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Leuzea or Rhaponticum carthamoides (Willd.) Iljin - Maral root, is a rare and threatened plant of unique properties. It contains phytoecdysteroids-biostimulants and takes a prominent position among other adaptogens by its ability to prevent many diseases, efficiently cure a great number of pathologies
The preparations of Leuzea do not have any age or seasonal restrictions. Their safety and the absence of side effects have stood a five-thousand-year test of usage in East medicine. Moreover, they are excellently combinable with classical drugs. Food additives of Leuzea are used as antidepressants and immunostimulants, concentrators of psychical energy, physical and sexual strength, anti-shock, -pain and wound-healing remedies.
The preparations cause an anabolic effect in vertebrates by stimulating the protein biosynthesis in muscle tissues. They are used as high technology products in numerous medicine, biotechnology, and agriculture fields. Till recent time, their inaccessibility for most people lied in absence of a cultivated source of raw materials.
At present, there are technologies contributing to a natural ecdysteroid biosynthesis in an artificial cenosis; problIs with loosing highly-active fractions during crop collection and treatment are solved. New highly-active pharmpreparations have been developed (daily doses 0.5-10.0 µg/kg biomass or 10-12...10-11 M, if 20-hydroxyecdysone).
Keywords: Leuzea, Rhaponticum carthamoides, medicinal plants, agropopulations, ecdysteroids, 20-hydroxyecdysone
Modern medicine seIs to be omnipotent. Information about tens of thousand diseases and hundreds of thousand symptoms, use of last achievements of chIistry and physics making the processes in organism even more differentiated and difficult to understand. Development of new drugs has no end. New preparations seI to have no limit of perfection. We buy the remedies offered without knowing what their real efficiency rate is, but believing that these preparations are even more better than those from yesterday.
However, the history of humans counts many millions of years, and their biology does not change every day. It means that the matter lies not in developing new medicines but in imperfection of the old ones. Let us analyze whether there are many remedies appeared two-three or ten years ago and still retaining their efficiency. They are few in number, all of them belong to elementary substances.
Are there unique matters from pharmacopeia which have been used by people for centuries and even thousands of years? Anybody says that even if they exist, then are very few in number. One of them is represented by Leuzea, an unfading "legend of East medicine", which the scientists propose to be "the future of green medicine of XXI century" (Slama, 1993).
The botanical history of the Rhaponticum plants goes back to the ancient times of East medicine where they were used over five thousand years ago under the name Lou Lu and Lou cao (Guo and Lou, 1992). From the three existing species, Rhaponticum carthamoides (Willd.) Iljin, a rare, fragile and threatened species, became most popular (Sobolevskaya, 1991; Siberian flora, 1997). It is a perennial (up to 75-150 living years) herbaceous, semi-rosulate plant growing in the subalpine meadows (Postnikov, 1995).
Pharmacological use of Leuzea never stopped beginning with the ancient Chinese, Tibet and Mongolian medicine till our days. In different times and at different places it was known as Sinops, Cnicus, Stemmacantha, Maral root, Swiss Centaury, Leuzea, Rhapontic, Rapontik, Rhaponticum carthamoides etc. In the Siberian and Mongolian folk medicine it composes herbal remedies curing lung and kidney diseases, jaundice, fever, and quinsy (Red Book of Mongolia, 1987). Leuzea preparations are recorded in the Drug State register (Lekarstvennye rastenia i syryo, 1995).
Leuzea extracts serve as tonic and stimulating drugs for functional nervous disorders, mental and manual fatigue, impaired organ functions, cardiovascular diseases and endocrine pathologies (Mashkovsky, 1993; Rabinovich, 2000).
