Integration of Ancient and Modern Medicine Towards a Sustainable System of Animal Production and Medical Care
Jen-Hsou Lin DVM PhD
Phil Rogers MVB MRCVS
Haruki Yamada PhD
Paper to the 24th IVAS Congress, Chitou, Taichung, Taiwan, August 1998
Part 1
Phil Rogers MVB MRCVS
Haruki Yamada PhD
Paper to the 24th IVAS Congress, Chitou, Taichung, Taiwan, August 1998
Part 1
Introduction
We use the word "sustainable" to mean a system that puts back, or replenishes, what we take out of the system, with minimal damage to the environment or to the creatures that depend on it. Our current western- and strictly profit- oriented approach to agriculture and food production is not sustainable indefinitely. When we use irreplaceable natural resources at grossly excessive rates, we are stealing them from our neighbours and our descendants. When we pollute our world, we lay the seeds of our own destruction, and we put future generations in danger. If we continue with our present systems, humanity will have a high price to pay. There is no greater human tragedy than the curse of children on the actions, or spirits, of their parents or ancestors.
We live in nature and we depend on nature. If we abuse nature, it will abuse us. Buddhist and many other ancient philosophies, eastern and western, teach that we should show care and compassion for each other, our animals and our environment. The human population is at its highest ever. Because of inequalities of food production and its distribution, famine and malnutrition occur regularly. Thus, the production of wholesome human food, and its distribution to people in need is an ongoing problem that needs international attention.
Apart from animals produced for human food, other species of domesticated animals suffer from many chronic diseases for which western medicine has only partially successful, or very expensive, answers. Examples are cancer and geriatric diseases in pets, and chronic musculoskeletal disorders in sports animals.
Public demand is increasing for a more natural system of animal production, care and welfare. Traditional Chinese medicine (TCM) is one of the most natural and sustainable systems of medicine known. It has very well documented laws and theories. Its laws have been proven by constant use in humans and animals over millennia; its theories have been tested in-vivo and proven or amended by constant criticism and dynamic discussion from within its peers. It uses mainly Chinese Herbal Medicine (CHM), physical medicine (acupuncture, thermotherapy (moxibustion) and mental therapy (Qigong, meditation etc). CHM is the oldest and best-documented system of medicine known. To understand CHM, one must understand the essential concepts of TCM. Its methods of diagnosis are complex and holistic: by a detailed process of pattern recognition, they determine the TCM Syndrome, the nature and location of energy (Qi) disorder in the subject. TCM is used both in prophylaxis and in therapy of humans and animals. This paper suggests some ways to integrate the art, philosophy and science of TCM and modern medicine to develop a more sustainable system of animal production and medical care.
Modern versus ancient philosophy in the prevention and control of animal diseases
Modern science has shown that animal species and genetics are main determinants of the efficiency of feed conversion to meat or milk. As it costs much less to produce a kilo of dry matter (DM) from maize or rice than a kilo of meat DM, one may argue that production of more rice, cereals and protein-rich crops from land used for grazing of ruminants could solve the increasing demand for human food. If we must produce animal-derived human food, one may argue also that governments should encourage the farming of efficient converters [fish, poultry and pigs] and discourage the farming of inefficient converters [ruminants]. However large areas of swamp, mountain, marginal- and arid areas are unsuitable for most farm-uses except grazing. Also, large tracts of grassland are in private ownership. Thus, ruminant farming seems likely to remain to be the main way to convert the earth's supplies of forage and cellulose to human food, unless governments revert to systems of state-control of national resources. Such systems have been discredited on social and economic grounds and are unlikely to be revived in most countries. Even China and Cuba, two of the last bastions of state-control of national resources, are moving slowly towards a market-based economy.
Intensive production of animal-based foods has been the international norm in recent decades. To maximise profits, and minimise costs, the industry depends on high stocking densities - increasing animal numbers in decreasing land or floor areas, and/or increasing numbers in confined air-spaces. This has greatly increased the risk of infectious and parasitic diseases, and the degree of stress to which the animals are exposed. Ignoring considerations of animal welfare, increased stress reduces the efficiency of animal reproduction, lactation and growth. It also reduces their immunocompetence, leaving them more prone to infections and parasitism.
To counter these problems, and enhance profit margins, the agricultural industry has become increasingly dependent on chemical control of these problems in animals. Routine use of vaccines, growth enhancing agents, antibiotics, hormones, pesticides, anthelmintics, herbicides, organophosphates, artificial fertilisers etc is widespread. However, the high cost of modern drugs, hormones and chemicals for routine use in animal husbandry can prove prohibitive for developing countries. Also, due to accidental emissions or low-level exposure to toxic agents used in, or generated by the production process, the manufacture of potent drugs and agrochemicals poses a real threat to the health and welfare of persons working in or living near the factories, and to the animals grazing nearby.
Overuse of western drugs and chemicals has led to adulteration of human food with chemical residues. Though it is not proven conclusively, some medical researchers blame increasing resistance to antibiotics to their abuse in animals. Falling sperm-counts in human males in heavily industrialised nations have been attributed to (amongst other factors) exposure to chronic pollution of air, water and food by substances with estrogenic activity. Exposure of farm workers to agrochemicals has caused acute and chronic toxicity in those workers, including an increase in miscarriage rates and birth deformities in babies of female workers.
In recent years, other issues also have highlighted the importance of consumer perception on the consumption of meat products. They are: the bovine spongiform encephalopathy (BSE) epidemic in Europe and associated fears of contracting new variant CJD from beef, outbreaks of fatal food poisoning by Escherichia coli O157 and Salmonella typhimurium DT104.
The European Union [EU] is trying to eliminate the chemical contamination of human food and raise the standards of food safety. However, it is difficult to enforce the plethora of EU regulations, and consumers are becoming increasingly cynical of government statements as to the safety of food.
Several factors have focussed public awareness on the need for a more natural system of animal production and medical care. These include fear of chemical residues in food, antibiotic resistance and zoonosis, and several other issues, including iatrogenic diseases. These issues have stimulated interest in the Green Movement. Also, public awareness of compromised animal welfare involved in intensive farming has led to rapid growth of the Animal Rights Movement and vegetarianism. Countries whose economies depend heavily on the sale of animal-derived foods must address these issues seriously if they want to protect their public image and market share at home and abroad.
TCM and the farming of domesticated animals in China date far before the birth of Christ. Globally, TCM is the most complete system of traditional medicine. Its documentation is ancient and extensive. Constant use over several millennia has proven TCM and its concepts to be of great clinical value. Several dozen textbooks, based on translations of ancient and modern texts, are devoted to the concepts of TCM. Some of the best (in English) are by Connolly (1979), Turner & Low (1982), Hsu (1982), Kaptchuk (1983), Matsumoto & Birch (1983), Porkert (1983), Wiseman & Ellis (1995), Anon (1993), Xie et al (1994) and Wiseman & Ye (1998).
TCM is a system of Energetics and Correspondences. It sees the body as interacting with and adapting to cosmic, terrestrial-climatic, traumatic and internal forces. It sees disease as a disturbance or disharmony (Full, Empty, Stagnant) of vital energy (Qi), or Blood (Xue), or Fluid (Ye), or as imbalances of the homeostatic dialectic mechanisms (Yin-Yang), or of a more complex Five Phase anabolic-catabolic control system of the body. It also recognises powerful interaction between the soma and the psyche; imbalanced emotions can cause organic disease, and vice-versa.
TCM practitioners use complex methods of pattern recognition, based on subjective and objective symptomatology and phenomenology, to detect which COSs have Qi imbalance and the nature of that imbalance (Qi Full, Empty, Stagnant etc). Therapy that can reestablish the free flow of Qi, or rebalance it, has lasting and beneficial effects on health. Rebalancing (homeostasis) of Qi automatically eliminates all the amenable symptoms and signs of ill health. Not all symptoms and signs are amenable, for example in cases of severe organic damage (advanced cancer, chronic cirrhosis of the liver, severed spinal cord, severe necrosis of the motor neurones etc).
Once a diagnosis is made, CHM uses formulations of 4-10 herbal ingredients, to apply a complex theory of holistic treatment. Treatment aims mainly to obtain and maintain harmony of body function (homeostasis) and to expel pathogens. Many ingredients are to enhance the effects, or to act as antidotes to the unwanted effects, of other ingredients. The formulation may be changed as the subject's Qi patterns change. The history of TCM, its fundamental concepts, Syndrome diagnosis, selection and alteration of remedies are beyond the scope of this paper.
HM is a valid science, with great potential for integration with WM to the benefit of human and animal health and welfare. As the pharmacological basis becomes better understood, it will be easier to integrate HM into conventional WM. However, HM needs more research, development, goodwill and education before it can reach its full potential. Problems of supply of raw ingredients, the protection of endangered species, quality control, registration of proven formulations and access to expert information need to be addressed urgently.
The science behind TCM
The World Health Organisation (WHO 1993) supports the use of effective and safe remedies and accepts Traditional Medicine (TM) as a valuable and readily available resource for primary health care.
Many of the world's cultures developed their own forms of HMs over centuries. Today, 75-80% of the world's population still relies on HM (plants, plant extracts etc) and other tools of TM in basic health care (Abelson 1990; Chan et al 1993; Cox & Balick 1994; Schwartz 1994; Yamada 1994a; Chaudhury 1995). In Asia, especially in China, Japan, Korea, Taiwan, Vietnam etc, medical practitioners are trained to prescribe TMs together with Western Medicines (WMs) (Chan et al 1993). WMs often are expensive. To research, develop, register and market a new pharmaceutical drug in the USA takes about 10 years and costs about 200 million dollars (Abelson 1990; Cox & Balick 1994). Also WMs have sometimes limited results in many chronic conditions and their use may cause development of drug resistance and iatrogenic disease, especially if they must be used for long periods.
Because of these factors, demand for TMs, especially CHM, is increasing and traditional HM therapy is used widely in the United States and Europe (Otsuka 1988; Yamada 1994a). Although many individual ingredients used in CHM are highly toxic if used wrongly, carefully prescribed CHMs can be used for relatively long periods with minimal or no adverse effects (Hsu 1982; Hosoya & Yamamura 1988; Dharmananda 1991; Chan et al 1993; Schwartz 1994; Yamada 1994a). However, most TM systems (including HM and AP) need more scientific research on aspects of safety and efficacy (Dharmananda 1991; Chaudhury 1995; Lin et al 1995a).
CHM uses a complex combination of medicinal plant- and other- natural products (Luo & Shi 1986; Ou 1989). Plant products include specifically selected parts (leaves, branches, stems, roots, tubers or bark etc) harvested from herbs, flowers or trees etc. The other natural products include parts of living or dead tissue (animal, insect, reptiles, venoms, shell, coral etc) and minerals (mineral salts, certain types of pulverised rocks and soils etc).
CHM formulas or remedies are carefully balanced mixtures of many ingredients. They are taken as decoctions, or as extracts in water or alcohol, or as dried extracts (as pills etc). Some are used externally. Other presentations of HMs are being developed: pills, tablets, powders, capsules, tinctures, syrups, suppositories, ointments and injections etc.
CHM uses TCM theory and a TCM diagnosis of the pathological condition of the patient. When the TCM Syndrome is established, suitable HMs are prescribed. Treatment aims mainly to maintain harmony of body function, including the psyche and to expel pathogens. Many ingredients are to enhance the effects, or to act as antidotes to the unwanted effects, of other ingredients. The overall aim, and the effect when successful, is to help the body to help itself to attain homeostasis between its own natural functions and the external environment.
History of scientific research into CHM
The ancient history of TCM and CHM is documented by Ou (1989), Schwartz (1994) and Xie et al (1994).
From the 19th century up to the beginning of this century, the influx of western ideas demolished much traditional Chinese culture and science. TCM nearly became extinct. In the past 40 years, shortage of WMs has renewed Chinese interest in the techniques of TCM. In 1990, Hong-Cheng Fong published two books on veterinary herbology, which contain more than 10000 formulas, probably the biggest collection of TCVM since antiquity. Today, there is a nation-wide TCVM Society in China, with thousands of members who practice TCVM daily. Foreign (non-Chinese) graduates may attend courses on TCVM and VAP in China (Lin & Panzer 1994). Development and research into TCM in humans and animals have become popular again throughout China, Japan, Korea and Taiwan (Hsu 1982; Hosoya & Yamamura 1988; Yamada 1994a; Lin et al 1995a). Traditional Oriental Medicine (TOM) and Kampo Medicine (KM) are forms of TM from east Asia and Japan respectively. Both came mainly from CHM, or were influenced strongly by it.
Kampo literally means Han's formulas. Most formulas of KM are from two texts, both written by Zhang Zhong-jing (Zhang Ji), about 210 AD and arranged some years later by Wang Shu-He (Wang Xi) (Hsu 1982; Xie et al 1994; Otsuka 1988). These are the Shang Han Lun (Treatise on Cold-induced (Febrile) Disorders and the Jin Kui Yao Lue Fang Lun (Essentials of the Golden Cabinet). Since 1976, the Japanese Ministry of Health and Welfare has approved 146 formulations of KM. National health insurance in Japan covers the use of the herb components of such approved KMs.
WHO has issued guidelines for evaluating the safety and efficacy of HMs. National and international conferences, such as those run by the World Veterinary Association, the Japanese Pharmaceutical Society and the Medical and Pharmaceutical Society for Wakan-Yaku (Japan) also discuss these topics. Appendix 1 lists Journals that publish research on the chemistry and pharmacology of HMs and phytotherapy.
Pharmacological research in HM
Pharmacognosy is the study of compounds sought out by humans or animals and ingested, or otherwise used, as supposed medicines; zoopharmacognosy is the study of the actions of these materials in animals (Robles et al 1995). These disciplines have led to the identification of many useful medicines. Phytotherapeutics is the therapeutic use of these compounds.
In 1985, worldwide, 3500 new chemical structures were discovered and 2619 of these were isolated from higher plants. In 1987, Japan captured 56% of patented natural products summarised in Phytotherapy Research. Germany also has been more active than the United States in this field (Abelson 1990).
Research in phytotherapy can be classified under many different headings. Research on pharmacological effects of HMs will be discussed under three headings:
a. individual herbs or extracts;
b. individual active compounds of individual herbs;
c. complex HM formulas.
The boundaries between these headings are not easy to maintain; thus there is some overlap between them.
a. Research on individual herbs or extracts
Documentation of TCM is more than 3000 years old. Thus there are extensive data and cumulative experience on the use of CHM, including recent textbooks (Hsu 1982; Xie et al 1994; Bensky et al 1986; Luo & Shi 1986; Tsung 1987; Hosoya & Yamamura 1988; Ou 1989; Dharmananda 1991 and Chaudhury 1995).
Bensky et al (1986), summarises the actions of some potent herbal ingredients. Ginseng radix (ren shen = Man Root, Man Essence) is sometimes man-shaped (like mandrake). The medicinal use of ginseng in China dates to before 100 BC. There are many varieties, Appalacian, Korean, Japanese, Chinese etc. Ginseng is attributed with great therapeutic and mystical potency. Much sought-after, it is very expensive. It is one of the most often cited herbs in TCM. Experimentally, it has potent effects on the CNS and peripheral nerves. Centrally, it improves nervous responses in a homeostatic way, enhancing both stimulatory and inhibitory processes, depending on their initial state of receptivity. In this way, it resembles the homeostatic effect of AP, in which stimulation of the same AP points can have diametrically opposed effects, depending on the state of the subject. Normally ginseng is a central stimulant like caffeine but, in large doses it is a sedative. It counteracts the stimulant effects of some other stimulants and the inhibitory effect of opiates. It enhances the acute hypnotic effect of pentobarbital. Small doses of ginseng have muscarinic effects on peripheral nerve; large doses have nicotinic effects. It shortens the latency of nerve reflexes, accelerates nerve transmission and strengthens conditioned reflexes. Over long periods, it tends to the middle (neither stimulatory nor inhibitory). Experimentally, it has cardiotonic effects, similar to cardiac glycosides; it is clinically useful in cardiac arrythmia.
Huang (1993, pp21-45) devotes a full chapter to the medicinal uses and pharmacology of the root of ginseng. In summary, it contains volatile oils, saponins (glycosides, panaxosides, ginsenosides), antioxidants, peptides, polysaccharides, fatty acids and vitamins and other active ingredients, many of whose chemical structures are known. It is known as the "Elixir of Life", as it has potent antiaging effects and antiirradiation effects, probably due to its antioxidants and immunostimulating properties. Experimentally, it increases endurance in animals and has potent antistress effects against many environmental stressors (Huang 1993). It has antidiabetic/hypoglycaemic effects and alpha-2-adrenergic and antihypertensive effects (blocked by yohimibin). It has ß-adrenergic blocker effects in oxygen starvation. It has antiinflammatory effects and activates the reticuloendothelial system, dilates cerebral and coronary vessels, stimulates haematopoiesis in the bone marrow, lowers serum cholesterol levels and has antiatherosclerotic effects, which protect against cardiac ischaemia. It has potent effects on the CNS, increases concentration and awareness, increases night-adaptation of the eyes, and has sedative/calming effects. It has antipyretic effects and increases the release of corticotropin releasing factor (CRF) from the hypothalamus. It activates the thyroid, testis and ovary and has clinical uses in male and female infertility and male potency via the hypothalamic-gonadal axis. Ginseng also activates the posterior pituitary, exerting an antidiuretic action. A most important use of ginseng is its ability to activate the immune system in clinical and experimental cancer, experimental radiation sickness and after exposure to cytotoxic agents. Symptomatically, it stimulates appetite, the sense of wellbeing and the will to live in convalescence from chronic diseases. Ginseng is non-toxic At normal dosage, but may be toxic at high doses; the LD50 in mice was 5 g ginseng powder/kg LW in mice. Clinically, ginseng is used in a myriad of conditions. Indications include: shock and emergencies (cardiac, haemorrhagic, septic and toxic); heart failure, acute myocarditis, angina, arteriosclerosis, cough, fevers, hormonal disorders (infertility, diabetes mellitus, diabetes insipidus, thyroid disorders), hypotension, hypertension, stress, insomnia, headaches, anaemia, neurasthenia, muscle atrophy, chronic debility, impotence, poor concentration, gastrointestinal disorders (inappetance, indigestion etc), cancer therapy, immunosuppression and senility (Huang 1993).
Huang (1993) categorised herbs under the following headings in a systematic study of the pharmacology of CHM: those acting on the cardiovascular system (multiple action-, cardiac-, antiarrythmic-, antihypertensive-, antianginal-, antihypercholesterolemic- and antishock- herbs); nervous system (anaesthetic- and muscle-relaxing- herbs; sedative- and hypnotic- herbs; anticonvulsive-, analgesic-, antipyretic-, antirheumatic- and central stimulating- herbs); alimentary system (stomachic- and "Wind"-dispelling herbs; herbs promoting digestion; antacid/antiulcer-, laxative-, antidiarrhoeal-, emetic-, antiemetic-, choleretic-, antihepatitis-, tonic- and supporting- herbs); respiratory system (antitussive-, expectorant- and antiasthmatic- herbs); genitourinary system (diuretic-, uterine-active- herbs); haematopoietic system (promoters of blood formation; haemostatic- and antistatic- herbs); endocrine system (herbs affecting the thyroid, adrenal cortex and pancreas); and chemotherapeutics (antibacterial-, antiviral-, antifungal-, antitubercular-, antiseptic-, disinfectant-, anthelmintic-, antiamoebic-, antitrichomonial-, antimalarial- and anticancer- herbs).
These and other modern texts and reviews show that medical compounds in HMs include immunomodulators, such as antiallergic, antiasthmatic, antiinflammatory, antiinfectious, antihepatotoxic, antineoplastic, antioxidant and antitoxic compounds. HMs also include antistress compounds (hypotensives, muscle relaxants, sedatives, vasodilators), hypoglycemics, and insect repellents (antifeedants).
The role of individual herbs or formulas (herb-combinations) in therapy are discussed under two headings: allergies and the immune system (including antiviral effects). Most of the data for these sections are from the review by Dharmananda (1991).
Antiallergic Herbs
(summarised from Tsung 1987): Important antiallergic herbs include: achyranthes, alisma, alpinia, apricot seed, arctium, asarum, astragalus, atractylodes, bezoar, bupleurum, cardamom, ching pi, cinnamon, citrus, cluster, cornus, ephedra (ma huang), galanga, ganoderma, gentian, ginger, ginseng, hoelen, licorice, magnolia, moutan, pinnelia, polyporus, pueraria, rehmannia, scute, stephania, tang-kuei, zedoaria, zizyphus (jujube).
Type 1 allergies (IgE- and chemically- mediated immediate disorders) are due to circulating IgE attached to mast cells, which releases chemical mediators (including histamine). They include: drug allergies, hay fever, hives and allergic asthma. Herbs that suppress IgE activity in stage 1 allergic response are: alisma, apricot seed, bupleurum, cardamom, gentian, ginseng (Japanese), licorice, tang-kuei, Zizyphi fructus (jujube). Herbs which suppress release of chemical mediators (such as histamine) following IgE binding to mast cells in stage 2 allergic response are: achyranthes, asarum, bezoar, ching pi, cinnamon bark, Ephedra (ma huang), ganoderma, magnolia flowers, moutan, scute, sinomenium. Those herbs have antiinflammatory and antimediator release action. Some of them have ß-adrenergic and/or antihistaminic effects: they suppress the reaction of the target organs (capillary permeability, smooth muscle contraction in nasal membranes, lungs, gut, skin; hypothyroidism etc) after release of chemical mediators in stage 3 allergic response. Asarum (contains methyleugenol and higenamine); atractylodes and sinomenium also have antihistaminic activity.
Formulas in Type 1 allergy:
Antiallergic (Stage 1): Bupleurum and Hoelen Formula; Minor Bupleurum Formula.
Antiallergic (Stage 2): Minor Bupleurum Formula; Minor Blue Dragon Formula; Ma Huang and Apricot Seed Formula.
Antiallergic (Stage 3): Minor Blue Dragon Formula; Pueraria and Magnolia Formula; Tang-kuei and Arctium Formula.
Antiinflammatory, detoxifying, anti chest-distention: Bupleurum + Scute.
Antiemetic, antinausea, digestive: Pinnelia + Ginger.
Stomachic and antiheartburn: ginseng + jujube + licorice.
Diuretic, antiascitic, antioedematous: Alisma + Polyporus + Hoelen + Atractylodes.
Type 2 allergies (complement-mediated disorders) are due to activation of complement by complement-fixing antibodies against cell-surface antigens. They include: anaphylactic shock (side effects of incompatible blood), haemolytic anaemia in autoimmune or drug reactions, decreased platelet numbers. Herbs with anticomplement activity include: cinnamon bark, ganoderma and licorice. Formulas for type 2 allergies have these as major ingredients.
Type 3 allergies (immune-complex disorders) are due to activation of complement after formation of antigen-antibody complexes. They include: bacterial glomerular nephritis, chronic hepatitis-B, atopic bronchial asthma, erythromatosis, chronic rheumatoid arthritis, thyroiditis. Therapy for type 3 allergies uses anticomplement or antiinflammatory drugs.
Herbs used in type 3 allergy include ganoderma, bupleurum, cinnamon, citrus, cornus, ginseng, licorice, ma huang, moutan and tang-kuei.
Formulas used in Type 3 allergy (and those used in kidney disorders) include: Atractylodes Formula, Bupleurum and Hoelen Formula, Bupleurum and Dragon Bone Formula, Ginseng and Astragalus Formula, Stephania and Astragalus Formula, Rehmannia Eight Formula. These formulas use various combinations of herbs listed in the previous paragraph; they have antiallergic and antiinflammatory effects, and anticomplement activity.
Type 4 allergies (no antibody involvement) are mediated by T-lymphocytes. They include: contact dermatitis, tubercular lesions, chronic hepatitis, bacterial glomerular nephritis, erythromatosis, rheumatoid arthritis, Hashimoto's thyroiditis and intestinal ulcers.
Herbs used in type 4 allergy include ganoderma, ginseng, hoelen, licorice, magnolia bark, pinellia and zizyphus.
Formulas used in Type 4 allergy include: Minor Bupleurum Formula, Bupleurum and Hoelen Formula, Bupleurum and Schizonpeta Formula, Cinnamon and Atractylodes Formula, Tang-kuei and Gardenia Formula, Minor Blue Dragon Formula and Pueraria Formula.
In WM, steroids are used widely in controlling allergies. Combination of HMs (which often contain plant steroids themselves) with WM steroids reduce the doses of the latter to 33-50%. This reduces the risk of steroidal side-effects.
Herbs with immunostimulatory, antiinflammatory, antitoxic, antiviral and antioxidant effects include: akebia, albizzia, alisma, astragalus, centella, cimicifuga, cistanche, codonopsis, dianthus, dioscorea, ginseng, lycium fruit, melia, mushrooms (coriolus, ganoderma, hoelen, lentinus, polyporus, tremella), platycodon, polygala, rehmannia, sambucus, zizyphus etc. They have been used for centuries to treat inflammation, fevers, intoxications, infectious and neoplastic diseases.
b. Research on individual active compounds
WM uses many drugs extracted from natural products: aspirin, atropine, cocaine, curare, digitalis, ephedrine, hyoscine (scopolamine), opiates (codeine, morphine), pilocarpine, primrose oil, quinine, reserpine, steroids, taxol, warfarin etc. Other WMs from natural materials include kaolin, bentonite (in preparations of mineral matter); antibiotics, ergotamine, ergometrine, mescaline (from fungi); allergens for desensitisation, antitoxins and antivenoms, heparin, hormones (steroids, HCG, PMSG, insulin etc), vaccines and venoms, etc (from animal tissue).
Most of these medicines have been discovered on the basis of information derived from traditional medicine and ethnopharmacognostics (Table 1). For instance, ephedrine was isolated from Ephedra sinica in 1885. Ephedra sinica and Ephedra distachia were used medicinally for centuries in Asia to treat asthma, hay fever, nasal congestion and hypotension. Ephedrine is closely related to epinephrine (adrenaline) and the amphetamines. It is still used widely today, as the first successful product of the modern pharmaceutical industry (Otsuka 1988), to relax the bronchioles in asthma and bronchitis, as a nasal decongestant in some allergies and as a mydriatic. It stimulates the CNS and is used to treat hypotension, cardiac failure and narcotic poisoning. Digitalis purpurea was used to treat ascites and oedema in congestive heart failure and its alkaloids are still used for that purpose. Cinchona bark is the source of several alkaloids, especially quinine and quinidine. Both have antimalarial, antifebrile and analgesic effects. Quinidine also is a cardiotonic, used in cardiac arrhythmia, fibrillation and heart block.
We use the word "sustainable" to mean a system that puts back, or replenishes, what we take out of the system, with minimal damage to the environment or to the creatures that depend on it. Our current western- and strictly profit- oriented approach to agriculture and food production is not sustainable indefinitely. When we use irreplaceable natural resources at grossly excessive rates, we are stealing them from our neighbours and our descendants. When we pollute our world, we lay the seeds of our own destruction, and we put future generations in danger. If we continue with our present systems, humanity will have a high price to pay. There is no greater human tragedy than the curse of children on the actions, or spirits, of their parents or ancestors.
We live in nature and we depend on nature. If we abuse nature, it will abuse us. Buddhist and many other ancient philosophies, eastern and western, teach that we should show care and compassion for each other, our animals and our environment. The human population is at its highest ever. Because of inequalities of food production and its distribution, famine and malnutrition occur regularly. Thus, the production of wholesome human food, and its distribution to people in need is an ongoing problem that needs international attention.
