advanced herbology lesson 3 lesson 3...anthraquinone-containing herbs are not often given by...

ADVANCED HERBOLOGY Glycosides Lesson 3

©2017 Wild Rose College of Natural Healing 1 Terry Willard Cl.H PhD.

Lesson 3

Glycosides

As we discovered in the previous chapter on carbohydrates, understanding plant constituents has an enormous value to herbalists. The study of plant constituents expands further now, from the relatively simple subgroup of carbohydrates to a much larger, diverse, and more chemically complex subgroup collectively referred to as ‘glycosides'. To classify these constituents together is rather arbitrary. There are other equally valid ways to group them. We are using this system, often followed in North America, instead of the more phenolic-based or polyphenolic classification used in Europe. We are doing this for no other reason than glycosides are theorized to have been the first group of plant constituents to evolve from carbohydrates. Though not very likely, most of these compounds do have, or at one time have had, a carbohydrate associated with them. Some phytochemists consider glycosides a format or a structure more than an entire classification unto itself.

Glycosides as a group have strong bioactivity, both within the plant's own physiology and from the point of view of activity when ingested by a human. This group is therefore of great interest from a therapeutic and economic standpoint. Glycosides have a widespread distribution throughout the plant kingdom. They can be found in all parts of plants.

Please read p. 101 – 102 in the text

Fig 3.0 Steviol glycosides “Stevia” (Stevia rebaudiana)



Glycosides, as we have just read, are most simply defined as a sugar residue (the ‘glycone' fraction), coupled to a non-sugar component (the ‘aglycone' fraction). They are formed by the combining of a nucleotide glycoside (e.g., uridine diphosphate glucose, UDP-glucose) with the alcoholic or phenolic group of a second compound, forming a linkage through oxygen (O-glycosides). These are the most abundant types of glycosidic linkages found in nature, though linkages through carbon (C-glycosides), nitrogen (N-glycosides) and sulfur (S-glycosides) also occur. Most glycosides have glucose as their sugar moiety (glucosides), however other sugars such as rhamnose, arabinose or di-, tri- or tetrasaccharides may also attach to the aglycone molecule.

Within the plant, glycosides are found in the cell sap and have important regulatory, protective and cleansing functions. The sugar fraction confers solubility within the human body, and is usually hydrolyzed by dilute acids in the gastrointestinal tract. When the molecule is in a glycoside state, the phytochemicals are more soluble, and thus better delivered as an infusion (tea), or ground botanical. The aglycone fraction of the glycoside confers most of the pharmacological activity. As noted in the text, when referring to glycosides it is usual to replace the "-ose" found in sugars and replace it with "-oside", such as cascaroside from Cascara, sennoside in Senna and ginsenoside found in Ginseng. However, some of the more common names end with a "-in", such as arbutin, in Arctostaphylos uva-ursi, salicin from Salix and digitoxin from Digitalis. The aglycones are extremely diverse in their nature and complexity. Because of the great variance in their physical and chemical properties, they also have great variety in their pharmacological actions. Based primarily upon their aglycone fraction, we have classified the glycosides into eleven functional groups:

1. Cardioactive glycosides

2. Anthraquinone glycosides

3. Saponin glycosides

Fig 3.1 Glycoside structure



4. Cyanophose glycosides

5. Isothiocyanate glycosides

6. Flavonoid glycosides

7. Alcohol glycosides

8. Aldehyde glycosides

9. Lactone glycosides

10. Phenol glycosides

11. Others

We will now look at each of these groups in greater detail (see Lesson 8 for Group 1, the Cardioactive Glycosides). It should be remembered that the classification of these groups is rather

arbitrary and could be organized by biochemists in other ways. It is very common to group all of the phenolic glycosides together, an approach often seen in European texts.

Please read p. 103 - 105 to Cascara sagrada

Anthraquinone Glycosides

Plants containing anthraquinone have been used for millennia as dyes and as purgatives. Anthraquinones are also known as anthracene glycosides, as anthracene was first isolated from them. They are yellow-brown, orange or red-orange, some of which have been used by the dye industry. A quinone is a six-carbon ring bearing two opposite ketone groups (para-ketones). They consist of two or more phenols linked with their carbon ring. Hydroxyl groups always occur at position 1 and 8 (often not shown in diagrams), hence they are 1,8 anthraquinones. Anthraquinone derivatives occur in many different botanical families, with the richest sources being the Rubiaceae, Rhamnaceae, and Polygonaceae. Within monocotyledons, they occur only in the Liliaceae family as the C-glycoside barbaloin, a 10 glucopyranosyl

derivative of aloe-emodin-anthrone. The basic anthraquinone structure is depicted in Fig. 4.2 of your textbook. Anthraquinone's found in plants convert very easily from one type of reduced derivative to another, such as the anthrones, anthranols and oxanthrones. This conversion occurs by way of a variety of natural and analytical processes such as aging and

Fig 3.2

Interrelationship of Anthraquinone derivatives



extraction. (see Fig. 4.3 of text and Fig 3.2 in workbook) Glycosides are often easily hydrolysed, making it difficult to determine the primary glycoside.

Anthraquinones include chrysophanol (chrysophanic acid), emodin, aloe-emodin and rhein. These are considered to be ‘stimulant' cathartics, that is, they increase peristalsis via stimulation of the Auerbach plexus, a group of autonomic nerve fibers and ganglia located in the muscle tissue of the intestinal tract. This stimulation, in turn, increases the tone of the smooth muscle in the wall of the large intestine and elicits a peristaltic response. They are not considered to be habit-forming, unlike the more griping, ‘drastic' cathartic action of the anthrones and anthranols, which cause bowel evacuation through simple local irritation. The action of anthraquinones seems to be dependent on the presence of bile in the digestive tract. They only work if ingested in the glycoside form. It also appears that intestinal flora interact with some anthraquinones. Isolated aglycones are inactive if ingested, but active if given intravenously. This makes one conclude that bile and the sugar moiety are both necessary for the absorption of anthraquinones. The mechanism is just theorized, but it appears that once the aglycone is absorbed into the bloodstream, it affects protein biosynthetic pathways, most likely leading to the formation of an enzyme. From here there seems to be a release of prostaglandins, thus stimulating nerve action. Some anthraquinones, such as sennoside A & B (found in Senna), pass through the stomach and the small intestine unaltered, converting to dianthrones by microorganisms in the cecum. Here they remain unabsorbed producing a cathartic effect by increasing peristalsis and inhibiting water and electrolyte resorption by intestinal mucosa. Though often theorized, no evidence of intestinal mucosa irritation has been found. Just because anthraquinones can have a cathartic action, it does not mean they are beneficial in all cases of constipation. Tension in the bowel muscle, as in a spastic intestine, may be a reflection of a wider systemic nervous state. In such cases relaxing herbs might be more indicated. Anthraquinone-containing herbs are not often given by themselves. They are usually combined with other herbs in formulas, including aromatic compounds as found in Fennel, Ginger and Dill, which are added to reduce griping. Besides the cathartic action of anthraquinone at least some derivatives such as rhein have significant antiseptic action and are especially toxic to enteric pathogens Shigella dysenteriae and Staphylococci. The bitter nature of anthraquinone has been shown to stimulate digestive secretions and bile flow in the upper digestive tract.



Please read p. 105 - 115 to end of Anthraquinones In this section we looked in greater detail at some of those herbs, which are noted for their quinone content and activity. Let's review them once again.

Cascara Sagrada (Rhamnus purshianus)

Cascara Sagrada contains two anthraquinone derivatives (emodin and chrysophanic acid), which are considered to have a regulating or balancing effect upon one another. These active principals are absorbed from the small intestine into the systemic circulation and subsequently stimulate the Auerbach plexus. Chrysophanic acid acts similarly to a “gas pedal” upon the parasympathetic nervous system, due to its strong stimulant effect on the smooth muscle of the colon. Its effect is regulated or controlled by the emodin present, which acts as a ‘brake'. Emodin works primarily upon the sympathetic component of the autonomic nervous system, slowing down peristalsis. The bark of Cascara Sagrada is traditionally aged for one year before use. This allows for the maturation of the more desirable anthraquinone cascarosides from the other constituent glycosides present, through the slow process of hydrolysis. During aging of the bark, it is necessary to avoid exposure of the inner surface of the bark to illumination as light suppresses anthraquinone formation. Large doses of this herb will act upon the small intestine and can mildly stimulate bile flow, while excessively large doses can cause extensive diarrhea accompanied by nausea, vomiting and cramping. These side effects may be countered by the addition of carminative agents such as Ginger, Dill or Fennel to the herbal preparation. Cascarosides are also known to enter breast milk and thus may have a laxative effect on the breast-fed infant.

Aloe Vera (Aloe vera, A. barbadensis)

Aloe juice, obtained from the fleshy leaves of Aloe vera or A. barbadensis, is used internally to cleanse the GI system via its action as a mild to moderate cathartic. The juice of the plant, when dried, becomes a powder, which is a very strong griping cathartic even in moderate doses. Aloe juice is not to be confused with ‘Aloe Vera gel', a product derived from the mucilage found in the parenchymatous cells of the Aloe vera leaf and often used as a soothing topical agent for burns and abrasions. Aloe juice originates from the pericyclic region of the leaves of various Aloe species, of which there are approximately 180 known species (an increase of 30 known species from the number suggested in the text).

