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Medicinal Plants of the Russian Pharmacopoeia, history and applications Alexander N. Shikov, Olga N. Pozharitskaya, Valery G. Makarov, Hildebert Wagner, Rob Verpoorte, Michael Heinrich

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S0378-8741(14)00282-7 http://dx.doi.org/10.1016/j.jep.2014.04.007 JEP8734

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Journal of Ethnopharmacology

Received date: 22 January 2014 Revised date: 31 March 2014 Accepted date: 4 April 2014 Cite this article as: Alexander N. Shikov, Olga N. Pozharitskaya, Valery G. Makarov, Hildebert Wagner, Rob Verpoorte, Michael Heinrich, Medicinal Plants of the Russian Pharmacopoeia, history and applications, Journal of Ethnopharmacology, http://dx.doi.org/10.1016/j.jep.2014.04.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Review Medicinal Plants of the Russian Pharmacopoeia, history and applications Alexander N. Shikova*, Olga N. Pozharitskayaa, Valery G. Makarova, Hildebert Wagnerb, Rob Verpoortec, Michael Heinrichd a

St-Petersburg Institute of Pharmacy, Bolshaja Porokhovskaja, 56, PoBox 16, 195248, St-

Petersburg, Russia b

Institute of Pharmacy, Pharmaceutical Biology, Ludwig Maximilian University, D - 81377

Munich, Germany c

Natural Products Laboratory, IBL, Leiden University, Sylvius Laboratory, PO Box 9505, 2300

RA Leiden, Sylviusweg 72 d

Research Cluster Biodiversity and Medicines. Centre for Pharmacognosy and Phytotherapy,

UCL School of Pharmacy, University of London. [email protected]

Correspondence: Dr. Alexander Shikov Saint-Petersburg Institute of Pharmacy, 47/5 Piskarevskiy pr. St.-Petersburg, 195067 Russia Fax +7-812-3225605 E-mail: [email protected]

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Abstract Ethnopharmacological relevance: Due to its location between West and East, Russian phytotherapy has accumulated and adopted approaches originating in European and Asian traditional medicine. Phytotherapy is an official and separate branch of medicine in Russia and thus herbal medicinal preparations are official medicaments. The aim of the present review is to summarize and critically appraise the data concerning plants used in Russian medicine. This review describes the history of herbal medicine in Russia, current situation and pharmacological effects of those specific plants of Russian Pharmacopoeia which are not included in European Pharmacopoeia. Materials and methods: Based on the State Pharmacopoeia of the USSR, 11th edition we selected plant species which have not been adopted yet in Western and Central Europe (e.g. via the inclusion in the European Pharmacopoeia) and systematically searched the scientific literature for data through library catalogs, the online service E-library.ru and in addition Medline/Pubmed, Scopus and Web of Science databases on the species, effectiveness, pharmacological effects and safety. Results: The Russian Federation follows the State Pharmacopoeia of the USSR, 11th edition which contains 83 individual monographs for plants. Fifty one plants are also found in the European Pharmacopoeia and have been well studied, while 32 plants are only found in the Pharmacopoeia of USSR. Many articles about these medicinal plants were newer translated in English and a lot of information collected by Russian scientists was not available for international community. Such knowledge can be applied in future studies aiming at a safe, evidence-based use of traditional Russian medicinal plants in European and global phytopharmacotherapy as well as for the discovery of novel leads for drug development. Conclusion: The review highlights the therapeutic potential of these Russian phytopharmaceuticals, but it also highlights cases where concern is raised about the products safety and tolerability and that would support their safe use.

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Keywords: Aralia elata, Bergenia crassifolia, Bidens tripartita, Centaurea cyanus, Gnaphalium uliginosum, Inonotus obliquus, Polemonium caeruleum, Rubia tinctorum, Tussilago farfara

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1. Introduction There are estimates that there are about 350,000 higher plants on earth (Heywood 2011). Relatively speaking, only a very few of the medicinal plants have been studied scientifically. Russia’s large size, different soils, varied topography and climates favored the growth of an extensive number of herbs, trees, and other plants. This led to active interest in locally grown plants, which stimulated serious study by traditional healers and early official physicians alike. Basically herbal and natural remedies are the product of hundreds of years of careful observation of their therapeutic effects and risks and that their properties and side effects are quite well known. In one approach, scientists have isolated one or more of the medicinal principles from a single herb in the laboratory (and possible enhanced them chemically) to create new medication that were often more powerful than the original plant. This approach eventually led to the development of a number of new herb-based medicines as well as to the creation of synthetic pharmaceuticals that duplicated the active medicinal element in original plant. Aspirin, codeine, digoxin and other drugs have their origins in herbal medicines (Yarnell, 2000). However, not all these efforts were successful. Scientists found that the herb itself with its unique combination of chemical components was often more effective than the chemical derivative along (Li, 2002). As a result, medical science also focused on the medicinal value of the herb themselves and how they could best be incorporated into medical practice. While the science of synthetic medicine moves ahead, the value of medicinal plants and and especially the highly developed and unique Russian herbal medical tradition are largely unknown in the West. Although the information about plants, referred in Russian Pharmacopoeia and its application is fragmentary. The aim of the present review is to fill this gap by summarizing the data concerning plants used in Russian officinal medicine. This review describes the history of herbal medicine in Russia, current situation and pharmacological effects of those specific plants of Russian Pharmacopoeia which are not included in European Pharmacopoeia. Such knowledge can be 4

applied in the expansion of the use of plants in the pharmacotherapy of European and other countries as well as for the further discovery of new drugs 2. History of herbal medicine in Russia In many regions of the world and in a very generic way the use of herbal medicines can be classfied into two main strands: popular orally transmitted traditions, passed on from generation to generation, and dogmatic or “official” traditions, which is based more on scientific investigations (Zevin et al., 1997). Until the tenth century in Russia the popular healing traditions existed with limited exchange of ideas between the various regigions, when herbal and medical literature was first introduced. At this time, copies of a number of Greek herbals found their way into Russia derived from monastic traditions and were eventually translated into Russian. Unlike herbal practice in other countries, however, the Russian herbal tradition was strong and well established. The first pharmacy (potion store) (Rus=   ) was opened in Russia in the hospital of KievPechora Lavra in 1005-1010 by the monk Makoveit from Athos – an event which is likely to hav strengthened the Greek influence on Russian medicie. According to the chronicles of the old city of Novgorod, Russian herbalists (called "knowledgists") were able to cure infected wounds with "banya mold" (Solovieva, 2005). In the thirteenth century they discovered the properties of the mold which was used as bandage on the wound. This predates the development of penicillin in England by seven centuries. Thus chronicles give good example of level of Russian popular medicine during this period. Starting in the mid-thirteenth century and for over three hundred years Russia was occupied by Tartars and Mongolians. They brought their own herbal traditions, which were incorporated in healing praxis by local herbalists. While practically no information is available for the next centuries, during the 15th to the -16th century the Russian empire expanded. Russia counted among her neighbors countries in Western Europe and Asia and herbalist started the accumulation and adaptation of herbal traditions of 5

Asian-Arabic herbal system and West European. This led to the development of the unique features and advantages of the Russian herbal system combining autochtonous and introduced knowledge and practice. State-contro over medicine in Russia can be traced back to the end of XVI century. First enterprise that held responsibility for medical affairs was the Apothecary's Chamber opened in Moscow in 1581 by Tsar Ivan the Terrible (Ivan Grozny). In 1620 it was reformed to the Apothecary's Order (Blinova, Yakovlev, 1990). The first head of the Apothecary's Order was oprichnik (a member of an organization established by Tsar Ivan the Terrible to govern the division of Russia known as the Oprichnina), Knjaz Afanasy Vjazemsky. Apothecary James Frencham from Great Britain is generally regarded as the founder of the first Moscow Court Pharmacy - the progenitor of the Russian medico-apothecary system. The exact date of its foundation is uncertain but it is likely to be in the years before 1581 (Appleby 1983). The Moscow Court Pharmacy in Apothecary's Chamber served exclusive needs of the Tsar and his family (Appleby, 1983). The first public pharmacy was opened within a public hospital on March 20, 1672 in Moscow. One of the famous herbalist manuscript "Cool vineyard" (rus=      ) was published in 1672. The main part of manuscript was "About the overseas and Russian potions and about wood and herbs" (Sokolov, 2000). In the XVIII century Tsar Peter the Great drove major reforms to the system. One of those reforms was the Apothecary's Reform that fixed European normative and European type of the pharmaceutical service. Under a decree by Peter the Great, Korpisaari Island in Saint-Petersburg was designated in 1714 for Apothecaries' Chancery and principal Pharmacy. And the local Apothecary's Garden was founded. Establishing of the State Academy of Science (1724) opened new horizons in systematization of knowledge and surveys of the rich resources of Russian flora. New medicinal plants were documented in a four volume work "Flora of Siberia", a result of expedition of I.I. Gmelin in

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Siberia (1732-1743). After exploration of Siberia and Volga river regions academician P.S. Pallas published the classical "Description of herbs of Russian State with pictures". Prof. I.I Lepehin (1740-1802) promoted the utilization of local flora and argued for a reduction of importing medicinal plants (Muraviova, 1991). Russia was among the first countries to compile a pharmacopoeia. In 1778 the Pharmacopoea Rossica was published in St. Petersburg by the Russian Academy of Science. It contains 770 monographs, including 316 of herbal medicinal preparations, 147 chemical substances, 29 medicinal preparations from animal sources and complex mixtures. Each entry is written mostly in Latin but does give the Russian name of the botanical simple or preparation. Entries for medicinal plants include their name, geographical origin, odor, taste, therapeutic qualities, uses, doses, and preparation (Tshibilaev et al., 2006). However, Russia's first National Pharmacopoeia wirten in Russian was published nearly a century later – in 1866. In XIX century European physicians had completely forgotten about the herbal traditions that once predominated in their countries, while Chinese healers had almost no awareness of the medical developments in the West. Russian doctors were unique because they knew of booth their own folk-herbal tradition and modern West medicine. The nineteenth century was marked by the beginning of the study of the chemical composition of medicinal plants. Starting with the isolation of atropince (1833), in the early 19th century it became apparent that the pharmaceutical properties of plants are due to specific compounds which can be isolated and characterized (Heinrich et al 2012). For example, Prof. G.G. Dragendorf (1879) has published series of articles "Relationship between the chemical constituents and botanical features of plants" in Pharmaceutical journal. By the early twentieth century, Russian scientists had generated much scientific data about medicinal plants. However, in 1917 after the October revolution, the Soviet Union became closed off from the rest of the world and this research progress was not shared for long time. Luckily Soviet Union government did not discard Russian medicine and herbalism. Many

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institutes and academies for the study of medicinal plants were established in all regions of Soviet Union. A new era of intensive study of medicinal plants was initiated in the middle of the XX century. On March 4, 1943, Iosif Stalin have signed Order No 4654-p of the People’s Commissars Council of the Union of Soviet Socialist Republics "… to study limonnik (Schisandra chinensis (Turcz.) Baill. (Schisandraceae) with the purpose of finding of tonic substances” for both soldiers and persons working in the USSR defense industry during the Second World War. In 1945 stimulant effects of Schisandra on nervous muscular excitability in human were published (Panossian, Wikman, 2008). In result of intensive work of scientists in all parts of big country the concept of herbal substances as compounds that would increase “the state of non-specific resistance” under conditions of stress and the term “adaptogens” were formalized between 1947 and 1960. The term adaptogen was introduced in 1947 by N.V. Lazarev while working on a synthetic compound, dibazol which was found to stimulate nonspecific resistance of organisms (Lazarev et al., 1959). Later the term ‘adaptogen’ was defined more precisely by famous herbalists I.I. Brekhman and I.V. Dardymov. Adaptogen must: produce a nonspecific response, i.e. increase the power of resistance against multiple (physical, chemical or biological) stressors; have a normalizing effect, irrespective of the nature of the pathology and be non toxic; be innocuous and not influence normal body functions more than required (Brekhman, Dardymov, 1969; Panossian et al., 1999).

3. Current situation In results of recent survey, 14% of Russian population use phytopreparations for regular treatment and 44% time to time (Shikov et al., 2011). Phytotherapy is a separate branch of medicine in Russia and herbal medicinal preparations (HMP) are official medicaments. Herbal medicinal preparation is the finished product and pertains to a medical preparation containing herbal materials and/or herbal preparations as its active ingredients. More than 600 HMP have

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been registered for medication and included in the Governmental Register of Medicinal preparation (Register Russia, 2012). All aspects relating to the development, preclinical and clinical studies, evaluation, state registration, standardisation and quality control, manufacturing, preparation, storing, transporting, importing and exporting, advertising, releasing, selling, using, and disposing of pharmaceutical preparations (including HMP) are regulated by Federal Law No. 61 FZ (dated 12.04.2010) “About circulation of drugs”. 4. Classification of HMP Depending on the processing method used, the herbal pharmaceutical formulations can be classified into the following categories (Severtsev et al., 2003): 1. Medicinal plant materials are dried or sometimes newly gathered parts of medicinal plants (rarely, entire plants) used for the production of medical drugs. Medical species are mixtures of a few kinds of crushed or integral plant materials with salts and ethers as additives. 2. Summarised non-refined or galenic formulations contain, along with biologically active substances, a number of related substances. In the course of production, inactive ingredients are removed from galenic formulations. These include herb infusions and decoctions, tinctures, extracts, and elixirs. • Infusions and decoctions are liquid medicinal preparations representing aqueous extracts from medicinal plant raw materials, as well as aqueous solutions of dried or liquid extractions (concentrates). • Tinctures are medicinal formulations in the form of alcoholic and aqueous/alcoholic extracts from medicinal plant materials (1:5 or 1:10) produced with no heating or removal of extractant. • Extracts are concentrated extractions from medicinal plant materials in the form of liquid (1:1), semi solid (moisture < 25%), or dried (moisture < 5%) mass.

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• Elixirs are liquid medicinal formulations in the form of a transparent mixture of alcoholic/aqueous extractions from medicinal plant materials with medical drugs, sugars and flavors as additives. 3. Novo-galenic formulations are phyto-preparations containing a mixture of biologically active substances that are free from inert and concomitant ingredients. They contain a mixture of alkaloids, coumarins, etc. Novo-galenic preparations also include such substances as flamine (dried extract of Helichrysum arenarium L flowers containing flavonoids), ergotal (mixture of ergot alkaloid phosphates), adonisid (extracted from Coronaria aerial part), etc. 4. Active pharmaceutical ingredients (API) – individual compounds isolated from plants (serotonin, morphine, rutin, lysergin, etc.). These compounds have direct action and a majority of them are used for the preparation of injection formulations. 5. Combined phyto-preparations contain, along with the substances extracted from plants, synthetic, endocrine and other types of ingredients such as "Allokhol" (based on dry extracts from garlic and nettle with coagulated active coal as additive), "Cholagolum"” (contains extract of Curcuma longa, emodin from bark of Frangula alni, magnesium salicylate ether oils, oliven oil and ethanol), "Valocormyde" (based on the tincture of valerian, lily of the valley and belladonna with sodium bromide and menthol as additives), etc.

5. Information in pharmacopoeia monographs The Russian Federation follows the State Pharmacopoeia of the USSR, 11th edition. Last issued in 1987 (part 1) and 1990 (part 2), this Pharmacopeia includes 83 individual monographs for plants. Each monograph of the State Pharmacopoeia of the USSR contain information about plant name (Russian and Latin), plant part, recommended collection time, macroscopic evaluation (for whole and ground plant material), microscopically observation, quantitative data (loss of drying, concentration of chemical constituents or biological activity), ash, ash insoluble in 10% HCl,

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broken parts, organic and mineral adulteration, qualitative assay (chemical reactions or chromatography), fraction sieve analysis (for grinded material), packaging, storage conditions, self life, and pharmacological group. Table 1. approx. here Different parts of plants are described in the Pharmacopoeia. There are 20 aerial parts (herb), 15 leafs, 14 fruits, 14 roots an rhizome, 8 flowers, 3 bark, 3 seeds, 2 buds, 1 mushroom, 1 cones, 1 alga, 1 columns with stigmas and 1 shoots. Based on main therapeutic indications there are 13 expectorants, 8 diuretic, 7 astringent, 6 antiinflammatory, 5 bitterness (appetite stimulants), 5 laxative, 3 tonic, 3 cardiotonic, 3 cholinolytic, 3 diaphoretic, 2 cardiovascular, 2 choleretic, 2 haemostatic, 2 antihelmintic, 2 polyvitamin, 2 sedative, 1 antiseptic, 1 ambient, 1 spasmolytic. Three plants have not direct indications in Pharmacopoeia and in on-line State Register of Medicinal preparations. Just "medicine of natural origin" is indicated belong to pharmacological application. Eleven plants have not pharmacological indications in Pharmacopoeia, while its use is claimed in on-line State Register of Medicinal preparations. Among them 4 are claimed as spasmolytic, 2 haemostatic, one is expectorant, one hypotensive, one diuretic, one tonic and one metabolism regulator. About 60 % of plants are referred in European Pharmacopoeia and well studied in Europe, while 32 plants are included in Pharmacopoeia of the USSR only. In the following we discuss these plants, which are only included in the Pharmacopoeia of the USSR focusing on their pharmacological effects, data on safety and clinical data.

5.1 Anti-inflammatory 5.1.1. HERBA BIDENTIS Bidens tripartita L. is an annual plant of Compositae family, 30-100 cm in height with yellow flowers (common names include threelobe beggarticks, water agrimony and burr marigold). In

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Russian traditional medicine infusion of aerial part of B. tripartita L. is widely used in the treatment of catarrhal rhinitis, angina, acute respiratory infection, and as an anti-inflammatory in colitis, gout, and infantile rickets (Sokolov, 2000). It is also used in oriental medicine as a diaphoretic and diuretic in nephrolithiasis (Sezik et al. 2004), as antiseptic and for children bath mainly at diathesis (antiallergic action) (Blinova, Yakovlev, 1990). The safety was studied in mice. An aqueous-ethanol extract (1:1) of the aerial parts administered intraperitoneally to mice had a median lethal dose of 750 mg/kg (Bhakuni et al., 1971). No adverse effects were reported in rats after oral acute administration of B. tripartita at the doses up to 20 ml/kg of aqueous infusion (1:20) (Pozharitskaya et al., 2010). Table 2 summarizes the pharmacological studies undertaken on B. tripartita and reported in the literature. Table 2 approx. here In an open clinical trial without a control group, a 70% ethanol extract of the aerial parts of the plant and an ointment containing 2.5% of the extract were administered to 53 patients with psoriasis. After oral administration of the extract (20 drops three times daily) and simultaneous application of the ointment to the affected areas of the skin once a day, the combination was found to have anti-inflammatory activity as well as an ability to stimulate adrenal functions. After one week of treatment, desquamation of the skin was decreased, and a decoloration of the psoriatic plaques was observed. A clinical recovery was recorded for 29 of the patients; an improvement in condition was recorded for 22 patients; and a failure of treatment for 2 patients (Faraschuk, 1972; Levin et al., 1974). Bidens tripartita was used in a clinical trial to treat 500 cases of dysentery, 65 cases of acute enteritis, 248 cases of chronic enteritis. Different forms of the herb were used to make the medicine for a one day dose, each time, divided into three doses: 200 grams of fresh whole herb in decoction; three divided doses; 100 grams dried herb in decoction; three divided doses; granules of aqueous extract, 5 grams each time, three times daily; 0.5 gram tablets of aqueous extract, 10 tablets each time, three times daily; injection 2 ml each time, 2-3 times daily. The

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granules and tablets from granules were administered in a total dose of 15 g/day (derived from about 75 g of dried herb). The herbal materials in various forms were administered for 3-10 days, and to patients who had already suffered from diarrhea for 7-15 days. In 500 cases of dysentery, 387 cases were reported cured; with 13 not responding in 3 days. In 313 cases of enteritis, all were cured (12 chronic cases relapsed later). The author of the study pointed out that there had been an epidemic of dysentery in Shandong Province for many years and that practitioners at village clinics and the county hospital in Jianan County had used bidens as a remedy for about 10000 patients (Zhang, 1989). Bidens tripartita is recommended for internal administration at the dose of 1 tablespoon of the infusion (1:20), 3-4 times a day and one glass of an infusion of 10 g of cut herb together with 100 g of cooking salt or sea salt per bath for external use (Sokolov, 2000). Bidens tripartita is a popular herb in Russia and its safety and efficacy is confirmed during long time. The special monograph Herba Bidentis was included in WHO monographs on medicinal plants commonly used in the Newly Independent States (NIS) in 2010. However there is lack information in the public literature about efficacy. In revealing more information about bidens, broad studies can better appreciate the extent of herb application in medicine.

5.2. Diaphoretic, anti-inflammatory 5.2.1. FRUCTUS VIBURNI Viburnum opulus L. known as guelder rose, water elder, European cranberrybush, cramp bark, and snowball tree is a deciduous shrub of Caprifoliaceae family growing to 4-5 m tall. In Russian traditional medicine infusion of fruit has been used for the treatment of hemorrhoids and fruit juice as laxative and for the treatment of cold either alone or mixed with honey (Utkin, 1931). Berries are recommended as a source of vitamins, tonic and diuretic (Turova and Sapozhnikova, 1989), hypotensive, choleretic, anti-inflammatory, and sedative in hypertension, insomnia, convulsions, hysteria (Yelina, 1993). The berries are astringent, therefore, they are

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seldom consumed directly, but the fruit juice is one of the best known products in the food market. People living in Middle Anatolia region of Turkey drink juice to prevent some stomach and kidney problems (Soylak et al., 2002) The fruits are non toxic (Ehrlen, Eriksson, 1993). The dry fruits of V. opulus are safe at recommended dose of 65 ml (10 g or fruits in 200 ml) for 3-4 times per day, and available in pharmacies without a prescription, (Sokolov, 2000). Table 3 summarizes the pharmacological studies undertaken on V. opulus fruits and reported in the literature. Table 3 approx. here No clinical data was found about V. opulus fruits in the available literature. Fruits of V. opulus are recommended for internal administration at the dose of 1/3 of glass of the infusion (1:20), 3-4 times a day (Sokolov, 2000). It may be concluded that V. opulus fruits can be regarded as a promising and under-explored fruit which have been used in food in Europe and Asia, and might find wider applications for medicinal purposes. However pharmacological effects are not well documented and this subject is interesting for further study.

5.3. Hypotensive, anti-inflammatory, choleretic 5.3.1. HERBA GNAPHALII ULIGINOSI The Gnaphalium uliginosum L. (syn Filaginella uliginosa (L.) Opiz), Compositae or Marsh cudweed is an annual plant widely used in Russian phytotherapy (Blinova, Yakovlev, 1999). In Russian and Bulgarian phytotherapy it is used in the treatment of hypertension and ulcer (Buturlin, 1953; Shchepotin et al., 1984; Ivancheva, Stantcheva, 2000). Decoction and infusion of aerial part of G. uliginosum are known to possess anti-inflammatory, astringent, and antiseptic properties (Sokolov, 2000). There is some information about application of the herb marsh cudweed for the treatment of the thrombophlebitis and phlebothrombosis (Turova and Sapozhnikova, 1989; Shikov et al., 2010). Hypotensive effect of marsh cudweed is associated

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with decrease of systolic blood pressure because decrease of cardiac output and inhibition of baroreceptor sensitivity (Turischev, 2008). Oil extracts are used both internally and externally in the treatment of laryngitis, upper respiratory catarrh and tonsillitis (Gammerman et al., 1984). According to Voronina (1952) aerial part of the plant is used for treatment of nervous disease. The aerial part of G. uliginosum was included in the VIII Pharmacopoeia of USSR in 1952. G. uliginosum herb is generally considered to be safe in infusion at the daily dose of 180-300 ml, and available in pharmacies without a prescription (Sokolov, 2000). The ethanol (40%) crude extract did not suppress the growth of human lymphoblastoid Raji cells at concentrations up to 200 g/mL (Spiridonov et al., 2005). Table 4 summarizes the pharmacological studies undertaken on G. uliginosum and reported in the literature. Table 4 approx. here An original method for the treatment of patients with peptic ulcer with a combined administration of infusions of Polemonium caeruleum and G. uliginosum is reported (Panchenkov, 1950) and discussed in the part of the article about P. caeruleum. No other clinical data were found. The aerial part of P. caeruleum is recommended for internal administration at the dose of 1/2 -1/3 of glass of the infusion (1:20), 2-3 times per day as anti-inflammatory and hypothensive (Sokolov, 2000). The safety and efficacy of G. uliginosum is confirmed during long time of application however publications about chemistry, pharmacological effects and safety are fragmentary. This herb should be an interesting subject for further investigations.

5.4. Bitterness (appetite stimulants) 5.4.1. HERBA CENTAURII In the monograph of Pharmacopoeia USSR Herba centaurii described as aerial parts of Centaurium erythraea Rafn [syn.: C. minus Moench, Erythraea Centaurium (L.) Borkh] and C. pulchellum (Sw.) Druce, (Centianaceae) collected during the flowering season. In European 15

Pharmacopoeia, C. majus (H. et L.) Zeltner and C. suffruticosum (Griseb.) Ronn. (syn.: Erythraea centaurium Persoon; C. umbellatum Gilibert; C. minus Gars.) are described additionally in the monograph Herba centaurii. As soon as pharmacological effects of these plants are similar it is not reasonable for this review to discuss pharmacological effects of C. pulchellum.

5.5. Astringent 5.5.1. FRUCTUS ALNI Fructus alni consist of the catkins of Alnus incana (L.) Moench (grey alder or speckled alder) or A. glutinosa (L.) Gaertn. (European black alder; Betulaceae), a small to medium size tree 15-20 m tall. Alder catkins are collected late autumn – winter. Decoctions of alder catkins are used in Russian traditional medicine for the treatment of stomach pain, diarrhea and dysentery (Nosal, Nosal, 1960). In 1942 A. incana catkins were introduced in officinal medicine by Prof. D.M. Rossijsky Rossijsky, 1942; Vereschagin et al., 1959) and dry extract of A. glutinosa catkin Catskin (themelini) was developed by V.E. Shatadze (Turova and Sapozhnikova, 1989). Due to their s astringent properties extract was recommended for the treatment of gastrointestinal tract. Recently it was shown that Fuctus alni has anti-inflammatory, UV- and radioprotective properties (Sokolov, 2000). The acute and chronic toxicity of a polyphenolic extract of A. glutinosa Catskin were studied in rodents after oral administration. The LD50 in acute toxicity study in mice and rats was 5420 mg/kg and 8500 mg/kg respectively. In the chronic toxicity study the extract showed hepatotoxicity in rats after 6 months administration at the dose of 50 mg/kg, while the therapeutic recommended dose is 1 mg/kg (Maloshtan, Serbina, 1999). Methanolic extract of A. incana exhibited very low toxicity and did not cause significant brine shrimp (Artemia salina)

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mortality even in concentration of 200 g/mL (Stevi et al., 2010). Table 5 summarizes the pharmacological studies on Fructus alni reported in the literature. Table 5 approx. here A group of 50 patients (32 female and 18 male, 19-78 years) suffering from salmonellosis was included in a clinical trial. Group 1 (25 patients) was treated with drugs therapy (control) and group 2 was treated with a polyphenole richc extract of A. glutinosa catskin at a dose of 20 mg 3 times per day, during 8 days. The publication did not give a full description of the controls, which makes that it is difficult to judge the results of this trial. The levels of malonyl-dialdehyde and lipid conjugated dienes as well as activity of superoxide dismutase in blood serum of the patients were statistically significant decreased with 33%, 44% and 10% respectively, and were similar to normal levels in healthy persons. Decrease of malonyl-dialdehyde, lipid conjugated dienes and superoxide dismutase in group 1 was in 16%, 17% and 30% respectively comparing to intact level. Based on the results the extract was recommended in the therapy of patients with salmonellosis (Popova, 2002). Taking in consideration literature data and application of Fructus alni in the USSR and Russia it may be considered as safe and effective. Fructus alni is recommended for internal administration at the dose of 1/2 - 1/3 of glass of the infusion (1:20), 2-3 times a day as astringent (Sokolov, 2000). The tablets "Altan" with 0.01 g of a polyphenolic extract of A. glutinosa catskin are registered in Ukraine as OTC medicine. Future study of alnus catskin should contribute to wider medicinal applications.

5.5.2. HERBA HYPERICI In the monograph of Pharmacopoeia USSR Herba hyperici described as aerial parts of Hypericum perforatum L., H. maculatum Crantz (syn. H. quadrangulum L.), Hypericaceae collected during the flowering season. As soon as pharmacological effects of booth plants are

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similar and H. perforatum is included in European Pharmacopoeia it is not reasonable for this review to discuss pharmacological effects of H. maculatum.

5.5.3. RHIZOMATA BERGENIAE Bergenia crassifolia (L.) Fritsch ( Saxifragaceae), commonly known as badan, Siberian tea, Mongolian tea, leather bergenia, or elephant's ears, is an evergreen perennial plant with rhizomes up to 1 meter long, 10-50 cm long leather-like large leaves and pink flowers. Infusions of Bergenia rhizomes have been used in Russian traditional medicine for the treatment of cold, gastritis, enterocolitis, head-ache, diarrhea and fever (Gammerman et al., 1984). In Russian ethnomedicine the leaves are widely used as a beverage. Buryats and Mongols are known to have used B. crassifolia leaves to make tea. However, in Altai old blackened wintered leaves, known as chagirsky tea, are preferred for this purpose as the green leaves contain higher amounts of tannins (Vereschagin et al. 1959). In officinal medicine rhizomes are claimed as haemostatic, astringent, anti-inflammatory and antimicrobial agents. Infusions are recommended in gynecology for excessive menstruation, bleeding after abortions, and cervical erosion treatment (Turova and Sapozhnikova, 1989). It is claimed to strengthen capillary walls, to have local vasodilatation activity, to decrease arterial blood pressure and to increase hearth rate (Sokolov et al., 2000). Bergenia rhizomes are used for the treatment of oral diseases: periodontal disease, stomatitis, gingivitis, bleeding gums (Lukomsky, 1955). Bergenia crassifolia is appearing to meet the criteria of being an adaptogen (Suslov et al., 2002; Panossian, 2003). Rhizomes of B. crassifolia are safe at the daily dose of 50-100 ml of decoction (1:20), and available in pharmacies without a prescription (Sokolov, 2000) An infusion of B. crassifolia both black and fermented leaves (10 g in 100 ml of water) were safe in mice after 7 days of continuous per-oral administration at the dose of 9 ml/kg (Shikov et al., 2010). At a single oral dose of 50 mg/kg per day of dry extracts of black and green leaves after one week no signs of toxicity were observed in the rats (Pozharitskaya et al., 2012). Bergenin and norbergenin, main 18

coumarines of Bergenia, were found to be safe up to 2000 mg/kg weight in mice after per oral acute administration with no sign of mortality or change in behavioral pattern (Nazir et al., 2007). The bergenan - pectic polysaccharide from B. crassifolia green leaves was found to be nontoxic and failed to influence the body weight or the length and weight of intestine (Popov et al., 2005). The LD50 for sulfated pectin derivatives of B. crassifolia after single intraperitoneal injection was more than 1000 mg/kg (Vityazev et al., 2012). Table 6 summarizes the pharmacological studies undertaken on B. crassifolia and reported in the literature. Table 6 approx. here In the available literature no clinical data for B. crassifolia were found. Rhizomes of B. crassifolia are recommended for internal administration at the dose of 1-2 tablespoon of the decoction (1:20), 3 times per day as astringent, haemostatic, and anti-inflammatory (Sokolov, 2000). Claims for an antimicrobial activity are not supported by the antimicrobial assays, which only show activity at very high concentrations. Anti-inflammatory activity can be associated with high concentration of polyphenols, polysaccharides, and -bisabololoxide B (Popov et al., 2005; Chernetsova et al., 2012; 2014) It is interesting that black leaves and rhizomes have been used in the traditional medicine, but rhizomes only are referred to in the Pharmacopoeia USSR. The safety and efficacy of B. crassifolia both leaves and rhizomes are confirmed during a long period of traditional application, however publications about chemistry, pharmacological effects and safety are fragmentary. This plant should be an interesting subject for further investigations especial in aspect of adaptogenic properties.

5.6. Choleretic 5.6.1. FLORES HELICHRYSI ARENARII Helichrysum arenarium (L.) Moench also known as dwarf everlast is a perennial plant of Compositae family, which grows to an average of 15-40 cm tall.