Apart from animals produced for human food, other species of domesticated animals suffer from many chronic diseases for which western medicine has only partially successful, or very expensive, answers. Examples are cancer and geriatric diseases in pets, and chronic musculoskeletal disorders in sports animals.
Public demand is increasing for a more natural system of animal production, care and welfare. Traditional Chinese medicine (TCM) is one of the most natural and sustainable systems of medicine known. It has very well documented laws and theories. Its laws have been proven by constant use in humans and animals over millennia; its theories have been tested in-vivo and proven or amended by constant criticism and dynamic discussion from within its peers. It uses mainly Chinese Herbal Medicine (CHM), physical medicine (acupuncture, thermotherapy (moxibustion) and mental therapy (Qigong, meditation etc). CHM is the oldest and best-documented system of medicine known. To understand CHM, one must understand the essential concepts of TCM. Its methods of diagnosis are complex and holistic: by a detailed process of pattern recognition, they determine the TCM Syndrome, the nature and location of energy (Qi) disorder in the subject. TCM is used both in prophylaxis and in therapy of humans and animals. This paper suggests some ways to integrate the art, philosophy and science of TCM and modern medicine to develop a more sustainable system of animal production and medical care.
Modern versus ancient philosophy in the prevention and control of animal diseases
Modern science has shown that animal species and genetics are main determinants of the efficiency of feed conversion to meat or milk. As it costs much less to produce a kilo of dry matter (DM) from maize or rice than a kilo of meat DM, one may argue that production of more rice, cereals and protein-rich crops from land used for grazing of ruminants could solve the increasing demand for human food. If we must produce animal-derived human food, one may argue also that governments should encourage the farming of efficient converters [fish, poultry and pigs] and discourage the farming of inefficient converters [ruminants]. However large areas of swamp, mountain, marginal- and arid areas are unsuitable for most farm-uses except grazing. Also, large tracts of grassland are in private ownership. Thus, ruminant farming seems likely to remain to be the main way to convert the earth's supplies of forage and cellulose to human food, unless governments revert to systems of state-control of national resources. Such systems have been discredited on social and economic grounds and are unlikely to be revived in most countries. Even China and Cuba, two of the last bastions of state-control of national resources, are moving slowly towards a market-based economy.
Intensive production of animal-based foods has been the international norm in recent decades. To maximise profits, and minimise costs, the industry depends on high stocking densities - increasing animal numbers in decreasing land or floor areas, and/or increasing numbers in confined air-spaces. This has greatly increased the risk of infectious and parasitic diseases, and the degree of stress to which the animals are exposed. Ignoring considerations of animal welfare, increased stress reduces the efficiency of animal reproduction, lactation and growth. It also reduces their immunocompetence, leaving them more prone to infections and parasitism.
To counter these problems, and enhance profit margins, the agricultural industry has become increasingly dependent on chemical control of these problems in animals. Routine use of vaccines, growth enhancing agents, antibiotics, hormones, pesticides, anthelmintics, herbicides, organophosphates, artificial fertilisers etc is widespread. However, the high cost of modern drugs, hormones and chemicals for routine use in animal husbandry can prove prohibitive for developing countries. Also, due to accidental emissions or low-level exposure to toxic agents used in, or generated by the production process, the manufacture of potent drugs and agrochemicals poses a real threat to the health and welfare of persons working in or living near the factories, and to the animals grazing nearby.
Overuse of western drugs and chemicals has led to adulteration of human food with chemical residues. Though it is not proven conclusively, some medical researchers blame increasing resistance to antibiotics to their abuse in animals. Falling sperm-counts in human males in heavily industrialised nations have been attributed to (amongst other factors) exposure to chronic pollution of air, water and food by substances with estrogenic activity. Exposure of farm workers to agrochemicals has caused acute and chronic toxicity in those workers, including an increase in miscarriage rates and birth deformities in babies of female workers.
In recent years, other issues also have highlighted the importance of consumer perception on the consumption of meat products. They are: the bovine spongiform encephalopathy (BSE) epidemic in Europe and associated fears of contracting new variant CJD from beef, outbreaks of fatal food poisoning by Escherichia coli O157 and Salmonella typhimurium DT104.
The European Union [EU] is trying to eliminate the chemical contamination of human food and raise the standards of food safety. However, it is difficult to enforce the plethora of EU regulations, and consumers are becoming increasingly cynical of government statements as to the safety of food.
Several factors have focussed public awareness on the need for a more natural system of animal production and medical care. These include fear of chemical residues in food, antibiotic resistance and zoonosis, and several other issues, including iatrogenic diseases. These issues have stimulated interest in the Green Movement. Also, public awareness of compromised animal welfare involved in intensive farming has led to rapid growth of the Animal Rights Movement and vegetarianism. Countries whose economies depend heavily on the sale of animal-derived foods must address these issues seriously if they want to protect their public image and market share at home and abroad.
TCM and the farming of domesticated animals in China date far before the birth of Christ. Globally, TCM is the most complete system of traditional medicine. Its documentation is ancient and extensive. Constant use over several millennia has proven TCM and its concepts to be of great clinical value. Several dozen textbooks, based on translations of ancient and modern texts, are devoted to the concepts of TCM. Some of the best (in English) are by Connolly (1979), Turner & Low (1982), Hsu (1982), Kaptchuk (1983), Matsumoto & Birch (1983), Porkert (1983), Wiseman & Ellis (1995), Anon (1993), Xie et al (1994) and Wiseman & Ye (1998).
TCM is a system of Energetics and Correspondences. It sees the body as interacting with and adapting to cosmic, terrestrial-climatic, traumatic and internal forces. It sees disease as a disturbance or disharmony (Full, Empty, Stagnant) of vital energy (Qi), or Blood (Xue), or Fluid (Ye), or as imbalances of the homeostatic dialectic mechanisms (Yin-Yang), or of a more complex Five Phase anabolic-catabolic control system of the body. It also recognises powerful interaction between the soma and the psyche; imbalanced emotions can cause organic disease, and vice-versa.
TCM practitioners use complex methods of pattern recognition, based on subjective and objective symptomatology and phenomenology, to detect which COSs have Qi imbalance and the nature of that imbalance (Qi Full, Empty, Stagnant etc). Therapy that can reestablish the free flow of Qi, or rebalance it, has lasting and beneficial effects on health. Rebalancing (homeostasis) of Qi automatically eliminates all the amenable symptoms and signs of ill health. Not all symptoms and signs are amenable, for example in cases of severe organic damage (advanced cancer, chronic cirrhosis of the liver, severed spinal cord, severe necrosis of the motor neurones etc).
Once a diagnosis is made, CHM uses formulations of 4-10 herbal ingredients, to apply a complex theory of holistic treatment. Treatment aims mainly to obtain and maintain harmony of body function (homeostasis) and to expel pathogens. Many ingredients are to enhance the effects, or to act as antidotes to the unwanted effects, of other ingredients. The formulation may be changed as the subject's Qi patterns change. The history of TCM, its fundamental concepts, Syndrome diagnosis, selection and alteration of remedies are beyond the scope of this paper.
HM is a valid science, with great potential for integration with WM to the benefit of human and animal health and welfare. As the pharmacological basis becomes better understood, it will be easier to integrate HM into conventional WM. However, HM needs more research, development, goodwill and education before it can reach its full potential. Problems of supply of raw ingredients, the protection of endangered species, quality control, registration of proven formulations and access to expert information need to be addressed urgently.
The science behind TCM
The World Health Organisation (WHO 1993) supports the use of effective and safe remedies and accepts Traditional Medicine (TM) as a valuable and readily available resource for primary health care.
Many of the world's cultures developed their own forms of HMs over centuries. Today, 75-80% of the world's population still relies on HM (plants, plant extracts etc) and other tools of TM in basic health care (Abelson 1990; Chan et al 1993; Cox & Balick 1994; Schwartz 1994; Yamada 1994a; Chaudhury 1995). In Asia, especially in China, Japan, Korea, Taiwan, Vietnam etc, medical practitioners are trained to prescribe TMs together with Western Medicines (WMs) (Chan et al 1993). WMs often are expensive. To research, develop, register and market a new pharmaceutical drug in the USA takes about 10 years and costs about 200 million dollars (Abelson 1990; Cox & Balick 1994). Also WMs have sometimes limited results in many chronic conditions and their use may cause development of drug resistance and iatrogenic disease, especially if they must be used for long periods.
Because of these factors, demand for TMs, especially CHM, is increasing and traditional HM therapy is used widely in the United States and Europe (Otsuka 1988; Yamada 1994a). Although many individual ingredients used in CHM are highly toxic if used wrongly, carefully prescribed CHMs can be used for relatively long periods with minimal or no adverse effects (Hsu 1982; Hosoya & Yamamura 1988; Dharmananda 1991; Chan et al 1993; Schwartz 1994; Yamada 1994a). However, most TM systems (including HM and AP) need more scientific research on aspects of safety and efficacy (Dharmananda 1991; Chaudhury 1995; Lin et al 1995a).
CHM uses a complex combination of medicinal plant- and other- natural products (Luo & Shi 1986; Ou 1989). Plant products include specifically selected parts (leaves, branches, stems, roots, tubers or bark etc) harvested from herbs, flowers or trees etc. The other natural products include parts of living or dead tissue (animal, insect, reptiles, venoms, shell, coral etc) and minerals (mineral salts, certain types of pulverised rocks and soils etc).
CHM formulas or remedies are carefully balanced mixtures of many ingredients. They are taken as decoctions, or as extracts in water or alcohol, or as dried extracts (as pills etc). Some are used externally. Other presentations of HMs are being developed: pills, tablets, powders, capsules, tinctures, syrups, suppositories, ointments and injections etc.
CHM uses TCM theory and a TCM diagnosis of the pathological condition of the patient. When the TCM Syndrome is established, suitable HMs are prescribed. Treatment aims mainly to maintain harmony of body function, including the psyche and to expel pathogens. Many ingredients are to enhance the effects, or to act as antidotes to the unwanted effects, of other ingredients. The overall aim, and the effect when successful, is to help the body to help itself to attain homeostasis between its own natural functions and the external environment.
History of scientific research into CHM
The ancient history of TCM and CHM is documented by Ou (1989), Schwartz (1994) and Xie et al (1994).
From the 19th century up to the beginning of this century, the influx of western ideas demolished much traditional Chinese culture and science. TCM nearly became extinct. In the past 40 years, shortage of WMs has renewed Chinese interest in the techniques of TCM. In 1990, Hong-Cheng Fong published two books on veterinary herbology, which contain more than 10000 formulas, probably the biggest collection of TCVM since antiquity. Today, there is a nation-wide TCVM Society in China, with thousands of members who practice TCVM daily. Foreign (non-Chinese) graduates may attend courses on TCVM and VAP in China (Lin & Panzer 1994). Development and research into TCM in humans and animals have become popular again throughout China, Japan, Korea and Taiwan (Hsu 1982; Hosoya & Yamamura 1988; Yamada 1994a; Lin et al 1995a). Traditional Oriental Medicine (TOM) and Kampo Medicine (KM) are forms of TM from east Asia and Japan respectively. Both came mainly from CHM, or were influenced strongly by it.
Kampo literally means Han's formulas. Most formulas of KM are from two texts, both written by Zhang Zhong-jing (Zhang Ji), about 210 AD and arranged some years later by Wang Shu-He (Wang Xi) (Hsu 1982; Xie et al 1994; Otsuka 1988). These are the Shang Han Lun (Treatise on Cold-induced (Febrile) Disorders and the Jin Kui Yao Lue Fang Lun (Essentials of the Golden Cabinet). Since 1976, the Japanese Ministry of Health and Welfare has approved 146 formulations of KM. National health insurance in Japan covers the use of the herb components of such approved KMs.
WHO has issued guidelines for evaluating the safety and efficacy of HMs. National and international conferences, such as those run by the World Veterinary Association, the Japanese Pharmaceutical Society and the Medical and Pharmaceutical Society for Wakan-Yaku (Japan) also discuss these topics. Appendix 1 lists Journals that publish research on the chemistry and pharmacology of HMs and phytotherapy.
Pharmacological research in HM
Pharmacognosy is the study of compounds sought out by humans or animals and ingested, or otherwise used, as supposed medicines; zoopharmacognosy is the study of the actions of these materials in animals (Robles et al 1995). These disciplines have led to the identification of many useful medicines. Phytotherapeutics is the therapeutic use of these compounds.
In 1985, worldwide, 3500 new chemical structures were discovered and 2619 of these were isolated from higher plants. In 1987, Japan captured 56% of patented natural products summarised in Phytotherapy Research. Germany also has been more active than the United States in this field (Abelson 1990).
Research in phytotherapy can be classified under many different headings. Research on pharmacological effects of HMs will be discussed under three headings:
a. individual herbs or extracts;
b. individual active compounds of individual herbs;
c. complex HM formulas.
The boundaries between these headings are not easy to maintain; thus there is some overlap between them.
a. Research on individual herbs or extracts
Documentation of TCM is more than 3000 years old. Thus there are extensive data and cumulative experience on the use of CHM, including recent textbooks (Hsu 1982; Xie et al 1994; Bensky et al 1986; Luo & Shi 1986; Tsung 1987; Hosoya & Yamamura 1988; Ou 1989; Dharmananda 1991 and Chaudhury 1995).
Bensky et al (1986), summarises the actions of some potent herbal ingredients. Ginseng radix (ren shen = Man Root, Man Essence) is sometimes man-shaped (like mandrake). The medicinal use of ginseng in China dates to before 100 BC. There are many varieties, Appalacian, Korean, Japanese, Chinese etc. Ginseng is attributed with great therapeutic and mystical potency. Much sought-after, it is very expensive. It is one of the most often cited herbs in TCM. Experimentally, it has potent effects on the CNS and peripheral nerves. Centrally, it improves nervous responses in a homeostatic way, enhancing both stimulatory and inhibitory processes, depending on their initial state of receptivity. In this way, it resembles the homeostatic effect of AP, in which stimulation of the same AP points can have diametrically opposed effects, depending on the state of the subject. Normally ginseng is a central stimulant like caffeine but, in large doses it is a sedative. It counteracts the stimulant effects of some other stimulants and the inhibitory effect of opiates. It enhances the acute hypnotic effect of pentobarbital. Small doses of ginseng have muscarinic effects on peripheral nerve; large doses have nicotinic effects. It shortens the latency of nerve reflexes, accelerates nerve transmission and strengthens conditioned reflexes. Over long periods, it tends to the middle (neither stimulatory nor inhibitory). Experimentally, it has cardiotonic effects, similar to cardiac glycosides; it is clinically useful in cardiac arrythmia.
Huang (1993, pp21-45) devotes a full chapter to the medicinal uses and pharmacology of the root of ginseng. In summary, it contains volatile oils, saponins (glycosides, panaxosides, ginsenosides), antioxidants, peptides, polysaccharides, fatty acids and vitamins and other active ingredients, many of whose chemical structures are known. It is known as the "Elixir of Life", as it has potent antiaging effects and antiirradiation effects, probably due to its antioxidants and immunostimulating properties. Experimentally, it increases endurance in animals and has potent antistress effects against many environmental stressors (Huang 1993). It has antidiabetic/hypoglycaemic effects and alpha-2-adrenergic and antihypertensive effects (blocked by yohimibin). It has ß-adrenergic blocker effects in oxygen starvation. It has antiinflammatory effects and activates the reticuloendothelial system, dilates cerebral and coronary vessels, stimulates haematopoiesis in the bone marrow, lowers serum cholesterol levels and has antiatherosclerotic effects, which protect against cardiac ischaemia. It has potent effects on the CNS, increases concentration and awareness, increases night-adaptation of the eyes, and has sedative/calming effects. It has antipyretic effects and increases the release of corticotropin releasing factor (CRF) from the hypothalamus. It activates the thyroid, testis and ovary and has clinical uses in male and female infertility and male potency via the hypothalamic-gonadal axis. Ginseng also activates the posterior pituitary, exerting an antidiuretic action. A most important use of ginseng is its ability to activate the immune system in clinical and experimental cancer, experimental radiation sickness and after exposure to cytotoxic agents. Symptomatically, it stimulates appetite, the sense of wellbeing and the will to live in convalescence from chronic diseases. Ginseng is non-toxic At normal dosage, but may be toxic at high doses; the LD50 in mice was 5 g ginseng powder/kg LW in mice. Clinically, ginseng is used in a myriad of conditions. Indications include: shock and emergencies (cardiac, haemorrhagic, septic and toxic); heart failure, acute myocarditis, angina, arteriosclerosis, cough, fevers, hormonal disorders (infertility, diabetes mellitus, diabetes insipidus, thyroid disorders), hypotension, hypertension, stress, insomnia, headaches, anaemia, neurasthenia, muscle atrophy, chronic debility, impotence, poor concentration, gastrointestinal disorders (inappetance, indigestion etc), cancer therapy, immunosuppression and senility (Huang 1993).
Huang (1993) categorised herbs under the following headings in a systematic study of the pharmacology of CHM: those acting on the cardiovascular system (multiple action-, cardiac-, antiarrythmic-, antihypertensive-, antianginal-, antihypercholesterolemic- and antishock- herbs); nervous system (anaesthetic- and muscle-relaxing- herbs; sedative- and hypnotic- herbs; anticonvulsive-, analgesic-, antipyretic-, antirheumatic- and central stimulating- herbs); alimentary system (stomachic- and "Wind"-dispelling herbs; herbs promoting digestion; antacid/antiulcer-, laxative-, antidiarrhoeal-, emetic-, antiemetic-, choleretic-, antihepatitis-, tonic- and supporting- herbs); respiratory system (antitussive-, expectorant- and antiasthmatic- herbs); genitourinary system (diuretic-, uterine-active- herbs); haematopoietic system (promoters of blood formation; haemostatic- and antistatic- herbs); endocrine system (herbs affecting the thyroid, adrenal cortex and pancreas); and chemotherapeutics (antibacterial-, antiviral-, antifungal-, antitubercular-, antiseptic-, disinfectant-, anthelmintic-, antiamoebic-, antitrichomonial-, antimalarial- and anticancer- herbs).
These and other modern texts and reviews show that medical compounds in HMs include immunomodulators, such as antiallergic, antiasthmatic, antiinflammatory, antiinfectious, antihepatotoxic, antineoplastic, antioxidant and antitoxic compounds. HMs also include antistress compounds (hypotensives, muscle relaxants, sedatives, vasodilators), hypoglycemics, and insect repellents (antifeedants).
The role of individual herbs or formulas (herb-combinations) in therapy are discussed under two headings: allergies and the immune system (including antiviral effects). Most of the data for these sections are from the review by Dharmananda (1991).
Antiallergic Herbs
(summarised from Tsung 1987): Important antiallergic herbs include: achyranthes, alisma, alpinia, apricot seed, arctium, asarum, astragalus, atractylodes, bezoar, bupleurum, cardamom, ching pi, cinnamon, citrus, cluster, cornus, ephedra (ma huang), galanga, ganoderma, gentian, ginger, ginseng, hoelen, licorice, magnolia, moutan, pinnelia, polyporus, pueraria, rehmannia, scute, stephania, tang-kuei, zedoaria, zizyphus (jujube).
Type 1 allergies (IgE- and chemically- mediated immediate disorders) are due to circulating IgE attached to mast cells, which releases chemical mediators (including histamine). They include: drug allergies, hay fever, hives and allergic asthma. Herbs that suppress IgE activity in stage 1 allergic response are: alisma, apricot seed, bupleurum, cardamom, gentian, ginseng (Japanese), licorice, tang-kuei, Zizyphi fructus (jujube). Herbs which suppress release of chemical mediators (such as histamine) following IgE binding to mast cells in stage 2 allergic response are: achyranthes, asarum, bezoar, ching pi, cinnamon bark, Ephedra (ma huang), ganoderma, magnolia flowers, moutan, scute, sinomenium. Those herbs have antiinflammatory and antimediator release action. Some of them have ß-adrenergic and/or antihistaminic effects: they suppress the reaction of the target organs (capillary permeability, smooth muscle contraction in nasal membranes, lungs, gut, skin; hypothyroidism etc) after release of chemical mediators in stage 3 allergic response. Asarum (contains methyleugenol and higenamine); atractylodes and sinomenium also have antihistaminic activity.
Formulas in Type 1 allergy:
Antiallergic (Stage 1): Bupleurum and Hoelen Formula; Minor Bupleurum Formula.
Antiallergic (Stage 2): Minor Bupleurum Formula; Minor Blue Dragon Formula; Ma Huang and Apricot Seed Formula.
Antiallergic (Stage 3): Minor Blue Dragon Formula; Pueraria and Magnolia Formula; Tang-kuei and Arctium Formula.
Antiinflammatory, detoxifying, anti chest-distention: Bupleurum + Scute.
Antiemetic, antinausea, digestive: Pinnelia + Ginger.
Stomachic and antiheartburn: ginseng + jujube + licorice.
Diuretic, antiascitic, antioedematous: Alisma + Polyporus + Hoelen + Atractylodes.
Type 2 allergies (complement-mediated disorders) are due to activation of complement by complement-fixing antibodies against cell-surface antigens. They include: anaphylactic shock (side effects of incompatible blood), haemolytic anaemia in autoimmune or drug reactions, decreased platelet numbers. Herbs with anticomplement activity include: cinnamon bark, ganoderma and licorice. Formulas for type 2 allergies have these as major ingredients.
Type 3 allergies (immune-complex disorders) are due to activation of complement after formation of antigen-antibody complexes. They include: bacterial glomerular nephritis, chronic hepatitis-B, atopic bronchial asthma, erythromatosis, chronic rheumatoid arthritis, thyroiditis. Therapy for type 3 allergies uses anticomplement or antiinflammatory drugs.
Herbs used in type 3 allergy include ganoderma, bupleurum, cinnamon, citrus, cornus, ginseng, licorice, ma huang, moutan and tang-kuei.
Formulas used in Type 3 allergy (and those used in kidney disorders) include: Atractylodes Formula, Bupleurum and Hoelen Formula, Bupleurum and Dragon Bone Formula, Ginseng and Astragalus Formula, Stephania and Astragalus Formula, Rehmannia Eight Formula. These formulas use various combinations of herbs listed in the previous paragraph; they have antiallergic and antiinflammatory effects, and anticomplement activity.
Type 4 allergies (no antibody involvement) are mediated by T-lymphocytes. They include: contact dermatitis, tubercular lesions, chronic hepatitis, bacterial glomerular nephritis, erythromatosis, rheumatoid arthritis, Hashimoto's thyroiditis and intestinal ulcers.
Herbs used in type 4 allergy include ganoderma, ginseng, hoelen, licorice, magnolia bark, pinellia and zizyphus.
Formulas used in Type 4 allergy include: Minor Bupleurum Formula, Bupleurum and Hoelen Formula, Bupleurum and Schizonpeta Formula, Cinnamon and Atractylodes Formula, Tang-kuei and Gardenia Formula, Minor Blue Dragon Formula and Pueraria Formula.
In WM, steroids are used widely in controlling allergies. Combination of HMs (which often contain plant steroids themselves) with WM steroids reduce the doses of the latter to 33-50%. This reduces the risk of steroidal side-effects.
Herbs with immunostimulatory, antiinflammatory, antitoxic, antiviral and antioxidant effects include: akebia, albizzia, alisma, astragalus, centella, cimicifuga, cistanche, codonopsis, dianthus, dioscorea, ginseng, lycium fruit, melia, mushrooms (coriolus, ganoderma, hoelen, lentinus, polyporus, tremella), platycodon, polygala, rehmannia, sambucus, zizyphus etc. They have been used for centuries to treat inflammation, fevers, intoxications, infectious and neoplastic diseases.
b. Research on individual active compounds
WM uses many drugs extracted from natural products: aspirin, atropine, cocaine, curare, digitalis, ephedrine, hyoscine (scopolamine), opiates (codeine, morphine), pilocarpine, primrose oil, quinine, reserpine, steroids, taxol, warfarin etc. Other WMs from natural materials include kaolin, bentonite (in preparations of mineral matter); antibiotics, ergotamine, ergometrine, mescaline (from fungi); allergens for desensitisation, antitoxins and antivenoms, heparin, hormones (steroids, HCG, PMSG, insulin etc), vaccines and venoms, etc (from animal tissue).
Most of these medicines have been discovered on the basis of information derived from traditional medicine and ethnopharmacognostics (Table 1). For instance, ephedrine was isolated from Ephedra sinica in 1885. Ephedra sinica and Ephedra distachia were used medicinally for centuries in Asia to treat asthma, hay fever, nasal congestion and hypotension. Ephedrine is closely related to epinephrine (adrenaline) and the amphetamines. It is still used widely today, as the first successful product of the modern pharmaceutical industry (Otsuka 1988), to relax the bronchioles in asthma and bronchitis, as a nasal decongestant in some allergies and as a mydriatic. It stimulates the CNS and is used to treat hypotension, cardiac failure and narcotic poisoning. Digitalis purpurea was used to treat ascites and oedema in congestive heart failure and its alkaloids are still used for that purpose. Cinchona bark is the source of several alkaloids, especially quinine and quinidine. Both have antimalarial, antifebrile and analgesic effects. Quinidine also is a cardiotonic, used in cardiac arrhythmia, fibrillation and heart block.
TABLE 1. Some important drugs isolated from plants
|
DRUG
Aspirin Codeine Digoxin, Digitoxin Ephedrine Forskolin Ipecacuanha Pilocarpine Quinine Reserpine Scopolamine Taxol Theophylline Vinblastine, Vincristine |
MEDICAL USE
Analgesic, antiinflammatory, reduces platelet stickiness Analgesic and antitussive Cardiac stimulant Bronchodilator Cardiac stimulant Emetic Antiglaucomic Antimalarial Antihypertensive Eases motion sickness Treats ovarian cancer Bronchodilator Treats Hodgkin's disease |
PLANT SOURCE
Filipendula ulmaria Papaver somniferum Digitalis spp. Ephedra sinica Coleus forskolin Psychotria ipecacuanha Pilocarpus jaborandi Cinchona pubescens Rauwolfia serpentina Datura stramonium Taxus brevifolia Camellia sinensis Catharanthus roseus |
Raw ingredients used in HMs contain pharmacologically active compounds of low- and/or high- molecular weight. Low molecular-weight compounds include primary metabolites (sugars, fatty acids, peptides etc) and secondary metabolites (alkaloids, terpenoids, saponins, flavonoids etc). High molecular-weight compounds include proteins, tannins and polysaccharides. The therapeutic activity of HMs derives from these compounds (Yamada 1994a, b). Clarification of the active principle(s) of HMs helps us to understand the modes of action at a molecular level, to evaluate efficacy and to maintain herbal quality. It also helps us to develop novel drugs by extraction from plants, biotechnology, or by synthetic methods. This may provide remedies for diseases incurable or poorly controlled by modern chemotherapeutics.
The following is summarised from the review by Dharmananda (1991). In WM and pharmacognosy, active compounds are classified in many different ways: by their physiological effects, by their clinical indications or by their chemical-pharmacological nature. The latter method groups medicines into 8 classes:
1. carbohydrates (sugars, polysaccharides (gums, mucilages, pectins));
2. steroids (steroid hormones, sterols, bile acids)
3. glycosides (antraquinones, flavonoids, lactones, phenols);
4. alkaloids (tropanes, quinolines, indoles)
5. tannins (catechols, pyrogallols);
6. lipids (fixed oils, waxes, fatty acids);
7. volatile oils (alcohols, aldehydes, ketones, phenols);
8. resins (oleo-resins, gum-resins, balsams);
HMs used to treat various disorders of the immune system, including allergies, inflammations, infections, cancer and AIDS contain one or more of these active compounds. Some HMs contain mixtures of these compounds, for example ginseng and hoelen contain potent polysaccharides and steroids.
