Dietary supplements: applying the knowledge. (Pharmacology Update).
Healthcare professionals' need for information is not adequately answered by the available research. This article helps bridge the gap by giving a brief comparative history of pharmaceutical and dietary supplement legislation, discussing legal challenges, and focusing on the application of this knowledge to the stroke patient.
FDA and Dietary Supplements
The dietary supplement industry has many characteristics of the pharmaceutical industry in its earlier stages of development. Therefore, an understanding of the evolution of the pharmaceutical industry is helpful in considering advancements and needed work in the dietary supplement industry. Tables 1 and 2 summarize the milestones in the history of the FDA and the dietary supplement industry.
Concerns about labeling of dietary supplements were addressed in the Dietary Supplement Health and Education Act of 1994 (DSHEA), following the historical pattern in which pharmaceutical labeling was regulated by the Food and Drug Act of 1906. Safety and efficacy concerns related to dietary supplements have not yet been addressed by legislative standards. DSHEA limits FDA's role in governing dietary supplements to labeling and guideline development related to good manufacturing practices. FDA is able to monitor compliance with the established labeling guidelines (FDA, 2001) primarily through a retrospective analysis of products on the shelf.
The current DSHEA requirements place considerable responsibility on manufacturers to develop appropriate formulations, contaminant-free manufacturing, safe ingredients, and matching of the label to the contents (FDA, 2001). Formulation guidelines are issued by the United States Pharmacopeia (USP), a not-for-profit organization that sets standards and guidelines in the pharmaceutical industry. The product designation USP simply means that the product meets USP's standards for formulation; it does not imply government approval of the product.
A dietary supplement is not manufactured under the same regulations as a pharmaceutical product and cannot be considered equivalent to a pharmaceutical product in safety or efficacy. Specific case challenges to the dietary supplement industry illustrate the importance of conscientious manufacturing.
Appropriate formulations. Hahm, Kujawa, and Augsburger (1999) tested melatonin products from various manufacturers against the USP standard for disintegration and dissolution (i.e., satisfactory tablet breakdown within 30 minutes). Half of the products tested took substantially longer--some more than 20 hours! Two sustained-release formulations were tested. One of them failed the test by releasing 80% of its contents within the first 2 hours, thus increasing the risk of adverse effects.
Contaminants. In 1989 the incidence of eosinophilia myalgia syndrome (EMS) increased dramatically. The Centers for Disease Control and Prevention found 1,500 cases of EMS linked to L-tryptophan, an herbal supplement marketed as a sleep aid. There were 38 associated deaths. The product was removed from the market in 1990. In 1991 the number of EMS cases again increased, this time in conjunction with 5-hydroxy-L-tryptophan (5HTP), an active metabolite of L-tryptophan; it was being marketed as an aid for insomnia, depression, and
attention-deficit disorder. The impurities in L-tryptophan were similar to the impurities found in 5HTP. Now the question remains: Are the impurities responsible for the rise in EMS, or is the metabolite 5HTP responsible? The issue is still under investigation (FDA, 1998a).
Hidden drugs. In 1999 FDA warned against Triax, a product marketed as a metabolic accelerator for weight loss. Triax actually contained an unapproved new drug that affects thyroid function. The distributor currently is embargoed from distributing this product to consumers (FDA, 1999b).
Mislabeled products. In 1997 a young woman was hospitalized with heart block after taking a dietary supplement for laxative purposes. The ingredients list included plantain. Investigation revealed that the entire lot of plantain had been contaminated with digitalis (FDA, 1997c).
Product safety. The National Fish and Wildlife Forensics Laboratory confiscated imported Chinese herbal balls to inspect them for ingredients made from endangered species. All the herbal ball preparations were factory-produced, patented agents. Significant amounts of mercury (7.8 mg-621.3 mg) and arsenic (0.1 mg-36.6 mg) were found in the preparations. The researchers concluded that "most of the herbal ball preparations we examined pose a potentially serious health risk to consumers" (Espinoza, Mann, & Bleasdell, 1995).
