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Editorials |
Dietary supplements, used widely by Americans, are regulated by the Dietary Supplement Health and Education Act of 1994 (1), an amendment to the Federal Food, Drug and Cosmetic Act. The Dietary Supplement Health and Education Act provides that any product marketed as a dietary supplement cannot contain an article that is approved as a new drug unless the product was marketed before the drug's approval. Any component of the product may be considered to be an article. Evidently, the law is intended to maintain the incentive for pharmaceutical companies to bring new drugs to market, a process that involves extensive and expensive preclinical and clinical evaluations.
In this issue of the Journal, Heber et al (2) report on a clinical trial of Cholestin (Pharmanex, Simi Valley, CA), a product related to red yeast rice. Red yeast rice has been used in China as a food colorant and flavor enhancer for centuries. Another related Chinese product, Xuezhikang, has been shown to lower plasma cholesterol concentrations. In the current double-blind clinical trial, 83 men and women with above average LDL-cholesterol concentrations were randomly assigned to receive Cholestin (4 capsules containing 2.4 g product) or rice powder placebo capsules for 12 wk. On average, LDL-cholesterol concentrations were reduced by 22% in those assigned to Cholestin and by 1% in those assigned to placebo after 12 wk of supplementation. Cholestin contains, by weight, 0.4% 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors of the statin class, and the authors conclude that "the reduced costs of the red yeast rice dietary supplement compared with prescription drugs could provide a new and novel approach for the maintenance of healthier cholesterol concentrations," as applied to the prevention of coronary artery disease.
Cholestin is currently sold in this country as a dietary supplement for healthy adults. The package insert instructs the user not to take more than 2 capsules twice daily (2.4 g) and warns of the possibility of toxicity of HMGCoA inhibitors of the statin class, including "diseases of the liver and skeletal muscle." The package insert states that Cholestin is intended to maintain "desirable cholesterol levels" and not to "diagnose, treat, cure or prevent any disease" (to conform with the Dietary Supplement Health and Education Act). The package insert notes that "too much cholesterol in your blood results in excess build-up on the walls of arteries" that "restricts or may even block the flow of blood" and "that's why blood cholesterol plays an important part in deciding your risk of getting coronary heart disease." The package insert also states: "The proprietary all-natural ingredient in Cholestin has been clinically proven in studies involving thousands of people at various dosages to promote healthy cholesterol concentrations by its ability to lower total cholesterol, lower LDL `bad' cholesterol and triglyceride levels, and to increase HDL `good' cholesterol levels."
On May 20, 1998, the Food and Drug Administration announced its conclusion that Cholestin is not a dietary supplement, but rather "an unapproved drug under the terms of the Federal Food, Drug and Cosmetic Act" (3). Pharmanex, Inc, the manufacturer of Cholestin, challenged this decision in Federal District Court, which (according to a press release) issued a preliminary decision on June 16, l998, stating that Cholestin is a dietary supplement and not a drug. The case, which has broad implications for the regulation of the dietary supplement industry, remains under litigation at this time.
Data provided in the report of Heber et al (2) indicate that Cholestin contains a large number of monacolins, ie, compounds of the statin class. Approximately three-quarters of the total complement of statins is monacolin K in its lactone or hydroxy-acid form, also known as lovastatin. The lactone form is marketed by Merck & Co, Inc, as Mevinolin. The remainder reportedly consists of other monacolins (I–VI), present in much smaller amounts. Heber et al state that "The quantities of the family of inhibitors of HMGCoA reductase contained in red yeast rice are inadequate to explain the magnitude of the lowering of cholesterol observed in this study." The amount of statins in 2.4 g Cholestin is 
10 mg. This amount of Mevinolin, taken once daily, was found in a study of patients with heterozygous familial hypercholesterolemia to reduce LDL cholesterol by 17% (4). If the other statin compounds in Cholestin are equal in activity to lovastatin, the total complement of reductase inhibitors evidently accounts for most of the product's cholesterol-lowering action.
Cholestin and Xuezhikang differ from the traditional red yeast rice that is sold in Chinese groceries. The latter contains undetectable or, at best, much lower amounts of lovastatin or other compounds of the statin class (5). Red yeast rice is prepared by growing red yeast (Monascus purpureus) on rice to produce a red-colored product. According to Heber et al (2), typical daily consumption is in the range of 14–55 g in many Asian countries. Consumption of statins from nonproprietary red yeast rice can nonetheless be presumed to be very low. Cholestin is manufactured by growing a single strain of M. purpureus on rice under carefully controlled conditions that increase the statin content, which is monitored during production (5). The product, containing 0.4% by weight of statin compounds, is then sterilized, dried, and powdered.
The May 20, 1998, ruling of the Food and Drug Administration did not address the safety of Cholestin. Heber et al (2) cite animal toxicity studies indicating no adverse effects of large amounts of Xuezhikang on liver function tests in rats treated for 90 d. However, no data are available on the short- or long-term toxicity of the individual statins contained in Cholestin except for lovastatin. Compactin, the first statin discovered by Endo (6) in Japan, was withdrawn by the manufacturer during phase 2 trials for unclear reasons. Compactin has one less methyl group than lovastatin. Heber et al (2) call for a study of the long-term safety of Cholestin in a larger number of individuals. Meanwhile, the product is for sale in more than 35000 stores (7).
As indicated earlier, the outcome of the litigation surrounding Cholestin may have wide ramifications. Interested readers owe it to themselves to become informed about the issues under dispute and to address them in appropriate venues.
FOOTNOTES
1 From the Cardiovascular Research Institute, University of California, San Francisco.
2 Address reprint requests to RJ Havel, Cardiovascular Research Institute, University of California, 505 Parnassus Avenue, San Francisco, CA 94143. E-mail: havelr{at}itsa.ucsf.edu.
3 RJ Havel was a member of the Scientific Advisory Board of Merck Therapeutic Institute from 1985 to 1990 and has participated in clinical trials of lovastatin sponsored by Merck & Co, Inc. He has no financial interest in Merck & Co, Inc or any other pharmaceutical company involved in the development or manufacture of lipid-lowering drugs.
REFERENCES
This article has been cited by other articles:
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  C.-C. Lin, T.-C. Li, and M.-M. Lai Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia Eur. J. Endocrinol., November 1, 2005; 153(5): 679 - 686. [Abstract] [Full Text] [PDF]
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 D. Heber Dietary supplement or drug? The case for Cholestin Am. J. Clinical Nutrition, July 1, 1999; 70(1): 106 - 106. [Full Text]
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R. Havel Reply to D Heber Am. J. Clinical Nutrition, July 1, 1999; 70(1): 106a - 108. [Full Text]
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