The following is summarised from the review by Dharmananda (1991). In WM and pharmacognosy, active compounds are classified in many different ways: by their physiological effects, by their clinical indications or by their chemical-pharmacological nature. The latter method groups medicines into 8 classes:
1. carbohydrates (sugars, polysaccharides (gums, mucilages, pectins));
2. steroids (steroid hormones, sterols, bile acids)
3. glycosides (antraquinones, flavonoids, lactones, phenols);
4. alkaloids (tropanes, quinolines, indoles)
5. tannins (catechols, pyrogallols);
6. lipids (fixed oils, waxes, fatty acids);
7. volatile oils (alcohols, aldehydes, ketones, phenols);
8. resins (oleo-resins, gum-resins, balsams);
HMs used to treat various disorders of the immune system, including allergies, inflammations, infections, cancer and AIDS contain one or more of these active compounds. Some HMs contain mixtures of these compounds, for example ginseng and hoelen contain potent polysaccharides and steroids.
Part 2
For the purposes of this chapter, four of the eight classes of active herbal compounds (Dharmananda 1991) will be summarised briefly: polysaccharides, steroids, flavonoids, lactones and alkaloids.
1. Polysaccharides
Plants contain many sugar molecules, in various combinations, sizes and chemical sequences. Monosaccharides are simple sugars. Long straight- (and/or branched-) chain monosaccharide polymers form polysaccharides. Most are not water-soluble (such as gums) but some are (such as the pectin ploysaccharides). Sugars, gums and celluloses have relatively little use in WM, except as fillers and binders. However, pectins can soothe the gastrointestinal tract and can help in diarrhoea and gastroenteritis. Pueraria, dioscorea and hoelen are used in this way. Inulin (from Compositae spp.) can soothe urinary irritation. Cellulose and gums can have a bulking effect and can help in constipation (Dharmananda 1991).
Some polysaccharides have potent effects on the immune system. The clinical results of HM in the therapy of cancer, AIDS/ARC and other disorders of the immune system led to their discovery. These HMs contain mushrooms (coriolus, ganoderma, hoelen, lentinus, polyporus, tremella etc), codonopsis, ginseng and other herbs. Polysaccharides from Coriolus versicolor (yun zhi) are registered as PSK in Japan and PSG in China. Krestin, the largest selling antineoplastic drug in Japan, contains mainly polysaccharides from coriolus. Lentinan is another immunostimlant and antineoplastic polysaccharide. It is a 6-branched glucan chain from Lentinus edotes (xiang ling, the shiitake mushroom). Polysaccharides from Ganoderma lucidum and japonicum (ling zhi) are indicated in myasthenia gravis and have similar uses to Krestin and lentinan in AIDS/ARC and cancer (Dharmananda 1991).
Ganoderma, the most widely used medicinal mushroom, is easy to cultivate. It has tonic and sedative effects and is said to prolong life. The Shen Nong Ben Cao Jing discussed medical uses of this mushroom. Different colours of ganoderma have different effects: red stimulates heart-, internal organ- and brain- function; black stimulates water metabolism and kidney function; blue helps liver- and eye- function and is sedative; white helps lung- and spleen- function and relieves cough; yellow helps stomach- and chest- problems and problems due to stress, overwork or abuse of food or drink. Some varieties can act as antiallergic, antithrombotic and antihyperlipemic agents.
Polyporus (Grifola) umbellata (zhu ling) is used in nephritis. Its polysaccharides are 6-branched ß-(1-3) glucans, which promote antibody production, normalize liver function and are antineoplastic.
Hoelen (Poria cocos) is a dense mushroom which grows near pine tree roots. Fu ling (Poria stalk) is the main part. It is one of the most frequently used CHMs; it is mild and helps all the organs. Its major polysaccharide (pachymaran) and triterpenoids are not immunologically active unless treated chemically, but its chemically modified pachymaran, a 6-branched ß-(1-3) glucan, shows antineoplastic activity. Fu shen (Poria spirit) is the part attached to the roots. The latter has sedative effects.
Tremella (bai mu er = white tree ear) is a tonic and helps expectoration. Its polysaccharides have antineoplastic effects, stimulate phagocytosis and counter the adverse effects of cortisone treatment.
Based on a ß-1,3 glucan structure, polysaccharides in astragalus, coriolus, ganoderma, lentinus, polyporus and tremella have the highest natural antineoplastic activity. These polysaccharides also have powerful effect in enhancing the immune-response to bacteria, fungi, protozoa and yeasts and help patients to recover more easily from radiation, chemotherapy or surgery (for cancer or other reasons). Coriolus polysaccharides also are used in hepatitis (infectious and toxic).
2. Steroids
In WM, steroids are used to treat dozens of clinical conditions, including Addison's disease (adrenal insufficiency); inflammation; allergy; male and female reproductive disorders; skin- and mental- problems associated with hormonal imbalance; menstrual disorders; impotence/frigidity; post-menopausal syndromes etc. They also have a sedative action and some are used as oral contraceptives.
Steroids are lipid-soluble organic compounds that occur naturally throughout the plant and animal kingdoms. All steroids have a four-ring structure. Steroids are diverse and include the sterols (such as cholesterol) of vertebrates, bile acids from the liver, all sex hormones and adrenal cortical hormones. Hormonal steroids in the body are synthesized from cholesterol. The biosynthetic mechanisms are similar in all steroid-secreting tissue (testis, ovary, placenta and adrenal cortex). There are two classes of corticosteroids. Glucocorticoids (i.e. cortisone) primarily affect carbohydrate and protein metabolism. They have limited use in the treatment of many immunologic and allergic diseases, such as arthritis. Mineralocorticoids (i.e. aldosterone) principally regulate salt and water balance. Because of the great therapeutic value of corticosteroids, many synthetic steroids have been produced, some more potent than the natural hormones.
Plant steroidal compounds belong to the general category called saponins. In CHM, triterpenes yield the most important steroids. The triterpenes of the HMs most commonly used in immunostimulation and allergies (bupleurum, ganoderma, ginseng, hoelen, licorice) have been studied most.
Sterols are chemically similar steroidal compounds with alcohol (hydroxyl, (OH)) groups attached to a series of fused rings. The principal sterol in vertebrates is cholesterol, especially abundant in nerve tissue and gallstones. Ergosterol, a sterol found in yeast, ergot and moulds, gives rise to vitamin D-2 (calciferol) when irradiated with ultraviolet light. Higher plant sterols include stigmasterol (from soybean oil) and several spinasterols (from spinach and cabbage). Natural sterols are poorly absorbed and transferred to the circulation by higher animals. Cholesterol is absorbed readily, but coprostanol and cholestanol, which are structurally similar, are not absorbed. Most animals can synthesize their essential sterols from smaller carbon compounds. Immunostimulatory herbs, such as ganoderma, ginseng, rehmannia and sophora, also contain sterols. Yams (Dioscorea) contain steroids or a steroid precursor, diosgenin, from which several steroids (cortisone, oestrogen, progesterone) are manufactured by chemical alteration. The Mexican yam (D. floribunda) is a rich source of steroid precursor.
Plant steroids usually have similar action to that of steroid hormones, but at a lower activity (often 10%). Unlike the action of many plant saponins, HMs do not cause haemolysis and their steroids have a mild action, with minimal side effects (unlike WM steroids, which often cause Cushing's disease). Licorice (Glycyrrhiza) steroids have aldosterone-like actions, for example in Addison's disease. Excessive ingestion of raw licorice candy can cause excessive corticoid production, which can cause heart irregularities, oedema and death. This does not happen with the amounts of licorice used in CHM.
In HM, plant steroids can be used for the same indications as WM steroids, but for many other indications also. Chinese and Japanese studies of triterpenes, steroids and sterols in HMs have shown the following actions: stomachic (pro-digestive), emmenagogue and tonic effects on the liver and lung. Some triterpenes, such as the ginsenosides, are immunostimulatory also. Immunostimulatory, antiinflammatory, antihepatotoxic, antiallergic (antihistaminic), sedative and antispasmodic effects of plant steroids will be discussed later.
Stomachic (pro-digestive) effects: HMs with triterpenes (alisma, asparagus root, bupleurum, dioscorea, ganoderma, ginseng, hoelen, licorice, zizyphus etc) assist digestion, relieve gastritis, stress ulcers, diarrhoea and colitis. Asparagus root is rich in spirostane saponins and strongly inhibits gastroduodenal ulcer.
Tonic effects on the lung: HMs which protect the lung and assist expectoration include albizzia, arisaemia, bupleurum, cinnamon, eleuthero, ganoderma, glehnia, hoelen, licorice, lily family (anaemarhena, asparagus, lily, ophiopogon), platycodon, polygala etc. Many of these have steroidal action via their saponins, triterpenes, or spirostane glycosides. They are useful clinically in bronchitis, asthma, cough, lung congestion and pneumonia.
Many other ingredients used in HM have steroidal activity. They include animal products, such as deer antler, gecko, pipefish, seahorse and extracts of ovary, testis, adrenal and placenta from many species. Their uses in TCM include strengthening of the Yin and Blood and the Kidney Yang.
Antiaging formulas aim to boost Yang, support Yin and avert shrivelling (for example, drying of membranes, wrinkles, impotence). They contain many HMs with steroidal action.
Agitation, fidgeting, fatigue and insomnia often accompany immunosuppression (as in AIDS/ARC, hepatitis, Epstein-Barr virus etc) and autoimmune disease (especially when pain is present). A combination of HMs with steroidal, immunostimulatory and sedative actions is especially useful in those conditions.
3. Flavones and flavonoids are found in the aerial parts of many plants (leaves, flowers fruits) but are less common in the underground parts. Most HM formulas contain herbs with some flavonoids; some formulas have flavonoids as the main active compounds. Herbs with flavonoids include astragalus, bauhinia, capillaris, citrus peel, eclipta, eucommia, forsythia, ginko (leaf and fruit), ho-shou-wu, ilex, ixeris, licorice, lonicera, millettia, pueraria, qingpi, rose fruit, salvia, scutellaria (scute), sophora, swertia, vitex, zhishi.
Medicinal effects of flavonoids include: increased vascular integrity (antihaemorrhagic ,antiascitic); antithrombotic; vasodilatory. Antiviral/antifungal; antiallergic and antihepatotoxic effects will be discussed later.
Increased vascular integrity: Agents which can enhance capillary integrity are useful clinically to prevent or treat bruising, haemorrhagic diseases, ascites etc. Flavonoids in citrus peel and eclipta have that effect.
Antithrombotic effects: Low doses of aspirin are used to reduce platelet aggregation to prevent thrombosis, heart attack and stroke. However, haemorrhage, possibly cerebral, is a side effect. Flavones and flavonoids in bauhinia, ixeris, millettia, scutellaria and vitex can have the same antithrombotic effect but their effect on vascular integrity would prevent haemorrhage.
Vasodilatory effects: Vasoconstriction is a significant clinical sign in many cardiovascular conditions (peripheral vasoconstriction, hypertension, migraine, angina, palpitations, some forms of cerebral vascular accident etc). Vasodilators used in WM can help such cases, but sometimes cause the "steal effect" (vasoconstriction elsewhere in the body). Flavonoids in ginko leaf and pueraria have marked vasodilatory effect in the heart and brain, without the "steal effect". Such flavonoids include ginkgetins and rutin. Kaempferol, quercetin and rhamnetin combined, or an extract of ginko, gave good results in a small study of Parkinson's disease. Flavonoids in ilex and scute are useful in cardiovascular disease, hypertension, headaches and sore throat (Dharmananda 1991).
Flavonex is a formula with 8 herbs high in flavonoids (eucommia, ginko, ho-shou-wu, ilex, lonicera, pueraria, rose fruit and salvia) and 6 other herbs (acorus, cistanche, lycium fruit, morus fruit, schizandra and tang-kuei). In TCM, the formula is used to promote Blood Circulation, nourish the Essence and prevent the effects of aging (especially on brain function). Clinical uses include allergies and poor cerebral circulation.
Ginseng, Astragalus and Pueraria Formula is used in tinnitus, Bell's palsy, early cataracts and senility. To aid circulation, especially cerebral, it contains 4 herbs (astragalus, licorice, pueraria and vitex) which are high in flavonoids. The formula also contains ginseng (a general stimulant, an immunostimulant, and antiallergic herb), cimicifuga, phellodendron (antitoxic and antiinflammatory herbs) and peony.
Tang-kuei and Anemarrhena Formula is used in dermatitis and arthralgia. It contains 5 herbs high in flavonoids (capillaris, licorice, pueraria, scute, sophora) and 9 others which are immunostimulatory and antiinflammatory (alisma, anemarrhena, atractylodes, chiang-huo, cimicifuga, ginseng, polyporus, siler, tang-kuei).
Sesquiterpene lactones: Recently, several of these have been identified in plants consumed by animals for presumed medicinal value. They include agents with antineoplastic- (parthenin and eupatoriopicrin), antiulcer- (dehydroleucodin) and cardiotonic- (helenalin) effects (Robles et al 1995).
4. Alkaloids, of which >200 are known, have at least one nitrogen atom, or an amine group. They end in "-ine". Examples are: Aconitine, andinine, atropine; Berbamine, berberine, berberrubine, brucine; Caffeine, cocaine, codeine, colchicine, coumbamine; Domesticine; Emetine, ephedrine, ergometrine, ergotamine; Hyoscine (scopolamine), hyoscyamine; Isobolidine, isoquinolines, isotetrandine; Jatorrhizine; magnoflorine, matrine, mescaline, morphine; Nicotine; Palmatine, papaverine, phellodendrine, pilocarpine, protoberberines; Quinidine, quinine, quinolizidines; Reserpine, ricinine; Solamargine, solanine, solasonine, strychnine; Tetrandine, theobromine, theophylline, tropanes; Veratrine, vinblastine, vincristine.
Alkaloids are alkaline in nature, are acid-soluble and can be isolated by acid-extraction, followed by ammonia-precipitation. Some are simple, monocyclic amines, but many are very complex, polycyclic amines. Various family groupings are possible according to basic ring structure, such as pyridine or quinoline alkaloids. Most are poorly soluble in water and taste very bitter. Thus, HMs which contain alkaloids are often taken as pills, syrups or vinegar extracts, rather than as decoctions.
Alkaloids usually are absorbed fast, act fast and are excreted fast. They act mainly via the nervous system. Most alkaloids have biphasic action. At low doses, many stimulate the heart and respiratory system. Clinically, they promote circulation, breathing, coughing and expectoration. At higher doses, many act as sedatives. Clinically, they relax the heart and respiratory centre, relax muscles and promote sleep. These effects are pronounced as the dose increases. At toxic doses, death may occur from cardiac or respiratory failure.
Many alkaloids induce nausea and vomiting as a side effect. This may be used clinically, for example syrup of ipecacuanha, or vinegar extract of lobelia, to induce vomiting. Some may induce vertigo (dizziness), altered perceptions or hallucinations (cocaine, codeine, mescaline, reserpine, scopolamine). Those with potent effects on the CNS have potential for addictive abuse and dosage tolerance.
Some Solanaceae, such as datura and atropa and hyoscyamus (henbane), contain large amounts of atropine, hyoscyamine and scopolamine (hyoscine). Henbane was used extensively as an anaesthetic and analgesic. Mandragora officinarum (mandrake), one of the Solanaceae, also contains hyoscyamine. These plants are toxic when consumed in large quantity but are invaluable medicinal agents when given in proper amounts. Atropine is used in WM as a mydriatic and anticholinergic; it inhibits the secretion of bodily fluids and is used in nasal decongestants. As a smooth muscle relaxant, atropine is useful in relieving some gastrointestinal problems. It is also used as an antidote to nerve gas and some insecticides. Overdoses of atropine can cause an accelerated heartbeat and shallow breathing, leading in some cases to death. Scopolamine is used as a hypnotic and as an antispasmodic to reduce gastrointestinal contractions. Hyoscyamine has potent effects on the CNS; it is used as a sedative, especially to control spasmodic conditions. Hyoscyamine and scopolamine have been used to treat alcohol and morphine addiction.
Differences in alkaloid structure influence the dose range needed to produce pharmacological effects. Some are relatively non-toxic and may be taken safely; others (such as aconitine) may induce potent sedation and may be very toxic at low doses. Sedative alkaloids (the majority) maintain a sedative effect at moderate doses. Stimulant alkaloids maintain a stimulant action over a very wide dose range.
Stimulant alkaloids: Many societies use indigenous plants containing stimulant alkaloids. The Sudanese chew kola nut (origin of Cola drinks) for its stimulant effects, due to its high caffeine content. South American Indians chew coca leaf, a source of cocaine, to attain increased energy, alertness and euphoria. Cocaine, isolated in 1855, was used in WM as a local anaesthetic (especially for the nose, throat, and cornea) and nasal decongestant. Used systemically, cocaine stimulates the central nervous system, producing feelings of excitation, elation, well-being, enhanced physical strength and mental capacity, and a lessened sense of fatigue. It also causes increased heart rate, blood pressure, and temperature; in large doses, it can cause death. It is strongly addictive and has become a major drug of abuse. Khat leaves contain norpseudoephedrine; they are chewed by Middle Eastern peoples. Betel nut, the seed of the betel palm, Areca catechu, contains arecholine. Many Asians and South Pacific Islanders chew the nut to obtain a mild narcotic stimulation and sense of well-being. In veterinary medicine, the nut was used for deworming.
Nicotine, in tobacco and snuff, is an addictive stimulant drug and other alkaloids have potential for dependency/addiction. Some (such as caffeine and cocaine) stimulate the CNS; others (such as hyoscyamine and morphine) depress the CNS. Via central and peripheral neural action, alkaloids influence muscle (especially smooth muscle), usually relaxing it. For example ephedrine and codeine cause broncho-relaxation, reduce coughing and assist expectoration; vasodilatory effects of alkaloids can help to reduce fevers, relieve muscle spasm and hypertension.
Alkaloids have potent pharmacological action and many are used daily as medicines in WM and HM. They are potentially toxic if misused; most plants containing them are classed as toxic. Curares are of different botanical origin, and each contains extracts of several plants. The toxiferins obtained from Strychos toxifera are the most potent curare alkaloids. Species of Chondrodendron are sources of tubocurarine. Curare alkaloids are inactive orally; parenterally they act as skeletal muscle relaxants by blocking muscle receptors for acetylcholine. The main clinical use of curare is as an adjuvant in surgical anaesthesia to obtain relaxation of skeletal muscle or to facilitate diagnostic procedures, such as laryngoscopy and endoscopy.
Most plant families (85-90%) contain no alkaloids but plants that do are seldom used for food. Exceptions are potatoes/tomatoes (solanine), coffee beans (caffeine), tea leaves (caffeine, theophylline), cocoa (caffeine, theobromine), kola extract (caffeine) etc, in which the levels in the consumed portions are relatively low. However, acute solanine toxicity can arise in animals who ingest excessive amounts of potato/tomato haulms.
Many alkaloids act as stimulant drugs, or analeptics. Stimulants excite the CNS, increasing alertness, decreasing fatigue, and delaying sleep. Some impair appetite are prescribed to promote weight loss in obese people. Most users of these drugs experience a sense of euphoria, but this reaction depends greatly on the drug taken and the dose. Signs of overstimulation by these drugs, such as muscle tremors or irregular heart rate, are common. Caffeine is the most widely used stimulant drug in the world. In small amounts, it acts as a mild stimulant and is harmless to most people. In large amounts, it may cause insomnia, restlessness, and anxiety. Caffeine increases heart rates and can cause heart irregularities; heavy coffee drinkers are more prone to coronary heart disease. Caffeine decreases blood flow to the brain, and has been used in treating migraine headaches. It is also used in treating poisoning by depressants such as alcohol and morphine, and studies suggest that it somewhat increases the effectiveness of common analgesics such as aspirin. By widening bronchial airways, caffeine and theophylline can help to relieve asthma attacks. Caffeine can cause chronic (low grade) adverse reactions in humans who consume excessive amounts. With increasing age caffeine users may experience for the first time insomnia or palpitations of the heart associated with irregular beats. Heavy users often become nervous, irritable, apprehensive, restless, and unable to sleep; such symptoms may be construed as a psychiatric disorder unless the history of caffeine misuse is known. Recognition of the drug effects of these beverages has led to the increased use of decaffeinated coffee.
Alkaloids have potent vasodilatory-hypotensive-sedative, antitussive-expectorant, antiinflammatory-analgesic-antiarthritic effects. Many have immunostimulatory effects, potent antibacterial action and stimulate leucocytosis and phagocytosis; some have antifungal and antiviral action also. Some alkaloids inhibit neoplastic cells and stimulate biliary secretion and uric acid excretion. They are used clinically to treat immunomediated disorders (allergies, asthma, immunosuppression, bronchitis, autoimmune diseases, arthritis, gout and allied conditions, infections, gastroenteritis, dysentery, constipation, neoplasia, etc), hypertension, stress, insomnia and the effects of chronic disease and senility. The alkaloids used in CHM are relatively safe, usually non-addictive and confer multiple therapeutic effects, especially when combined with other HMs.
Alkaloid-containing medicinal herbs include: aconite, aristolochia, berberis, chin-chiu, cocculus, coptis, corydalis, erythina, Fangji, gentiana, ipecacuanha, lobelia, lycopodium, mahonia, nandina, phellodendron, rauwolfia, sinomenium, solanum, sophora, stemona, stephania and veratrum.
Commonly used herbs, in which alkaloids are the main active compounds, come from two main families: the Berberidaceae and the Menispermaceae. Within each family, the alkaloid structures and clinical effects are similar. Both families contain species which contain berbamine and tetrandine.
Berberidaceae have antiinflammatory action, inhibit gastrointestinal bacteria and relieve irritation of mucous membranes in the eye, digestive and respiratory system. They are used to treat fever, cough with excessive phlegm, gastroenteritis, dysentery and inflammation of the eyes, throat, mouth and joints. They include many species of Berberis root (high in berberine, palmatine, berbamine, jatorrhizine). Mahonia contains similar alkaloids and magnoflorine. Nandina contains domesticine, andinine, isobolidine and other alkaloids, similar to those in mahonia and berberis.
Menispermaceae include cocculus, stephania, sinomenium. These have potent clinical effect with minimal side-effects and are used interchangeably. They contain alkaloids with antiarthritic, antiallergic, antioedematous, hypotensive and antimicrobial effects, used to treat arthritis, allergies, oedema, hypertension and gastroenteritis.
Miscellaneous alkaloid-containing herbs: Antiinflammatory herbs used in arthritis include aconite, aristolochia, chin-chiu, corydalis, erythina, lycopodium and solanum. Antiinflammatory herbs used in irritation of skin and mucous membranes include coptis, gentiana, phellodendron, solanum, sophora. Antiinflammatory herbs used in cough and bronchitis include solanum and stemona. The solanum used in CHM (S. nigra) contains solasonine and solamargine, but little solanine. It is contraindicated in pregnancy but its roots, seeds and leaves are used extensively in China to treat cancer.
Opiate alkaloids are considered the most effective of all analgesics. Papaver somniferum yields 26 alkaloids, of which the most important are morphine, codeine and papaverine. All opiates can be abused, but heroin, a morphine derivative, is the most notorious. Because of their abuse, opiates are restricted and used less and less in routine WM, except in terminal illness.
Alkaloid-containing herbs are a relatively small part of most formulas used in CHM. They are used mainly to supplement the effects of other herbs. However, the following formulas contain a high content of alkaloids:
a. Coptis and Scute Formula (coptis, phellodendron; gardenia and scute). The first two herbs rely mainly on alkaloids for their action. The formula is used in fever, haemorrhagic diseases, insomnia, gastroenteritis, pruritus and hypertension.
b. Coptis and Evodia Pills (berberis, coptis, evodia, phellodendron; licorice, peony and saussurea). The first four herbs contain alkaloids with sedative, hypotensive and antiinflammatory effects. The formula is used to treat gastrointestinal disorders associated with stress or agitation, including chronic colitis, associated with immunodeficiency.
Dharmananda's review of the effects of polysaccharides, steroids, flavonoids and alkaloids (above) shows that HMs containing these (and other, not discussed,) compounds can have potent therapeutic action on inflammation, membrane stability, lipid peroxidation, infections, immunomediated disorders, cancer, nervous, cardiac, pulmonary, hepatic and renal disease etc.
The rest of this section will discuss other data on active compounds in HMs: immunomodulators; antiinflammatories; antioxidants; antimicrobials; antivirals; antineoplastics; sedatives/hypotensives and insect antifeedants.
Immunomodulators
Immunomodulation is critical to the treatment of immunomediated disorders (infections, inflammations, autoimmune disease, allergies etc). Many systemic diseases, such as autoimmune diseases, immunosuppression, AIDS and cancer are poorly, if at all, controlled by WMs. Based on TCM, Sino-Japanese concepts of homeostasis suggest that there is a regulatory effect on the immune-, endocrine- and cardiovascular- systems.
a. Autoimmune disease: Several HMs are clinically effective in autoimmune diseases, such as chronic hepatitis, rheumatoid arthritis, nephrosis, and systemic lupus erythematosus. These HMs are thought to act by modulating the immune system (Labadie et al 1989; Wagner 1990). Active compounds (polysaccharides, steroids, flavones and alkaloids etc) in HMs have potent action on immunomediated disorders (Dharmanada 1991), as discussed earlier.
b. Antiallergic effects: Bupleurum contains saikosaponins (steroids with antiinflammatory and antiallergic activity). Sophora alkaloids have antiallergic action (Dharmananda 1991). Scute contains baicalin, baicalein and skullcapflavone II; these inhibit release of chemical mediator from mast cells.
Herbs with antihistaminic effects (due to ß-eudesmol and nerolidol) are: alpinia, cardamom, cluster, galanga, ginger, zedoaria. Zizyphi fructus (jujube) contains a compound which increases cAMP production in the body, a ß-adrenergic compound and ethyl-Ó-D-fructofuranoside. These compounds suppress IgE activity. Hot water-extract of ganoderma suppressed histamine release from mast cells and the passive cutaneous anaphylactic (PCA) reaction (Tsung 1987). Steroidal activity in ganoderic acids (in ganoderma), ginsenosides (in ginseng) and extracts of bupleurum and licorice have antiallergic/antihistaminic effects. They inhibit, or reduce, mediator release (see allergies, in section a, above). Antiallergic effects also include other antiinflammatory mechanisms.
