What else is this mountain of reports used for besides corroboration of other ADRs? Jones enumerated some of the many applications: • Analysis by DDE's drug use analysis branch of trends in drug use and misuse to identify populations at risk; • Hypotheses for drug epidemiology studies; • Profile of drug actions; • Risk assessment and benefit risk analysis (a combined activity of the ADR, epidemiology, and drug use analysis branches). Pharmacists' Vital Role Jones outlined several areas in which pharmacist participation can be particularly useful. "For example, drug information centers are important, and both hospital and community pharmacists can serve as conduits for reporting adverse reactions and educating the medical community about them. Pharmacists often help other health professionals in deciding whether a drug really contributed to a specific clinical event." Another way in which pharmacists can provide input is through hospital pharmacy and therapeutics committees. The Joint Commission on Accreditation of Hospitals is promoting the idea that every hospital should have an adverse reaction reporting program. * "We get hundreds of letters from
'Both hospital and community pharmacists can serve as conduits for reporting adverse reactions and educating the medical community about t~em.'
P&T committees asking how to go about it," said Jones. She recently published an article presenting some of the options-which, incidentally, don't always relate to FDA objectives. "Each hospital has to develop its own goals in such a program," sa'i d Jones. "Some facilities may prefer to concentrate on quality of care and preventable ADRs such as insulin reactions. Others may want to focus on the rare birds that come along once a year. Ideally, of course, you'd like to look at both kinds." Here, too, pharmacists-especially those with strong clinical training --can be primary movers. Jones is advising on a project with the Veterans Administration where pharmacists will act in a surveillance capacity to review adverse reactions. "There is considerable interest in developing a number of methods of monitoring both inpatient and outpatient use 'of drugs," she said. Since hospital and long-term care
facility pharmacists perform most drug utilization reviews, Jones feels that these people are the logical choice for developing a comprehensive national hospital drug utilization system. But there are still a number of logistical problems that pharmacists could help solve, and DDE would like to enlist their aid . "Opportunities exist within the division for short-term training and/ or experience," said Jones. "For example, there are some special fellowship and part-time employment opportunities for 700 hours or less for interested pharmacists. We've had COSTEP pharmacists in the division for a number of years. In fact, one of our evaluators is a former COSTEP pharmacist. . It's a good way for professionals inpharmacy to get an overview of what happens in the FDA." To Jones it is clear that pharmacists are in a unique position to monitor drug use. By using their frequent contact with physicians, colleagues, and other members of the medical community they can have easy access to suspected new, rare, and unpublished adverse reactions. "But," Jones emphasized, "the system can function only when we have nationwide participation. With pharmacists' participation we will have one of the most valuable tools for understanding drugs as they are actually used in practice." -JSW
• A booklet put out by the FDA Bureau of Drugs, "Adverse
Drug Reaction Reporting-Guidelines for Hospital Reporting Programs," is available. To receive a copy, or for additional information on any aspect of the adverse reaction reporting program, write: Bureau of Drugs, HFD-21O, Food and Drug Administration , 5600 Fishers Lane, Rockville, MD 20857.
American Pharmacy VoI.NS19, No,9, August 1979/497
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Biochemical Individuality And the Case fur Supplemental Vitamins
and megadosing are organizations such as the FQod and Drug Administration and the American Medical Association. Proponents include many renowned researchers, among them Linus Pauling. The FDA's position is clearly stated: 1 "So-called average or normal eaters probably never need supplemental vitamins. Anyone who eats 'all over the store,' meaning a reasonably varied diet, should normally never need supplemental vitamins." . The AMA is just as firm:2 "All recommended nutrient intakes considered essential to maintenance of health in normal individuals can be provided by a balanced diet of commercial foods including fortified items." Herbere,4 carries this viewpoint to its conclusion. He takes the position, as he says all medical texts do, that most diseases have little to do with diet, that most people are not poorly nourished, and that processing and storage do not remove large amounts of nutritive value from food. To maintain a positive . state of health, all one needs to eat is a moderate amount of food from the four basic categories-meats, dairy products, legumes and cereals, and fruits and vegetables. These amounts will supply vitamins equal to the recommended daily dietary allowance (RDA). Any excess is a waste. Biochemical Individuality
By WARREN D. KUMLER America today is becoming more and more conscious of nutrition. Knowing that many ,loods arrive in our grocery stores stripped of their
Warren D. Kumler, PhD, is professor of chemistry and pharmaceutical chemistry emeritus at the University of California School of Pharmacy, San Francisco, CA 94143. Dr. Kumler reports that he became interested in vitamins and nutrition several years ago when he was able to correct his poor dark adaptation by taking vitamin A supplements.
