PHARMACOGNOSY

Pharmacognosy is the study of medicinal drugs derived from plants or other 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".^[1] It is also defined as the study of crude drugs.

Introduction

The word "pharmacognosy" is derived from two Greek words: φάρμακον pharmakon (drug), and γνῶσις gnosis (knowledge). The term "pharmacognosy" was used for the first time by the Austrian physician Schmidt in 1811 and 1815 by Crr. Anotheus Seydler in a work titled Analecta Pharmacognostica.
Originally—during the 19th century and the beginning of the 20th century—"pharmacognosy" was used to define the branch of medicine or commodity sciences (Warenkunde in German) which deals with drugs in their crude, or unprepared, form. Crude drugs are the dried, unprepared material of plant, animal or mineral origin, used for medicine. The study of these materials under the name pharmakognosie was first developed in German-speaking areas of Europe, while other language areas often used the older term materia medica taken from the works of Galen and Dioscorides. In German the term drogenkunde ("science of crude drugs") is also used synonymously.
As late as the beginning of the 20th century, the subject had developed mainly on the botanical side, being particularly concerned with the description and identification of drugs both in their whole state and in powder form. Such branches of pharmacognosy are still of fundamental importance, particularly for pharmacopoeial identification and quality control purposes, but rapid development in other areas has enormously expanded the subject. The advent of the 21st century brought a renaissance of pharmacognosy and its conventional botanical approach has been broadened up to molecular and metabolomic level.^[2]
Although most pharmacognostic studies focus on plants and medicines derived from plants, other types of organisms are also regarded as pharmacognostically interesting, in particular, various types of microbes (bacteria, fungi, etc.), and, recently, various marine organisms.
In addition to the previously mentioned definition, the American Society of Pharmacognosy also defines pharmacognosy as "the study of natural product molecules (typically secondary metabolites) that are useful for their medicinal, ecological, gustatory, or other functional properties."^[3] Other definitions are more encompassing, drawing on a broad spectrum of biological subjects, including botany, ethnobotany, marine biology, microbiology, herbal medicine, chemistry, biotechnology, phytochemistry, pharmacology, pharmaceutics, clinical pharmacy and pharmacy practice.

• medical ethnobotany: the study of the traditional use of plants for medicinal purposes;
• ethnopharmacology: the study of the pharmacological qualities of traditional medicinal substances;
• the study of phytotherapy (the medicinal use of plant extracts); and
• phytochemistry, the study of chemicals derived from plants (including the identification of new drug candidates derived from plant sources).
• zoopharmacognosy, the process by which animals self-medicate, by selecting and using plants, soils, and insects to treat and prevent disease.
• marine pharmacognosy, the study of chemicals derived from marine organisms.

At the 9th congress of Italian society of pharmacognosy it was stated that current return of phyto-therapy was clearly reflected by the increased market of such products. In 1998 the latest figures available for Europe, the total OTC market for herbal medicinal products reached a figure of $6 billion, with consumption for Germany of $2.5 billion, France $1.6 billion and Italy $600 million. In the US, where the use of herbal products has never been as prevalent as in continental Europe, the market for all herb sales reached a peak in 1998 of $700 billion.^{[citation needed]} This welcomed the scientific investigation of a rigorous nature.
The plant kingdom still holds many species of plants containing substances of medicinal value which have yet to be discovered. Large numbers of plants are constantly being screened for their possible pharmacological value.

Biological background

The carotenoids in primrose produce bright red, yellow and orange shades. On average, people consuming diets rich in carotenoids from natural foods, such as fruits and vegetables, are healthier and have lower mortality from a number of chronic illnesses

All plants produce chemical compounds as part of their normal metabolic activities. These phytochemicals are divided into (1) primary metabolites such as sugars and fats, which are found in all plants; and (2) secondary metabolites—compounds which are found in a smaller range of plants, serving a more specific function.^[4] For example, some secondary metabolites are toxins used to deter predation and others are pheromones used to attract insects for pollination. It is these secondary metabolites and pigments that can have therapeutic actions in humans and which can be refined to produce drugs—examples are inulin from the roots of dahlias, quinine from the cinchona, THC and CBD from the flowers of cannabis, morphine and codeine from the poppy, and digoxin from the foxglove.^[4]
Plants synthesize a bewildering variety of phytochemicals but most are derivatives of a few biochemical motifs:^[5]