As these examples illustrate, there is a need for industry self-regulation in the absence of government controls. For the consumer, learning about the manufacturer should be an important part of choosing a dietary supplement.
Implications for the Stroke Patient
Healthcare professionals always should consider the possibility that patients are using dietary supplements as an adjunct to traditional therapy. Dietary supplements can interact with prescribed medications, cause effects directly related to action of the supplement, or be formulated in such a way that adverse effects and interactions are more likely.
Of the people who suffer a stroke, 72% are older than 65. Approximately 4.5 million stroke survivors are alive today in the United States (American Heart Association & American Stroke Association, 2001). Patients who have had a stroke may use dietary supplements for reasons including economics, tradition, and the hope dietary supplements seem to offer when traditional medicine fails. It is well known that polypharmacy (i.e., administration of an excessive number of drugs) is common in elderly people; it increases the likelihood of an interaction. Toxicity thresholds may be lower in elderly people because of changes in drug metabolism and excretion, and therapeutic indexes may shrink. Many drugs and dietary supplements can precipitate symptoms that mimic pathologies, or they can precipitate a pathologic event.
Ephedrine, an active central nervous system (CNS) agent frequently found in weight loss products, is one dietary supplement whose effects mimic stroke symptoms. Its CNS stimulant properties can cause altered mentation, increased heart rate, trembling, weakness, and paresthesias. Ephedrine also may be associated with the actual stroke event. A search of FDA's voluntary Special Nutritionals Adverse Event Monitoring System for key words specifically chosen for their relationship to stroke revealed associations between ephedrine and weakness (in 11 of 40 reports of weakness), bleeding (in 7 of 35 reports of bleeding), stroke (in 24 of 42 reports of stroke), and intracerebral hemorrhage/cerebrovascular accident/subdural hematoma (in all 4 reports) (FDA, 1998b). FDA reviewed more than 600 pre-1996 adverse events related to ephedrine. Of these events, 56% occurred in people less than 40 years old. This finding prompted a FDA proposal to limit the amount of ephedrine to 8 mg/serving, with a maximum of 24 mg/day. The proposal also suggested that ephedrine should not be combined with other stimulants such as caffeine or yohimbe (FDA, 1997b).
The example of one common, commercially available product underscores the need for consumers and healthcare professionals to be informed about the risks. This product, marketed for weight loss, contains 12 mg of ephedrine and 40 mg of caffeine per tablet. Its directions for use suggest 1 to 2 tablets as often as three times daily--as much as 92 mg ephedrine and 320 mg caffeine daily, more than three times the FDA's recommended limit (Beckwith, 1999; Metabolife International, Inc., 2000).
Warfarin (Coumadin[R]), frequently prescribed for stroke patients, is quite prone to interactions with both pharmaceutical agents and dietary supplements. Its metabolism and unusual mechanism of action contribute to a variety of interactions with varying periods of onset. Warfarin interrupts the vitamin K-dependent process for manufacturing clotting factors in the liver through a competitive inhibition mechanism. Clotting factors VII, IX, II, and X gradually decline over a period of about 3 days. Depending on the nature of the drug interaction, dietary supplements have a delayed effect--augmenting warfarin's natural effect--or an immediate effect--exerting a different effect through a different mechanism (Corrigan & Ulfers, 1981; Megavitamin E Supplementation and Vitamin K-Dependent Carboxylation, 1983; Vitamin K, Vitamin E, and the Coumarin Drugs, 1982).
When dietary supplements are being evaluated for possible interaction with warfarin, it is useful to narrow the field with some preliminary questions: What comorbidities are common in the stroke patient? What dietary supplements would be used in these comorbidities? Two common comorbidities, depression and diabetes, can demonstrate the usefulness of this approach. The incidence of depression is estimated at 30%-60% in the 2-year period following stroke (Hanson, Degraba, Villar-Cordova, & Yatsu, 1998). Wolf and D'Agostino (1998) conclude that "at all ages both men and women with glucose intolerance have approximately double the risk of ABI (atherothrombotic brain infarction) compared with nondiabetics" (page 14). Table 3 summarizes common dietary supplements taken to treat depression that can interact with warfarin. Table 4 summarizes common dietary supplements used to treat diabetes mellitus that can interaction with warfarin. Many of the interactions listed in Tables 3 and 4 are theoretical and should be pursued only in the absence of other, more viable possible causes of the symptoms. For patients with persistent International Normalized Ratio (INR) instability, the entire spectrum of possible causes for warfarin-therapy instability should be catalogued and ranked by probability. Multiple supplements may have additive interactions with warfarin that may contribute to the overall therapy instability.