Polymethoxyflavones have high antiallergic and high antithrombotic activity. Nobeletin, tengeretin and heptamethoxyflavone are the active antiallergic compounds in the Chinese citrus products zhishi and qingpi. These gave marked inhibition of passive cutaneous anaphylactic reaction (PCA) in experimental allergic challenge in rats. Nobeletin has a similar structure to koganebananin and skullcapflavones (baicalin, baicalein and skullcapflavone II) from scute. The latter inhibit mediator release from mast cells. Baicalin increases the levels of CAMP and PGE1, which inhibit mediator release. Capillaris and scute are used to treat urticaria and dermatitis. Capillaris contains cirsimaritin, which has a similar structure to baicalin. Antiasthmatic HM formulas often contain ginko fruit. Ginkolide, both natural and synthetic, is effective in human asthma and allergic inflammation and reduces rejection of transplanted grafts in animals. Daidzein, and similar compounds, are the active compounds in pueraria and sophora, which are important antiallergic herbs, for example in urticaria, dermatitis, sinusitis, migraine, asthma etc (Dharmananda 1991).
c. Antihepatotoxic effects: In WM, as in TCM, many allergic conditions, autoimmune, inflammatory, metabolic and toxic disorders involve seriously disturbed liver functions. These include food- and drug- allergies, gastro-duodenal-colonic irritation/ulceration, photosensitisation, dermatitis, conjunctivitis, migraine, irritability, gout, rheumatoid arthritis, hepatitis etc. Therapy which protects or enhances liver function also helps in liver-mediated disorders. Polysaccharides, steroids and flavones in HMs with hepatoprotective action are also useful in such conditions (Dharmananda 1991). HMs which protect the liver against toxins and are useful clinically in hepatotoxic disorders and hepatitis include andrographis, bupleurum, coriolus, eleuthero, ganoderma, gentiana, ginseng, gynostemma, licorice, paeonia, phyllanthus, picrorrhizia, polyporus, sophora etc. The effects are mediated by their polysaccharides, steroids and saponins. Other important HMs used in hepatitis and liver disease are Capillaris, scute and sophora; they have potent antihepatotoxic action, mediated by their flavonoids. Flavonoids capillarisin, arcapillin, isorhamnetin and quercetin are hepatoprotective in carbon tetrachloride cytotoxicity. Swertia flavonoids (homoorientin, swertiajaponin, swertisin) are hepatoprotective in galactosamine cytotoxicity (Dharmananda 1991).
The bitter taste of most alkaloids, especially berberine alkaloids, stimulates bile secretion. HMs containing such alkaloids are used as appetite stimulants, mild laxatives and to treat biliary stasis, cholecystitis and ascariasis of the bile ducts. Their combination with HMs which stimulate liver function increases their efficacy (Dharmananda 1991).
In controlled experiments in rats, ginseng had a protective effect on liver; injections of a water-extract of ginseng significantly decreased liver enzyme levels (AST, ALT) induced by injections of dexamethasone (Lin et al 1995c).
Antiinflammatories
Steroids in akebia, alisma, dianthus, licorice and poria (hoelen), as in the formula Ba Zhen Tang (see c, below) have antiinflammatory effects and are used to treat nephritis and urinary infections. Steroids are thought to underlie the efficacy of bupleurum in allergies, hepatitis, gastroenteritis and dermatitis. The alkaloids tetrandine and isotetrandine have antiinflammatory, antiallergic and antianaphylactic action. Alkaloids in Fangji, a HM based on any one, or combination, of aristolochia, cocculus, stephania or sinomenium, activate the self-defence system in infection and inflammation (Dharmananda 1991).
Alkaloids from the Berberidaceae are used mainly to treat inflammation of the skin and mucous membranes; those from the Menispermaceae are used to treat inflammation of the joints (Dharmananda 1991).
Accumulation of urates in tissue, especially in the tendons and joints can cause gout and gouty arthritis. Classical signs are irritability and pain, especially in the big toe (the "Liver Toe" in TCM). Berberis, coptis and phellodendron increase uric acid excretion and are used to treat gout. Their alkaloids are thought to be involved in urate elimination. Colchicine, from Colchicum autumnale, is used in WM for the same purpose. Other herbs with antiinflammatory and hepato-protective effect are also useful in gout.
Protoberberines and isoquinolines have analgesic effect in hot plate-induced experimental pain. Corydalis, menisperma and sinomenium are used to treat pain, especially in trauma and arthritis. They contain protoberberines, such as corydalimine, stepholidine and synactine. Cocculus, menisperma and stephania are used to treat pain in arthritis. They contain isoquinolines, such as berbamine, coclobine, dauricine and tetrandine.
Ginsenoside Ro, isolated from the roots of Panax ginseng, reduced acute paw edema (induced by 40/80 or carrageenin) in rats; it also inhibited the increase in vascular permeability (induced by acetic acid) in mice (Matsuda et al 1990). An extract of ginseng increased the phagocytotic ability of white cells in bovine blood and milk (Hu et al 1995).
Ginseng is used in TCM for its tonic and restorative effects in stress, neurasthenia, convalescence. Ginseng extract restored adrenal and thyroid functions inhibited by the dexamethasone treatments; the effects of the extract on adrenal and thyroid function may explain some of its effects as a general tonic and antistress herb (Lin et al 1995c).
New diastereoisomers and sulphur-containing compounds, isolated from onion, Allium cepa L, had potent inhibitory effects for collagen-induced aggregation, as well as ADP- or arachidonate- induced aggregation of human platelets in vitro. The most active compound was a diastereoisomer of cis-3-ethyl-2,4,5-trithia-6-octene 2-S-oxide (Morimitsu & Kawakishi 1990).
Antioxidants
Many disease processes involve the generation of reactive oxygen species (superoxide anionic radical (O2-), hydrogen peroxide (H2O2), hydroxyl-radical (OH-) etc). If not neutralised, these oxidative radicals cause cellular oxidative stress, increase lipid peroxidation and cause instability of cellular membranes. The presence of these radicals also compromises the microbicidal activity of polymorphonuclear leucocytes and other phagocytic cells (macrophages, reticuloendothelial calls etc).
Pro-oxidants increase the risk of all disorders associated with reactive oxygen species (free radicals) in the body. In the future, antioxidants in HMs may be a very important method of maintaining life in a polluted environment. Anthropogenic pollution is a serious threat to life on earth. We burn organic materials to generate power (electricity, heat, transport (engines)) and to dispose of municipal- or domestic- waste by incineration. Fires also combust organic material. Unless these emissions are removed and/or recycled by expensive technology, they enter our atmosphere. Particulate (fly-ash) and gaseous emissions return to earth by deposition/precipitation. Emissions of combustion, or from industrial sources (smelters, refineries, pharmaceutical and chemical plants, fertiliser factories etc), contain xenobiotic organic compounds such as 2,4,5-trichlorophenol (phenoxyacetic acid), halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, pentachlorophenols, polychlorinated dibenzofurans, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, tetrachlorodibenzo-p-dioxins and related xenobiotics. Some herbicides and pesticides also contain them.
Organic hydrocarbon emissions include dioxins, the most toxic anthropogenic chemicals known. Organic toxins enter the food chain, persist for long periods in the environment and pose toxic hazards to soil, plant, animal and human life. Xenobiotic effects of dioxins to humans and animals include: increased lipid peroxidation and cellular oxidative stress (exaggerating any environmental deficiencies of copper, selenium and vitamins, especially E); immunotoxicity (thus, increasing susceptibility to cancer, AIDS, viral and bacterial infections and inflammatory processes); thyrotoxicity (thus, exaggerating environmental deficiencies of I and Se and compromising reproduction, neonatal survival, lactation, growth and general metabolism); inhibited sexual differentiation of the central nervous system and disorders of the liver, kidney, skin, heart and lungs. Dioxins also adversely influence female and male reproduction; they compromise pregnancy and induce birth defects. They reduce growth and they influence (and are influenced by) Vitamin A in serum and tissues (Rogers 1995).
Animals have an extensive antioxidant defence system to minimise the untoward effects of oxygen. Antioxidants alleviate the oxidative load by directly quenching reactive oxygen species before they damage vital cellular components. Mammalian intracellular antioxidants include the selenium-dependent glutathione peroxidases, the copper-dependent superoxidase dismutases, vitamins E and C, b -carotene, uric acid.
Medicinal plants also contain large amounts of antioxidants (ascorbic acid, tocopherol, ubiquinone, glutathione, phenolics, etc). Therefore, it is not surprising that these natural sources are used medicinally in many conditions, including aging, atherosclerosis and immunomediated diseases (immunosuppression, inflammation, infection, neoplasia etc)...
Gypenoside saponins of Gynostemma pentaphyllum have antioxidant properties which counter oxidative stress in phagocytes, liver microsomes and vascular endothelial cells. The extensive antioxidant effect of gypenosides may be valuable to prevent and treat various diseases such as atherosclerosis, liver disease and inflammation (Li et al 1993).
Tannins are polyphenols widely present in plants. Since phenolic compounds have antioxidant activities, tannins also could be developed to prevent lipid peroxidation and biological damage caused by free radicals formed under oxidative stress. Of 25 tannins and related compounds tested, catechin, benzylthioether and procyanidin ß-2 benzylthioether were the most potent in inhibiting lipid peroxidation, with inhibitory effects stronger than Trolox, a water-soluble analogue of vitamin E. Also, conjugation of tannins with a benzylthioether group did not enhance the free radical scavenger activity of tannins. However, it may increase the inhibitory effect on lipid peroxidation (Hong et al 1995). Recently, magnolol and honokiol, isolated from Magnolia officinalis, were shown to be 1000 times more potent than Trolox (Lo et al 1994). Antioxidant (free radical-scavenging) effects of bupleurum polysaccharide are discussed under section (c), below.
Antimicrobials
Many plants and HMs contain antimicrobial compounds. Such compounds are of interest because of their relationship to phytoalexin production. Phytoalexins are antimicrobial compounds of low molecular-weight. They act as a defence against microbial infection of the plant; plants synthesize and accumulate them after exposure to micro-organisms (Dixon & Lamb 1990). Most herbs have weak antimicrobial activity in comparison with that of synthetic antibiotics, or those from microbial or fungal origin but some have antibacterial and/or antifungal activity of practical value in medical and veterinary therapy (Cousins 1995a,b).
Oryzalide A is a novel C19-kaurane type of diterpene. It was isolated from the healthy leaves of a rice plant which was resistant to Xanthomonas campestris pv. oryzae. That organism is a cause of leaf-blight in susceptible rice plants (Wabanabe et al 1990). At 150 ppm, Oryzalide A inhibited approximately 60% of the colony-forming ability of X. campestris. Because similar diterpenes were isolated from rice as phytoalexins, it is thought that the biosynthetic pathway of diterpenes may play an important role in the mechanisms of disease resistance in rice plants. In tropical countries, plants from the Meliaceae family are used widely in TM to treat fever. A limonoid, gedunin, recently isolated from Meliaceae spp., had moderate antimalarial activity (IC50, 0.72 mg/ml) against Plasmodium falciparum (Bay et al 1990).
Protoberberines (including jatorrhizine, coumbamine, berberine and phellodendrine) have effective antimicrobial activity. They occur in berberis, coptis and phellodendron, herbs which are used to treat gastroenteritis and bacillary dysentery, or to treat wound infection by local application. Matrine and other alkaloids in sophora are strongly antiseptic and antifungal. Stemona alkaloids are antibacterial and antifungal. Flavonoids have very good antifungal activity in the treatment of candidiasis and thrush. Condensed flavonoids form tannins, useful as astringents and antiseptics. HMs with flavonoid/tannin effect are useful in gastrointestinal infection (Dharmananda 1991).
Antivirals
Some herbs have antiviral activity which may have practical value in veterinary therapy (Cousins 1995a). Several antiviral compounds have been isolated from herbs (Dharmananda 1991). The Lonicera and Forsythia Formula (Yinqiao Jiedu San in TCM) is the world's most commonly used medication for colds and 'flu. The flavonoid quercetin gave some protection to animals experimentally inoculated with many viruses. It also inactivated herpes simplex, polio, rabies and some 'flu viruses. Catechin is more potent than quercetin against herpes virus. Stemona alkaloids are antiviral (Dharmananda 1991); 5-0-methyl-genistein 7-0-ß-D-glucopyranoside from Ulex europaeus, inhibited the replication of Herpes simplex virus (HSV) and poliovirus (De Rodriguez et al 1990). Three proanthocyanidins from Pavetta owariensis (Guinean TM), proanthocyanidin A2 (dimeric proanthocyanidin), cinnamtannin B1 (trimeric anthocyanidin) and cinnamtannin B2 (tetrameric anthocyanidin), had pronounced antiviral properties against HSV and Coxsackie viruses. It seems that both anti-herpetic potency and the cytotoxicity of tannins depends on the molecular-weight, as well as the number of polyphenolic groups (Fukuchi et al 1989; Balde et al 1990). Recently, two of 134 flavonoids, isolated from Scutellaria radix (scute), were shown to have highly potent anti-influenza activities in vitro and in vivo (Nagai et al 1995).
Antineoplastics
Drug resistance is common when single drugs are used to treat a specific cancer. WM usually uses many drugs simultaneously in cancer chemotherapy, as tumours are less likely to becomes resistant to drug therapy by the combination technique. Combination chemotherapy has been most successful in treating cancer, especially leukemia, Hodgkin's disease, testicular cancer and ovarian carcinoma. Recent cancer therapies combine less radical forms of surgery with radiation, chemotherapy, "preventive" therapy and support therapy.
WM uses two main types of chemotherapy: cytotoxic chemotherapy and immunotherapy (Dharmanada 1991; Ogilvie & Moore 1995). (a) Cytotoxic chemotherapy aims to kill neoplastic cells by a direct toxic action. The side effects can be severe and may need to be controlled by symptomatic medication. Several types of naturally occurring compounds, which react directly with DNA, are used. These include steroids, antibiotics, alkaloids and alkylating agents. WM also uses antimetabolites. These resemble normal metabolites in structure and compete with them for some metabolic function, thus preventing further utilization of normal metabolic pathways. (b) Immunotherapy aims to enhance the body's innate ability to recognize, attack and destroy the neoplastic cells. Active immunotherapy aims to stimulate lymphocytes that are effective in destroying cancer cells. Passive, specific, or nonspecific immunotherapy is by injection of antibodies specific for the neoplasm (such as specific monoclonal antibodies), administration of nonspecific immunoglobulins, interferon, cytokines (such as Tumour Necrosing Factor (TNF), interleukin 2 (IL2)) etc. It also includes the use of antioxidants (vitamin E, trace-elements (especially selenium)) and non-specific immunostimulants and immunomodulators. The latter act by boosting the body's production of cytokines and other protective agents (Dharmananda 1991; Ogilvie & Moore 1995).
Many cytotoxic antineoplastic agents have been isolated from plants, especially the polysaccharide fraction of mushrooms (as in the Japanese formula Krestin) and astragalus (see Dharmanada 1991, summarized above). Vinblastine and vincristine (alkaloids from Vinca rosea, or Catharanthus roseus) are used to treat Hodgkin's disease and acute leukaemia, respectively. Taxol, from the bark of Pacific yew trees (Taxus brevifolia), gave promising results in advanced ovarian-, breast- and other- cancers (Borman 1991). Mallotus japonicus husks contain 3-(3,3-di-methylallyl)-5-(3-acetyl-2,4-dihydroxy-5-methyl-6-methoxybenzyl)-phloracetophenone. This compound had excellent cytotoxic activity against target neoplastic cells such as human carcinoma cells (larynx (HEp-2) and lung (PC-13)) and mouse B16 melanoma, leukaemia P-338 and L5178Y cells. It increased significantly the lifespan of mice bearing L5178Y leukaemia (Arisawa et al 1990).
Novel diterpene acids, pseudolaric acid-A and pseudolaric acid-B, isolated from Pseudolarix kaempferi (Tu-Jin-Pi in CHM), are cytotoxic against human cancer cell lines. Pseudolaric acid-A is more effective on leukaemia P-388 and melanoma SK-MEL-5, whereas pseudolaric acid-B is more active against leukaemia HL-60TB and P-388, CNS cancer TE671, melanoma SK-MEL-5, and ovarian cancer A2780 (Pan et al 1990). Bryophillin B, a potent cytotoxic bufadienolide, has been isolated from Bryophyllum pinnatum. It shows potent cytotoxicity (ED50 <80 ng/ml) against in vitro growth of KB tissue culture cells (Yamagishi et al 1989).
Cantharidin, isolated from Mylabris spp., possesses antihepatoma properties and induces leucocytosis (Wang 1989). However it is highly toxic and it decreases synthesis of steroids (Lin et al 1995b). As it may be fatal, it seldom is used clinically. Fortunately, several analogues (such as disodium norcantharidate, norcantharidin, dehydronorcantharidin and methylcantharidimide) have been synthesized. Those analogues may have important uses in antineoplastic therapy (Wang 1989).
Indirubin, a potent antileukemic agent, was isolated from Danggui Liuwei Wan (Six Flavour Tang-kuei Pill). That Formula is used to treat cancer in China. Indirubin was the main active compound in an extract of Qingdai (Baphicacanthus cusia), another herb used to treat cancer (Dharmananda 1991).
Certain glucosides are immunoactive but only those with immunostimulant effects are indicated in cancer therapy. For example, two new phenylalcohol glucosides, jionosides A1 and B1 were isolated from Rehmannia glutinosa (Sasaki et al 1989). They have immunosuppressive effects, as have related glucosides. A new sesquiterpene glucoside, sphaeranthanolide, from the flowers of Sphaeranthus indicus has immunostimulant activity; it enhanced the antibody response to sheep red blood cells (SRBC) (Shekhani et al 1990).
In immunomediated disorders, alkaloids of the protoberberine, isoquinoline and quinolizidine groups are of special interest as immunostimulants. Berbamine enhances the antineoplastic effects of cyclophosphamide in chemotherapy of cancer. It also increases white cell counts and counteracts cyclophosphamide-induced leukopaenia. Berbamine and isotetrandine activate lymph glands and the cellular reaction of plasmoblasts and plasma cells. Berberrubine is a potent inhibitor of sarcoma 180. Tetrandine and isotetrandine inhibit many forms of cancer, including Erlich Ascites Tumour and carcinoma of the liver. Sophora alkaloids increase white cell counts and counteract radiation-induced leukopaenia. Water extract of Sophora inhibits sarcoma 180 and tumour growth of transplanted cervix tumour cells and prolongs survival of animals experimentally inoculated with ascitic and carcinoma cells (Dharmananda 1991). TJ-48 is a Japanese pharmaceutical preparation used in KM. TJ-48, and its original prescription (JTT), are powerful immunostimulants and have potent effects on cancer patients. These effects are discussed under JTT, below.
Lien & Li (1985) and Zhang (1989) give much more detailed reviews of the pharmacology of CHMs and their uses in the treatment of cancer.
Sedatives, antispasmodics and hypotensives
The sedative and hypotensive effects of HMs containing triterpenes and alkaloids, and the anticonvulsive effects of saponin-containing HMs are useful in many clinical indications (Dharmananda 1991).
Polysaccharides in blue ganoderma and poria have sedative effects. HMs containing saponins, such as arisaemia, bamboo, gleditsia and typhonium have anticonvulsant effects similar to phenobarbital. These are useful clinically in epilepsy and febrile convulsions etc. In TCM, insomnia, agitation and restlessness are due to disturbed Shen (spirit), often due to weak Heart Yin. HMs which calm the Shen by strengthening Heart Yin have sedative effects. HMs with such effect include albizzia, eleuthero, ganoderma, hoelen, lily, ophiopogon, polygala, poria, rehmannia, zizyphus. The sedative effects are due to a steroidal action via their saponins and triterpenes. Such herbs prolong the effects of phenobarbital. HMs with sedative effects not due to steroids include acorus, biota, lotus seed and tang kuei. HMs with sedative action are useful clinically in stress, insomnia, agitation etc.
The Coptis and Scute Formula is used to treat hypertension. Potent hypotensive agents include the protoberberine alkaloids (at high levels in coptis and phellodendron) and isoquinoline alkaloids (e.g. cyclanoline in stephania). Tetrandine, palmatine and berberis alkaloids are hypotensive also. Jatorrhizine and related alkaloids, such as palmatine, occur in berberis, coptis, corydalis and phellodendron. They are sedative and prolong sleep induced by phenobarbital. Domesticine and andinine, in the antitussive nandina fruit, have morphine-like effects (Dharmananda 1991). Rauwolfia serpentina, which contains reserpine, was used for centuries as a sedative in snakebite, in mental disease and insomnia, and for many other purposes. WM also uses reserpine to treat hypertension and as a sedative in psychiatric disorders, such as schizophrenia. Its mechanism of action involves the depletion of catecholamines and serotonin.
The pharmacological activity of the benzodiazepine sedative group is mediated by a specific channel receptor (benzodiazepine-x-gamma-aminobutyric acidA-chloride, BDZ-GABA) complex. Many HMs contain compounds which bind to BDZ receptors in the central nervous system. BDZ-like compounds in plants can be detected by gas chromatography-mass spectroscopy (Unseld & Klotz 1989), or by their specific interaction with a monoclonal antibody to BDZ (Medina et al 1989). The clinical significance of these compounds for humans and animals should be explored.
Insect antifeedants
Some plants possess highly active insect antifeedants. These active compounds can be used as novel insecticides. Under laboratory conditions, tylophorine, isolated from Tylophora asthamatica, completely inhibited feeding by Spilosama obliqua under laboratory conditions. The effect persisted in field trials for 2 days, as determined by damage-rating scores (Tripathi et al 1990). Tylophorine may be used as a prototype for the synthesis of safer and more economical molecules to deter insects from feeding. These may have future industrial use.
Four new sesquiterpene alkaloids, 1Ó-nicotinoyloxy-2Ó-acetoxy-6ß-acetoxy-9ß-furoyloxy-11-isobutyryloxy 4ß-hydroxydihydro-ß-agarofuran and related compounds, isolated from the root-bark of Celastrus angulatus, showed strong antifeedant action with several different insect spp. (Liu et al 1990). Treated insects were paralysed for many hours after ingesting a small dose of the test sample. They then recovered, fed and became paralysed again. As a result, the insects gradually starved to death.
Miscellaneous known medicinal effects of active herbal compounds
The active compounds in HMs can have multiple medicinal effects. The following is summarised from Akerson (1995):
Allium sativa (garlic) is used as a spice, a medicine and a germicide. Its juice contains the antibiotic oil allicin (diallyl thiosulphinate). Effects include inhibition of platelet aggregation; enhanced mesenteric circulation, and antimicrobial effects in bacterial, viral, protozoal and fungal diseases.
Gentiana lutea (gentian glycosides, gentiopicrin, gentiopicroside etc): Effects include antiinflammatory, antibacterial and antimalarial effects; choleretic and digestive effects (useful in hyper- and hypo- chlorhydria); diuretic and liver-protective effects.
Hydrastis canadensis (isoquinoline alkaloids, berberine and hydrastine): Effects include antiprotozoal and broad spectrum antibacterial effects, especially against candida and gastrointestinal pathogens. The herb has antispasmodic effects on the gut and is used to treat gastroenteritis, ulcers and indigestion etc.
Jugulans nigra (naphthoquinone, juglone): Effects include antifungal, antiviral, antibacterial and anthelmintic effects, similar to Hydrastis.
Quassia amara (quassinoids, gutulactone, simalikalactone): Effects include antiprotozoal, antineoplastic and antiviral activity and anthelmintic activity against nematodes (ascaris, pinworms).
Future research on herbal compounds?
Chaudhury (1995) reviewed pharmacological research, folk medicine and traditional texts. The following HMs have good clinical efficacy in the following indications. This justifies the need for detailed research on the identification and clinical potency of the active compounds in the following HMs (Chaudhury 1995):
1. Polysaccharides
Plants contain many sugar molecules, in various combinations, sizes and chemical sequences. Monosaccharides are simple sugars. Long straight- (and/or branched-) chain monosaccharide polymers form polysaccharides. Most are not water-soluble (such as gums) but some are (such as the pectin ploysaccharides). Sugars, gums and celluloses have relatively little use in WM, except as fillers and binders. However, pectins can soothe the gastrointestinal tract and can help in diarrhoea and gastroenteritis. Pueraria, dioscorea and hoelen are used in this way. Inulin (from Compositae spp.) can soothe urinary irritation. Cellulose and gums can have a bulking effect and can help in constipation (Dharmananda 1991).
Some polysaccharides have potent effects on the immune system. The clinical results of HM in the therapy of cancer, AIDS/ARC and other disorders of the immune system led to their discovery. These HMs contain mushrooms (coriolus, ganoderma, hoelen, lentinus, polyporus, tremella etc), codonopsis, ginseng and other herbs. Polysaccharides from Coriolus versicolor (yun zhi) are registered as PSK in Japan and PSG in China. Krestin, the largest selling antineoplastic drug in Japan, contains mainly polysaccharides from coriolus. Lentinan is another immunostimlant and antineoplastic polysaccharide. It is a 6-branched glucan chain from Lentinus edotes (xiang ling, the shiitake mushroom). Polysaccharides from Ganoderma lucidum and japonicum (ling zhi) are indicated in myasthenia gravis and have similar uses to Krestin and lentinan in AIDS/ARC and cancer (Dharmananda 1991).
Ganoderma, the most widely used medicinal mushroom, is easy to cultivate. It has tonic and sedative effects and is said to prolong life. The Shen Nong Ben Cao Jing discussed medical uses of this mushroom. Different colours of ganoderma have different effects: red stimulates heart-, internal organ- and brain- function; black stimulates water metabolism and kidney function; blue helps liver- and eye- function and is sedative; white helps lung- and spleen- function and relieves cough; yellow helps stomach- and chest- problems and problems due to stress, overwork or abuse of food or drink. Some varieties can act as antiallergic, antithrombotic and antihyperlipemic agents.
Polyporus (Grifola) umbellata (zhu ling) is used in nephritis. Its polysaccharides are 6-branched ß-(1-3) glucans, which promote antibody production, normalize liver function and are antineoplastic.
Hoelen (Poria cocos) is a dense mushroom which grows near pine tree roots. Fu ling (Poria stalk) is the main part. It is one of the most frequently used CHMs; it is mild and helps all the organs. Its major polysaccharide (pachymaran) and triterpenoids are not immunologically active unless treated chemically, but its chemically modified pachymaran, a 6-branched ß-(1-3) glucan, shows antineoplastic activity. Fu shen (Poria spirit) is the part attached to the roots. The latter has sedative effects.
Tremella (bai mu er = white tree ear) is a tonic and helps expectoration. Its polysaccharides have antineoplastic effects, stimulate phagocytosis and counter the adverse effects of cortisone treatment.
Based on a ß-1,3 glucan structure, polysaccharides in astragalus, coriolus, ganoderma, lentinus, polyporus and tremella have the highest natural antineoplastic activity. These polysaccharides also have powerful effect in enhancing the immune-response to bacteria, fungi, protozoa and yeasts and help patients to recover more easily from radiation, chemotherapy or surgery (for cancer or other reasons). Coriolus polysaccharides also are used in hepatitis (infectious and toxic).
2. Steroids
In WM, steroids are used to treat dozens of clinical conditions, including Addison's disease (adrenal insufficiency); inflammation; allergy; male and female reproductive disorders; skin- and mental- problems associated with hormonal imbalance; menstrual disorders; impotence/frigidity; post-menopausal syndromes etc. They also have a sedative action and some are used as oral contraceptives.
Steroids are lipid-soluble organic compounds that occur naturally throughout the plant and animal kingdoms. All steroids have a four-ring structure. Steroids are diverse and include the sterols (such as cholesterol) of vertebrates, bile acids from the liver, all sex hormones and adrenal cortical hormones. Hormonal steroids in the body are synthesized from cholesterol. The biosynthetic mechanisms are similar in all steroid-secreting tissue (testis, ovary, placenta and adrenal cortex). There are two classes of corticosteroids. Glucocorticoids (i.e. cortisone) primarily affect carbohydrate and protein metabolism. They have limited use in the treatment of many immunologic and allergic diseases, such as arthritis. Mineralocorticoids (i.e. aldosterone) principally regulate salt and water balance. Because of the great therapeutic value of corticosteroids, many synthetic steroids have been produced, some more potent than the natural hormones.