The widest popularity was gained by Leuzea in the last decades as an adaptogen its stimulating effect in regard to the central nervous system and general organism functions is a well known fact. Without producing any full-blown effect, adaptogens are most efficient for border-line disturbances, as supportive therapeutic agents, by overexertion, general weakness, and after diseases in case of different pathologies they recover and optimize impaired organism functions while removing metabolic and energy metabolic imbalance. They increase the efficiency rate of internal homeostasis regulators and prevent possible abnormalities in organism. Besides, adaptogens are known to increase the endurance power under physical and psychical stress conditions, protect the organism, also the brain, from negative influence on the cell level (Brekhman, 1980; Hobbs, 1996).
The Leuzea preparations are weakly toxic and on meeting certain conditions leave no negative aftereffect even by elderly people. By the action efficiency rate and possibility of usage for a great number of pathologies, they have an advantage compared to both plant (Panax-ginseng, Eleutherococcus, Schizandra, licorice, Rhodiola, Echinacea, Suma etc.) and artificially synthesized remedies (Yakovlev et al., 1990; Novikov et al., 1992; Miller, 1998). Their application has neither age nor seasonal restrictions, repeated overdosing does not lead to any negative aftereffects.
Therapeutic action of the "East medicine living legend", its safety and absence of side effects proven by long application has provoked its deep scientific study. In the last 20s, work on its cultivating was initiated, whereas in the 40-50s its pharmacological and clinical investigation began (Kushke and Aleshkina, 1955; Polozhy and Nekratova, 1986).
Leuzea became especially popular with the western countries in the 90s which initiated its broad use as a food additive. The consumer market offers numerous commercial products varying by their application purpose produced by the firms Gero Vita, Natural Elixir, LifeScience Technologies, Cytodyne Technologies, Mirra etc. via extraction from Leuzea rhizomes and revealing small differences in the formulas of biopreparations.
1.1. Active agents - ecdysteroid
During the last years, Leuzea is being intensively studied for the properties of chemical substances composing it. It was established that its unique biological activity is determined by the complex of substances including mono-and poly-saccharides, inulin, organic acids, steroids, phytoecdysones, saponins, rhaponticosides, vitamins, poly-acetylenic compounds, caoutchouc, phenol-carboxylic acids and their derivatives, lignin, catechins, tanning agents, kinons, essential oil, alkaloids, coumarins, flavonoids, anthocyans, fatty oil, waxes, lipids (Rastitelnye resursy, 1993; Golovko et al., 1996), as well as gums, lemon salt crystals, phosphates, macro- and microelIents
From this row, phytoecdysteroids are all-important substances (Baltayev and Abubakirov, 1987; Baltayev, 2000) with the main mass fraction represented by 20-hydroxyecdysone (20E, ecdysterone, beta-ecdysone, crustecdysone; Appendix 1). 20-hydroxyecdysone is present in every plant organ (Akhrem and Kovganko, 1989; Volodin et al., 1993) and causes various physiological effects in organisms of human and haIatherms. Following the special experiments conducted comparing between nonpurified overground shoots of Leuzea and chemically pure ecdysteroid extracts from the same shoots (Slama et al., 1996), the latter were responsible for the physiological reaction.
Apart from main ecdysteroids, plants contain a wide range, "cocktail", of minor ecdysteroids (integristerone, polypodine, rapisterone, inokosterone with their derivatives, etc.). A broad spectrum of ecdysteroid forms is accompanied by their conjugations with other secondary metabolic products: inorganic (sulphates, phosphates) and organic acids (acetates, benzoates, cinnamates), sugars etc. There are also derivations from standard structures in form of spatial isomers, additional double bonds, oxy-groups, and hydroxylic groups present in different positions of steroid nucleus and in side chains (Lafon, 1998; Golbraikh A. et al., 2001).
Theoretically possible are any combinations of these derivations in form of thousands of different molecules, responsible for the unique biological activity of the nonpurified extracts. Consequently, the activity rate of the extracts is significantly higher compared to that of the highly purified drugs.
The nonpurified Leuzea extracts were proven to occupy a prior position towards the tablets produced from 20-hydroxyecdysone by many works and firms of Russia, Uzbekistan, and the USA (Volodin et al., 1996; Timofeev and Ivanovsky, 1996a). Even pharmindustry waste products can be repeatedly used as raw material for new preparations (Kolkhir et al., 1996).