Fig 3.3 Cascara Sagrada (Rhamnus purshianus)

Fig 3.4 Aloe vera (Aloe vera, A. barbadensis)



Aloes contain resins and C-glycosides, primarily barbaloin. Though most Aloes contain between 5-30% barbaloin, A. vera actually contains little, if any at all. Other anthraquinone derivatives present include free, non-

glycosidal aloe-emodin, anthranol, and chrysophanic acid. The cathartic action of Aloe is due to strong stimulation of peristalsis, especially of the lower bowel. It is even more irritating than Senna, though this is dose-dependent. As Aloe can also stimulate uterine contractions, it should not be taken during pregnancy. Turkey Rhubarb, Chinese Rhubarb

(Rheum officinale, R. palmatum)

Turkey (or Chinese) Rhubarb rhizome, stripped of its bark, contains anthraquinones such asemodin, chrysophanol, aloe-emodin and rhein. As with Cascara Sagrada, the combination of emodin and chrysophanol produces a regulating effect upon the bowel musculature, with astringent qualities provided by tannins which are also present. Rhubarb (excepting Rheum rhaponticum, the common garden “false” rhubarb) is noted for its efficacy in reducing bleeding of gastric and duodenal ulcers (over 90% efficacy). Its use throughout history is extensive, being mentioned in the Chinese materia medica from 2700 B.C. The leaves

of all varieties of rhubarb are very poisonous and will cause severe vomiting, along with kidney and liver damage. Senna (Cassia acutifolia)

The principal active constituents of Senna are, as noted in the textbook, aloe-emodin and/or rhein, with rhein being comprised primarily of the dianthrones, sennosides A and B (aglycones sennidin A and B). These are located in the dried leaflets, though the seed pods are also used. The seed pods have basically the same constituent makeup as the leaflets, along with a very cathartic, 10-sugar rhein dianthrone. Senna is noted for its strong purgative action accompanied by griping. For this reason it is best combined with a carminative such as ginger, although other carminatives may also be used. Senna increases peristalsis, once thought to be through locally-induced irritation of the intestinal wall, as opposed to the systemically-induced action of the previous cathartics discussed. It is now thought that senna arrives in the cecum intact and is converted by micro-organisms (as mentioned above). Here it affects both water level and electrolyte transfer in the intestinal mucosa (especially the left and the sigmoid colon), thus producing a cathartic action. Senna can become ‘addictive', that is, one needs increasingly larger doses in order to maintain the same cathartic effect. As well, extended use can cause damage to the

Fig 3.5 Turkey Rhubarb (Rheum palmatum)

Fig 3.6 Senna (Cassia acutifolia)

Fig 3.5a

Rhein



colon. For these reasons, it is best used only for the short-term relief of constipation (less than 30 day of continuous use), with other measures implemented for a long-term treatment regime.

Pau d'Arco, LaPacho, Taheebo (Tabebuia avellanedae)

Although LaPacho does contain anthraquinones, it is its napthoquinones which have attracted most of the research interest. These include lapachol and alpha- and beta-lapachone. Lapachol acts as a respiratory poison, interfering with electron transport in the mitochondrial respiration of many pathogenic organisms including bacteria, fungi and parasites. It has been shown to inhibit malarial parasites (Plasmodium spp.), Candida albicans, and some Gram-positive bacteria including a number of Staph. spp. Mycobacterium tuberculinum (a causative organism of tuberculosis) has also demonstrated sensitivity to lapachol. Lapachol exhibits antiviral activity and has proven effective against HSV I and HSV II (Herpes Simplex Virus). It has been shown to inhibit the enzyme reverse

Fig 3.8 Pau d’Arco (Tabebuia avellanedae)

Fig 3.7

Quinones



transcriptase, and is thus being studied for its potential use against the retrovirus associated with AIDS (HIV – Human Immunodeficiency Virus. In this same Quinone classification we can include Hypericin found in Saint John’s Wort (Hypericum perforatum). As you can see in the fig of

hypericin, the two anthraquinones are joined together by a napthoquinone. This makes it a bianthroquinone or napthodianthrone. This phytochemical is known to have antiviral properties as well as anti-tumor activity. The plant is also famous for its antidepressant activity.

Please read pages 115 - 119 to Licorice

Saponin Glycosides

The characteristic physical property of saponins is their solubility in water, leading to a decrease in surface tension and frothing upon agitation. Saponins are known to cause hemolysis when injected into the bloodstream, which makes them potentially highly toxic. When ingested orally though, and broken down through normal digestive processes, they are rendered quite safe. Many saponin-containing mixtures are used as fish poisons by indigenous peoples of the Amazon. When the fish is eaten, there is no harm to humans. At first this might seem like a cheap way to fish, but when considering that Piranhá infests the same waters, it leaves very little choice. Any fish caught by net or hook will cause the Piranhá to attack, leaving few fish for the people to retrieve from the water, not to mention the considerable danger to the fishermen.



Based upon their structural nucleus (the sapogenin aglycone fraction) saponin glycosides are divided into two groups:

1. Steroidal (tetracyclic) triterpenoids 2. Pentacyclic triterpenoids

Both types of saponins share a common origin from mevalonic acid (three acetyl coenzyme A molecules linked together) and isoprenoid units. For bioactivity to be conferred, the glycosidal linkage must occur at the carbon-3 position. (marked ‘3’ in above diagram).

Isoprene (C5H8) The isoprene molecule is a fundamental building block from which many plant constituents are constructed. Triterpenoids, which include the saponins we are studying here, contain six isoprene units (thirty carbon atoms) and form the steroidal tetracyclic and pentacyclic structures shown above. Other isoprene-based plant constituents, which we will be studying in greater detail as we cover the remaining lessons include:

Monoterpenes - two isoprene units together (10 carbons); commonly found as volatile oils, e.g., limonene, camphor.

Sesquiterpenes – three isoprenoids (15 carbons) linked together; also very volatile, e.g., zingiberene.

Diterpenes - four isoprenoids (20 carbons); e.g., Vitamin A. Triterpenes - six isoprenoids (30 carbons); e.g., glycyrrhetinic acid,

various resins. Tetraterpenes - eight isoprenoids (40 carbons); e.g., carotenoids, plant

pigments such as lycopene from tomatoes, Vitamin K. Polyterpenes - greater than 40 carbons; e.g., rubber.

Let's look now in more depth at the triterpenes and their value in herbal medicine.

Fig 3.7

Saponin structural nuclei



Triterpenes Triterpenes are the largest group of terpenoids with over 4,000 different structures known. As noted above, triterpenes are considered to be of two types, the steroidal and the pentacyclic. In actual fact there is a third category, the aliphatic triterpenes, which includes squalene from animals and the unsaponifiable matter in olive oil. For our purposes here though, we will be limiting our discussion to the first two. We will be looking further into the chemistry of triterpenes in later lessons. From the botanical point of view, it is believed that saponins protect the plant from insects, predators and fungal infestation. Many herbs containing triterpenoid saponins are considered ‘adaptogenic' for humans. They improve an individual's resistance to a wide range of stresses, whether physical, mental, emotional, environmental or of other origin. It has been hypothesized that, because of the similarity of triterpenoids to certain hormones produced by the human body, they are able to ‘amplify' the effects of the hormone-secreting glands. At the same time, there is a decrease in the actual workload placed upon these glands, allowing them to manufacture fewer hormones and have more energy for conservation and repair. This “adaptogenic effect” has almost called for a rewriting of pharmaceutical theory, as it doesn't fit into the strict cause and effect model beloved by the scientific community ... suggesting that a medical substance interacts with the patient, rather than the more likely effect of a chemical causing another chemical to produce a predicted action. Knowing what we now know about the extremely subtle control mechanisms existing within a living body, this chemical interaction theory really does make sense. When considering the subtle exchanges between the endocrine and nervous system, especially by the cytokines, we see a complex system of receptor sites, activation sites and whole lines of communication vaguely understood. We can easily extrapolate that a remedy is state-specific, meaning the remedy would have a different reaction depending on the state of the body on which it is acting. If a remedy works by coordinating communication of the central control system of the body, it would certainly increase adaptability of the body, thus having an adaptogenic action. This means that instead of a remedy correcting a fault in the body, it helps maintain some sort of balance or homeostasis when the body is under threat.



This, of course, not only lets us treat illness before it becomes a serious problem, it lets us increase the overall resistance of the body so the threat is minimized. Practitioners can look at the system not just in terms of fixing pathologies, but also in terms of supporting the vitality of the system. By helping a person to cope with stress, adaptogens can aid in learning, improved memory, increased athletic performance, and increased stamina. They can also alleviate small complaints, and cut down on infections of a prophylactic nature. This makes triterpenes similar in nature to the immunomodulating branched polysaccharides. It is of no wonder that many adaptogenic botanicals (especially the fungi) contain both saponins and polysaccharides. How do adaptogenic herbs work? Well, there is intense ongoing research in this area. One of the major players, Prof. H. Wagner from University of Munich, gives us a little bit more insight beyond the ideas advanced by Fuller as reviewed in the text. Again this is but one model. It appears that stress affects the hypothalamus-pituitary-adrenal gland axis. Stress stimulates the hypothalamus to produce corticoliberin CRF, producing activity in the pituitary gland, releasing corticotrophin ACTH (adrenocorticotropic hormone) to stimulate the adrenal glands to produce corticosteroid, which has an effect on the system tissue. In many animal models, botanicals such as Siberian Ginseng will:

• prolong maintenance of body temperature following cold temperature stress

• show improvement in coordination function • improve cognitive ability • increase locomotor and explorative activity • show improvement in emotional behavior • prevent stomach ulceration by aspirin, cold stress or

immobilization • decrease resistance to dairy allergies • improve general immune defenses

Some adaptogenic herbs are: Panax ginseng (and related species), Siberian Ginseng, Licorice, Sarsaparilla, Wild yam, Bupleurum spp. Reishi, Codonopsis spp., and Ashwagandha.

