science/technology
END RUN AROUND FDA? Memory enhancer that works like Alzheimer's drugs is being sold via the Internet and will be marketed in stores as 'nutraceutical' StuBorman C&EN Washington
T
he over-the-counter sale of huperzine A, a natural product with an activity similar to that of two commercial Alzheimer's therapeutics, is riling some Alzheimer's researchers and clinicians. The plant extract, considered to be a potential treatment for Alzheimer's disease, is being made commercially available in the U.S. without having undergone any human clinical trials in the U.S. Huperzine A, an alkaloid extracted from the leaves of the Chinese club moss plant Huperzia serrata, is already being sold over the Internet by PanoLife Products, Mountain View, Calif. And another company, Nutrapharm, New York City, plans to market it as a dietary supplement, or "nutraceutical," at stores that sell vitamin and nutrition products. It will thus be widely accessible to Alzheimer's disease patients. The release of the compound as a nutraceutical is totally legal and aboveboard. Under current law, natural products generally can be sold as over-thecounter dietary supplements without a prescription, providing they are safe and the product packaging does not characterize them as disease treatments. Huperzine A has been shown in clinical trials in China to improve memory and cognition. It has been used in China as a traditional folk medicine to treat fever and inflammation and is now commercially available there as a prescription drug for dementia. It acts by inhibiting the enzyme acetylcholinesterase—a mechanism of action shared by Cognex (tacrine) and Aricept (donepezil), the two major commercial Alzheimer's disease drugs. Alzheimer's—a progressive and ultimately fatal disease that impairs memory, reasoning, and behavior—is characterized by abnormally low brain levels of
acetylcholine, a neurotransmitter involved in learning and memory. Acetylcholinesterase catalyzes acetylcholine breakdown. Drugs like tacrine and donepezil inhibit the enzyme, boosting acetylcholine levels and thus improving the memory and cognition of some Alzheimer's patients. Huperzine, which acts similarly, will now be available without prescription to Alzheimer's patients and to others interested in improving their cognition. "This is really very different from the usual way drugs are provided for Alzheimer's patients," comments Neil Buckholtz, chief of the dementias of aging branch of the neuroscience program at the National Institute on Aging, in Bethesda, Md. "Huperzine seems to be, from what I understand, about as potent as tacrine or [donepezil], and yet it's going to be provided to people without the same kind of clinical trial background as the other compounds have. . . . Since huperzine is a plant product, there's nothing, as I understand it, to stop the company from doing this. But look at Taxol—it's a plant product, but would you want people to be able to buy it at GNC?" GNC is a chain of stores that sells health foods and dietary supplements.
Structure determined by Sussman and coworkers shows huperzine A (green, purple, and orange) bound to acetylcholinesterase (gold). Image by Shaomeng Wang and Xiongwu Wu of the Drug Discovery Program, Georgetown University Medical Center
Kenneth L. Davis, chairman of the department of psychiatry and director of the Alzheimer's disease research center at Mount Sinai School of Medicine, Bronx, N.Y., says: "I think this is very sad. This is a clear attempt to go around the regulatory process for a compound that is quite clearly a drug. As a consequence, this drug has not been tested, its efficacy has not been established, and it doesn't have to meet the usual efficacy and stability standards." What is even more troubling, says Davis, "is that a drug that is a cholinesterase inhibitor—a potent compound that can have serious adverse effects and can even be life-threatening—will be readily available without instruction over the counter. It can very well wind up being combined with drugs like donepezil by people who think they are going to get enhanced efficacy from a natural product plus a drug," and the resulting drug interaction can potentially be toxic. "This is a very dangerous circumstance." The commercial release of huperzine A to stores is being carried out by Nutrapharm (http://www.nutrapharm.com). The product, tradenamed Cerebra, will be marketed as softgel capsules. Nutrapharm is a joint venture of the pharmaceutical company Hi-Tech Pharmacal, Amityville, N.Y., and the trading firm Marco International, New York City. Nutrapharm carried out a short-term 20-person human tolerance study of huperzine, looking for possible side effects, and found none. Cerebra contains purified huperzine A, not simply a crude extract of the Chinese club moss plant. Chinese research has shown that other components found in crude extracts of Huperzia serrata interfere with the activity of huperzine. Nutrapharm President Reuben Seltzer says, "We have long-term supply agreements with the three major Chinese producers of huperzine and a patent position on the synthetic side, giving us control of the sourcing of huperzine." Nevertheless, PanoLife Products also is marketing Huperazon—a formulation of huperzine, gingko biloba, and ginseng extract—over the Internet. According to the company's web page (http://www. pano.com/), Huperazon is appropriate for "anyone who could benefit from improved cognitive functioning—in particular, individuals showing signs of dementia, memory loss, or concentration problems." Alan P. Kozikowski, director of the Drug Discovery Program at Georgetown University Medical Center, Washington, JUNE 1, 1998 C&EN 45
science/technology D.C., and a consultant to Nutrapharm, has played a key role in the development of huperzine. He achieved the first total synthesis of the compound when he was a chemistry professor at the University of Pittsburgh [/. Am. Chem. Soc, 111, 4116 (1989)] and has used this method to synthesize analogs. The X-ray structure of huperzine in complex with acetylcholinesterase was reported last year by crystallographer Joel Sussman and coworkers at Weizmann Institute of Science, Rehovot, Israel, working in collaboration with Kozikowski [Nat. Struct. Biol, 4, 57 (1997)]. Kozikowski continues to work on huperzine derivatives. "We have developed new analogs that are more potent than the natural product," he says. "Those are going to go through the full IND [investigational new drug] clinical trials process. The funding for those trials is probably going to come from a rather substantial drug company." According to Kozikowski, many Alzheimer's patients are interested in getting hold of huperzine. "A woman in New York City who obtained the material . . .