Vitamin E and garlic supplements are known to affect INR stability. Their use can result in prolongation of the patient's bleeding time in a dose-dependent fashion. Vitamin E acts in the same clotting factor synthesis pathway as warfarin but at a different location (Megavitamin E Supplementation and Vitamin K-Dependent Carboxylation, 1983; Vitamin K, Vitamin E, and the Coumarin Drugs, 1982). Another likely cause of altered INRs is St. John's wort, due to enzyme induction of 2C9. Fish oils also should be looked at because of their synergistic effect with warfarin (through a different mechanism), which can result in prolonged bleeding times. At the bottom of the list of suspects are vitamin C, psyllium, wheat grass, Panax ginseng, and coenzyme Q10. The vitamin K contained in wheat grass is almost negligible in usual doses. The absorptive effects of psyllium are minor at best and, if there is a concern about interaction, can be avoided by giving warfarin and psyllium at least 2 hours apart. Not enough is known about coenzyme Q10 to state anything other than that there possibly is an interaction (coenzyme Q10 is structurally similar to vitamin K) (Natural Medicines Comprehensive Database, 2001). There is a great opportunity for research in this area.
Regulating the anticoagulation therapy of some patients is a challenge to clinicians. A patient's use of unreliable, unregulated supplements may jeopardize safe therapy more than is known.
Mr. H, an 80-year-old white male, experienced left upper-extremity paresis for 2-3 days before seeking medical attention. He presented with left shoulder-to-fingertip tingling and left leg paresis that kept him from walking. A positive Babinski response was found on the left side. He was alert, oriented, and displayed a jovial attitude. His medical history included hypertension, degenerative joint disease, 10 years of benign pro-static hypertrophy with an elevated prostate specific antigen, 60 years of smoking a pack of cigarettes a day, and alcohol intake of 3 drinks a night for about 60 years. His daily medications included lisinopril 20 mg, hydrochlorothiazide 25 mg, terazosin 2 mg, a multivitamin, and enteric-coated aspirin 325 mg. After a workup for stroke causality, he was placed on warfarin in place of enteric-coated aspirin for recurrent stroke prevention and was asked to stop smoking. Mr. H's INR values were kept between 2 and 2.5 until 3 months later, when he experienced a left eye subconjunctival hemorrhage. During an interview he told the nurse that he had discontinued the terazosin and replaced it with one saw-palmetto capsule a day. He also had added magnesium, calcium, zinc, vitamin-B complex, 400 I.U. vitamin E, and garlic tablets to his daily medication regimen, as well as acetaminophen with codeine for arthritis pain. He was asked to discontinue taking the garlic and the vitamin E. The nurse counseled Mr. H not to take any additional over-the-counter supplements or vitamins without conferring with his physician. He agreed not to change his medications while his warfarin dose was being stabilized after his eye cleared.
Mr. H had been stabilized at an INR of 2.2 for 2 months when, for no apparent reason, his INR reached 4.49. A careful interview revealed that he again was taking garlic and had changed the brands of his garlic and saw palmetto supplements.
Mr. H was stabilized on the new supplements. But he continued to follow a pattern of fluctuating normal-to-high INR levels that prompted his primary care physician to discontinue warfarin and reinstitute enteric-coat ed aspirin therapy to avoid recurrent stroke. Whether Mr. H's alcohol intake was fluctuating was unknown. He had returned to cigarette smoking.