Fig 3.8

Model of adaptogenic effect on the endocrine system



Steroidal Triterpenoids (tetracyclic)

These are found less commonly in nature than the pentacyclic triterpenoids, but are of great clinical significance. They are present in many families including the Dioscoreaceae and Liliaceae. Diosgenin, a steroidal triterpenoid from Mexican Wild Yam (Dioscorea mexicana, D. floribunda), served as the original source for the production of steroidal contraceptives and sex hormones, and has also been used for the production of corticosteroids (though most of these are now totally synthesized). Please note, however, that diosgenin, which through laboratory procedures is converted to the hormone progestin (a synthetic progesterone), will not convert to progesterone through physiological processes in vivo. Much media hype has spread through the misconception that Wild Yam, either through oral ingestion or topical application, can be used to directly supplement natural progesterone production. The steroidal saponins exhibit a relationship with our innate hormones, exerting a ‘hormone-like' action within the body. Their molecular structure, which is analogous to cholesterol, resembles a variety of the body's hormones including the sex hormones (e.g., estrogen, progesterone, testosterone), cortisone from the adrenal cortex, and vitamin D. These hormones are all built using cholesterol as the nucleus. Included in the category of steroidal triterpenoid adaptogens are Ginseng (ginsenosides from Panax spp., which also contains pentacyclic triterpenoids), Siberian Ginseng (eleutherosides from Eleuthrococcus senticosus), Sarsaparilla (Smilax spp.) and Reishi mushroom (Ganoderma lucidum). Many of these adaptogens also contain the immunomodulating branched polysaccharides (as covered in previous lesson), e.g., gandelans A and B from Reishi, panaxans A-E from Ginseng, and eleutherans from Siberian Ginseng. Thus we see that the triterpenoids and the branched olysaccharides both contribute to the overall adaptogenic effects of these herbs. There are some other benefits to saponins that are often overlooked by modern pharmacology. Most saponins have a notable stimulating expectorant effect on the respiratory tract. This appears to be a reflex reaction of stimulation in the stomach wall. Most saponin-containing compounds, if taken in large amounts, will have an emetic effect. This is due to the detergent action promoted by hydrolyzation in the stomach. At a sub-emetic dosage, an expectorant action often occurs. This effect might also contribute to a saponin-containing plant's action on the urinary tract or even as an anti-inflammatory. Some saponins are known to increase the absorption of minerals. It appears the saponins in spinach, asparagus, beets, oats and many of the legumes might be useful in this way.



The detergent action of saponins may have significant wound healing properties as we find many saponins in wound-healing plants such as Calendula officinalis and Arnica montana. Some other herbs that contain large amounts of saponins are: Expectorant: Goldenrod, Pokeroot, Mullein, Squill, Violet leaves, Soapwort, Seneca, Bittersweet Diuretics: Corn silk, Primula, Scarlet Pimpernel Anti-inflammatories: Wild Yam, Chickweed, Yucca spp., Bupleurum

Please read from p. 119 - to end of Saponins

Let's now review the herbs, which were covered in the textbook for this section on steroidal saponins.

Asian Ginseng (Panax ginseng)

American Ginseng (P. quinquefolium)

Ginseng is long renowned for its ‘panacea' or adaptogenic effects, with its reputation extending back well over 2000 years. When considering all of the ‘active ingredients' in this herb, along with all of its therapeutic actions, it is easy to see why the Asians had strong stories or myths around choosing the right root for the various applications. Walking around in the great botanical auction houses in China (some the size of several football fields), one sees extremely astute grading systems at play. Taste, shape, wild or cultivated, age, environment harvested in; all play a major role at least on the economic side of the Ginsengs. The great Masters of the Orient have used these attributes, rather than a plant’s chemistry, to determine the root's action. Here is a clear case of the ‘personality' of the root playing as important (if not more important) a role as the constituents. The roots of Asian Ginseng contain triterpenoid saponins, called ginsenosides by Japanese researchers (also referred to as panaxosides by Russian researchers). They are not two separate groups of constituents as once thought and as suggested in the text. There still is some confusion in this area trying to dovetail the two naming systems. The Ginsengs contain at least 18 different saponins and are designated as Ra, Rb ... Rg-1, R g-2, etc.

Fig 3.9 Asian Ginseng (Panax ginseng)



Compared to American Ginseng (P. quinquefolium), Asian Ginseng is higher in the Rg ginsenosides (which is higher in Rb to Rg1 and does not contain Rf and Rg2 ginsenosides). Asian Ginseng has more of a tonic or adaptogenic effect and produces other results in both humans and animals that include: raising blood pressure (hypertensive effect), stimulating central nervous system activity, enhancing mental acuity, lessening fatigue, and improving stamina. It is also anabolic in its effect, that is, it has been demonstrated to stimulate DNA and RNA, protein and lipid syntheses. The capacity of skeletal muscle to produce cellular energy, through the preferential oxidization of free fatty acids over glucose, has been demonstrated in animal test models using an extract of Asian Ginseng. It has also been shown to have a remedial effect on radiation sickness, diabetes, neurosis, and cancer. It has been shown to have an antagonizing effect on depressants, such as alcohol, chloral hydrate and barbiturates as well as an antihepatotoxic effect in vitro. The ginsengs stimulate sexual response in both males and female, but have no sex hormone effects. It is interesting to note that some of the individual constituents seem to have opposite action to each other; Rg1 (found highest in Asian Ginseng) raises blood pressure and is a central nervous system stimulant, while Rb1 (found highest in American Ginseng) lowers the blood pressure and is a central nervous system depressant. These attributes might seem to cancel each other out, but in reality they don't. These attributes seem to be cumulative, not reducing the action of the ginsengs. This dual ability lends itself to the overall adaptogenic interaction of the herb and the body. This also leads us to see how the state of the body reflects the action of the herb. The conflict does two major things: 1) it makes reading the literature occasionally quite confusing, and 2) it shows that choosing different ‘personalities' for herbs by traditional herbalists reflects some of the contradictions confirmed by science. Many

Fig 3.10 American Ginseng (Panax quinquefolium)



conflicts in the results of clinical data can also be attributed to the route of administration, type of preparations, dosage and, of course, the ratio of constituents. Traditional herbalists have learned to determine these qualities by means other than chemical analysis. Energetically, Asian Ginseng has an overall warming property while American Ginseng is cooling in nature. It is surprising to note that many Asians prefer the calming action attributed to American Ginseng over the Asian Ginseng. The opposite is the case in North America. Maybe this reflects the mental state of the respective societies. Experiments on the ginsengs have found (as noted earlier) these herbs to have a profound sensitizing effect upon the hypothalamus, a gland located in the brain, which controls and directs the response of other endocrine (hormone-secreting) glands. In response to ginseng's effect, this gland then secretes Corticotropin Releasing Hormone (CRH). CRH in turn increases secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary, which then stimulates the adrenal cortex to increase production of glucocorticoids, primarily cortisol. The result of this is an overall increase of plasma corticosteroid content (and subsequent increase in urine output of corticosteroid by more than 60%) and thus an increased resistance to stress. Cortisol also helps to regulate metabolism and is anti- inflammatory. Ginseng enhances the ability of the adrenal glands to stop secreting adrenalin (produced in the adrenal medulla in response to nervous system input) when the stress-inducing situation is no longer present. This decreases the adrenalin load placed on the body, lessening the duration of sympathetic nervous system stimulation (the "fight or flight" response). Chronic stimulation of this type can lead to "adrenal burnout" and an overall decreased resistance to stress. Some researchers believe that the foundation of ginseng's adaptogenic effects is through its ability to reduce the amount of time the body operates under decreased amounts of vitamin C, while under stress. Reducing the need for vitamin C when under stress, or just reducing refractory time of stress might cause this. I don't feel that vitamin C is a cause of the adaptogenic effect, but a symptom of it. Vitamin C is used up very quickly, not only during times of increased stress but also simply through its many and varied functions in the body. These functions include its role as an antioxidant, in collagen formation and in stimulation of the immune system. Humans lack the ability to synthesize vitamin C endogenously and must rely on exogenous sources such as diet and supplementation. Only very small amounts are stored in organs of high metabolic activity such as the adrenal glands, pituitary, brain, eyes, ovaries, and testes.