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The inflorescence of H. arenarium has been used in folk medicine of Russia for its choleretic, diuretic, anti-inflammatory and detoxifying properties; and applied in the form of infusion for cystitis, arthritis, rheumatism, gout, for stimulating gastric secretion and for the treatment of gallbladder disorders (Shass, 1952; Vereschagin et al., 1959). The choleretic, cholagogues, hepatoprotective and detoxifying activity of the inflorescence of H. arenarium has been known for a long time in Europe (Kroeber, 1951; Szadowska, 1962; Wagner H, 1993). The correct administration of H. arenarium (decoction, 1:20, 100 ml 2-3 times per day) or "Flamin" tablets (purified flavonoids) at therapeutic dose 50 mg 3 times per day during 40 days is safe. However longer administration may cause development of bile congestion (Sokolov, 2000). Helichrysi flos has cholagogue and choleretic activity and stimulates the secretion of gastric juice (Krivenko et al., 1989; Litvinenko et al., 1992). Tablets "Flamin" are used in cases of cholecystopathy. They affect the chemical composition of bile (increase of cholesterol cholate coefficient), regulate function of gastrointestinal tract and increase diuresis (Petrovsky et al., 1953; Skakun, Stepanov, 1988). Table 7 summarizes the pharmacological studies undertaken on H. arenarium and reported in the literature. Table 7 approx. here Increase of bile secretion, reduction of bilirubin and cholesterol levels were observed in patients with cholecystitis, cholangitis, gallstones and hepatitis treated with H. arenarium. Helichrysum arenarium prevent the stagnation of bile, improve the metabolic function of the liver, and decrease the viscosity and relative density of bile. It promotes leaching of sand and small stones in patients with chronic calculous cholecystitis (Sokolv, 2000). However, no more details are provided. Aerial part of H. arenarium is recommended for internal administration at the dose of 1/2of glass of the decoction (1:20), 2-3 times per day as choleretic. "Flamin" tablets with 0.05 g of

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flavonoids are recommended for internal administration at the dose 1 tablet 3 times per day during 10-40 days by patients with cholecystitis (Sokolov, 2000). The special monograph Flos Helichrysi arenarii was included in WHO monographs on medicinal plants commonly used in the Newly Independent States (NIS) in 2010. However publications about chemistry, pharmacological effects are fragmentary and no special publication about safety. This plant should be an interesting subject for further investigations.

5.7. Antihelmintic and choleretic 5.7.1. FLORES TANACETI Tanacetum vulgare L., known by the common name of tansy is a flowering herbaceous plant (Compositae), with finely divided compound leaves and yellow, button-like flowers 50-150 cm tall. In Russian traditional medicine tansy has been used to treat intestinal worms (ascaris and enterobius), diarrhea, digestive problems, as antipyretic and diaphoretic (Nosal, Nosal, 1960). Tansy has been proposed for use as an insect repellent. Powder of aerial parts caused 100% paralysis of flies in 15 minutes (Zemlinsky, 1949). It is also mentioned to use in treating hysteria, migraine, neuralgia, rheumatism, kidney weakness, stomach problems, and fever. Tanacetum vulgare have antihelminthic, carminative, antispasmodic, stimulant to abdominal viscera, tonic, emmenagogue, antidiabetic, diuretic and antihypertensive properties. In larger doses, the plant can induce abortion. Externally, tansy is used as a poultice on swellings, sprains, gout, contusions, and some eruptive skin diseases and to kill lice and fleas, treats scabies (Abad et al., 1995; Sokolov, 2000). Tanaceholum®, purified complex extract of flavonoids and phenolcarbonic acids of tansy flowers (0.05 g/ tablet), is registered in Russia as choleretic, spasmolytic agent for chronic cholecystitis and biliary dyskinesia (Sokolov, 2000). The acute and chronic toxic effects of a lyophilized aqueous extract of tansy were studied in rodents. The no-observed adverse effect levels (NOAEL) of the crude aqueous tansy extract in 21

mice were 7.0 g/kg and 1.0 g/kg, and the lowest-observed adverse effect levels (LOAEL) were 9.0 g/kg and 1.5 g/kg, when given by the oral and intraperitoneal routes, respectively. Mortality increased with increasing doses, with LD50 of 9.9 g/kg and 2.8 g/kg for the oral and intraperitoneal modes of administration, respectively. The LD50 was lower for female mice (oral dose: 8.70 g/kg; intraperitoneal dose: 2.25 g/kg) than for male mice (oral dose: 11.30 g/kg; intraperitoneal dose: 3.25 g/kg). In the chronic study in rats, daily oral administration of the crude aqueous extract of tansy up to the dose of 600 mg/kg for 90 days did not result in death or significant changes in the biological (except for hypoglycemia) and hematological parameters (Lahlou et al., 2008a). Safety of Tanaceholum®, was tested on rats, mice, dogs, and guinea pigs. The LD50 was 1.27 g/kg in rats after intraperitoneal administration and 7.42 g/kg in mice after intragastric administration. It was not toxic and no histopathological effects were detected after 90 days administration by rats and dogs at the dose of 100 mg/kg. No allergenic effects were fixed in guinea pigs (Vichkanova et al., 2009). Table 8 summarizes the pharmacological studies undertaken on T. vulgare and reported in the literature. Table 8 approx. here The effect of oral treatment with Tanaceholum® was studied in 291 patients with chronic cholecystitis. Patients were treated with Taneceholum® tablets (0.05 g) at the dose of 2 tablets 3 times per day in 20-30 min before ingestion during 25 days. The publication did not give a full description of the controls, which makes it is practically difficult to judge the outcomes of this trial. The positive effect was registered in 74.9% of patients. The treatment led to a decrease in bitter taste in the mouth and nausea after 6-7 days, reduced pain in the right upper quadrant after 9-10 days, and dyspepsia disappeared after 15-20 days. No side effects were observed (Vichkanova et al., 2009). Flowers of T. vulgare are recommended for internal administration at the dose of 1 table spoon of the decoction (1:20), 3 times per day as choleretic and antihelmintic. Tanaceholum® tablets

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with 0.05 g of purified complex extract of flavonoids and phenolcarbonic acids are recommended for internal administration at the dose 1-2 tablets 3-4 times per day during 20-30 days by patients with biliary system and liver diseases (Sokolov, 2000). However publications about pharmacological effects and clinical trials are far too limited to allow conclusions about its therapeutic potential. This botanical drug clearly is an interesting subject for further investigations especially in a clinical context.

5.8. Expectorants 5.8.1. CORMUS LEDI PALUSTRI Ledum palustre L. (syn. Rhododendron tomentosum Harmaja), commonly known as marsh labrador tea, northern labrador tea or wild rosemary, is a low shrub growing to 50 cm (rarely up to 120 cm) tall with evergreen leaves. It belongs to the family Ericaceae. In Russian traditional medicine shoots are used in form of aqueous infusion or decoction. The infusion has been used for treating diverse respiratory and lung disorders including bronchitis, tuberculosis, (whooping) cough, asthma, for lowering blood pressure, to prevent seizures (Shass, 1952; Vereschagin et. al., 1959), the decoction - as anthelmintic (Utkin, L.A., 1931), the ointment on the base of animal fats - topically in eczema, scabies, insect stings (Vereschagin et. al., 1959). In Swedish traditional medicine it has been used for the treatment of headache, toothache, pain and shingles (Tunón et al., 1995). The leaves are also used as marsh tea, which is considered to act as abortifacient, diaphoretic, diuretic, emetic, expectorant, and lactagogue (Jin et al., 1999). In the Norwegian Sami community the decoction of dried "guohcarassi" - "stinking plant", was considered a good remedy for cold and whooping cough, for rheumatism as pain reliever, for frost damage of the joints, to lower blood pressure, for bladder catarrh and diphtheria (Alm, Iversen, 2010). Ledum palustre leaves and shoots are used in China for treatment of cough, asthma, lowering blood pressure and as antifungal (Li et al., 2002).

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Ledum palustre is regarded as a poisonous plant due to the content of toxic volatile compounds, especially the sesquiterpenoid ledol. Ledol can affect the central nervous system, initially leading to psychomotor stimulation, then to seizures and cramps, finally to paralysis, breathing problems and even death (Dampc, Luczkiewicz, 2013). As it was suggested, the chronic and extended exposure to ledol and presumably its overdosage is crucial in causing the serious adverse reactions, such as dizziness, exhaustion, nausea, vomiting and loss of consciousness (Dampc, Luczkiewicz, 2013). The essential oil of marsh rosemary applied orally can cause the irritation of kidneys, urinary tract and the gastrointestinal tract with vomiting and diarrhea (Aronson, 2009; Habermehl, 1998). However, the only side effects reported for "Ledin", an USSR medicine for cough, containing 50 mg of ledol in one tablet, recommended total daily dose of 50-100 mg, divided over 3-5 administrations per day, during 3-10 days, are allergic reactions (Mashkovskii, 2002). The maximal tolerated dose of L. palustre extract in mice after oral administration was more than 30 g/kg. Extract at doses of 2.5, 5.0 and 10.0 g/kg had no observable genotoxicity in mice and could inhibit cyclophosphamide, a well known anti-tumor drug, induced genotoxicity in mice (Jing et al., 2011). Acute toxicity of 40% EtOH extract and chloroform and hexane fractions of EtOH extract of L. palustre shoots was studied in mice. The LD50 for 40% EtOH extract was 2800-3200 mg/kg after intraperitoneal administration and no mortality of mice was observed after intragastric administration of extract at the dose of 10000 mg/kg. The LD50 for chloroform fraction was 350 mg/kg (intraperitoneal), and 2600 mg/kg (intragastric) and for hexane fraction 420 mg/kg (intraperitoneal), and 5100 mg/kg (intragastric) respectively (Basova, 2004). The acute toxicity of ursolic acid extracted from L. palustre was tested in mice. The LD50 after oral administration was considered as 9.26 g/ kg. The frequencies of micronucleus in mice administered with high, medium and low doses of the ursolic acid extract were 2.0, 2.0 and 1.8, respectively. No significant differences in frequency of micronucleus were observed between the mice administered with the ursolic acid extract and normal mice. The chromosomal aberration

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rates in the mice administered with high, medium and low doses of the ursolic acid extracts were 1.2%, 1.2% and 1.0%, respectively, and were not significantly different from normal mice. The results suggest that the ursolic acid extract from L. palustre is safe with low acute toxicity but without genetic toxicity (Jing et al., 2009). Pharmacological properties of L. palustre shoots depend on the essential oil, which after intragastric administration partially are excreted through the mucous membranes of the respiratory system. Volatile compounds of L. palustre eliminated through the bronchi, have a moderate effect on the local irritating mucous membranes, increase secretion of bronchial glands and increase the activity of ciliated airway epithelium. Spasmolytic effect of L. palustre on airway smooth muscle was observed (Sokolov 2000). It has been reported that the expectorant and antitussive effect of L. palustre is caused by ledol (Belousov et al., 1998). Table 9 summarizes the pharmacological studies undertaken on L. palustre and reported in the literature. Table 9 approx. here The traditional applications of shoots of L. palustre in different countries are mostly for cough, bronchitis, lung disorders, and lowering blood pressure. Effects and safety of L. palustre has been demonstrated in number of experiments and it is recommended in Russian officinal medicine as an effective expectorant for the treatment of bronchitis and other lung diseases accompanied with cough in form of infusion (1:20) at the dose of ¼ of glass, 2-3 times per day (Sokolov, 2000). The film-coated tablets “Ledin” (contain 50 mg of ledol) are recommended for acute and chronic bronchitis, pneumonia and bronchitis caused by chemicals, gases, fumes and vapors, asthma, pulmonary tuberculosis, cystic fibrosis and frequent, mostly dry cough with the dose of 1-2 tablets3–5 times a day during 3-10 days (Mashkovskii, 2002). However, additional study about safety (especial chronic toxicity) and efficacy are needed.

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5.8.2. FOLIA FARFARAE Tussilago farfara L. (Compositae) commonly known as coltsfoot, is a perennial herbaceous species of 10 - 30 cm in height. The traditional use of leaves of T. farfara in Russia is to treat respiratory illnesses such as asthma, bronchitis, or the common cold as expectorant and sedative. Additional uses include the improvement of digestion, treatment of diarrhea, topical application for furunculosis and as analgesic (Vereschagin et al., 1959). The leaves are components of pectoral and diaphoretic teas (Gammerman et al., 1984). In China the dried flower buds of T. farfara are used to treat cough, bronchitis and asthmatic conditions (Committee for the Pharmacopoeia of People’s Republic of China, 2010). There is extensive discussion in the literature about the safety of T. farfara. Besides acidic polysaccharides, which are considered to be responsible for the cough relieving effect (Franz, 1969), T. farfara contains (generally comparatively low levels) pyrrolizidine alkaloids, which are known to be liver toxic. The main alkaloid is senkirkine with traces of senecionine. The content of senkirkine in samples of T. farfara flowers was found to vary from 19.5 ppm to 46.6 ppm (Jiang et al., 2009). The concentration of senkirkine in commercial samples of coltsfoot leaves was 2.5-11.2 ppm as determined by capillary zone electrophoresis after different methods of extraction. Senecionine in leaves was either below the detection limit (by gas chromatography) or present in less than 0.9 ppm when measured by capillary zone electrophoresis (Lebada et al., 2000). A small lifetime study of rats fed 32% young, pre-blooming flowers of coltsfoot in their diet for 4 days, and subsequently 16% diet until the 380 days was performed. All the rats survived beyond 380 days after the start of feeding, but 8 out of 12 rats developed hemangio-endothelial sarcoma in the liver (Hirono et al., 1976). In the absence of epidemiological data, the International Agency for Research on Cancer listed senkirkine as an agent not classifiable as carcinogenic to humans (Group3) (Barceloux, 2008).

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Roulet et al. (1988) have reported on a case of a newborn female infant from Switzerland with fatal hepatic vaso-occlusive disease. Her mother revealed the occasional consumption of cannabis and hallucinogenic mushrooms some months before the actual pregnancy, and the daily consumption of a single cup of the herbal tea represenings a toxic amount of senecionine (0.60 mg/kg dry weight) during her entire pregnancy. The exact composition of the incriminated cough tea was obtained from the manufacturer; of the 10 different plants in this preparation, leaves of T. farfara made up 9% (w/w). In a comment responding to this article, Röder assumed that the herb containing pyrrolizidine alkaloids was not tussilago but petasites, because the typical leading alkaloid of Tussilago, senkirkine, was not found by the authors (Röder, 1988). He argued that leaves of petasites had most probably been confused with Tussilago because both plants grow wild in alpine regions and can be easily confused when gathered after the blossom period. The result of the future research showed that the cough tea, contrary to the presentation in the publication of Roulet, contained not only leaves and flowers of T. farfara but also roots of Petasites hybridus (L.) G.Gaertn., B.Mey. & Scherb. (discussed as Petasites officinalis Moench) (Spang, 1989)). The next report concerned an 18-month-old boy from the Southern Tyrol with reversible hepatic Veno-occlusive disease as a result of over 15 months consumption of herbal tea which contained large amounts of seneciphylline (about 60 g/kg body weight per day) was published in 1995. Leaves from Adenostyles alliariae (Alpendost) were mistakenly taken for T. farfara (coltsfoot) by parents. Also these two plants can easily be confused especially after the flowering period. The child was given conservative treatment only and recovered completely within 2 months (Sperl et al., 1995). Both clinical cases were because of adulteration of coltsfoot with other more toxic plants. However, in order to avoid any risks for consumers, the German public health authorities (Bundesgesundheitsamt, 1992) limited the daily intake of toxic pyrrolizidine alkaloids to 1 g. Intravenous injection of the alcoholic extracts or decoctions of T. farfara to cats induced a primary depression effect which was followed by a more rapid acute rise in mean blood pressure

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and finally a sustained pressor response for several minutes. No tachyphylaxis was observed. The blood pressure response was associated with increases of heart rate and respiratory stimulation. It was suggested that the mechanism of action of Tussilago on blood pressure may be due to stimulation of the vasomotor center of medulla, and the vascular -receptor and constriction of the peripheral blood vessels (Wang, 1979). Significant antimutagenic activity of juice prepared from fresh leaves of T. farfara in dilution 1:10 and 1:100 was observed against genotoxic nalidixic acid in SOS chromotest (Karamova et al., 2010). Water-soluble polysaccharides of coltsfoot reduce the toxic effect of paclitaxel on the blood system in mice with Lewis lung carcinoma (Safonova et al., 2010). Table 10 summarizes the pharmacological studies undertaken on T. farfara and reported in the literature. Table 10 approx. here The efficacy of mixtures with T. farfara was been shown in the complex treatment of rhinosinusitis in miners with chronic bronchitis (Lavrenov et al., 1988). But no details are provided by author. The leaves of T. farfara are used in Russian traditional medicine and were included in the VIII Pharmacopoeia of USSR in 1952. Since this time no adverse effects or toxicity were reported in Russian publications. Taking into account the long history of application in traditional medicine infusion of T. farfara leaves (5 g in 300 ml of water) can be considered as a safe medicine at the recommended therapeutical dose of 1/2-1/3 of a glass 2-3 times per day as expectorant (Sokolov, 2000). The possibilities of adulterations must, however, be carefully monitored (Roulet et al. 1988, Sperl et al. 1995). Publications about chemistry and pharmacological effects are fragmentary. This plant should be an interesting subject for further studies.

5.8.3. FOLIA PLANTAGINIS MAJORIS Plantago major L. is a perennial plant that belongs to the family Plantaginaceae. The leaves of P. major have long been used in Russia for wound healing and as expectorant, antiphlogistic, 28

pain-relieving herb (Turova and Sapozhnikova, 1989; Sokolov, 2000). Whole or fragmented, dried leaves and scape of Plantago lanceolata L. are approved by European Pharmacopoeia. As soon as pharmacological effects of booth plants are similar it is not reasonable for this review to discuss pharmacological effects of P. major.

5.8.4. GEMMAE PINI Gemmae pini consist of the buds of Pinus silvestris L., of Pinaceae family collected early spring. The pine buds are widely used in Russian traditional medicine as expectorant, slightly diuretic, in the treatment of chronic bronchitis and tuberculosis. It can be used for aromatic baths that improve skin condition and supportive treatment of arthritis (Vereschagin et. al., 1959; Gammerman et al., 1984). Pine buds are safe, available without a prescription, and recommended for decoction (10 g of buds in 200 ml of water) or inhalation. The decoction is used at the dose of 60-100 ml 2-3 times per day as expectorant (Sokolov, 2000). Buds are used as raw material for steam distillation of essential oil. The Pini sylvestris aetheroleum is included in European Pharmacopoeia. Therefore we don't discuss pharmacological profile of oil.

5.8.5. RHIZOMATA ET RADICES INULAE Elecampane (Inula helenium L.), also called horse-heal, is a perennial composite plant from 90 cm to 150 cm high, belonging to Compositae family. In Russia roots of elecampane are used as an expectorant in chronic respiratory diseases: bronchitis, tracheitis, tuberculosis and bronchitis with lots of mucus (Turova and Sapozhnikova, 1989). A decoction made from elecampane roots is often prescribed as an antiphlogistic and haemostatic for treating problems of the gastrointestinal tract. It increases stomach and intestinal secretion thus stimulating the appetite and improving digestion (Zevin et al., 1997). Preparations of its roots are used in the folk

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medicine of several ethnic groups against a variety of ailments including asthma, (whooping) cough, bronchitis, lung disorders, tuberculosis, indigestion, chronic enterogastritis, infectious and helminthic diseases (List and Hörhammer, 1976; Cantrell et al., 1999; Huo et al., 2008). The safety of elecampane was evaluated in mice, rats, rabbits and other animals. The LD50 of infusion, tincture, liquid extracts of I. helenium roots was over 5000 mg/g booth in mice and rats. Median lethal dose of tincture was 14043 mg/kg for mice and 12684 mg/kg for rats. Median lethal dose of liquid extract was 13230 mg/kg for mice and 12285 mg/kg for rats (Gurskaya et al., 2009a). Safety of I. helenium infusion, tincture, liquid and dry extracts was evaluated in irritating tests on guinea pigs, rabbits, sheep and piglets. There was no irritating effect after transdermal application of all forms of I. helenium. Irritating activity of infusion after application to eye conjunctiva was evaluated as light, while the effect of dry extract (10-20% suspension in water) was estimated as a limited one, which disappeared in 24 hours. Irritating activity of tincture and liquid extract (70% ethanol) was evaluated as a pronounced one, which did not disappear in 24 hours (Gurskaya et al., 2009b). Table 11 summarizes the pharmacological studies undertaken on I. helenium as reported in the literature. Table 11 approx. here A clinically tested and approved extract of I. helenium root (standardized by the sum of sesquiterpene lactones), which is marketed in Russia under name "Alanton" (since 1979), is prescribed for the treatment of acute and chronic infectious and inflammatory diseases of the respiratory system, accompanied by a persistent cough with thick viscous mucus, to stimulate blood circulation in the stomach and to accelerate the healing of stomach ulcers (Mashkovskii, 2002). In an open clinical trial without a control group, "Alanton" tablets were administered to 24 patients with peptic ulcer. After oral administration of the tablets (0.1 g three times daily during 3 weeks), a clinical recovery was recorded for all of the patients. The level of protein in blood serum, primarily due to albumin and -globulins was increased. The decrease of pyrosis, nausea, and vomiting were registered on 7-10 days, appetite of patients was improved and body

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weight was increased in approximately 3 kg. The treatment was resulted in regeneration of gastric epithelium and decrease of ulcer size. It was concluded that "Alanton" have antiinflammatory activity, contributes to the mucus production and mucus membrane regeneration (Luchkova, 1978). Roots of I. helenium are recommended for internal administration at the dose of ½ glass of the decoction (16:200), 2-3 times per day as expectorant at the upper respiratory tract infections. "Alanton" tablets with 0.1 g of the sum of sesquiterpene lactones are recommended for internal administration at the dose 1 tablet 3 times per day during 6-8 weeks by patients with inflamed or scarred stomach ulcer (Sokolov, 2000). The extracts and isolated compounds of I. helenium have been determined to have interesting biological activities, suggesting that Radix Inulae could be a lead to develop further potential drugs.

5.8.6. RHIZOMATA CUM RADICIBUS POLEMONII Polemonium caeruleum L., (Jacob's ladder or Greek valerian; Polemoniaceae) is a hardy perennial flowering plant a height about 35-140 centimeters and has been used in Russian traditional medicine as sedative similar to valerian, tuberculosis, and whooping cough. In Ukraine it was used for childrens bath. The infusion of the roots drinks in fever (Turova and Sapozhnikova, 1989, Sokolov, 1990). In modern medicine it is recommended as expectorant for bronchitis, neurosis, and stomach and intestinal ulcers in combination with Gnaphalium uliginosum L. (Mashkovskii, 2002). Varlakov first studied this plant in 1932 in connection with the medicinal flora of Eastern Sayan. He proposed it as an expectorant to replace imported Polygala senega L. (Varlakov, 1943). It was shown in experiments on rabbits with cholesterol induced atherosclerosis that saponins of P. caeruleum have a hypocholesterolemic effect, decrease development of atherosclerosis and reduce lipid levels in skin, aorta and liver (Sokolov, 1990). The Rhizomata cum Radicibus

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Polemoni were included in the State Pharmacopoeia of USSR in 1961 (Maltseva and Sorokina, 2010) and a limited number of pharmacological studies are available (Table 12). Table 12 approx. here No toxicity was observed after treatment of patients with 45 mL of infusion of P. caeruleum (6g of roots in 200 mL of water) a day during two weeks, but because some irritating effect it should be taken after a meal (Panchenkov, 1950; Turova and Sapozhnikova, 1989). In an open clinical trial without a control group, a group of patients with tuberculosis, acute and chronic bronchitis and lung abscess was treated with 0.75 mL of P. caeruleum liquid extract, to be taken 3 times a day, and 45-75 mL of infusion (6 g of roots in 200 mL of water) for 30 days. The therapeutic effects were observed in 60% of the patients, but no clear scale for primary outcome parameters seem to have been defined. Treatment of patients resulted in increased phlegm and facilitation of its evacuation. Catarrhal conditions of the lungs were improved with the result that cough diminishes (Turova, 1955). Another group of patients with psychiatric disorders was treated with 15 mL of infusion of P. caeruleum (6g of roots in 200 mL of water) to be taken three time a day after a meal for a 2 weeks period. Sedative effect was observed in all patients (Turova and Sapozhnikova, 1989), but details are lacking. A specific method for the treatment of patients with peptic ulcer with a combined administration of infusions of P. caeruleum and G. uliginosum was reported. The rationality of this therapy is due to a sedative effect of P. caeruleum and a local effect of G. uliginosum that accelerates ulcer healing. Seventy patients with ulcers were treated with 15 mL of infusion of P. caeruleum (6 g of roots in 200 mL of water) and 50 mL of infusion of G. uliginosum (10 g in 200 mL of water) to be taken three times a day after a meal for 2 weeks period. No side effects were observed. Most of patients showed diminished gastric pain and less blood in the stool. Based on radiographic examination the gastric ulcer lesions (called ‘niches’) disappeared and the gastric pH was usually normalized. Treatment of patients with only one of the infusions was not effective (Panchenkov, 1950).

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Roots and rhizomes of P. caeruleum are recommended for internal administration at the dose of 1 table spoon of infusion (6:200), 3-5 times per day as expectorant, and at the dose of 1 table spoon 3 times per day together with an infusion of the aerial part of G. uliginosum as antiinflammatory agent in case of stomach ulcer (Sokolov, 2000). Polemonium caeruleum has been used clinically for a long time, roots and rhizomes are OTC. However, the chemical and pharmacological evidence to support the medical applications especially as expectorant is from the early 50th of last century and needs further confirmation.

5.9. Diuretics 5.9.1. CORTEX VIBURNI Viburnum opulus L. (Adoxaceae) known as guelder rose, water elder, European cranberrybush, cramp bark, and snowball tree is a deciduous shrub growing to 4-5 m high. Infusion of bark is used in Russian traditional medicine in the treatment of scrofula in children, asphyxia, cold, uterine, gastric and hemorrhoidal bleeding (Vereschagin et al. 1959). The bark has been used to treat high blood pressure, heart troubles, tuberculosis, shortness of breath, stomach pain, digestive troubles, duodenal ulcers and bleedings, kidney and bladder affections, coughs and colds, has astringent activity (Smirnova, Iadrova, 1968, Velioglu et al., 2006, Zayachkivska et al., 2006; Sokolov, 2000). The tannins of V. opulus bark bind the mucous proteins after intragastric administration, causing them to precipitate and to cover and protect the sensitive stomach cells. As a consequence, the local pain is decreased, vessels are contracted, secretion of gastric juice is decreased and membranes density is increased resulting in a reduction of the inflammatory reaction. In 1952 the bark was included in the State Pharmacopoeia of the USSR (Vereschagin et al. 1959). In the available literature there is no data about toxic effects of V. opulus bark. The bark of V. opulus is available without a prescription in pharmacies in Russia and safe in decoctions form at

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the dose of 18-36 ml 3-4 times per day (Sokolov, 2000). Table 13 summarizes the pharmacological studies undertaken on V. opulus bark and reported in the literature. Table 13 approx. here In the literature found no clinical data are reported. Bark of V. opulus is recommended for internal administration at the dose of 1-2 table spoon of the decoction (1:20), 3-4 times per day as diuretic and antiseptic. It has been used clinically for a long time as OTC. However, the information about chemical and pharmacological effects is not enough and the bark should be studied in more detail.

5.9.2. FLORES CENTAUREAE CYANI Centaurea cyanus L. also called blue cornflower or bachelor’s button is an annual plant of Compositae family, with grey-green branched stems. Flowers are used in Russian traditional medicine as a diuretic, for the treatment of cystitis, cough, nervous and gastric diseases, uterine bleeding, in children against diarrhea and for eye’s washing (Vereschagin et al., 1959). Flowerheads are a well-known crude drug used in European traditional medicine in the treatment of minor ocular inflammation (Bruneton, 1995), fever, gynecological problems, digestive complaints (Kern et al., 1972; Hansel et al., 1992), wounds and dermatological complaints (Pieroni et al., 2004). Dried flowers of C. cyanus are used to relieve diarrhea, gain energy, increase appetite, and to relieve chest tightness (Arif et al., 2004). Centaurea cyanus is recommended as component of herbal mixtures for the treatment of edema associated with kidney diseases, as well as diseases of the urinary tract (nephritis, cystitis, urethritis), diseases of the liver and biliary tract (Turova, Sapozhnikova, 1989). There is no data about toxic effects of C. cyanus available in the literature. In a recently published review of retrospective observational case reports of ocular side effects or systemic side effects from medications used for the eye from herbal medicines and nutritional supplements Fraunfelder (2004) has mentioned that cornflower is used for the treatment of 34

conjunctivitis and ophthalmia. No side effects for C. cyanus were found in the reports submitted to the WHO, the Food and Drug Administration, and the National Registry of Drug- Induced Ocular Side Effects (Fraunfelder, 2004). The dry flowers of C. cyanus are available without a prescription in pharmacies in Russia and safe in decoctions at the dose of 18 ml 3 times a day (Sokolov, 2000). Only a limited number of pharmacological studies of C. cyanus are available and these are summarized in Table 14. Table 14 approx. here No clinical data were found about C. cyanus. Flower-heads of C. cyanus are recommended for internal administration at the dose of 1 table spoon of infusion (1:20), 3 times per day as diuretic. It has been used clinically for a long time as OTC. However, the information about chemical and pharmacological effects is limited and this subject is interesting for further study.

5.9.3. FOLIA VITIS-IDAEA Vaccinium vitis-idaea L., (lingonberry, or cowberry, Ericaceae) is a short evergreen shrub up to 25 cm tall, with leathery evergreen leaves. In Russian traditional medicine infusions or decoctions from leaves have been used as an astringent and diuretic for leaching of kidney stones, in cases of stomach pain, diarrhoea, and rheumatism (Vereschagin et al., 1959; Nosal, Nosal, 1960). Vaccinium vitis-idaea leaves are used as an anti-inflammatory medicine in China in order to treat respiratory system infections (Wang et al., 2005). Decoction of V. vitis-idaea leaves is recommended in modern medicine in Russia as diuretic, cholagogue, antiseptic and astringent for the treatment of kidney and bladder diseases, gastroenteritis, diarrhea, as well as in case of rheumatism, gout and arthritis (Sokolov, 2000). The leaves of V. vitis-idaea were included in the VIII Pharmacopoeia of the USSR in 1952. In the literature there is no data on toxic effects of V. vitis-idaea leaves. The acute toxicity of polyherbal mixture "Brusniver" which contains 50% V. vitis-idaea leaves, 20% Hypericum perforatum L. (Hypericaceae) aerial part, 20% Rosa spp. L (Rosaceae) pseudo fruits and 10% 35

Bidens tripartita L (Compositae) aerial part was studied in mice. Concerning acute toxicity the intragastric administration of the infusion was found to be safe as no mortality of mice was observed after administration of the extract at the dose of 30 g/kg (equivalents of dry mixture), and LD50 was not reached. No toxicity signs were observed in female rats after intragastric administration of the infusion (20 and 40%) of the mixture at the doses up to 8 g/kg during 21 days (Vichkanova et al., 2004). Table 15 summarizes the pharmacological studies undertaken on V. vitis-idaea as reported in the literature. Table 15 approx. here The effect of an oral treatment with "Brusniver" infusion (200 ml/day, during 14 days) was studied in 31 patients with pyelonephritis, urolithiasis and urethritis. The publication did not give a full description of the controls, which makes it difficult to judge the outcomes of this trial. The positive effect was registered in 83.8% of patients, but it seems that no clear primary outcome parameters were defined. All patients well tolerated the treatment and no side effects were observed (Vichkanova et al., 2004). Leaves of V. vitis-idaea are available in Russia in pharmacies as OTC and recommended for internal use at a dose of 1/2 - 1/3 glass of the decoction (6:200), 2-3 times per day as diuretic, cholagogue and antiseptic (Sokolov, 2000). However, the information about chemical and pharmacological effects is insufficient and this is of interest for further study.