Recent scientific findings in the field of bioorganic chIistry deal with "restoration of the initial ecdysteroid state". For example, artificial induction of acetyl groups into a molecule of 20-hydroxyecdysone essentially increases the anti-microbial and wound-curing activity rates of the acetates (Volodin et al., 1999). The methods on synthesizing 20-hydroxyecdysone acyl-derivatives varying from each other by number, position, and nature of substitutes with further incorporation into liposoms have been developed (Pshunetleva, 2000). In one of their patents (cosmetic preparation for hair growth), the Japanese scientists suggest using selective combination of 117 different phytoecdysteroids and their derivatives as increasing the biological activity rate (Tsuji et al., 1999).
Forty five years have already gone since first ecdysteroids were discovered in animals, and thirty five years since they were first detected in plants. Their role in nature, nevertheless, still rIains unintelligible being one of the most interesting scientific puzzles. Ecdysteroids are studied by tens of research laboratories world-wide; international experience interchange symposiums and conferences are organized, but they also leave many questions open.
Ecdysteroids support the life activity of almost all classes of organisms being responsible for a variety of functions. In most cases, they are transferred from ecdysteroid-synthesizing plants to the lower food chain links. Certain is only that 20-hydroxyecdysone is a true moulting hormone for arthropoda (insects and cancroids).
Some sea inhabitants secrete thI for defense and attack. As for mammals, people, and plants, they play some universal hormone-like role, but are not hormones. Ecdysteroids rather control over the hormone balance while taking a higher position in the biologically active substances hierarchy.
Their most important function consists in supporting the growth and development processes in organism. Besides, they play a great role in interspecific interactions. In other words, they are efficient coordinating the life activity functions of one single specimen and a variety of different ecosystI components.
Being introduced into the organism, ecdysteroids are transported within the blood flux to internal organs causing rapid and prolonged effects, lasting for a few minutes or 2-3 days, correspondingly. On subcutaneous injection, elimination starts in 4-10 minutes, in 2 hours the radioactive marker in blood is no more discernable. On oral introduction, absorption proceeds in a slower rate.
Elimination presents a through way via liver, intestines, and faeces (urine in part). In a day after introduction, 20-hydroxyecdysone is completely eliminated from the organism (Lafont et al., 1988). It is not destructed by the acid-base content of digestive tract and does not affect its inhabitants, e.g. microorganisms association (Selepcova, 1993). A one-time course of treatment for 7-10 days accounts for a period of afteraction up to 2 months (Yakovlev at al., 1990).
Quite large are therapeutic indications for Leuzea as decoctions, tinctures, extracts, and biopreparations. Ecdysteroid-containing preparations regulate mineral, carbohydrate, and protein metabolism, reveal anti-oxidant and -radical properties (Osinskaya et al., 1992; Kuzmenko et al., 1999).
They normalize the blood level of glucose being helpful in case of diabetes mellitus (Molokovsky et al., 1989; Takahashi and Nishimoto, 1992); lower the cholesterol level (Uchiyama and Yoshida, 1974;Mironova et al., 1982); remove liver inflammation by toxic hepatitis (Syrov et al., 1986). Ecdysteroids contain substances, which act as vitamin D3 having an anti-rachitic effect (Akhmed I., 1993).
Extracts from Leuzea improve mIory and mIorization (Mosharrof, 1987), rIove alcoholic intoxication and depression states (Ipatov, 1995). They are useful for atherosclerosis and epilepsy (Ryosuke Hanaya et al., 1997). Moreover, they hamper tumour development (Bespalov et al., 1992; Bocharova, 1999) and because of their anti-inflammatory properties are more efficient than many synthetic preparations (Kormukov and Syrov, 1988).