Though no fatalities have occurred from therapeutic dosages of Asian Ginseng, documented side effects of ginseng toxicity include anxiety, hypertension, irritability, insomnia, breast pain and menstrual changes when used long term in some people. It is often suggested that women, during reproductive years, not take Asian Ginseng long term as it may create secondary male sexual characteristics (like facial hair) in some individuals. It is often employed in post-menopause. Commission E in Germany lists no contraindications, no side effects, and no known drug interactions. The Asian pharmacopeias suggest that Asian Ginseng should be avoided in the following conditions: deficient yin patterns with Heat signs, Damp Heat or Excess Heat patterns, ascending Liver Yang, patients with high blood pressure (systolic over 180 mmHg).

Sarsaparilla (Smilax spp.)

The steroidal triterpenoid saponins in Sarsaparilla make up approximately 2% of the dried root and are comprised chiefly of two isomeric aglycones, sarsasapogenin and smilagenin. Also notable in Sarsparilla is its volatile oil content which appears to enhance the absorption of other herbs and also some drugs. This characteristic makes it a useful addition in combination formulas. Similar to the effect found with alkaloids of the Yucca plant, the alkaloids present in Smilax may also penetrate and soften hard masses. Some of Sarsaparilla's main therapeutic uses have been in the treatment of psoriasis and other skin diseases, syphilis, rheumatism and gout. It is theorized that Sarsaparilla's effectiveness may be due in part to the ability of the saponin molecules to bind endotoxins in the gut and thus stop their absorption across the intestinal wall. Endotoxins are released from the cell wall of Gram-negative bacteria and, once absorbed into the systemic circulation, place an extra burden of stress upon the liver. High endotoxin levels are associated with psoriasis, eczema, arthritis, and ulcerative colitis. Though sarsaparilla has been used in a manner similar to anabolic steroids for increasing muscle mass in bodybuilders, this benefit has not been irrefutably proven. I have had several patients who feel it does increase muscle mass. This is a realm where anecdotal information may not be reliable, but the benefits might be in the eye of the beholder. Contrary to what is written in the text, there is now an analytic test which shows sarsaparilla metabolites in the urine and Smilax is now banned in international athletic competition. It also finds use as a flavoring agent in soft drinks.

Fig 3.11 Sarsaparilla (Smilax spp.)

Fig 3.12 Smilagen



Wild Yam (Dioscorea villosa, D. spiculifora, D. floribunda) Synonym: Mexican Wild Yam

As mentioned previously, these species of Yam (not to be confused with common table yams) provide a rich source of steroidal precursors, primarily the tetratriterpenoid, diosgenin. Diosgenin, as previously mentioned, is used for the production of various synthetic hormones including progestin, other sex hormones, and corticosteroids (cortisone). Yams also serve as a source of beta-carotene for supplement production. Other species, such as Wild Yam (D. villosa), are widely employed in herbal medicine. They are valued for their antispasmodic properties, with particular focus on the smooth muscle of the intestinal tract and entire

abdominal region. It is thought that the alkaloids contained within Wild Yam act as a sedative on local nerves and thus have a relaxing effect on the associated muscles.

Pentacyclic Triterpenoids

This group of saponins is abundant in many of the dicotyledon families including the Berberidaceae, Papaveraceae, Lobeliaceae and Compositae (Asteraceae), however are rare in the monocotyledons. One herb of especially notable significance containing pentacyclic triterpenoids is Licorice (Fam. Leguminosae). Licorice, Asian Licorice (Glycyrrhiza glabra , G. uralensis)

The root and rhizome of licorice have been used as medicine for thousands of years, with many of the historic uses finding validation today by modern pharmacological research. Within the root, in concentrations varying between 6 - 13%, is the pentacyclic triterpene, glycyrrhetic acid. To aid in clarification of the many different ‘glycyrr' prefixes associated with licorice, following is a breakdown of the various terms:

Glycyrrhetic acid - the sapogenin, i.e., aglycone fraction Glycyrrhetinic acid - synonym for glycyrrhetic acid Glycyrrhizinic acid - the saponin glycoside, i.e., the

diglucopyranosidic acid variant of glycyrrhetic acid Glycyrrhizic acid - synonym for glycyrrhizinic acid Glycyrrhizin - mixture of the sodium and calcium salts of

glycyrrhizinic acid

Fig 3.13 Mexican Wild Yam (Dioscorea villosa)

Fig 3.14 Diosgenin

Fig 3.15

Licorice (Glycyrrhiza glabra)



Glycyrrhizin hydrolyses in the upper GI, to yield glycyrrhetinic acid and two molecules of glucuronic acid. Some consider glycyrrhetinic acid to have ACTH-like action on a functional to semi-functional adrenal cortex. The characteristic sweet flavour of licorice is due to the triterpenoid glycyrrhizin, which is 50 times (not 150 times as suggested in the text) sweeter than sucrose (table sugar). Also within the roots of licorice are flavonoids such as liquiritin and isoliquirtin, which impart a yellowish colour. Flavonoid-rich fractions of licorice have been noted for their antigastric effects and have been proven effective in the treatment of peptic ulcers. This flavonoid fraction is not only spasmolytic and capable of reducing the pain associated with ulcers, but also enhances healing, is antimicrobial and anti- ulcerogenic. Glycyrrhetic acid has been found to demonstrate cortisol-like action in vivo, making it useful in the treatment of inflammatory conditions such as rheumatoid arthritis. Also attributed to glycyrrhetic acid is an aldosterone-like action. This may lead to sodium retention, potassium depletion and high blood pressure, though the degree of these effects varies greatly between individuals. A high-potassium, low-sodium diet can help prevent these unwanted side effects. Licorice extracts have been used successfully even in those individuals with hypertension and angina. Because of the aldosterone-like action of glycyrrhetic acid, licorice can be of benefit in the treatment of Addison's disease. Using deglycyrrhizinated licorice (DGL) products in the treatment of other conditions will eliminate the potential occurrence of the above mentioned side effects, while still providing excellent results. Other pharmacological actions exhibited by licorice include antitussive, expectorant, estrogenic, anti-hepatotoxic and antiviral (for a wide range of viruses).

Fig 3.16 Licorice constituents



Cyanophose Glycosides

Cyanophose (cyanogenic) glycosides are natural, organic sources of cyanide derived from nitrile compounds. Within the plant kingdom, cyanophose glycosides are present in over 3,000 plants, including 110 families (most prevalently in the Rosaceae family) and in some ferns and fungi. Like most other glycosides, they are colorless and soluble in water. Along with their medicinal uses, cyanophose glycosides are often used as flavoring agents and in the cosmetic industry. They all contain the element nitrogen in the form of hydrocyanic acid (HCN) or hydrogen cyanide, also known as prussic acid. This group of chemicals can be very toxic, therefore, caution should be employed when using these herbs.

Please read p. 127 to top of p. 128, Apricot Kernels The most common cyanophose glycosides are amygdalin and mandelonitrile. As depicted in Fig. 4.21 of the text, the hydrolysis of amygdalin (present in large quantities in Bitter Almonds), produces hydrocyanic acid (HCN). Please note that the diagram for HCN as found in the text (fig 4.21) is right and that figure 4.22 should really be labeled Prunasin. Amygdalin is the source of the bitter taste found in this species of almonds, as well as in the seeds of apricots, cherries, plums and other members of the Rosaceae family. Because benzaldehyde is a byproduct of amygdalin hydrolysis, this cyanophose glycoside could be considered an aldehyde glycoside. Cyanogenic glycosides can also be found in Clover, Chamomile, Yarrow, Flax, Elder and of course Hawthorn. These are heavily used medicinal plants without any side effects of cyanide poisoning. Even though hydrocyanic acid is a violent poison, oral intake in this form doesn't usually cause intoxication. The amount needed to produce a toxic effect (over 0.5 - 3.5 mg/Kg; 30 - 270 mg) only can be achieved if a person consumes very large amounts of these usually distasteful herbs. The glycoside would also have to be hydrolyzed in the digestive tract. Fortunately the human system has an amazing ability to rapidly detoxify cyanides to thiocyanates (about 1 mg per hour), resulting in elimination through the urine. This is a clear example of why we shouldn’t condemn an herb simply because of a single ingredient. Toxicity is caused by cyanide ions combining with cytochrome C oxidase of cytochrome C, thus inhibiting the cellular use of oxygen. This will result in a change in respiratory rhythm, as well as headaches, high facial color, dizziness and inebriation. After this, conscious disturbances are noticed, followed by a deep coma and respiratory depression. If the dose doesn’t cause rapid death, an appropriate treatment would be immediate stomach pumping, oxygen therapy, and chelation of cyanide ion by hydroxyl-cobalamin infusion, and stimulation of detoxification with sodium thiosulfate. EDTA is often employed in these cases.



After all this talk of toxicity, it should be noted that large amounts of cyanophose glycosides can be found in cassava or manioc, the food staple of South American indigenous people. They prepare a ‘flour’ after boiling and leaching out the toxin. This is another amazing example of how indigenous people have an intimate understanding of local flora. In small amounts cyanophose glycosides can have very good therapeutic activity. Some, such as those found in Wild Cherry bark, are antitussive agents, employed in cough drops and cough syrups and have significant antispasmodic and sedative action. They increase the activity in the parasympathetic nervous system and thus increase vagal tone, slowing heart rate and improving digestion. The folk application of these effects can be observed in the habitual eating of almonds and almond desserts in the Middle East. We can also see that these compounds, in low doses, increase respiration (again, Wild Cherry bark).

Please read p. 128 through p. 129 Included in this discussion of cyanophose glycosides are three of the most

important sources: Apricot Kernels, Wild Cherry Bark, and Bitter Almonds.

