Pharmacognosy

Pharmacognosy is the study of medicines from natural sources. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources".

Introduction
The word "Pharmacognosy" derives from the Greek words pharmakon (drug), and gnosis or knowledge. The term pharmacognosy was used for the first time by the Austrian physician Schmidt in 1811. Originally - during the 19th century and the beginning of the 20th century - pharmacognosy was used to define the branch of medicine or of commodity sciences ("Warenkunde" in German), which dealt with drugs in their crude, or unprepared, form. A "crude drug" means a dried unprepared natural material of plant, animal or mineral origin, which is used for medicine. The term drug derives from the Lower Saxon/Dutch "Droog", which means "dried" as in dried herbs (and has little to do with the modern pharmaceutical meaning of the term). The term "Pharmakognosie" and it discipline developed in German speaking areas of Europe - where it is a synonym of "Drogenkunde" ("science of the crude drugs").

Even though most of the pharmacognostic studies are focused on medicinal plants/herbal medicines, also other organisms are regarded pharmacognostically interesting. Particularly this is true for different types of microbes, i.e. bacteria nad fungi. More recently, also many marine organisms have become targets of pharmacognostic studies.

Pharmacognosy is interdisciplinary, drawing from a broad spectrum of biological and even socio-scientific subjects: botany, ethnobotany, marine biology, microbiology, herbal medicine, chemistry (phytochemistry), pharmacology, pharmaceutics, clinical pharmacy and pharmacy practice related to the evaluation and clinical uses of medicines from natural sources, as well as their implications in health care management and public health.

The different fields within today's pharmacognosy include
 * Ethnobotany or ethnopharmagocology; study of the traditional use of plants in the society. Ethnobotany refers to any use of the plants, whereas ethnopharmacology refers more specifically to the madical use of the plants.
 * Phytotherapy; study of crude drugs, i.e. extracts from natural sources in medical use
 * Phytochemistry, or natural product chemistry; a field closely related to organic chemistry, studying the chemical composition of living organisms. It is also closeöy connected to the process of finding new drug candidates from natural sources.

Ethnopharmacology
When studying the effectiveness of herbal medicines and other nature-derived remedies, the information of the traditional uses of certain extracts of even extract combinations plays a key role. The lack of studies proving the use of herbs in traditional care is especially an issue in the United States where the use of herbal medicine has fallen out of use since the Second World War and was considered suspect since the Flexner Report of 1910 led to the closing of the eclectic medical schools where botanical medicine was exclusively practiced. Without an intact tradition of the use of herbal products, and contrasted to the presence of studies for pharmaceutical drugs, doctors and pharmacists lack a level of confidence in herbal and other crude drugs. This is further complicated by most herbal studies in the latter part of the 20th Century having been published in languages other than English such as German, Dutch, Chinese, Japanese, Korean and Farsi. The US Food and Drug Administration "FDA" does not draw upon most foreign language publications or international assessments of drug safety in its determinations of drug safety As a result one does not hear about every study on herbal medicine. The costs of testing drugs are sizable, and without the patent protection available to synthetic drugs, companies are reluctant to test herbal medicines. In 1994 the US Congress passed the Dietary Supplement Health and Education Act (DSHEA), regulating labeling and sales of herbs and other supplements. Most of the 2000 US companies making herbal or natural products choose to market their products as food supplements that do not require substantial testing.

Issues in Phytotherapy
The part of pharmacognosy focusing on use of crude extracts or semi-pure mixtures originating from nature, namely phytotherapy, is probably the best known and also the most debated area in pharmacognosy. Even though the term itself is sometimes connected to alternative medicine, phytotherapy may be defined as the scientific study on the effects and clinical use of herbal medicines.

Controversy about Active Constituents
In herbal medicine circles the very concept of "active ingredient" is controversial since most phytopharmaceuticals rely upon constituent synergy for their activities. Plants with high levels of assumed active constituents like ginsenosides or hypericin may not correlate with the strength of the herbs. Many herbs are poorly characterized or while well-characterized will rely upon the synergy of otherwise weak principles. In phytopharmaceutical or herbal medicine the active ingredient may be either unknown or may require cofactors in order to achieve therapeutic goals. One way manufacturers have attempted to indicate strength is to engage in standardization to a marker compound. companies use different markers, or different levels of the same markers, or different methods of testing for marker compounds. Many herbalists believe that the active ingredient in a plant is the plant itself.

