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amount of red yeast rice sufficient to meet its sales projections. In February 1999, the FDA's ban on the import of red yeast rice was lifted, but it appealed the decision, and the saga is still going on (Israelsen, 1999). At the same time, Merck, which manufactures lovastatin, and Bristol-Myers Squibb, which produces pravastatin, a successful analogue, requested permission to sell to the general public their pharmaceutical-grade products at doses comparable to those found in the red yeast rice extracts (Gorman, 2000). These requests were, however, turned down.

The Cholestin issue will certainly become a test case for the dietary supplement industry, shaping its future legal state. Hopefully, it will also foster interesting research. Thus, at the doses indicated by the producer (2.4g per day, corresponding to c. 10 mg lovastatin), Cholestin contains lovastatin in insufficient quantity for a significant reduction of the cholesterol blood level, which requires dosages of 20—80 mg per day. Nevertheless, a random double-blind study carried out in China on hyperlipi-daemic patients to compare the effects of a Monascus extract and lovastatin, showed a comparable activity. Furthermore, a decrease of the triglyceride level was only observed for the Monascus extract, whose activity apparently increased in the course of the treatment (Chang, 2000). These observations were substantially confirmed in further studies, but larger trials, financially challenging for dietary companies, are needed. The bioavailability of lovastatin as a pure active principle is poor. Only 30 per cent of an oral dose is absorbed, and hepatic activation by hydrolysis to the 8-hydroxy acid form is required for activity (Moghadasian, 1999). It is therefore possible that certain constituents of Monascus extracts boost the bioavailability of lovastatin, which is well known, for instance, to be markedly increased by meals. Another attractive hypothesis is that Monascus constituents like fatty acids and sterols interact in a syner-gistic way with the lipid-lowering properties of statins (Heber, 1999).

Myopathy, the major side-effect of statins, was apparently not observed with Monascus extracts, but the number of patients enrolled in the studies and the low frequency (<0.2 per cent) of this lovastatin side-effect make the observation of limited, if any, value. Lovastatin has teratogenic effects in animals, and is contra-indicated in pregnant women and in women of child-bearing age who might become pregnant. Furthermore, statins were introduced in therapy only in the late 1980s, and their long-term side-effects are not known. The cost of a treatment with Cholestin is only a quarter to a tenth of one with statins, and the 'Cholestin affair' is obviously more than an entangled regulatory matter, opening questions having far-reaching ethical implications.


Purine alkaloids have a rather limited distribution in nature, but are accumulated by the coffee and tea plants, as well as in the seeds of the cacao and cola trees and the leaves of the maté bush (Dewick, 1997). The enormous and global relevance of these plants reflects in the thousands of articles available on all aspects of their history, botany, chemistry, pharmacology and social relevance (Hobhouse, 1987). We will therefore only highlight the biomedical relevance of the two most important dietary purine alkaloids, namely caffeine and theophylline.

Coffee is the most important source of caffeine (12a) in the Western diet, and the 'more than a food, less than a drug' status of this beverage has long been recognized, with the stimulating effects rather than the flavour having largely contributed to its popularity (Wills, 1994). Caffeine is used today mainly in association with antipyretic and antalgics, to treat fever, aches and the symptoms of flu. Caffeine is also employed to increase the intestinal absorption of ergotamine in anti-migraine preparation and, topically, to activate lipolysis and reduce subcutaneous fat deposits (Rall, 1990). Caffeine is efficiently absorbed after oral ingestion, and beverage consumption provides the major route of dietary exposure. A cup of coffee contains from 30 to 150 mg caffeine, depending on the method of preparation and the variety employed. Also tea and cola drinks provide significant amounts of this alkaloid (from 10 to 100 mg per serving) (Wills, 1994). It should be pointed out, however, that the bioavailability of caffeine from a food matrix can be strongly reduced by polyphenols, which are abundant particularly in tea.

Caffeine is readily available as a by-product of the preparation of decaffeinated coffee. Theophylline (12b) is only a minor component of tea leaves and cola nuts, and is more conveniently synthesized than isolated. The major pharmaceutical use of theophylline is for the treatment of acute attacks of asthma and of bronchospasm associated with chronic obstructive pulmonary disease. These applications can be traced back to the seminal observation by Salter in 1860 that strong black coffee can relieve the breathing problems of asthmatic patients. Interestingly, theophylline is much more potent as a bronchodilatator in vivo than in vitro, and one therefore ponders if this important drug might ever have been discovered without the clinical observations on coffee drinkers by the physicians of the nineteenth century (Sneader, 1996). The two best characterized molecular actions of caffeine and theophylline are the antagonism of adenosine and the inhibition of phosphodiesterases. Natural xanthines lack discrimination between the various subclasses of adenosine receptors, but suitable substitution can produce selective agents. They also show phosphodiesterase inhibiting activity, and have served as a lead for the synthesis of analogues, one of which (pentoxyfylline) is currently employed as a peripheral vasodilator (Rall, 1990). The increased knowledge of the molecular mechanism of the activity of xanthines undoubtedly underlies the resurgence of interest in the natural purine alkaloids.

With more than 20 per cent of the human population consuming it daily and almost 8,000 km2 dedicated to its cultivation, chilli pepper (Capsicum annuum L.) is the most popular spice on the planet, and its pungent principle capsaicin (13a) is possibly the most important pharmacological agent we get from our diet (Naj, 1992). No compound better than capsaicin exemplifies the blurred boundaries between food and medicine. Hot pepper contains a mixture of N-acylvanillamides (NAVA) which are responsible for its pungent taste and most of the pharmacological activity traditionally

Me 12a

Me 12b

Capsaicine ascribed to this spice. The contents of NAVA depends on the variety of pepper, and can reach 1 per cent in the variety Habanero. The major (c. 50 per cent) NAVA of hot pepper is capsaicin, a compound first isolated from chilli in 1849. Among the analogues, the dihydro derivative (13b) and the nordihydro derivative are the most abundant (c.35 per cent and 7 per cent, respectively) (Suzuki and Iwai, 1984), but the so-called synthetic capsaicin (N-pelargonylvanillamide or nonivamide, 13c) has also been isolated from the chilli oleoresin (Constant et al., 1996). Interestingly, these compounds are replaced by the corresponding non-pungent esters (capsiates) in sweet pepper, where, apparently, transamination of vanillin is blocked, while the polyketide route to extend a valine starter is still operative.

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