Leuzea preparations are effective by poisonings with chlororganic compounds and heavy metals (Chabanny et al., 1994). They have been proven as healing the circulatory system diseases (Vershinina, 1967), strengthening the processes of haemopoiesis, improving the coronary blood flow by means of decreased blood viscosity, and relaxed blood vessels and internal organs nonstriated muscles; under critical state they also recover a normal pulse, are helpful by arrhythmia, ischemia heart disease, angina pectoris attacks, prevent myocardial infarction (Syrov et al., 1997; Opletal et al., 1997).
Applied for 5-10 days, Leuzea leads to development of nonspecific organism resistance to unfavorable factors of physical, chemical and biological nature, which, in turn, is much hopeful for rehabilitation and change processes in human immune system (Lamer-Zarawska, 1996), humoral immunity development (Azizov et al., 1997).
In regard to healthy people, Leuzea preparations increase the threshold of organism defense against stress conditions, supercooling, superheating, gas pollution, extensive moisture, atmospheric pressure changes, ionizing radiation exposure, pathogenic microflora aggression etc. The activity rate of the blood protective system elements, lymphocytes and neutrophils, rises (Trenin S., Volodin V., 1999); the phagocytosis functions increase (Sakhibov et al., 1989; Kuzmitsky et al., 1990).
Ecdysteroids produce an anabolic effect in vertebrates stimulating the protein biosynthesis in liver, kidneys, and muscles (Otaka et al., 1969; Syrov and Kurmukov, 1976; Ayzikov et al., 1978). This feature is broadly used in professional sport in order to achieve high results (Chermnykh et al., 1988; Gaydzhieva et al., 1995).
In contrast to synthetic steroids, ecdysteroids (e.g., 20-hydroxyecdysone) cause a high predisposition to protein synthesis in organism without producing any life-dangerous aftereffects. Therefore, they appear to be a deserved substitute for such a popular but forbidden toxic preparation as dianabol, methandrostenolon, anabol, reforfit, nerobol, pronabol, etc.) used in speed and power sport arts (Syrov et al., 1997; Portugalov, 1997).
1.3. Application of Leuzea preparations
Peoples health of today is threatened with loss of natural organism resistance to complex unfavorable and even harmful environmental factors. Immunity loss is ascribed considerably to stress situations and nerve overload in social life. Pathologic states can also appear due to extreme production technologies, high tension level of the environment, namely chemical contamination, natural insolation deficiency, abrupt photoperiodic changes, influence of the Earths magnetic index, electromagnetic cosmic radiation.
All these factors abate the protective organism functions, result in explicit- and implicit-defined diseases, often in untimely ageing and death. Classical direct and all-strong medicaments are often helpless.
Strict therapeutic measures produce other side effects and complications; they make one drug-dependent and let the pathologic process develop further in a new, even more severe form. At the same time, the unspecific resistance rate is to be successfully increased via natural immunostimulating drugs. A special position from them occupy plants producing phytoecdysteroids as secondary metabolites.
Official medicine has recognized only few preparations from Leuzea; all of them are made from rhizomes: the ethyl extract (70 %), tablets from fined roots only or in a mixture with microcrystalline cellulose. A chemically pure substance (20-hydroxyecdysone) isolated from the Leuzea rhizomes as a white creamish crystalline powder was patented under the name "esdyctene" (Abubakirov et al., 1980).
Further it was used to produce a drug formulation and composed a wide range of biologically active additives, different by form and structure. Clinical trials in acute experiments have shown that even the largest 20-hydroxyecdysone doses do not kill the animals. The LD50 barrier, which means fist negative reactions, varies between 6 to 9 g/kg body weight (Matsuda et al., 1970; Ogawa et al., 1974). The last circumstance presenting evidence for the safety of 20-hydroxyecdysone has opened new ways for its application as food additive.
The consumer market of ecdysteroid-containing compounds involves the market segments concerning:
Ecdysteroid-containing preparations can compose many clones. Extracts from other adaptogenic, vitamin-containing and aromatic plants, micro- and macroelements, chocolate, vanilla, lipids, honey, flowers pollen, neutral fillers serve as further components.