5.9.4. GEMMAE BETULAE Gemmae betulae consist of the buds of Betula pendula Roth and B. pubescens Ehrh. (Betulaceae). The birch buds are widely used in Russian traditional medicine as diuretic, expectorant, cholagogue, diaphoretic, blood-purifying, analgesic, anti-infective and antiseptic for wound healing, furunculosis and as a wash to remove skin spots (Vereschagin et al., 1959; Nosal, Nosal, 1960; Zevin et al., 1997). Infusions and decoctions of birch buds are used in stomatology and otolaryngology as anti-inflammatory, for stomatitis, gingivitis, periodontitis, 36

glossitis, sore throat, chronic tonsillitis, acute respiratory diseases as a rinse and application of gauze pads, moistened with infusions or decoctions (Lavrenova and Lavrenov, 1997). The use of birch buds since centuries, in adequate doses, presents no toxicity or contraindications except ingestion because of ether oils of buds. However, we have not found the data about toxic effects of Gemmae betulae in the available literature. Table 16 summarizes the pharmacological studies undertaken on Gemmae betulae as reported in the literature. Table 16 approx. here A group of 108 patients with purulent wounds (83 had superficial wounds, 10-deep wounds, 15cavitary wounds) was treated with 20% tincture of birch buds in 70% EtOH. The publication did not give a full description of the controls, which makes it is practically difficult to judge the outcomes of this trial. Positive results were obtained after using the birch buds tincture in all the patients, including patients with antibiotic-resistant microbial flora, but it seems that no clear primary outcome parameters were defined (Zakharov et al., 1980). Birch buds have been used in the patients with the edema of cardiac origin as a diuretic. A significant increase in diuresis (urine) and a sharp decrease in edema were observed. However in case of functional kidney failure, this type of treatment is not recommended because of possible irritation of the renal tissue with resinous substances (Sokolov, 2000). A beneficial effect of birch buds was shown in the treatment of patients with acute and chronic forms of eczema (Pevzner, Raitsina, 1954). Birch buds are available in Russia pharmacies as OTC and recommended for internal administration at the dose of 1/2 - 1/3 glass of the infusion (1:20), 2-3 times per day as diuretic and cholagogue (Sokolov, 2000). However, the information about chemical composition and pharmacological effects is insufficient and this is of interest for further study.

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5.10. Cardiotonic 5.10.1. HERBA ADONIDIS VERNALIS Adonis vernalis L., known as, among others, pheasant's eye, spring pheasant's eye, yellow pheasant's eye and false hellebore, is a perennial flowering plant of the family Ranunculaceae. It is included in German Homoeopathic Pharmacopoeia. Traditionally, in Siberia a water infusion of the aerial parts has been used against malaria, edema, cardiac edema and several other heart-related problems, kidney diseases (Utkin, 1931; Nosal, Nosal, 1960). In 1879 alcoholic extracts of A. vernalis were first introduced into medicine by the Russian medical doctor N.O. Bubnow, who employed them as a cardiac stimulant (Heyl et al., 1918). In 1898 the famous Russian neurologist Vladimir Bekhterev suggested a mixture of A. vernalis with sodium bromide (or potassium bromide) or codeine for the treatment of light forms of heart failure, panic disorder, dystonia, and epilepsy (Bekhterev, 1898). The biological activity of the A. vernalis aerial parts (1:20 EtOH 95% extract) was defined as 50-66 frog units or 6.3-8.0 cat units according to the State Pharmacopoeia of the USSR 11th ed. The toxicity of A. vernalis leaves was assayed by the one-hour frog method which is official for tinctures of digitalis, strophanthus, and squill. The average minimum dose producing a permanent systole (M.S.D.) of the frog’s ventricle at the end of exactly one hour for the tincture of A. vernalis (1:10, 95% alcohol) was 0.0045 ml/g frog. (Heyl et al., 1918). The LD50 of cymarin (one of active glycoside) after intravenous injection in rats was 24.8±1.8 mg/kg (Vogel, Kluge, 1961) and intravenous injection in cats was 95.4±3.0 g/kg (Chen et al., 1942). The M.S.D. for adonitoxin and cymarin are 0.621±0.046 g/g and 0.880±0070 g/g frog respectively (Chen, Anderson, 1947). The LD for adonitoxin after intravenous injection in cats was 191.3±17.5 g/kg (Chen, Anderson, 1947). The preparation of Adonis slows, regulates and strengthens heart contractions, increase blood pressure and has a mild diuretic action. It reduces dyspnea and relaxes smooth muscle in the lungs allowing deeper breathing. It is especially indicated in congestive heart failure with 38

arrhythmia, feeble force of contractions with dyspnea and dropsy. In case of heart failure, accompanied by cardiac conduction disturbance, Adonis can be as effective as Digitalis, however it is not cumulative and doesn’t cause the phenomenon of a heart block as Digitalis (Turova and Sapozhnikova, 1989). Table 17 summarizes the pharmacological studies undertaken on A. vernalis as reported in the literature. Table 17 approx. here In first half of XXth century pharmacological effects of A. vernalis were studied extensively in Russia but the literature from that time is poorly accessible. The novo-galenic preparation "Adonisid" (specific extract of A. vernalis) was produced in USSR in form of tablets, but nowadays it is excluded from the State Register of drugs. "Adonisid" is used in modern medicine as a part of the complex phytomedicine "Cardiovalen" (consist of 17.2 mL of pressed juice of Erysimum diffusum Ehrh. (Brassicaceae), 30.3 ml of "Adonisid" with 85 frog units in 1 mL, 48.6 mL of tincture of Valeriana officinalis L. (Valerianaceae), 2.2 mL of liquid extract of Crataegus, 0.4 g of camphor, and 2 g of NaBr). Aerial part of A. vernalis is prescribed in Russia for internal use at a dose of 1 table spoon of the infusion (7:200), 3-5 times per day as cardiotonic. "Cardiovalen" is prescribed at a dose of 15-20 drops, 1-2 times per day (Sokolov, 2000).

5.10.2. HERBA CONVALLARIAE et FOLIA CONVALLARIAE et FLORES CONVALLARIAE In terms of the Pharmacopoeia of the USSR, Herba Convallariae, Folia Convallariae and Flores Convallariae consists of the whole or cut dried aerial part, leaves or flowers of Convallaria majalis L. (syn: C. transcaucasica Utkin ex Grossh.), C. keiskei Miq. (Asparagaceae), respectively, which are harvested during the flowering period or its beginning (for leaves). Depending on the region the harvesting time can be shifted to obtain high quality raw plant material. Particularly in the St-Petersburg region optimal harvesting time for Herba Convallariae

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is the late budding and early flowering stage (Borisova et al., 1984). Convallaria majalis is commonly known as the lily of the valley and has been recognized by clinicians to have an antiarrhythmic effect. Felter found it particularly useful for treating tachycardia and mitral insufficiency. He found it less useful for addressing aortic valve problems (Felter, 1922). Unlike the much stronger and more dangerous Digitalis spp., lily of the valley glycosides do not accumulate and are safer and produce milder effects (Yarnell, Abascal, 2003). The flavonoids of C. majalis are also considered to be important for the activity of the botanical drug and this supports the use of the whole plant and not just the cardiac glycosides in isolation (Weiss, 1988). Flowers of C. majalis have been used in Russian traditional medicine for the treatment of epilepsy, cardiac dropsy and for people with mild congestive heart failure (Nosal, Nosal, 1960; Gammerman et al., 1984). According to the State Pharmacopoeia of the USSR 11th ed, the biological activity of C. majalis should be at least 120 frog units or 20 cat units for aerial part (1:20 EtOH 95% extract), 200 frog units or 33 cat units for flowers (1:20 EtOH 95% extract) and 90 frog units or 15 cat units for leaves (1:20 EtOH 95% extract). Convallaria majalis has been reported to be toxic owing to its content of cardioactive glycosides convallarin and convallamarin. The LD50 for convallarin in rabbits after intravenous administration was 1500 g/kg (Marhold, 1986). Lowest published lethal dose for convallarin in rabbits after subcutaneous administration was 10 mg/kg, in frogs after oral administration 200 mg/kg and after subcutaneous administration - 15 mg/kg (Abderhalden, 1935). The LD50 for convallarin in rabbits after oral administration was 320 mg/kg (Marhold, 1986). Table 18 summarizes the pharmacological studies undertaken on Convallaria as reported in the literature. Table 18 approx. here The novo-galenic preparation "Corglycon" (0.06% aqueous solution of purified total glycosides from C. majalis leaves) was developed in Ukraine SSR during the Soviet period. It is clinically approved and standardized to 11-16 frog units, or 1.8-2.2 cat units per 1 mL. The pharmacological effect of "Corglycon" is similar to that of strophanthin, but more prolonged. It

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is prescribed for patients with acute and chronic class II and III heart failure, cardiac decompensation, for cupping of paroxysmal tachycardia (Mashkovskii, 2002). A group of 34 patients having stage II-III atherosclerotic dyscirculatory encephalopathy with coexisting ischemic heart disease in the presence of stenosing and occlusive lesions of major brain arteries were evaluated for effects pentoxiphyllin and corglycon on the clinical course of this medical condition as well as systemic and cerebral haemodynamics. In this series, 82.7 % of patients derived benefit from a single intravenous infusion of pentoxiphyllin and corglycon and course treatment with this drug preparation showed an improvement in the parameters of systemic and cerebral hemodynamics and regression of neurologic symptomatology. The results of these studies were the basis for recommending pentoxiphyllin in combination with corglycon for treatment of patients with eukinetic and hypokinetic type systemic haemodynamics, whereas pentoxiphyllin alone is recommended for those with hyperkinetic type of haemodynamics, taking into consideration its cardiodepressive effects (Ishchenko et al., 1996). The publication did not give a full description of the controls, which makes it difficult to judge the outcomes of this trial. Crude drug preparations of Convallaria are not available in Russian pharmacies, but the tincture (1:10 EtOH 70%) is prescribed in Russia for internal use at a dose of 15-20 drops, 2-3 times per day as cardiotonic. "Corglycon" is used for intravenous injection at the dose of 0.5-1.0 mL in 1020 mL of glucose (20 or 40% solution), 1-2 times per day (Sokolov, 2000).

5.11. Cardiovascular 5.11.1. FLORES CRATAEGI et FRUCTUS CRATAEGI In term of Pharmacopoeia USSR, Flores crataegi and Fructus crataegi consists of flowers Crataegus sanguinea Pall. and flowers and fruits of . laevigata (Poir.) DC., C. chlorosarca Maxim (syn. . korolkowii hort. ex Dippel), C. wattiana Hemsl. & Lace (syn. . altaica (Loud.) Lange), . chlorocarpa Lenn, & K. Koch, C. dahurica Koehne ex C.K.Schneid. . monogyna

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Jacq. (syn. . alemanniensis Cinovskis, . orientobaltica Cinovskis), C. rhipidophylla Gand. (syn. . curvisepala Lindm.), C. rhipidophylla var. lindmanii (Hrabtová) K.I.Chr. (syn. .  dunensis Cinovskis), . pentagyna Waldst. & Kit. ex Willd., all belong to Rosaceae family. Dried false fruits and whole or cut, dried flower-bearing branches of of Crataegus monogyna Jacq. (Lindm.), or C. laevigata (Poir.) D.C. (synonym: C. oxyacantha L.) or their hybrids or a mixture of these false fruits and whole or cut, dried flower-bearing branches of other European Crataegus species including C. pentagyna Waldst. et Kit. ex Willd., C. nigra Waldst. et Kit., C. azarolus L. are included in European Pharmacopoeia. The pharmacological profile and indications of crataegus are similar in Russia and Europe. Therefore these questions will be not discussed in the review.

5.12. Haemostatic 5.12.1. HERBA POLYGONI HYDROPIPERIS Persicaria hydropiper (L.) Delarbre (syn. Polygonum hydropiper L., Polygonaceae), water pepper is an annual growing to 0.8 m tall plant, and in Russian popular medicine the leaves are used to stop bleeding and for treating haemorrhoids (Turova and Sapozhnikova, 1989). Water pepper has been used long time as haemostatic in uterine bleeding, during heavy and painful menstruation, abortion, and postpartum (Kravkov, 1912, Rossijsky, 1934). The leaves of this plant have been used to treat cancer, colds, and coughs (Onitsev, 1962). The infusion has been prescribed for treating rheumatism, chronic ulcers, haemorrhoid, tympanitis, and erysipelas (Yang et al., 2012). Women of Assam (India) have traditionally used the powdered dry root of P. hydropiper for the prevention of unwanted pregnancies (Hazarika and Sarma, 2006). Water pepper is a hot-tasting spice known in China, Japan, and Europe. The sprout of water pepper, called "mejiso" or "benitade" in Japanese, is a well-known relish for "sashimi," and the seed was sometimes used as a substitute for pepper in Europe (Matsumoto and Tokuda, 1990). A

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"Hydropiperinum", chemically characterized extract of P. hydropiper leaves with flavonoid glycosides, increases blood clotting, reduces the duration of bleeding, and strengthens uterus contractions (Fedukovich, 1960). Since 1946 aerial parts and liquid extract of P. hydropiper are included in the State Pharmacopoeia of the USSR (Vereschagin et al. 1959). The LD50 for the chloroform extract of P. hydropiper leaves was determined to be 760 mg/kg in male albino mice. Subcutaneous injection of a sub-lethal dose of extract into male mice once a week for 6 weeks failed to show any significant influence on white and red blood cell count and blood cholesterol (Rahman et al., 2005). A subchronic toxicity study of water pepper extract (WPE) was conducted in groups of 10 male and 10 female F344 rats fed powdered diets containing 62.5, 250, 1000 or 4000 ppm concentrations for 13 weeks. WPE was prepared by two-step extraction from leaves of P. hydropiper initially with N-hexane and then with ethanol, containing 7.0% polygodial as a major ingredient. Suppression of body weight gain due to decreased food consumption was observed in both sexes at 4000 ppm. At this dose, slight increases of blood urea nitrogen in both sexes and serum alanine aminotransferase, Na and Cl in females, were observed, suggestive of weak hepatic and renal toxicity, at least in females. The same females also exhibited slight decrease of red blood cells and haematocrit, slight increase of mean corpuscular volume and mean corpuscular haemoglobin, and minimal increase of splenic haemosiderin deposition, providing evidence of slight haemolytic anemia. In addition, enhanced accumulation of mast cells in the mesenteric lymph nodes induced by WPE treatment might be related with the complex biological actions on the gastrointestinal environment of polygodial and/or related ingredients included in this extract. The no-observed-adverse-effect level of WPE was 1000 ppm translating into 57.4 and 62.9 mg/kg/day for male and female rats, respectively (Kuroiwa et al., 2006). Table 19 summarizes the pharmacological studies undertaken on Polygonum hydropiper and reported in the literature. Table 19 approx. here

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No clinical data were found on P. hydropiper in the literature available. Aerial part and extract (70% EtOH) are available in Russia in pharmacies as OTC and recommended for internal administration at the dose of 1/3 of glass the infusion (1:10), 3-4 times a day or 30-40 drops of extract, 3-4 times a day as haemostatic (Sokolov, 2000). Polygonum hydropiper is a popular herb in Russia and its safety and efficacy is confirmed during long time. However, there is lack information in the public literature about efficacy. Further clinical studies are required to evaluate the claimed activity in patients and more details on the drug’s safety would be desirable.

5.13. Spasmolytic 5.13.1. FRUCTUS ANETHI GRAVEOLENTIS Anethum graveolens L (dill, Apiaceae) grows up to 40-60 cm tall. The fruits (seeds) of A. graveolens have had diverse uses in Russian traditional medicine: in powder form and tincture as carminative, expectorant and diuretic; decoctions are reported to possess antispasmodic, sedative, and galactagogue properties; infusion has been recommended as hypothensive (Gammerman et al., 1984; Lavrenova and Lavrenov, 1997). Dill is also a common household plant with a very long history of more than 2000 years of use as spice and condiment in food because of its flavor, as well as preservative. Dill water is believed to have a soothing effect and is given to babies to treat influenza, relieve hiccups and colics. Chewing the seeds reduces bad breath. Dill is also a galactagogue that is known to increase the flow of milk in nursing mothers and is passed to the baby via the milk to help prevent colics. Dill can be used as a regulatory agent of the menstrual cycle. Dill has been reported to possess antihyperlipidaemic and antihypercholesterolaemic activity (Heamalatha et al., 2011). The toxicity of A. graveolens was studied in mice after intraperitoneal injection. The maximum non-fatal doses of aqueous and ethanolic extracts of A. graveolens fruits were 0.45 g/kg and 5 g/kg (i.p.), respectively. LD50 values of the aqueous and EtOH extracts were 3 g/kg, and 7 g/kg,

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respectively (Hosseinzadeh et al., 2002). Table 20 summarizes the pharmacological studies undertaken on A. graveolens and reported in the literature. Table 20 approx. here A prospective randomized clinical trial was carried out on 30 hyperlipidemic patients of both sexes with an age range 44-63 years and a disease duration of 5-10 years. Patients were allocated into: Group A composed of 15 patients treated with lovastatin tablets 20mg once daily for four weeks period; Group B composed of 15 patients treated with 500 mg of fine powder of leaves of A. graveolens, be taken twice daily for four weeks period; in addition 15 healthy subjects serve as control. Treatment of patients with dill leaves powder results in highly significant P0.01 reduction in the values of total cholesterol (TC) (19.9%), triglyceride (29.5%), LDL-Chol (22.2%) and VLDL-Chol (25.2%). Statistically significant (P0.05) decrease in TC/HDL-Chol and LDL-Chol/HDL-Chol after four weeks of treatment, and reduction in TG/HDL-Chol even to less than that of healthy control was observed. In contrast, treatment with lovastatin significantly P0.05 decreased all lipid ratios in hyperlipidemic patients after four weeks duration. During the course of treatment, no side effects were recorded indicating the safety and tolerability of administered agent (Sahib et al., 2012). Taking into consideration literature data and the common use of Fructus anethi graveolentis in Russia and other countries the drug and its preparatiosn should be considered as safe and effective. Seeds of A. graveolens are available in Russia in pharmacies as OTC and recommended for internal administration at the dose of 1/3 of glass of the infusion (1:20), 3-4 times per day as spasmolytic (Sokolov, 2000). However publications about clinical trials are far too limited to allow conclusions about its therapeutic potential. This botanical drug clearly is an interesting subject for further investigations especially for further clinical tests.

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5.13.2. RHIZOMATA ET RADICES RUBIAE In the monograph of Pharmacopoeia USSR Rhizomata et radices Rubiae described as rhizome and roots of Rubia tinctorum L. (syn. R. iberica (Fish. ex DC). K. Koch). Rubia tinctorum, the common madder or dyer's madder, is a perennial plant species in the family Rubiaceae with a height of 60 to 100 cm. Roots of R. iberica have been used in traditional medicine of Kaukaz and Middle Asia as diuretic (Gammerman et al., 1984). Extract of rubia were reported to decrease the tension and increase amplitude of renal pelvic and ureter contractions. It promotes motility of stones and their elimination from kidney and urinary tract (Turova and Sapozhnikova, 1989). The safety of R. tinctorum was evaluated in mice, rats, and cats. Acute toxicity of an aqueous extract of madder root was studied during 14-day administration by gavage to (C57Bl/6 × C3H)F1 mice. The maximum tolerated dose of extract was between 3500 and 5000 mg/kg body weight. A subacute toxicity test was performed using 62 mice of each sex, mixing their diets with R. tinctorum extract at concentrations of 0, 0.3, 0.6, 1.25, 2.5, and 5% for 90 days. All mice tolerated these doses well. The body weight gains of either sex were not affected by the treatment. None of the mice treated with extract showed clinical signs of toxicity. Histopathological examinations showed retention cysts of the kidneys and epidermal vaginal cysts in a few of the treated or control mice. No hyperplastic, preneoplastic, and neoplastic lesions and no pathological findings of toxicity were found. It was concluded that dietary exposure to madder root extract at the doses tested had no significant acute or subacute toxic effects on mice (Ino et al., 1995). Acute intragastric administration of dry extract of R. tinctorum root at the doses of 125-15000 mg/g in mice was safe and no side effects were observed. No side effects were registered after 12 days intragastric administration of dry extract of madder roots (100 mg/kg) in rats. Extract at the doses of 20-200 mg/kg (intragastric) was safe for cats. However, an increased dose of up to 400 mg/kg was followed by vomiting, excitation during 3 hours, and subsequent sleeping. The normalization of physiological conditions was after 5 hours (Vichkanova et al., 2009).

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Male and female ACI/SegHsd rats, weighing 150–200 g, received a diet supplemented with 1 or 10% R. tinctorum root for 780 days. This root contained lucidin (0.34%), alizarin (0.67%; 1,2dihydroxyanthraquinone) and the primeverosides of both compounds. In the groups receiving 10% madder root diet, 2/16 males and 3/17 females developed hepatocellular adenomas, whereas none were observed in the controls or the 1% madder root group of either sex. Renal tubule-cell adenomas were observed in 1/16 males and 2/16 females in the 10% madder root group and a renal tubule-cell carcinoma in 1/14 males in the 1% madder root group (Westendorf et al., 1998). Male and female F344 rats were fed diet containing 0%, 2.5%, and 5.0% of 50% ethanol extract of madder root for 104 weeks. Body weights were significantly decreased in treated groups of both sexes throughout the feeding period. However, survival rates at week 104 were higher in treated groups of both sexes than in controls. Relative weights of the kidneys and liver were significantly increased in treated groups of both sexes. Histopathologically, karyomegaly and atypical tubules/hyperplasias, as well as renal cell adenomas and carcinomas were significantly increased in treated groups of both sexes with dose-dependence. Results indicate that extract exerts carcinogenic potential in the kidney and liver, even with the lower dose studied (Inoue et al., 2009). There have been a number of genotoxicity studies of madder color (50% ethanol extract of madder root) and its constituents. Madder color (MC) was found to be negative in bacterial DNA repair assays, but positive in reverse mutation assays with or without S9 mix in TA98, TA100 and TA1537 strains (Hachiya et al., 1985). Anthraquinone constituents of MC such as lucidin-3O-primeveroside and its deglycosylated metabolite, lucidin caused DNA adducts in rodents (Westendorf et al., 1998). Compounds, mollugin, 1-hydroxy-2-methylanthraquinone, 2ethoxymethyl-anthraquinone, rubiadin, 1,3-dihydroxyanthraquinone, 7-hydroxy-2methylanthraquinone, lucidin, 1-methoxymethylanthraquinone and lucidin-3-O-primeveroside, isolated from the roots of R. tinctorum showed mutagenicity with Salmonella typhimirium TA 100 and/or TA 98 (Kawasaki et al., 1992). Alizarin, a metabolite of 1-hydroxyanthraquinone,

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was weakly mutagenic in S. typhimurium TA1537 in the presence of S9 and in rat hepatocyte DNA-repair assays, but it was consistently inactive in transformation experiments with C3H/M2 mouse fibroblasts and in Hprt mutation assays with Chinese hamster V79 cells (Westendorf et al., 1990). Taking in account literature data, International Agency for Research of Cancer (IARC, 2002) has concluded that there is limited evidence in experimental animals for the carcinogenicity of R. tinctorum and it is not classifiable as to its carcinogenicity to humans (Group 3), however 1hydroxyanthraquinone is possibly carcinogenic to humans (Group 2B). However, the possibility of a human cancer hazard must be taken into consideration when madder is used chronically for therapeutic purposes. Table 21 summarizes the pharmacological studies undertaken on Rhizomata et radices Rubiae and reported in the literature. Table 21 approx. here Alizarin, a constituent of the madder root, is employed in phytotherapy to prevent recurrences of calcium-containing urinary stones. Pharmacokinetic studies were carried out in human subjects. After giving a single oral dose of 210 mg of alizarin there were two maxima in the serum concentration curves, the first at 2-4 h and the second at 6-8 h. Alizarin and its glucuronide conjugate were detected in both maxima by TLC. The mean elimination half-life was 12 h. The amounts excreted in the urine within 6 days ranged from 18.1 to 36.3%, and the amounts in the faeces from 21.6 to 33.0% (total recovery: 40-60%). In bile from a patient who had undergone cholecystectomy only 0.6% of the dose was recovered. To exclude any possibility that alizarin might be bound to calcium ions in bone, bone trephine specimens were examined from patients with oxalate stones who had previously been treated with alizarin for several years. No alizarin was detectable in these samples (Lorenz et al., 1985). A group of patients (15 male and female, 29-63 years old) with renal pelvis stones (1.5-7 cm) was treated with 0.5 g of R. tinctorum root extract, to be taken three times a day for 30 days. The therapeutic results were observed in 11 patients. The publication did not give a full description of

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the controls, which makes it is difficult to judge the outcomes of this trial. Treatment of patients results in removal of sand, small stones, and reduction of pyuria. However, the extract was not effective in 4 patients with big stones. In an other study tablets (0.25 g) of dry extract of R. tinctorum were used in a clinical trial to treat 22 patients with nephrolithiasis with different urinary stones localization: kidney (11 patients), urethra (9 patients), bladder (2 patients). Tablets were administered 3 times per day at the dose of 0.5 g (2 tablets) during 25 days. Positive effects were observed in 5 patients. The treatment led to removal of sand with urine, and reduction of pain. But no size decrease of big stones was registered according X-ray examination. No side effects were registered during both trials (Vichkanova et al., 2009). Tablets (0.25 g of dry extract standardized with min 8% of ruberitrinic acid) of R. tinctorum roots are available in Russian pharmacies as OTC and recommended for internal administration at the dose of 1 tablet, 3 times per day (max 3 tablets, 3 times per day) in 100 mL of warm water as spasmolytic (Sokolov, 2000). However, the information about chemical composition and pharmacological effects is insufficient and this is of interest for further study.

5.14. Sedative 5.14.1. HERBA LEONURI In terms of Pharmacopoeia USSR, Herba Leonuri (motherwort) consists of aerial parts of Leonurus cardiaca L. and Leonurus quinquelobatus Gilib. (syn. Leonurus cardiaca L. subsp. villosus (Desf. ex d'Urv.) Hyl.), Lamiaceae collected during the flowering season. The two species are similar in morphology, the only difference being the degree of hairiness. L. quinquelobatus has hairs all around the stem, not only on the angles, and the hairs are 1 mm long and erect. As soon as pharmacological effects of booth plants are similar and L. cardiaca is included in European Pharmacopoeia it is not reasonable for this review to discuss pharmacological effects of L. quinquelobatus.

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5.15. Polyvitamin 5.15.1. FRUCTUS SORBI Sorbus aucuparia L. (rowan, European rowan, mountain-ash, or European mountain-ash), is a small to medium-sized deciduous tree typically growing to 8-10 m tall belonging to the Rosaceae family. The fruit is a small pome of ca. 6-9 mm (rarely up to 14 mm) diameter. The edible fruits of S. aucuparia have been traditionally used in Russia for diuretic, antiinflammatory, anti-diarrheal, vasoprotective, and vasorelaxant activities, and also as vitamin source (Turova and Sapozhnikova, 1989; Sokolov, 2000). In Central and Lower Valais (Switzerland) rowan fruits are used for the treatment of gastrointestinal tract as antiflatulent, antibloating and against colics (Abbet et al., 2014). As it documented in the VOLKSMED database fruits of S. aucuparia are used in Austria as tea, syrup, jelly or liqueur for the treatment of respiratory tract related ailments, like infections, colds, flu, as well as fever, rheumatism and gout (Vogl et al., 2013). Rowanberry is a good source of vitamin C (up to 490 mg/kg) (Häkkinen et al., 1999) and it has been used for dietary jellies and jams and as component of syrups and polyherbal mixtures (Shass, 1952). Rowanberry is considered of low toxicity. The toxicity is related to the cyanogenic glycoside amygdalin, and also parascorbic acid, which is irritant to mucous membranes. They are present in very low concentrations and therefore rarely cause more than gastrointestinal effects (Campbell, Chapman, 2000). Table 22 summarizes the pharmacological studies undertaken on S. aucuparia and reported in the literature. Table 22 approx. here Capillary protective effect of S. aucuparia in combination with vitamin C and rutin was shown in patients with myocardial infarct and angina pectoris (Golubenko, 1967). But no details are available. And no other clinical data was found in the literature. Dry fruits of S. aucuparia are available in Russia in pharmacies as OTC and recommended for internal administration at the dose of 1/2 of glass of the infusion (1:20), 2 times a day as

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polyvitamin (Mashkovskii, 2002). It may be concluded that S. aucuparia fruits can be regarded as a promising and under-explored fruit which have been used in food in Europe and Asia, and might find wider applications for medicinal purposes. However pharmacological effects are not well documented and this subject is interesting for further study.

5.16. Regulation of metabolism, anti-inflammatory 5.16.1. INONOTUS OBLIQUUS According to the systematic classification, Chaga - also known as birch fungus (Fungus betulinus) - represents the terrestrial polypore fungus Inonotus obliquus (Pers.) Pil (Polyporaceae). Chaga has to be collected only from living or freshly cut old birch trees. On dry standing and fallen trees, chaga is destroyed and the content of active compounds decreases dramatically (Shashkina et al., 2006). Traditionally since the 12th century, chaga has been used in Russia for the treatment of gastrointestinal disorders, cardiovascular diseases, diabetes and even cancer. Allegedly, the Russian duke Vladimir Monomach was cured from lip cancer by chaga (Artemova, 2001). Chaga (in various combinations with other medicinal plants) was used for the treatment of gastric and duodenal ulcers and various forms of gastritis (Artemova, 2001; Kaukin, 2002). The chaga tea produces an increase of general stamina and has a pain relieving action, is used for treatment of heart, stomach and liver diseases (Gammerman et al., 1984; Saar, 1991). Safety of chaga extract was tested on mice, rabbits, dogs, and cats. The extract was well tolerated in large doses: LD50 for mice was 6.5 g/kg body weight. The extract administered per os in doses up to 1.0 g/kg did not cause any change in the behavior of rabbits, dogs, and cats (Lazovskaya, 1959). In a chronic administration test, rats and rabbits received a chaga extract in a daily dose of 1.0 and 0.3 g/kg body weight respectively over a period of 5 - 6 months. It was concluded that chaga is well tolerated in the doses indicated and does not exhibit accumulative toxic effects.

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The same tests also showed no evidence of pyrogenicity upon per oral administration of chaga in rabbits (Lazovskaya, 1959) (see Table 23). Table 23 approx. here Clinical data indicate that when chaga is administered for extended periods, it has beneficial effects in the treatment of patients with stage III – IV of cancer, irrespective of the tumor location. In most of these patients without pronounced cachexia, a 3- to 4-week administration of chaga led to a decrease and termination of the pain syndrome, which allowed the administration of narcotic drugs to be stopped (Bulatov et al., 1959; Pyaskovskii, Rikhter, 1961; Shashkina et al., 2006). The commercial chaga extract Befungin®, contains EtOH (10%) extract of chaga with 1.76% of chloride or 2.0% sulfate of cobalt, is manufactured in 8 factories all around Russia. A group of 50 patients (14 women and 36 men) suffering from psoriasis were treated with Befungin® and chaga extract paste. In 37 of these patients the development of psoriasis was preceded by diseases of the gastrointestinal tract or liver (hyperacid or hypoacid gastritis, hepatocholecystitis, gastric ulcer or duodenal ulcer, colitis). In 9 patients these gastrointestinal tract problems appeared during the existing psoriasis conditions, another 4 patients had accompanying chronic pharyngonasal cavity conditions. Almost all patients with gastrointestinal disorders were complaining about pyrosis, belching, unstable stool, intolerance to fatty foods, pain in the right upper quadrant of epigastric area etc. The patients noted that exacerbation of psoriasis often coincided with exacerbation of gastrointestinal tract disorders. Duration of the psoriasis condition before Treatment with Chaga preparations was 1 year in 5 patients, up to 3 years in 7 patients, 7 to 5 years in 8 patients, up to 10 years in 13 patients, from 10 to 15 years in 7 patients, more than 15 years in 10 patients. Among the patients, 3 were suffering from psoriatic erythroderma, 1 had psoriatic arthritis, 18 had extensive psoriasis with a massive infiltration of plaques, 20 had extensively spread small plaque rashes, 8 had localized psoriatic plaques. Forty three patients started the treatment with Chaga during the acute stage of psoriasis, 7 during the

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steady-state. Chaga extract was heated au-bain-marie and 1 table spoon of extract was diluted in a glass of boiled water at room temperature. One table spoon of this solution was taken orally, 3 times a day, 20-30 minutes before meals. Water solutions of Befungin® were prepared by mixings 1 dessert spoon of Befungin® in 100 mL of boiled water (room temperature). The intake instructions were the same as above. Both Chaga preparations have no unpleasant odor or taste, and are well tolerated by the patients even after several months of continuous intake. Most of the patients (42) only used a Chaga preparation for internal use, 8 were also using ointments and one of the preparations for internal use. Twenty four patients were using Chaga preparations 3-6 months, 18 patients up to 12 months, 8 patients for more than 2 years. The therapeutic effect of Chaga was manifesting itself only slowly, reaching a maximum at the 3rd month of regular intake. In most cases disappearance of psoriatic rashes started at the torso, then the scalp, upper limbs and finally hips and low legs. The Chaga treatment’s normalizing effect on nail plates was noted after 2-3 months. Extensive psoriasis with massive plaques was completely cured in 14 patients, and improvements were mentioned for 2 patients. Extensive psoriasis with localized plaques was completely cured in 16 patients, and improvements were mentioned in 3 patients. Limited psoriasis lesions and erythrodermic lesions were completely cured in 5 and 3 patients, respectively. Psoriasis-therapy with chaga was especially successful in cases when psoriasis occurs in combination with chronic inflammatory diseases of gastrointestinal tract, liver and biliary system. The maximum efficiency of treatment was noted after 9 to 12 weeks of continuous intake. Additionally, improvement in gastrointestinal functions, increased vitality and general tonus in all patients was noted after long and regular chaga intake what evidenced about adaptogenic properties of I. obliquus (Dosychev, Bystrova, 1973). Chaga and Befungin® are available in Russia in pharmacies as OTC and recommended for internal administration at the dose of 1/2 of glass the infusion (1:10), 6 times a day or 1 table spoon of Befungin®, 3 times a day during 3-5 months as regulator of metabolism and in complex therapy of gastrointestinal diseases (Mashkovskii, 2002). Chaga is well known and popular in

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Russia and its safety and some evidence for efficacy is based on a long tradition of empirical use. However, there is lack of information in the public literature about efficacy under controlled conditions. Further clinical studies are required to evaluate the claimed activity in patients and more details on the drug’s safety would be desirable. With the recent findings of the importance of the GI-tract microbiome, studying the effect of chaga on this biome would be of great interest.

