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Dr Roberfroid: I will defer that answer to Dr Crowell, since I am unfamiliar with that evaluation.
Dr Crowell: Commission E basically wrote pharmacopeia-type reviews on the effects of herbal products that are prescribed in Germany and Europe, such as St John's Wort, which is now being used extensively in the United States.
Dr Roberfroid: Later, I will discuss prebiotics and probiotics as functional foods. Taking a prebiotic will increase the number of potentially health-promoting bacteria in the colon. This has been accepted in France as a functional claim, but the authority stated clearly that you cannot make any reference to any disease. All you can say is that the composition of the colon bacteria will be improved by consuming the product. In my view, this is what we understand as a functional claim.
Similarly, if something improves calcium absorption by 30%, that is a functional claim. It is not a specific health claim, but we know that calcium absorption could be important at some period during a person's life.
Dr Green: Dr Meydani, in the observations on effects of vitamins E or C versus E plus C on mortality, it looked as if there was a significant interaction that potentiated the response. If that is true, it raises this question: If I drink green tea and take vitamin E, vitamin C, and selenium, are there interactions, either positive or negative? People commonly take several of these things together. What are the advantages and disadvantages of this?
Dr Meydani: There are appropriate controls in most studies of multivitamin supplements. Interactions of vitamins E and C have been studied extensively in vitro, particularly by Niki [Niki E. Interaction of ascorbate and alpha-tocopherol. Ann N Y Acad Sci 1987;498:186–9]. A positive interaction has been reported, but we don't yet know whether it is a sparing effect, regeneration, or something else.
Although interactions have been observed in in vitro systems, I have not seen a human study showing interaction between vitamins E and C. This is the first epidemiologic study showing such an interaction. This does not mean that there is a specific sparing effect of vitamin C or an effect on regeneration of vitamin E. As you said, people are taking not only vitamins E and C but other nutrients as well, so interactions may be complex. We are trying to sort these by testing nutrients one by one, which is difficult and time consuming.
Dr Milner: Do you think it is time to permit a health claim for vitamin E?
Dr Meydani: There is now good evidence that vitamin E intake beyond the RDA [recommended dietary allowance] level, at about 200 IU•L-1•d-1, has an effect on the immune system. There are some indications that this level has effects on cardiovascular disease as well. We are doing studies in the elderly population in a nursing home that will tell us if a supplement will, in fact, reduce the number of infections per year.
Dr Craig: Dr Fernstrom, do you think that some herbs might show more promise than specific nutrients?
Dr Fernstrom: I am more concerned at this moment about safety than about efficacy. Because of dietary supplement legislation passed by Congress in 1994, herbal products listed as dietary supplements are not required to meet standards of safety (or efficacy). Moreover, the FDA [Food and Drug Administration] is severely hampered by this legislation in investigating dietary supplements suspected of being hazardous. The law thus increases the potential for mischief and harm, with the consequences clearly evidenced in a series of articles in the September 17, 1998, issue of The New England Journal of Medicine [eg, Angell M, Kassirer JP. Alternative medicine—the risks of untested and unregulated remedies. N Engl J Med 1998;339:839–41]. An example of the problem can be seen with ephedrine, a compound that releases norepinephrine from sympathetic nerve terminals and, as a result, can elevate blood pressure. When too much ephedrine is taken, the blood pressure rise can be so great as to promote sudden death, presumably from heart attacks and stroke [Josefson D. Herbal stimulant causes US deaths. BMJ 1996; 312:1441]. Because herbal preparations used as dietary supplements are not regulated in any manner, the amount of ephedrine in a ma huang preparation can be highly variable and thus sometimes very high. Until such time as uniform standards of purity, safety, and efficacy are set and enforced, herbal products should be viewed as potentially hazardous, not helpful.
Dr Marriott: In the docosahexaenoic acid (DHA) study, you looked at visual evoked potential. Was there a behavioral effect?
Dr Fernstrom: The study lasted only 57 wk. I am not aware of a study that was continued for a longer time (when behavioral effects might be more readily identified).
Dr Marriott: Was it an effect on something like delay in neuronal branching?
Dr Fernstrom: Nobody knows. That's the remarkable thing about these observations; the biochemical and anatomic underpinnings have not been examined.
Dr Milner: You talked about unsaturated fatty acids and brain development. Do antioxidants have an impact on this? Isn't there some evidence that vitamin E is of some benefit to Alzheimer's patients?
Dr Fernstrom: Yes. A double-blind study suggested that vitamin E can retard the loss of routine functions in everyday life in patients with moderately severe Alzheimer's dementia [Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 1997;336:1216–22]. However, no benefit was noted when specific cognitive functions were assessed. Further studies are needed, although vitamin E has not proven efficacious in other neurologic diseases such as Parkinson's or Huntington's disease.
Dr Hathcock: With regard to folic acid and neural tube defects, I would argue that the case is even stronger than you presented. The Medical Research Council (MRC) trial on folic acid was discounted by some regulatory authorities because the level of 4 mg that was tested was clearly in the so-called pharmacologic range. It was the first double-blind, placebo-controlled intervention trial on recurrence, not occurrence. A decade earlier, Smithells et al [Smithells RW, Sheppard S, Schorah CJ, et al. Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet 1980;1:339–40], reporting the results of a nonblinded intervention trial with 360 µg of folic acid on recurrence, found a 75% protection rate. The study was not blinded because the Investigational Review Board would not allow it.
The MRC study was followed a couple of years later with the publication of the Hungarian trial on occurrence rates [Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832–5]. In that study, 800 µg of folic acid provided about the same ratio of protection.
Dr Bistrian: I thought that in the trials with DHA supplementation, although there was a difference in the evoked visual and behavioral responses between the supplemented and unsupplemented groups at 3 mo, at 6 mo they were no longer distinguishable.
Dr Fernstrom: From my perspective, the DHA supplementation issue is a work in progress. I chose it as an example because of the demonstration of unambiguous physiologic differences that occur early in life in animal and human infants exposed to different levels of intake. It makes good experimental sense to search for functional changes soon after treatment, and it is exciting that such changes were found. The search for long-term sequelae is experimentally much more challenging; they may be there but difficult to demonstrate given the complexity of the physiologic variables (eg, vision) being examined. We must wait and see.