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essential nutrients, people are going "back to basics"-baking their own bread with unbleached whole grain flour, growing their own fruits and vegetables-in an effort to obtain the vitamins and minerals they need to stay healthy. Some, however, have opted to supplement natural sources with vitamin supplements-many take them in amounts far exceeding the recommended daily allowance (megadoses). Advocates and opponents heatedly debate the relative risks and benefits of vitamin therapy. Speaking against supplemental vitamins
On the other side of the vitamin argument are experts such as Roger J. Williams, PhD, former pr~sident of the Anterican Chemical Society. He finds that biochemical individuality in the same species of animals, including humans, varies sometimes tens and hundreds of times. 5 Since the RDAs were set at about a 50% increase over the minimum daily requirement-that is, the minimum amount of any particular vitamin necessary to prevent the occurrence of the disease associated with the vitamin deficiency-it is appa- ( rent that these amounts are not suf-
ficien Will zyme duals to fif comp certa essar quan be su neces Some • A psori took retur disco again • A eyes reme of ab • S patie ribofl • A durin by 25 , acid d • C ferer" thenic daily) min w The norma tain v enoug these to cor likely norma mins.
Vitam
Let' mins. do no constr body. formin maint provid norma level o Alth do not
American Pharmacy Vol.NS19, No.9, August 1979/498 American P
= ficient to account for such variances. Williams's documentation 5 ,6 of enzyme deficiencies in normal individuals, which varied from threefold to fiftyfold, indicates strongly that comparable increased quantities of certain vitamins also would be necessary for maximum effect. Such quantities could not be expected to be supplied by food and thus would necessitate the use of supplements. Some of his case studies: • A skin condition diagnosed as psoriasis cleared when the patient took 25,000 units of vitamin A daily, returned when the vitamin A was discontinued, then disapppeared again after therapy was resumed; • A woman's inability to use her eyes for continuous reading was remedied completely by daily intake of about 10 mg of thiamine; • Sensitivity to glare in another patient was abolished by 15 mg of riboflavin daily; • Allergy symptoms apparent during desert travel were improved by 25 mg or more of pantothenic , acid daily; • Constipation in a "lifelong sufferer" disappeared with pantothenic acid therapy (about 25 mg daily) but returned when the vitamin was discontinued. These people evidently had abnormally high requirements for certain vitamins. They were fortunate enough to find out that they had these requirements and so were able to correct their disorder. It is highly likely that many people have abnormal requirements for some vitamins.
are not the fuel that is metabolized in the body to produce energythey do function in a sense as energy catalysts. If the vitamins are not present in sufficient amounts, metabolic reactions will proceed ineffectively or not at all. The FDA argument is analogous to saying that if an automobile engine is not producing sufficient power because of dirty spark plugs, there is no point in cleaning them, because spark plugs do not provide energy. Vitamins have a number of functions beyond those for which they were originally designated. For example, vitamin C, originally used to prevent scurvy, is involved in building hydroxyproline and hydroxylysine into collagen6 and acts as a reducing agent and free radical scavenger. For these additional functions the necessary intake is
many times the few milligrams daily needed to prevent scurvy. Today's "refined" foods often do not provide adequate amounts of vitamins and minerals. The milling process to produce white flour removes 22 known essential nutrients from the wheat, including 90% of the vitamin E; flour is labeled "enriched" when four of these nutrients are returned, namely, thiamine, riboflavin, niacin, and iron. The refining of sugar to produce 99.9% sucrose removes virtually all of the vitamins and minerals necessary for its metabolism. Most vegetable oils now are heated to 200-250° in processing, which removes lecithin, essential fatty acids, and vitamins A and E. Cooked and reheated potatoes contain only one tenth the amount of vitamin C as the raw product. 7
Vitamins and Nutrition Let's look at the functions of vitamins. FDA says:1 "They (vitamins) do not provide energy, nor do they construct or build any part of the body. They are needed for transforming foods into energy and body maintenance .... Vitamins will not provide extra pep, vitality beyond normal expectations, or an unusual level of well-being." Although it is true that vitamins do not provide direct energy-they
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American Pharmacy VoI.NS19, No.9, August 1979/499