By production form, they can be tablets, capsules, liquid (in bottles) and dry phytotea, extracts, drinks, creams, balms, lotions and shampoos, alcohol-free tonics and vodka drinks. By induction form to people, they can be induced orally, intramuscularly, intravenously, as well as via massage, inhalation, aromalamp. As for domestic animals, they are included into mixed fodders, different healing fodder additives or used as veterinary preparations.
For most of people, the Leuzea preparations are necessary to support whole vitality of the organism, remove disturbances associated with metabolic imbalance and menstrual irregularities, for rehabilitation during the postoperative period, to assure recovering after a severe disease. Being introduced as food additives, they remove irritability states, neuroses, psychastenic conditions, hyperexcitibility and flaccidity, fears, consternations, and phobias. An important property is that the Leuzea can still any pain in the organism, no matter where it is located. The Leuzea preparations can be efficiently used at home in case of alcoholic inebriations, food poisoning, as well as to stabilize arterial pressure and the sugar blood level, quicken the wound and fracture healing.
Brain workers who have to memorize a large body of information, concentrate attention, do everything with accuracy, overcome logic problems, need these remedies too. Introduction of the Leuzea provides us with an ability to foresee the course of events and events themselves, which is explainable by the intensive brain action without side irritants.
The Leuzea is recommended for application to the emergency services when the work is to be done in tense psychoemotional surroundings with strong irritants, always time deficiency, and lack (abundance) of information.
The biologically active food additives of Leuzea were designed with the purposes of gaining physical power and endurance in professional sport, building up muscle fibers in body-building. Their mode of action here is connected with an active behavior of 20-hydroxyecdysone, affecting the metabolic processes of protein synthesis and energy consumption in cells and being responsible for removing the muscular tiredness during extensive exercise (Gadzhieva et al., 1995). These processes also cause burning up excessive fat deposits.
Along with sport medicine, adaptogens take an important part in sea, cosmic, and military medicine as helping healthy people to overcome physical and mental overstrain (Seyfulla, 1994). Since allowing for repeated concentration of psychical energy via refining the organs of sense, and making one sleep-resistant, the preparations of Leuzea can serve as a base component in the "elixir of fearlessness". The Leuzea presents an irreplaceable remedy for tiredness, speaking about mushroom gatherers, berry-pickers, tourists et al.
Its positive effects on the psychoemotional state, cardiovascular system, and dynamic working capacity of organism make the preparations improving the sexual function and increasing libido. The Leuzea is one of best preparations to recover and sustain the sexual activity, to get ride of frigidity and potency disorder. By women, improvement of reproduction functions (capacity to conceive and give birth to new generations) is observed.
Based on the properties of ecdysteroids to strengthen the blood circulation in capillaries, improve its physical and chemical composition, speed up cell regeneration in epidermis and cornea (Meybeck et al., 1997; Kovler et al., 1998), the Leuzea can be used in cosmetic production, namely compose preparations for hair growth (recovery), products curing wounds, sores, and burns, removing wrinkles, rejuvenating and protecting the skin from ultraviolet sun radiation. Ecdysteroids application in cell cultures while transplantation of mans organs and skin is patented (Tsuji et al., 1999).
Last years, reasoning from the identical properties of 20-hydroxyecdysone to the key insect moulting hormone, intensive scientific investigations aiming at new anti-pest formulations for harmful arthropoda and hook-worms are carried out.
The Leuzea is an ideal remedy for animal farming intensification that has been tested in practice (Moiseev et al., 1963; Kudzinay et al., 1980; Timofeev, 1999a). It is used in breeding of animals for furs, cattle and small cattle breeding, poultry farming, equestrian sport. Also, the preparation forms part of food additives as a biostimulant increasing milk yields and average daily weight increments (by 35-40 %), eliminating mortality of any newborn animals or birds (by 2.1 times). Induction of the Leuzea removes listlessness and reduces the service-period of cattle (Kochanov et al., 1994), increases the strength of bee family.