Herb and Drug Interactions
Although herbs and drugs have been combined for centuries in Asia and Europe, and worldwide most drugs are herbal, the disrupted relationship between traditional herbal medicine and pharmaceutical allopathic medicine in the United States has created a climate whereby herbs are considered dangerous to combine with pharmaceuticals and information developed in other countries is not readily available. As a result websites like that of the University of Maryland Medical Center, which purport to show information on herbal safety show cases that may lack the appropriate pharmacokinetics to produce the adverse results inferred. The Sloan Kettering Memorial Cancer Center site is even more problematic, suggesting that antioxidants interfere with chemotherapy despite numerous studies to the contrary. A study of herb drug interactions indicated that the vast majority of drug interactions occurred in four classes of drugs with narrow therapeutic windows, the chief class being blood thinners, but also including protease inhibitors, cardiac glycosides and certain antibiotics like cyclosporin.

The major herbs that have caused interactions include St. Johnswort, which will counteract immunosupressive drugs and interfere with digoxin and protease inhibitors. A complete list can be found at: http://www.herbological.com/images/SJW_table.pdf  Ginkgo biloba may have anti-platelet effects, although the results are not clear as it also contains flavanoids that improve blood function. Although constituents of garlic, peppermint and milk thistle have been shown to have effects on the CYP3A4 enzymes in vitro, it is not clear that the whole herb will have a similar effect in vivo. Many herbs that are listed as "potentiating" merely have an additive effect, and including laxative herbs as antagonistic to anti-diarrheal medications is tautological.

Confusion of Constituents with Whole Products
One characteristic of crude drug material is that constituents may have an opposite, moderating or enhancing effect. Hence when any constituent is isolated it does not follow that its actions represent the whole herb. For instance, ephedra has constituents that increase the heart rate and constituents that decrease it. The drug ephedrine only used the constituents that increased the heart rate and had side effects absent from the traditional preparation of the herb. A significant number of studies have been done on plant isolates for the pharmacological industry, but they are frequently mischaracterized as representing the actions of the herb as a whole. This is particularly true in indexing in services such as Medline.

Natural products chemistry
Instead of studying compound mixtures (crude extract or partially purified, eg. by fractionation), this part pf pharmacognosy concentrates on isolated, pure compounds originating from nature. Most bioactive compounds of natural origin are seconary metabolites, i.e. species-specific chemical agents that can be groped into various categories. A typical protocol to isolate a pure chemical agent from natural origin is bioassay-guided fractionation, meaning step-by-step separation of extracted components based on differences in their physicochemical properties, and assessing the biological activity, follewed by next round of separation and assaying. The most commpn means for separation is high-performance liquid chromatography (HPLC), but other chromatographical methods, such as thin-layer chromatography (TLC) are also used for these preparative purposes. After isolation of aa pure substance, the task of elucidating its chemical structure can be addressed. For this purpose, the most powerful methodologies available are nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS).

Indexing Issues and Megastudies
With the rise of megastudies and the advent of computerized researching, the structure of search engines such as MEDLINE tend to increase medical misinformation. For instance, a substantial number of studies are classified under misspellings. A search of MEDLINE for papers published on ginkgo misses 160 or 8% of potentially important reports because they are entered under the misspelled name "gingko" (sic). Misspellings are not only significant for loss of indexing but because they frequently are correlated with the failure to properly identify the species.

Herbalist Jonathan Treasure, NIMH, traces the growth of misinformation on an alleged adverse herb-drug interaction between the monoamine oxidase inhibitor phenelzine and Asian ginseng (Panax ginseng C.A. Meyer). This originally was mentioned in a 1985 editorial by the then editors of the Journal of Clinical Psychopharmacology, Shader and Greenblatt where they devoted a couple of lines to the case of 64 year-old woman who took an undisclosed dose for an undisclosed time of a combination dietary supplement product called “Natrol High” while concurrently taking phenelzine 60 mg qd. She experienced symptoms of “insomnia, headache, and tremulousness”. Treasure contacted Natrol by email and discovered within ten minutes that there was no Panax ginseng in the formula, but instead eleutherococcus which was then called by the popular name "Siberian ginseng" and it was given in a subclinical dosage mixed with a variety of other herbs. The purported interaction effects are well-known side effects of phenelzine alone, which had been given in a high dosage and are not at all suggestive of eleutherococcus. However this misinformed article with a misidentified herb has been picked up in literature searches, megastudies and is now is documented by conventional medical authorities such as Stockley’s, and is repeated in several botanical monographs e.g. World Health Organization (WHO 1999).

This occurs because of what Treasure calls the "cascading effect" of Medline. He states that "primary observations shown to be significant by tertiary analyses are deemed to be validated ‘real’ effects. [He states] that the system actually works in reverse, with successive generations of secondary reviews amplifying the errors of previous derivative articles that were in turn based on erroneous primary data or speculation."