Much scientific work remains to be done concerning dietary supplements. The current stage of development of the supplement industry has much in common with the early stages of the pharmaceutical industry. An understanding of the challenges of supplement therapy, as related to current regulations, can help the healthcare practitioner guide patients to an overall therapy in which the risks and benefits of supplement use are taken into consideration and balanced with the treatment goals. With respect to the stroke patient, warfarin, a narrow-therapeutic-index drug, has a plethora of potential and actual supplement interactions. In the absence of an immediately identifiable cause for unstable therapy, monitoring warfarin use in light of supplements the patient may be taking for comorbidities may help in troubleshooting.
Table 1. Brief History of the FDA Year Event Significance 1906 Food and Drug Act The scope of this act is limited to the interstate transfer of drugs that are falsely labeled (misbranded) or had unnecessary components (adulteration). 1937 Elixir of sulfanilamide This was a sentinel event that formulated resulted in the death of 107 persons, mostly children, due to a poorly formulated antibiotic. 1938 Federal Food, Drug, and This act provided that new drugs Cosmetic Act (FDC) must be shown to be safe before marketing, established tolerance levels for necessary poisons, and authorized factory inspections by the government to assess compliance. 1962 The Kefauver-Harris Drug These amendments added the Amendments added to the FDC requirements that manufacturers prove to the FDA that their products are efficacious before marketing them. 1970 Court ruling--Upjohn vs The court ruled that evidence for Finch drug safety and efficacy needs to be established by objective, scientific evidence. Relying on commercial success alone as evidence of a drug's efficacy or safety is insufficient. Source: Food and Drug Administration, 1999c Table 2. Brief History of Modern Dietary Supplement Industry Year Event Significance 1994 Dietary Supplement Health Reclassified agents with previously and Education Act (DSHEA) questionable status such as vitamins, herbs, and amino acids as foods. FDA has authority restricted to label claims and the development of Good Manufacturing Practice (GMP) guidelines. 1997 Proposed GMP Leaves several issues inadequately addressed. A final ruling on dietary supplement GMP is not available as yet. 1999 New labeling requirements Manufacturers are required to have the suggested serving size, the plant part, and all other ingredients declared on the label. 2000 Structure function claims The FDA requires a label that indicates the dietary supplement is not approved by the FDA. Structure/function claims must be approved by the FDA in order to appear on the label. 2010 FDA goals The FDA hopes to have GMP standards for dietary supplements published, an adverse event monitoring system in place, maintain routine compliance activities, develop a broad research agenda, and develop science based standards for studies. Sources: Food and Drug Administration, 1997a, 2000a, 200Ob, 2001; U.S. Department of Health and Human Services, 1999. Table 3. Depression and Dietary Supplements * Agents Used Implications for for Depression Warfarin Proposed Mechanism St. John's Wort Decreased effect Stimulation of cytochrome 2C9, which is responsible for metabolizing a major warfarin racemate Acerola/Vitamin C Antagonistic effect Excessive amounts of vitamin C associated with a procoagulant effect Fish Oils Synergistic effect Presumably through a decrease in platelet aggregation * Condensed from Natural Medicines Comprehensive Database, 2001 Table 4. Diabetes and Dietary Supplements * Agents Used Implications for for Diabetes Warfarin Proposed Mechanism Blond Psyllium Decreased effect Potential decreased GI absorption with concomitant administration. Rose Hip Antagonistic effect Excessive amounts of vitamin C are associated with a procoagulant effect. Wheatgrass Decreased effect Theoretically, the amount of vitamin K ingested may be significant. Coenzyme Q1O Decreased effect Has an action similar to vitamin K. Panax Ginseng Mixed effect Decreases platelet aggregation and exerts a procoagulant effect on the clotting cascade. * Condensed from Natural Medicines Comprehensive Database, 2001
American Heart Association & American Stroke Association. (2001). 2002 heart and stroke statistical update. Retrieved April 2, 2002, from www.americanheart.org
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Corrigan, J., & Ulfers, LL (1981), Effect of vitamin E of prothrombin levels in warfarin-induced vitamin K deficiency. American Journal of Clinical Nutrition, 34, 1701-1705.