Furthermore, the formulations of Leuzea can be used as plant growth and development regulators. Judging from their chemical structure, ecdysteroids are the closest analogues of brassinosteroids, a new class of phytohormones. The nonpurified extracts containing modified ecdysteroid forms are essentially more active than the chemically pure 20-hydroxyecdysone.
In fact, they combine positive features of several classes of phytohormones: increase plant germinating power, contribute to development of strong photosynthetic apparatus, make plants resistant to frost and pathogens. The Leuzea biopreparations significantly increase the plant productivity rate per unit area and commodity output (Timofeev, 1999b).
2.1. Sources of raw materials for ecdysteroid-containing preparations
The commercial preparations based on the chemically pure 20-hydroxyecdysone (ecdystene, retibol, leveton, Russ-Olympic, Prime 1, Prime Plus, Triboxin, Cytodin ZM, FirmEase etc.) are very easy-to-use compared to the rhizomes though extremely expensive and inaccessible to the broad masses. The minimum daily dose costs $ 1.2-1.5 and the maximum dose is even more expensive.
The recent deficiency in crude drug of Leuzea contributed to 20-hydroxyecdysone isolated from other ecdysteroid-containing plants. Used are such species as Pfaffia paniculata, Polypodium vulgare, Polypodium decumanum, Serratula coronata; representatives of the genera Silene, Lychnis, Ajuga, Paris, Helleborus etc. are tested for as well.
In most cases they are low-height grasses growing in scattered groups in shadow taiga forests and hollows, along shadow Russian peat-bogs or in swamps of the Amazon jungle. The dug out rhizomes or the pulled out overground parts of them are used as crude drug. Some grasses are quite poisonous, others are not recommended for use as drug plants.
By the productivity value, cultivation and processing technological effectiveness, ecdysteroid content in mass organs, these plants cannot compete with Leuzea. That what is extremely important for science to discover the biosynthesis pathways of ecdysteroids, in the nearest future has no prospects for the industrial production of pharmpreparations. Even if some culture is recommended for cultivation, there are no reasons to consider the preparations from the substitute plants having the same biological activity power as those prepared from Leuzea.
As it was mentioned above, the physiological effect of crude drug is a combination of thous nds of other modified components, in addition to the chemically pure 20-hydroxyecdysone. Complains of the unstable biological activity of ecdysteroid-containing plants on the Internet-pages may be associated with the alternative sources.
Besides, ecdysteroids cannot be chemically synthesized; though being real theoretically, the process is highly expensive in practice. The biochemical technologies on ecdysteroid isolation from natural materials are quite well developed. The international market sells 20-hydroxyecdysone with the chemical purity value over 95 % for 3.5-6.0 money units against 1 mg (the firms Aldrich-Sigma, Latoxan, Northern Biochemical Company).
Therefore, based upon a wide range of practically valuable reasons, Leuzea is commonly considered to take a central position among ecdysteroid-containing plants with no substitutes able to substitute it fully (Syrov, 1994; Stransky et al., 1998). Todays great demand for Leuzea at the world market has arisen a question of the cultured source of raw materials for pharmacological industry.
2.2. Overground phytomass instead of rhizomes
When tracing the history of Leuzea, it is worth mentioning that it has been researched by scientific organizations already since a year of 1929 as a source of unique pharmpreparations (Polozhy and Nekratova, 1986). Its high potential was recognized, but, unfortunately, it was not put into production (Rege et al., 1999). The reasons are as follows:
From the short problem analysis above, it is possible to conclude that new pharmpreparations from Leuzea need to be developed in order to solve the existing problems, reasoning from the following approach:
Thus, it has been revealed as having no prospects to use the rhizomes in mass production of plant crude drug. Scientific research should aim at working out new classes of pharmacological drugs from the overground phytomass, optimization the doses applied by now, and lowering the end price
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Agropopulations Leuzea - Rhaponticum carthamoides (Willd.) Iljin |
2.3. Technological problems of crude drug production
Though they are no less biologically active than the rhizomes, there are no officially recognized pharmpreparations from the overground parts of Leuzea except of the green tea preparation "Maralan" (Herba Leuzea) being produced in Czechia (Kren et al., 1992). Influence of overground phytomass of Leuzea on animals has been already surveyed in the former USSR and abroad. They were experimentally proven as non-toxic if introduced in the doses up to 0.3-0.5 kg dry substance per 1 kg body weight (Koudela et al., 1995; Selepcova et al., 1995).