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Vitamin requirements are also known to increase from smoking, air pollution, some drugs, bacterial and viral infections, surgery, worry, burns, aging, and other factors. 8 The human species is one of the few animals known that do not manufacture their own vitamin C. Some idea of how much vitamin C human beings require could be obtained by studying how much is produced daily by animals that synthesize vitamin C and then extrapolating on the basis of body weight. J When this estimation was made with the rat as a standard of comparison, the results for humans were 2-4 g without stress and 15 g under moderate stress. In other animals the equivalent rate is about 10 g per day for 154 pounds body ~eight. These amounts are about 160 times the RDA of 60 mg for humans--an indication that the current RDA for this vitamin is far too low. This theory may help explain why some people are more prone to bacterial and viral infections--their natural defense mechanisms are lowered by inadequate intake of essential nutrients. Williams says, "That malnutrition-unbalanced or inadequate nutrition-at the cellular level should be thought of as a major cause of human disease, seems crystal clear to me. It is the inevitable conclusion to be drawn from facts produced by decades of 'biochemical research.' I
Benefits vs. Risks What benefits are likely from relatively large doses of some vitamins, and how do they stack up against the possible toxic effects and the cost? Let's look at the risks first . Just how harmful are vitamin intakes tha t exceed several times the RD As? A list of the possibilities has been developed but without much evidence at what level the assumed harmful effects may occur. However, specific studies have documented these findings: • Overdoses of vitamin A are known to cause nausea, irritability,
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hair loss, and headaches, but daily doses of 100,000 IV have been administered to adults for months without ill effect. 7 "All reported cases (of hypervitaminosis A) in children have been associated with chronic ingestion of 50,000-500,000 units per day."lO From the above, it is evident that doses for adults up to 20,000-30,000 IV daily should be safe, and this is the amount recommended in "The Book of Vitamin Therapy." • With vitamin 0, evidence indicates that a level of 100,000-150,000 IV daily for several months must be reached before harm in adults can resul t. Although the RD A is 400 IV, doses of 800-1,200 IV would appear safe by many factors . • The B vitamins have all been reported to be relatively nontoxic. • In the case of vitamin E, the Food and Nutrition Board notes: "Toxicity symptoms have not been reported even at intakes of 800 IV per kilogram of body weight daily for five months.,,7 For a 154-pound person this amounts to a daily intake of 56,000 IV, 18,000 times the RDA. However, vitamin E is known to improve the efficiency of the heart, raise the blood pressure, and
increase the imbalance between the two sides ~of the heart. Thus it should be used with caution by hypertensive and rheumatic fever patients. • A number of side effects have been reported for megadoses of vitamin C: 3 rebound scurvy has occurred in· offspring of mothers and in others who suddenly stopped megadose therapy; certain ethnic groups, including some Sephardic Jews, Orientals, and American Blacks, who have congenital gIticose-6-phosphate dehydrogenase deficiency may develop hemolytic anemia; some people develop diarrhea; the uric acid level may be raised; gout may be precipitated in predisposed individuals; and glucose and daily blood-in-stool tests may show false positive results. It has also been contended that 0. 5 g of vitamin C daily in a hospital diet will destroy a substantial part of the vitamin B12 in the diet. This statement, however, has been disputed, and the results attributed tq the use of an unreliable method of analysis. A high intake of vitamin C was reported to cause abortions; however, this finding is based on only one paper, and when the authors were asked whether any test for pregnancy was carried out, no reply was received. II Nobelist Linus Pauling, a strong vitamin C advocate, has given detailed consideration to all these side effects and reports that in almost all cases, large doses can be taken without any harmful side effects. 1 1 This contention is substantiated by the report of Hoffer,I2 who has used daily megadoses of 3-30 g of vitamin C in more than 1,000 patients since 1953 without one case of .miscarriage, kidney stone formation, excessive hydration, or any other serious toxicity. KIenner has given patients 10 g of vitamin C daily for more than 30 years without any serious toxic effects. 13.14 Thus the reports on toxicity of most vitamins indicate that, except for vitamin E in individuals with rheumatic heart and specific indi-
American Pharmacy VoI.NS19, No.9, August 1979/500