Plant steroidal compounds belong to the general category called saponins. In CHM, triterpenes yield the most important steroids. The triterpenes of the HMs most commonly used in immunostimulation and allergies (bupleurum, ganoderma, ginseng, hoelen, licorice) have been studied most.
Sterols are chemically similar steroidal compounds with alcohol (hydroxyl, (OH)) groups attached to a series of fused rings. The principal sterol in vertebrates is cholesterol, especially abundant in nerve tissue and gallstones. Ergosterol, a sterol found in yeast, ergot and moulds, gives rise to vitamin D-2 (calciferol) when irradiated with ultraviolet light. Higher plant sterols include stigmasterol (from soybean oil) and several spinasterols (from spinach and cabbage). Natural sterols are poorly absorbed and transferred to the circulation by higher animals. Cholesterol is absorbed readily, but coprostanol and cholestanol, which are structurally similar, are not absorbed. Most animals can synthesize their essential sterols from smaller carbon compounds. Immunostimulatory herbs, such as ganoderma, ginseng, rehmannia and sophora, also contain sterols. Yams (Dioscorea) contain steroids or a steroid precursor, diosgenin, from which several steroids (cortisone, oestrogen, progesterone) are manufactured by chemical alteration. The Mexican yam (D. floribunda) is a rich source of steroid precursor.
Plant steroids usually have similar action to that of steroid hormones, but at a lower activity (often 10%). Unlike the action of many plant saponins, HMs do not cause haemolysis and their steroids have a mild action, with minimal side effects (unlike WM steroids, which often cause Cushing's disease). Licorice (Glycyrrhiza) steroids have aldosterone-like actions, for example in Addison's disease. Excessive ingestion of raw licorice candy can cause excessive corticoid production, which can cause heart irregularities, oedema and death. This does not happen with the amounts of licorice used in CHM.
In HM, plant steroids can be used for the same indications as WM steroids, but for many other indications also. Chinese and Japanese studies of triterpenes, steroids and sterols in HMs have shown the following actions: stomachic (pro-digestive), emmenagogue and tonic effects on the liver and lung. Some triterpenes, such as the ginsenosides, are immunostimulatory also. Immunostimulatory, antiinflammatory, antihepatotoxic, antiallergic (antihistaminic), sedative and antispasmodic effects of plant steroids will be discussed later.
Stomachic (pro-digestive) effects: HMs with triterpenes (alisma, asparagus root, bupleurum, dioscorea, ganoderma, ginseng, hoelen, licorice, zizyphus etc) assist digestion, relieve gastritis, stress ulcers, diarrhoea and colitis. Asparagus root is rich in spirostane saponins and strongly inhibits gastroduodenal ulcer.
Tonic effects on the lung: HMs which protect the lung and assist expectoration include albizzia, arisaemia, bupleurum, cinnamon, eleuthero, ganoderma, glehnia, hoelen, licorice, lily family (anaemarhena, asparagus, lily, ophiopogon), platycodon, polygala etc. Many of these have steroidal action via their saponins, triterpenes, or spirostane glycosides. They are useful clinically in bronchitis, asthma, cough, lung congestion and pneumonia.
Many other ingredients used in HM have steroidal activity. They include animal products, such as deer antler, gecko, pipefish, seahorse and extracts of ovary, testis, adrenal and placenta from many species. Their uses in TCM include strengthening of the Yin and Blood and the Kidney Yang.
Antiaging formulas aim to boost Yang, support Yin and avert shrivelling (for example, drying of membranes, wrinkles, impotence). They contain many HMs with steroidal action.
Agitation, fidgeting, fatigue and insomnia often accompany immunosuppression (as in AIDS/ARC, hepatitis, Epstein-Barr virus etc) and autoimmune disease (especially when pain is present). A combination of HMs with steroidal, immunostimulatory and sedative actions is especially useful in those conditions.
3. Flavones and flavonoids are found in the aerial parts of many plants (leaves, flowers fruits) but are less common in the underground parts. Most HM formulas contain herbs with some flavonoids; some formulas have flavonoids as the main active compounds. Herbs with flavonoids include astragalus, bauhinia, capillaris, citrus peel, eclipta, eucommia, forsythia, ginko (leaf and fruit), ho-shou-wu, ilex, ixeris, licorice, lonicera, millettia, pueraria, qingpi, rose fruit, salvia, scutellaria (scute), sophora, swertia, vitex, zhishi.
Medicinal effects of flavonoids include: increased vascular integrity (antihaemorrhagic ,antiascitic); antithrombotic; vasodilatory. Antiviral/antifungal; antiallergic and antihepatotoxic effects will be discussed later.
Increased vascular integrity: Agents which can enhance capillary integrity are useful clinically to prevent or treat bruising, haemorrhagic diseases, ascites etc. Flavonoids in citrus peel and eclipta have that effect.
Antithrombotic effects: Low doses of aspirin are used to reduce platelet aggregation to prevent thrombosis, heart attack and stroke. However, haemorrhage, possibly cerebral, is a side effect. Flavones and flavonoids in bauhinia, ixeris, millettia, scutellaria and vitex can have the same antithrombotic effect but their effect on vascular integrity would prevent haemorrhage.
Vasodilatory effects: Vasoconstriction is a significant clinical sign in many cardiovascular conditions (peripheral vasoconstriction, hypertension, migraine, angina, palpitations, some forms of cerebral vascular accident etc). Vasodilators used in WM can help such cases, but sometimes cause the "steal effect" (vasoconstriction elsewhere in the body). Flavonoids in ginko leaf and pueraria have marked vasodilatory effect in the heart and brain, without the "steal effect". Such flavonoids include ginkgetins and rutin. Kaempferol, quercetin and rhamnetin combined, or an extract of ginko, gave good results in a small study of Parkinson's disease. Flavonoids in ilex and scute are useful in cardiovascular disease, hypertension, headaches and sore throat (Dharmananda 1991).
Flavonex is a formula with 8 herbs high in flavonoids (eucommia, ginko, ho-shou-wu, ilex, lonicera, pueraria, rose fruit and salvia) and 6 other herbs (acorus, cistanche, lycium fruit, morus fruit, schizandra and tang-kuei). In TCM, the formula is used to promote Blood Circulation, nourish the Essence and prevent the effects of aging (especially on brain function). Clinical uses include allergies and poor cerebral circulation.
Ginseng, Astragalus and Pueraria Formula is used in tinnitus, Bell's palsy, early cataracts and senility. To aid circulation, especially cerebral, it contains 4 herbs (astragalus, licorice, pueraria and vitex) which are high in flavonoids. The formula also contains ginseng (a general stimulant, an immunostimulant, and antiallergic herb), cimicifuga, phellodendron (antitoxic and antiinflammatory herbs) and peony.
Tang-kuei and Anemarrhena Formula is used in dermatitis and arthralgia. It contains 5 herbs high in flavonoids (capillaris, licorice, pueraria, scute, sophora) and 9 others which are immunostimulatory and antiinflammatory (alisma, anemarrhena, atractylodes, chiang-huo, cimicifuga, ginseng, polyporus, siler, tang-kuei).
Sesquiterpene lactones: Recently, several of these have been identified in plants consumed by animals for presumed medicinal value. They include agents with antineoplastic- (parthenin and eupatoriopicrin), antiulcer- (dehydroleucodin) and cardiotonic- (helenalin) effects (Robles et al 1995).
4. Alkaloids, of which >200 are known, have at least one nitrogen atom, or an amine group. They end in "-ine". Examples are: Aconitine, andinine, atropine; Berbamine, berberine, berberrubine, brucine; Caffeine, cocaine, codeine, colchicine, coumbamine; Domesticine; Emetine, ephedrine, ergometrine, ergotamine; Hyoscine (scopolamine), hyoscyamine; Isobolidine, isoquinolines, isotetrandine; Jatorrhizine; magnoflorine, matrine, mescaline, morphine; Nicotine; Palmatine, papaverine, phellodendrine, pilocarpine, protoberberines; Quinidine, quinine, quinolizidines; Reserpine, ricinine; Solamargine, solanine, solasonine, strychnine; Tetrandine, theobromine, theophylline, tropanes; Veratrine, vinblastine, vincristine.
Alkaloids are alkaline in nature, are acid-soluble and can be isolated by acid-extraction, followed by ammonia-precipitation. Some are simple, monocyclic amines, but many are very complex, polycyclic amines. Various family groupings are possible according to basic ring structure, such as pyridine or quinoline alkaloids. Most are poorly soluble in water and taste very bitter. Thus, HMs which contain alkaloids are often taken as pills, syrups or vinegar extracts, rather than as decoctions.
Alkaloids usually are absorbed fast, act fast and are excreted fast. They act mainly via the nervous system. Most alkaloids have biphasic action. At low doses, many stimulate the heart and respiratory system. Clinically, they promote circulation, breathing, coughing and expectoration. At higher doses, many act as sedatives. Clinically, they relax the heart and respiratory centre, relax muscles and promote sleep. These effects are pronounced as the dose increases. At toxic doses, death may occur from cardiac or respiratory failure.
Many alkaloids induce nausea and vomiting as a side effect. This may be used clinically, for example syrup of ipecacuanha, or vinegar extract of lobelia, to induce vomiting. Some may induce vertigo (dizziness), altered perceptions or hallucinations (cocaine, codeine, mescaline, reserpine, scopolamine). Those with potent effects on the CNS have potential for addictive abuse and dosage tolerance.
Some Solanaceae, such as datura and atropa and hyoscyamus (henbane), contain large amounts of atropine, hyoscyamine and scopolamine (hyoscine). Henbane was used extensively as an anaesthetic and analgesic. Mandragora officinarum (mandrake), one of the Solanaceae, also contains hyoscyamine. These plants are toxic when consumed in large quantity but are invaluable medicinal agents when given in proper amounts. Atropine is used in WM as a mydriatic and anticholinergic; it inhibits the secretion of bodily fluids and is used in nasal decongestants. As a smooth muscle relaxant, atropine is useful in relieving some gastrointestinal problems. It is also used as an antidote to nerve gas and some insecticides. Overdoses of atropine can cause an accelerated heartbeat and shallow breathing, leading in some cases to death. Scopolamine is used as a hypnotic and as an antispasmodic to reduce gastrointestinal contractions. Hyoscyamine has potent effects on the CNS; it is used as a sedative, especially to control spasmodic conditions. Hyoscyamine and scopolamine have been used to treat alcohol and morphine addiction.
Differences in alkaloid structure influence the dose range needed to produce pharmacological effects. Some are relatively non-toxic and may be taken safely; others (such as aconitine) may induce potent sedation and may be very toxic at low doses. Sedative alkaloids (the majority) maintain a sedative effect at moderate doses. Stimulant alkaloids maintain a stimulant action over a very wide dose range.
Stimulant alkaloids: Many societies use indigenous plants containing stimulant alkaloids. The Sudanese chew kola nut (origin of Cola drinks) for its stimulant effects, due to its high caffeine content. South American Indians chew coca leaf, a source of cocaine, to attain increased energy, alertness and euphoria. Cocaine, isolated in 1855, was used in WM as a local anaesthetic (especially for the nose, throat, and cornea) and nasal decongestant. Used systemically, cocaine stimulates the central nervous system, producing feelings of excitation, elation, well-being, enhanced physical strength and mental capacity, and a lessened sense of fatigue. It also causes increased heart rate, blood pressure, and temperature; in large doses, it can cause death. It is strongly addictive and has become a major drug of abuse. Khat leaves contain norpseudoephedrine; they are chewed by Middle Eastern peoples. Betel nut, the seed of the betel palm, Areca catechu, contains arecholine. Many Asians and South Pacific Islanders chew the nut to obtain a mild narcotic stimulation and sense of well-being. In veterinary medicine, the nut was used for deworming.
Nicotine, in tobacco and snuff, is an addictive stimulant drug and other alkaloids have potential for dependency/addiction. Some (such as caffeine and cocaine) stimulate the CNS; others (such as hyoscyamine and morphine) depress the CNS. Via central and peripheral neural action, alkaloids influence muscle (especially smooth muscle), usually relaxing it. For example ephedrine and codeine cause broncho-relaxation, reduce coughing and assist expectoration; vasodilatory effects of alkaloids can help to reduce fevers, relieve muscle spasm and hypertension.
Alkaloids have potent pharmacological action and many are used daily as medicines in WM and HM. They are potentially toxic if misused; most plants containing them are classed as toxic. Curares are of different botanical origin, and each contains extracts of several plants. The toxiferins obtained from Strychos toxifera are the most potent curare alkaloids. Species of Chondrodendron are sources of tubocurarine. Curare alkaloids are inactive orally; parenterally they act as skeletal muscle relaxants by blocking muscle receptors for acetylcholine. The main clinical use of curare is as an adjuvant in surgical anaesthesia to obtain relaxation of skeletal muscle or to facilitate diagnostic procedures, such as laryngoscopy and endoscopy.
Most plant families (85-90%) contain no alkaloids but plants that do are seldom used for food. Exceptions are potatoes/tomatoes (solanine), coffee beans (caffeine), tea leaves (caffeine, theophylline), cocoa (caffeine, theobromine), kola extract (caffeine) etc, in which the levels in the consumed portions are relatively low. However, acute solanine toxicity can arise in animals who ingest excessive amounts of potato/tomato haulms.
Many alkaloids act as stimulant drugs, or analeptics. Stimulants excite the CNS, increasing alertness, decreasing fatigue, and delaying sleep. Some impair appetite are prescribed to promote weight loss in obese people. Most users of these drugs experience a sense of euphoria, but this reaction depends greatly on the drug taken and the dose. Signs of overstimulation by these drugs, such as muscle tremors or irregular heart rate, are common. Caffeine is the most widely used stimulant drug in the world. In small amounts, it acts as a mild stimulant and is harmless to most people. In large amounts, it may cause insomnia, restlessness, and anxiety. Caffeine increases heart rates and can cause heart irregularities; heavy coffee drinkers are more prone to coronary heart disease. Caffeine decreases blood flow to the brain, and has been used in treating migraine headaches. It is also used in treating poisoning by depressants such as alcohol and morphine, and studies suggest that it somewhat increases the effectiveness of common analgesics such as aspirin. By widening bronchial airways, caffeine and theophylline can help to relieve asthma attacks. Caffeine can cause chronic (low grade) adverse reactions in humans who consume excessive amounts. With increasing age caffeine users may experience for the first time insomnia or palpitations of the heart associated with irregular beats. Heavy users often become nervous, irritable, apprehensive, restless, and unable to sleep; such symptoms may be construed as a psychiatric disorder unless the history of caffeine misuse is known. Recognition of the drug effects of these beverages has led to the increased use of decaffeinated coffee.
Alkaloids have potent vasodilatory-hypotensive-sedative, antitussive-expectorant, antiinflammatory-analgesic-antiarthritic effects. Many have immunostimulatory effects, potent antibacterial action and stimulate leucocytosis and phagocytosis; some have antifungal and antiviral action also. Some alkaloids inhibit neoplastic cells and stimulate biliary secretion and uric acid excretion. They are used clinically to treat immunomediated disorders (allergies, asthma, immunosuppression, bronchitis, autoimmune diseases, arthritis, gout and allied conditions, infections, gastroenteritis, dysentery, constipation, neoplasia, etc), hypertension, stress, insomnia and the effects of chronic disease and senility. The alkaloids used in CHM are relatively safe, usually non-addictive and confer multiple therapeutic effects, especially when combined with other HMs.
Alkaloid-containing medicinal herbs include: aconite, aristolochia, berberis, chin-chiu, cocculus, coptis, corydalis, erythina, Fangji, gentiana, ipecacuanha, lobelia, lycopodium, mahonia, nandina, phellodendron, rauwolfia, sinomenium, solanum, sophora, stemona, stephania and veratrum.
Commonly used herbs, in which alkaloids are the main active compounds, come from two main families: the Berberidaceae and the Menispermaceae. Within each family, the alkaloid structures and clinical effects are similar. Both families contain species which contain berbamine and tetrandine.
Berberidaceae have antiinflammatory action, inhibit gastrointestinal bacteria and relieve irritation of mucous membranes in the eye, digestive and respiratory system. They are used to treat fever, cough with excessive phlegm, gastroenteritis, dysentery and inflammation of the eyes, throat, mouth and joints. They include many species of Berberis root (high in berberine, palmatine, berbamine, jatorrhizine). Mahonia contains similar alkaloids and magnoflorine. Nandina contains domesticine, andinine, isobolidine and other alkaloids, similar to those in mahonia and berberis.
Menispermaceae include cocculus, stephania, sinomenium. These have potent clinical effect with minimal side-effects and are used interchangeably. They contain alkaloids with antiarthritic, antiallergic, antioedematous, hypotensive and antimicrobial effects, used to treat arthritis, allergies, oedema, hypertension and gastroenteritis.
Miscellaneous alkaloid-containing herbs: Antiinflammatory herbs used in arthritis include aconite, aristolochia, chin-chiu, corydalis, erythina, lycopodium and solanum. Antiinflammatory herbs used in irritation of skin and mucous membranes include coptis, gentiana, phellodendron, solanum, sophora. Antiinflammatory herbs used in cough and bronchitis include solanum and stemona. The solanum used in CHM (S. nigra) contains solasonine and solamargine, but little solanine. It is contraindicated in pregnancy but its roots, seeds and leaves are used extensively in China to treat cancer.
Opiate alkaloids are considered the most effective of all analgesics. Papaver somniferum yields 26 alkaloids, of which the most important are morphine, codeine and papaverine. All opiates can be abused, but heroin, a morphine derivative, is the most notorious. Because of their abuse, opiates are restricted and used less and less in routine WM, except in terminal illness.
Alkaloid-containing herbs are a relatively small part of most formulas used in CHM. They are used mainly to supplement the effects of other herbs. However, the following formulas contain a high content of alkaloids:
a. Coptis and Scute Formula (coptis, phellodendron; gardenia and scute). The first two herbs rely mainly on alkaloids for their action. The formula is used in fever, haemorrhagic diseases, insomnia, gastroenteritis, pruritus and hypertension.
b. Coptis and Evodia Pills (berberis, coptis, evodia, phellodendron; licorice, peony and saussurea). The first four herbs contain alkaloids with sedative, hypotensive and antiinflammatory effects. The formula is used to treat gastrointestinal disorders associated with stress or agitation, including chronic colitis, associated with immunodeficiency.
Dharmananda's review of the effects of polysaccharides, steroids, flavonoids and alkaloids (above) shows that HMs containing these (and other, not discussed,) compounds can have potent therapeutic action on inflammation, membrane stability, lipid peroxidation, infections, immunomediated disorders, cancer, nervous, cardiac, pulmonary, hepatic and renal disease etc.
The rest of this section will discuss other data on active compounds in HMs: immunomodulators; antiinflammatories; antioxidants; antimicrobials; antivirals; antineoplastics; sedatives/hypotensives and insect antifeedants.
Immunomodulators
Immunomodulation is critical to the treatment of immunomediated disorders (infections, inflammations, autoimmune disease, allergies etc). Many systemic diseases, such as autoimmune diseases, immunosuppression, AIDS and cancer are poorly, if at all, controlled by WMs. Based on TCM, Sino-Japanese concepts of homeostasis suggest that there is a regulatory effect on the immune-, endocrine- and cardiovascular- systems.
a. Autoimmune disease: Several HMs are clinically effective in autoimmune diseases, such as chronic hepatitis, rheumatoid arthritis, nephrosis, and systemic lupus erythematosus. These HMs are thought to act by modulating the immune system (Labadie et al 1989; Wagner 1990). Active compounds (polysaccharides, steroids, flavones and alkaloids etc) in HMs have potent action on immunomediated disorders (Dharmanada 1991), as discussed earlier.
b. Antiallergic effects: Bupleurum contains saikosaponins (steroids with antiinflammatory and antiallergic activity). Sophora alkaloids have antiallergic action (Dharmananda 1991). Scute contains baicalin, baicalein and skullcapflavone II; these inhibit release of chemical mediator from mast cells.
Herbs with antihistaminic effects (due to ß-eudesmol and nerolidol) are: alpinia, cardamom, cluster, galanga, ginger, zedoaria. Zizyphi fructus (jujube) contains a compound which increases cAMP production in the body, a ß-adrenergic compound and ethyl-Ó-D-fructofuranoside. These compounds suppress IgE activity. Hot water-extract of ganoderma suppressed histamine release from mast cells and the passive cutaneous anaphylactic (PCA) reaction (Tsung 1987). Steroidal activity in ganoderic acids (in ganoderma), ginsenosides (in ginseng) and extracts of bupleurum and licorice have antiallergic/antihistaminic effects. They inhibit, or reduce, mediator release (see allergies, in section a, above). Antiallergic effects also include other antiinflammatory mechanisms.
Polymethoxyflavones have high antiallergic and high antithrombotic activity. Nobeletin, tengeretin and heptamethoxyflavone are the active antiallergic compounds in the Chinese citrus products zhishi and qingpi. These gave marked inhibition of passive cutaneous anaphylactic reaction (PCA) in experimental allergic challenge in rats. Nobeletin has a similar structure to koganebananin and skullcapflavones (baicalin, baicalein and skullcapflavone II) from scute. The latter inhibit mediator release from mast cells. Baicalin increases the levels of CAMP and PGE1, which inhibit mediator release. Capillaris and scute are used to treat urticaria and dermatitis. Capillaris contains cirsimaritin, which has a similar structure to baicalin. Antiasthmatic HM formulas often contain ginko fruit. Ginkolide, both natural and synthetic, is effective in human asthma and allergic inflammation and reduces rejection of transplanted grafts in animals. Daidzein, and similar compounds, are the active compounds in pueraria and sophora, which are important antiallergic herbs, for example in urticaria, dermatitis, sinusitis, migraine, asthma etc (Dharmananda 1991).
c. Antihepatotoxic effects: In WM, as in TCM, many allergic conditions, autoimmune, inflammatory, metabolic and toxic disorders involve seriously disturbed liver functions. These include food- and drug- allergies, gastro-duodenal-colonic irritation/ulceration, photosensitisation, dermatitis, conjunctivitis, migraine, irritability, gout, rheumatoid arthritis, hepatitis etc. Therapy which protects or enhances liver function also helps in liver-mediated disorders. Polysaccharides, steroids and flavones in HMs with hepatoprotective action are also useful in such conditions (Dharmananda 1991). HMs which protect the liver against toxins and are useful clinically in hepatotoxic disorders and hepatitis include andrographis, bupleurum, coriolus, eleuthero, ganoderma, gentiana, ginseng, gynostemma, licorice, paeonia, phyllanthus, picrorrhizia, polyporus, sophora etc. The effects are mediated by their polysaccharides, steroids and saponins. Other important HMs used in hepatitis and liver disease are Capillaris, scute and sophora; they have potent antihepatotoxic action, mediated by their flavonoids. Flavonoids capillarisin, arcapillin, isorhamnetin and quercetin are hepatoprotective in carbon tetrachloride cytotoxicity. Swertia flavonoids (homoorientin, swertiajaponin, swertisin) are hepatoprotective in galactosamine cytotoxicity (Dharmananda 1991).
The bitter taste of most alkaloids, especially berberine alkaloids, stimulates bile secretion. HMs containing such alkaloids are used as appetite stimulants, mild laxatives and to treat biliary stasis, cholecystitis and ascariasis of the bile ducts. Their combination with HMs which stimulate liver function increases their efficacy (Dharmananda 1991).
In controlled experiments in rats, ginseng had a protective effect on liver; injections of a water-extract of ginseng significantly decreased liver enzyme levels (AST, ALT) induced by injections of dexamethasone (Lin et al 1995c).
Antiinflammatories
Steroids in akebia, alisma, dianthus, licorice and poria (hoelen), as in the formula Ba Zhen Tang (see c, below) have antiinflammatory effects and are used to treat nephritis and urinary infections. Steroids are thought to underlie the efficacy of bupleurum in allergies, hepatitis, gastroenteritis and dermatitis. The alkaloids tetrandine and isotetrandine have antiinflammatory, antiallergic and antianaphylactic action. Alkaloids in Fangji, a HM based on any one, or combination, of aristolochia, cocculus, stephania or sinomenium, activate the self-defence system in infection and inflammation (Dharmananda 1991).
Alkaloids from the Berberidaceae are used mainly to treat inflammation of the skin and mucous membranes; those from the Menispermaceae are used to treat inflammation of the joints (Dharmananda 1991).
Accumulation of urates in tissue, especially in the tendons and joints can cause gout and gouty arthritis. Classical signs are irritability and pain, especially in the big toe (the "Liver Toe" in TCM). Berberis, coptis and phellodendron increase uric acid excretion and are used to treat gout. Their alkaloids are thought to be involved in urate elimination. Colchicine, from Colchicum autumnale, is used in WM for the same purpose. Other herbs with antiinflammatory and hepato-protective effect are also useful in gout.
Protoberberines and isoquinolines have analgesic effect in hot plate-induced experimental pain. Corydalis, menisperma and sinomenium are used to treat pain, especially in trauma and arthritis. They contain protoberberines, such as corydalimine, stepholidine and synactine. Cocculus, menisperma and stephania are used to treat pain in arthritis. They contain isoquinolines, such as berbamine, coclobine, dauricine and tetrandine.
Ginsenoside Ro, isolated from the roots of Panax ginseng, reduced acute paw edema (induced by 40/80 or carrageenin) in rats; it also inhibited the increase in vascular permeability (induced by acetic acid) in mice (Matsuda et al 1990). An extract of ginseng increased the phagocytotic ability of white cells in bovine blood and milk (Hu et al 1995).
Ginseng is used in TCM for its tonic and restorative effects in stress, neurasthenia, convalescence. Ginseng extract restored adrenal and thyroid functions inhibited by the dexamethasone treatments; the effects of the extract on adrenal and thyroid function may explain some of its effects as a general tonic and antistress herb (Lin et al 1995c).
New diastereoisomers and sulphur-containing compounds, isolated from onion, Allium cepa L, had potent inhibitory effects for collagen-induced aggregation, as well as ADP- or arachidonate- induced aggregation of human platelets in vitro. The most active compound was a diastereoisomer of cis-3-ethyl-2,4,5-trithia-6-octene 2-S-oxide (Morimitsu & Kawakishi 1990).
Antioxidants
Many disease processes involve the generation of reactive oxygen species (superoxide anionic radical (O2-), hydrogen peroxide (H2O2), hydroxyl-radical (OH-) etc). If not neutralised, these oxidative radicals cause cellular oxidative stress, increase lipid peroxidation and cause instability of cellular membranes. The presence of these radicals also compromises the microbicidal activity of polymorphonuclear leucocytes and other phagocytic cells (macrophages, reticuloendothelial calls etc).
Pro-oxidants increase the risk of all disorders associated with reactive oxygen species (free radicals) in the body. In the future, antioxidants in HMs may be a very important method of maintaining life in a polluted environment. Anthropogenic pollution is a serious threat to life on earth. We burn organic materials to generate power (electricity, heat, transport (engines)) and to dispose of municipal- or domestic- waste by incineration. Fires also combust organic material. Unless these emissions are removed and/or recycled by expensive technology, they enter our atmosphere. Particulate (fly-ash) and gaseous emissions return to earth by deposition/precipitation. Emissions of combustion, or from industrial sources (smelters, refineries, pharmaceutical and chemical plants, fertiliser factories etc), contain xenobiotic organic compounds such as 2,4,5-trichlorophenol (phenoxyacetic acid), halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, pentachlorophenols, polychlorinated dibenzofurans, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, tetrachlorodibenzo-p-dioxins and related xenobiotics. Some herbicides and pesticides also contain them.