5.17. Tonic 5.17.1. RADICES ARALIAE MANDSHURICAE Aralia elata (Miq.) Seem. syn A. mandshurica Rupr. & Maxim or Japanese angelica tree (Araliaceae) is an upright deciduous small tree or shrub growing up to 6 m in height, native to eastern Russia, China, Korea, and Japan. Itse stem and root bark Aralia elata have been used as a traditional and local medicine in East Asian countries and Russia for the treatment of cough, diabetes, gastric ulcer, hepatitis, and inflammatory diseases such as rheumatoid arthritis (Namba, 1980; Perry, 1980; Turova and Sapozhnikova, 1989; Ma et al., 2005). The Nanai (“nanaitsy”in Russian) a Tungusic people of the Russian Far East, have used roots of A. elata for toothache and stomatitis, as tonic and in liver diseases (Vostrikova, 1973). The Ainu, aboriginal peoples who once dominated Hokkaido in Japan, have used roots of A. elata (Ayus-ni, enenkeni in Japan) as a stomachic (Mitsuhashi, 1976). In Russian codified medicine Aralia belongs to the group of classical adaptogens (Brekhman, Dardymov, 1969). The toxic acute and subchronic effects of A. mandshurica dried root extract standardized to a minimum of 3% of aralosides were studied on Sprague-Dawley rats of both sexes after per oral administration. In the acute toxicity experiment an extract was administered twice a day in different concentrations. The LD50 was estimated to be 16.5 g/kg and 16.8 g/kg for male and female rats, respectively. Before death, the animals showed nervous depression, diminution of the motor activity, frequent micturition, respiratory difficulty and diarrhea. In a subchronic toxicity the extract was administered per oral at the doses of 0.2, 1.7, 3.4 g/kg over a period of 90

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days. Depression of the CNS response was not observed. There was an increase in the levels of aspartate aminotransferase (AST) and serum alkaline phosphatase (SAP) enzymes with a dose of 3.4 g/kg in both sexes on day 90 of administration, but no changes were observed in urea and serum protein. A significant decrease of the body weight was recorded in both sexes with a dose of 3.4 g/kg. Moreover, the animals treated with doses of 1.7 and 3.4 g/kg showed a diminution of fecal consistence. An increase of the liver weight was produced with all the doses of A. mandshurica, but neither macroscopic nor histological alterations were observed, as in the rest of the organs. Authors concluded that the extract of Aralia might be accumulated to produce its toxic effect in the long term (Burgos et al., 1994). The hepatotoxic effect of a dried root extract of A. mandshurica (standardized to a minimum of 3% of aralosides) was studied over a period of 60 days (0.16 g/kg, 1.5 g/kg and 3 g/kg) in Landrace pigs of both sexes. No changes in behaviour, external appearance, consumption of food, or body weight was observed. The levels of alanine amino transferase (ALT) and -glutamil transpeptidase (gGT) were increased significantly with all the concentrations of A. mandshurica at day 60. SAP did not show significant differences during the whole experiment. A subclinical hepatitis characterized by the presence of lymphocytes and polymorphonuclears in the portal and periportal region was observed (Burgos et al., 1997). The LD50 for mice after per oral administration of the sum of aralosides (A, B, and C) was 0.47 g/kg (Brekhman, Dardymov, 1969). The acute toxicity of araloside A (chikusetsusaponin IV) isolated from A. elata was studied in ICR male mice. The LD50 after 1-week of oral administration was 3.22 g/kg (Lee et al., 2005). Table 24 summarizes some pharmacological studies undertaken on Aralia and reported in the literature. Table 24 approx. here In an open, single arm study including 106 patients treated for various asthenic conditions a success rate of about 90% using Aralia was reported The administration (3 times per day during 30 days) of 2 mL of A. mandshurica tincture (1:15, EtOH 70%) standardized for aralosides to patients aged 23 to 60 years with a diagnosis of long-term effects of traumatic brain injury with

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associated asthenic syndrome and neurotic reactions, depression, neurasthenia, and psychasthenia significantly increase their working capacity, appetite and sleeping. Decrease of complaints of fatigue, headaches, and general weakness was observed. Some patients have reported about increase of sexual potency and libido (Gubina, 1988). Positive effect in patients with myasthenia syndrome accompanied by chronic post-influenza arachnoiditis was registered after 2 weeks of treatment with Aralia tincture (Gubina, 1959). The normalization of body function is one of the main attributes of adaptogens. There were no statistically significant effects of Aralia tincture on patients with normal blood pressure, although normalization of blood pressure was observed in patients with hypotension (Turova and Sapozhnikova, 1989). Aralia has a pronounced positive effect in clinical trials on introverts and people with high levels of neuroticism. Maximal positive effect was observed during first 4 months of treatment (Markin, Makrina, 2007; Markina, Makrin, 2008). The effects of oral treatment with a phytopreparation Aralox containing A. mandshurica and Engelhardtia chrysolepis Hance (Juglandaceae) extracts on some parameters of lipid metabolism was studied. Randomized placebo-controlled study was carried out over 15 weeks and included 32 women with nondiabetic obesity. The patients received Aralox (main group, n=16) or placebo (control group, n=16) 3 times daily 30-45 min before meals. A single dose of Aralox included 150 mg A. mandshurica extract containing at least 20% triterpene saponines (aralosides) and 150 mg extract from Engelhardtia chrysolepis leaves containing at least 20% flavonoid (dehydroquercetin-3-rhamnoside). Thirteen women from the main group and 14 controls completed the 15-week study. No appreciable differences in physical characteristics and nutrition of examined patients in the two groups were detected before Aralox/placebo treatment. Patients receiving Aralox 3 times daily lost 4.3±0.7 kg (pkatchenko, Ye.\., Skiba, $.I., \labin, Yu.V., D. M. Pykhtyeyev, 2008. Induction of inflammatory-destructive changes in the oral epithelium by delagil, emotional-painful stress and their inhibition by combinatiun of the ellagic and gallic acids. Dosyagnenny biologii ta mediciny 2, 20-24. Molokovskii, D.S., Davydov, V.V., Khegai, M.D., 2002. Antidiabetic activities of adaptogenic formulations and extractions from medicinal plants. Rastitelnye Resursy 38, 15-28. Monsefi, M., Ghasemi, M., Bahaoddini, A., 2006. The effects of Anethum graveolens L. on female reproductive system. Phytotherapy Research 20(10), 865-868. Montiel-Ruiz, R.M., Roa-Coria, J.E., Patiño-Camacho, S.I., Flores-Murrieta, F.J., DécigaCampos, M., 2012. Neuropharmacological and toxicity evaluations of ethanol extract from Rhodiola rosea. Drug Development Research 73, 106-113. Morikawa, T., Wang, L-B., Nakamura, S., Ninomiya, K., Yokoyama, E., Matsuda, H., Muraoka, O., Wu, L-J., Yoshikawa, M., 2009. Medicinal Flowers. XXVII. New flavanone and chalcone glycosides, arenariumosides I, II, III, and IV, and tumor necrosis factor- inhibitors from everlasting, flowers of Helichrysum arenarium. Chemical and Pharmaceutical Bulletin 5, 361-367. Moskalenko, S.A., 1986. Preliminary screening of fareastern ethnomedicinal plants for antibacterial activity. Journal of Ethnophannacology 15, 231-259. Muraviova, D.A. 1978. Pharmacognosy. Medicine, Moscow. Muto, Y., Ichikawa, H., Kitagawa, O., Kumagai, K., Watanabe, M., Ogawa, E., Seiki, M., Shirataki, Y., Yokoe, I., Komatsu, M., 1994. Studies on antiulcer agents. I. The effects of

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various methanol and aqueous extracts of crude drugs on antiulcer activity. Yakugaku Zasshi 114, 980-994. Myronchenko, S.I., Zvyagintseva, T.V., 2008. Effect of altan preparation on lipid peroxidation after local irradiation. Fundamental research 6, 83-84. Namba, T., 1980. The Encyclopedia of Wakan-Yaku with Color Pictures. Vol. II, Hoikusha Publ. Co., Ltd., Osaka, p. 180. Narimanov, A.A., 1992. Reproductive capacity of male mice protected from supralethal effect of gamma-radiation by the administration of a mixture of extracts from Archangelica officinalis and Ledum palustre. Radiobiologia 32, 271-275. Narimanov, A.A., Myakisheva, S.N., Kuznetsova, S.M., 1991. The radioprotective effect of Archangelica officinalis Hoffm. and Ledum palustre L. extracts on mice. Radiobiologia 31, 391-393. Nartowska, J., Sommer, E., Pastewka, K., Sommer, S., Skopinska-Rozewska, E. 2004. Antiangiogenic activity of convallamaroside, the steroidal saponin isolated from the rhizomes and roots of Convallaria majalis. Acta Poloniae Pharmaceutica 61, 279-282. Naseri, M., Mojab, F., Khodadoost, M., Kamalinejad, M., Davati, A. Choopani, R., Hasheminejad, A., Bararpoor, Z., Shariatpanahi, S., Emtiazy, M., 2012. The study of antiinflammatory activity of oil-based dill (Anethum graveolens L.) extract used topically in formalin-induced inflammation male rat paw. Iranian Journal of Pharmaceutical Research 11, 1169-1174. Nazir, N., Koul, S., Qurishi, M.A., Taneja, S.C., Ahmad, S.F., Bani, S., Qazi, G.N., 2007. Immunomodulatory effect of bergenin and norbergenin against adjuvantinduced arthritis a flow cytometric study. Journal of Ethnopharmacology 112, 401-405. Nicholson, J.A., Darby, T.D., Jarboe, C.H., 1972. Viopudial, a hypotensive and smooth muscle antispasmodic from Viburnum opulus. Experimental Biology and Medicine. 140(2), 457461.

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Nikolaeva, V.G., Khokhlova, A.A., 1981. Effect of tincture of buds of Betula verrucosa on Staphylococc. Rastitelnye Resursy 17(3), 410-413. Nistor Baldea, L.A., Martineau, L.C., Benhaddou-Andaloussi, A., Arnason, J.T., Lévy, É., Haddad, P.S., 2010. Inhibition of intestinal glucose absorption by anti-diabetic medicinal plants derived from the James Bay Cree traditional pharmacopeia. Journal of Ethnopharmacology 132(2), 473-482. Nohynek, L.J., Alakomi, H., Kähkönen, M.P., Heinonen, M., Helander, I.M., OksmanCaldentey, K., Puupponen-Pimiä, R., 2006. Berry phenolics: antimicrobial properties and mechanisms of action against severe human pathogens. Nutrition and Cancer 54, 18-32. Nosal, M.A., Nosal, I.M., 1960. Lekarstvennuiye Rasteniya i Sposobui ikh Primrniya v Narodye (Medicinal plants and the ways that they are used by people). State medical publishing, Kiev, 256 p. Olsson, E.M.G., von Scheele, B., Panossian, A.G., 2009. A randomized double-blind placebo controlled parallell group study of SHR-5 extract of Rhodiola rosea roots as treatment for patients with stress related fatigue. Planta Medica75, 105-112. Onitsev, P.I., 1962. Biological evaluation of preparations from Polygonum hydropiper. Aptechnoe Delo 11, 49-52. Ovodova, R. G., Golovchenko, V.V., Popov, S.V., Shashkov, A.S., Ovodov, Yu.S., 2000. The isolation, preliminary structural studies, and physiological activity of water-soluble polysaccharides from the squeezed berries of the snowball tree Viburnum opulus. Russian Journal of Bioorganic Chemistry 26, 54-59. Ozaki, H., Nagase, H., Urakawa, N., 1985. Interaction of palytoxin and cardiac glycosides on erythrocyte membranes and Na+ + K+ ATPase. European Journal of Biochemistry 152, 475–480.

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Palombo, E.A., 2006. Phytochemicals from traditional medicinal plants used in the treatment of diarrhoea: modes of action and effects on intestinal function. Phytotherapy research 20, 717-724. Panchenkov M.M, 1950. Combined treatment of peptic ulcer disease with Gnaphalium uliginosum and Polemonium caeruleum. Clinical Medicine 3, 86-87. Panossian, A, Wikman, G. 2008. Pharmacology of Schisandra chinensis Bail.: An overview of Russian research and uses in medicine. Journal of Ethnopharmacology 118, 183-212. Panossian, A., 2003. Adaptogens: Tonic herbs for fatigue and stress. Alternative and Complementary Therapies 9, 327-332. Panossian, A., Wagner, H., 2005. Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration. Phytotherapy Research 19, 819-838. Panossian, A., Wikman, G. Wagner, H. 1999. Plant adaptogens III. Earlier and more recent aspects and concepts on their mode of action. Phytomedicine 6(4), 287-300. Panossian, A., Wikman, G., 2009. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Current Clinical Pharmacology 4, 198-219. Panossian, A., Wikman, G., Sarris, J., 2010. Rosenroot (Rhodiola rosea): Traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 17, 481-493. Pardo, E.G., Garcia-Tellez, D., del Pozo, E.C., 1951. The action of several principles anid extracts of the digitalis group on ischemic skeletal muscle. Journal of Pharmacology and Experimental Therapeutics 101, 63-67 Park, Y.M., Won, J.H., Kim, Y.H., Choi, J.W., Park, H.J., Lee, K.T. (2005). In vivo and in vitro anti-inflammatory and anti-nociceptive effects of the methanol extract of Inonotus obliquus. Journal of Ethnopharmacology 101, 120-128.

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Pawlaczyk, I., Czerchawski, L., Pilecki, W., Lamer-Zarawska, E., Gancarz, R., 2009. Polyphenolic-polysaccharide compounds from selected medicinal plants of Asteraceae and Rosaceae families: Chemical characterization and blood anticoagulant activity. Carbohydrate Polymers 77(3), 568-575. Peev, C., Dehelean, C., Mogosanu, C., Feflea, S., Tiulea, C., 2010. Spring drugs of betula pendula Roth. : Biologic and pharmacognostic evaluation. Studia Universitatis "Vasile Goldis" Arad. Seria Stiintele Vietii (Life Sciences Series) 3, 41-43. Perfumi, M., Mattioli, L., 2007. Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice. Phytotherapy Research 21, 37-43. Perry, L.M., 1980. Medicinal Plants of East and Southern Asia. The MIT Press, Cambridge, p. 41. Petrovsky, Yu.A., Skakun, N.P., Turko, I.P., 1953. Flamin Helichrysum arenarium as cholagogic preparation. Pharmacology and toxicology 5, 50. Pevzner, E.S., Raitsina, M.Z., 1954. Experience in birch buds treating of patients with eczema. In: Collection of scientific works of Belorussian skin and venereal diseases institute 4, 368. Pieroni, A., Quave, C.L., Villanelli, M.L., Mangino, P., Sabbatini, G., Santini, L., Boccetti, T., Profili, M., Ciccioli, T., Rampa, L.G., Antonini, G., Girolamini, C., Cecchi, M., Tomasi, M., 2004. Ethnopharmacognostic survey on the natural ingredients used in folk cosmetics, cosmeceuticals and remedies for healing skin diseases in the inland Marches, CentralEastern Italy. Journal of Ethnopharmacology 91, 331-344. Pirvu, L., Dragomir, C., Schiopu, S., Mihul, S.C., 2012. Vegetal extracts with gastroprotective activity. Part. I. Extracts obtained from Centaurea cyanus L. raw material. Romanian Biotechnological Letters 17(2), 7169-7176.

91

Popov, S.V., Popova, G.Y., Nikolaeva, S.Y., Golovchenko, V.V., Ovodova, R.G., 2005. Immunostimulating activity of pectic polysaccharide from Bergenia crassifolia (L) Fritsch. Phytotherapy Research 19, 1052-1056. Popova, T.M., 2002. Study of lipid peroxidation and altan antioxidant activity in case of salmonellosis. Visnik of Kharkiv National University 546, 74-75. Pozharitskaya, O.N., Ivanova, S.A., Shikov, A.N., Makarov, V.G., Galambosi, B., 2007. Separation and evaluation of free radical-scavenging activity of phenol components of green, brown, and black leaves of Bergenia crassifolia by using HPTLC-DPPH method. Journal of Separation Science 30, 2447-2451. Pozharitskaya, O.N., Shikov, A.N., Makarova, M.N., Kosman, V.M., Faustova, N.M., Tesakova, S.V., Makarov, V.G., Galambosi, B. 2010. Anti-inflammatory activity of a HPLCfingerprinted aqueous infusion of aerial part of Bidens tripartita L. Phytomedicine 17, 463468. Prakash, A.O., 1985. Biological evaluation of some medicinal plant extracts for contraceptive efficacy in females, in Runnebaum, B., Rabe, T., Kiesel, L. (eds.), Future Aspects in Contraception. MTP Press Limited. pp. 115-128. Pyaskovskii, S., Rikhter, S., 1961. Complex investigation of physiologically active substances of lower plants. Academy of Science USSR, Moscow - Leningrad, pp. 258 - 263. Qiu, J., Luo, M., Wang, J., Dong, J., Li, H., Leng, B., Zhang, Q., Dai, X., Zhang, Y., Niu, X., Deng, X., 2011. Isoalantolactone protects against Staphylococcus aureus pneumonia. FEMS Microbiology Letters 324(2), 147-155. Rahman, E., Goni, S.A., Rahman, M.T., Ahmed, M., 2002. Antinociceptive activity of Polygonum hydropiper. Fitoterapia 73, 704-706. Rahman, I., Gogoi, I., Dolui, A.K., Handique, R., 2005. Toxicological study of plant extracts on termite and laboratory animals. Journal of Environmental Biology 26 , 239-241.

92

Rasina, L.N., 2002. The criopreparation chaga (Inonotus obliquus) effect both on deposition or decorporation of 90Sr and on influence of external prolonged -irradiation. Radiatsionnaya Biologiya. Radioekologiya 42, 399 - 403. Register Russia 2012. On line State Register of Medicinal preparations by the Ministry of Public Health and Social Development of the Russian Federation., http://grls.rosminzdrav.ru/GRLS.aspx (accessed 2012). Rezaee-Asl, M., Bakhtiarian, A., Nikoui, V., Sabour, M., Ostadhadi, S., Yadavar-Nikravesh, MS., Giorgi, M. 2013. Antinociceptive properties of hydro alcoholic extracts of Anethum graveolens L. (dill) seed and aerial parts in mice. Clinical and Experimental Pharmacology 3(2), 122. doi: 10.4172/2161-1459.1000122 Rhee, J.K., Baek, B.K., Ahn, B.Z., 1985. Structural investigation on the effects of the herbs on Clonorchis sinensis in rabbits. The American Journal of Chinese Medicine 13, 119-125. Rifat-uz-Zaman, M.S,, Akhtar, M.S., Khan, M.S., 2004. Preliminary eva-luation of Anethum graveolens fruit in indomethacin-ulcer induced rats. Journal of Biological Sciences 4, 151156. Rikalo, N.A., 2005. Efficacy of phytoremedy altanum on experimental klebsiellosis. Teoretichna i experimentalna medicina (Ukraine) 2, 41-44. Röder, E., 1988. Wie gef~ihrlich ist Huflattich als Hustentee? Deutsche Apotheker-Zeitung 128, 43, 2321-2322. Rop, O., Reznicek, V., Valsikova, M., Jurikova, Mlcek, T.J., Kramarova, D., 2010. Antioxidant properties of European cranberrybush fruit (Viburnum opulus var. edule). Molecules 15, 4467-4477. Rossijsky, D.M., 1934. Water pepper (Polygonum hydropiperi) as bleeding stop medicine. Kazansky medicinsky zhurnal 5, 448. Rossijsky, D.M., 1942. About therapeutical use of preparations from alder (lnus incana). Farmatsiya-Moscow 5, 27.

93

Roulet, M., Laurini, R., Rivier, L., Calame, A., 1988. Hepatic veno-occlusive disease in newborn infant of a woman drinking herbal tea. Journal of Pediatrics 112, 433-436. Ryu, J.H., Jeong, Y.S., Sohn, D.H., 1999. A new bisabolene epoxide from Tussilago farfara, and inhibition of nitric oxide synthesis in LPS-activated macrophages. Journal of Natural Products 62, 1437-1438. Saar, M. 1991. Fungi in Khanty folk medicine. Journal of Ethnopharmacology 31, 175–179. Safonova, E.A., Razina, T.G., Lopatina, K.A., Fedorova, E.P., Zueva, E.P., 2010. Reduction in paclitaxel toxic effect on blood system with the help of water-soluble polysaccharides from Tussilago farfara and Acorus calamus. Siberian Journal of Oncology 2, 42-46. Sagdic, O., Aksoy, A., Ozkan, G., 2006. Evaluation of the antibacterial and antioxidant potentials of cranberry (gilaburu, Viburnum opulus L.) fruit extract. Acta Alimentaria 35, 487-492. Sahib, A.S., Mohammad, I.H., Al-Gareeb, A.I., 2012. Effects of Anethum graveolens leave powder on lipid profile in hyperlipidemic patients. Spatula DD 2, 153-158. Samarina, G.I., 1948. About pharmacology of Polygonum persicaria. Farmakologiya i Toksikologiya 5(2), 32-36. Samarina, G.I., 1950. About pharmacology of preparations from Polygonum persicaria herb. Izvestia Academy of sciences Kazakhstan SSR. Seria Phyziologicheskaya 92(3), 61. Saratikov, A.S., Krasnov, E.A., 2004. Rhodiola rosea (Golden root) Fourth edition, Revised and Enlarged. Tomsk State University Publishing House, 292 p. Saratikov, A.S., Krasnow, E.A., 1987. Rhodiola rosea is aValuable Medicinal Plant. Medical Institute Tomsk, Tomsk p.252. Schinella, G.R., Giner, R.-M., Del Carmen Recio, M., De Buschiazzo, P.M., Ríos, J.-L., Máñez, S., 1998. Anti-inflammatory effects of South American Tanacetum vulgare. Journal of Pharmacy and Pharmacology 50(9), 1069-1074.

94

Sedykh, T.N., Mesherskaya, K.A., Kabantsev, V.V., 1986. The influences of the Aralia mandshurica tincture, aminalon or their combination on memorization of tests. In New Medicinal Preparation from Plants of Siberia and the Far East. Tomsk, 132. Sezik, E., Yesilada, E., Shadidoyatov, H., Kulivey, Z., Nigmatullaev, A.M., Aripov, H.N., Takaishi, Y., Takeda, Y., Honda, G., 2004. Folk medicine in Uzbekistan I. Toshkent, Djizzax, and Samarqand provinces. Journal of Ethnopharmacology 92, 197-07. Shashkina, M.Ya., Shashkin, P.N., Sergeev, A.V., 2006. Chemical and medicobiological properties of chaga. Pharmaceutical Chemistry Journal 40, 560–568. Shass, E.Yu., 1952. Phytotherapy. Academy of Medicinal science of USSR, Moscow Shchepotin, B.M., Shchulipenko, I.M., Prisiazhniuk, M.S., 1984. Use of infusions of medicinal plants in patients with hypertensive disease. Vrachebnoe Delo 6, 18-22. Shevtsov, V.A., Zholus, B.I., Shervarly, V.I., Vol’skij, V.B., Korovin, Y.P., Khristich, M.P., Roslyakova, N.A., Wikman, G., 2003. A randomized trial of two different doses of a SHR5 Rhodiola rosea extract versus placebo and control of capacity for mentalwork. Phytomedicine 10, 95-105. Shikov, A.N., Kundracikova, M., Palama, T.L., Pozharitskaya, O.N., Kosman, V.M., Makarov, V.G., Galambosi, B., Kim, H.J., Jang, Y.P., Choi, Y.H,, Verpoorte, R., 2010. Phenolic constituents of Gnaphalium uliginosum L. Phytochemistry Letters 3, 45-47. Shikov, A.N., Pozharitskaya, O.N., Kamenev, I.Yu., Makarov, V.G., 2011. Arznei und Gewurzpflanzen in Russland. Zeitschrift fur Arznei & Gewurzpflanzen 16, 135–137. Shikov, A.N., Pozharitskaya, O.N., Makarova, M.N., Dorman, H.J.D., Makarov, V.G., Hiltunen, R., Galambosi, B., 2010. Adaptogenic effect of black and fermented leaves of Bergenia crassifolia L. in mice. Journal of Functional Foods 2, 71-76. Shikov, A.N., Pozharitskaya, O.N., Makarova, M.N., Kovaleva, M.A., Laakso, I., Dorman, H.J.D., Hiltunen, R., Makarov, V.G., Galambosi, B., 2012. Effect of Bergenia crassifolia

95

L. extracts on weight gain and feeding behavior of rats with high-caloric diet-induced obesity. Phytomedicine 19, 1250-1255. Skakun, N.P., Stepanov, N.Yu., 1988. Comparative evaluation of the hepatoprotective, antioxidant and choleretic activity of flavonoid drugs. Vrachebnoe Delo, 12, 52-54. Smirnova, A.S., Iadrova, V.M., 1968. Comparative study of the astringent effect of liquid extracts from Viburnum opulus L. Farmatsiya-Moscow 17, 42-45. Sokolov, P.D., 1990. Plant resources of USSR. Flowering plants, its chemical composition, application. Families Caprifoliaceae - Plantaginaceae. Nauka, Leningrad. Sokolov, S., Monogarov, V.D., Sobolev, V.L., 1971. The influence of the saponins of the Aralia mandshurica on the processes of recovery on athletes after intensive physical work loads. In Biologically Active Substances of Flora and Fauna of the Far East and Pacific Ocean. Vladivostok: Far East Scientific Center of the Academy of Science of the USSR, 113-114. Sokolov, S.Ya., 2000. Phytotherapy and Phytopharmacology: The Manual for Doctors. Medical News Agency, Moscow. Solovieva, V.A. 2005. Traditional methods of health promotion [Narodnye metody ukreplenija zdorovja]. Izdatelsky dom "Neva", St-Petersburg. 352 p. Sorokina, A.A., Maltseva, A.A., Brezhneva, T.A., Slivkin, A.I., 2010. Evaluation of the hypoglycemic activity of great valerian (Polemonium caeruleum) preparation. FarmatsiyaMoscow 2, 18-20. Soylak, M., Elci, L., Saracoglu, S., Divrikli, U., 2002. Chemical analysis of fruit juice of European cranberrybush (Viburnum opulus) from Kayseri – Turkey. Asian Journal of Chemistry 14, 135-138. Spang, R., 1989. Toxicity of tea containing pyrrolizidine alkaloids. Journal of Pediatrics 115, 1025. Spasov, A.A., Wikman, G.K., Mandrikov, V.B., Mironova, I.A., Neumoin, V.V., 2000. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of

96

Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine 7, 85-89. Sperl, W., Stuppner, H., Gassner, I., 1995. Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea. European Journal of Pediatrics 154, 112-116. Spiridonov, N.A., Konovalov, D.A., Arkhipov, V.V., 2005. Cytotoxicity of some Russian ethnomedicinal plants and plant compounds. Phytotherapy Research 19, 428-432. Stepanova, E.F., Krikova, A.V., Mikaelian, A.S., Goncharova, V.V., Korochinsky, A.V., 2006. Effect of complex fractions of Bidens tripartita on circulatory dynamics of normotensive rats. Modern problems of education and science 2, 105-107. Stevi, T., Šavikin, K., Zduni, G., Stanojkovi, T., Jurani, Z., Jankovi, T., Menkovi, N., 2010. Antioxidant, cytotoxic, and antimicrobial activity of Alnus incana (L.) ssp. incana Moench and A. viridis (Chaix) DC ssp. viridis extracts. Journal of Medicinal Food 13(3), 700-704. Suslov, N.I., Churin, A.A., Skurikhin, E.G., Provalova, N.V., Stal'bovskii, A.O., Litvinenko, V.I., Dygai, A.M., 2002. Effect of the natural nootrope and adaptogen preparations on the bioelectric cortex activity in rats. Eksperimental'naya i Klinicheskaya Farmakologiya 65, 7-10. Szadowska, A. 1962. Pharmacology of galenic preparations and flavonoids from Helichrysum arenarium. Acta Poloniae Pharmaceutica 19, 465-479. The State Pharmacopoeia of the USSR, 11th ed., part 2, 1990. Medizina, Moscow. Tomczykowa, M., Tomczyk, M., Jakoniuk, P., Tryniszewska, E. 2008. Antimicrobial and antifungal activities of the extracts and essential oils of Bidens tripartita. Folia Histochemica et Cytobiologica 46, 389-393. Tournier, H., Schinella, G., De Balsa, E.M., Buschiazzo, H., Mañez, S., De Buschiazzo, P.M., 1999. Effect of the chloroform extract of Tanacetum vulgare and one of its active

97

principles, parthenolide, on experimental gastric ulcer in rats. Journal of Pharmacy and Pharmacology 51, 215-219. Tshibilaev, Ch.S., Severtsev V.A., Tshibilaev T.Ch. 2006. History of development of pharmaceutical production in Russia. Russian Academy of natural history. Moscow. Tunón, H., Olavsdotter, C., Bohlin, L., 1995. Evaluation of anti-inflammatory activity of some Swedish medicinal plants. Inhibition of prostaglandin biosynthesis and PAF-induced exocytosis. Journal of Ethnopharmacology 48, 61-76. Turischev, S., 2008. Medicinal plants with sedative effects. Vrach 3, 69-71. Turova, A.D., 1955. Pharmacological study and clinical application of Polemonium caeruleum. In: Polemonium caeruleum [in Russian], Moscow. Turova, A.D., Sapozhnikova, E.N., 1989. Medicinal Plants of USSR and their applications. Medizina, Moscow. [in Russian] Tzankova, V., Danchev, N., 2007. Cytisine - from ethomedical use to the development as a natural alternative for smoking cessation. Biotechnology & Biotechnological Equipment 21(2), 151-160. Ulger, H., Ertekin, T., Karaca, O., Canoz, O., Nisari, M., Unur, E., Elmali, F., 2012. Influence of gilaburu (Viburnum opulus) juice on 1,2-dimethylhydrazine (DMH)-induced colon cancer. Toxicology and Industrial Health DOI: 10.1177/0748233712445049. Urban, J., Kokoska, L., Langrova, I., Matejkova, J., 2008. In Vitro anthelmintic effects of medicinal plants used in Czech Republic. Pharmaceutical Biology, 46(10-11), 808-813. Utkin, L.A., 1931. Traditional Medicinal plants of Siberia. Proceedings of scientific research institutes of industry, 434, 24. Varlakov, M.N., 1943. Substitution of imported senega with the roots of Polemonium caeruleum. Farmatsiya-Moscow, 1.

98

Velioglu, Y.S., Ekici, L., Poyrazoglu, E.S., 2006. Phenolic composition of European cranberrybush (Viburnum opulus L.) berries and astringency removal of its commercial juice. International Journal of Food Science and Technology 41, 1011-1015. Vereschagin, V.I., Sobolevskaya, K.A., Yakubova A.I. 1959. Useful plants of West Siberia. Publishing of Academy of Science of USSR, Moscow-Leningrad. Vichkanova, S.A., Adgina, V.V., Fateeva, T.V., Trumpe, T.E., 1992. Brusniver – new herbal mixture with antimicrobial, anti-inflammatory and diuretic activity. Proceedings of the II Russian National Congress Man and health. Moscow, p. 195. Vichkanova, S.A., Derevjanko, I.I., Adgina, V.V., Fateeva, T.V., 2004. Experimental-clinical study of plyherbal mixture Brusniver. In: Genetical resources of medicinal and aromatic plants. Moscow, VILAR, 262-265. Vichkanova, S.A., Kolkhir, V.K., Sokolskaya, T.A., Voskoboinikova I.V., Bykov V.A., 2009. Medicinal preparations from plants (experience of VILAR). Ardis, Moscow, 432 p. Vityazev, F.V., Paderin, N.M., Golovchenko, V.V., 2012. In vitro Binding of Human Serum Low Density Lipoproteins by Sulfated Pectin Derivatives. Russian Journal of Bioorganic Chemistry 38, 319-323. Vogel, V.G., Kluge, E., 1961. Comparative studies on the diuretic action of some steroids with cardiac action. Arzneimittelforschung 11, 848-850. Vogl, S., Picker, P., Mihaly-Bison, J., Fakhrudin, N., Atanasov, A.G., Heiss, E.H., Wawrosch, C., Reznicek, G., Dirsch, V.M., Saukel, J., Kopp, B., 2013. Ethnopharmacological in vitro studies on Austria's folk medicine - An unexplored lore in vitro anti-inflammatory activities of 71 Austrian traditional herbal drugs. Journal of Ethnopharmacology 149(3), 750-771. Voronina, K.V., 1952. Results of study of South-East traditional medicinal plants. Uchenie zapiski SGU, Vol. 35, Saratov, USSR.