Loss of Biodiversity
One major source of species loss is the rate of habitat destruction. Less than 50% of the area covered by prehistoric tropical rainforests remains, yet tropical rainforests are still being cut and burned at a rate of approximately l42,000 square kilometres each year, equal in area to the countries of Switzerland and the Netherlands combined. (Wilson l992). It is this destruction which is primarily responsible for the mass extinction of the world's species. There are an estimated l0 million to l00 million different species on Earth. Based upon a conservative estimate of 20 million total world species, then l0 million species would be found in tropical rainforests, and at current rates of tropical deforestation, this would mean 27,000 species would be lost in tropical rainforests alone each year, or more than seventy-four per day, three each hour

Plant, animal and microbial species are themselves the sources for some of today's most important medicines and make up a significant proportion of the total pharmacopoeia. Farnsworth for example, has found that 25% of all prescriptions dispensed from community pharmacies in the United States from l959 to l980 contained active ingredients extracted from higher plants. A much higher percentage is found in the developing world. As many as 80% of all people living in developing countries, or roughly two thirds of the world's population, rely almost exclusively on traditional medicines using natural substances, mostly derived from plants.

The knowledge held by traditional healers, often passed down orally over centuries, has led to the discovery of many medicines that are widely used today - quinine, physostigmine, d-tubocurarine, pilocarpine and ephedrine, to name a few  But that knowledge is fast disappearing, particularly in the Amazon, as native healers die out and are replaced by more modern medical practitioners. Botanists and pharmacologists are racing to learn these ancient practices, which, like the forest plants they employ, are also endangered

Scientists have analysed the chemistry of less than 1% of known rainforest plants for biologically active substances - as well as a similar proportion of temperate plants and even smaller percentages of known animals, fungi and microbes. But there may be tens of millions of species as yet undiscovered in the forests, in soils, and in lakes and oceans which with massive extinctions currently in progress, we may be destroying new cures for many old and newly emerging illnesses.

A more controversial explanation for some species loss is habitat lost to invasive species introduction. While Farnsworth and others suggest that this is a major danger, others like David Theodoropoulos argue that species have always moved and data shows, for instance that purple loosestrife, identified as invasive, may result in higher levels of native pollinators than displaced drossera and that development of land has had a greater effect on the native species Probably the truth lies in the middle: it is difficult to deny the effect of Kudzu (Pueria spp.) overtaking native species in the Southern American states, yet other species may have less effect than the growth of shopping centers on previously wild land. Herbalist David Winston has suggested that a high proportion of nonnative species seen as invasive (kudzu, Japanese knotweed, mimosa, lonicera, St. Johnswort and purple loosestrife) be harvested for the domestic herbal medicine market. However species extinction is not only due to habitat loss. Overharvesting of medicinal species of plants and animals also contributes to species loss. This is particularly notable in the matter of Traditional Chinese Medicine where crude drugs of plant and animal origin are used with increasing demand. People with a stake in TCM often seek chemical and biological alternatives to endangered species because they realize that plants and animals lost from the wild are also lost to medicine forever but different cultural attitudes bedevil conservation efforts. Still conservation is not a new idea: Chinese advice against overexploitation of natural medicinal species dates from at least Mencius, a philosopher living in the 4th century BC.

Cooperation between western conservationists and practitioners have been beset by cultural difficulties. Western conservationists often speak with combative urgency, while less confrontational Chinese who hear their medicine denigrated as unscientific often view conservationists as rude and arrogant. One repeated fallacy is that rhinoceros horn is used as an aphrodisiac in TCM. It is, in fact, prescribed for life-threatening fevers and convulsions and has been clinically shown to have fever-reducing properties. Still in 1995 when representatives of the oriental medicine communities in Asia met with conservationists at a symposium in Hong Kong, organized by TRAFFIC. The two groups established a clear willingness to cooperate through dialogue and mutual understanding. This has led to several meetings, including the 1997 First International Symposium on Endangered Species Used in Traditional East Asian Medicine where China was among 136 nations to sign a formal resolution recognizing that the uncontrolled use of wild species in traditional medicine threatens their survival and the continuation of these medical practices. The resolution, drawn up by the UN Convention on International Trade in Endangered Species (CITES), aims to initiate new partnerships in conservation.