Organic hydrocarbon emissions include dioxins, the most toxic anthropogenic chemicals known. Organic toxins enter the food chain, persist for long periods in the environment and pose toxic hazards to soil, plant, animal and human life. Xenobiotic effects of dioxins to humans and animals include: increased lipid peroxidation and cellular oxidative stress (exaggerating any environmental deficiencies of copper, selenium and vitamins, especially E); immunotoxicity (thus, increasing susceptibility to cancer, AIDS, viral and bacterial infections and inflammatory processes); thyrotoxicity (thus, exaggerating environmental deficiencies of I and Se and compromising reproduction, neonatal survival, lactation, growth and general metabolism); inhibited sexual differentiation of the central nervous system and disorders of the liver, kidney, skin, heart and lungs. Dioxins also adversely influence female and male reproduction; they compromise pregnancy and induce birth defects. They reduce growth and they influence (and are influenced by) Vitamin A in serum and tissues (Rogers 1995).
Animals have an extensive antioxidant defence system to minimise the untoward effects of oxygen. Antioxidants alleviate the oxidative load by directly quenching reactive oxygen species before they damage vital cellular components. Mammalian intracellular antioxidants include the selenium-dependent glutathione peroxidases, the copper-dependent superoxidase dismutases, vitamins E and C, b -carotene, uric acid.
Medicinal plants also contain large amounts of antioxidants (ascorbic acid, tocopherol, ubiquinone, glutathione, phenolics, etc). Therefore, it is not surprising that these natural sources are used medicinally in many conditions, including aging, atherosclerosis and immunomediated diseases (immunosuppression, inflammation, infection, neoplasia etc)...
Gypenoside saponins of Gynostemma pentaphyllum have antioxidant properties which counter oxidative stress in phagocytes, liver microsomes and vascular endothelial cells. The extensive antioxidant effect of gypenosides may be valuable to prevent and treat various diseases such as atherosclerosis, liver disease and inflammation (Li et al 1993).
Tannins are polyphenols widely present in plants. Since phenolic compounds have antioxidant activities, tannins also could be developed to prevent lipid peroxidation and biological damage caused by free radicals formed under oxidative stress. Of 25 tannins and related compounds tested, catechin, benzylthioether and procyanidin ß-2 benzylthioether were the most potent in inhibiting lipid peroxidation, with inhibitory effects stronger than Trolox, a water-soluble analogue of vitamin E. Also, conjugation of tannins with a benzylthioether group did not enhance the free radical scavenger activity of tannins. However, it may increase the inhibitory effect on lipid peroxidation (Hong et al 1995). Recently, magnolol and honokiol, isolated from Magnolia officinalis, were shown to be 1000 times more potent than Trolox (Lo et al 1994). Antioxidant (free radical-scavenging) effects of bupleurum polysaccharide are discussed under section (c), below.
Antimicrobials
Many plants and HMs contain antimicrobial compounds. Such compounds are of interest because of their relationship to phytoalexin production. Phytoalexins are antimicrobial compounds of low molecular-weight. They act as a defence against microbial infection of the plant; plants synthesize and accumulate them after exposure to micro-organisms (Dixon & Lamb 1990). Most herbs have weak antimicrobial activity in comparison with that of synthetic antibiotics, or those from microbial or fungal origin but some have antibacterial and/or antifungal activity of practical value in medical and veterinary therapy (Cousins 1995a,b).
Oryzalide A is a novel C19-kaurane type of diterpene. It was isolated from the healthy leaves of a rice plant which was resistant to Xanthomonas campestris pv. oryzae. That organism is a cause of leaf-blight in susceptible rice plants (Wabanabe et al 1990). At 150 ppm, Oryzalide A inhibited approximately 60% of the colony-forming ability of X. campestris. Because similar diterpenes were isolated from rice as phytoalexins, it is thought that the biosynthetic pathway of diterpenes may play an important role in the mechanisms of disease resistance in rice plants. In tropical countries, plants from the Meliaceae family are used widely in TM to treat fever. A limonoid, gedunin, recently isolated from Meliaceae spp., had moderate antimalarial activity (IC50, 0.72 mg/ml) against Plasmodium falciparum (Bay et al 1990).
Protoberberines (including jatorrhizine, coumbamine, berberine and phellodendrine) have effective antimicrobial activity. They occur in berberis, coptis and phellodendron, herbs which are used to treat gastroenteritis and bacillary dysentery, or to treat wound infection by local application. Matrine and other alkaloids in sophora are strongly antiseptic and antifungal. Stemona alkaloids are antibacterial and antifungal. Flavonoids have very good antifungal activity in the treatment of candidiasis and thrush. Condensed flavonoids form tannins, useful as astringents and antiseptics. HMs with flavonoid/tannin effect are useful in gastrointestinal infection (Dharmananda 1991).
Antivirals
Some herbs have antiviral activity which may have practical value in veterinary therapy (Cousins 1995a). Several antiviral compounds have been isolated from herbs (Dharmananda 1991). The Lonicera and Forsythia Formula (Yinqiao Jiedu San in TCM) is the world's most commonly used medication for colds and 'flu. The flavonoid quercetin gave some protection to animals experimentally inoculated with many viruses. It also inactivated herpes simplex, polio, rabies and some 'flu viruses. Catechin is more potent than quercetin against herpes virus. Stemona alkaloids are antiviral (Dharmananda 1991); 5-0-methyl-genistein 7-0-ß-D-glucopyranoside from Ulex europaeus, inhibited the replication of Herpes simplex virus (HSV) and poliovirus (De Rodriguez et al 1990). Three proanthocyanidins from Pavetta owariensis (Guinean TM), proanthocyanidin A2 (dimeric proanthocyanidin), cinnamtannin B1 (trimeric anthocyanidin) and cinnamtannin B2 (tetrameric anthocyanidin), had pronounced antiviral properties against HSV and Coxsackie viruses. It seems that both anti-herpetic potency and the cytotoxicity of tannins depends on the molecular-weight, as well as the number of polyphenolic groups (Fukuchi et al 1989; Balde et al 1990). Recently, two of 134 flavonoids, isolated from Scutellaria radix (scute), were shown to have highly potent anti-influenza activities in vitro and in vivo (Nagai et al 1995).
Antineoplastics
Drug resistance is common when single drugs are used to treat a specific cancer. WM usually uses many drugs simultaneously in cancer chemotherapy, as tumours are less likely to becomes resistant to drug therapy by the combination technique. Combination chemotherapy has been most successful in treating cancer, especially leukemia, Hodgkin's disease, testicular cancer and ovarian carcinoma. Recent cancer therapies combine less radical forms of surgery with radiation, chemotherapy, "preventive" therapy and support therapy.
WM uses two main types of chemotherapy: cytotoxic chemotherapy and immunotherapy (Dharmanada 1991; Ogilvie & Moore 1995). (a) Cytotoxic chemotherapy aims to kill neoplastic cells by a direct toxic action. The side effects can be severe and may need to be controlled by symptomatic medication. Several types of naturally occurring compounds, which react directly with DNA, are used. These include steroids, antibiotics, alkaloids and alkylating agents. WM also uses antimetabolites. These resemble normal metabolites in structure and compete with them for some metabolic function, thus preventing further utilization of normal metabolic pathways. (b) Immunotherapy aims to enhance the body's innate ability to recognize, attack and destroy the neoplastic cells. Active immunotherapy aims to stimulate lymphocytes that are effective in destroying cancer cells. Passive, specific, or nonspecific immunotherapy is by injection of antibodies specific for the neoplasm (such as specific monoclonal antibodies), administration of nonspecific immunoglobulins, interferon, cytokines (such as Tumour Necrosing Factor (TNF), interleukin 2 (IL2)) etc. It also includes the use of antioxidants (vitamin E, trace-elements (especially selenium)) and non-specific immunostimulants and immunomodulators. The latter act by boosting the body's production of cytokines and other protective agents (Dharmananda 1991; Ogilvie & Moore 1995).
Many cytotoxic antineoplastic agents have been isolated from plants, especially the polysaccharide fraction of mushrooms (as in the Japanese formula Krestin) and astragalus (see Dharmanada 1991, summarized above). Vinblastine and vincristine (alkaloids from Vinca rosea, or Catharanthus roseus) are used to treat Hodgkin's disease and acute leukaemia, respectively. Taxol, from the bark of Pacific yew trees (Taxus brevifolia), gave promising results in advanced ovarian-, breast- and other- cancers (Borman 1991). Mallotus japonicus husks contain 3-(3,3-di-methylallyl)-5-(3-acetyl-2,4-dihydroxy-5-methyl-6-methoxybenzyl)-phloracetophenone. This compound had excellent cytotoxic activity against target neoplastic cells such as human carcinoma cells (larynx (HEp-2) and lung (PC-13)) and mouse B16 melanoma, leukaemia P-338 and L5178Y cells. It increased significantly the lifespan of mice bearing L5178Y leukaemia (Arisawa et al 1990).
Novel diterpene acids, pseudolaric acid-A and pseudolaric acid-B, isolated from Pseudolarix kaempferi (Tu-Jin-Pi in CHM), are cytotoxic against human cancer cell lines. Pseudolaric acid-A is more effective on leukaemia P-388 and melanoma SK-MEL-5, whereas pseudolaric acid-B is more active against leukaemia HL-60TB and P-388, CNS cancer TE671, melanoma SK-MEL-5, and ovarian cancer A2780 (Pan et al 1990). Bryophillin B, a potent cytotoxic bufadienolide, has been isolated from Bryophyllum pinnatum. It shows potent cytotoxicity (ED50 <80 ng/ml) against in vitro growth of KB tissue culture cells (Yamagishi et al 1989).
Cantharidin, isolated from Mylabris spp., possesses antihepatoma properties and induces leucocytosis (Wang 1989). However it is highly toxic and it decreases synthesis of steroids (Lin et al 1995b). As it may be fatal, it seldom is used clinically. Fortunately, several analogues (such as disodium norcantharidate, norcantharidin, dehydronorcantharidin and methylcantharidimide) have been synthesized. Those analogues may have important uses in antineoplastic therapy (Wang 1989).
Indirubin, a potent antileukemic agent, was isolated from Danggui Liuwei Wan (Six Flavour Tang-kuei Pill). That Formula is used to treat cancer in China. Indirubin was the main active compound in an extract of Qingdai (Baphicacanthus cusia), another herb used to treat cancer (Dharmananda 1991).
Certain glucosides are immunoactive but only those with immunostimulant effects are indicated in cancer therapy. For example, two new phenylalcohol glucosides, jionosides A1 and B1 were isolated from Rehmannia glutinosa (Sasaki et al 1989). They have immunosuppressive effects, as have related glucosides. A new sesquiterpene glucoside, sphaeranthanolide, from the flowers of Sphaeranthus indicus has immunostimulant activity; it enhanced the antibody response to sheep red blood cells (SRBC) (Shekhani et al 1990).
In immunomediated disorders, alkaloids of the protoberberine, isoquinoline and quinolizidine groups are of special interest as immunostimulants. Berbamine enhances the antineoplastic effects of cyclophosphamide in chemotherapy of cancer. It also increases white cell counts and counteracts cyclophosphamide-induced leukopaenia. Berbamine and isotetrandine activate lymph glands and the cellular reaction of plasmoblasts and plasma cells. Berberrubine is a potent inhibitor of sarcoma 180. Tetrandine and isotetrandine inhibit many forms of cancer, including Erlich Ascites Tumour and carcinoma of the liver. Sophora alkaloids increase white cell counts and counteract radiation-induced leukopaenia. Water extract of Sophora inhibits sarcoma 180 and tumour growth of transplanted cervix tumour cells and prolongs survival of animals experimentally inoculated with ascitic and carcinoma cells (Dharmananda 1991). TJ-48 is a Japanese pharmaceutical preparation used in KM. TJ-48, and its original prescription (JTT), are powerful immunostimulants and have potent effects on cancer patients. These effects are discussed under JTT, below.
Lien & Li (1985) and Zhang (1989) give much more detailed reviews of the pharmacology of CHMs and their uses in the treatment of cancer.
Sedatives, antispasmodics and hypotensives
The sedative and hypotensive effects of HMs containing triterpenes and alkaloids, and the anticonvulsive effects of saponin-containing HMs are useful in many clinical indications (Dharmananda 1991).
Polysaccharides in blue ganoderma and poria have sedative effects. HMs containing saponins, such as arisaemia, bamboo, gleditsia and typhonium have anticonvulsant effects similar to phenobarbital. These are useful clinically in epilepsy and febrile convulsions etc. In TCM, insomnia, agitation and restlessness are due to disturbed Shen (spirit), often due to weak Heart Yin. HMs which calm the Shen by strengthening Heart Yin have sedative effects. HMs with such effect include albizzia, eleuthero, ganoderma, hoelen, lily, ophiopogon, polygala, poria, rehmannia, zizyphus. The sedative effects are due to a steroidal action via their saponins and triterpenes. Such herbs prolong the effects of phenobarbital. HMs with sedative effects not due to steroids include acorus, biota, lotus seed and tang kuei. HMs with sedative action are useful clinically in stress, insomnia, agitation etc.
The Coptis and Scute Formula is used to treat hypertension. Potent hypotensive agents include the protoberberine alkaloids (at high levels in coptis and phellodendron) and isoquinoline alkaloids (e.g. cyclanoline in stephania). Tetrandine, palmatine and berberis alkaloids are hypotensive also. Jatorrhizine and related alkaloids, such as palmatine, occur in berberis, coptis, corydalis and phellodendron. They are sedative and prolong sleep induced by phenobarbital. Domesticine and andinine, in the antitussive nandina fruit, have morphine-like effects (Dharmananda 1991). Rauwolfia serpentina, which contains reserpine, was used for centuries as a sedative in snakebite, in mental disease and insomnia, and for many other purposes. WM also uses reserpine to treat hypertension and as a sedative in psychiatric disorders, such as schizophrenia. Its mechanism of action involves the depletion of catecholamines and serotonin.
The pharmacological activity of the benzodiazepine sedative group is mediated by a specific channel receptor (benzodiazepine-x-gamma-aminobutyric acidA-chloride, BDZ-GABA) complex. Many HMs contain compounds which bind to BDZ receptors in the central nervous system. BDZ-like compounds in plants can be detected by gas chromatography-mass spectroscopy (Unseld & Klotz 1989), or by their specific interaction with a monoclonal antibody to BDZ (Medina et al 1989). The clinical significance of these compounds for humans and animals should be explored.
Insect antifeedants
Some plants possess highly active insect antifeedants. These active compounds can be used as novel insecticides. Under laboratory conditions, tylophorine, isolated from Tylophora asthamatica, completely inhibited feeding by Spilosama obliqua under laboratory conditions. The effect persisted in field trials for 2 days, as determined by damage-rating scores (Tripathi et al 1990). Tylophorine may be used as a prototype for the synthesis of safer and more economical molecules to deter insects from feeding. These may have future industrial use.
Four new sesquiterpene alkaloids, 1Ó-nicotinoyloxy-2Ó-acetoxy-6ß-acetoxy-9ß-furoyloxy-11-isobutyryloxy 4ß-hydroxydihydro-ß-agarofuran and related compounds, isolated from the root-bark of Celastrus angulatus, showed strong antifeedant action with several different insect spp. (Liu et al 1990). Treated insects were paralysed for many hours after ingesting a small dose of the test sample. They then recovered, fed and became paralysed again. As a result, the insects gradually starved to death.
Miscellaneous known medicinal effects of active herbal compounds
The active compounds in HMs can have multiple medicinal effects. The following is summarised from Akerson (1995):
Allium sativa (garlic) is used as a spice, a medicine and a germicide. Its juice contains the antibiotic oil allicin (diallyl thiosulphinate). Effects include inhibition of platelet aggregation; enhanced mesenteric circulation, and antimicrobial effects in bacterial, viral, protozoal and fungal diseases.
Gentiana lutea (gentian glycosides, gentiopicrin, gentiopicroside etc): Effects include antiinflammatory, antibacterial and antimalarial effects; choleretic and digestive effects (useful in hyper- and hypo- chlorhydria); diuretic and liver-protective effects.
Hydrastis canadensis (isoquinoline alkaloids, berberine and hydrastine): Effects include antiprotozoal and broad spectrum antibacterial effects, especially against candida and gastrointestinal pathogens. The herb has antispasmodic effects on the gut and is used to treat gastroenteritis, ulcers and indigestion etc.
Jugulans nigra (naphthoquinone, juglone): Effects include antifungal, antiviral, antibacterial and anthelmintic effects, similar to Hydrastis.
Quassia amara (quassinoids, gutulactone, simalikalactone): Effects include antiprotozoal, antineoplastic and antiviral activity and anthelmintic activity against nematodes (ascaris, pinworms).
Future research on herbal compounds?
Chaudhury (1995) reviewed pharmacological research, folk medicine and traditional texts. The following HMs have good clinical efficacy in the following indications. This justifies the need for detailed research on the identification and clinical potency of the active compounds in the following HMs (Chaudhury 1995):
|
Clinical Indication
Antiinflammatory, for example in arthritis Asthma Cardiac disease Hyperlipaemia, atherosclerosis and obesity Hyperglycaemia, diabetes mellitus Hypertension Liver disease, hepatitis Malaria, antiprotozoals, fever Respiratory disease To improve quality of life To increase interferon levels |
Herb
Azadirachta indica, Commiphora wightii and Curcuma longa Albizzia laback Terminalia arjuna Commiphora wightii (gum guggal, steroids, diterpenoids, aliphatic esters and carbohydrates) Gymnema sylvestre, Momordica charantia Moringa oleifera Andrographis paniculata, Glycyrrhiza, Picrorrhizia kurroa, Phyllanthus amarus Artemisia annua (sesquiterpene lactones and flavones, artemesinin, artemetin, casticin), Dichroa febrifuga, Xanthium strumarum Adhala vasica Tinosporia cordifolia Glycyrrhiza (licorice) |
c. Pharmacological effects of complex HM formulas
Due to the number of herbal ingredients in each complex formula, the variety of active compounds and the probability of interactions between the compounds, research on the effects of traditional formulas is very challenging. In spite of the difficulties, research is ongoing in this area. Traditional formulas in CHM may be evaluated from the perspectives of TCM and WM. Two examples of traditional formulas, KHHT and JTT, are discussed from Chinese and western perspectives. They illustrate the historical and scientific background of Chinese herbology.
KHHT from the perspective of TCM
The word "Tang" means decoction. Koken-Huanglien-Huangchin-Tang (KHHT) is discussed in the treatise Shang Han Lun (about 210 AD). The Formula contains four herbs: pueraria (Koken), coptis (Huanglien), scute (Huangchin) and licorice in a ratio of 20:10:10:3.
Weber (1992) lists the following pharmacological properties of the individual main ingredients: pueraria (Koken, Gegen): Analgesic, anticonvulsant, antidiarrhoeal, antipyretic, coronary vasodilator, salivation stimulant; coptis (Huanglien): anticonvulsive, antidiarrhoeal, antifungal, anthelmintic, stomachic; scute (Huangchin): antiallergic, antiasthmatic, antidermatitic, antiemetic, antihypertensive, antipyretic, cholegogue, sedative, stomachic; licorice (Gancao, Glycerrhiza): antiallergic, antidiarrhoeal, antiinflammatory, antipharyngitic, antispasmodic, antitoxic, antitussive, antiulcerative (gastroduodenal), expectorant, harmoniser for all drugs, immunostimulant, stomachic, tonic.
In combination, KHHT is a common Formula to treat human gastroenteritis and dysentery. It also controls symptoms of flu, fever, erysipelas, measles, some eye disorders, headache, toothache (Luo & Shi 1986; Ou 1989). In TCM, Huanglien (Ministerial drug) clears Damp Heat from the Middle Heater; Huangchin (Assistant drug) clears Damp Heat from the Upper Heater. Together, they help Koken (Principal drug for the digestive system) to stop diarrhoea, mainly by releasing Heat and boosting Yang Qi of the Earth Channel-Organ Systems (ST (Stomach) and SP (Spleen)). Licorice (Guiding drug) acts to harmonise and enhance the total action of the other three drugs and to detoxify possible side effects of those drugs.
KHHT from the perspective of WM
Experimentally, KHHT and gentamycin were highly (and equally) effective (85 and 88% respectively) in curing piglet scour within 4 days, but only 52% of untreated controls had recovered by then (Lin et al 1988). However, this does not mean that KHHT works like antibiotics. The mechanism of KHHT is a holistic treatment. The basic principle behind therapy using TCM is to regulate the homeostasis of the whole body through the compound actions of several herbs and to restore the abnormal state to normal. Huanglien and Huangchin (Ministerial and Assistant drugs) have antiviral and broad spectrum antibacterial activities in vitro and in vivo (Nagai et al 1995). Whatever the mechanism, as postulated by western or eastern views, KHHT enhances the body defences, improves gastrointestinal function and has anti-bacterial and antiviral action.
JTT from the perspective of TCM
Shiquan Dabu Tang is called Juzen-Taiho-To (JTT) in KM. JTT is another example of a very old Formula from CHM, which still is used widely today. JTT has a great tonic effect in patients with chronic debilitating diseases. Given after surgery, it promotes fast postoperative recovery (Xie et al 1994).
Shiquan Dabu Tang (or JTT) contains 10 herbs to tonify body functions (Table 2) (Xie et al 1994): Ba Zhen Tang (Eight Precious Herb Decoction, see below) + cinnamon + astragalus. Ba Zhen Tang is a combination of Si Wu Tang (Four Material Decoction) and Si Jun Zi Tang (Four Gentleman Decoction). Si Wu Tang and Si Jun Zi Tang are recorded in Tai Ping Hui Min He Ji Ju Fang (Prescription of Peaceful Benevolent Dispensary, Song Dynasty). Shiquan Dabu Tang (Decoction of Ten Good Herbs) was described in the same source.
Due to the number of herbal ingredients in each complex formula, the variety of active compounds and the probability of interactions between the compounds, research on the effects of traditional formulas is very challenging. In spite of the difficulties, research is ongoing in this area. Traditional formulas in CHM may be evaluated from the perspectives of TCM and WM. Two examples of traditional formulas, KHHT and JTT, are discussed from Chinese and western perspectives. They illustrate the historical and scientific background of Chinese herbology.
KHHT from the perspective of TCM
The word "Tang" means decoction. Koken-Huanglien-Huangchin-Tang (KHHT) is discussed in the treatise Shang Han Lun (about 210 AD). The Formula contains four herbs: pueraria (Koken), coptis (Huanglien), scute (Huangchin) and licorice in a ratio of 20:10:10:3.
Weber (1992) lists the following pharmacological properties of the individual main ingredients: pueraria (Koken, Gegen): Analgesic, anticonvulsant, antidiarrhoeal, antipyretic, coronary vasodilator, salivation stimulant; coptis (Huanglien): anticonvulsive, antidiarrhoeal, antifungal, anthelmintic, stomachic; scute (Huangchin): antiallergic, antiasthmatic, antidermatitic, antiemetic, antihypertensive, antipyretic, cholegogue, sedative, stomachic; licorice (Gancao, Glycerrhiza): antiallergic, antidiarrhoeal, antiinflammatory, antipharyngitic, antispasmodic, antitoxic, antitussive, antiulcerative (gastroduodenal), expectorant, harmoniser for all drugs, immunostimulant, stomachic, tonic.
In combination, KHHT is a common Formula to treat human gastroenteritis and dysentery. It also controls symptoms of flu, fever, erysipelas, measles, some eye disorders, headache, toothache (Luo & Shi 1986; Ou 1989). In TCM, Huanglien (Ministerial drug) clears Damp Heat from the Middle Heater; Huangchin (Assistant drug) clears Damp Heat from the Upper Heater. Together, they help Koken (Principal drug for the digestive system) to stop diarrhoea, mainly by releasing Heat and boosting Yang Qi of the Earth Channel-Organ Systems (ST (Stomach) and SP (Spleen)). Licorice (Guiding drug) acts to harmonise and enhance the total action of the other three drugs and to detoxify possible side effects of those drugs.
KHHT from the perspective of WM
Experimentally, KHHT and gentamycin were highly (and equally) effective (85 and 88% respectively) in curing piglet scour within 4 days, but only 52% of untreated controls had recovered by then (Lin et al 1988). However, this does not mean that KHHT works like antibiotics. The mechanism of KHHT is a holistic treatment. The basic principle behind therapy using TCM is to regulate the homeostasis of the whole body through the compound actions of several herbs and to restore the abnormal state to normal. Huanglien and Huangchin (Ministerial and Assistant drugs) have antiviral and broad spectrum antibacterial activities in vitro and in vivo (Nagai et al 1995). Whatever the mechanism, as postulated by western or eastern views, KHHT enhances the body defences, improves gastrointestinal function and has anti-bacterial and antiviral action.
JTT from the perspective of TCM
Shiquan Dabu Tang is called Juzen-Taiho-To (JTT) in KM. JTT is another example of a very old Formula from CHM, which still is used widely today. JTT has a great tonic effect in patients with chronic debilitating diseases. Given after surgery, it promotes fast postoperative recovery (Xie et al 1994).
Shiquan Dabu Tang (or JTT) contains 10 herbs to tonify body functions (Table 2) (Xie et al 1994): Ba Zhen Tang (Eight Precious Herb Decoction, see below) + cinnamon + astragalus. Ba Zhen Tang is a combination of Si Wu Tang (Four Material Decoction) and Si Jun Zi Tang (Four Gentleman Decoction). Si Wu Tang and Si Jun Zi Tang are recorded in Tai Ping Hui Min He Ji Ju Fang (Prescription of Peaceful Benevolent Dispensary, Song Dynasty). Shiquan Dabu Tang (Decoction of Ten Good Herbs) was described in the same source.
