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Letters to the Editor |
University of California, San Francisco Cardiovascular Research Institute 505 Parnassus Avenue, L1337 San Francisco, CA 94143-0130 E-mail: havelr{at}itsa.ucsf.edu
Dear Sir:
In his response to my editorial (1) concerning his recent article (2), Heber complains that I failed to deal with the merits of his paper. The purpose of my editorial, however, was to call attention to the litigation between Pharmanex, Inc, Simi Valley, CA (the manufacturer of Cholestin, the supplement studied by Heber et al), and the US Food and Drug Administration (FDA). The litigation concerns the administrative FDA ruling that Cholestin is a drug and not a food supplement under the Dietary Supplement Health and Education Act of 1994 (3). Cholestin contains sufficient statin compounds, principally monacolin K (also known as lovastatin) to appreciably alter cholesterol metabolism and lower plasma cholesterol concentrations, as documented by Heber et al (2).
Heber takes issue with 2 "facts" that are major points in my editorial. The first concerns the issue of litigation. Heber believes that my statement that "Cholestin is manufactured...under carefully controlled conditions that increase the statin content, which is monitored during production," is "incorrect." Rather, he maintains that "the strain [of Monascus purpureus] is selected as one that produces a family of monacolins, one of which is related to lovastatin." My editorial referenced Public Docket no. 97P-0441, which is accessible on the World Wide Web. The decision of the FDA contained therein is in a lengthy letter from William B Schultz, Deputy Commissioner for Policy of the FDA, to Stuart M Pape, an attorney for Pharmanex, Inc. The letter cites a company promotional document indicating that Pharmanex developed its own "proprietary process" in 1993 to make a red-yeast-rice product containing amounts of lovastatin that could "maximize red yeast's health-enhancing properties." The letter goes on to cite 3 ways in which this has been done.
"First, Pharmanex is deliberately controlling temperature conditions during the manufacturing process to promote consistently high levels of lovastatin in Cholestin... Key factors for production [are] both temperature and oxygen tension." (The letter cites data indicating that little or no lovastatin is produced by M. purpureus at temperatures 
30°C and that the optimum temperature for statin production is 
25°C.) "Second, Pharmanex tracks the level of HMG-CoA [ß-hydroxy-ß-methylglutaryl-CoA] reductase inhibitors in Cholestin, of which lovastatin is the most abundant, during the production process. This tracking ensures significant levels of the drug in the final Cholestin product." (The letter points out that the HMG-CoA inhibitors in Cholestin are secondary metabolites, the concentrations of which "do not follow fungal growth," contrary to the company's statement that it does the monitoring as "a biochemical marker with which to monitor the level of yeast.") "Third, Pharmanex's careful selection of a particular fungal strain to manufacture Cholestin indicates that the company seeks to manufacture lovastatin. Only select strains of Monascus fungus are capable of producing lovastatin." The letter goes on to state that "Pharmanex itself has admitted that Cholestin is not traditional red yeast rice." It points out that traditional red yeast rice is made from a mixture of strains, and, notably, that traditional red yeast rice contains little or no material of the statin class. Data contained in the letter indicate that the content of statins produced by M. purpureus is inversely related to the content of red pigment. Thus, Cholestin would not be suitable for the traditional purposes of red yeast rice.
My own calculations show that the average content of lovastatin in 33 samples of traditional red yeast rice tested by the FDA was 3% of the amount contained in Cholestin (30 samples contained no detectable amount). Finally, the letter includes the following summary statement: "FDA does not believe that...Cholestin is traditional red yeast rice. This conclusion is supported by evidence in the record indicating that: (1) Cholestin was developed in l993 pursuant to a proprietary process, while traditional red yeast rice has existed for centuries; (2) traditional red yeast rice comes from a mixture of fungal strains while Cholestin is manufactured from only one fungal strain; (3) traditional red yeast rice contains pigments, which indicates that the traditional product does not contain significant levels of lovastatin, as does Cholestin; (4) traditional red yeast rice is fermented at temperatures that preclude the production of significant levels of lovastatin, such as those found in Cholestin; and (5) test results indicate that traditional red yeast rice on the market today does not contain lovastatin at the levels found in Cholestin, if at all." This evidence fully supports the statement in my editorial that is now challenged by Heber.
The decision of the FDA contained in Public Docket no. 97P-0441 was recently overturned by the US District Court for the District of Utah (4). The court based its decision on a particular interpretation of the meaning of terms in the Dietary Supplement Health and Education Act of 1994 and not on any distinction between Cholestin and traditional red yeast rice. I believe that the court's decision, if sustained, will materially affect the production and marketing of food supplements in this country.
Concerning the second "fact" that Heber takes issue with, he states that I misinterpreted the statin content of Cholestin and that my "comparison of the cholesterol-lowering effects of the dietary supplement with those of 10 mg lovastatin...is inappropriate." Heber erroneously states that a more appropriate comparison would be with "monacolin K, of which there is only 5 mg per tablet." Actually, there is 5 mg monacolin K in 4 tablets of Cholestin, which comprises about one-half of the total amount of statin compounds. However, my statement, "The amount of statins in 2.4 g Cholestin is 10 mg." is correct. Furthermore, I indicated that "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." I stand by this statement.
Heber states, "Because this dietary supplement is based on a traditional Asian food, it is reasonable to assume that it is safe..." However, the safety of the several monacolins in Cholestin other than lovastatin is unknown. Furthermore, lovastatin has low bioavailability, related to intestinal CYP3A enzymes, which are subject to inhibition not only by several other drugs, but also by grapefruit juice. In a recent study, prior ingestion of large amounts of grapefruit juice increased serum concentrations of lovastatin 5–20-fold (5). Interactions between monacolins and grapefruit juice and several drugs have the potential for serious adverse consequences, such as rhabdomyolysis, for persons taking Cholestin (but not traditional red yeast rice). I sympathize with Heber's concern about his patients, but I do not believe that a preparation that contains significant amounts of HMG-CoA reductase inhibitors should be available to people who may not be under medical supervision.
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