99

Voskanyan, V.L., Vasilenko, Yu.K., Ponomarev, V.D., 1983. Hypolipidemic properties of saparal and oleanolic acid. Pharmaceutical Chemistry Journal 17(2), 123-126. Vostrikova, G.G., 1973. K izucheniju lekarstvennych sredstv narodnoi meditsiny nanaitsev. Voprosy pharmatsii na Dalnem Vostoke. Khabarovsk, 1, 60-69. Vu^i, D., omi, L., Petkovi, M., Stefanovi, O., 2009. Antibacterial effects of leaves of Vaccinium vitis-idaea L. Planta medica 75, 1044. Wagner, H., 1993. Pharmazeutische Biologie. Drogen und ihre Inhaltsstoffe, Gustav Fischer Verlag, Stuttgart, New York. Wagner, H., Wierer, M., Bauer, R. 1986. In vitro Hemmung der Prostaglandin-Biosynthese durch etherische Ole und phenolische Verbindungen. Planta Medica 3, 184-187. Wang, H., Ding, Y., Zhou, J., Sun, X., Wang, S., 2009. The in vitro and in vivo antiviral effects of salidroside from Rhodiola rosea L. against coxsackievirus B3. Phytomedicine 16(2-3), 146-155 Wang, X., Sun, H., Fan, Y., Li, L., Makino, T., Kano, Y., 2005. Analysis and bioactive evaluation of the compounds absorbed into blood after oral administration of the extracts of Vaccinium vitis-idaea in rat. Biological and Pharmaceutical Bulletin 28(6), 1106-1108. Wang, Y.M., 1979. Pharmacological studies of extracts of Tussilago farfara L. (II) Effects on the cardiao-vascular system. Yao Xue Xue Bao. 14, 268-276. Weeks, J.R., Holck, H.G.O., 1943. The potency of a new extract of convallaria majalis leaves: III. Assays by the papillary muscle procedure and the U.S.P. XII cat method. Journal of Pharmacology and Experimental Therapeutics 78, 180-186. Weiss, R.F., 1988. Herbal Medicine. Beaconsfield, UK: Beaconsfield Publishers 146. Westendorf, J., Marquardt, H., Poginsky, B., Dominiak, M., Schmidt, J., Marquardt, H., 1990. Genotoxicity of naturally occurring hydroxyanthraquinones. Mutation Research 240, 1-12.

100

Westendorf, J., Pfau, W., Schulte, A., 1998. Carcinogenicity and DNA adduct formation observed in ACI rats after long-term treatment with madder root, Rubia tinctorum L. Carcinogenesis, 19, 2163-2168. Wiegant, F.A., Surinova, S., Ytsma, E., Langelaar-Makkinje, M., Wikman, G., Post, J.A., 2009. Plant adaptogens increase life span and stress resistance in C. elegans. Biogerontology. 10, 27-42. Wolniak, M., Tomczykowa, M., Tomczyk, M., Gudej, J., Wawer, I., 2007. Antioxidant activity of extracts and flavonoids from Bidens tripartita. Acta Poloniae Pharmaceutica - Drug Research 63, 441-447. Xi, S., Zhou, G., Zhang, X., Zhang, W., Cai, L., Zhao, C., 2009. Protective effect of total aralosides of Aralia elata (Miq) Seem (TASAES) against diabetic cardiomyopathy in rats during the early stage, and possible mechanisms. Experimental and molecular medicine 41, 538-547. Xie, G., Schepetkin, I.A., Quinn, M.T., 2007. Immunomodulatory activity of acidic polysaccharides isolated from Tanacetum vulgare L. International Immunopharmacology 7, 1639-1650. Yan, G., Jin, G., Li, L., Qin, X., Zheng, C., Li, G., 2011. Protective effects and mechanism of Inonotus obliquus on asthmatic mice. Zhongguo Zhong Yao Za Zhi 36(8), 1067-1070. Yang, Y., Yu, T., Jang, H.J., Byeon, S.E., Song, S.Y., Lee, B.H., Rhee, M.H., Kim, T.W., Lee, J., Hong, S., Cho, J.Y., 2012. In vitro and in vivo anti-inflammatory activities of Polygonum hydropiper methanol extract. Journal of Ethnopharmacology 139, 616-625. Yano, H.M., Bacchi, E.M., Hayashi, L.S.S., de Lucia, R., 2011. Anti-inflammatory activity and effect on locomotion of Polygonum persicaria L. (Polygonaceae) extract in rats. Latin American Journal of Pharmacy 30, 1635-1638. Yarnell, E. 2000. The botanical roots of pharmaceutical discovery. Alternative & Complementary Therapies. June 2000, p. 125-128.

101

Yarnell, E., Abascal, K., 2003. Botanicals for regulating heart rhythms. Alternative and Complementary Therapies 9, 125-129. Yelina G.A., 1993. Pharmacy on the bog. Nauka, Saint-Petersburg, p. 236-239. Yoon, T.J., Lee, S.J., Kim, E.Y., Cho, E.H., Kang, T.B., Yu, K.-W., Suh, H.J., 2013. Inhibitory effect of chaga mushroom extract on compound 48/80-induced anaphylactic shock and IgE production in mice. International Immunopharmacology 15(4), 666-670. Yoshikawa, M., Murakami, T., Harada, E., Murakami, N., Yamahara, J., Matsuda, H., 1996. Bioactive saponins and glycosides. VII. On the hypoglycemic principles from the root cortex of Aralia elata Seem.: structure related hypoglycemic activity of oleanolic acid oligoglycoside. Chemical Pharmaceutical Bulletin, 44, 1923-1927. Youn, M.-J., Kim, J.-K., Park, S.-Y., Kim, Y., Park, C., Kim, E.S., Park, K.-I., So, H.S., Park, R., 2009. Potential anticancer properties of the water extract of Inontus obliquus by induction of apoptosis in melanoma B16-F10 cells. Journal of Ethnopharmacology 121(2), 221-228. Yu, L., Jinfeng, L., Zhenhong, L., Yanju, L., Mingna, L., Jing J., Wanhai, Xu., 2011. The antitumor effects of Araloside A extracted from the root bark of Aralia elata on human kidney cancer cell lines. African Journal of Pharmacy and Pharmacology 5, 462-467. Zakharov, N.A., Pridantseva, N.M., Khokhlova, A.A., Nikolaeva, V.G., 1980. Use of a tincture of birch buds for treating suppurative wounds. Vestnik Khirurgii Imeni I.I.Grekova 124, 82-85. Zayachkivska, O.S., Gzhegotsky, M.R., Terletska, O.I., Lutsyk, D.A., Yaschenko, A.M., Dzhura, O.R., 2006. Influence of Viburnum opulus proanthocyanidins on stress-induced gastrointestinal mucosal damage. Journal of Physiology and Pharmacology 57 (SUPPL. 5), 155-167.

102

Zelenskaya, K.L., Povet'eva, T.N., Pashinskii, V.G., Fomina, T.N., Timina, E.A., Perova, A.V., 2005. Stress-inducing effect of hypoxia of different origin and its correction with Inula helenium L. tincture. Bulletin of Experimental Biology and Medicine 139, 414-417. Zemlinsky, S.E., 1949. Medicinal plants of USSR, Moscow Zevin, I., Altman, N., Zevin, L., 1997. A Russian herbal: traditional remedies for health and healing. Healing Arts Press, Vermont 250 p. Zhang, J., Wang, H., Xue, Y., Zheng, Q., 2013. Cardioprotective and antioxidant activities of a polysaccharide from the root bark of Aralia elata (Miq.) Seem. Carbohydrate Polymers 93(2), 442-448. Zhang, S., 1989. Treatment of 500 cases of dysentery with Bidens tripartita. Shandong Journal of Traditional Chinese Medicine 8, 11-12. Zhu, J., Wan, X., Zhu, Y., Ma, X., Zheng, Y., Zhang, T., 2010. Evaluation of salidroside in vitro and in vivo genotoxicity. Drug and Chemical Toxicology 33, 220-226 Zhu, Z., Zhao, B., He, S., Zhou, Y.,Cao, G., 2003. A toxicity experiment of general alkaloid of Thermopsis lanceolate on mice. Journal of Northwest Sci-Tech University of Agriculture and Forestry 31(2), 25-28. Zlobin, A.A., Martinson, E.A., Litvinets,S.G., Ovechkina, I.A., Durnev, E.A., Ovodova, R.G., 2012. Pectin polysaccharides of rowan Sorbus aucuparia L. Russian Journal of Bioorganic Chemistry 38, 702-706. Zofina, A.A., 1946. Greek valerian as a sedative medicine. Pharmakologia i toxicologia 6. Zvyagintseva, T.V., Myronchenko, S.I., Zhelnin, Ye.V., 2009. Photoprotective action of altan and thiotriazoline ointment in experiment. Experimentalna i klinichna medicina (Ukraine) 2, 63-67.

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Table 1. Monographs for medicinal plants included in the State Pharmacopoeia of the USSR, 11th edition Monograph title

1. CORMUS LEDI PALUSTRI 2. CORTEX FRANGULAE ALNI 3. CORTEX QUERCUS 4. CORTEX VIBURNI 5. FLORES CALENDULAE 6. FLORES CENTAUREAE CYANI 7. FLORES CHAMOMILLAE 8. FLORES CRATAEGI

9. FLORES HELICHRYSI ARENARII 10. FLORES SAMBUCI NIGRAE 11. FLORES TANACETI 12. FLORES TILIAE 13. FOLIA BELLADONNAE 14. FOLIA DIGITALIS

15. FOLIA EUCALYPTI VIMINALIS 16. FOLIA FARFARAE

Latin name of plant, family (as in the State Pharmacopoeia of the USSR) Ledum palustre L., Ericaceae

Expectorant

Frangula alnus Mill., Rhamnaceae

Laxative

Quercus robur L. Querqus petrae Liebl., Fagaceae Viburnum opulus L, Caprifoliaceae Calendula officinalis L., Asteraceae

Astringent

Centaurea cyanus L., Asteraceae Chamomilla recutita (L.) Rauschert (Matricaria recutita L., M. chamomilla L.), Asteraceae Crataegus sanguinea Pall.; . laevigata (Poir.) DC. [syn. . oxyacantha sensu Pojark.] . korolkowii L. Henry . altaica (Loud.) Lange . chlorocarpa Lenne et . Koch . dahurica Koehne ex Schneid. . monogyna Jacq. . alemanniensis Cin. . orientobaltica Cin. . curvisepala Lindm. .  curonica Cin. .  dunensis Cin. . pentagyna Waldst. et Kit., Rosaceae Helichrysum arenarium (L.) Moench, Asteraceae Sambucus nigra L., Caprifoliaceae Tanacetum vulgare L., Astera Tilia cordata Mill. T. platyphyllos Scop., Tiliaceae Atropa bella-donna L., Solanaceae Digitalis purpures L. D. grandiflora Mill. (syn. D. ambigua Murr.), Scrophulareaceae Eucalyptus viminalis Labill., Myrtaceae Tussilago farfara L., Asteraceae

Pharmacological group

Diuretic Antiseptic and antiinflammatory Diuretic Anti-inflammatory, spasmolytic Cardiovascular

Choleretic Diaphoretic (sudorific) Antihelminthic and choleretic Diaphoretic (sudorific) Cholinolytic (spasmolytic) Cardiotonic

Anti-inflammatory Expectorant 104

17. FOLIA HYOSCYAMI

Hyoscyamus niger L., Solanaceae

18. FOLIA MENTHAE PIPERITAE 19. FOLIA MENYANTHIDIS TRIFOLIATAE 20. FOLIA PLANTAGINIS MAJORIS 21. FOLIA ORTHOSIPHONIS STAMINEI 22. FOLIA SALVIAE 23. FOLIA SENNAE 24. FOLIA STRAMONII

Mentha piperita L., Lamiaceae

25. FOLIA URTICAE 26. FOLIA UVAE URSI

Urtica dioica L., Urticaceae Arctostaphylos uva-ursi (L.) Spreng., Ericaceae Vaccinium vitis-idaea L., Ericaceae. Diuretic Alnus incana (L.) Moench Astringent A. glutinosa (L.) Gaertn., Betulaceae Anethum graveolens L., Apiaceae Not claimed, Spasmolytic* Pimpinella anisum L. Not claimed, (Anisum vulgare Gaertn.), Apicae Expectorant* Carum carvi L. Apiaceae Not claimed, Spasmolytic* Crataegus laevigata (Poir.) DC. Cardiovascular (C. oxyacantha sensu Pojark.) . korolkovii L., Henry . altaica (Lond.) Lange C. chlorocarpa Lenne . dahurica Koehne ex Schneid. . monogina Jacq. . alemanniensis Cin. . pentagyna Waldst. et Kit. . orientobaltica Cin. . curvisepala Lindm. .  curonica Cin. .  dunensis Cin., Rosaceae Foeniculum vulgare Mill., Apiaceae Not claimed, Spasmolytic* Juniperus communis L., Diuretic Cupressaceae Vaccinium myrtillus L., Ericaceae Astringent Padus avium Mill. Astringent P. asiatica Kom., Rosaceae Rhamnus cathertica L., Laxative Rhamnaceae Rosa majalis Herrm. Polyvitamin

27. FOLIA VITIS-IDAEA 28. FRUCTUS ALNI

29. FRUCTUS ANETHI GRAVEOLENTIS 30. FRUCTUS ANISI VULGARIS 31. FRUCTUS CARVI 32. FRUCTUS CRATAEGI

33. FRUCTUS FOENICULI 34. FRUCTUS JUNIPERI 35. FRUCTUS MYRTILLI 36. FRUCTUS PADI 37. FRUCTUS RHAMNI CATHARTICAE 38. FRUCTUS ROSAE

Menyanthes trifoliata L., Menyanthaceae Plantago major L., Plantaginacea

Cholinolytic (spasmolytic) Spasmolytic and choleretic Bitterness (appetite stimulant) and choleretic Expectorant

Orthosiphon stamineus Benth., Lamiaceae

Diuretic

Salvia officinalis L., Lamiaceae Cassia acutifolia Del., Fabaceae Datura stramonium L., Solanaceae.

Anti-inflammatory Laxative Cholinolytic (spasmolytic) Haemostatic Diuretic

105

39. FRUCTUS SORBI 40. FRUCTUS VIBURNI 41. GEMMAE BETULAE 42. GEMMAE PINI 43. HERBA ADONIDIS VERNALIS 44. HERBA ARTEMISIAE ABSINTHII FOLIA ARTEMISIAE ABSINTHII 45. HERBA BIDENTIS 46. HERBA BURSAE PASTORIS 47. HERBA CHELIDONII 48. HERBA CENTAURII

49. HERBA CONVALLARIAE FOLIA CONVALLARIAE FLORES CONVALLARIAE 50. HERBA EQUISETI ARVENSIS 51. HERBA GNAPHALII ULIGINOSI

52. HERBA HYPERICI

(R. cinnamomea L.), R. acicularis Lindl., R. davurica Pall., R. beggeriana Schrenk, R. fedtschenkoana Regel, R. canina L., R. corymbifera Borkh., R. micrantha Smith, R. kokanica (Regel) Regel ex Juz., R. psammophila Chrshan., R. tomentosa Smith, R. zangezura P. Jarosch., R. rugosa Thunb., Rosaceae Sorbus aucuparia L., Rosaceae Viburnum opulus L., Caprifoliaceae Betula pendula Roth B. pubescens Ehrh., Betulaceae. Pinus silvestris L., Pinaceae Adonis vernalis L., Ranunculaceae

Polyvitamin Diaphoretic, antiinflammatory Diuretic Expectorant Cardiotonic

Artemisia absinthium L., Asteraceae.

Bitterness (appetite stimulant) and choleretic

Bidens tripartita L., Asteraceae.

Anti-inflammatory for external use Not claimed, Haemostatic* Anti-inflammatory for external use Bitterness (appetite stimulant)

Capsella bursa - pastoris (L.) Medik., Brassicaceae Chelidonium majus L., Papaveraceae Centaurium erythraea Rafn [syn.: C. minus Moench, C. umbellatum Gilib., Erythraea Centaurium (L.) Borkh] C. pulchellum (Sw.) Druce [syn.: Erythraea pulchella (Sw.) Hornem], Centianaceae  nvallaria majalis L., C. transcaucasica Utkin ex Grossh. C. keiskei Mig. Liliaceae Equisetum arvense L., Equisetaceae Gnaphalium uliginosum L., Asteraceae

Hypericum perforatum L. H. maculatum Crantz (H. quadrangulum L.),

Cardiotonic

Diuretic Not claimed, Hypotensive, antiinflammatory, choleretic* Astringent, antiseptic

106

53. HERBA MILLEFOLII

54. HERBA LEONURI

55. HERBA ORIGANI 56. HERBA POLYGONI AVICULARIS 57. HERBA POLYGONI HYDROPIPERIS 58. HERBA POLYGONI PERSICARIAE 59. HERBA THERMOPSIDIS LANCEOLATAE 60. HERBA SERPYLLI 61. HERBA THYMI VULGARIS 62. HERBA VIOLAE 63. INONOTUS OBLIQUUS

64. RADICES ALTHAEAE 65. RADICES ARALIAE MANDSHURICAE 66. RADICES GINSENG 67. RADICUS ONONIDIS

68. RADICES RHEI 69. RADICES TARAXACI 70. RHIZOMATA BERGENIAE 71. RHIZOMATA BISTORTAE 72. RHIZOMATA CALAMI 73. RHIZOMATA ET RADICES INULAE 74. RHIZOMATA CUM

Hypericaceae Achillea millefolum L., Asteracea

Leonurus cardiaca L. (L. cardiaca L. subsp. villosus (Desf.) Jav. Leonurus quinquelobatus Gilib., Lamiaceae. Origanum vulgare L., Lamiaceae Polygonum aviculare L., Polygonaceae Polygonum hydropiper L., Polygonaceae

lygonum persicaria L., Polygonaceae. Thermopsis lanceolata R. r., Fabaceae Thymus serpyllum L., Lamiaceae. Thymus vulgaris L., Lamiaceae Viola tricolor L. V. arvensis Murr., Violaceae Inonotus obliquus (Pers.) Pil., Hymenochaetaceae

Althaea officinalis L. A. armeniaca Ten., Malvaceae. Aralia elata (Miq.) Seem. (A. mandshurica Rupr. et maxim.), Araliaceae. Panax ginseng `. {. !|., Araliaceae Ononis arvensis L., Fabaceae

Rheum palmatum L. var tanguticum Maxim., Polygonaceae Taraxacum officinale Wigg., Asteraceae Bergenia crassifolia (L.) Fritsch, Saxifragaceae. Polygonum bistorta L. P. carneum `. Koch, Polygon. Acorus calamus L., r

Not claimed, Haemostatic, antiinflammatory Sedative

Expectorant Not claimed, Diuretic* Haemostatic Not claimed, medicine of natural origin Not claimed, medicine of natural origin Expectorant Expectorant Expectorant Not claimed, Regulation of metabolism, antiinflammatory* Expectorant Not claimed, Tonic* Tonic Not claimed, medicine of natural origin Laxative Bitterness (appetite stimulant) and choleretic Astringent, for external use Astringent

Inula helenium L., Asteraceae

Bitterness (appetite stimulant) and choleretic Expectorant

Polemonium caeruleum L.,

Expectorant 107

RADICIBUS POLEMONII 75. RHIZOMATA ET RADICES RHODIOLAE ROSEAE 76. RHIZOMATA }> RADICES RUBIAE 77. RHIZOMATA CUM RADICIBUS VALERIANAE 78. SEMINA CUCURBITAE

Polemoniaceae. Rhodiola rosea L., Crassulaceae

Rubia tinctorum L. R. iberica (Fish. ex DC). `. Koch, Rubiaceae Valeriana officinalis L., Valerianaceae Cucurbita pepo L., C. maxima Duch. C. moschata (Duch.) Poir., Cucurbitaceae Linum usitatissimum L., Linaceae Schisandra chinensis (Turcz.) Baill., Schisandraceae Picea abies (L.) Karst., Pinaceae

Tonic

Not claimed, Spasmolytic* Sedative Antihelminthic

79. SEMINA LINI Ambient 80. SEMINA Tonic SCHISANDRAE 81. STROBILI PICEAE Anti-inflammatory ABIETIS 82. STYLI CUM Zea mays L.,  Choleretic STIGMATIS ZEAE MAYDIS 83. THALLI LAMINARIAE Laminaria saccharina (L). Lam., Laxative Laminariaceae *Pharmacological group according to the on line State Register of Medicinal preparations.

108

Table 2. Summary of Pharmacological Studies for B. tripartita Activity Model Plan Extract Admin Dosage/ tested used t type duratio part n used Methylen 96 well 10 g Anticance In vitro. Not per well speci e chloride plate r Mouse extract, leukemi fied soxhlet a cells L1210, AntiIn vivo. inflammat Carrage ory enaninduced edema in rats

Antimicro In vitro. bial Broth microdil ution method In vitro. Disc diffusio n test

Per oral Crude aqueous infusion (1:20 w/v). Active compoun ds: (±)catechin, chlorogen ic acid, caffeic acid, luteolin7-Oglucoside, chicoric acid, rosmarini c acid, luteolin, hydroxyci nnamic acid, glycoside of luteolin, polyacetyl enes Aqueous, In vitro. Dry flow MeOH/w ater, er head acetone/w s and ater and herbs MeOH. MeOH extract partitione d between diethyl ether, Aeri al part

Control

Results

Refere nce

Positive control Methotre xate Negative control Negative 4, 10, , 20 Indomet mL/kg 12 h and hacin, 5 mg/kg at 2 h before, and immedi ately after, injectio n of carragee nan

100% growth inhibitio n

Goun et al., 2002

51.1% inhibitio n of edema at the dose of 20 mL/kg, compara ble to indomet acin. Antipyr etic effect (normali zation of paw temperat ure) in 1 h

Pozharit skaya et al., 2010

No data

Weak activity against Grampositive bacteria (MIC>1. 5 mg/mL) no effect on Gram-

Tomczy kowa et al., 2008

Grampositive: Bacillus subtilis, Microco ccus luteus, Staphylo coccus aureus. Gramnegative:

109

EtOAc and nBuOH. Dominati ng flavonoid in herb: cynarosid e; in flower heads flavanoma rein Essential oils by hydrodist yllation

Antioxida nt

Escheric hia coli, E. coli (lactamas e+), Klebsiell a pneumon iae (ESBL+) , Pseudom onas aerugino sa, Fungi: Candida albicans, C. parapsil osis, Aspergill us fumigatu s, A. terreus

In vitro. DPPH assay

Dry flow ers and herb

Aqueous, MeOH/w ater, acetone/ water and MeOH crude extracts

In vitro. DPPH assay

Aeri al part

Isoookani In vitro. n 7-Oglucoside, luteolin 7O glucoside, luteolin

In vitro.

negative . Oil from flower heads activity fourtime higher than from the herb. Fungista tic effect of oils, highest gainst C. albicans and C. parapsil osis

Radical scavengi ng for MeOH/ water extract of flowers - 68% ; for acetone/ water extract of herb 66% Radical scavengi ng : 25% for luteolin 7-O glucosid e, 41% for luteolin

Wolnia k et al. 2007

Wolnia k et al. 2007

110

Negative control

100% thrombi n inhibitio n

Goun et al., 2002

Intragast 500 ric mg/kg

No data

Muto et al., 1994

Crude EtOH extract (20-96%), crude chlorofor m extract

Per oral

200 mg/kg, 6 days

Negative , Carsil, 100 mg/kg

Crude EtOH extract (40, 96%), crude chlorofor m extract

Intraperi toneal

Negative 100 control mg/kg, single administ ration

Antiulce r activity against aspirininduced, but not against indomet hacininduced ulcers. EtOH extract (40%) was most effective . Decreas e of ALT (51%), ALP (40%), TG (53%), increase of glycoge n (117%) in liver Decreas e of systolic blood pressure in 35% after 50 min (40% EtOH extract). Decreas

In vitro. Thrombi n solution from bovine plasma In vivo. Aspirininduced ulcer. Indomet hacininduced ulcer of rats

Not speci fied

Methylen e chloride extracts, soxhlet

96 well plate

Aeri al part

Crude MeOH and aqueous extracts

In vivo. CCl4 induced hepatitis of rats

Aeri al part

Hypotensi In vivo. ve Outbree d rats

Aeri al part

Antithro mbin

Antiulcer

Hepatopr otective

50L

Mikaeli an et al., 2006

Stepano va et al., 2006

111

e of blood pressure 20% during 5-60 min of experim ent (chlorof orm extract)

112

Table 3. Summary of Pharmacological Studies for V. opulus fruits Activity Model Pla Extract Admin Dosage/ Control tested used nt type duratio pa n rt use d Drinking Negative Fru Juice (65% Per oral Anticanc In control of juice it pulp, 45% er vivo. instead water) Mice, of water. 1,230 dimeth weeks ylafter hydraz first ine DMH (DMH injection )), 18 induce after last d DMH colon injection cancer

Antimicr obial

In vitro. Agar well diffusi on metho

Fru Fresh In vitro. it juice, standardize d by phenolics and anthocyani

Wells with 50 l of juice

Grampositive: S. aureus, S. epidermi dis, B.

Results

Refere nce

Higher number of lowgrade dysplasia and lower number of other type lesions (highgrade dysplasia , intramuc osal carcinom a and invasive carcinom a) in treated groups indicate that juice prevents progress of establish ed tumors but not chemical inductio n of colonic tumors. Strong inhibitio n of S.typhim urium (inhibitio n zone

Ulger et al., 2012.

esonie n et al., 2012

113

d

Antimicr

In

ns.

Fru MeOH

In vitro.

No data

subtilis, Listeria monocyt ogenes, Enteroco ccus faecalis, Micrococ cus luteus. Gramnegative: Pseudom onas aerugino sa, E. coli, Salmonel la typhimur ium, S. agona Yeast: Debaryo myces hansenii, Trichosp oron cutaneu m, Kluyvero myces marxianu s var. lactis, Torulasp ora delbruec kii, Saccharo myces cerevisia e, Saccharo myces cerevisia e 12R, Candida parapsilo sis Negative

25.330.3 mm), S. agona (23.327.7 mm), L. monocyt ogenes (26.5±0. 35 mm), E. faecalis (25.7 mm), and S. aureus (24.1 mm). Most resistant: P. aerugino sa, M. luteus, S. epidermi dis. No or little antifung al activity was observed

Most

Sagdic 114

obial

vitro. Agar well diffusi on metho d

Antioxida In nt vitro. DPPH assay

In vitro. DPPH assay

In vitro. ABTS assay, DPPH assay, NO scaven ging, supero xide anion scaven ging, inhibiti on of lipid

its

extract (10 and 15%)

Fru Flesh, In vitro. it standardize d by malic, oxalic, citric acids, total phenolic, total flavonoid, and total anthocyani n contents Fru Seeds, In vitro. it standardize d by malic, oxalic, citric acids, total phenolic, total flavonoid, and total anthocyani n contents Fru Fruit In vitro. it extract (25%) standardize d by total phenolic and ascorbic acid contents

control.

sensitive : Aeromon as hydrophi la, most resistant Yersinia enteroco litica EC50 = 24.56 mg/mg

et al., 2006

No data

Negative control.

No data

Negative control.

EC50 = 2.35 mg/mg

Cam et al. 2007

No data

Negative control.

Inhibitio n of NO (21.8925.44%), superoxi de anion (25.1328.50%), and lipid peroxidat ion (11.20– 13.90%). In DPPH test 8.69.8 ascorbic

Rop et al., 2010

Cam et al. 2007

115

peroxid ation

Gastropro In tective vivo. Rats, water immer sion restrai nt stress

Dr y fru its

Proanthocy Intragastri 25, 50, anidins, no c 75 compositio mg/kg n

Fru WaterImmuno- In it soluble stimulatin vitro. Periton polysaccha g eal ride cells of fractions rats. from the squeezed

96 well plate Activity of myeloper oxidase in the

Polisach arides, 10 g/mL

Negative control

Negative control

acid equivale nt/kg of fresh fruits (AAE/kg FM) and 9.1-11.1 AAE/kg FM in ABTS test Potent gastrodu odenoprotectiv e activity via an increase in endogen ous NO generatio n, suppressi on of lipid peroxida tion and mobiliza tion of antioxida nt activity and changes in glycocon jugate content of the gastrodu odenal mucosa of rats Increase the phagocyt ic index in 31% and the secretion

Zayach kivska et al., 2006

Ovodov a et al., 2000

116

fruits. Acidic polysaccha rides with -l,41inked residues of Dgalacturoni c acid, galactose, arabinose, and rhamnose. Neutral polysaccha rides composed of galactose and mannose.

macropha ges Petri dishes, phagocyti c index of the macropha ges by light microsco py

of lysosom al enzymes with peritonea l macroph ages in 68%

117

Table 4. Summary of Pharmacological Studies for G. uliginosum Activity Model Plan Extract Admi Dosage/ tested used t type n duration part used 10 g 96 Anticance In vitro. Aeri Methylene per well well chloride al r Mouse and MeOH plate leukemia part extracts, cells soxhlet L1210,

Antidiabe tic

In vivo. Rats, epinephr ine induced hypergly cemia. Rats, alloxan induced diabetes

Aeri al part

Crude aqueous decoction (1 g in 10 mL)

Intrag astric

Antithro

In vitro.

Not

Methylene

96

Contro l

Results

45% growth inhibition by methylen e chloride extract, 38% growth inhibition by MeOH extract Negativ The level 25 of mL/kg, 6 e control glucose days was decreased 25%, and glycogen in liver was increased 1.7 fold compared to control the glucose tolerance test (epinephr ine induced hypergly cemia). Decrease of glucose 19% but no effect on blood insulin level (alloxan induced diabetes). 50L Negativ 75% Positive control Methotr exate Negativ e control

Refere nce

Goun et al., 2002

Molok ovskii et al., 2002

Goun 118

well plate

Thrombi n solution from bovine plasma Gastropro In vivo. tective Experim ental gastric dystroph y by stomach alteratio n in reserpini zed or immobili zed mice

speci fied

chloride and MeOH extracts, soxhlet

Not speci fied

Per Isolated gnaphalosid oral e A ([7-(6''Ocaffeoyl]O--Dglucopyran osido-5,4'dihydroxy6,3'dimethoxyf lavone)

Hypotens

Aeri

Crude

mbin

In vivo.