Apricot Kernels (Prunus armeniaca)

Amygdalin is extracted from the kernels of Apricots. It is the source of laetrile (vitamin B17). Laetrile is used in some cancer therapy regimes, primarily in clinics in Mexico. It is believed to accumulate in cancerous tissues and cause anoxia in these tumor cells, due to the inability of cancer cells to detoxify cyanide. Laetrile's effectiveness in this regard is still controversial, as no animal model research has supported the theory of antitumor activity for amygdalin. There are a large number of people who seemed to go into ‘remission', with tumor reduction after the use of laetrile. If laetrile does work, the accumulation of toxic cyanide in the tumor is a bit closer to a concept of plant-based chemotherapy, than traditional natural healing. On the other hand, there have been several

cases of deaths reported in individuals taking laetrile, with evidence of hydrocyanic acid poisoning present. A fixed oil extracted from apricot kernels is used extensively in many massage oil products. It is less expensive to produce than almond oil, and has a softening effect upon the skin. It can be toxic if taken internally.

Fig 3.16

Apricot (Prunus armeniaca)



Wild Cherry (Prunus serotina, P. virginiana)

The bark of this tree is best collected in the autumn when it is greenish in color. The month in which it is harvested will greatly affect the yield of its major cyanophose glycoside, prunasin (not a separate glycoside). (See Fig 4.27 in text and Fig 3.24 in this lesson). The greenish tinge in the bark is due to the presence of chloroplastids, formed by increased photosynthesis, and is an indicator of an increased percentage of prunasin. Prunasin, the major cyanophose glycoside found in Wild Cherry bark, is hydrolyzed by the enzyme, prunase (please note errata in text; it is prunase not pronase), to yield hydrocyanic acid. After harvesting, the bark is dried and then utilized primarily in cough preparations, both for its pleasant flavor and its excellent expectorant and sedative actions. Interestingly, in China Cherry bark is used to treat toxicity of another cyanophose glycoside such as in Apricot kernel poisoning.

Bitter Almond (Prunus amygdalus)

As the name suggests, Bitter Almonds are a high source of the bitter-tasting cyanophose glycoside, amygdalin, and contain almost 50 times more cyanide than Wild Cherry bark (Bitter Almonds measured 1819 ppm CN vs. Wild Cherry's 38 ppm). Its attributes are comparable to Wild Cherry bark and can be used similarly. Bitter Almond has much stronger antitussive action than Cherry bark. It is used extensively for persistent cough in Chinese preparations. It is not to be confused with Sweet Almond (Prunus dulclis, syn. P. amygdalus), which contains only trace amounts of amygdalin. While the fixed oil of Bitter Almond seed is extracted for use as a massage or bath oil, the volatile oil is largely used as a flavoring agent. Isothiocyanate Glycosides

The isothiocyanate glycosides (also classified as glucosinolates) are a group of colorless compounds common in the seeds of the mustard family (Cruciferae), having a characteristic sharp, irritating odor and the ability to

Fig 3.17

Wild Cherry (Prunus serotina)

Fig 3.18 Amygdalin converting to

Prunasin

Fig 3.19 Amygdalin

(laetrile; Vitamin B17)

Fig 3.20

Bitter Almond (Prunus serotina) (Unripe in picture)



raise blisters on the skin. The most widely studied of the isothiocyanates are: sinalbin, from white mustard; sinigrin, from black mustard; and gluconapin, from canola (syn. rapeseed). These glycosides are hydrolyzed by the enzyme myrosin, producing volatile mustard oils, which in the plant itself, serve a protective function against parasites. (Please note an errata: in the first paragraph of page 131, myrosin is misspelled, missing the ‘r'). The isothiocyanate glycosides are also antimicrobial, and in recent findings, cruciferous vegetables in the diet have been shown to have an important preventative role in cancer of the colon. It can be noted that this group of glycosides, especially those found in cabbages, can depress thyroid function, possibly producing goiters. This has really only been noted in cattle, but might be present in inland communities where the human diet is very low in iodine. This effect may be useful though, in the cases of patients who have hyperthyroidism. One might not want to consume large amounts of these foods if on a weight loss program, as they will tend to reduce the metabolic rate. This is unfortunate; as such vegetables usually contain very few calories. Please read from p. 130 through to Flavonol Glycosides, p. 132

Now, let's review three herbs which are representative of the isothiocyanate glycosides, Mustard, Horseradish Root and Nasturtiums.

Mustard (Brassica nigra, B. juncea)

In this plant, the principal constituent is the isothiocyanate glycoside, sinigrin (potassium myronate). When the seeds of the Mustard plant are crushed and powdered, the hydrolytic enzyme, myrosin, is liberated from adjacent cells. When the powder is subsequently mixed with water, the

myrosin will hydrolyze sinigrin to the pungent Mustard oil, allyl isothiocyanate. Allyl isothiocyanate is very effective in increasing local vasodilation, thus its traditional use as a rubefacient (local irritant) in external mustard packs on the chest. Used in this way, Mustard aids in breaking up congestion in the respiratory tract, especially in the bronchioles and lungs. Always ensure that the skin is protected from direct contact with the Mustard pack, as excessive irritation and blistering can occur. Small amounts of Mustard oil taken internally may be used to stimulate digestion, while large amounts should be avoided unless an emetic effect is desired.

Fig 3.21

Mustard (Brassica juncea)



Horseradish Root (Cochlearia armoracia) Horseradish is also known to produce allyl isothiocyanate from sinigrin, present in its root. This volatile oil can be easily produced by mixing the freshly grated root with either water or apple cider vinegar. When this combination is chewed in the mouth, the volatile oil vapors rise into the sinus cavities. These vapors help to cleanse and restore the mucous membranes there, while also having an antimicrobial effect. In the stomach, Horseradish root is mildly stimulating to digestion.

Nasturtium (Tropoeolum majus)

This commonly grown ornamental contains flavonoids and glucotropaeoline (which hydrolyzes to release benzyl isothio-cyanate). This constituent is known to have strong antibacterial and antifungal properties. Nasturtium has been used to treat skin, nails and dandruff. It is applied topically on the itching and peeling scalp. It can also be employed for sunburns, superficial burns and diaper rash. Orally it has traditionally been used for acute benign bronchial problems.

Flavonol Glycosides

Flavonol glycosides and their free state aglycone fractions, the flavonoids, comprise over 3000 different compounds and are the largest group of naturally-occurring phenols. This of course has many scholars classifying them under a polyphenolic system, instead of a glycoside one. A common feature of flavonoids is the coloration, which they impart to plants, ranging from yellow, orange, and red, through blue and deep purple. There are several colors of flavonoid we cannot see, as they absorb near-UV radiation. Insects can only see these ‘colours’ and use them as a guide to the pollination areas. These compounds are also toxic to the insect, protecting the flower from predators. Many flavonoids also protect the plant from UV-light ("plant sun screen") as seen in leaves. Flavonoids are thought to have a growth-regulating effect in the plant. Plants often respond to injury by producing large amounts of flavonoids. Their taste can be either bitter or sweet. With very slight changes in their structure,

Fig 3.22

Horseradish Root (Cochlearia armoracia)

Fig 3.23

Nasturtium (Tropaeolum majus)



humans will perceive a huge difference in taste. It shows us that the bitter and sweet receptors on our tongue must be very similar. As a group we can say flavonoids are often very bioactive, with many health benefits. They have been used in cancer prevention, in anti-aging protocols, and as anti-oxidants. Every green plant creates flavonoids to some degree.

Please read from p. 132 to beginning of Ginkgo, p. 134

The flavonoid “skeleton” is a molecule which contains two benzene rings (C6 groups), with a heterocyclic oxygen ring between them. There can be many variations on this general structure, depending on the side chains and linkages present. Even though this whole group can be called flavonoids, many authors split the classification into more detail. Below you can see the different structure of the most common groups. Flavones, a type of flavonoid, often imparts a yellow (Latin flavus, yellow) color to plants and are abundant in the Umbelliferae and Compositae

Fig 3.24

Types of Flavonoids



families. Two of the most commonly encountered flavones are rutin and hesperidin, commonly referred to as "Vitamin P" — the permeability factor — for their vasoprotective properties. They can be found in the white pulpy parts of oranges, between the segments and lining the peel, and have the ability to decrease both capillary permeability and fragility. Anthocyanidins (the aglycone of anthocyanins) are another type of flavonoid and confer various shades of red and blue, as are found in the Rosaceae and Vacciniaceae families. Bilberry (Vaccinium myrtillus) is one example of an anthocyanin-containing herb.

Flavanols, are also known as flava-3-ols, indicating that they have a hydroxyl group attached to C3 of the saturated central ring. The most famous in this group are catechin and epicatechin (and derivatives) found in green tea. These have been shown to have antioxidant, antiangiogenic, anticancer, anti-atherosclerosis, antihypertensive and cardioprotective properties. Flavonoids are often referred to as "biological stress modifiers" since they can help protect us from a large array of environmental stresses. They are anti-inflammatory and anti-allergic, finding great usefulness in allergy-related conditions. Quercetin is a flavone found in many foods, such as the yellow parts of yellow onion, russet potatoes, and in broccoli, and is especially effective as an anti-inflammatory in IgG-mediated food allergies. It is also very useful in asthma and in IgE-mediated hay fever allergies. Chalcone, a flavonoid found in Licorice, functions similarly to quercetin by blocking the formation of certain leukotrienes associated with asthma.