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Huperzine A
has had her husband using it under a physician's care for two years with good effects," he says. "But anyone who is feeling some problem with memory recall will probably want it. I have many boxes in my office, and I've tried it myself. It does make you feel more alert." Did Nutrapharm want to put huperzine through clinical trials? "Here's a natural product for which you'd have to put up $50 million to pay for U.S. clinical trials," says Kozikowski, "whereas, since it's a natural product from a club moss, you could just take it and sell it as a nutraceutical. It's most cost-effective, and [Nutrapharm] wanted to get it out there to help the patients. For safety reasons, [it] paid
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for the human tolerance study, but [the firm was] not required to do that." Pharmacological, animal-testing, and clinical data from China show that huperzine A is a good acetylcholinesterase inhib itor. Xi-Can Tang of the department of pharmacology at Shanghai Institute of Materia Medica reported in a 1996 review article that huperzine A "has good penetration through the blood-brain barrier, high oral bioavailability, and longer duration of inhibitory action on acetylcholinesterase [compared with tacrine]. Animal and clinical studies showed that huperzine A was devoid of unexpected toxicity, particularly the dose-limiting hepatotoxicity produced by tacrine. These findings suggest that huperzine A is a promising candidate for palliating therapy of cognitive deficits in patients with Alzheimer's disease." Herbal remedies and other natural products can be sold in the U.S. without having to clear the stringent hurdles the Food & Drug Administration sets for new drugs—providing the seller doesn't claim the supplements cure or prevent disease. According to consumer safety officer Jeanne Latham of FDA's Division of Pro-
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grams & Enforcement Policy: "Dietary supplements are regulated under the Federal Food, Drug & Cosmetic Act, as amended by the Dietary Supplement Health & Education Act of 1994 (DSHEA), and under the Fair Packaging & Labeling Act. There is generally no requirement that a firm obtain a license or approval from FDA before marketing dietary supplements in the U.S." DSHEA defines dietary supplement as "a product (other than tobacco) intended to supplement the diet, that contains one or more of certain dietary ingredients, such as a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract, or combination of the preceding ingredients." The term dietary supplement does not include products that are approved drugs or have been authorized for investigation as new drugs, unless the product was marketed as a dietary supplement prior to approval of the drug or before publicly disclosed clinical trials began.
DSHEA regulations proposed in late April [Fed. Regis., 63, 23623 (1998)] specify that dietary supplements can be labeled with "structure/function" claims, such as "improves cognition" or "supports the immune system," but not with claims for the treatment, diagnosis, cure, or prevention of disease, such as "protects against cancer" or "reduces nausea associated with chemotherapy." In the case of Nutrapharm's Cerebra product, no claims for treatment of Alzheimer's disease are being made on the label. Instead, the packaging will refer to enhancements in "focus, memory, and concentration," according to Nutrapharm Vice President Alan Kestenbaum. Two weeks ago, FDA banned the sale of Cholestin, a natural dietary supplement marketed by Pharmanex, Simi Valley, Calif. Cholestin contains mevinolin, a compound chemically identical to lovastatin, the cholesterol-lowering active ingredient in the prescription drug Mevacor marketed by Merck, Whitehouse Station, N.J. Pharmanex is challenging FDA's decision in court. It contends that mevinolin, which is produced by fermen-
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tation of Chinese red yeast rice, is distinct from lovastatin, which is made synthetically and then isolated, purified, and crystallized. Huperzine represents a fundamentally different issue because it has never been approved as a drug in the U.S. and thus is not subject to FDA action. Asked to comment on huperzine's commercial release, Leon Thai, chairman of the department of neurosciences at the University of California, San Diego, says that like Buckholtz and Davis, he too is alarmed that it will be available over the counter. "I think it is most likely an active agent that will require physician monitoring," he says. "I am not sure that we can do anything except alert the Alzheimer's community that this is a drug derivedfroma plant that has potent pharmacological activity." Thai adds, "The only thing that one can do is petition Congress to change the law. I think it's unreasonable for FDA to allow these kinds of compounds to be marketed. The problem is that it's not within their regulatory purview to prevent it. So I think we're stuck."^
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