viduals with rare diseases, most adults can take all vitamins in amounts several times the ROA without any toxic side effects. Another consideration in evaluating the effects of vitamin therapy is whether na tural vitamins carry more risk than synthetic ones. Vitamins are chemical compounds that have the same structure and properties whether produced in nature or in a laboratory or factory. But natural vitamins are far more costly than their synthetic analogs. Morel over, natural products may contain impurities that result in deleterious effects. Cases in point are lead poisoning from herbal health pills and powdered bone. 15 So far, no clear evidence has been presented that any impurities in natural vitamins have beneficial effects. The benefits likely to accrue from megadose vitamin therapy are: • Better health from better resistance to disease (vitamins A, C, E, and possibly others); • Better metabolism; • More energy; • A possible slowing down of the aging process from the free radical scavenger effect of vitamins C and
E; • Possible improved circulation from vitamin E. Plen tiful amounts of vitamin 0, calcium, and magnesium are likely to reduce the chances of developing osteoporosis, arthritis, and other problems with bones and joints with which many people suffer in later years, particularly women. Supplemental doses of vitamin E have been shown to be beneficial 16 in cases of hemolytic anemia in premature infants, in treating malabsorption of fats and oils in postgastrectomy patients, and in patients with cystic fibrosis, liver cirrhosis, obstructive jaundice, and pancreatic insufficiency. In double-blind studies, vitamin E relieved intermittent claudication or calf pain when walking. Any approach to supplemental vitamins and megavitamin therapy would appear to call for expert pro-
American Pharmacy VoI.NS19, No.9, August 1979/501
fessional consultation to confirm that there is indeed a vitamin deficiency. If what is meant by a deficiency is a condition where symptoms such as pellegra, scurvy, beriberi, rickets, and night blindness are evident, then one's physician should recognize them. However, we are concerned here with deficiencies which are present long before these extreme manifestations are apparent. 6 Furthermore, we should be concerned with optimum vitamin dosages, not just those that prevent the aforementioned five condi tions. The Best Approach In view of the wide range and universal presence of biochemical individuality, it is likely that virtually everyone has need for, and would benefit from, supplemental vitamins. The methods of determining each individual's optimum requirements for each vitamin are not now readily available. However, with advances in biochemistry and computerized techniques, such analyses hopefully will be available and affordable some time in the future. Until that time, a considered approach would be for people to take large but safe doses of each vitamin and mineral, one at a time, for several weeks, along with the ROAs of the other vitamins and minerals, and to see whether their well-being improved. In this way they could determine for which vitamins and minerals they had an abnormal requirement. However, this procedure requires powers of observation and a diligence that most people do not possess. My approach is to take large but safe doses of all of the vitamins and adequate doses of minerals. I have stated previously what can be logically considered large but safe doses of vitamins based on the doses at which toxicity is reported. In the tables are listed the amounts of vitamins and minerals which I take. The foundation of my supplementation is the Vitamin and Mineral Insurance Formula recommended and
developed by Dr. Roger Williams. To this are added additional amounts of vitamins A, 0, E, C, B1 , B2 , B6 , B12 , biotin, folic acid, and the minerals calcium, magnesium, and zinc. Although much of the intake of these supplements might be wasted, the improvement in health should justify the few extra cents per day (as little as 27 cents) as money well spent. The cost of this supplementation is given in Table 2. 0 References 1. G .E. Damon, FDA COliSII mer, May 1974. 2. C.E. Butterworth in " Psychodietetics, " E. Cheraskin, W .M . Ringsdorf Jr ., Eds ., Bantam Books, New York, NY (1977) p . 157. 3. V.D . Herbert, COlltemp. Nlltr ., 2 (10) , Oct. 1977. 4. " The Health Robbers," S. Barrett and G . Knight. Eds ., George F. Stickley Co ., Philadelphia , PA, 1976. 5. R.J. Williams, " Biochemical Individuality," Wiley, New York, NY, 1963. 6. "Physician's Handbook of Nutritional Science," R.J. Williams, Charles C Thomas, Springfield, IL, 1975. 7. H . Rosenburg and A.N . Feldzamer, "The Book of Vitamin Therapy," Berkeley Publishing Corp., New York, NY, 1974. 8. I. Stone, "The Healing Factor: Vitamin C against Disease," Grosset & Dunlap, New York, NY, 1972, p .5l. 9. R.J. Williams, "Nutrition against Disease," Bantam, New York, NY, 1973. 10. "A Pharmacological Basis of Therapeutics," 5th ed ., L.S . Goodman and A. Gilman, Eds., Macmillan , New York, NY, 1977. 11 . L. Pauling, "Vitamin C, the Common Cold and the Flu," W .H . Freeman & Co., San Francisco, CA, 1976. 12. A. Hoffer, N .EnKl.J.Med. , 285, 635 (1971). 13. F.R. Klenner, J.lllt .Acad.Prev.Med ., L 15 (1974). 14. F.R. Klenner, J.Appl .Nlltr . 23 , 61 (1971). 15. W .H. Crosby, J.Am .Med . Assoc., 238, 1544 (1977) . 16. M .B. Sporn, Nutr.Rev ., 35. 57 (1977).
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