TABLE 2. The herbal ingredients of Shiquan Dabu Tang (or Juzen-Taiho-To, JTT, TJ-48)
Herbs classified by Chinese rationale
Herbs classified by Chinese rationale
si wu tang1
Clinical Uses: Blood Deficiency
Principal: angelica
Ministerial: rehmannia
Assistant: paeonia
Guiding: cnidium
Principal: angelica
Ministerial: rehmannia
Assistant: paeonia
Guiding: cnidium
si jun zi tang2
Clinical Uses: Qi Deficiency
Principal: ginseng
Ministerial: atractylodes
Assistant: hoelen
Guiding: licorice
Principal: ginseng
Ministerial: atractylodes
Assistant: hoelen
Guiding: licorice
shiquan dabu tang3
Clinical Uses: Qi/Blood Deficiency
Principal: Both
Ministerial: Both
Assistant: Both + cinnamon
Guiding: Both + astralagus
Principal: Both
Ministerial: Both
Assistant: Both + cinnamon
Guiding: Both + astralagus
1Four Material Decoction; 2Four Gentleman Decoction; 3Decoction of Ten Good Herbs
a. Si Wu Tang (Four Material Decoction) is a TCM Formula to treat Blood Deficiency (Xie et al 1994). It contains angelica, rehmannia, paeonia and cnidium. Its function in TCM is to tonify and regulate Blood. It is used for the Syndrome of Deficiency and Stagnation of Blood, with symptoms such as menstrual disorders, abdominal pain, threatened abortion, lochia etc. Other diseases, such as malnutrition anaemia, insomnia, vertigo etc, can respond well to this remedy. The Principal drug (angelica) tonifies the Blood (haematopoetic system), relieves stagnation and pain, helps bowel movements and relieves constipation. The Ministerial drug (rehmannia) tonifies the Blood and Yin. The Assistant drug (paeonia) tonifies Yin, the Blood, Liver and haemopoietic system. The Guiding drug (cnidium) tonifies the free circulation of Qi and Blood and expels Damp. Together, the four ingredients effectively tonify the haematopoetic system (Blood formation) and the circulation.
b. Si Jun Zi Tang (Four Gentleman Decoction) is a TCM Formula to treat Qi Deficiency. It contains ginseng, atractylodes, hoelen and licorice. Its Function in TCM is to tonify Qi, the abdominal Organ-Bowels and digestion. It is used to tonify Qi in Qi Deficiency, especially in malfunction of abdominal Organ-Bowels, anaemia, fatigue, etc. This remedy is mainly used for dysfunction of Earth COSs (SP, ST). The Principal drug (ginseng) tonifies Qi, Yang and the functions of the abdominal Organ-Bowels, such as Stomach, Spleen, Kidney, Liver etc. It also calms the mind. The Ministerial drug (atractylodes) tonifies Spleen to transform Substance into Qi. The Assistant drug (hoelen) helps ginseng and atractylodes to tonify Spleen to transform Substance into Qi; hoelen tonifies Kidney. It has diuretic effects which can expel Damp. It expels Stagnated Water from the body. The Guiding drug (licorice) regulates the internal organs, via enhancing Qi flow through the Channels. Together, the four ingredients tonify digestive function, to produce more Qi from Substance and to normalise the body defence system.
c. Ba Zhen Tang (Eight Precious Herb Decoction) is a combination of (a) and (b) above. Sometimes, the physician adds ginger and date to increase the Assistant and Guiding effects. See (a) and (b) for functions.
d. Shiquan Dabu Tang (Decoction of Ten Good Herbs), also, Juzen-Taiho-To (JTT) is a combination of (c) above + cinnamon + astragalus (Table 2). In TCM, this Formula is a Master Remedy for Syndromes of Deficiency of Qi and/or Blood. Indicative symptoms are remittent fever, muscle spasms, coarse skin, nocturnal emissions, pallor, coldness, anaemia, weakness and anxiety. The Principal drugs (angelica and ginseng) tonify the Blood and Qi respectively and ginseng also tonifies the functions of the abdominal Organ-Bowels and calms the mind. The Ministerial drugs are rehmannia (to tonify Yin and Blood and atractylodes to tonify Spleen to transform Substance into Qi and tonifies digestion and decreases Damp Syndrome (oedema)). Its Assistant drugs are paeonia (to tonify Yin, the Blood, Liver and haemopoietic system) and hoelen (to tonify Kidney; it has diuretic effects which can expel Damp). The Guiding drugs are cnidium (to tonify the free circulation of Qi and Blood and expel Damp) and licorice (to regulate the internal organs, via enhanced Qi flow through the Channels; to adjust and detoxify all the other herbs, making them more effective and safe). Finally, astragalus tonifies Qi and Yang, to tonify Spleen and Stomach and digestive function and cinnamon Warms the body and expels Cold, or sensations of chill; it also tonifies the Lung, Heart and Kidney. It is antifebrile in chills, antierythematous; coordinates diuretic effects of other herbs. The combination of the 10 ingredients in JTT is a Master Tonic; it treats a wide variety of symptoms in patients debilitated after surgery or childbirth, and after acute or chronic illness. It is very useful in anaemia, dysmenorrhoea, inappetance, fatigue and weakness (Xie et al 1994).
JTT from the perspective of Western Medicine (WM)
As mentioned above, JTT is given to patients recovering from surgery or suffering from chronic diseases to promote improvement of their debilitated general conditions. JTT has been shown to modulate the defence system. It is a powerful immunostimulant. It significantly enhanced antibody responses to SRBC (Komatsu et al 1986), phagocytosis (Maruyama et al 1988) and mitogenic activities against splenic B cells in mice (Takemoto et al 1989). Peripheral blood cell counts in patients treated concomitantly with JTT orally and antineoplastic drug (mitomycin C) were higher than in patients treated with the antineoplastic drug alone (Nabeya & Ri 1983). Concomitant dosing of JTT with mitomycin C gave significantly longer survival periods in p-388 cancer-bearing mice than those treated with mitomycin C alone (Aburada et al 1983). JTT facilitated haematopoietic recovery from mitomycin C-induced bone marrow or radiation injuries (Kawamura et al 1989; Ohnishi et al 1990; Yamada et al 1990). These immunostimulating activities may relate closely to the clinical effects of JTT. Thus, the efficacy of JTT can be evaluated if immunomodulators are isolated and characterised from the preparation.
TJ-48 is a Japanese spray-dried powder of JTT extract. TJ-48 improved the general condition of cancer patients receiving chemotherapy and/or radiation therapy. Patients who took TJ-48 orally with an antineoplastic drug maintained higher peripheral blood counts than patients not taking TJ-48. It accelerated haemopoietic recovery from bone-marrow injury by mitomycin C (MMC) (Kawamura et al 1989). It also had many immunostimulating activities, including mitogenic activity against B lymphocytes and anticomplement activity. These effects were due to pectic polysaccharides in TJ-48. These activities may relate closely to the clinical effects of TJ-48 (Yamada et al 1994a).
TJ-48 enhanced antibody and interleukin 2 (IL-2) production and promoted granulocyte-macrophage colony forming cells (GM-CFC), anticomplement and mitogenic activities. To isolate these immunopharmacologically active substances, TJ-48 was fractionated into low- and high- molecular-weight fractions. These were F1 (methanol-soluble), F2 (methanol/water-insoluble), F3 (methanol-dialysable), F4 (ethanol-soluble but non-dialysable) and F5 (crude polysaccharide). Although F2 had anticomplement activity, F1 and F3 had GM-CFC enhancing activity. The crude polysaccharide fraction (F5) enhanced antibody and IL-2 production and also showed anticomplement and mitogenic activities (Yamada et al 1990; Kiyohara et al 1991, 1993; Ikehara et al 1992). Of the TJ-48-derived fractions, F5 displayed anti-SRBC antibody response in vivo when the polysaccharide fraction was given to Balb/c mice, either intraperitoneally or orally (Kiyohara et al 1995a). Oral dosing of aged mice with F5, or TJ-48, from 6 days before immunisation with SRBC gave a significant increase in anti-RBSC IgG, but at a lower level than that of young mice (Kiyohara et al 1995a). When the antineoplastic agent, cisplatin, was given to mice, the anti-SRBC antibody response decreased significantly (Kiyohara et al 1995a). Both F5 and TJ-48 enhanced the anti-SRBC IgM level similarly to those of their respective oral doses in cisplatin-immunosuppressed mice on post injection day 7 (Kiyohara et al 1995a). Oral dosing of the other fractions (F1 and a mixture of F3 + F4) also stimulated the anti-SRBC response (Kiyohara et al 1995a). Cisplatin inflicted toxic effects on the kidneys. As with the action of TJ-48, high values of blood urea nitrogen (BUN) induced by cisplatin treatment were reduced by dosing with either F1, a mixture of F3 and F4, or F5. Cisplatin-induced toxic effects were relieved markedly by the use of F5 (Kiyohara et al 1995b). Hitherto, the mechanism(s) of action of this toxicity-attenuating effect remains unknown. The acidic polysaccharide fraction, F5-2, showed anticomplement and mitogenic activities, while both F5-3 and F5-4 merely showed anticomplement effects. The neutral polysaccharide fraction (F5-5) enhanced both anticomplement activity and IL-2 production. Further fractionation of the individual acidic and neutral polysaccharide fractions (F5-2, F5-5) per se by DEAE-Sephadex, gave 22 different polysaccharides with varied immunostimulating activities (Kiyohara et al 1991, 1993).
Recently, a pectic polysaccharide with free radical scavenging activities was isolated from Bupleuri radix (Matsumoto et al 1993a). This compound may be related to the anti-ulcer effect of the medicinal herb. This suggests that the antioxidant (free-radical scavenging) activity in cisplatin-induced toxicity may be involved in the attenuating effect of the polysaccharide fraction.
These results suggest that JTT's immunomodulating activities are due to a combination effect of several different pectic polysaccharides which may have different immunomodulating effects, in addition to the effects of compounds of low molecular weight. These activities may contribute to the clinical effects of JTT.
b. Si Jun Zi Tang (Four Gentleman Decoction) is a TCM Formula to treat Qi Deficiency. It contains ginseng, atractylodes, hoelen and licorice. Its Function in TCM is to tonify Qi, the abdominal Organ-Bowels and digestion. It is used to tonify Qi in Qi Deficiency, especially in malfunction of abdominal Organ-Bowels, anaemia, fatigue, etc. This remedy is mainly used for dysfunction of Earth COSs (SP, ST). The Principal drug (ginseng) tonifies Qi, Yang and the functions of the abdominal Organ-Bowels, such as Stomach, Spleen, Kidney, Liver etc. It also calms the mind. The Ministerial drug (atractylodes) tonifies Spleen to transform Substance into Qi. The Assistant drug (hoelen) helps ginseng and atractylodes to tonify Spleen to transform Substance into Qi; hoelen tonifies Kidney. It has diuretic effects which can expel Damp. It expels Stagnated Water from the body. The Guiding drug (licorice) regulates the internal organs, via enhancing Qi flow through the Channels. Together, the four ingredients tonify digestive function, to produce more Qi from Substance and to normalise the body defence system.
c. Ba Zhen Tang (Eight Precious Herb Decoction) is a combination of (a) and (b) above. Sometimes, the physician adds ginger and date to increase the Assistant and Guiding effects. See (a) and (b) for functions.
d. Shiquan Dabu Tang (Decoction of Ten Good Herbs), also, Juzen-Taiho-To (JTT) is a combination of (c) above + cinnamon + astragalus (Table 2). In TCM, this Formula is a Master Remedy for Syndromes of Deficiency of Qi and/or Blood. Indicative symptoms are remittent fever, muscle spasms, coarse skin, nocturnal emissions, pallor, coldness, anaemia, weakness and anxiety. The Principal drugs (angelica and ginseng) tonify the Blood and Qi respectively and ginseng also tonifies the functions of the abdominal Organ-Bowels and calms the mind. The Ministerial drugs are rehmannia (to tonify Yin and Blood and atractylodes to tonify Spleen to transform Substance into Qi and tonifies digestion and decreases Damp Syndrome (oedema)). Its Assistant drugs are paeonia (to tonify Yin, the Blood, Liver and haemopoietic system) and hoelen (to tonify Kidney; it has diuretic effects which can expel Damp). The Guiding drugs are cnidium (to tonify the free circulation of Qi and Blood and expel Damp) and licorice (to regulate the internal organs, via enhanced Qi flow through the Channels; to adjust and detoxify all the other herbs, making them more effective and safe). Finally, astragalus tonifies Qi and Yang, to tonify Spleen and Stomach and digestive function and cinnamon Warms the body and expels Cold, or sensations of chill; it also tonifies the Lung, Heart and Kidney. It is antifebrile in chills, antierythematous; coordinates diuretic effects of other herbs. The combination of the 10 ingredients in JTT is a Master Tonic; it treats a wide variety of symptoms in patients debilitated after surgery or childbirth, and after acute or chronic illness. It is very useful in anaemia, dysmenorrhoea, inappetance, fatigue and weakness (Xie et al 1994).
JTT from the perspective of Western Medicine (WM)
As mentioned above, JTT is given to patients recovering from surgery or suffering from chronic diseases to promote improvement of their debilitated general conditions. JTT has been shown to modulate the defence system. It is a powerful immunostimulant. It significantly enhanced antibody responses to SRBC (Komatsu et al 1986), phagocytosis (Maruyama et al 1988) and mitogenic activities against splenic B cells in mice (Takemoto et al 1989). Peripheral blood cell counts in patients treated concomitantly with JTT orally and antineoplastic drug (mitomycin C) were higher than in patients treated with the antineoplastic drug alone (Nabeya & Ri 1983). Concomitant dosing of JTT with mitomycin C gave significantly longer survival periods in p-388 cancer-bearing mice than those treated with mitomycin C alone (Aburada et al 1983). JTT facilitated haematopoietic recovery from mitomycin C-induced bone marrow or radiation injuries (Kawamura et al 1989; Ohnishi et al 1990; Yamada et al 1990). These immunostimulating activities may relate closely to the clinical effects of JTT. Thus, the efficacy of JTT can be evaluated if immunomodulators are isolated and characterised from the preparation.
TJ-48 is a Japanese spray-dried powder of JTT extract. TJ-48 improved the general condition of cancer patients receiving chemotherapy and/or radiation therapy. Patients who took TJ-48 orally with an antineoplastic drug maintained higher peripheral blood counts than patients not taking TJ-48. It accelerated haemopoietic recovery from bone-marrow injury by mitomycin C (MMC) (Kawamura et al 1989). It also had many immunostimulating activities, including mitogenic activity against B lymphocytes and anticomplement activity. These effects were due to pectic polysaccharides in TJ-48. These activities may relate closely to the clinical effects of TJ-48 (Yamada et al 1994a).
TJ-48 enhanced antibody and interleukin 2 (IL-2) production and promoted granulocyte-macrophage colony forming cells (GM-CFC), anticomplement and mitogenic activities. To isolate these immunopharmacologically active substances, TJ-48 was fractionated into low- and high- molecular-weight fractions. These were F1 (methanol-soluble), F2 (methanol/water-insoluble), F3 (methanol-dialysable), F4 (ethanol-soluble but non-dialysable) and F5 (crude polysaccharide). Although F2 had anticomplement activity, F1 and F3 had GM-CFC enhancing activity. The crude polysaccharide fraction (F5) enhanced antibody and IL-2 production and also showed anticomplement and mitogenic activities (Yamada et al 1990; Kiyohara et al 1991, 1993; Ikehara et al 1992). Of the TJ-48-derived fractions, F5 displayed anti-SRBC antibody response in vivo when the polysaccharide fraction was given to Balb/c mice, either intraperitoneally or orally (Kiyohara et al 1995a). Oral dosing of aged mice with F5, or TJ-48, from 6 days before immunisation with SRBC gave a significant increase in anti-RBSC IgG, but at a lower level than that of young mice (Kiyohara et al 1995a). When the antineoplastic agent, cisplatin, was given to mice, the anti-SRBC antibody response decreased significantly (Kiyohara et al 1995a). Both F5 and TJ-48 enhanced the anti-SRBC IgM level similarly to those of their respective oral doses in cisplatin-immunosuppressed mice on post injection day 7 (Kiyohara et al 1995a). Oral dosing of the other fractions (F1 and a mixture of F3 + F4) also stimulated the anti-SRBC response (Kiyohara et al 1995a). Cisplatin inflicted toxic effects on the kidneys. As with the action of TJ-48, high values of blood urea nitrogen (BUN) induced by cisplatin treatment were reduced by dosing with either F1, a mixture of F3 and F4, or F5. Cisplatin-induced toxic effects were relieved markedly by the use of F5 (Kiyohara et al 1995b). Hitherto, the mechanism(s) of action of this toxicity-attenuating effect remains unknown. The acidic polysaccharide fraction, F5-2, showed anticomplement and mitogenic activities, while both F5-3 and F5-4 merely showed anticomplement effects. The neutral polysaccharide fraction (F5-5) enhanced both anticomplement activity and IL-2 production. Further fractionation of the individual acidic and neutral polysaccharide fractions (F5-2, F5-5) per se by DEAE-Sephadex, gave 22 different polysaccharides with varied immunostimulating activities (Kiyohara et al 1991, 1993).
Recently, a pectic polysaccharide with free radical scavenging activities was isolated from Bupleuri radix (Matsumoto et al 1993a). This compound may be related to the anti-ulcer effect of the medicinal herb. This suggests that the antioxidant (free-radical scavenging) activity in cisplatin-induced toxicity may be involved in the attenuating effect of the polysaccharide fraction.
These results suggest that JTT's immunomodulating activities are due to a combination effect of several different pectic polysaccharides which may have different immunomodulating effects, in addition to the effects of compounds of low molecular weight. These activities may contribute to the clinical effects of JTT.
Part 3
Other aspects of phytopharmacological research
Although extensive knowledge and cumulative experience of the clinical uses of KM have been acquired from CHM, Japanese workers have made great contributions to the scientific understanding of KM in the last two decades. Every year, hundreds of scientific papers are published. Most support the application of KM. Similarly, many hundreds of CHMs have potent therapeutic effects.
The literature on research into the mode of action of medicinal herbs has documented well the low molecular-weight fractions, but the larger molecules, such as polysaccharides have come under study only recently (Yamada 1994b; Matsumoto & Yamada 1995).
The Kitasato team is researching the action of JTT polysaccharides at the cellular and intracellular level. For example recent work on Bupleurum has given valuable new findings. Bupleurum is a very common CHM, mainly to treat liver disease. Recently, bupleuran 2IIb, a pectic polysaccharide isolated from Bupleurum falcatum, was shown to up-regulate the expression of Fc-receptors (FcRs) on macrophages; this action was mediated by enhancing the transcription of both Fc-gamma RI and Fc-gamma RII genes (Matsumoto et al 1993).
The regulation of intracellular signal transduction pathways can be determined by measuring second messengers in response to the presence of specific inhibitors. Macrophages from the peritoneal cavity of mice were used to study whether protein kinase C and A (PKC and PKA) were involved in FcR up-regulation by bupleuran 2IIb. Neither the PKC inhibitor, 1-(5-isoquinolinylsulphonyI)-2-methylpiperazine dihydrochloride, nor the PKA inhibitor, N-[2-(methylamino)ethyl]-5-isoquinoliny-sulphonamide dihydrochloride, inhibited bupleuran 2IIb-induced up-regulation of FcR. However, when macrophages were treated with Ca-antagonist, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzate hydrochloride, bupleuran 2IIb-induced up-regulation of FcR was inhibited in a dose-dependent manner. The two calmodulin antagonists, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalensulphonamide hydrochloride also blocked the action. Also, fluorescence image analysis, using the Ca-sensitive dye, Fura-2, showed that bupleuran 2IIb induced a rapid increase in intracellular levels of Ca. These results suggest that bupleuran 2IIb induced the up-regulation of FcR on macrophages by a mechanism dependent on an increase in intracellular Ca2+, followed by activation of the calmodulin, but not by a PKC or PKA pathway (Matsumoto & Yamada 1995).
HM: Controversial issues and possible solutions
HM, as with WM, has negative/unresolved as well as positive/resolved aspects and the status will change (a Law of TCM). It is possible to make the changes positive. To do this, leaders and workers in the fields of science, medicine and national government need to recognize the disadvantages of HM and work to solve them. Some disadvantages and possible solutions will be discussed now.
The supply of raw herbal ingredients
Some important raw materials used in HM are found only in a few areas of the world and, thus, are in limited supply. Some animal-derived ingredients used in the east (such as monkey tissues, tiger bone, rhino- or elephant- horn, antler velvet from deer etc) are banned in the west on grounds of unnecessary cruelty to animals, or conservation of endangered species.
Some countries have specific national legislation which bans the use of certain ingredients, such as ruminant brain tissue, due to public fear of bovine spongiform encephalopathy; tiger bone, due to conservation policy etc. Solutions could include guaranteed exclusion of banned ingredients from the marketplace, research into natural propagation of the rarer permitted ingredients and in-vitro production of active ingredients or suitable alternatives. This could include use of biotechnology and genetic engineering to clarify the active components, or synthesize similar alternatives (Chaudhury 1995).
It would be useful also to study substitutes for some rare or special ingredients. It is warranted now to find good substitutes for certain human tissues (for example, human placenta is used in some HMs). Certain animal tissues (bone, horn, penis, testis, ovary etc) from domestic animals (buffalo, cattle, deer, pigs) might be used instead of similar tissues from rare or preserved species (tigers, primates, rhinos, elephants etc). Common tissues might be used instead of rare material (for example bovine bile instead of bovine gallstones.
It would also be useful to cultivate medicinal herbs which might have actions similar to much rarer or more expensive herbs, for example, Danhseng (Codonopsis pilosula) instead of ginseng.
Quality control
Used properly HM is very safe but, if overused, the ingredients used in HM also are toxic. Thus, great care is needed in their combinations and dosage. Quality control needs to be improved and increased (Chaudhury 1995; Dharmananda 1991).
The levels of active ingredients in the raw materials in HMs vary with time/place of collection, the parts of the plants used, methods of processing and other factors. For example, although the root is used, ginseng leaves contain more active compounds than the root (Dharmananda 1991; Sun et al 1992). At present, there is little or no quality control on the levels of active ingredients in the final prescriptions of many formulas. This is unacceptable to many professionals in WM.
A solution would be to develop guaranteed methods and standards of quality control. Product labelling and datasheets could be made mandatory. These should state clearly the dosage, the clinical indications, contraindications, side-effects, emergency procedures and/or antidotes (if known) in case of severe adverse reaction etc, as is the case with WMs.
Research is needed on the processing and purification of HMs. Decoctions usually are prepared by the patient from the dried crude formulas. Patient-errors may occur in the preparation and dosage of decoctions. They are bulky, hard to preserve and transport; they are tedious to decoct properly and may be unpalatable (Yamada 1994a). Unit-doses of pills or powders, made from the dried extracts, have many advantages over decoctions. Their preparation, purification and packaging as pillules and unit-doses would be beneficial. Sometimes, however, decoctions must be used. As a guide to doctors on their relative palatabilities, decocted KMs were submitted to a taste panel, who assigned a taste-rank score to each for the strength or weakness of the taste. A table of mean taste-ranks, with dosage guidelines is available (Kim et al 1995). Quality control should build on this work and see if flavouring agents, or other methods of preparation, could offset the more unpalatable tastes.
Registered versus unregistered medicines
Many countries, such as the United States and the European Union, make it difficult and expensive to register therapeutic drugs for use in humans or animals. A dossier on each formulation must list details of the type of animal, indications, dosage, contraindications, safety, toxicity studies, antidotes, labelling, levels of active ingredients, quality control procedures, shelf-life, residue levels, withholding time (in meat- and milk- animals) etc. These statements must be supported by research findings, especially by independent agencies.
HMs usually are unregistered as therapeutic products in most western countries. In the United Kingdom, at least 40 HMs are freely available without prescription (Chaudhury 1995). Use of unregistered products (or adverse interactions between registered and unregistered products) could present professionals with legal problems in the event of untoward (or adverse) effects in their patients. Most HMs used in animals are based on human prescriptions. Research is needed on their use in animals. Application of stringent rules to the main remedies or formulas used in HM would probably make it impossible to register them. Until then, most Veterinary Associations would not recognize HM as a valid therapy.
It would be unrealistic to expect western authorities and insurance companies to give a carte blanche to professionals to use anything they please as a medical therapy. There are at least possible solutions.
The State could adopt the Japanese medical model: to endorse the use of specific HMs in specific conditions by authorised professionals. It could authorise a list of HMs, mainly complex Formulas, validated as to their safety and efficacy by centuries of documentation and usage (Chaudhury 1995). The approved list could be drawn up in association with recognized experts in HM. Each State also could decide on what constitutes minimal competence before licensing the professionals. Use by registered professionals of Expert TCM Databases (see below) could qualify in that respect.
The State could licence the use and dosage of specific approved HMs in combination with accepted (conventional) therapies. Contraindications and adverse interactions between WMs and the approved HMs would need to be listed formally (Chaudhury 1995).
The State also could encourage the use of specific HMs as experimental unregistered health products or supplements. In that case, their use would require that the professional obtain from the client a written consent for their experimental use and an indemnity against claims for negligence or malpractice in the event of untoward reactions (Schwartz 1994).
How to develop HM further
WM is highly developed today. The prevalence of acute infectious diseases of humans and animals has fallen significantly since the discovery, development and use of antibiotics and vaccines, and the use of improved auxiliary techniques (intensive care, fluid therapy, dialysis, blood filtration etc). Also essential to this success are improved diagnostic screening techniques and overall improvement of personal- and food- hygiene, improved overall nutrition, housing and control of the environment etc.
However, drug-resistant "superbugs", especially Staphylococcus aureus, are becoming prevalent. These and some chronic infectious diseases, such as AIDS, viral hepatitis and bovine tuberculosis, are especially difficult to eradicate. Also, the prevalence of other chronic diseases, especially those related to stress, environmental pollution, immunosuppression etc. seems to be increasing.
TCM is underdeveloped, mainly through lack of adequate funding for basic and clinical research and also due to lack of good information for education and training of practitioners. Even so, complementary therapies, using HMs, are used widely in the United States and Europe and their use is growing (Otsuka 1988; Yamada 1994a; Micozzi 1995). Although some regard the scientific nature of TCM as inferior to WM, each system has its validity, its strengths and weaknesses. HM will continue to grow in popularity and use, as an adjunct to WM. TCM has great potential to prevent and cure many chronic diseases (Dharmananda 1991) but one can not expect TCM to make great impact in WM without a pro-active approach from both sides and greatly increased international inputs in funding for research, education and training in TCM.
Personal effort, group effort, the activities of interested organisations, teaching and training at university level and financial support from governments and industries are the main factors in the development of all sciences. Recent development in biotechnology has shown that. Although modern veterinary medicine in China is underdeveloped, all these factors are present. However, most other countries lack these factors. Fortunately, the developed countries may use their modern facilities in veterinary science and their educational systems to study and develop HM. Some suggestions to help such developments are presented elsewhere (Lin & Panzer 1994).
Easy access to expert information on HM is essential
Why do practitioners prescribe the drugs which they use daily? Apart from the constraints of the availability of the product(s) and the ability of the client to pay for them, most practitioners prescribe the best drug(s), or other therapies, that they know for the diagnosed problem(s). In other words, the key factors in prescribing the "best drug(s)" are knowledge (especially of diagnostics and therapeutics) and belief (that the prescription will give satisfactory results). In any medical system (WM or TCM) the knowledge and belief of the practitioner are conditioned by his/her culture and limited by his/her education and by ongoing access to credible information.
With some exceptions, expert use of HM requires fast, easy access to Oriental medical theory and the ways to select the most appropriate ingredients or formulas (Otsuka 1988). Busy WM professionals who wish to learn HM must face this problem. Most are unable or unwilling to take 1-3 years or more out of their practice or research to study the huge volume of novel data that must be learned and assimilated. Unless professionals in WM can access the data rapidly and reliably, they are unlikely to use HM, even on an experimental basis.
If they can be developed, expert Windows-based TCM software could offer solutions to the knowledge problem. User-friendly, expert, interactive PC-based databases could incorporate all the key aspects of TCM, HM, the relevant HM remedies and formulas, TCM Syndromes and Diagnosis. All of these could be cross-referenced to the equivalent WM syndromes and medications. Novice (but professional) users could key-in the clinical findings. The software could prompt the user to add other relevant data. A preliminary cross-matching of the input data with the database could activate prompts for further relevant input. The database could then display the TCM diagnosis and the indicated (and contraindicated) HMs etc. Such databases would enable professionals to key in the clinical signs, receive prompts on other signs and make a TCM diagnosis. On the basis of the diagnosis, the software would suggest appropriate treatments. In this way, naive professionals could use HM quickly and effectively, and alter the HMs with changes in the Syndrome or Sho. Further refinements could allow users to browse the various files for study purposes, to enter hypothetical clinical data for self-testing purposes etc.
Such databases could be efficient learning aids for inexperienced professionals, as has been demonstrated some years ago by an expert Database in WM, developed in Harvard Medical School. Such technology is available to professionals interested in homeopathy and certain aspects of AP, both complementary therapies which MSM professionals find very difficult to master.