Their action as enzyme inhibitors (or sometimes stimulators) has significant therapeutic value. Some enzymes which are inhibited are listed below:

Aldose reductase - which causes diabetic cataract, is inhibited by quercetin, as well as by luteolin and kampferol.

Xanthine oxidase - causes hyperuricemia (leading to gout and kidney stones), inhibited by a flavonoid with free hydroxyl-groups at C-5 & C-7.

Tyrosine protein kinase - increases premalignant cells, is inhibited by flavonoids.

Lipoxygenase & cycloxygenase - producers of inflammatory prostaglandins, leukotrienes & thromboxanes (arachidonic acid derivatives), are inhibited by some flavonoids.

Cyclic nucleotide phosphodiesterase (PDE) - a key enzyme in the promotion of platelet aggregation, is inhibited by many flavonoids. Other attributes of flavonoids include antiviral, antithrombotic and anticarcinogenic.

They also function exceptionally well as antioxidants, covering a wider range of free radicals than most other antioxidants. Before we go on to discuss several of the flavonoid plants we should take a short look at isoflavones, which are only found in the legume (Fabaceae) family. These are classified loosely under the flavonoids, even though they rarely occur in a glycosidic form. Their structures are very similar to estrogen and are sometimes called phytoestrogens. They bind to estrogen receptor sites, but have relatively low estrogen activity. The most studied of these is genistin, as found in soya milk. It has been shown to reduce breast cancer, as well as other tumor systems. We can also find isoflavones

in Licorice, Alfalfa and Red Clover, possibly contributing to their activity.

Please read from Ginkgo, p.134, through end of p. 138 Let us now review four herbs renowned for their bioflavonoid activity, Ginkgo, Milk Thistle, Hawthorn and Bilberry.

Ginkgo (Ginkgo biloba)

Ginkgo, also called the Maidenhair Tree, is considered a "living fossil." It is at least 200 million years old and is the oldest tree

species on the planet, with each tree capable of living as long as 1000 years. Its bi-lobed, fan-shaped leaf is a distinctive feature, as is its dioecious nature (male and female flowers borne on separate trees). Ginkgo is very resistant to all kinds of pests including viruses and fungi. It is also resistant to many types of pollution, being planted along city streets and in temples

Fig 3.24

Ginkgo (Ginkgo biloba)



not only for its beauty but also to help clean the air. In Taoist tradition, Ginkgo is considered to represent "unity within duality". Traditionally, the nut (fruit) of the tree has been used medicinally, primarily as a bronchial tonic. In more contemporary Western usage, the leaf is used medicinally. The bi-lobed morphology of the leaf may be considered a signature of the plant and is represented in its usefulness for conditions associated with bi-lobed organs such as the brain and lungs. Ginkgo biloba contains flavone glycosides (flavoglycosides, or Ginkgo heterosides), proanthocyanidins, other flavonoids, terpenes, organics acids, and lactones. The major medicinal constituents in Ginkgo are its flavone glycosides, with quercitin being the primary of these. Ginkgo products are often standardized to contain 24% flavoglycosides, 10% of which should be quercetin. The most commonly used Ginkgo product used in studies and sold to the public, is Ginkgo biloba extract (GBX). This extract, as stated above, is standardized to 24% flavoglycoside. This means that it takes anywhere from 50 - 75 lbs. of Ginkgo leaves to create 1 lb. of extract. The amount depends on the quality of the raw material and the amount lost in processing. In the process of making this extract, there is heavy use of industrial solvents, and this doesn't fit into some peoples' view of natural healing. We really cannot call a substance that has to undergo this amount of concentration for extraction, a natural herbal product. The best we can claim is this substance is a naturally-extracted pharmaceutical drug. This has lead many practitioners to eliminate this substance from their herbal repertory and instead make a simple 1:1 extract of Ginkgo leaves. It is doubtful these simple tinctures share the same degree of activity as the GBX imported from Europe. Many herbalists, including myself, do use the GBX in their practices. As can be predicted by the high flavonoid content, the most notable effect of Ginkgo is its profound influence upon the circulation. It affects the entire circulatory system, including the microcirculation (capillaries). It has a vasodilating effect on all vessels via stimulation of the release of endogenous relaxing factors in the arterial endothelium. These, in turn,

lower blood pressure by decreasing resistance to flow. Cerebral blood flow (both arterial and venous) is increased, greatly reducing difficulties associated with chronic cerebral vascular insufficiency such as tinnitus, headaches, vertigo and loss of short-term memory. Ginkgo also influences the carotid and peripheral circulation, and is one of the premier herbs of choice for diabetes mellitus. It is very useful when there is insufficient arterial blood flow to the lower limbs, a common complication of diabetes. As well as increasing blood flow and supply in general, Ginkgo also increases cellular oxygen and glucose utilization. This has been shown to be helpful in cases of age-related macular degeneration, a condition of increasing opacity in the pupils. We can also observe significant antiasthmatic and bronchial dilation effects from GBX.

Fig 3.25 Ginkgo’s Flavones



Ginkgo's activities are not limited to the circulatory system. Its effects upon the nervous system are also very important. In the brain, Ginkgo has been shown to increase the number of acetylcholine receptor sites, as well as increasing neurotransmitter release into the synapses. This can be of benefit for enhancing overall neural transmission, including alleviating depression and increasing concentration ability. Considered the premier medicine for increasing memory, it can be effective at the first stages of Alzheimer's disease. It has also been shown to reduce cerebral edema and neurotoxicity, while modulating cerebral energy metabolism. Like other flavonoids, Ginkgo's heterosides function very effectively as free-radical scavengers (antioxidants). A significant indication of this is its ability to inhibit lipid peroxidation. Ginkgo has also been found to inhibit PAF (platelet-activating factor) thus minimizing blood clots due to platelet aggregation. This might be another reason why GBX reduces inflammation, as well as, cardiovascular and respiratory disorders.

Milk Thistle (Silybum marianum, Carduus marianum)

This member of the Compositae family is rich in a group of flavolignans collectively referred to as ‘silymarin.' Silymarin consists of silybin, the component that yields the most biological activity of this group, silydianin and silychristin. The plant normally has between 4 - 6% silymarin, while products currently used in scientific studies and sold to the public are usually 70% silymarin. It takes 15 - 20 pounds of Milk Thistle seeds to produce 1 lb. of extract. Just as in the case of GBX for Ginkgo, strong solvents are used. The same argument raised with Ginkgo applies here. One of the most substantive arguments raised by detractors against these strong extracts, can be at least partially addressed. It is felt by some that residues of the solvent in the final products might damage the liver. However, studies have shown there are no traceable amounts of these solvents left in the final product. Still, some very sensitive patients do have allergies to these products, similar to allergies related to industrial chemicals. Milk Thistle is a hepatoprotectant and is therefore useful in many liver dysfunctions including liver toxicity, hepatitis, and cirrhosis. It is most notably effective for its ability to fully counteract the extremely poisonous effects of Amanita phalloides, the Death-cap mushroom. Silymarin's ability to enhance liver function is thought to occur, in part, through its ability to prevent depletion of glutathione and glutathione-requiring enzymes. Glutathione is extremely important in cells for its role as an antioxidant, with levels of glutathione increasing as much as 35% with the use of silymarin. Increased glutathione levels enhances the body's ability to detoxify and metabolize poisons as well as free radicals. Silymarin also

Fig 3.26

Milk Thistle (Silybum marianum)



prevents the formation of leukotrienes. Silymarin has also been shown to stimulate RNA polymerase A, enhancing ribosome protein synthesis, increasing the regenerative capacity of liver cells. Silymarin protects the liver from aromatic hydrocarbons such as those found in organic solvents (e.g., carbon tetrachloride), and from heavy metals. It has been shown to interact with liver cell membranes, blocking binding sites and, therefore, hindering uptake of toxins. This results in reducing damage caused by alcohol, and psycho-pharmaceuticals. The flavolignans also limit fatty degeneration of the liver associated with cirrhosis (alcohol or chemical-induced). Silymarin is also a very strong antioxidant (10-fold stronger than vitamin E), blocking the release of malonyldialdehyde, producing an antiperoxidative activity. There is a valuable role for Milk Thistle in long-term treatment of chronic hepatotoxicity as well as any ‘de-tox' program. Milk Thistle also functions as a cholagogue, increasing the secretion and flow of bile from the liver and gall bladder, and as a galactagogue, promoting the secretion of breast milk.