Department of Health and Human Services. (1999, March 23). Dietary supplements now labeled with more information. HHS News. Retrieved April 2, 2002, from www.cfsan.fda.gov/~lrd/hhssupp2.html
Espinoza, E., Mann, M.J., & Bleasdell, B. (1995). Arsenic and mercury in traditional Chinese herbal balls. New, England Journal of Medicine, 333, 803-804,
Food and Drug Administration. (1997a, February 6). Current good manufacturing practice in manufacturing, packing, or holding dietary supplements. FDA Proposed Rule 21 (to be codified at 62 C.F.R. 62 5699-5709). Retrieved April 2, 2002, from www.cfsan.fda.gov/~lrd/fr970206.html
Food and Drug Administration. (1997b, June 4). Dietary supplements containing ephedrine alkaloids. FDA Proposed Rule 21 (to be codified at C.F.R. 62 30677-30724). Retrieved April 2, 2002, from www.cfsan.fda.gov/~lrd/fr97064a.html.
Food and Drug Administration. (1997c, June 12). FDA warns consumers against dietary supplement products that may contain digitalis mislabeled as "plantain" [Statement]. Retrieved April 2, 2002, from www.fda.gov/bbs/topics/NEWS/NEW0070.html
Food and Drug Administration. (1998a, August 31). Impurities confirmed in dietary supplement 5-hydroxy-L-tryptophan. FDA Talk Paper. Retrieved April 2, 2002, from www.cfsan.fda.gov/~lrd/tp5htp.html
Food and Drug Administration. (1998b, October 20). SN/AEMS Web report. Retrieved April 2, 2002, from www.cfsan.fda.gov/~dms/aemsfull.html
Food and Drag Administration. (1999a, January) An FDA guide to dietary supplements. FDA Consumer. Retrieved April 2, 2002, from www.cfsan.fda.gov/~dms/fdsupp.html
Food and Drug Administration. (1999b, November). FDA warns against consuming Triax metabolic accelerator. FDA Talk Paper. Retrieved April 2, 2002, from www.cfsan.fda.gov/~lrd/tptriax.html
Food and Drug Administration. (1999c, May 3). Milestones in U.S. food and drug law history. FDA Backgrounder. Retrieved April 2, 2002, www.cfsan.fda.gov/mile stone.html
Food and Drug Administration. (2000a, January). Dietary supplement strategy: Ten-year plan. Retrieved April 2, 2002, from www.cfsan.fda.gov/~dms/ds-strat.html#shalala
Food and Drug Administration. (2000b, January 5). FDA finalizes roles for claims on dietary supplements. FDA Talk Paper. Retrieved April 2, 2002, from www.cfsan.fda.gov/~lrd/tpdsclm.html
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Hahm, H., Kujawa, J., & Augsburger L. (1999). Comparison of melatonin products against USP's nutritional supplements standards and other criteria. Journal of the American Pharmaceutical Association 39(1), 27-31.
Hanson, S., Degraba, T.J., Villar-Cordova, C., & Yatsu, F.M. (1998). Medical complications of stroke. In H.J.M Barnett, J.P. Mohr, & B.N. Stein (Eds.), Stroke: Pathophysiology, Diagnosis, and Management (3rd ed., chapter 49). New York: Churchill Livingstone.
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Metabolife International, Inc. (2000). Frequently asked questions.. What are the ingredients? Retrieved April 2, 2002, from www.metabolife.com/products/356_faq.html
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Wolf, P.A., & D'Agostino, R.B. (1998). Epidemiology of stroke. In H.J.M Barnett, J.P. Mohr, & B.N. Stein (Eds.), Stroke: Pathophysiology, Diagnosis, and Management (3rd ed., chapter 1). New York: Churchill Livingstone.
Questions or comments about this article may be directed to: Michael Van Ornum, RPh RN, American HomePatient, Infusion, 1695 Empire Boulevard, Webster, NY 14580. He is director of infusion at American HomePatient in Webster, NY.
Cheryl Weber, MS CNRN, is a clinical nurse specialist at Rochester General Hospital, Rochester, NY.
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|Author:||Van Ornum, Michael; Weber, Cheryl|
|Publication:||Journal of Neuroscience Nursing|
|Date:||Jun 1, 2002|
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