Sustainable Sources of Plant and Animal Drugs
As species face loss of habitat or overharvesting, there have been new issues to deal with in sourcing crude drugs. These include changes to the herb from farming practices, substitution of species or other plants altogether, adulteration and cross-pollination issues. For instance, ginseng which is field farmed may have significant problems with fungus, making contamination with fungicides an issue. This may be remedied with woods grown programs, but they are insufficient to produce enough ginseng to meet demand. The wildcrafted echinacea, black cohosh and American ginseng often rely upon old growth root, often in excess of 50 years of age and it is not clear that younger stock will have the same pharmaceutical effect. Black cohosh may be adulterated with the related Chinese actea species, which is not the same. Ginseng may be replaced by ginseniodes from Jiaogulan which will have a different effect than the full panax root.

The problem may be exacerbated by the growth of pills and capsules as the preferred method of ingesting medication as they are cheaper and more available than traditional, individually tailored prescriptions of raw medicinals but the contents are harder to track. Seahorses are a case in point: Seahorses once had to be of a certain size and quality before they were accepted by practitioners and consumers. But declining availability of the preferred large, pale and smooth seahorses has been offset by the shift towards prepackaged medicines, which make it possible for TCM merchants to sell previously unused juvenile, spiny and dark-coloured animals. Today almost a third of the seahorses sold in China are prepackaged.

The farming of medicinal species has difficulties as well as Rob Parry Jones and Amanda Vincent write:


 * One solution is to farm medicinal animals and plants. Chinese officials have promoted this as a way of guaranteeing supplies as well as protecting endangered species. And there have been some successes—notably with plant species, such as American ginseng—which is used as a general tonic and for chronic coughs. Red deer, too, have for centuries been farmed for their antlers, which are used to treat impotence and general fatigue. But growing your own is not a universal panacea. Some plants grow so slowly that cultivation in not economically viable. Animals such as musk deer may be difficult to farm, and so generate little profit. Seahorses are difficult to feed and plagued by disease in captivity. Other species cannot be cultivated at all. Even when it works, farming usually fails to match the scale of demand. Overall, cultivated TCM plants in China supply less than 20 per cent of the required 1.6 million tonnes per annum. Similarly, China's demand for animal products such as musk and pangolin scales far exceeds supply from captive-bred sources.


 * Farming alone can never resolve conservation concerns, as government authorities and those who use Chinese medicine realise. For a start, consumers often prefer ingredients taken from the wild, believing them to be more potent. This is reflected in the price, with wild oriental ginseng fetching up to 32 times as much as cultivated plants. Then there are welfare concerns. Bear farming in China is particularly controversial. Around 7600 captive bears have their bile "milked" through tubes inserted into their gall bladders. According to Chinese officials, 10 000 wild bears would need to be killed each year to produce as much bile. But many Westerners argue that bear farming is cruel.


 * One alternative to farming involves replacing medical ingredients from threatened species with manufactured chemical compounds. In general, this sort of substitution is difficult to achieve because the active ingredient is often not known. In addition, most TCM uses compounds which may act synergistically—several ingredients may interact to give the required effect. Also, people prefer and trust the wild source. Tauro ursodeoxycholic acid, the active ingredient of bear bile, can be synthesised and is used by some Western doctors to treat gallstones, but many TCM consumers reject it as being inferior to the natural substance from wild animals.

Pharmacognosy Education
Prior to the 1950’s every pharmacy student learned about crude drugs in pharmacognosy class. Pharmacognosy includes the study of the proper horticulture, harvesting and uses of the raw medicinals found in nature. Its scope includes the identification or authentication of crude drugs (using macroscopical, microscopical, radiological or chemical methods), and their bio-pharmacological and clinical evaluations. Although today pharmacognosy is still taught in a small number of university pharmacy schools in US and in the UK, this subject is still obligatory within the pharmacy curricula in all universities of continental Europe. As more Americans are engaging in the use of herbal medicine, traditional Chinese medicine and other uses of natural products, there is increasing pressure to revive pharmacognosy training in pharmacy and medical schooling.

The need for pharmacognosy education is acute as we enter into a post antibiotic age and as traditional ethnobotanical medicines are revived. The growth of TCM and Ayurvedic medicine as well as the increase in western herbalists means that the identification, quality selection and appropriate processing of crude drugs is especially needed. And those disciplines with the pao zhi or rasayana processing offer traditional western pharmacognosy new techniques to alter crude drugs. Simultaneously pharmaceutical companies and supplement companies are looking at crude drugs as sources for effective drugs and nutraceuticals. One factor in the low quality of research on crude drugs is the low number of people who know how to select, process or dose them appropriately due to the closing of US pharmacognosy classes at the university level. Given that such classes are available in Europe, India, China, Korea and Japan, it is likely that information on new drugs will come from other countries than the United States.