Hawthorn (Crataegus oxyacantha)

The blossoms, berries and leaves of Hawthorn contain many biologically-active flavonoids, particularly anthocyanidins and proanthocyanidins. These impart the characteristic red and blue colours of the berries. Hawthorn flowers are especially rich in proanthocyanidins and also contain substantial amounts of other flavonoids such as quercitin. The proanthocyanidins of Hawthorn berries and flowers are of great significance in their effects upon the cardiovascular system, though the cardiotonic amines also present contribute to Hawthorn's overall effects. The flavonoids in Hawthorn help to decrease capillary permeability and fragility while also increasing intracellular vitamin C levels. Together, flavonoids and vitamin C stabilize collagen fibers by preventing destructive cross-linkage formation. They are also free-radical scavengers and inhibit certain mediators of inflammation. Crataegus is primarily used as a cardiac tonic. It improves blood supply to the heart by its dilating effect upon the coronary blood vessels. This occurs through its ability to potentiate relaxation of vascular smooth muscle and inhibit vasoconstriction triggered by substances such as histamine and acetylcholine. In addition, there is an overall improvement of metabolic processes within the heart aside from the increased blood and oxygen provided by the dilated vessels. Flavonoids in Crataegus interact with the intracellular enzyme cyclic AMP phosphodiesterase (cAMP-PDE), resulting in increased levels of cAMP within the myocardium. Increased cAMP leads to a positive inotropic effect, i.e., an increased force of contraction of the heart muscle. All of these factors help in eliminating

Fig 3.27

Hawthorn (Crataegus oxyacantha)



certain rhythm disturbances and reducing angina attacks. Hawthorn's effectiveness as a hypotensive agent is by way of a number of mechanisms, chiefly the ability of its proanthocyanidins to inhibit angiotensin-converting enzyme (ACE), its coronary vasodilating effect, and its action as a mild diuretic. Both Hawthorn extract and decoction have been shown to have antibacterial action on Shigella flexneri, S. sonneni, Proteus vulgaris and Escherichia coli. There are several other botanicals that could be included in this discussion; one of particular note is Bilberry. Bilberry (Vaccinium myrtillus)

The most important constituents of this herb are 3% anthocyanoside (such as procyanidin B1, B2, B3 and B4); other flavonoids (quercitin, hyperoside, isoquercitin and more), and several astringent substances like catechin, gallic acid. Both the fruit and the berries have been shown to have an astringent and diuretic activity. It strengthens capillaries as demonstrated in reducing venous insufficiency of the lower limbs, varicose veins, arteriosclerosis, and degenerative retinal conditions. The

anthocyanosides have been shown to protect the heart, reduce angina, protect the retina, and have a hypoglycemic and anti-edema effects. The herb has also been shown to reduce platelet aggregation, and lower blood cholesterol and triglycerides. By accelerating the regeneration of retinal purple (visual purple, rhodopsin), Bilberry anthocyanoside markedly affects the course of several visual disorders. It does this by increasing the strength of blood capillaries and reducing their permeability. The anthocyanosides in Bilberry have been shown to speed up the regeneration of rhodopsin and produce remarkably fast dark adaptation (making it easier to see in darker places, especially in the evening). The initial study has been followed by several other studies and all results have been very favourable. Bilberry's anthocyanosides have a positive effect on critical enzymes in retinal cellular metabolism and function (glucose-6-phosphatase and phosphoglucomutase). Over a series of years, Bilberry has been shown to stimulate increased vision in cases of night blindness, severe myopia, and retinal disturbances of various types and chronic visual fatigue. The most significant thing is that no side effects have been found. Anthocyanosides have been shown to be completely non-toxic when taken orally. Several other products containing the flavonoids found in pine bark and grape seeds and skins are starting to have a significant impact on the North American market.

Fig 3.28

Bilberry (Vaccinium myrtillus)



Alcohol Glycosides

As the name suggests, these glycosides are classified by the presence of an alcohol (OH) side chain as part of their basic structure. As well, the aromatic acid, cinnamic acid, serves as a common derivative for many of them. Many alcohol glycosides could also be classified as phenol glycosides. Salicyl alcohol (also called saligenin), is the aglycone of salicin and populin. Within the body, salicin is hydrolyzed by bacteria in the gut into its aglycone fraction, saligenin, and then oxidized in the blood and liver into salicylic acid. Salicin is found in Populus (Poplar), Salix (Willow), Filipendula and Spirea (Meadowsweet) and Viburnum prunifolium (Black Haw), while populin is found in Poplar. Populin appears to have a slightly stronger nervine effect than salicin, while both exhibit anti-rheumatic properties. Gaultherin, found in Gaultheria (Wintergreen) and Betula (Birch), hydrolyzes to methyl salicylate and has similar properties to salicyl alcohol. We can further break this down into the following derivatives of salicylic acid: Glycosides

Salicin - as found in Willow, Poplar and Viburnum barks Populin - Poplar species Gaultherin - Wintergreen, Birches Spiraein - Meadowsweet

Esters

Methyl salicylates - Meadowsweet, Wintergreen Salicylaldehyde - Meadowsweet Acetylsalicylic acid Asprin - synthetic derivative of salicylic acid

Salicin (rarely found freely as salicylic acid in a plant) has strong antipyretic properties acting to increase peripheral blood flow and sweat production by acting directly on the thermogenic center in the hypothalamus. This only happens if the body temperature is too high. It will actually increase body heat production if temperature is low to normal. This group of constituents increases bile volume and concentration. They are catabolic, increasing protein breakdown, increasing urinary urea and sulphur excretion. It also increases concentration of uric acid, but actively decreases uric acid excretion and thus is contraindicated in gout (even though short term relief may appear).

Fig 3.29

Salicin

Fig 3.30 Populin

Fig 3.31

Salicylic acid



The analgesic action of this group is well known, and appears to center on lowering prostaglandin metabolism and the perception of pain. This factor makes them strongly anti-inflammatory, used in rheumatic conditions. Salicylates have been shown to thin the blood and are often recommended as a prophylactic treatment for thrombotic conditions. The best known side effect of the salicylates is their ability to produce hemorrhages in the stomach, if given in high concentration. This symptom is not as common in plant-based medicine, as the concentrations are low and the breakdown often occurs further past the stomach in the digestive system.

Please read p. 139 and p. 140, to Aldehyde Glycosides

Poplar Winter Bud (Populus candicans, P. spp.)

The winter buds of the Poplar tree are rich in a resinous substance traditionally called "Balm of Gilead". This resin contains both populin and salicin glycosides, as well as up to 2% of a volatile oil (primarily umulene). As in their over-the-counter (OTC) counterpart, acetylsalicylic acid (ASA, aspirin), populin and salicin in Poplar both demonstrate anti-pyretic, anti-rheumatic and analgesic properties in the body. The volatile oil, humulene (a terpene; see lesson on Volatile Oils), is also thought to contribute to the therapeutic effects of Balm of Gilead. The bud resin can be infused into oil and applied externally to sore muscles as a very good muscle relaxant and general anti-rheumatic. Internally, salicylic acid from Poplar and Willow functions as a good analgesic and has no action on platelets. This lack of effect upon platelets is beneficial when clotting of blood is a desired result, such as with surgery. The analgesic action of salicin and populin is believed to derive from the ability of the salicylates to act on local tissue and associated sensory nerve endings, inhibiting inflammatory prostaglandins (of the E2 series).

Please read section on Aldehyde Glycosides, p.140

Fig 3.32

Poplar Winter Buds (Populus candicans)



Aldehyde Glycosides

Vanilla (Vanilla planifolia (syn. V. fragrans), V. tahitensis)

This plant is cultivated in various countries, with the majority of the annual crop being grown in Mexico and Tahiti. Today Vanilla is chiefly used in confections as a flavouring agent, and in perfumery for its pleasant fragrance. It has also been reported to be an aphrodisiac, emmenagogue and vulnerary, among other actions. Vanilla contains two aldehyde glycosides, glucovanillin and glucovanillic acid, which are hydrolyzed and/or oxidized to the aglycone, vanillin. These glycosides may also be classified as phenol glycosides, as they contain both

aldehyde and phenol structures

Lactone Sesquiterpenoid Glycosides

There are about 3,000 known structures in this classification. They have often been called "bitters" in old text. The lactone ring takes its name from lact = milk, which can be found concentrated in the milky-white latex-like sap of dandelion and wild lettuce. Even though in the past little attention has been given to this group therapeutically, we can now say that they generally have antibacterial, antiparasitic, anti-inflammatory and anticancer qualities. They have also found some activity as antispasmodics as well as being digestive stimulants. We will cover some of these botanicals in this classification under other parts of this course like artichoke (phenolic acid), chamomile and Yarrow (flavonoids), Matricaria (essential oils), chicory, dandelions (polysaccharides) and burdock (polyalkynes). The ones we will look at in this lesson are Arnica, Feverfew and Sweet Annie.

Arnica (Arnica montana) Family Asteraceae (Compositae)

Constituents: The flower of arnica contains from 0.3% to 1.0% of a viscous volatile oil which in turn is made up of approximately 50% fatty acids. The most prominent fatty acids are palmitic, linoleic, myristic and linolenic acid. The aromatic constituents are terpenes, thymol, thymol methyl ether and derivatives. Arnica also contains a resin, arnicin (a bitter principle, helenalin, dihydrohelenalin), tannin, a steroid ( arnisterin, arnidiol), flavones,

choline, betaine, inulin, luteine, phytosyerol, trimethylamine, xanthophyll and carotenoids.

