Standardization of Herbal Medicines
Standardization of Herbal Medicines
July 1999; Volume 1: 57-59
By Dennis V.C. Awang, PhD, FCIC
Manufacturers of herbal products commonly purvey "standardized" extracts, often with the implied promise of guaranteed potency. Physicians who use botanical medicines want to be assured of consistent high quality, efficacious products, and comparable responses from the same dose of an herbal product.
However, ensuring the potency of herbal products is much more complicated than ensuring the potency of drugs. Standardization of conventional drugs normally indicates a guaranteed range of concentration of the known active ingredient, for which a clear dose-effect relationship has been established. After the expiration date for a given lot, the percentage of the active ingredient is expected to decline below a value sufficient to ensure a satisfactory therapeutic effect.
With herbal products, the identity of the plant’s active constituent (or constituents) rarely is clearly established. Herbs contain hundreds of compounds, often ranging between extremes of hydrophilicity (water-solubility) and lipophilicity (fat-solubility). In herbal medicine, an herb’s actions often are known long before a mechanism of action and the entities responsible for its activity are clarified. Often, numerous compounds are active to different degrees. There is relatively little research in this complex area; characteristically, advances in research cause emphasis to shift among the wide variety of classes of compounds, as well as their individual components.
Standardizing to known active compounds is sometimes impossible and may not always be necessary. Occasionally nature provides a plant with uniquely characterizing secondary compounds (e.g., ginkgolides in Ginkgo biloba), but this is an exception. The presence of "marker" compounds, even if they are known to be inactive, can be used to support botanical identity. Also, the presence of marker compounds (at levels consistent with those normally observed in efficacious preparations) can be a useful quality control parameter.
Echinacea, St. John’s wort, and ginseng are three of the most popular herbal preparations sold in "standardized" preparations. Echinacea is used to mitigate cold and flu symptoms; ginseng is used as a tonic/adaptogen; and St. John’s wort is used to relieve mild or moderate depression. The cases of echinacea, St. John’s wort, and ginseng serve admirably to illustrate the complexity of applying a drug-like standardization concept to herbal medications.
Echinacea1,2
Standardizing echinacea to an active compound or group of compounds is difficult because the claimed immunomodulatory effects of preparations of the three commercial echinacea species (E. purpurea, E. angustifolia, and E. pallida) have been said to reside in five classes of constituents, namely, caffeic acid derivatives ("total phenolics"), alkylamides, "polyacetylenes" (ketoalkenes/ketoalkynes), glycoproteins, and polysaccharides. Although alkylamides are widely regarded to be the most active chemical complement, it is unclear which of the alkylamides in echinacea root extracts should be used for standardization or whether (and how) the demonstrated in vitro activity of isolated alkylamides (phagocytotic or enzyme inhibitory effects) is related to the medicinal effect. In the language of Professor Rudolf Bauer (University of Dusseldorf), "the most effective constituent remains to be found." While it would be easy to standardize the extract to the most dominant alkylamide (the dodecatetraenoic acid isobutylamide 10-E/Z isomeric pair), that makes little sense because this compound exhibits only weak activity. In addition, the alkylamides of E. purpurea are structurally different from those in E. angustifolia. Lipophilic (chloroform) extracts of the three species exhibit identical activities to the granulocyte smear test, even though E. pallida root contains no alkylamides.
In Germany, most of the clinical research on echinacea has focused on the freshly expressed juice of aerial parts of E. purpurea, often administered parenterally. Other prominent commercial preparations include root extracts of E. angustifolia and E. purpurea. Cichoric acid, the caffeic acid derivative, is regarded as perhaps the most active constituent of fresh squeezed juice preparations (the predominant effect of caffeic acid derivatives appears to be antioxidant). Although it would be possible to standardize E. purpurea preparations to cichoric acid, it would be unsuitable for standardizing extracts made from the roots of E. angustifolia because cichoric acid is present only in trace amounts in the root extracts.
Echinacoside, another caffeic acid derivative, is often used to "standardize" commercial echinacea preparations. However, although echinacoside is present in the roots of E. angustifolia and E. pallida, it is almost absent in the roots of E. purpurea. Also, it has been reported by Bauer and associates to lack immunostimulatory effect.
