American mayapple and Podophyllotoxin Podophyllum peltatum / Berberidaceae
American mandrake or American mayapple is a poisonous weed which was commonly used in many regions of North America for many centuries. Its main use (e.g., by the Cherokee, Delaware, Iroquois) was as a laxative and the resin had been included in the American pharmacopoeia of 1820 for this purpose. Another use for the resin is the treatment of warts. It is one of the main sources of podophyllotoxin, a lignan which has resulted in semisynthetic derivatives essential in the chemotherapy, for example, of leukemia, especially teniposide, which was introduced into clinical use in 1967. It is well known that this substance revolutionized the chemotherapy of leukemia and has saved untold numbers of young lives.
Californian yew, Pacific yew Taxus brevifolia / Taxaceae
Taxus brevifolia or Californian yew has been used by a variety of West-American Indian groups in the United States and Canada as a medicine, and also for producing a variety of other useful products (canoes, brooms, combs). Very diverse pharmaceutical uses of the root and the bark are recorded and include several reports of the treatment of stomachache and, in the case of the Tsimshian (British Columbia, Canada), the treatment of cancer.
However, this ethnobotanical information was not the basis for the development of a pharmaceutical product. In 1962 several samples of Taxus brevifolia were collected at random for the National Cancer Institute (NCI, United States) and the United States Department of Agriculture. These samples were included in a large screening program at the NCI. A potent cytotoxic effect was documented in one in vitro system. However, the in vivo effects (especially in cases of leukemia) were less promising and demonstrated a general toxicity of the samples. Bioassay-guided fraction-ation led to the isolation of 0.5 g of an active substance from a total of 12 kg of bark. The substance was named taxol. It took from 1961 until 1971 to establish the compound’s structure. It is a diterpenoid with fifteen carbon atoms forming a complex ring system — a pentadecene ring system.
Clinical studies started 13 years later in 1984. Prior to this, studies on the compound’s toxicology and the pharmacological mechanism of its action were conducted. It took a further ten years before taxol was approved in the treatment of anthracyclin-resistant metastasis-forming breast cancers. In the meantime the compound has been approved for a variety of other cancers, and semisynthetic derivatives are now also employed.
Some fascinating questions arise out of the use of this species and the compound isolated from it:
• Taxus brevifolia is a very slow-growing species and produces the relevant active ingredients only in very small amounts. Because taxol was isolated from the bark for many years, the trees had to be felled in order to obtain the botanical drug. The amount of taxol required to cover the annual therapy requirements of patients with ovarian cancer in the United States is estimated to be 15-20 kg. If other cancers common in the United States are to be treated with this compound, around 200 to 300 kg will be required per year. This amount can only be isolated from approximately 1.45 thousand tons of bark. Collecting such amounts would have been completely unsustainable and would have resulted in the extinction of the species within a few years. In the 1990s the semisynthetic production of taxol from natural products in other Taxus species (10-desacetylbaccatin II isolated from the European yew, Taxus baccata) enabled the production of large amounts of taxol. Up to this point an enormous conflict of interests between conservation and medicine/pharmacy was unavoidable. An alternative proposal is the production of taxol in in vitro plant cell cultures Goodman and Walsh (2001) have discussed the economic and political rise and fall of the Californian yew as a source of taxol in great detail.
This example again raises a series of important questions:
• Californian yew is native to a region in the main industrial power of the temperate zones. What sort of consequences would these studies have had if the species had been from a “developing” country? And specifically, what would have happened with respect to this conflict between conservation and medicine/pharmacy?
• Today the drug is produced from the needles of another species of Taxus — T. baccata — and more and more is produced biochemically in large-scale fermenting processes. The Californian yew is no longer needed for the production of the drug and this has also meant that the local economy no longer profits from this drug first developed from a native tree. What means are there to assure adequate benefit-sharing between the regions of origin and the industrial partners?
Echinacea Echinacea angustifolia / Asteraceae
Species of echinacea have been used widely in the indigenous medical systems of North America. Particularly common is the use of E. augustifolia — indigenous groups in North America frequently used it in the treatment of pain and, topically, of inflammatory skin conditions. The following uses of E. angustifolia by the Winnibago tribe (modern Wisconsin, United States) were recorded.
- The juice serves as a remedy for pain and for treating burns (several reports).
- The species is used, in the form of incense, in the treatment of headache.
- It is an antidote for snakebites.
- Topical applications of a compress are used for treatment of enlarged lymph nodes (mumps).
- It is applied topically for treatment of toothache.
- It is used as a veterinary medicine for horses suffering from distemper.
According to Bauer, the various species of this genus were used ethnopharmaceutically all over their natural area. In the second half of the 19th century, settlers of European origin started to use echinacea. The “medical doctor” H.G.E Meyer is particularly well known, who widely advertised “Meyer’s Blood Purifier” as a remedy for rheumatism, headache, digestive problems, tumors and boils, open wounds, vertigo, scrofula (tendency to get tuberculosis), bad eyes, intoxications resulting from plants or snakes. The plant used in this preparation was subsequently identified as E. angustifolia. Once larger amounts of echinacea were required, E. pallida with its larger rootstock became popular. In 1916 the rootstock of echinacea was included in the National Formulary of the United States. Both species were allowed for pharmaceutical use. At the beginning of the 20th century, echinacea became popular in Europe and has recently become an important immunostimu-lant, and an enormous number of (mostly ill-defined) herbal preparations are on the market both in Europe and in the United States. For some standardized extracts, sound clinical data are available that indicate that these extracts are clinically superior to placebo in the treatment of some common respiratory problems. However, the compounds responsible for the effect have not yet been identified.
Two aspects of the cultural history of these species deserve special mention:
- It is a phytomedicine, i.e., not a single compound but an extract, which hopefully is standardized to a series of lead compounds (in order to assure reproducible quality) as the active “drug.”
- The modern phytomedicines with echinacea as an active ingredient were developed on the basis of the indigenous uses in North America. If such a product were to be developed based on modern ethnobotanical studies, appropriate steps would have to be taken in order to adequately compensate the traditional bearers of this knowledge.