Per

e control

thrombin inhibition by methylen e chloride extract Negativ Decrease 50 total e mg/kg Immedia control number of tely stomach before lesions and 5 h (by 1.6 after fold), immobili including zation or small reserpine pulverize injection d (l.7 fold) and large bandlike (2.3 fold) lesions compared with control (reserpini zed mice). Decrease of number of lesions of any type (by 2.6 to 3.l fold) and number of animals with various gastric lesions (2.5 fold) compared with control (immobil ized mice.). 50 Negativ Decrease

et al., 2002

Barnau lov et al., 1984

Makaro 119

ive

SHR rats

al part

oral aqueous extract. gnaphalosid e A; 6"-caffeyl7--Dglucopyran osyloxy4',5dihydroxy3',6' dimethoxyf lavone; 3',4',5,7tetrahydrox y-6methoxyfla vone 7-0(6"O-caffeyl-Dglucopyran oside); 6methoxylut eolin, 6hydroxylute olin 7-O-  -Dglucopyran oside

mg/kg, 14 days

e control. Positive control: enalapri l, 2 mg/kg, atenolol 10 mg/kg

of systolic pressure by 12% and 19% after 3 and 6 h each day. Decrease of diastolic pressure by 34% and 37% after 3 and 6 h each day. Cumulati ve affect after 10 days.

va, Makaro v, 2010

120

Table 5. Summary of Pharmacological Studies for A. incana Activity Model Pla Extract Admi Dosa Control tested used nt type n ge/ par durat t ion use d Negative 200, Cat MeOH 96 Anticance In vitro, control. 100, kins extract, well r Positive 50, soxhlet plate control: 25, with Human Cisplatin and 381.3±7 cervix 12.5 .2 mg adenocarci g/m gallic noma L, acid HeLa cell equival ents/g extract Negative 1 Cat Polyphe Per In vivo Antioral mg/k control kins nolic inflammat Rats, g, 30 extract ory chloroquin days (ellagic e induced and irritation gallic of mucous acid) membrane accompani ed with emotionalpainful stress

Antiinflammat ory (photopro tective)

Cat In vivo. kins Guinea pigs; ultravioletinduced erythema

AntiIn vivo. inflammat Rats,

Cat kins

Polyphe Intrag astric nolic extract (ellagic and gallic acid)

1 mg/k g, 40 min befor e and 2h after UV irradi ation

Polyphe Intrag nolic astric

1 mg/k

Results

Ref ere nce

IC50 = 39.9 g/mL

Stev i et al., 201 0

Positive effect on structures of vessels of the microcirculatory bloodstream, subepithelial connective tissue and integumentary epithelium of tunica mucosa. Effect by endocellular regeneration in combination with expressed compensatory hypertrophy of part epithelium integument cells. Negative Decrease of erythema (61%) control. accompanied Positive with decrease of control: methylura lipid conjugated dienes and cil, sea buckthorn increase of superoxide oil (39%)dismutase and catalase (16%) compared to control group Negative Decrease of control. malonyl-

Moi seye v et al., 200 8

Zvy agin tsev a et al., 200 9

Myr on121

extract (ellagic and gallic acid)

g, 40 min befor e and durin g 10 days after irradi ation

Cat Antimicro In vivo. kins bial Newborn rat. Gastroente rocolitis induced by Klebsiella pneumonia e

Polyphe Per oral nolic extract (ellagic and gallic acid)

1.0, 2.5, 5.0, 10.0, 20.0 mg/k g 14 days

Cat Antimicro In vitro. kins bial Broth microdiluti on method

MeOH extract, Soxhlet with ca. 381.3 mg of gallic acid equival ents/g of extract

ory (radioprot ective)

ionizing radiation of skin (dose 80 Gy)

96 well plate

No data

dialdehyde and lipid conjugated dienes, increase of antioxidant enzymes activity and quick epithelization and healing of skin comparing with control group Negative Bacteriostatic control effect at 1.0 and 2.5 mg/kg (31.5 % and 62.5% survival of rats resp.) Bactericidal effect at 10.0 and 20.0 mg/kg; 100% survival of rats. No effect on normal microflora at 1.0-20.0 mg/kg MIC = 0.117E. coli, Salmonell 0.129 mg/mL a typhimuriu m, Enterobac ter cloacae, Pseudomo nas aeruginos a, P. tolaasii, Proteus mirabilis, Grampositive Staphyloc occus aureus, S. epidermidi s, Streptococ cus faecalis, Bacillus

Positive control: methylura cil

che nko, Zvy agin tsev a, 200 8

Rik alo, 200 5

Ste vi et al., 201 0

122

Antioxida nt

Hepatopr otective

catk In vitro. ins DPPH assay, phospholip id degradatio n

In vitro. DPPH assay

Cat kin

In vivo. Rats, CCl4 induced hepatitis

Cat kins

MeOH extract, Soxhlet with ca.381. 3 mg of gallic acid equival ents/g of extract Crude 70% aqueous EtOH (1:40, w/v) extract; pedunc ulagin, glutinoi n, praecox in D Polyphe nolic extract (ellagic and gallic acid)

subtilis Micrococc us luteus, M. flavus, Sarcina lutea, Listeria monocytog enes; yeast: Candida albicans. Negative control, streptomy cin, nystatin Negative control. Positive control: Trolox

IC50 = 18.9 g/mL (DPPH), IC50 = 48.6 g/mL (phospholipid)

Ste vi et al., 201 0

In vitro.

100 L

96well micro plate

10 mg/m L

Negative control. Positive control: Gallic acid Ascorbic acid

IC50= 2.7±0.1 g/mL (crude extract) IC50 = 1.0±0.1 g/mL for individual compounds)

Iva nov et al., 201 2

Intrag astric

1 mg/k g

Negative control. Positive control: Carsil.

It limits choleopoiesis disorder, has an antiinflammatory and membrane stabilizing effect, recovers physiological

Bun iatia n et al., 199 8

123

Hepatopr otective

In vivo. Rats CCl4 induced hepatitis, ethanolinduced hepatitis

Cat kins

Polyphe Intrag astric nolic extract (ellagic and gallic acid)

1 mg/k g

Negative control

antioxidant system, increase of bile secretion and cholesterol content in bile. Repaired functional activity of mitochondria to the intact level in ethanolinduced hepatitis and increased microsome hydroxylase activity in CCl4 induced hepatitis

Gor dien ko, Yak ovle va, 199 9

124

Table 6. Summary of Pharmacological Studies for B. crassifolia Activity Model Plant Extract Admi Dosag Control tested used part type n e/ used durati on 9.0 Negativ Leave Aqueous Per Adaptog In vivo. mL/kg e infusion oral s, enic Mice, , control. black (1:10, forced 7 days Positive w/v), swimming and control: ferme fingerpri test. nt by nted Rhodiol a rosea arbutin, extract bergenin , ellagic, gallic, protocate chuic acids, hydroqui none.

Antican cer

In vitro. Human lymphobla stoid Raji cells

Rhizo mes, green leaves

Crude EtOH (40%) extract

In vitro

Antimic robial

In vitro. Liquid dilution method

Rhizo mes, leaves

EtOH (80%) extract

In vitro.

Results

2 fold Enhanced swimming time, increased glucose utilization and decreased lactate levels compared to control . Increased fat utilization and a decreased body weight of 15–18% in groups treated with black and fermented leaves. 10, Positive 99% 50, control: inhibition 200 methotr at 200 g/mL by g/mL exate fluorour rhizomes extract; acil, cycloph 82% inhibition osphamide by leaves extract. , vinblasti ne. Negativ e control MIC No B. (mg/mL) data cereus, for E. coli, leaves/rhiz P. aerugin omes:

Referen ce

Shikov et al. 2010

Spiridon ov et al., 2005

Kokosk a et al., 2002

125

B. cereus: 62.50 / 15.63; E. coli: 62.50/15.6 3; P. aeruginosa , 15.63/ 62.50; S. aureus: 62.50/62.5 0; C. albicans: 250.00/ 15.63 Positive Inhibition control: production predniso proinflamm lone atory Th1 cytokines (IL-2, IFN and TNF). Negativ Extract normalized e control. content Positive antibodycontrol: forming enalapril cells in spleen after ,2 stimulation mg/kg, atenolol by antigen in both 10 immunode mg/kg pression models. Extract decreased expression inflammato ry processes under delayed hypersensit ivity reaction conditions, by preventing accumulati on of T-

osa, S. aureus, C. albicans . Positive control: erythro mycin, gentami cin, amphote ricin B

AntiIn vivo. inflamm Mice, adjuvantatory induced arthritis

Not specif ied

Bergenin Per (main oral coumari ne) of plant

5, 10, 20, 40, 80 mg/kg

In vivo. Antiinflamm Mice, immobiliza atory tion stress or cyclophosp hamide injections

Rhizo mes

Per Dry oral extract standardi zed by arbutine min 18%.

50 mg/kg , 5 days

Nazir et al., 2007

Churin et al., 2005

126

Antiobe sity

In vivo. Rats with highcalorie dietinduced obesity

Leave s, black and ferme nted

Per Crude aqueous oral extract standardi zed by arbutin, bergenin , ellagic, gallic, protocate chuic acids, hydroqui none.

Antioxi dant

In situ. DPPH assay after HPTLC separation.

Leave s, green, brown , black.

In vitro. DPPH assay.

Rhizo mes

MeOH extract, with arbutin, bergenin , ellagic, gallic acids, hydroqui none. EtOH (70%) extract, (+)-

50 mg/kg ,7 days

In vitro.

1 mg/m L

In vitro.

10 mg/m L

lymphocyte s in the inflammati on focus and reducing the ability of cells to produce antiinflammato ry cytokines Negativ Daily dietary e control. intake Positive reduced to control: 40% sibutram compared with ine hydroch control. Improveme loride nt in glucose tolerance after 7 d treatment. Black leaves extract reduced serum triglyceride level by 45% compared to control in rats. Negativ ID50 (nmol) e gallic acid control. 0.49; Positive ellagic acid control: 0.94; ascorbic arbutin acid 0.88; hydroquino ne 1.23. Negativ e control. Positive

SC50 (g/mL) 3.7 for extract,

Shikov et al., 2012

Pozharit skaya et al. 2007

Ivanov et al., 2011

127

catechin 3,5-diOgallate, (+)catechin 3-Ogallate

control: gallic acid, catechin , 2,6-ditertbutyl -4methylp henol Negativ e control. Positive control: (-)Catechi n 3-Ogallate, (-)Epicatec hin 3-Ogallate

Antioxi dant

In vitro. Human pancreatic lipase inhibition

Rhizo mes

EtOH (70%) extract, (+)catechin 3,5-diOgallate, (+)catechin 3-Ogallate

96well plate

25 L

Cerebro protecti ve

In vivo. Hypoxia in rats,

Leave s

Dry extract

Intrag astric

300 mg/kg ,5 days

Negativ e control. Positive control: piraceta m

Immuno stimulat ing

In vivo. Mice, delayed type hypersensit ivity

Green leaves

Isolated Per bergenan oral – polysacc haride comprise

2 mg/m L in drinki ng water

Negativ e control. Positive control: apple

1.0 for (+)catechin 3,5-di-Ogallate, 1.3 for (+)catechin 3O-gallate.

IC50 (g/mL) 3.4±0.2 for extract, 0.42±0.04 for (+)catechin 3,5-di-Ogallate, 2.02±0.11 for (+)catechin 3O-gallate. Extract prevented the death of rats which occurred in 33-45% cases of control group after hypoxic exposure. Extract exerted cerebroprot ective effect by preventing inhibition of the succinate oxidaze system. Increase of DTH reaction in vivo. Bergenan enhanced

Ivanov et al., 2011

Khazan ov, Smirnov a 2000

Popov et al. 2005

128

Hypoten In vivo. sive SHR rats

ad libitu m (6 mg/da y) 3 weeks . 10 L for phago cytic activit y. 50 L for perito neal cells assay.

mainly Dgalacturo nic acid, galactose , rhamnos e, arabinos e, glucose residues; appeared to be pectin.

(DTH) reaction to aggregated ovalbumin on footpad swelling. In vitro. phagocytic activity of human blood neutrophils . In vitro. Mouse peritoneal cells.

Leave s

Dry extract.

Per oral

50 mg/kg , 14 days

pectin

uptake capacity of human neutrophils at 100 g/mL and stimulated generation of oxygen radicals by mouse peritoneal macrophag es in vitro. Bergenan increased spontaneou s adhesion of peritoneal leukocytes but did not influence adhesion stimulated by PMA or adhesion of peritoneal leukocytes. Negativ Decrease of systolic e control. pressure by Positive 20-25 control: mmHg enalapril after 3-6 h after each ,2 daily mg/kg, atenolol administrat ion. 10 Decrease mg/kg of diastolic pressure by 20-25 mmHg after 1 h each day. Cumulative effect after 7 days.

Makaro va, Makaro v, 2010

129

Table 7. Summary of Pharmacological Studies for H. arenarium Activity Model Plant Extract Admin Dosa Control tested used part type ge/ used durat ion 100, Aerial MeOH Antibact In vitro, Aeromon In as 50, vitro. extract, erial agar-well part 25, Soxhlet diffusion hydrophil a, 10 with method g/m Bacillus gallic, pbrevis, B. L hydroxybe cereus, B. nzoic, subtilis, chlorogeni E. coli, c, caffeic, syringic, Klebsiella pneumoni pae, coumaric, ferulic, Morganel rosmarinic la morganii, acids, catechin, Mycobact epicatechi erium n, rutin, smegmati s, Proteus resveratrol mirabilis, , hesperidin Pseudom , apigeninonas 7aeruginos a, S. glucoside, aureus, eriodictyol , Yersinia quercetin, enterocoli tica, C. naringenin albicans, , Saccharo luteolin, apigenin, myces and cerevisiae acacetin. . Positive control: amoxicilli n, and 11 other antibiotic s. Anticanc In vitro. Aerial Methylene 96 well 10 g Positive part chloride plate per control er Mouse and well Methotre leukemia MeOH xate cells extracts, Negative L1210, soxhlet control

Results

Refere nce

No activity against E. coli, B. subtilis, M. morganii, M. smegmatis, P. mirabilis, Y. enterocolit ica, S. cerevisiae. Inhibition diameter (mm at 100 g/mL): A. hydrophila (28.0), B. brevis (22.5), B. cereus (22.5), K. pneumonia e (17.0), P. aeruginos a (28.0), S. Aureus (23.5).

Albayr ak et al., 2010

96% growth inhibition by methylene chloride extract,

Goun et al., 2002

130

Anticoag In vitro. ulant Clotting assays of activated partial thrombop lastin time (APTT) and of prothrom bin time (PT) AntiIn vitro, inflamm TNF-, 1 ng/mL atory induced cytotoxic ity in L929 cells

Antioxid ant

In vitro. DPPH assay, reducing iron(III), H2O2:OH – luminol–

Flowe Crude rs extract with polypheno licpolysacch aride fraction

In vitro.

0.112.5 mg/m L

Negative control

Flowe MeOH rs extract, 50 constituen ts including new flavanone and chalcone glycosides named arenarium osides I, II, III, IV.

96-well 3-100 microp M late

Negative control. Positive control: sylibin, piperine.

Infloresce nces

In vitro Crude aqueous infusion (5g in 200 mL), lyophilizat es (fingerprin

1 mg/m L

Negative control. Positive control: silibinin

85% growth inhibition by MeOH extract APTT > 600 sec at 12.5 mg/mL and 479 sec at 6.25 mg/mL. Pt 81.7 sec at 12.5 mg/mL

20.8-40.7 % inhibition of TNF- induced cytotoxicit y in L929 cells at 30 M by naringenin 7-O--Dglucopyra noside, apigenin 7-O--Dglucopyra noside, apigenin 7-Ogentiobiosi de, apigenin 7,4'-di-O-Dglucopyra noside. For lyophilizat es: IC50 =0.14 mg (DPPH), 380-1049 asc. acid equivalent

Pawlac zyk et al., 2009

Morika wa et al., 2009

Czinne r et al., 2000

131

microper o-xidase system

In vitro. DPPH assay, phosphomolybde num method

t by TLC: apigenin, naringenin , kaempfero l, luteolin, quercetin, caffeic Acid, helichrysi n, apigenin7-Oglucoside, luteolin7-Oglucoside, quercetin3-Oglucoside, chlorogeni c acid) Aerial MeOH In vitro part extract, Soxhlet with gallic, phydroxybe nzoic, chlorogeni c, caffeic, syringic, pcoumaric, ferulic, rosmarinic acids, catechin, epicatechi n, rutin, resveratrol , hesperidin , apigenin7glucoside, eriodictyol , quercetin, naringenin , luteolin,

s/mg, IC90 =0.154 g (H2O2/OH luminolmicropero xidase system)

1 mg/m L

Negative control. Positive control: butylated hydroxytoluene, ascorbic acid

IC50 = 2348 g/mL (DPPH) 106-162 mg asc. acid equivalent s/g

Albayr ak et al., 2010

132

In vitro. Lipid peroxidat ion in rats liver microso mes

Inflor escence s.

apigenin, and acacetin. Lyophilize In vitro d water extracts standardiz ed by polypheno ls and flavonoids

MDA production was decreased in 23-50%, cytochrom ec reductase activity was increased in 20-50% Virusatic effect with inhibition zone 15-30 mm for all viruses, inactive against poliovirus type 1.

0.010.02 mg/m L

Negative control. Positive control: sylibin.

Herpes virus Hominis HVP 75 (type 2), influenza virus A2 (Manhei m 57), Vaccini virus, poliovirus type 1. Negative control. Negative Hypotensi control ve effect

Flowe 10% Antiviral In vitro. rs aqueous Agar extract diffusion, method. HeLa cells

Petri dishes

0.02 mL

Hypothe nsive

In vivo. Rats, dogs

Aerial Ether, part EtOH, aqueous extracts

Intrave nous

Spasmol ytic

In vivo. Rats

Aerial Aqueous part solutions of naringenin -5glucoside, kaempfero l-3glucoside) , apigenin dissolved in phosphate

Intrave nous

50 mg/k g (dogs ), 500 mg/k g (rats) 4 mg/1 00 g bw

50 mg/1

Negative control. Positive control: dehydroc holic acid

Spasmolyt ic activity and choleretic effects (approxim ately 33% of that of dehydroch olic acid) for individual

Czinne r et al., 2001

May, Willuh n, 1978

Szado wska, 1962

Szado wska, 1962

133

-buffered sodium hydroxide. EtOH extract containing all fl avonoids and aqueous extract containing no flavonoids .

00 g bw

compound s. The flavonoids extract demonstrat ed spasmolyti c activity similar to individual compound s. The flavonoids free extract elicited a spastic response in smooth muscles from rat intestine and gallbladder.

134

Table 8. Summary of Pharmacological Studies for T. vulgare Activity Model Plan Extract Admi Dosage/ tested used t type n duratio part n used 10 g Anticanc In vitro. Aeri Methylene 96 per well well chloride al er Mouse plate leukemi part and MeOH a cells extracts, L1210, soxhlet

Antihelm In vitro. inthic Egg hatching assay (Ascaris suum), larval migratio n inhibitio n (L3 larvae from Trichost rongylus colubrif ormis) AntiIn vivo, inflamm mouseear atory edema induced by 12-0tetradeca noylphorbo l 13acetate; carragee naninduced mouse

Control

Results

Refere nce

Positive control Methotrexa te Negative control

99% growth inhibitio n by methyle ne chloride extract, 95% growth inhibitio n by MeOH extract 46% ovicidal effect on A. suum eggs at 2000 μg/mL; 49.5% larval migratio n inhibitio n at 2000 μg/mL

Goun et al., 2002

93% edema inhibitio n ID50=0. 18 mol/ea r by parthen olide; 92% inhibitio n by chlorofo rm

Schinel la et al., 1998

Aeri al part

EtOH (80%) extract.

96 well plate.

62.52000 μg/mL

Negative control. Positive control: albendazole

Aeri al part

Dichlorme thane, MeOH, chlorofor m extracts; parthenoli de, methoxyfl avones jaceosidin, eupatorin, chrysoerio l, diosmetin.

Topica l applic ation in ear. Per oral.

0.5mg/e ar 100 mg/kg per oral

Negative control. Positive control: indometacin , phenylbutaz one

Urban et al., 2008

135

paw edema

Antioxid ant

In vivo, Rats, formalin induced edema

Inflo rescen ce

Polysacha ride complex (ammoniu m oxalate extract)

Intraga 0.3 g/kg, stric 7 days

In vitro. DPPH assay,

Aeri al part

MeOH crude extract, 3,5-Odicaffeoyl quinic acid, axillarin, luteolin

In vitro.

1 mg/mL

extract; 80% inhibitio n with ID50=0. 50 mol/ea r by jaceosid in. 24% paw edema reductio n after 1 h. by parthen olide. 61.9% Negative oedema control. inhibitio Positive n after 4 control: indometacin h, 100% inhibitio . n after 3 days of treatme nt. Concent ration leucocyt es and erythroc yte sedimen tation rate was equivale nt to control group after 7 days. EC50= Positive control: 37μg/m quercetin L (MeOH extract); IC50=9. 7 μmol for 3,5O-

Kiriche nko et al., 2012

JuanBadatu ruge et al., 2009

136

Antithro mbin

Antiviral

In vitro. Thrombi n solution from bovine plasma In vitro, antiviral and time-ofaddition assay

96 well plate

Aeri al part

MeOH extracts, soxhlet

Aeri al part

96 Crude well MeOH plate extract, fractionati on using: petroleum ether, chlorofor m, EtOAc, BuOH, water; 3,5-Odicaffeoyl quinic acid, axillarin, luteolin, parthenoli de.

50L

Negative control

5-500 g/mL

Herpes simplex viruses HSV-1, HSV-2. Positive control: acyclovir

dicaffeo ylquinic acid Goun 87% thrombi et al., 2002 n inhibitio n

CE50 = 31.1 g/mL, 69.9 g/mL, 95.7 g/mL for 3,5Odicaffeo ylquinic acid, petroleu m ether and EtOAc extracts respecti vely against HSV-1. CE50 = 42.7 g/mL, 47.0 g/mL, 58.4 g/mL, 61.1 g/mL for axillarin , 3,5-Odicaffeo ylquinic acid, EtOAc, and petroleu m ether extracts

Alvare z et al., 2011

137

Cholereti In vivo. c Rats, CCl4 induced hepatitis

Aeri al part

Tanaceholum®

Per oral.

50, 100 mg/kg, single administ ration

Negative control.

Gastropr otec-tive

Aeri al part

Chlorofor m extracts; parthenoli de

Per oral.

2.5-80 mg/kg (chlorof orm extract), 5-40 mg/kg partheno lide, single dose.

Negative control.

In vivo. Rats, EtOHinduced gastric ulcer

respecti vely against HSV-2. Effect in rats treated with 50 mg/kg observe d during 3 h. After administ ration of 100 mg/g bile volume increase d 80.9% after 1 h, and 76.2% after 2 h. Concent ration of bile acids increase d in 2.7, 2.1 and 1.8 fold compare d to control after 1, 2, and 3 h. 100% inhibitio n of damage for extract (10 mg/kg) and parthen olide (40

Vichka nova et al., 2009

Tourni er et al., 1999

138

Immuno modulatory

In vitro. Activati on of NF-B; NO, ROS, and TNF- producti on.

Flo wers

Polysacch arides with Mr = 326, 151, 64 and 9 kDa

96 well plate

0-1600 g/mL

Negative control. Positive control: LPS.

mg/kg). Adminis tration extract (80 mg/kg) or parthen olide (40 mg/kg) 24 h before ethanol treatme nt restored numbers mucosal -SH groups to values near controls Xie et Potent macrop al., 2007 hageactivatin g properti es, resultin g in modulat ion of NO, ROS, and TNF- producti on. Polysac charides stimulat ed neutrop hil MPO release and activate 139

Spasmol ytic

In vitro. Rats isolated aorta

Aeri al part

Crude aqueous decoction, lyophilize d.

In vitro.

50, 100, 200, 400, 800 g/mL

Negative control.

In vitro. Serotoni n release inhibitio n.

Leav EtOH es extract, parthenoli de

In vitro.

120024000 μg/mL for EtOH extract; 1.146.04 M for panheno lide

Negative control.

d NFB signalin g in monocy tic cells. Biphasi c concentr ationdepende nt relaxati on: a first rapid effect within 10 min after addition of extract (50 g/mL) and maximu m at 200 g/mL, which relaxed contract ion by about 30% Serotoni n release inhibitio n with IC50= 9797 μg/mL fresh weight for EtOH extract and IC50= 3.03

Lahlou et al., 2008b

Marles et al., 1992

140

mol for parthen olide

141

Table 9. Summary of Pharmacological Studies for L. palustre Activity Model Pla Extract Adm Dosage/ tested used nt type in duration part use d 1/20Antibact In vitro. Sho Aqueous In erial Broth ots extract vitro 1/160 dilution and method. isolated polysacch aride complex

Anticanc In vitro. er Mouse leukemia cells L1210,

Aeri al part

Methylen 96 e chloride well and plate MeOH extracts, soxhlet

Anticanc In vitro. er Human lymphoblastoid Raji cells

Aeri al part

Crude EtOH (40%) extract

In vitro

Control

Tested microbes Staphyloc occus aureus, E. coli, Pseudomo nas aeruginos a, Klebsiella pneumoni ae 10 g per Positive well control Methotrex ate Negative control

10, 50, 200 g/mL

Positive control: methotrex ate fluorourac il,

Results

Refere nce

Bacteriost atic effect at 1/160 dilution, excluding to P. aeruginos a (1/20 dilution) for polysacch aride complex. 99% growth inhibition by methylene chloride extract. This extract is not attractive as a potential source of drugs because of the possibility of causing necrosis of the cells. 71% growth inhibition by MeOH extract. 99% inhibition at 200 g/mL

Belous ov et al., 2006

Goun et al., 2002

Spirido nov et al., 2005

142

Antidiab etic

Lea In vitro. ves C2C12 murine skeletal myoblast s and the 3T3-L1 murine preadipoc yte cell lines

EtOH (80%, 1:10) extract with 153.5 g/mg total phenolic

Antidiab etic

In vitro. Caco2/15 cells;

EtOH (80%, 1:10) extract

Lea ves

In vitro.

1.1 mmol/L (glucose deprivatio n) or 150 mmol/L glucose (glucose toxicity)

25-100 g/mL (in vitro); 250

cyclophos -phamide, vinblastin e. Negative control Negative control. Positive control rosiglitazo ne

Negative control. Positive control:

Cytoprote ctive properties under conditions of glucose toxicity and glucose deprivatio n at 6.25 g/mL. Exhibited the effect on the basal and insulin stimulated 3Hdeoxyglucose uptake in differentia ted 3T3L1 Adipocyte s at 50 g/mL. Triglyceri de level was increased by 3-fold. Effect was comparabl e with levels induced by10 mmol/L rosiglitazo ne 100 g/mL instantane ous

Harbila s et al., 2009

Nistor Baldea et al., 2010 143

western blot analysis. In vivo. Rats, oral glucose tolerance test

Antifung In vitro. al Microbroth dilution method.

Lea ves

with 153.5 g/mg total phenolic

mg/kg (in vivo)

Quercetin 96 3--D-(6- well plate pcoumaroy l) galactosi de and quercetin 3--D-(6phydroxybenzoyl)

100 L

inhibition of differentia ted Caco2/15 intestinal cells glucose absorption . Reduced SGLT1 protein expression . In vivo reduction AUC of blood glucose levels compared with control in the periods 0– 30 min, 0–50 min, 0–120 min after glucose administra tion. Cryptococ MIC=16- Jin et 63 g/mL al., cus 1999 neoforma for C. neoforma ns, Saccharo ns, S. cerevisiae myces Cerevisia and A. niger. e, Aspergillu MIC= 0.16-10 s niger, g/mL for Candida albicans. amphoteri cin B and Positive fluconazol control amphoteri e. MIC=250 cin B, fluconazol g/mL for C. e albicans.

cytochalas in B, phlorizin, phloretin.

144

Aqueous In extract, vitro lyophilize d.

0.2 mg/mL (for prostaglan din) 0.25 mg/mL (for PAF)

Ether oil

In vitro.

37 Mol

Per oral

50 mg/kg / Single dose

In vitro.

Not indicated

Antiinflamm atory

Aeri In vitro. Prostagla al part ndin biosynthe sis assay; PAFinduced exocytosi s

Antiinflamm atory

In vitro. Prostagla ndinsynthesiz ing cyclooxy gena-se system from sheep seminal vesicles and HPLC separatio n

Aeri al part

Antiinflamm atory

In vivo. Carragee naninduced edema in rats

Shot Dry s extract aqueous, EtOH 40%, EtOH 70%

Antioxid In vitro. ant DPPH assay, Fe3+EDTA-

Aeri al part

Essential oil. 37 compounds

Moderate inhibition of prostaglan din biosynthes is (50%) and platelet activating factor (PAF)induced exocytosis (71%) Ether oil Positive inhibited control: cyclooxyg eugenol, carvacrol, enase in vitro with thymol, guajazule 46.6% and carvacrol n, was urushiol, curcumin, reported to be one piperin, capsaicin, of the compound apiol, s cubebin, isoalantol responsibl e with acton, 94% ledol inhibition. However, ledol, did not inhibit the enzyme. Negative, 51.5±4.6 % Positive inhibition control: butadione, of edema 50 mg/kg by EtOH 40% extract, comparabl e to butadione. Negative IC50=1.6 control. g/mL in DPPH assay; IC50=2.7 Negative control. Positive control: indometac in, eugenol, quercetin, saligenin.

Tunón et al., 1995

Wagner et al., 1986

Belous ov et al., 2006

Kim, Nam, 2006

145

H2O2 deoxyrib ose assay, nonenzy matic lipid peroxidat ion of rat liver homogen ate

50 L

Negative control

88% thrombin inhibition

Goun et al., 2002

Shot Dry s extract (EtOh 40%)

Per oral

100 mg/kg / Single dose

Negative control.

Belous ov et al., 2007

Aeri al part

Singl e inject ion

Not indicated, 5-15 min before lethal dose

Negative control.

Extract reduces hexobarbit al sleeping time in 1.4 (rats), and 3.2 (mice) folds. Improves functional -metabolic and morpholo gical parameter s of liver. 100% of animals survived after a dose of 6 Gy

Aeri al part

Radiopr o-tective

In vivo. Mice irradiated with irradiatio n

g/mL in Fe3+EDTAH2 O2 deoxyribo se system; IC50=13.5 g/mL in nonenzym atic lipid peroxidati on of rat liver homogena te

96 well plate

In vitro. Thrombi n solution from bovine plasma Hepato- In vivo. protectiv Rats, mice, e CCl4 intoxicati on

Antithro mbin

identified among them sabinene (1617%), terpinen4-ol (7.6%), myrtenal (3.5%), Selinene, selinene, elemene,  -caryophyllene (2-6% range) MeOH extract, soxhlet

Combinat ion of Archange lica officinalis and L.

Narima nov et al., 1991

146

irradiation

palustre extracts

In vivo. 30 days albino mongrel male mice irradiated with irradiatio n (LD90/30)

Aeri al part

Combinat ion of Archange lica officinalis and L. palustre extracts

Singl e inject ion

Not indicated

Negative control: nonirradia ted animals

(LD50/30); 70% survived after a dose of 7.5 Gy (LD90/30), and 25% after a dose of 8 Gy (LD100/12) by day 30. Offspring Narima nov, were 1992 obtained from 11 of 12 experimen tal males. The number of mouse pups was 10.2 ± 0.6 and 7.4 ± 0.7 in experimen tal and nonirradia ted groups respective ly. The number of both sexes in the posterity of nonirradia ted parents was equal, in offspring of experimen tal groups, the number of female pups was 2.3 times 147

larger than that of males.

148

Table 10. Summary of Pharmacological Studies for T. farfara Activity Model Plant Extract Ad Dosag tested used part type min e/ used durat ion 10 g Aeria Methylene 96 Anticanc In vitro. well per l part chloride er Mouse and MeOH plate well leukemia extracts, cells soxhlet L1210,

Antiinflamma tory

Antiinflamma tory

Antimicr obial

Control

Results

92% growth inhibition by methylene chloride extract. 71% growth inhibition by MeOH extract. Negative, Inhibition Positive of control: arachidoni G N c acid monometh metabolis m and iyl -LNOS arginine (71.1%) with IC50 =8.9 M. Positive control Methotrex ate Negative control

In vitro. Murine macropha ge cell line (RAW 264.7), lipopolysa c-charideactivated macropha ges In vitro. Murine macropha ge cell line (RAW 264.7), lipopolysa c-charideactivated macropha ges

Flow er buds

96 Isolated well 1,5 bisacetoxy- plate 8angeloylox y-3,4epoxybisabola7(14),- 10dien-2-one

No data

Flow er buds

Isolated tussilagone

96 well plate

0-30 M

Negative, Positive control: zinc protoporp hyrin IX, copper protoporp hyrin IX

In vitro. Liquid dilution method

Aeria EtOH l part, (80%) rhizo extract me

In vitro .

No data

B. cereus, E. coli, P. aeruginos a, S. aureus, C. albicans.

Inhibition of production of NO, TNF-, and PGE2 aswell as i-NOS and COX-2 LPSstimulated RAW264. 7 cells and murine peritoneal macropha ges MIC (mg/mL) for aerial part/rhizo me B. cereus:

Refere nce

Goun et al., 2002

Ryu et al., 1999

Hwang bo et al., 2009

Kokos ka et al., 2002

149

Positive control: erythromy cin, gentamici n, amphoteri cin B Negative control.

Antioxida In vitro. nt Lipid peroxidati on in rat brain homogena tes, DPPH assay. Antioxida In vitro. nt DPPH assay, pyrogallol autoxidati on assay

Flow er buds

EtOAc fraction from MeOH extract

In vitro .

Not indica ted

Flow er buds

EtOAc, In BuOH, vitro aqueous fractions from EtOH (70% extract). Main compounds : chlorogeni c and 3, 5Odicaffeoylq uinic acids.