• Alkaloids are a class of chemical compounds containing a nitrogen ring. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals, and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and are used as medications, as recreational drugs, or in entheogenic rituals. Examples are the local anesthetic and stimulant cocaine; the psychedelic psilocin; the stimulant caffeine; nicotine; the analgesic morphine; the antibacterial berberine; the anticancer compound vincristine; the antihypertension agent reserpine; the cholinomimetic galantamine; the spasmolysis agent atropine; the vasodilator vincamine; the anti-arrhythmia compound quinidine; the anti-asthma therapeutic ephedrine; and the antimalarial drug quinine. Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly invoke a bitter taste.
• Polyphenols (also known as phenolics) are compounds that contain phenol rings. The anthocyanins that give grapes their purple color, the isoflavones, the phytoestrogens from soy and the tannins that give tea its astringency are phenolics.
• Glycosides are molecules in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme hydrolysis, which causes the sugar part to be broken off, making the chemical available for use. Many such plant glycosides are used as medications. In animals and humans, poisons are often bound to sugar molecules as part of their elimination from the body. An example is the cyanoglycosides in cherry pits that release toxins only when bitten by a herbivore.
• Terpenes are a large and diverse class of organic compounds, produced by a variety of plants, particularly conifers, which are often strong smelling and thus may have had a protective function. They are the major components of resin, and of turpentine produced from resin. (The name "terpene" is derived from the word "turpentine"). Terpenes are major biosynthetic building blocks within nearly every living creature. Steroids, for example, are derivatives of the triterpene squalene. When terpenes are modified chemically, such as by oxidation or rearrangement of the carbon skeleton, the resulting compounds are generally referred to as terpenoids. Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers. Essential oils are used widely as natural flavor additives for food, as fragrances in perfumery, and in traditional and alternative medicines such as aromatherapy. Synthetic variations and derivatives of natural terpenes and terpenoids also greatly expand the variety of aromas used in perfumery and flavors used in food additives. Vitamin A is an example of a terpene. The fragrance of rose and lavender is due to monoterpenes. The carotenoids produce the reds, yellows and oranges of pumpkin, corn and tomatoes.

A consortium of plant molecular researchers at Washington State University, the Donald Danforth Plant Science Center, the National Center for Genome Resources, and the University of Illinois at Chicago began an NIH-sponsored study of over thirty medicinal plant species late 2009. The initial work, to develop a sequence reference for the transcriptome of each, has led to the development of the Medicinal Plant Transcriptomics Database.

Issues in phytotherapy

The part of pharmacognosy focusing on the 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. Although phytotherapy is sometimes considered as alternative medicine, when critically conducted, it can be considered the scientific study on the effects and clinical use of herbal medicines. Consequently, herbal products might also become officially approved for clinical application as botanical drugs (e.g., Veregen (sinecatechins), a green tea leaves extract, approved for use by FDA).^[6]

Constituents and drug synergism

One characteristic of crude drug material is that constituents may have an opposite, moderating or enhancing effect. Hence, the final effect of any crude drug material will be a product of the interactions between the constituents and the effect of each constituent on its own. To effectively study the existence and effect of such interactions, scientific studies must examine the effect that multiple constituents, given concurrently, have on the system. Herbalists assert that as phytopharmaceuticals rely upon synergy for their activities, plants with high levels of active constituents like ginsenosides or hypericin may not correlate with the strength of the herbs. In phytopharmaceuticals or herbal medicine, the therapeutic effects of herbs cannot be determined unless its active ingredient or cofactors are identified or the herb is administered as a whole. One way to indicate strength is standardization to one or several marker compound that are believed to be mainly responsible for the biological effects. However, many herbalists believe that the active ingredient in a plant is the plant itself.^[7]

Herb and drug interactions

Main article: Herb-drug interactions

A study of herb drug interactions indicated that the vast majority of drug interactions occurred in four classes of drugs, the chief class being blood thinners, but also including protease inhibitors, cardiac glycosides and the immuno-suppressant ciclosporin.^[8]

Natural products chemistry

Digoxin is a purified cardiac glycoside that is extracted from the foxglove plant, Digitalis lanata. Digoxin is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication.