The rats can live on the ration, 50 % of which consists of Leuzea grassy flour. In long-term experiments, when cut small green pieces of plants were added to the rations, there were no negative reproduction effects observed.
Ecdysteroids compose all organs of Leuzea, and their concentrations can serve as one of most important quality characteristics of crude drug. Ecdysteroid accumulation in different phytomass elements depends on combination of many factors, quite often human-independent. The absolute concentrations of 20-hydroxyecdysone in crude drug are spread in values from 0.022 to 0.87 %.
Quite often it contains only the less active ecdysteroid fraction firmly bound to cell molecules, and no highly active mobile part. Reasoning from concentrations of active substances, the empirical doses are, then, comparable with the classical dose of "firm" 20-hydroxyecdysone (5-20 µg/kg) and, consequently, if rhizomes, are not applicable to large-scaled production.
The crude drug producer has to: a) form those conditions in cenosis favoring the natural biosynthesis and accumulation of physiologically active ecdysteroid fractions in the particular plant organs; b) retain the initial content of target substances in crude drug during all processes of its collection and conservation; c) provide the end production with technological longevity, i.e. minimize reacting substances losses during conservation (Timofeev, 2001).
Under optimal cultivation conditions, the ecdysteroid concentrations reach their stable level beginning with the fourth-fifth living years. Content of ecdysteroids is influenced by weather and climatic conditions: air temperature, spectral composition of light, atmospheric and soil moisture, stress factors. An important position among them takes the reutilization factor that can increase the content of target substances in phytomass by 25-60 %.
The biosynthesis is followed by ecdysteroid redistribution within vegetative and generative organs, and transition to the roots with escape into the soil afterwards. Agricultural engineering methods (terms, repetition factor and norms of biomass collection, kinds of fertilizers, inter-row treatment) considerably influence concentration and the distribution gradient of ecdysteroids to different spheres.
The ecdysteroid-containing crude drug reveals a strong trophic dependence of retained effective substances on plant age, climatic conditions of cultivation, way of collection, elementary composition of crude drug. The commonly accepted methods of processing do not assure the reacting substances of safety. The kinetics of drying the plant material being of high water-holding ability is in direct proportion to its physical structure, whereas the latter has a negative correlation to ecdysteroid retaining.
In general, the drug-processing technology, equipment and modes applied cause multiple variation in ecdysteroid content. The production shelf life depends, in addition to growing conditions, processing and mode of conservation, on the packing, gaseous mixture composition, its physical structure (20-hydroxyecdysone can vary within the limits of 0.004 to 0.460 %).
3.1. New generation of pharmacological preparations
In the past years the scientific bases for agropopulations of Leuzea as an industrially cultured drug plant have been developed. Estimated are its life cycle peculiarities, resistance factors in cenosis, biomass structure and ecdysteroid accumulation dynamics in single organs and in ontogenesis; optimal terms and methods of collection, modes of plant material processing; economic factors in production are determined (Timofeev et al., 1996-2001). All these moments offer rich possibilities for new and cheap pharmacological preparations with high anabolic and immunostimulating activity, isolated from overground Leuzea biomass (Appendix 2). For example, first two preparations of new generation are already developed - "BIOINFUSIN" and "BCL-PHYTO" (BCL-BactoCelloLactin).