5-8 mg/m L

Negative control.

Antitussi ve

Flow er buds and rachi s

Aqueous extract

Flowe r bud (2.8 g/kg), rachis (3.5 g/kg). 5 days.

Negative control. Positive control: pentoxyve rine

In vivo. Mice, ammonia induced coughing.

Per oral

16.63/62.5 ; S. aureus: 62.50/62.5

IC50=6.3 g/mL in lipid peroxidati on assay, IC50=14.3 g/mL in DPPH assay EtOAc and BuOH fractions exhibited more potent activities than aqueous fraction in all tested concentrat ions. The scavengin g activity of all extracts was found in a concentrat iondependent manner After treatment with flower bud extract latent period of cough was prolonged in 47% and cough

Cho et al., 2005

Li et al., 2012a

Li et al., 2012b

150

Expector ant

In vivo. Mice, intraperito neal injection of phenol red solution.

In vitro. Neuroprotective Cortical cell cultures

Flow er buds and rachi s

Aqueous extract

Per oral

Flowe r bud (2.8 g/kg), rachis (3.5 g/kg). 5 days.

Flow er buds

EtOAc fraction from MeOH extract

In vitro .

Not indica ted

frequency was decreased in 48% compared to control. Rachis extract has no significant effect. Flower Negative bud control. enhance Positive tracheal control: ammoniu phenolsul m chloride phonphthalein excretion in 42% compared to control, indicating strong expectora nt effect. No effect for the rachis extract Negative Inhibition control. of neuronal damage induced by arachidoni c acid with IC50= 0.64 g/mL. Attenuate d neuronal damage induced by spermine NONOate. Cell viability increased

Li et al., 2012b

Cho et al., 2005

151

to 30-40% at 10 g/mL and above. Inhibited A (25-35)induced neurotoxic ity with IC50= 30.9 g/mL and glutamateor N-methylD-aspartic acidinduced excitotoxi city was inhibited with IC50= 76.3 and 53.7 g/mL respectivel y. 90% of cells were protected from Fe2+/ascor bic acidinduced damage at 30 g/mL. H2O2induced damage was not inhibited until 300 g/mL. Viability of cells exposed to xanthine/ xanthine oxidase was increased 152

at 30 g/mL and above.

153

Table 11. Summary of Pharmacological Studies for I. helenium Activit Model Plant Extract type Admin Dosag y used part e/ tested used durati on 10, Root Crude EtOH In vitro Antican In vitro. (40%) extract 50, Human cer 200 helenin (40% lymphobla g/mL alantolactone -stoid and 60% Raji cells isoalantolact one)

Root In vitro. Human tumor cell lines HT29, MCF7, Capan-2 and G1. MTT assay for adherent cell lines and propidium iodide staining and FACS analysis for PBL

Acetone: MeOH (2:1 v/v) extract

96 well plate

10, 1, 0.1, 0.05, 0.01, 0.005 L/m L

Contro Results l

Positiv e control: methotr exate fluorou racil, cyclop hosphamid e, vinblas tine. Negati ve control

Negati ve control

100% inhibition at 50 g/mL by EtOH extract; and at 10 g/mL by helenin. Helenin exceeded activity cyclophos phamide and fluorourac il and approache d the activity of methotrex ate. Cytotoxic effect with LD50 (L/mL) of 0.015 for HT29, of 0.017 for MCF-7, of 0.020 for Capan-2 and of 0.018 for G1 and LD90 (L/mL) of 0.05 for HT-29, of 0.20 for MCF7, of 0.10 for Capan-2 and of 0.10 for

Refer ence

Spirid onov et al., 2005

Dorn et al., 2006

154

Antihel mintic

Antihy

G1. The cytotoxicit y on healthy human PBLs has LD50 of 2.4- 3.0 (L/mL) and LD90=8.09.0 (L/mL) Cytotoxici ty over 100-times higher in tumor cell lines than in PBLs. Positiv Athelmint Urban 62.5et al., ic effect e 2000 g/mL control: on the egg 2008 albenda embryogenesis at zole. Negati 250-000 g/mL. ve control. LMI at the dose of 125 g/mL and higher.

In vitro. Egg hatching assay (eggs Ascaris sum) larval migration inhibition (LMI) (Trichostr on-gylus colubrifor mis) In vivo. Rabbits infected with Clonorchi s sinensis

Rhiz omes and roots

EtOH (80%) extract

96 well plates

Root

Boiled water extract

In vivo.

In vivo.

Stem

Tincture

Injection 2.5

30 days, begin ning at the end of 3rd day of inocul ation.

Negati Recovery ve rates of control. worms from rabbits was 2%. Degenerat ion, atrophy, necrosis, dilatation, etc. of viscera of the worms was observed Negati Life-span

Rhee et al. 1985

Zelen 155

poxant

Mice, single hemic hypoxia, repeated hemic hypoxia, single tissue hypoxia, repeated tissue hypoxia, single circulatory hypoxia, repeated circulatory hypoxia.

(1:10) by EtOH 40%. Contain 1.63% of flavonoids, dry residue > 2.25%

mL/kg ve control , 5 days and 1 h before the hypox ic expos ure.

skaya of mice increased et al., 2005 by 35% after single hemic hypoxia and by 76% after repeated hypoxia. Stressprotective effect was realized through prevention of adrenal hypertrop hy and splenic involution . The lifespan after single intoxicatio n with sodium fluoride was prolonged by 59%, of those exposed to repeated hypoxia by 29%. Severity of stress decreased by 5 and 4 points, respective ly, compared to control due to the protective effect on gastric mucosa. 156

Antimi crobial

In vitro. Broth dilution assay

Root

Helenin (a crystalline mixture of eudesmanoli des)

In vitro.

In vitro. Broth microdilut ion method

Root

Stepwise supercritical fluid extract (SFE), hydrodistillate (HD). Main compounds: Alantolactone, isoalantolactone and  elemene

In vitro.

The MIC (g/mL) against several strains of S. aureus was 10400, E. coli and P. aeruginos a 200750, C. albicans 200-750. Negati MIC 10from ve 750 g/mL control. 0.009 Positiv mg/mL to >14 e control: mg/mL. strepto HD and mycin, SFE bifonaz extracts active ole against Bacillus cereus, Staphyloc occus aureus, Enterococ cus faecium clinical strain resistant to ampicillin , erythromy cin, penicillin and tetracyclin e (MIC>0.0 3 mg/mL). Candida strains were most susceptibl

Negati 10ve 750 g/mL control. Several strains of S. aureus, E. coli, P. aerugin osa, C. albican s

Kowa lewski et al., 1976

Deriu et al., 2008

157

In vitro. Root Radiorespi rometric bioassay against Mycobacterium tuberculos is

Isolated alantolactone, isoalantolact one, 11H, 13-dihydroisoalantolactone

In vitro.

Antimi crobial

Root In vivo. Mice inoculated with Staphyloc oc-cus aureus suspension in the left nare

Isoalantolactone

Subcuta neously

Antiprolifer ative

In vitro. MK-1, HeLa, B16F10 cell lines, MTT assay

Root

MeOH In vitro. extract , isolated 1,3,11(13)elematrien8,12-olide, igalan; 5epoxyalantol actone; 4 , 5 -epoxy1(10),11(13)germacradien e-8,12-olide;

50 mg/kg ,2h after infecti on with S. aureu s and at 12h interv als therea fter for a total of 6 doses.

e, with MIC= 0.0090.12 mg/mL. MIC for Negati alantolact one and ve control. isoalantol Positiv actone was 32 e control: g/mL. encelin from Montan oa specios a Marked Negati alleviation of ve control: pulmonar phosph y inflammat atebuffere ion; d saline treated mice less accumulat ion of cellular infiltrates in alveolar space.

Negati ve control. Positiv e control: 5fluorou racil

GI50 (M) for 5epoxyalan -tolactone was 3.66.9, for alantolact one – 4.76.9. 1,3,11(13) elematrien -8,12-

Cantr ell et al, 1999

Qiu et al., 2011

Konis hi et al., 2002

158

olide, igalan exhibited almost the same potency, but GI50 against HeLa cells was 2 folds lower.

alantolactone, isoalantolactone, 11 ,13-dihydroalantolactone, 11,13dihydroisoala ntolactone

Antithr ombin

In vitro. Thrombin solution from bovine plasma

Not speci fied

Methylene chloride extract, soxhlet

96 well plate

50L

Negati ve control

100% thrombin inhibition

Goun et al., 2002

159

Table 12. Summary of Pharmacological Studies for P. caeruleum Activity tested

Model used

Hypoglyc emic

In vivo. Mice, glucose tolerance test.

Hypotensi ve

Plant part used Roots with rhizo me

Extra Admin ct type EtOH Intraperito neal 70% extract with 65% saponi ns

Dosage/ duratio n 10 mg/kg

In vivo. Mice, glucose tolerance test.

Roots with rhizo me

EtOH Intraperito 10, 30 neal mg/kg 70% extract with 65% saponi ns

In vivo. Rabbits with experimen tal atheroscle rosis

Roots with rhizo me

Isolate Per oral d saponi ns, no details

Contr ol

Results

Refere nce

Negati ve control . Positiv e control : extract of roots of Beta vulgari s

Glucose concentra tion in the blood decreased by half in 30 min after glucose injection. Maximu m of glucose in the blood was in 50 min after injection. Glucose concentra tion in the blood was decreased by half after injection of 10 mg/kg of extract in 30 min after glucose injection. Decrease of cholester ol and blood pressure. Accordin g to histologic al evaluatio n, saponins

Boyeva et al., 2007.

Negati ve control .

Not Negati provided ve control .

Soroki na et al., 2010.

Turova , 1955

160

Sedative

In vivo. Mice exited with phenamin e.

Roots Infusi with on rhizo me

Sedative

In vivo. Rats, prolongati on of soporific effect of sodium ethaminal

Intragastri Roots Dry with powde c rhizo r me

Per oral

0.010.03 g (equival ents of dry mass)

Negati ve control . Positiv e control : valeria n infusio n

30, 60, 120 mg/kg

Negati ve control . Positiv e control : V. officin alis powde r

reduce lipid cell infiltratio n of the aortic intima and large vessels Sedative effect was 8-10 times stronger compared with valerian and more pronounc ed in mice exited with phenamin e. Combinat ion of P. caeruleu m and V. officinali s (1:1, 60 mg/kg) prolonge d the soporific effect of sodium ethaminal in 2.5 fold.

Zofina, 1946

Khisho va et al., 2013

161

Table 13. Summary of Pharmacological Studies for V. opulus bark Activity Model Pla Extract Admin Dosage Contr tested used nt type / ol part durati use on d In vitro 0.4 No Antispasmo In vitro. Bar MeOH g/mL data k extract Single dic with uterine yield horns 4%. from virgin Holtzma n rats 0.025- No In vitro. Bar Isolated In vitro k scopolet 0.150 data Single in mg/mL uterine horns from virgin Holtzma n rats In vitro. Barium stimulat ed rat uterus. Hypotensive In vivo. Rats, cats, dogs.

Bar k

Isolated viopudi al

In vitro

No data

No data

Bar k

Isolated viopudi al

Intraveno us

250 g/kg 2 mg/kg

Negati ve control

Results

Referen ce

Complete Jarboe et relaxation al., 1966 of muscle at 1 mL

Relaxatio n of muscle tension and spasms in uterus, IC50=0.09 mg/mL ED50 for spasmolyt ic effect 24 g/ml

Jarboe et al., 1967

In rats hypotensi ve effect at 250 g/kg. At 1 mg/kg effects were sustained and decrease in blood pressure with decrease in heart beat. In dogs and cats effective dose 2 mg/kg.

Nichols on et al., 1972

Nichols on et al., 1972

162

Table 14. Summary of Pharmacological Studies for C. cyanus Activity Model Plan Extract Admin Dosage/ tested used t type duratio part n used Intraperit 30, 60, Flow WaterAntiIn vivo. 80 oneal soluble erinflamm Rats, mg/kg; topical carrageen head ethanolatory insoluble applicati 30 min s anbefore polysacch on induced edema arides and inductio fraction zymosann. induced 100, edema. 200, Mice, 400 and croton 800 g oilper ear induced inflamma tion of ear.

Control

Results

Refere nce

Negative control. Positive control: indomet hacin, acetylsal icylic acid,

Reductio n of carrageen aninduced edema by 40% at 30 mg/kg, by 69% at 60 mg/kg. Reductio n of zymosaninduced edema by 52% at 400 g. Induced the formation of an anaphylat oxin-like activity from 10 g/mL. At higher concentra tions (1000 g/mL), reduced haemolyt ic activity of rat serum. Gastropr o-tective effect was 100%, 89% and 83% respectiv

Garbac ki et al, 1999

In vitro. Haemoly tic activity of complem ent. Anaphyla toxin activity in rat serum

Flow erhead s

Watersoluble ethanolinsoluble polysacch arides fraction

In vitro.

10, 50, 250, 1000 g/mL (haemol ytic) 0.01, 0.1, 0.5, 1, 5, 10 mg/mL (anaphy latoxin)

Negative control. Positive control: rosmarin ic acid

Gastro- In vivo. protectiv Rats with e stressinduced ulcer (immersi on and

Herb , flow ers

Vegetal product (combinat ion of polysaccharides and polyphen

Per oral

500mg/ kg, one h before stress

Negative control. Positive control: ranitidin e.

Antiinflamm atory

Garbac ki et al, 1999

Pirvu et al., 2012

163

ols fractions)

immobilization of rats into cold water, on dorsal position)

Diuretic

In vivo. Dogs with chronic fistula of urinary and gall bladders.

Flow erhead s

Infusion Intragastr No (1:10) and ic details EtOH extract

No details.

ely, in the specific case of deep, medium and superficia l gastric lesions, respectiv ely, superior to that of ranitidine (89%, 59%, and 54% respectiv ely on the same type of lesions. Stimulati Bashm urin, on of diuresis 1951 and choleresi s.

164

Table 15. Summary of Pharmacological Studies for V. vitis-idaea Activity Model Plant Extract Ad Dosage/ Control tested used part type min duratio used n Negative 25-100 Not EtOH Antidiab In vitro. In control. indic (80%, etic Cacovitro g/mL Positive 96- (in 1:10) 2/15 ated control: well vitro); extract intestinal cytochala plat 250 cells; sin B, mg/kg e. western (in vivo) phlorizin, blot In phloretin. vivo analysis. per In vivo. oral Rats, oral glucose tolerance test (OGTT) Negative 0.2 Leav Aqueous AntiIn In vitro. control. extract, inflamm Prostagla es vitro mg/mL Positive (for lyophilize ndin atory prostagla control: d. biosynthe indometa ndin) sis assay; cin, 0.25 PAFeugenol, mg/mL induced quercetin (for exocytosi , PAF) s saligenin.

Antiinflamm atory

In vivo. Mice, acetic acidinduced vascular permeabil ity test.

Stem s and leave s

EtOH extract, isolated arbutin, fraxin

Antimic robial

In vitro. Agar dilution assay, Porphyro monas gingivalis , Prevotell a intermedi a

Leav es

Isolated procyanidi n B-1, procyanidi n, B-3, proanthoc yanidin A1, cinnamtan nin B1, epicatechi n-(

Results

Refere nce

100 g/mL instantane ous inhibition glucose absorption inCaco2/1 5 cells. In vivo No effect in OGTT.

Nistor Baldea et al., 2010

Moderate inhibition prostaglan din biosynthes is (45% ) and strong inhibition PAFinduced exocytosis (96% ) Negative Decrease Per 5 g/kg in vascular oral. (extract), control. permeabili 0.25g/kg Positive , 0.5 control: ty by g/kg dexameth fraxin (0.5 g/kg) (arbutin, asone similar fraxin) todexamet hasone (1 g/kg). 0-100 Negative Epicatechi In n-(4-8)control. vitro g/mL epicatechi Positive . n-(4-8, control: tetracycli 2-O-7)catechin, ne had strong antimicrob ial activity against Porphyro monas

Tunón et al., 1995

Wang et al., 2005

Ho et al., 2001

165

Antimic robial

In vitro. Tube dilution assay, eleven strains of Escherich ia coli.

Leav es

4-8)epicatechi n-(4-8, 2-O-7)catechin, epicatechi n-(4-6)epicatechi n-( 4-8, 2O-7)catechin. Aqueous, EtOAc, EtOH extracts

gingivalis and Prevotella intermedia with MIC of 25 g/ml.

0-100 In vitro g/mL .

Negative control. Positive control: amoxicill in

Leav Antioxid In vitro. ant Anti-lipid es. peroxidati on activity (thiobarbi turic acid test). Antisuperoxid e formation : xanthine oxidase inhibition test. Free radical scavenger activity: cytochro me C test

Isolated procyanidi n B-1, procyanidi n, B-3, proanthoc yanidin A1, cinnamtan nin B1, epicatechi n-( 4-8)epicatechi n-(4-8, 2-O-7)catechin, epicatechi n-(4-6)epicatechi n-( 4-8, 2O-7)catechin.

No data In vitro .

Negative control

Antithro mbin

MeOH extract,

96 well

Negative control

In vitro. Thrombin

Not speci

50L

MIC = 5mg/mL for aqueous extract. MBC= 5mg/mL for nine strains. Cinnamtan nin B1 strongest anti-lipid peroxidati on activity IC50=2.25 M, proanthocy anidin A-1 strongest superoxide scavenging activity IC50=10.14 M, picatechin(4-6)epicatechi n-(4-8, 2-O-7)catechin strongest antisupero xide formation effect IC50=308 M 94% thrombin

Vu^i et al., 2009

Ho et al., 1999

Goun et al., 166

solution from bovine plasma In vitro. Cells infected with HSV-2. XTT assay. Plaque reduction assay

fied

soxhlet

plat e

Dried whol e plant s

Isolated proanthoc yanidin A1

96 well plat e, 24 well plat e

Coughsuppresa nt

In vivo. Mice, in upset beaker saturated with 25 % NH4OH

Stem s and leave s

EtOH extract, isolated arbutin, fraxin

Per 5 g/kg oral. (extract), 0.25g/kg , 0.5 g/kg (arbutin, fraxin)

Diuretic

In vivo. Rats, 5

Leav es

Infusion of Per 0.5 polyherbal oral. mL/100

Antivira l

0.5-200 Mol

Negative control. Positive control: acyclovir

Negative control. Positive control: carbetape ntane citrate

Negative control.

inhibition

2002

Proanthoc yanidin A1 antiHSV-2 activity. IC50=73.3 Mol for XTT assay. IC50=41.9 Mol IC90=62.8 Mol for plaque reduction assay 100.0 Mol proanthocy anidin A-1 completely suppressed HSV-2 replication when added at 12 h postinfection. Number of coughing decreased 43%, latency period increased 53% compared to control (EtOH extract). Effect of fraxin (0.5 g/kg)simil ar to carbetapen tane citrate Increase of diuresis in

Cheng et al., 2005

Wang et al., 2005

Vichka nova et 167

Phlegm removin g

and 17 h diuresis with 5% water load In vivo. Mice, injected with phenol red solution.

mixture "Brusniver "

Stem s and leave s

EtOH extract, isolated arbutin, fraxin

g, 1 mL/100 g

Per 5 g/kg oral. (extract), 0.25g/kg , 0.5 g/kg (arbutin, fraxin)

Negative control. Positive control: NH4Cl

11.9% comparing to the control group. Ethanol extract and fraxin (0.5 g/kg) showed the strongest phlegmremoving effect. The phlegmremoving effect of arbutin (0.5 g/kg) was similar to that of NH4Cl (1 g/kg).

al., 1992

Wang et al., 2005

168

Table 16. Summary of Pharmacological Studies for Gemmae betulae Activity Model Plant Extract Admin Dosage Control tested used part type / used durati on Buds Crude 10, 50, Positive Anticanc In vitro. In vitro control: EtOH 200 er Human (40%) g/mL methotre lymphoxate extract blastoid fluorour Raji cells acil, cyclopho sphamide , vinblasti ne. Negative control 10 g Positive Methyle 96 well Not Anticanc In vitro. plate per control speci ne er Mouse chloride, well Methotre leukemia fied MeOH xate cells Negative extracts, L1210 control soxhlet

Antimicr obial

In vitro. Bacillus subtilis, Staphyloc occus aureus, Escherich ia coli, Pseudom onas aeruginos a. Agar diffusion assay, agar dilution assay.

Buds

Acetone In vitro. extract (1:5), reextracte d with MeOH, decoctio n (1:10)

0.0395%

Results

Referen ce

63% inhibitio n at 50 g/mL and 95% inhibitio n at 200 g/mL,

Spiridon ov et al., 2005

99% growth inhibitio n by m ethylene chloride extract and 91% growth inhibitio n by MeOH extract. Negative Inhibitio n zones control. Positive for control: MeOH ciproflox extract and acin, gentamic decoctio n were in sulphate, against penicilli S. n aureus: 11.2 and 10.2 mm, against B. subtilis: 11 and 8 mm, against P.

Goun et al., 2002

Duric et al., 2013

169

Antimicr obial

Antioxid ant

Buds In vitro. Agar dilution assay, antibiotic -resistant forms of 144 strains of Staphyloc occi isolated from patients with mastitis, furunculo sis, abscesses, peritonitis . Buds In vitro. DPPH assay, ABTS+ assay,

EtOH (70%) tincture (1:5)

In vitro.

EtOH extract

In vitro

aerugino sa: 11.6 and 0 mm. MIC for MeOH extract against P. aerugino sa: 1.25%, against B. subtilis: 2.5%, against S. aureus: 2.5%. Negative Antibact erial control. activity was observed for all strains with MIC in dilution 1:901:100

0.011.0 mg/mL

Negative control. Positive control: trolox, ascorbic acid

IC50=0.5 11 mg/mL in DPPH assay, IC50=0.2 90 mg/mL in ABTS+· assay.

Nikolae va, Khokhl ova, 1981

Mashent seva et al., 2011

170

Antioxid ant

Buds In vivo. Mice, acute hypoxia. Phospholi pids level in brain.

EtOH extract

Per oral

Diuretic

In vivo. Wistar rats, after NaCl solution load (25 mL/kg)

Buds

6% aqueous extract

Intraperit oneal

Heavy metals binding

In vivo. Wistar rats, feed normal diet with additional 25 mg/kg of Pb and 25 mg/kg of Cd during 10 days

Buds. EtOH extract, no details about concentr ation and method.

Per oral.

Negative Preventi 5.0 ve mg/kg, control. 20 days Positive administr control: ation of tocopher extract resulted yl in acetate. normaliz ation of phosphol ipid level. Effect was compara ble with tocopher yl acetate. 1 mL Negative Increase of uric per control. animal, Positive acid control: eliminati single injectio furosemi on in 5 folds n d comparin g to control group and effect was similar compare d to furosemi d. Negative The Pb 0.5 concentr mL/kg, control. ation in 32 days animal after 10 organs days of and intoxic tissues ation was by decrease heavy d by metals 45.771.3% and Cd, by 10.492.2%

Mashent seva et al., 2011

Peev et al., 2010

Bokova, Vasil’ts ova, 2011

171

compare d with control.

172

Table 17. Summary of Pharmacological Studies for A. vernalis Activity Model Plant Extract Admin Dosage tested used part type / used duratio n 96 well 500 Aerial MeOH AntiIn vitro, plate L/mL part 50% inflamm human extract. whole atory blood cell culture system stimulate d with lipopolys accharide activated macroph ages. Petri 0.02 Aerial 10% Antiviral In vitro. mL part aqueous dishes Agar extract diffusion, method. HeLa cells

Cardiac inotropic and constrict or

In vivo. Cats

Not mentio ned.

SCOA, a product which contains extracts from Scilla, Convall aria, Oleande r and Adonis

Intrave nous

Control

Results

Negative control.

Das et 35% inhibition al., 2007 TNF- productio n

Herpes virus Hominis HVP 75 (type 2), influenza virus A2 (Manhei m 57), Vaccini virus, polioviru s type 1. Negative control. Positive 21.5control: 100 GPU/k cymarin, g (GPU convallat oxin, = guinea- proscillar idin, and pig scillaren units, i.e. cardiot oxic equival ents related to 1 g body weight

Cytotoxic effect with inhibition zone 1530 mm, virustatic effect with inhibition zone over 30 mm for all viruses,

Refere nce

May, Willuh n, 1978

Lehma Positive inotropic nn, 1984 and constricto r effect on veins and arteries. Pure glycoside s cymarin, convallat oxin, proscillar idin, and scillaren 173

of guineapigs)

exert equal effects. Effect on veins and on the heart may differ for the glycoside s tested. Effect equal guineapig units of Adonis extract on capacitan ce vessels twice as much as Scilla, Oleander and Convalla ria extracts. Cymarin (main glycoside of Adonis), has stronger effect on veins than expected from its cardiotox ic effect.

174

Table 18. Summary of Pharmacological Studies for Convallaria Activit Model Plant Extract Admin Dosage/ y used part type duration tested used 5, 10, 20, AntiIn vivo, Rhizo Convallama Per oral 50, 100 g roside, the mes tumor Balb/c of steroidal and mice convallam induced roots saponin. aroside / 3 by days human kidney tumor cells and by sarcoma L1 cells Antivir al

In vitro. Leave s Agar diffusio n, method. HeLa cells

Cardia c inotrop ic

In vivo, beating rabbit atria

Aqueous extract (1:10)

Aerial Aqueous part extract (1:5), dry, convallatox in

Control

Results

Negative Antitumo control. r effect on human kidney tumors, and mouse sarcoma through inhibition angiogen esis Cytotoxi Herpes In vitro 0.02 mL c effect virus Hominis with HVP 75 inhibition (type 2), zone 15influenz 30 mm, virustatic a virus effect A2 (Manhei with inhibition m 57), Vaccini zone over 30 mm virus, polioviru for all s type 1. viruses Negative excludin control. g polioviru s Ex vivo 0.003; 0.03 Negative Extract mg/mL for control. significa ntly extract and increased 0.0001 atrial mM for stroke convallato volume, xin pulse pressure, and cAMP efflux. and markedly increase the K+ concentra

Refer ence Narto wska et al., 2004

May, Willuh n, 1978

Choi et al., 2006

175

Cardia c inotrop ic

In vitro. Not Rabbit specif erythroc ied ytes, (Na+ + K+)ATPase , from hog cerebral cortex

Cardia c inotrop ic and constri ctor

In vivo. Cats

Not specif ied.

Convallato xin.

In vitro.

Intrave SCOA, a nous product which contains extracts from Scilla, Convallaria , Oleander and Adonis

0.01 - 10 M

21.5-100 GPU/kg

tion in the beating atriaderived perfusate. Convallat oxin increased atrial stroke volume and pulse pressure but did not alter the cAMP efflux level. Negative Inhibitio control. n of Positive palytoxin control: -induced ouabain, K+ digoxin, release digitoxin with . IC50=0.9 M. Inhibitio n of Na++K+ ATPase with IC50=0.8 4 M. No inhibition by aglycone s, even at 10 M Positive Positive control: inotropic cymarin, and convallat moderate ly strong oxin, proscilla vasocons trictor ridin, effect on and scillaren veins and arteries. Pure

Ozaki et al, 1985

Lehma nn, 1984

176

Cardiot In vivo. Leave onic Cats wit s modulat ed ischemi a

Tincture, no details about preparation

Intrave nous

Leave s

Convara – an aqueous extract, treated with ferric hydroxide, concentrate d under reduced pressure until 1 g was equivalent to 30 g of dried leaves.

Extract 0.1 g direct additio n to the Locke’ s solutio n.

Cardiot In vivo. onic Cats, and isolated papillar y muscle of the cat heart.

0.2 mL

glycoside convallat oxin, exert equal effects. Negative The control. maximal Positive increase control: in the tinctures amplitud e of of A. vernalis, ischemic Digitalis skeletal purpure muscle contracti a, ons and Narium oleander has lower lethal . dose comparin g with positive control. Negative Increased control. strength isometric contracti ons of isolated papillary muscle.

Pardo et al., 1951

Weeks , Holck, 1943

177

Table 19. Summary of Pharmacological Studies for P. hydropiper Activity Model Pla Extract Admin Dosage Control tested used nt type / par duratio t n use d Transd 1.7, 17, Negative Fres Isolated Anticanc In vivo. 170 nM control. warburgan ermal h er Mice Positive / 1h initiated spro al and prior to control: uts polygodial with Salicylal each 7,12promoti dehyde dimethyl on with benz TPA []anthra cene (DMBA) and promote d with 12-Otetradeca noylphorbol13acetate (TPA) Negative Antifertil In vivo. Roo EtOH Per 100control. ity Pregnan ts (90%) oral 200 cy rats. extract mg/kg/ single dose Negative AntiIn vitro. Lea Commerci 96 well 0-200 g/mL control. plate ves al MeOH inflamm Murine extract macroph atory (99% age cell purity) line (RAW 264.7), lipopoly saccharideactivated macroph ages

Results

Referen ce

Delayed the formation of papilloma s, and markedly reduced rate of papillomabearing mice and the number of papilloma s per mouse.

Matsum oto, Tokuda, 1990

66% antifertilit y in early pregnancy

Prakash, 1985

Suppresse Yang et al., 2012 d release of NO, TNF-, and prostaglan din PGE2. Inhibited mRNA expression of proinflammat ory genes such as iNO synthase, COX-2, and TNF by suppressin 178

Per oral

Antiinflamm atory

In vivo. Mice with dextran sulphate sodium (DSS)induced colitis

Lea ves

Commerci al MeOH extract (99% purity)

Antimicr obial

In vitro. Broth microdil ution method.

Lea ves

Confertifol In in isolated vitro. from essential oil.

100 mg/kg/ 7 days

Negative control, DSS

Initial concent ration 0.5 mg/mL

Negative control. Positive control: fluconaz ole, ketocona

g the activation of NF-B, activator protein (AP-1), and cAMP responsive element binding protein (CREB), and simultane ously inhibited its upstream inflammat ory signaling cascades, including cascades involving Syk, Src, and IRAK1 Extract strongly ameliorate d the DSSinduced decrease in colon length that had been triggered by DSSinduced colon inflammat ion MIC (g/mL ) was 1.56 against Erwinia sp, 6.25 against S.

Yang et al., 2012

Duraipa ndiyan et al., 2010

179

zole, streptom ycin

Antinoci ceptive

In vivo. Mice, acetic acidinduced writhing

Aer ial part

Hexane, EtOAc MeOH extracts (yield 1.22, 1.81, 2.28% of dried plant material).

Per oral

Antioxid ant

In vitro. DPPH assay

Aer ial part

Hidropiper oside B and vanicoside sA isolated from MeOH extract

96 well No data plate

In vitro. Ferric thiocyan ate method

Lea ves

Isolated 7,4'dimethylq uercetin, 3'methylque rcetin

In vitro.

Citotoxic

In vitro. Lea Sensitize ves d sheep erythroc

250, 500 mg/kg,

0-10 ppm

Isolated Microti No data drimaneter type plates sesquiterpe

Negative control. Positive control: aminopy rine 50 mg/kg

Negative control.

Negative control. Positive control: tocopher ol

Negative control.

aureus and K. pneumoni ae, 7.82 against E. floccosum, C. Lunata, and Scopulari opsis sp., and 16.62 against T. mentagrop hytes and T. rubrum Suppressi on of the number of writhing in 1955%. Maximal effect for EtOAc extract at 500 mg/kg. IC50 = 23.4 g/mL for hidropiper oside B, 26.7 g/mL, for vanicoside s A. ID50= 1.5 ppm for 4’dimethylq uercetin and 3.0 ppm for 3'methylque rcetin. Anticompl ement activity at 10.5

Rahman et al., 2002

Kiem et al., 2008

Haraguc hi, 1992

Fukuya ma et al., 1980

180

Estrogen ic

ytes and guinea pig serum (comple ment) In vivo. Ovaryintact and ovariect omized (OVX) rats

g/mL.

ne dialdehyde polygodial .

Roo MeOH ts extract

Per oral

1000 mg/kg / 12 days

Negative control. Positive control: estradiol17 (E2)

In uterine tissues of ovaryintact and OVX rats, extract induced hyperplasi a in places of luminal epithelium and degenerati on of endometri al glands. In OVX rats, the effect of extract on uterine endometri um was corroborat ive with the effect of E2.

Hazarik a and Sarma, 2006

181

Table 20. Summary of Pharmacological Studies for A. graveolens Activity Model Plan Extract Admin Dosage Control tested used t type / part duratio used n Antibact In vitro Seed Aqueous, In vitro. 0.1 mL Negative control. s hexane, erial Agar Positive EtOAc, diffusio control: acetone, n assay. ampicillin, EtOH cefixime, extracts chlorampheni col, cotrimoxazole, gentamicin, imipenem, pipericillin/ta zobactam, tobramycin

Antibact In vitro. Aeri erial Microdi al part lution assay. E. coli, P. aerugin osa, Proteus mirabili s, K. pneumo niae, Acineto bacter

Essential oil by hydrodist il-lation

Micropl ates

No data.