Other unsatisfactory options for standardizing echinacea include ketodialkenes and ketodialkynes; these dominate the lipophilic complement of E. pallida roots but are absent from the roots of E. angustifolia and E. purpurea. Hydrophilic polysaccharides and glycoproteins are present most prominently in echinacea-expressed juice, and in extracts of its aerial parts; lesser concentrations exist in the plant roots. These compounds would be unacceptable as marker compounds, however, because of the differences in preparations available in Europe and North America. These high molecular weight polymeric substances may only be bioavailable in parenterally administered preparations. (Parenteral preparations of echinacea have been common in Germany but are not available commercially in North America.) Oral administration would be expected to result in breakdown of these products. Also, athough extracts with a high alcohol content are popular in North America, high alcohol concentrations lead to appreciable precipitation and subsequent unavailability of these compounds.
In light of the above complexity, standardization of echinacea preparations for therapeutic effect appears to be a truly daunting proposition. Extensive chemical characterization of clinically efficacious preparations appears to be the only sensible path to pursue toward that objective.
Ginseng3
While the traditional Chinese preparation of ginseng (the root of Panax species) is a hot water infusion of ginseng, modern preparations of the plant are dominated by alcoholic root extracts. These alcohol-based extracts, relative to aqueous extracts, are richer in the characteristic triterpene saponins called ginsenosides, and deficient in more polar constituents such as polysaccharides, peptides, and other protein-like factors.
There are more than 30 of the so-called ginsenosides; there are eight major representatives, many of which have demonstrated some pharmacologic activity (for example, Rg1 has a mild CNS stimulant activity, while Rb1 demonstrates CNS depressant activity). Traditional Chinese Medicine practitioners have always held that North American and Asian species of Panax are very different and cannot be substituted for each other. In energetic terms Asian ginseng is perceived as hot (yang) and North American ginseng as cool (yin); differences may in fact be due to different ratios of these ginsenosides. Even without that controversy, commercial ginseng preparations do contain different components than traditional preparations. Some argue that the tonic benefit associated with traditional preparations (either a boiled infusion or mastication of the whole ginseng root) cannot be confidently expected from commercial alcohol ginseng root extracts enhanced for ginsenoside content.
St. John’s Wort4
Hypericin has long been thought to be the main active compound in St. John’s wort; however, recent research indicates that hyperforin may be the prime active principle. Most trials of St. John’s wort have been done with extracts standardized to 0.3% hypericin. In fact, the 0.3% hypericin standard is less standard than it appears because analysis is done by several methods: "hypericin" may represent HPLC determination of hypericin (the gold standard) or the much less specific UV determination of total hypericins.
Hyperforin-standardized extracts are available and are usually standardized to a level of 3%. Hypericin-standardized extracts may contain hyperforin, and hyperforin-standardized extracts probably contain hypericin. In general, it is preferable to standardize to the currently recognized most active principles. Recently, flavonoids such as amentoflavone have received consideration as possible active compounds.
Conclusion
It seems clear that the promise of herbal standardization is very far from realization. As the respected Swiss researcher, Otto Sticher, has noted: "The standardization (chemical) of phytomedicines serves primarily as a precaution for the quality of medicinal plant extracts."5 The worthy goal of standardization, i.e., to achieve a consistent level of the main therapeutically effective active plant constituent, remains remote. The only scientifically sound approach is to continually refine our efforts at chemical characterization, bioactivity assessment, and correlation with clinical end points.
Beyond all of this, there is a dire need, particularly in North America, for the establishment of certification processes for the assurance of the botanical identity of commercial plant products, and for a program of periodic analytical testing of marketed materials for quality and strength.
References
1. Bauer R. "Echinacea: Biological effects and active principles." In: Lawson LD, Bauer R, eds. Phytomedicines of Europe. Chemistry and Biological Activity. Washington, DC: American Chemical Society; 1988; 140-157.
2. Bauer R, Wagner H. "Echinacea species as potential immunostimulatory drugs." In: Wagner H, Farnsworth NR, eds. Economic and Medicinal Plant Research. Vol. 5. New York, NY: Academic Press; 1991;253-321.
3. Shibata S, et al. "Chemistry and pharmacology of Panax." In: Wagner H, et al, eds. Economic and Medicinal Plant Research. Vol. 1. New York, NY: Academic Press; 1985; 227-283.
4. American Herbal Pharmacopoeia. St. John’s Wort Monograph. Santa Cruz, CA; 1998.
5. Sticher O. Quality of ginkgo preparations. Planta Medica 1993;59:2-11.
The presence of "marker" compounds, even if they are known to be inactive, can be used to support botanical identity.
a. True
b. False
Recent research indicates that the prime active compound in St. John’s wort is:
a. hypericin.
b. hyperforin.
c. amentoflavone.
The goal of standardization is to achieve a consistent level of the main therapeutically effective active plant constituent.
a. True
b. False
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