"Chinese Herbal Medicine (Green Medicine, Version 1.1)" is a database for Apple MacIntosh and Windows PCs (Weber 1992). This seems to be the first attempt to put TCM at the fingertips of PC users. It contains a wealth of data on clinical signs and symptoms, TCM Syndromes, herbal actions, indications, CHM formulas and dosages. However, it needs major revision to make it faster, more user-friendly and more "intuitive".
Computers can store and recall information faster and more accurately than many humans. But, for best results, skilled humans must interpret the data; one should not rely on computers for basic medical knowledge any more than one should rely blindly on fixed herbal formulations as a cure for all ills. However, computers and formulations have one thing in common; both can help the doctor to help the patient to cure him/her self. Also, computers can help doctors to better manage and reinforce their medical knowledge and can stimulate them to master that knowledge. However, no matter how good they are, computers can not replace adequate medical knowledge and skill, nor can they replace compassion for and desire to heal the patient. Compassion, love, and service is at the core of healing.
Additional research
Further pharmacological experiments are needed to evaluate plant compounds as clinically useful medicines. Plant cell culture, chemical synthesis, or biotechnological production methods of the compounds, may be needed to obtain sufficient amounts for sampling purposes. In the chemical synthesis of medicinal compounds, structure-activity relationships should be considered in order to prepare compounds that are more active and safe, and which exhibit bioavailability. The search for new drugs from HMs is justified because of the long term clinical evidence of their clinical value in humans and animals. Such research proves the experimental applications of HMs to be true and helps to explain their clinical effects (Dharmananda 1991). As with WMs, some HMs are toxic. It may be necessary to check for undesirable residues or metabolites in food products from HM-treated animals, for example the level of plant alkaloids in milk, cheese, meat etc.
Future prospects
The main aim of all good medicine is to improve the quality of human or animal life. TCM and WM have this aim. Advantages of TCM are the lower costs and the absence of side-effects relative to those of WMs. Also, most HMs come from natural biologically renewable sources. Cultivation and processing of HMs could be a valuable source of income for developing countries.
Development of TCM on the Internet
Information Technology in Acupuncture and Traditional Chinese Medicine is discussed in detail elsewhere (Rogers 1998).
Western professionals who wish to learn or use complementary therapies often feel isolated. They may have few colleagues nearby with whom to exchange information. Internet Bulletin Boards on TCM could be developed on all aspects, including HM. The Internet, also called the electronic information superhighway, is an electronic, computer-based worldwide communication web. Via the Internet, those with sufficient money and computer-based technology can communicate, almost instantly, with colleagues anywhere in the world with similar interests.
HM Abstracts: Occidental researchers have great difficulty accessing information written in oriental languages and vice-versa. Advances in optical scanning devices allow printed data to be scanned in ASCII text into computer files. Advances in computer software now allow articles digitised in one language to be translated into another. Scanners, translation- and communications- technology could convert documents in any of the main languages into many other languages for uploading onto the Internet or CD ROM. Access to the these media could radically enhance the exchange of research and clinical data on HM. Development of specialist areas on the Internet for HM Research Abstracts and HM Clinical Abstracts would accelerate its development.
Register of drug reactions: Though most states have a formal reporting system to record adverse effects of medication (or their suspicions of them), professionals may have difficulty accessing the data. Also, they may not be able to check if data submitted by them were actually recorded. Requests to commercial companies for data on adverse reactions may be futile: because of vested interest, companies may deny or play down reported iatrogenic disease. The Internet could help to solve this problem: a password-protected Register of Drug Toxicity/Iatrogenic Disease would allow validated professionals to record (against their name) adverse reactions to specified drugs (WMs and/or HMs). Other professionals anywhere in the world, who have authorised access to the Internet register, could read those data anytime.
Discussion and Conclusions
Ancient and modern medicine each contain a blend of art and science, as do most successful systems of animal production, managemant and husbandry. In this paper, we had no time to discuss the many positive aspects of western science and technology in animal production and welfare. It has much to offer in areas of animal breeding and genetics (sire selection, sperm sexing, AI/embryo transfer, synchronisation etc), housing design, mechanisation, automation etc. Modern concepts of epidemiology, record-keeping, routine monitoring of weight gains and production indices, animal nutrition, mineral and vitamin supplementation, optimum management of pastures, conservation of high quality animal feedstuffs etc are most valuable. Microelectronic sensors, telemetry and recording equipment are cheaper than ever before. Remote sensing technology offers the possibility of cost-effective routine automated monitoring of physiological states, and early detection of pathological states.
However, on its own, western-style intensive farming, depends heavily on high inputs of expensive and dangerous chemicals. Consumer perceptions are that it can not produce the high quality of human food for which demand is increasing rapidly.
We suggest that more humane and considerate handling and management of animals will reduce their stress levels. We argue for a greater input of love, respect, compassion, and common sense into animal management. In most cases, this is an economic investment; animals that are cared for well are more contented; they produce more than animals roughly or poorly treated. This may involve a move towards less intensive production systems [a policy of the EU now], a reduced input of potent synthetic chemicals into the systems, and their replacement with natural and less toxic forms of prophylaxis and therapy. In this area, there is a huge potential for the incorporation of CHM into an integrated system which takes the best from the East and combines it with the best from the west.
Widespread research, development and use of HM, could save billions of dollars annually on the international cost of conventional drugs, hospitalisation and lost time at work. This would force major changes in the modern (western-oriented) pharmaceutical industry and in agricultural production. Initially at least, this could have serious effects on investment and employment. If the major pharmaceutical industries can be persuaded to diversify slowly into HM, they could save many old jobs and create new jobs. New areas of work would include biological research, breeding, refining, tending, processing and replenishing the herbs, researching the active principles, upgrading quality control, refining the combinations of medicines to eliminate any risk of toxicity or adverse side-effects, etc. Also, governments could reinvest their savings on drug-bills into improved systems of health care for all.
TCM and HM have been used empirically over thousands of years in billions of human and animal patients, and their use is increasing. Those facts, are strong evidence of their overall safety and efficacy. As discussed above, recent research, both clinical and basic, has confirmed these claims.
In contrast to WMs, properly used CHMs can be given for long periods with minimal or no adverse effects (Hsu 1982; Hosoya & Yamamura 1988; Dharmananda 1991; Chan et al 1993; Schwartz 1994; Yamada 1994a). Thus, OM/TCM/HM shows great promise, especially for sustainable use of medicinal resources (Lin et al 1995a).
The problems of TCM are due mainly to lack of easily accessible information and lack of funding. Their solution needs greatly increased inputs from researchers, clinicians, relevant industries and governments. These problems must be resolved if the advantages of both medical systems (TCM and WM) are to be put to better use internationally. Resolution of the problems would lead to the dawn of a new age of medicine and animal welfare. The integration of the best aspects of WM and TCM, would be safer, less expensive and more sustainable than is the case today.
Acknowledgements
We thank the National Science Council, Republic of China for financial support to Professor JH Lin (32056F), without which this article could not have been finished. We thank all the cited authors, especially Drs. A Ackerson, D Bensky, RR Chaudhury, S Dharmananda, PK Tsung, whose material was reproduced in summary form. Finally, we thank Ms. A Yamasaki for excellent clerical assistance.
Although extensive knowledge and cumulative experience of the clinical uses of KM have been acquired from CHM, Japanese workers have made great contributions to the scientific understanding of KM in the last two decades. Every year, hundreds of scientific papers are published. Most support the application of KM. Similarly, many hundreds of CHMs have potent therapeutic effects.
The literature on research into the mode of action of medicinal herbs has documented well the low molecular-weight fractions, but the larger molecules, such as polysaccharides have come under study only recently (Yamada 1994b; Matsumoto & Yamada 1995).
The Kitasato team is researching the action of JTT polysaccharides at the cellular and intracellular level. For example recent work on Bupleurum has given valuable new findings. Bupleurum is a very common CHM, mainly to treat liver disease. Recently, bupleuran 2IIb, a pectic polysaccharide isolated from Bupleurum falcatum, was shown to up-regulate the expression of Fc-receptors (FcRs) on macrophages; this action was mediated by enhancing the transcription of both Fc-gamma RI and Fc-gamma RII genes (Matsumoto et al 1993).
The regulation of intracellular signal transduction pathways can be determined by measuring second messengers in response to the presence of specific inhibitors. Macrophages from the peritoneal cavity of mice were used to study whether protein kinase C and A (PKC and PKA) were involved in FcR up-regulation by bupleuran 2IIb. Neither the PKC inhibitor, 1-(5-isoquinolinylsulphonyI)-2-methylpiperazine dihydrochloride, nor the PKA inhibitor, N-[2-(methylamino)ethyl]-5-isoquinoliny-sulphonamide dihydrochloride, inhibited bupleuran 2IIb-induced up-regulation of FcR. However, when macrophages were treated with Ca-antagonist, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzate hydrochloride, bupleuran 2IIb-induced up-regulation of FcR was inhibited in a dose-dependent manner. The two calmodulin antagonists, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalensulphonamide hydrochloride also blocked the action. Also, fluorescence image analysis, using the Ca-sensitive dye, Fura-2, showed that bupleuran 2IIb induced a rapid increase in intracellular levels of Ca. These results suggest that bupleuran 2IIb induced the up-regulation of FcR on macrophages by a mechanism dependent on an increase in intracellular Ca2+, followed by activation of the calmodulin, but not by a PKC or PKA pathway (Matsumoto & Yamada 1995).
HM: Controversial issues and possible solutions
HM, as with WM, has negative/unresolved as well as positive/resolved aspects and the status will change (a Law of TCM). It is possible to make the changes positive. To do this, leaders and workers in the fields of science, medicine and national government need to recognize the disadvantages of HM and work to solve them. Some disadvantages and possible solutions will be discussed now.
The supply of raw herbal ingredients
Some important raw materials used in HM are found only in a few areas of the world and, thus, are in limited supply. Some animal-derived ingredients used in the east (such as monkey tissues, tiger bone, rhino- or elephant- horn, antler velvet from deer etc) are banned in the west on grounds of unnecessary cruelty to animals, or conservation of endangered species.
Some countries have specific national legislation which bans the use of certain ingredients, such as ruminant brain tissue, due to public fear of bovine spongiform encephalopathy; tiger bone, due to conservation policy etc. Solutions could include guaranteed exclusion of banned ingredients from the marketplace, research into natural propagation of the rarer permitted ingredients and in-vitro production of active ingredients or suitable alternatives. This could include use of biotechnology and genetic engineering to clarify the active components, or synthesize similar alternatives (Chaudhury 1995).
It would be useful also to study substitutes for some rare or special ingredients. It is warranted now to find good substitutes for certain human tissues (for example, human placenta is used in some HMs). Certain animal tissues (bone, horn, penis, testis, ovary etc) from domestic animals (buffalo, cattle, deer, pigs) might be used instead of similar tissues from rare or preserved species (tigers, primates, rhinos, elephants etc). Common tissues might be used instead of rare material (for example bovine bile instead of bovine gallstones.
It would also be useful to cultivate medicinal herbs which might have actions similar to much rarer or more expensive herbs, for example, Danhseng (Codonopsis pilosula) instead of ginseng.
Quality control
Used properly HM is very safe but, if overused, the ingredients used in HM also are toxic. Thus, great care is needed in their combinations and dosage. Quality control needs to be improved and increased (Chaudhury 1995; Dharmananda 1991).
The levels of active ingredients in the raw materials in HMs vary with time/place of collection, the parts of the plants used, methods of processing and other factors. For example, although the root is used, ginseng leaves contain more active compounds than the root (Dharmananda 1991; Sun et al 1992). At present, there is little or no quality control on the levels of active ingredients in the final prescriptions of many formulas. This is unacceptable to many professionals in WM.
A solution would be to develop guaranteed methods and standards of quality control. Product labelling and datasheets could be made mandatory. These should state clearly the dosage, the clinical indications, contraindications, side-effects, emergency procedures and/or antidotes (if known) in case of severe adverse reaction etc, as is the case with WMs.
Research is needed on the processing and purification of HMs. Decoctions usually are prepared by the patient from the dried crude formulas. Patient-errors may occur in the preparation and dosage of decoctions. They are bulky, hard to preserve and transport; they are tedious to decoct properly and may be unpalatable (Yamada 1994a). Unit-doses of pills or powders, made from the dried extracts, have many advantages over decoctions. Their preparation, purification and packaging as pillules and unit-doses would be beneficial. Sometimes, however, decoctions must be used. As a guide to doctors on their relative palatabilities, decocted KMs were submitted to a taste panel, who assigned a taste-rank score to each for the strength or weakness of the taste. A table of mean taste-ranks, with dosage guidelines is available (Kim et al 1995). Quality control should build on this work and see if flavouring agents, or other methods of preparation, could offset the more unpalatable tastes.
Registered versus unregistered medicines
Many countries, such as the United States and the European Union, make it difficult and expensive to register therapeutic drugs for use in humans or animals. A dossier on each formulation must list details of the type of animal, indications, dosage, contraindications, safety, toxicity studies, antidotes, labelling, levels of active ingredients, quality control procedures, shelf-life, residue levels, withholding time (in meat- and milk- animals) etc. These statements must be supported by research findings, especially by independent agencies.
HMs usually are unregistered as therapeutic products in most western countries. In the United Kingdom, at least 40 HMs are freely available without prescription (Chaudhury 1995). Use of unregistered products (or adverse interactions between registered and unregistered products) could present professionals with legal problems in the event of untoward (or adverse) effects in their patients. Most HMs used in animals are based on human prescriptions. Research is needed on their use in animals. Application of stringent rules to the main remedies or formulas used in HM would probably make it impossible to register them. Until then, most Veterinary Associations would not recognize HM as a valid therapy.
It would be unrealistic to expect western authorities and insurance companies to give a carte blanche to professionals to use anything they please as a medical therapy. There are at least possible solutions.
The State could adopt the Japanese medical model: to endorse the use of specific HMs in specific conditions by authorised professionals. It could authorise a list of HMs, mainly complex Formulas, validated as to their safety and efficacy by centuries of documentation and usage (Chaudhury 1995). The approved list could be drawn up in association with recognized experts in HM. Each State also could decide on what constitutes minimal competence before licensing the professionals. Use by registered professionals of Expert TCM Databases (see below) could qualify in that respect.
The State could licence the use and dosage of specific approved HMs in combination with accepted (conventional) therapies. Contraindications and adverse interactions between WMs and the approved HMs would need to be listed formally (Chaudhury 1995).
The State also could encourage the use of specific HMs as experimental unregistered health products or supplements. In that case, their use would require that the professional obtain from the client a written consent for their experimental use and an indemnity against claims for negligence or malpractice in the event of untoward reactions (Schwartz 1994).
How to develop HM further
WM is highly developed today. The prevalence of acute infectious diseases of humans and animals has fallen significantly since the discovery, development and use of antibiotics and vaccines, and the use of improved auxiliary techniques (intensive care, fluid therapy, dialysis, blood filtration etc). Also essential to this success are improved diagnostic screening techniques and overall improvement of personal- and food- hygiene, improved overall nutrition, housing and control of the environment etc.
However, drug-resistant "superbugs", especially Staphylococcus aureus, are becoming prevalent. These and some chronic infectious diseases, such as AIDS, viral hepatitis and bovine tuberculosis, are especially difficult to eradicate. Also, the prevalence of other chronic diseases, especially those related to stress, environmental pollution, immunosuppression etc. seems to be increasing.
TCM is underdeveloped, mainly through lack of adequate funding for basic and clinical research and also due to lack of good information for education and training of practitioners. Even so, complementary therapies, using HMs, are used widely in the United States and Europe and their use is growing (Otsuka 1988; Yamada 1994a; Micozzi 1995). Although some regard the scientific nature of TCM as inferior to WM, each system has its validity, its strengths and weaknesses. HM will continue to grow in popularity and use, as an adjunct to WM. TCM has great potential to prevent and cure many chronic diseases (Dharmananda 1991) but one can not expect TCM to make great impact in WM without a pro-active approach from both sides and greatly increased international inputs in funding for research, education and training in TCM.
Personal effort, group effort, the activities of interested organisations, teaching and training at university level and financial support from governments and industries are the main factors in the development of all sciences. Recent development in biotechnology has shown that. Although modern veterinary medicine in China is underdeveloped, all these factors are present. However, most other countries lack these factors. Fortunately, the developed countries may use their modern facilities in veterinary science and their educational systems to study and develop HM. Some suggestions to help such developments are presented elsewhere (Lin & Panzer 1994).
Easy access to expert information on HM is essential
Why do practitioners prescribe the drugs which they use daily? Apart from the constraints of the availability of the product(s) and the ability of the client to pay for them, most practitioners prescribe the best drug(s), or other therapies, that they know for the diagnosed problem(s). In other words, the key factors in prescribing the "best drug(s)" are knowledge (especially of diagnostics and therapeutics) and belief (that the prescription will give satisfactory results). In any medical system (WM or TCM) the knowledge and belief of the practitioner are conditioned by his/her culture and limited by his/her education and by ongoing access to credible information.
With some exceptions, expert use of HM requires fast, easy access to Oriental medical theory and the ways to select the most appropriate ingredients or formulas (Otsuka 1988). Busy WM professionals who wish to learn HM must face this problem. Most are unable or unwilling to take 1-3 years or more out of their practice or research to study the huge volume of novel data that must be learned and assimilated. Unless professionals in WM can access the data rapidly and reliably, they are unlikely to use HM, even on an experimental basis.
If they can be developed, expert Windows-based TCM software could offer solutions to the knowledge problem. User-friendly, expert, interactive PC-based databases could incorporate all the key aspects of TCM, HM, the relevant HM remedies and formulas, TCM Syndromes and Diagnosis. All of these could be cross-referenced to the equivalent WM syndromes and medications. Novice (but professional) users could key-in the clinical findings. The software could prompt the user to add other relevant data. A preliminary cross-matching of the input data with the database could activate prompts for further relevant input. The database could then display the TCM diagnosis and the indicated (and contraindicated) HMs etc. Such databases would enable professionals to key in the clinical signs, receive prompts on other signs and make a TCM diagnosis. On the basis of the diagnosis, the software would suggest appropriate treatments. In this way, naive professionals could use HM quickly and effectively, and alter the HMs with changes in the Syndrome or Sho. Further refinements could allow users to browse the various files for study purposes, to enter hypothetical clinical data for self-testing purposes etc.
Such databases could be efficient learning aids for inexperienced professionals, as has been demonstrated some years ago by an expert Database in WM, developed in Harvard Medical School. Such technology is available to professionals interested in homeopathy and certain aspects of AP, both complementary therapies which MSM professionals find very difficult to master.
"Chinese Herbal Medicine (Green Medicine, Version 1.1)" is a database for Apple MacIntosh and Windows PCs (Weber 1992). This seems to be the first attempt to put TCM at the fingertips of PC users. It contains a wealth of data on clinical signs and symptoms, TCM Syndromes, herbal actions, indications, CHM formulas and dosages. However, it needs major revision to make it faster, more user-friendly and more "intuitive".
Computers can store and recall information faster and more accurately than many humans. But, for best results, skilled humans must interpret the data; one should not rely on computers for basic medical knowledge any more than one should rely blindly on fixed herbal formulations as a cure for all ills. However, computers and formulations have one thing in common; both can help the doctor to help the patient to cure him/her self. Also, computers can help doctors to better manage and reinforce their medical knowledge and can stimulate them to master that knowledge. However, no matter how good they are, computers can not replace adequate medical knowledge and skill, nor can they replace compassion for and desire to heal the patient. Compassion, love, and service is at the core of healing.
Additional research
Further pharmacological experiments are needed to evaluate plant compounds as clinically useful medicines. Plant cell culture, chemical synthesis, or biotechnological production methods of the compounds, may be needed to obtain sufficient amounts for sampling purposes. In the chemical synthesis of medicinal compounds, structure-activity relationships should be considered in order to prepare compounds that are more active and safe, and which exhibit bioavailability. The search for new drugs from HMs is justified because of the long term clinical evidence of their clinical value in humans and animals. Such research proves the experimental applications of HMs to be true and helps to explain their clinical effects (Dharmananda 1991). As with WMs, some HMs are toxic. It may be necessary to check for undesirable residues or metabolites in food products from HM-treated animals, for example the level of plant alkaloids in milk, cheese, meat etc.
Future prospects
The main aim of all good medicine is to improve the quality of human or animal life. TCM and WM have this aim. Advantages of TCM are the lower costs and the absence of side-effects relative to those of WMs. Also, most HMs come from natural biologically renewable sources. Cultivation and processing of HMs could be a valuable source of income for developing countries.
Development of TCM on the Internet
Information Technology in Acupuncture and Traditional Chinese Medicine is discussed in detail elsewhere (Rogers 1998).
Western professionals who wish to learn or use complementary therapies often feel isolated. They may have few colleagues nearby with whom to exchange information. Internet Bulletin Boards on TCM could be developed on all aspects, including HM. The Internet, also called the electronic information superhighway, is an electronic, computer-based worldwide communication web. Via the Internet, those with sufficient money and computer-based technology can communicate, almost instantly, with colleagues anywhere in the world with similar interests.
HM Abstracts: Occidental researchers have great difficulty accessing information written in oriental languages and vice-versa. Advances in optical scanning devices allow printed data to be scanned in ASCII text into computer files. Advances in computer software now allow articles digitised in one language to be translated into another. Scanners, translation- and communications- technology could convert documents in any of the main languages into many other languages for uploading onto the Internet or CD ROM. Access to the these media could radically enhance the exchange of research and clinical data on HM. Development of specialist areas on the Internet for HM Research Abstracts and HM Clinical Abstracts would accelerate its development.
Register of drug reactions: Though most states have a formal reporting system to record adverse effects of medication (or their suspicions of them), professionals may have difficulty accessing the data. Also, they may not be able to check if data submitted by them were actually recorded. Requests to commercial companies for data on adverse reactions may be futile: because of vested interest, companies may deny or play down reported iatrogenic disease. The Internet could help to solve this problem: a password-protected Register of Drug Toxicity/Iatrogenic Disease would allow validated professionals to record (against their name) adverse reactions to specified drugs (WMs and/or HMs). Other professionals anywhere in the world, who have authorised access to the Internet register, could read those data anytime.
Discussion and Conclusions
Ancient and modern medicine each contain a blend of art and science, as do most successful systems of animal production, managemant and husbandry. In this paper, we had no time to discuss the many positive aspects of western science and technology in animal production and welfare. It has much to offer in areas of animal breeding and genetics (sire selection, sperm sexing, AI/embryo transfer, synchronisation etc), housing design, mechanisation, automation etc. Modern concepts of epidemiology, record-keeping, routine monitoring of weight gains and production indices, animal nutrition, mineral and vitamin supplementation, optimum management of pastures, conservation of high quality animal feedstuffs etc are most valuable. Microelectronic sensors, telemetry and recording equipment are cheaper than ever before. Remote sensing technology offers the possibility of cost-effective routine automated monitoring of physiological states, and early detection of pathological states.
However, on its own, western-style intensive farming, depends heavily on high inputs of expensive and dangerous chemicals. Consumer perceptions are that it can not produce the high quality of human food for which demand is increasing rapidly.
We suggest that more humane and considerate handling and management of animals will reduce their stress levels. We argue for a greater input of love, respect, compassion, and common sense into animal management. In most cases, this is an economic investment; animals that are cared for well are more contented; they produce more than animals roughly or poorly treated. This may involve a move towards less intensive production systems [a policy of the EU now], a reduced input of potent synthetic chemicals into the systems, and their replacement with natural and less toxic forms of prophylaxis and therapy. In this area, there is a huge potential for the incorporation of CHM into an integrated system which takes the best from the East and combines it with the best from the west.
Widespread research, development and use of HM, could save billions of dollars annually on the international cost of conventional drugs, hospitalisation and lost time at work. This would force major changes in the modern (western-oriented) pharmaceutical industry and in agricultural production. Initially at least, this could have serious effects on investment and employment. If the major pharmaceutical industries can be persuaded to diversify slowly into HM, they could save many old jobs and create new jobs. New areas of work would include biological research, breeding, refining, tending, processing and replenishing the herbs, researching the active principles, upgrading quality control, refining the combinations of medicines to eliminate any risk of toxicity or adverse side-effects, etc. Also, governments could reinvest their savings on drug-bills into improved systems of health care for all.
TCM and HM have been used empirically over thousands of years in billions of human and animal patients, and their use is increasing. Those facts, are strong evidence of their overall safety and efficacy. As discussed above, recent research, both clinical and basic, has confirmed these claims.
In contrast to WMs, properly used CHMs can be given for long periods with minimal or no adverse effects (Hsu 1982; Hosoya & Yamamura 1988; Dharmananda 1991; Chan et al 1993; Schwartz 1994; Yamada 1994a). Thus, OM/TCM/HM shows great promise, especially for sustainable use of medicinal resources (Lin et al 1995a).
The problems of TCM are due mainly to lack of easily accessible information and lack of funding. Their solution needs greatly increased inputs from researchers, clinicians, relevant industries and governments. These problems must be resolved if the advantages of both medical systems (TCM and WM) are to be put to better use internationally. Resolution of the problems would lead to the dawn of a new age of medicine and animal welfare. The integration of the best aspects of WM and TCM, would be safer, less expensive and more sustainable than is the case today.
Acknowledgements
We thank the National Science Council, Republic of China for financial support to Professor JH Lin (32056F), without which this article could not have been finished. We thank all the cited authors, especially Drs. A Ackerson, D Bensky, RR Chaudhury, S Dharmananda, PK Tsung, whose material was reproduced in summary form. Finally, we thank Ms. A Yamasaki for excellent clerical assistance.
Part 4
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Appendix 1
Journals that publish research on the chemistry and pharmacology of HMs and phytotherapy include:
- Agric. Biol. Chem.
- Am. J. Chin. Medicine
- Am. J. Dis. Child.
- Am. J. Trop. Med. Hyg.
- Ann. Trop. Med. Parasit.
- Antimicrobial Agents and Chemotherapy
- Antiviral Res.
- Archives Internationales de Pharmacodynamie et de Therapie
- Asia Pacific Journal of Pharmacology
- Biochem. Biophys. Res. Commun.
- Biochem. Pharmacol.
- Biol. Pharm. Bull.
- C and EN.
- Canadian J. Microbiol.
- Cancer Biother.
- Carbohydrate Polymers
- Carbohydrate Res.
- Chem. Pharm. Bull.
- China J. Chin. Materia Medica
- Current Opinion in Biotechnology
- Excerpta Medica (Amsterdam)
- Experimental Hematology
- Folia Pharmacol. Jap.
- Ind. J. Med. Res.
- Ind. Pedriatr.
- Int. J. Immunopharmacol.
- Int. J. Immunotherapy
- J. Alternative and Complementary Med.
- J. Chin. Med (Taiwan)
- J. Ethnopharmacol.
- J. Inf. Dis.
- J. Natural Products
- J. Natural Toxins
- J. Ortho. Med.
- J. Pharm. Pharmacol.
- J. Pharma. Soc. Jap.
- J. Pharmacobio-Dynamics
- J. Trad. Med.
- Jap. J. of Inflammation
- Jap. J. of Oriental Medicine
- Lancet
- Life Sci.
- Med. Hyp.
- Natural Med.
- Nature
- Pharmacol. Res.
- Phytochemistry
- Phytomedicine
- Phytother. Res.
- Plant Mol. Biology.
- Planta Med.
- Pure Appl. Chem.
- Rev. sci. tech. Off. int. Epiz.
- Science
- Tokai J. Exp. Clin. Med.
- Vet. Bull.
- Vet. Rec.
- Vet Res
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