Fig 3.34 Vanillin

Fig 3.33

Vanilla (Vanilla planifolia)

Fig 3.35

Arnica (Arnica montana)



Mode of Action: Arnica extract increases resistance to bacterial infection by stimulating phagocytosis of the bacteria involved, notably Listeria monocytogenes and Salmonella typhimurium. Arnica is commonly applied for its sprain- and bruise-healing capability. Large doses taken internally can cause severe irritation to the mucous membranes of the stomach and bowel. The flavones are considered to be adrenalin-like precursors, which can cause a fall in blood pressure, with a cardiotonic substance. Dihydrohelenalin and helenalin and their esters are analgesic, antibiotic and anti-inflammatory. Helenalin can be allergenic and causes contact dermatitis in sensitive people. Arnica in small doses is known to immunostimulate. Arnica is very commonly used in homeopathic formulas. Feverfew (Tanacetum parthenium) (syn. Chrysanthemum parthenium) Family Asteraceae (Compositae)

Constituents: This plant is rich is sesquiterpene lactones (with a-methylenebutyrolactone structures) specifically parthenolide (0.1 - 0.9%), others including , 3-beta-hydroxyparthenolide, seco-tanapartholides A & B, canin ( chrysartemin A), artecanin, epoxyartemorin and others. There are several other sesquiterpenes that are more volatile, such as camphor, farnesene and germacrene as well as monoterpene volatile oils such as pinene, bornyl acetate and bornyl angelate. The most thoroughly studied use of Feverfew is its ability to stop or reduce migraine headaches. The exact mechanism has not been worked out, yet what is known is that Feverfew inhibits blood platelet aggregation and secretory activity in platelets and polymorphonuclear leucocytes. The migraine prophylactic action is thought to be due to a serotonin (5-HT) antagonist action, inhibiting its release into the blood, thus reducing platelet aggregation. This might be due to neutralizing of sulphydryl (thio) groups on specific enzymes that are fundamental to platelet aggregation and secretion. This mechanism is thought to be due to the a-methylenebutyrolane group as this group is known to have anti-inflammatory action. Serotonin is the most important vasoactive amine mediating vascular headaches, while also acting to lower pain threshold. Feverfew has been shown to inhibit prostaglandin biosynthesis, interfering with the action PA2 at the beginning of the arachidonic acid cascade rather than at the cyclo-oxygenase stage. Parthenolide has been shown to markedly interfere with both contractile and relaxant mechanism in blood vessels. One authority (D Awang) now feels that parthenolide is not the active constituent, or at least not the sole active ingredient, as one study showed no clinical results for migraine when there was adequate amounts of parthenolide.

The anti-inflammatory action of Feverfew has been demonstrated in clinical settings continuously. This is probably due to inhibition of the

Fig 3.36

Feverfew (Tanacetum parthenium)



release of damaging material from white blood cells in the inflamed area. The inflammatory action of Feverfew has been disputed in a double-blind study on rheumatoid arthritis patients. This study showed little effect. In this study, patients took only small amounts of Feverfew (75 mg dried herb) along with ASA, which may have reduced the effectiveness of Feverfew. The amount of parthenolides varies greatly between ecotypes. Some ecotypes have no parthenolides. This herb depends on the parthenolides as well as possibly other constituents for its mode of action. Feverfew, therefore, should only be used for the above conditions when these active constituents are of a guaranteed potency.

Feverfew is often used in weight loss formulas to enhance the function of thermogenesis, by blocking c-AMP from epinephrine receptor sites.

Phenol Glycosides

Phenol glycosides are widespread in nature and have as their basic structure an aromatic ring with an alcohol group attached. As mentioned earlier, many other classifications of glycosides could be correctly considered phenol glycosides. This would include some of the alcohol glycosides, such as salicin and populin, and glucovanillin, an aldehyde glycoside. Hesperidin, discussed under the flavonol glycosides, is another example of a potential overlapping classification of glycosides.

Please read p. 141 through bottom of p. 142

One herb in particular, which contains an important medicinal phenol glycoside, is Uva-ursi, also known as Bearberry. Let's take a closer look at this important botanical.

Uva-ursi/Bearberry (Arctostaphylos uva-ursi)

The dried leaf of Uva-ursi contains the phenolic glycoside, arbutin, which upon hydrolysis yields hydroquinone and glucose. It is not entirely known whether this hydrolysis takes place solely in the GI tract or partially in the glomerulus of the kidney, but its effect as an excellent antiseptic in the entire urinary tract is well proven. Hydroquinone has been shown to work most effectively when the urine is of an alkaline nature and a low specific gravity. As well as being antiseptic, Uva-ursi is diuretic and astringent. Its diuretic effect derives from quercitin, isoquercitin and ursolic acid, while the astringency can be attributed to the tannins present.

Bearberry is an excellent herb for many urinary tract conditions, including cystitis and pyelitis, especially when used in combination with other herbs.

Fig 3.35

Uva-ursi (Line drawing)

(Arctostaphylos uva-ursi)

Fig 3.36

Uva-ursi (Arctostaphylos uva-ursi)



It is also used as a solvent for renal calculi. Traditionally, the leaves of Uva-ursi are included in the ceremonial smoking mixture, kinnikinnick.

Other Glycosides

Other important glycosides include gentiopicrin, a bitter glycoside found in Gentian, and crocin and picrocrocin, found in Saffron. Let's review these two herbs.

Please read p. 143 to bottom of p. 144

Gentian (Gentiana lutea)

The bitter quality of Gentian, primarily due to the glycoside gentiopicrin, explains its use as a stomachic and a choleretic for enhancing digestive powers. It has been used historically for many centuries as an excellent digestive tonic, helping to regulate both hyper- and hypo-acidity conditions. It is best used in small doses for this effect, as larger doses can sedate digestion and may cause nausea

or even vomiting. Its contraindications for use include pregnant women and individuals with hypertension. Gentiopicrin has been shown to be lethal to mosquito larvae. Saffron (Crocus sativus)

The stigmas of Crocus yield glycosides, crocin, crocetin, and picrocrocin, as well as other constituents including a volatile oil. Picrocrocin, upon hydrolysis, yields glucose and safranal, giving this plant its characteristic odor. Though Saffron is chiefly used as a coloring and flavoring agent, it also has therapeutic value as a respiratory stimulant in asthma and other respiratory conditions. Crocetin has been shown to increase diffusion of oxygen in blood plasma by as much as 80%. It will bind to serum albumin and lower serum cholesterol. It has the ability to lower blood pressure and has also been used as an abortifacient (stimulating the uterus), with deaths attributed to its usage in this latter regard. Current studies are looking at in vitro indications that it can reduce cancer growths.

Fig 3.37 Arbutin

Fig 3.38

Gentian (Gentiana lutea)

Fig 3.39

Saffron (Crocus sativus)



Summary

As evidenced by the length and complexity of this lesson, glycosides are of great therapeutic importance in botanical medicine. When hydrolyzed, glycosides yield one or more sugars plus a non-sugar aglycone fraction.

Please read to bottom of p. 146 Let's complete this chapter by reviewing the eleven classifications of glycosides.

1. Cardiac Glycosides - discussed in a later chapter. 2. Anthraquinone Glycosides - important anthraquinone-containing

herbs discussed: Cascara Sagrada, Aloe, Rhubarb, Senna and Lapacho. A general characteristic of this category of glycosides is their cathartic action.

3. Saponin Glycosides - contain steroid-like compounds, often exhibiting hormone-like activity. The effects of these are varied and include anti-inflammatory and adaptogenic actions. Examples which we examined from this group include Licorice, Sarsaparilla, Wild Yam, and Ginseng.

4. Cyanophose Glycosides - these glycosides hydrolyze to yield hydrocyanic acid, a bitter agent found effective as a sedative and expectorant. Herbs with cyanophose glycosides include Wild Cherry and Bitter Almond, as well as other members of the Rosaceae family.

5. Isothiocyanate Glycosides - herbs discussed in this category include Mustard, Horseradish and Nasturtium. The volatile oil released upon hydrolysis of sinigrin in these plants is a strong local irritant, useful in chest packs for respiratory congestion or chewed to cleanse the sinuses.

6. Flavonol Glycosides - these glycosides number over 3000 and include quercitin, hesperidin and rutin. They work synergistically with vitamin C to help decrease capillary permeability and fragility and to stabilize collagen structures. The herbs we looked at which are particularly renowned for their flavonoid activity include Ginkgo, Hawthorn, Milk Thistle and Bilberry.

7. Alcohol Glycosides - included here were the glycosides salicin and populin, which convert to salicylic acid in the body and exert an analgesic and nervine effect. They are found in Willow and Birch and are especially noted in the resin of the buds of the Poplar tree.

8. Aldehyde Glycosides - vanillin from the Vanilla bean was discussed, with its usefulness limited primarily to that of a flavouring agent.

9. Lactone Glycosides - included the sprain- and bruise-reducing quality of Arnica; the migraine reduction of Feverfew and anti-malaria properties of Artemisia annua.



10. Phenol Glycosides - this group contains arbutin, found in the herb covered in this section, Uva-ursi. Arbutin is hydrolyzed, either in the GI tract or in the glomeruli, to yield the powerful urinary tract antiseptic, hydroquinone.

11. Other Glycosides - in this section we reviewed Gentian, renowned for its bitter stomachic action, and Saffron, which has been used as a respiratory stimulant, blood lipid-lowering ability and an abortifacient.

This chapter has given us a glimpse of some specific plants which contain therapeutic glycosides. The list of herbs we have discussed is not exhaustive, as there are many other glycoside-containing plants of equally great medicinal benefit.

advanced herbology lesson 3 lesson 3...anthraquinone-containing herbs are not often given by...

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