Most bioactive compounds of natural origin are secondary metabolites, i.e., species-specific chemical agents that can be grouped into various categories.^{[citation needed]} 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, followed by next round of separation and assaying. Typically, such work is initiated after a given crude drug formulation (typically prepared by solvent extraction of the natural material) is deemed "active" in a particular in vitro assay. If the end-goal of the work at hand is to identify which one(s) of the scores or hundreds of compounds are responsible for the observed in vitro activity, the path to that end is fairly straightforward:

1. fractionate the crude extract, e.g. by solvent partitioning or chromatography.
2. test the fractions thereby generated with in vitro assay.
3. repeat steps 1) and 2) until pure, active compounds are obtained.
4. determine structure(s) of active compound(s), typically by using spectroscopic methods.

In vitro activity does not necessarily translate to activity in humans or other living systems.
The most common means for fractionation are solvent-solvent partitioning and chromatographic techniques such as high-performance liquid chromatography (HPLC), medium-pressure liquid chromatography, "flash" chromatography, open-column chromatography, vacuum-liquid chromatography (VLC), thin-layer chromatography (TLC), with each technique being most appropriate for a given amount of starting material. Countercurrent chromatography (CCC) is particularly well-suited for bioassay-guided fractionation because, as an all-liquid separation technique, concern about irreversible loss or denaturation of active sample components is minimized. After isolation of a 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 spectrometry (MS).^{[citation needed]} In the case of drug discovery efforts, structure elucidation of all components that are active in vitro is typically the end goal. In the case of phytotherapy research, the investigator may use in vitro BAGF as a tool to identify pharmacologically interesting or important components of the crude drug. The work does not stop after structural identification of in vitro actives, however. The task of "dissecting and reassembling" the crude drug one active component at a time, in order to achieve a mechanistic understanding of how it works in phytotherapy, is quite daunting. This is because it is simply too difficult, from cost, time, regulatory, and even scientific perspectives, to study experimental fractions of the crude drug in humans. In vitro assays are therefore used to identify chemical components of the crude drug that may rationally be expected to have a given pharmacological effect in humans, and to provide a rational basis for standardization of a crude drug formulation to be tested in [and sold/marketed to] humans.

Loss of biodiversity

See also: Biodiversity

Farnsworth for example, has found that 25% of all prescriptions dispensed from community pharmacies in the United States from 1959 to 1980 contained active ingredients extracted from higher plants. In some countries in Asia and Africa 80% of the population relies on traditional medicine (including herbal medicine) for primary health care.^[9] Native American cultures have also relied on traditional medicine such as ceremonial smoking of tobacco, potlatch ceremonies, and herbalism, to name a few, prior to European colonization.^[10] Constituents of substances used by traditional healers, have rarely been incorporated into modern medicine. Quinine, physostigmine, d-tubocurarine, pilocarpine and ephedrine, have been demonstrated to have active effects^[11] Knowledge of traditional medicinal practices is 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,^{[citation needed]} which, like the forest plants they employ, are also endangered.^[12][13][14]
Some species loss is habitat lost due to introduction of invasive species such (kudzu, Japanese knotweed, mimosa, lonicera, St. Johnswort and purple loosestrife) which themselves have medicinal uses.
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 .^{[citation needed]} 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.^{[citation needed]}
Cooperation between Western conservationists and practitioners have been beset by cultural difficulties. Westerners may emphasise urgency in matters of conservation, while Chinese may wish for the products used in TCM to remain publicly available. One repeated fallacy^{[citation needed]} is that rhinoceros horn is used as an aphrodisiac in TCM. It is, in fact, prescribed for fevers and convulsions by TCM practitioners. There are no peer-reviewed studies showing that this treatment is effective.^[15] In 1995 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.^[16]

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.^{[citation needed]} For instance, ginseng which is field farmed may have significant problems with fungus, making contamination with fungicides an issue.^{[citation needed]} This may be remedied with woods grown programs, but they are insufficient to produce enough ginseng to meet demand.^{[citation needed]} 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.^[17] 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 has been stated to have a different effect than the full panax root.^[18]
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.^{[citation needed]} 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.^{[citation needed]} 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.^{[citation needed]} Today almost a third of the seahorses sold in China are prepackaged. ^[19]
The farming of plant or animal species for medicinal purposes has caused difficulties. 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. World Animal Protection states that bear bile farming "causes intense, unjustified suffering to bears".^[20] Chinese officials state that 10,000 wild bears would need to be killed each year to produce as much bile, making bear farming the more desirable option. World Animal Protection, however, states that "it is commonly believed in China that the bile from a wild bear is the most potent, and so farming bears for their bile cannot replace the demand for the product extracted from wild animals".
• 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 users believe that TCM compounds may act synergistically so several ingredients may interact to give the required effect. Thus TCM users often prefer 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.^[19