Results Referen ce

Antibac terial activity against E. faecalis , S. aureus, E. coli, P. aerugin osa, S. typhi, S. typhim urium, S. flexneri with MIC=5 -10 mg/mL for acetone extract and 2050 mg/mL for aqueou s extract. MIC=1 Negative -4 control. g/mL Positive for al control: microb ampicillin, es gentamicin, (exclud ofloxacin, levofloxacin, ing ketoconazole clinical , fluconazole; isolates ) and 918 g/mL for all fungi.

Kaur and Arora, 2009

Erdoan Orhan et al., 2012.

182

bauman nii S. aureus, Enteroc occus faecalis , B. subtilis, and clinical isolates. C. albican s, C. parapsi losis Antibact In vitro. Not speci erial Broth dilution fied method. S. aureus, E. coli.

Antican cer

In vitro. Aeri Mouse al leukemi part a cells L1210,

Commer cial essential oil

96 well plate

0-0.5% (v/v)

Negative control.

Methylen 96 well e plate chloride and MeOH extracts, soxhlet

10 g per well concent ration of the extract

Positive control Methotrexate Negative control

300 mg/kg

Negative control. Positive control:

AntiIn vivo, inflamm Mice, atory formali n induced inflam mation

Aeri al part, seed s

Hydroalc hoholic extract

In vivo, Rats, formali

Fres h aeria

Sesame oil extract

Intraperit oneal

morphine.

Topical 100 applicati mg/ 8 on on days

Negative control. Positive

MIC(v/ v) = 0.37% against S. aureus and 0.47% against E. coli 98% growth inhibiti on by methyl ene chlorid e extract, Analge sic effect 15-45 min after formali ne injectio n by both extracts . Reduci ng of the paw

Delaquis et al., 2002

Goun et al., 2002

RezaeeAsl et al., 2013

Naseri et al., 2012

183

l part (10:4) n induced edema

paw

Antispa smodic

In vitro. Seed Rats s isolated ileum contract ions induced by KCl, acetylc holine and BaCl2

EtOH (70%) extract

Direct addition of extract to the media with ileum

0.1, 1, 2, 4 mg/mL /cumul ative

Antivira l

In vitro, Aeri antivira al part l

Essential oil by hydrodist il-lation

96 well plate

0.0250.8 g/mL

Diuretic

In vivo. Seed Mongre s l dogs.

EtOH (70%) extract. Volatile oil by steam distillatio n.

Intraven ous.

Volatil e oil 0.004m L/kg. Extract 12.5, 25 mg/kg.

inflam mation even stronge r than applicat ion of Diclofe nac. Negative Maxim control. al spasmo lytic effect was for BaCl2 induced contrac tion with IC50=0. 96 mg/mL . Antivir Herpes al simplex viruses HSV- activity against 1, parainfluenza HSV-1 type-3 (PI-3). at 0.025Positive 0.8 control: g/mL acyclovir, and oseltamivir against PI-3 at 0.4-0.8 g/mL. Negative Increas control. e in urine flow 2.2 folds at 12.5 mg/kg no effect on blood pressur e. 25

control: diclofenac gel 0.01%.

Gharib Naseri, Heidari, 2007

Erdoan Orhan et al., 2012.

Mahran et al., 1991).

184

Gastrop rotective

In vivo. Seed s Rats, EtOH and HClinduced gastric ulcer

Aqueous and EtOH (70%) extracts

Per oral, intraperi toneal.

0.050.45 g/kg aqueou s extract, 0.5-5 g/kg EtOH extract.

Negative control. Positive control: sucralfate, cimetidine

mg/kg produc ed a further but insignif icant increas e in urine flow accomp anied by a marked hypote nsion that lasted for 1 h. Volatil e oil increas ed Na+ and Cl‚ excreti on Decrea Hossein sed zadeh et gastric al., 2002 lesions induced by HCl with ED50= 0.12 g/kg for both extracts , induced by EtOH with ED50=0 .34 g/kg for aqueou s and 185

In vivo. Seed s Rats, indome thacin induced gastric ulcer after ligation of pylorus. In vitro pepsin binding .

Dry powder, aqueous and EtOH (95%) extracts.

Per oral.

1.73 g/kg for EtOH extracts . Both extracts at higher doses antisecr etory activity as effectiv e as cimetid ine. The Negative 1, 1.5, powder control. 2 g/kg of Positive of seeds powder control: indomethacin dose . depend Aqueou ent s and decreas EtOH e extracts gastric equival acid ent of 2 output, g/kg of increas powder e pH, . and 14 reduce days. gastric ulcer index. Effects of aqueou s and EtOH extracts were signific ant but lower. Pepsin binding capacit y of powder

Rifat-uzZaman et al., 2004

186

Hypolip idemic

In vivo. Rats fed with high cholest erol (Chol) diet, rats with normal diet.

Aeri al part

Essential oil by hydrodistillatio n with phellandr ene (32%), limonene (28%) and carvone (28%). Dry powder.

Per oral

Essenti al oil: 45, 90, 180 mg/kg for high Chol diet rats. Dry powder : 10% (w/w) additio n for normal diet rats / 2 weeks

Negative control. Positive control: clofibrate

was 70.4% at 0.5 g/mL. Treatm ent with essentia l oil resulted in dosedepend ent reducti on of total Chol, triglyce ride and LDLChol and increas e of HDLChol by 2433%. Additio n of powder reduced the total Chol in 20%, LDLChol in 2 folds and triglyce ride in 14% and increas ed the HDLChol concent ration

Hajhash emiand Abbasi, 2008

187

Regulati on of menstru al cycle

In vivo. Rats in estrus phase of estrous cycle.

Seed s

Aqueous and EtOH (80%) extracts.

Per oral

Negative 0.045, control. 0.45 g/kg of aqueou s and 0.5, 5 g/kg EtOH extracts . 10 days

in 30% compar ed to control. Increas Monsefi et al., e in duratio 2006. n of estrous cycle and in diestrus phase and progest erone concent ration in high dose extract treatme nt.

188

Table 21. Summary of Pharmacological Studies for Rhizomata et radices Rubiae Activity tested

Model used

Antidiarrho In vivo. eal Rats, castor oil-induced diarrhea. Mice, small intestinal transit.

Pla nt pa rt use d Ro ot

Extract type

Ad min

Dosage/ duration

Control

Results

Refere nce

Aqueous extract, 12.5% yield.

Per oral

300, 600, 800 mg/kg / single dose administr ation.

Negativ e control. Positive control: loperam ide

Karim et al., 2010

No data In vitro .

Protected rats, in a dosedependen t fashion, against diarrhoea l dropping by 3764%. Inhibited by 41% the gastrointe stinal transit of charcoal in mice at 800 mg/kg . 43% inhibition of Trichoder ma viride, 41% inhibition of Doratom yces stemoniti s and 35% inhibition of Penicilliu m verrucosu m. The lesion of mice

Antifungal

In vitro. Disc diffusion method.

Ro ot

MeOH extract with 6.3% yield

Antileishm aniasis

In vivo. BALB/c mice

Ro ot

EtOH Per (80%, oral 60, 40%)

No data.

Negativ e control. Positive control: alizarin, emodin, parietin.

Negativ e control.

Manojl ovic et al., 2005

Bafghi et al., 2008 189

infected with leishmania (L) major [MRHO/IR/ 75/ER].

extracts

Antilithiasi s

Ro In vivo. Rabbits, ot foreign-body bladder calculus model

Hydroxy anthraqu inone derivativ es

Per oral

Antilithiasi s

In vitro.

Ro ot

5% aqueous solution of extract.

Kidney In vitro stone 20 mg

No

Ro ot

Aqueous , EtOH, MeOH and EtOAc extracts

10-100 In vitro L in 6 mm disc. .

Negativ e control. Positive control: erythro mycin

Antimicrob In vitro. ial Agar-disc diffusion method.

No data

No data

treated with 40, 60 and 80% extract in water were wet, without secondar y infection and necrosis. Pronounc ed calciumcomplex binding effect and reduction in the growth rate of the calculi After 15 days the weight of stone was decreased by 25% and the stone structure became friable Full inhibition of Aspergill us flavus, Fusarium oxysporiu m, and Streptom yces murinus at 100 g/mL by EtOH and MeOH

Berg et al., 1976.

Vichka nova et al., 2009

Kalyon cu et al., 2006

190

extracts.

191

Table 22. Summary of Pharmacological Studies for S. aucuparia fruits Activity tested

Model used

Anticanc er

In vitro. Mouse leukem ia cells L1210,

AntiIn inflamma vitro. PPAR tory or PPAR activati on in human embryo nic kidney (HEK) 293 cells. Antimicr In obial vitro. Liquid culture.

Antimicr obial

Pla nt par t use d Fru its

Extract type

Ad min

Dosage/ duration

Methylene chloride extract, soxhlet

96 well plate

10 g per Positive 98% growth inhibition well control Methotre xate Negative control

Fru its

Detannifie d MeOH extract

96 well plate

10 g/mL

Negative control. Positive control GW7647 and pioglitaz one

Strong activation (75-100%) of PPAR and PPAR

Fru its

Polypheno l-rich fraction

In vitro .

1 mg/mL

Negative control.

Strong growth inhibition of Bacillus cereus. Bacteriostatic effect against Campylobacte r jejuni and Staphylococc us aureus. Weak inhibition of Salmonella enterica, and Escherichia coli. Inhibitory effect on hemagglutination of E. coli HB101 (pRR7), which

Fru In its vitro. Liquid culture. Inhibiti on of bacteri al hemagglutinat ion

Polypheno In l-rich vitro fraction . with anthocyani ns, flavonols, 5caffeoylqu inic and 3caffeoylqu inic acids.

Control

Negative 1 control. mg/mL. 0.5-2.0 g of total phenolics /mL for hemagglutinatio n

Results

Refere nce

Goun et al., 2002

Nohyne k et al., 2006

Kylli et al., 2010

192

Antioxid ant

Antiproliferat ive

2.1, 4.2, Negative control. 8.4 g/mL of phenolics for liposome s. 25, 50, and 100 g/g of phenolics for emulsion

expresses the M hemagglutinin . In liposome model 9097% inhibition of hexanal formation; 6877% inhibition formation of conjugated diene hydroperoxid es. In emulsion oxidation model 8695% inhibition hexanal formation; 8087% inhibition formationconj ugated diene hydroperoxid es. The FRAP value 61-105 M Fe2+/g of fresh weight and the DPPH radical scavenging activity: 9.721 g of berries/g of DPPH radical.

Kylli et al., 2010

In vitro. Liposo me and emulsi on oxidati on assays.

Fru its

Polypheno In l-rich vitro . fraction with anthocyani ns, flavnols, 5caffeoylqu inic and 3caffeoylqu inic acids.

In vitro. Ferric reducin g antioxi dant power (FRAP ). DPPH assay.

Fru its

Acetone (70%) extracts of fresh fruits

96 well plate

30 L of 1/40 diluted samples for FRAP assay and 50 L for DPPH assay

Negative control.

In vitro. DPPH assay.

Fru its

In vitro .

0.5 mg/mL

Negative control. Positive control: trolox

35-53% of the activity of trolox taken as100%

Zlobin et al., 2012

In vitro. HeLa

Fru its

Water soluble polysaccha rides (yield 4.2%). Polypheno l-rich fraction

96 well plate

50 g/mL

Negative control.

Reduced viability of HeLa cell to

McDou gall et al.,

Hukkan en et al., 2006

193

cell viabilit y assay

50% of control

2008

194

Table 23. Summary of Pharmacological Studies for I. obliquus Activity Model Plant Extract Admin Dosage/ tested used part type duratio used n Antialler In vivo. Fruitin Aqueous Intraperit 0.1, 0.5, extract oneally 2.5, gic Mice g bodies Per oral. 0.1, 1, 10 mg/mou se

Antiastmathi c

In vivo. Asthmat ic mice.

Sclerot ium

EtOH extract

Intraperit oneally

Antican cer

In vitro. Mouse leukemi a cells

Not specifi ed

Methyle ne chloride and

96 well plate

Contro l

Results

Negativ 100% inhibition e control anaphylact ic shock induced by compound 48/80 at 2.5 mg Oral administrat ion reduced total IgE levels and slightly affected production of IgG1. Spleen cell cultures from OVAsensitized mice that had received extract orally showed an increase in IFN- No data. Negativ Inhibition expression e control. of phosphorp38 MAPK, balancing IFN-/IL-4 ratio and decreasing number inflammat ory cells 10 Positiv 100% g/well e growth control: inhibition Methot by

Refer ence Yoon et al., 2013.

Yan et al., 2011

Goun et al., 2002

195

Antican cer

MeOH extracts, soxhlet

In vivo. Sclerot ium Mice with melano ma. In vitro. Melano ma B16F10 cells.

Aqueous extract

Intraperit oneally, per oral 48 well plates

Fruitin g bodies

Aqueous extract with glucoserich polysacc harides 149 kDa

96 well plate

Antidiab In vitro. etic 3T3-L1 Preadip ocytes.

Methylene chloride and 92% by MeOH extracts. Initial Negativ Intraperito neal concentr e ation 50 control. administrat mg/mL Positiv ion reduced e control tumor 20 growth to mg/kg/d 33% of ay (i.p) positive 200mg/ control. kg/day Inhibited (p.o) growth of during B16-F10 10 days cells by causing cell cycle arrest at G0/G1 phase. Negativ Extract 10, 25, enhanced 50, 100 e control. differentiat g/mL Positiv ion of 3T3-L1 e control: preadipocy insulin tes, and dosedependent increased TG accumulati on. It stimulated gene expression of CCAAT/e nhancerbinding protein  and PPAR during adipocyte differentiat ion, and induced rexate Negativ e control

L1210,

Youn et al., 2009

Joo et al., 2010

196

Antiinflamm atory

Antiinflamm atory

In vivo. Acetic acidinduced abdomin al constrict ion, hot plate tests in mice. Carrage enaninduced edema in rats. In vivo. Mice with dextran sulphate sodium (DSS)induced colitis

Sporop hores

MeOH extract (29.8% yield)

Per oral

100, 200 mg/kg / 7 consecu tive days (in rats), 100, 200 mg/kg /single dose in mice

Fruitin g bodies

Aqueous extract

Per oral

MeOH extract (29.8% yield)

96 well plate

50, 100 mg/kg / twice a day, 7 days before and during DSS administration, for 14 days. Twice a day 7 day concurrent with DSS administ ration 45, 90, 135 g/mL

In vitro. Sporop Murine hores macroph age cell line (RAW

the expression of PPAR target genes such as aP2, LPL and CD36. Negativ Dose e dependant control. reduction Positiv of paw e edema in control: rats and aspirin, analgesic ibuprof activity in en. mice

Park et al., 2005

Negativ e control, DSS

Diminishin g colitis by suppressin g expression of inflammat ory mediators TNF-, IFN-, IL1 and IL6, and iNOS in colonic tissues.

Mishr a et al., 2012

Negativ e control. Positiv e control:

Inhibition of iNOS and COX2 expression via the

Park et al., 2005

197

In vitro. Ames test

Sclerot ium

Subfracti ons from MeOH extract

Agar plates

50 g /plate

Antioxid In vitro. ant DPPH assay

Sclerot ium

Subfracti ons from MeOH extract

In vitro.

5–500 g/mL

Antimut agenic

downregulation of NF-B binding activity and reduction in nuclear p65 protein levels Negativ Inhibition of e control mutagenes is induced in Salmonella typhimuriu m strain TA100 by the directly acting mutagen MNNG (0.4 g /plate) by 77.380.0%. Inhibition of 0.15 g /plate 4NQOinduced mutagenes is in TA98 and TA100 by 52.6– 62.0%. Mutagenes is in TA100 by Trp-P-1 and B()P was reduced by 70.5– 87.2%. Negativ IC50 = 69 e g/mL for control. subfraction Positiv 1 e l-N6(1iminoet hyl) lysine

264.7), lipopoly saccharideactivate d macroph ages

Ham et al., 2009

Ham et al., 2009

198

In vitro. Sclerot ium DPPH, hydroxy l radicals, superoxi de anion radicals, H2O2 assays In vitro. Fruitin g ABTS, bodies DPPH, superoxi de anion radicals assays

Immuno modulat ory

In vivo. Balb/c mice

Sclerot ium

Polysacc In vitro. haride fractions OP40, IOP60, IOP80 with yield 2.2%, 11.6%, 0.84%, Isolated In vitro. inonobli ns A, B, and C, phelligri dins D, E, and G.

62.5– 1000 g/mL

Aqueous extract

1–100 mg/kg/ up to 8 weeks

Per oral

No data

control: ascorbi c acid, tocophe rol, BHA Negativ e control. Positiv e control: ascorbi c acid

Order of reducing power in DPPH, H2O2, and hydroxylscavenging activity was IOP60 > IOP40 > IOP80 Negativ Inonoblin C was e control. most Positiv active in ABTS e control: assay (0.65 trolox, TEAC), caffeic phelligridi n D in acid superoxide anion radicals assay (IC50=85.5 M), Phelligridi n E in DPPH assay (1.57 TEAC) Negativ Increased in 1.5-3.5 e control. fold the proliferativ e activity of splenocyte s transforme d in vitro by a polyclonal Con A mitogen or an

Du et al., 2013

Lee et al., 2007

Shash kina et al., 2006

199

Immuno modulatory

In vivo. Sclerot Ovalbu ium min (OVA)sensitize d BALB/c mice. Ex vivo. LPSstimulat ed peritone al macroph ages.

Aqueous extract

Per oral

Daily 50, 100, 200 mg/kg

alloantigen in a mixed culture of lymphocyt es (MCL) from allogenic mice spleen. Induced formation of additional T-killers in the MCL. 8 weeks administrat ion stimulated cytotoxic activity of peritoneal macrophag es. Negativ IgG2a was Ko et e suppressed al., 2011 control. after the second immunizat ion with OVA. ConA stimulation in spleen cells isolated from OVAsensitized mice treated with 100 mg/kg resulted in 5.2% decrease in IL-4 production and a 102.4% increase in 200

Radiopr In vivo. o-tective Rats irradiate d with cesium (2.0 Gy)

Sclerot ium

Chromog Per oral. enic complex

Radiopr In vivo. o-tective Wistar rats Balb/c mice irradiate d (0.025

Sclerot ium

Aqueous, Per oral EtOH extracts, aqueous suspensi on

IFN-, compared to controls. IL-4, IFN, and IL-2 were reduced after ConA stimulation in isolated CD4+T cells. Extract inhibits the secretion of NO from LPSstimulated peritoneal macrophag es ex vivo. Negativ Between 3 4.0 and 10 e mg/kg /30 days control. days after exposure, recovery of hemopoieti c tissue function and bone marrow cellularity. Stimulatio n of cells participati ng in the immune protection of neutrophils (micropha ges) and lymphocyt es. Negativ Decrease Dose in the e not indicate control. extent of radionucli d/ single de administ deposition ration in in the bone rats 2-3

Gavri lov et al., 2003

Rasin a, 2002

201

sGr/min ) 30 days.

min after the intraven ous injectio n of 90Sr isotope irradiati on. 30 days administ ration of suspensi on in mice

and soft tissues and increase of radionucli de eliminatio n in 3335% in rats. Extension of average lifespan of mice up to 305 days (against 186 days in the untreated control group) and prevented a sharp drop of leukocytes and lipid peroxidati on.

202

Table 24. Summary of Pharmacological Studies for Aralia Activity Model Pla Extract Admin Dosage/ tested used nt type duration par t use d Intragastr 16 Antiarrhyt In vivo. Ro Aqueous ots extract ic mg/kg, 5 hmic Rats, days coronar y occlusio n and reperfus ion

Anticance r

In vitro. Human kidney

Ro ots

Isolated araloside A

In vitro

1, 3, 10, 30, 100 M

Control

Results

Refere nce

Negativ e control

Improve ment heart resistance to arrhythm ogenic effect of ischemia and reperfusio n. 86% of animals receiving extract before coronary occlusion developed no arrhythmi as, vs. 19% in controls. Severity of arrhythmi a in treated rats was 74% lower during ischemia and coronary blood flow recovery than controls. Reduction of cellular viability

Maslo v et al., 2009

Negativ e control

Yu et al., 2011 203

cancer cell lines GRC-1 and 786-O

Anticatara ct

Anticatara ct

Ex vivo. Rat lenses from male Sprague Dawley rats. Sugar cataract was induced by adding of (+)xylose to media In vivo. STZ-

Bar Aqueous k extract with 7% yield

24 well plate

0.5, 1 mg/mL

Negativ e control

Bar Aqueous k extract

Per oral

300, 600 mg/kg

Negativ e

of booth cells in a dose- and timedependent manner. Number of Tunnelpositive cancer cells was higher in cells treated with Araloside A than untreated cells. Araloside A increased expressio n of bax mRNA and inhibited expressio n of bcl-2 mRNA. Chung After treatment et al., 2005 at 1 mg/mL lens opacity was lowered by 36.4 and 31.3% after 24 and 48 h, respective ly

After treatment

Chung et al., 204

daily, 11 control weeks after STZ administ ration

with 7% yield

induced diabetic rats

Antiinflammat ory

In vitro. Murine macrop hage cell line (RAW 264.7), lipopoly saccharideactivate d macrop hages

Ro ots

Isolated saponin elatoside F

96-well plates 24-well plates

Antiulcer

In vivo. Aspirininduced ulcer. HClEtOH induced gastric lesions.

Ro ot bar k

Isolated araloside A

Per oral

with 300 or 600 mg/kg extract the opacities of lenses decreased by 15% and 12% respective ly. 0.96, 9.6, Negativ Inhibition of LPSe, 48, 96 Positive induced M control: NO productio tosyl phenylal n in 28.8, 43.2, anyl chlorom 67.9, and 81.2% at ethyl ketone, 0.96, 9.6, 48, and 96 M. Inhibition of NF-B activity in 20.4, and 33.7% at 48 M, and 96 M respective ly. 50, 100 Negativ Reduction of mg/kg e control. HClPositive EtOHcontrol: induced cimetidi gastric lesions ne. and aspirininduced gastric ulcers. Antiulcer action may be due to the inhibition of gastric

2005

Lee et al., 2009

Lee et al., 2005

205

Cardioprot In vivo. ective Cardiac dysfunc tion in STZ induced diabetes rats.

Ro ots

Per oral Total aralosides, no details about isolation.

4.9, 9.8, 19.6 mg/kg, for 8 weeks

acid secretion Xi et Prevents diabetes- al., 2009 induced cardiac dysfuncti on by increased absolute value of left ventricula r systolic pressure and maximum rates of pressure developm ent, and enhanced amplitude of ICa2+-L in cardiac cells and decreasin g connectiv e tissue growth factor expressio n. High dose, but not low prevented cardiac ultrastruct ural changes in diabetic rats, indicated by closely lining up of myofilam ents and almost normal 206

Cardioprot In vtrvo. ective Injury induced by H2O2, in H9c2 cells

Ro ot bar k

96-well Waterplates soluble polysacch aride AEP-w1 (Mr 4.5×104 Da). Monosacc haride componen ts: arabinogal actan, consisting of arabinose, galactose and trace glucose with molar ratios of 6.3:3.5:0.2 .

Gastroprot In vivo. ective Rats, coldrestraint stress (CRS), pylorus ligation

Ro ots

EtOH (50%) extracts

Intraperit oneal

100, 200, Negativ e 400 g/mL control

50 mg/kg, 30 min pretreat ment

Negativ e control.

structure of mitochon dria AEP-w1 suppresse d cardiomy ocyte apoptosis, the mitochon drial membran e potential change and cytochro me C release in H2O2treated H9c2 cells. Intracellul ar reduced glutathion e (GSH) reduction caused by H2O2 in H9c2 cells was restored by AEPw1 pretreatm ent. Pretreatm ent reduced incidence and severity of CRSinduced gastric glandular lesions.

Zhang et al., 2013

Herna ndez et al., 1988

207

Hypoglyc emic

In vivo. Rats, glucose toleranc e test (GTT)

Ro ot bar k

Isolated Per oral oleanolic acid and 9 oligoglyos ides

100 mg/kg, single administ ration

Negativ e control.

Hypoglyc emic

In vivo. Rats, rabbits with high choleste rol diet.

Ro ot

Saparal (mixture of ammoniu m salts of aralosides A, B, C)

Per oral

10, 23, 58 mg/kg, 3 days (rats), 58 mg/kg (rabbits)

Negativ e control.

Gastric secretory volume was reduced, increased intralumi nal gastric pH and decreased acid output. 3-Omonodes mo-sides elatosides A and E, stipuleano -side R1 and oleanolic acid 3-Oglycoside s showed potent inhibitory activity in GTT Blood serum cholestero l in rats was reduced by 29.8% comparin g to control at 58 mg/kg. Level of cholestero l in the aorta was reduced by 31.7%. In rabbits blood cholestero l was reduced by 61.4%.

Yoshik awa et al., 1996

Voska nyan et al., 1983

208

Table 25. Summary of Pharmacological Studies for R. roseae Activity Model Plant Extract Admin Dosage/ tested used part type duratio used n Roots Comme Intraga 10, 15, Adaptoge In vivo. stric 20 rcial Mice, nic and mg/kg / EtOH forcedCNS single extract swimming dose (contain test, ing 3% swimming rosavin to and 1% exhaustio salidros n, ide) light/dark exploratio n, open field, tailflick Intraga 50 Rhizo EtOH Adaptoge In vivo. stric mg/kg me (60% nic Rats, /single v/v) exhaustiv and dose roots extract e with swimming 3.02% rosavin es and 0.89% salidros ide

Anticance r

In vitro. Human lymphobl astoid Raji cells

Antiarrhyt In vivo. hmic Rats, isolated heart.

Roots

Crude EtOH (40%) extract

In vitro

Roots

EtOH (40%) extract

Per oral

Control

Results

Negativ Induction e control antidepres sant-like, adaptogen ic, anxiolytic -like and stimulatin g effects. Bell shaped doseactivity curve Negativ Prolonged e control duration of swimmin g (by 24.6%). Activated the synthesis or resynthesi s of ATP in mitochon dria. Positive 99% 10, 50, control: growth 200 methotr inhibition g/mL at 200 exate fluorour g/mL; 75% acil, cycloph inhibition at 50 osphamide g/mL with , vinblasti formation of giant ne. Negativ polyploid e control cells. 3.5 Negativ Preventio mL/kg, 8 e n days control, reperfusio Positive n control: arrhythmi

Refere nce Perfum i and Mattiol i, 2007

Abidov et al., 2003

Spirido nov et al., 2005

Maslov et al., 1997

210

Naloxon e, ICI 174,864

Antiviral

Roots In vitro. Plaque reduction assay In vivo. BALB/c mice, SpragueDawley (SD) rats Coxsackie virus B3 (CVB3)

Salidros Per ide oral (purity 99%)

20, 60, 80 mg/kg / 7 days

Negativ e control. Positive control: ribavirin

as and elicitation protective effect in experime nts on isolated heart in interrupti ng the perfusion with Krebs-Henseleit solution followed by reperfusio n. Antiarrhyt hmic effect was mediated through activation of opiate receptors in myocardi um. Antiviral Wang et al., effects 2009 both in vitro and in vivo. Salidrosid e modulate the mRNA expressio n of interferon -, interleuki n-10 (IL10), TNF, and interleuki n-2 (IL2). 211

EtOAc extract EC50= 102.1 g/mL against H1N1 and 145.4 g/mL against H9N2. Aqueous extract EC50=78. 5 g/mL against H1N1 and 139.7 g/mL against H9N2. For kaempfer ol, herbacetin , and rhodiolini n EC50= 30.2, 35.0, and 41.7 M against H1N1and 18.5, 23.0, and 29.3 M against H9N2. 70.4% inhibition of HIV-1 protease

Antiviral

Roots In vitro. Virusinduced cytopathic effect (CPE) in MadinDarby canine kidney (MDCK) cells Viruses: H1N1 (A/PR/8/3 4) and H9N2 (A/Chicke n/ Korea/ MS96/96) .

Aqueou In vitro. s, EtOAc extracts . Isolated kaempf erol, herbace tin, rhodioli nin, rhodion in, and rhodiosi n

Initial concentr ation 5 mM

Negativ e control. Positive control: oseltami vir (Tamifl u)

Antiviral

In vitro. HIV-1 protease inhibition

Roots

MeOH extract

In vitro.

100 g/mL

Negativ e control. Positive control: acetyl pepstati n

Hypotensi In vivo. ve SHR rats.

Roots

Aqueou s extract with

Per oral

35, 50, 75 mg/kg

Lee, et Negativ Dosee control dependent al., 2013. decrease systolic

Jeong et al., 2009

Min et al., 1999

212

Neurotrop In vivo. ic Mice, thiopental -induced sleep

Roots

salidros ide (8.4mg/ g) and ptyrosol (1.9mg/ g). EtOH extract

blood pressure and increase endorphin release. Per oral

10-500 mg/kg

Negativ Stimulatio Kurkin et al., e control n at 10 2003 mg/kg (sleep period reduced by 12.5 times), sedation at 500 mg/kg (sleep period was increased 3-fold)

213

Table 26. Summary of Pharmacological Studies for Herba polygoni persicariae Activit Model used y tested

Antican cer

In vitro. Cervical carcinoma HeLa, acute monocytic leukemia THP-1 cell lines.Sulphor hodamine B cell growth inhibition assay

Antifun gal

In vitro. Microbroth dilution assay. Candida albicans, Saccharomyc es cerevisiae, Cryptococcus neoformans, Aspergillus flavus, As. fumigatus, As. niger, Trichophyton rubrum, Tr. mentagrophyt es, Microsporum gypseum

Pla nt par t use d Aer ial par t

Extract type

Aer ial par t

Admin

Dosage / duratio n

Control Results

96 well Isolated cardamom plate in, pinostrobi n

1, 10, 30, 50, 100 g/mL

Negativ e control. Positive control: paclitax el

In vitro. Dichloro methane extract. Isolated polygodia l, isopolygo dial, and cardamoni n.

Initial concent ration 100 L

Negativ e control. Positive control: retocon azole, amphot ericin, terbinaf ine

For cardamo min IC50 = 1.8 g/mL against THP-1 and 17 g/mL against HeLa. For pinostrobi n IC50 = 9 g/mL against THP-1 MIC (g/mL ) for dichloromethane extract was 31.2 against Tr. Mentagro phytes; polygodia l 3.9 against C. albicans, 7.8 against C. neoforma ns, Tr. rubrum, Tr. Mentagro phytes, and 15.6 against S. cerevisiae ; cardamon

Refer ence

Dzoy em et al., 2012

Derita , Zacch ino, 2011

214

Antiinflam matory

In vivo. Carrageenaninduced edema in rats

Aer EtOH ial extract par t

Intraperi toneal

Not provide d

Negativ e control.

in 15.6 against Tr. rubrum, and Tr. mentagro phytes Yano Antiinflammat et al., 2011 ory activity.

215

Abstract Ethnopharmacological relevance: Due to its location between West and East, Russian phytotherapy has accumulated and adopted approaches originating in European and Asian traditional medicine. Phytotherapy is an official and separate branch of medicine in Russia and thus herbal medicinal preparations are official medicaments. The aim of the present review is to summarize and critically appraise the data concerning plants used in Russian medicine. This review describes the history of herbal medicine in Russia, current situation and pharmacological effects of those specific plants of Russian Pharmacopoeia which are not included in European Pharmacopoeia. Materials and methods: Based on the State Pharmacopoeia of the USSR, 11th edition we selected plant species which have not been adopted yet in Western and Central Europe (e.g. via the inclusion in the European Pharmacopoeia) and systematically searched the scientific literature for data through library catalogs, the online service E-library.ru and in addition Medline/Pubmed, Scopus and Web of Science databases on the species, effectiveness, pharmacological effects and safety. Results: The Russian Federation follows the State Pharmacopoeia of the USSR, 11th edition which contains 83 individual monographs for plants. Fifty one plants are also found in the European Pharmacopoeia and have been well studied, while 32 plants are only found in the Pharmacopoeia of USSR. Many articles about these medicinal plants were newer translated in English and a lot of information collected by Russian scientists was not available for international community. Such knowledge can be applied in future studies aiming at a safe, evidence-based use of traditional Russian medicinal plants in European and global phytopharmacotherapy as well as for the discovery of novel leads for drug development. Conclusion: The review highlights the therapeutic potential of these Russian phytopharmaceuticals, but it also highlights cases where concern is raised about the products safety and tolerability and that would support their safe use.

216

graphical abstract