"BIOINFUSIN" is meant for intramuscular and intravenous introduction. It is used to increase the whole organism resistibility during pathologic states of different etiology, strengthen the sexual potency, cure respiratory diseases. The action mechanism specificity of new preparation lies in a stimulating activity of small doses and inhibiting effects on proliferative organism processes in large doses. The preparation causes a strong biostimulating effect on the organism (Ivanovsky, 2000). This is accounted for by such blood serum indices responsible for natural resistance of organism as whole protein and its lysozymic, bactericidal, neurophyll and antibody-forming fractions, phagocytic cell activity.
On the seventh day of treatment all indices go up by about 15-30 % and more, compared to the control group. The biological activity rate detectable with values for antibody-forming spleen cells and gamma globulins in blood cerum exceeds the control figures by 1.5-2 times. One-time introduction has anabolic effect of 10-12 %.
Intravenous introduction has once a day repetition factor, the course duration includes 5-7 days. The doses comprise 0.02-0.05 ml/kg. Intramuscular introduction needs 2 times higher daily doses. The daily doses for 20-hydroxyecdysone account for 0.1-0.5 µg/kg (10-12...2·10-13 M). Testing the preparation for acute toxicity rate, the LD50 (lethal dose quantity) was equal to 9.5 g/kg proving its absolute safety. The "BIOINFUSIN" is produced in the hermetically capped glass bottles for 10 20, 50, 100 and 200 ml and contains 0.0005 % of 20-hydroxyecdysone.
"BCL-PHYTO" is meant for therapeutic and preventive treatment in veterinary medicine, it is used for gastrointestinal tract diseases of calves, pigs, and birds. Providing additional clinical trials, it can be applied in respect to man. The preparation presents a mixture of strong probiotic preparation "BCL-PHYTO" (three different synergist microorganisms) with Rhaponticum carthamoides. It is packed into glass bottles or cellophane packages for 50 to 500 ml and contains 0.005 % of 20-hydroxyecdysone. The "BCL-PHYTO" has a high antagonistic activity rate against colon bacilli, streptococci, Proteus, staphylococci, and dysentery causative agents.
It possesses a high cellulolytic activity rate, which makes impossible the pathogenic and conditional pathogenic microflora development. In addition to antibacterial properties, the preparation produces anabolic and immunostimulating effects, as well. The "BCL-PHYTO" does not have a negative influence on the end production quality or cause complications by animals. It serves as a powerful substitute of many antimicrobial drugs: antibiotics, sulfanilamides, nitrofuranes, and represents an ecologically safe product. There are no contraindications established by now.
For prevention the preparation is induced 1-2 times a day (added to fodder or drink) on the basis of 0.1 g/kg biomass, age-invariably. The daily dose, if 20-hydroxyecdysone, is equal to 5-10 µg/kg (1...2·10-11M). The course duration comprises from 3-5 to 30 days. After a long-term introduction period a pause in a month is required. If diarrhea, the effective doses are increased to 1 g/kg and used on dissolution in hot water once a day for 3-5 days.
Organizations and juridical persons interested are offered:
ACKNOLEGMENTS
The author thanks Elena S. Kuzmina (Institute of Biology Komi SC UrD RAS, Syktyvkar, Russia) for translation of the manuscript.
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20-Hydroxyecdysone
Table 1
Biochemical blood indices by introduction of the pharmpreparation "Bioinfusin"
for respiratory diseases, % (course 5 days, autumn)
Table 2
Anabolic activity rate of the preparation "Bioinfusin"
by one-time intramuscular introduction, % (trials on white mice)
Table 3
Anabolic effect of
Leuzea carthamoides in production conditions (1635 pigs)
Table 4
Anabolic effect of
Leuzea carthamoides in industrial poultry farming
(rooms with 45-61 thousand chickens)
Table 5
Direct immunoresistant action of Leuzea carthamoides
on chickens (murrain level in farm rooms)
Table 6
Immunostimulating aftereffect of
Leuzea carthamoides in production conditions
(death rate of young pigs, %)
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