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WHO Monographs on Selected Medicinal Plants - Volume 2
(2004; 358 pages) View the PDF document
Table of Contents
View the documentIntroduction
View the documentGeneral technical notices
View the documentRadix Althaeae
View the documentHerba Andrographidis
View the documentRadix Angelicae Sinensis
View the documentFlos Calendulae
View the documentFlos Caryophylli
View the documentRhizoma Cimicifugae Racemosae
View the documentFolium cum Flore Crataegi
View the documentRadix Eleutherococci
View the documentAetheroleum Eucalypti
View the documentFolium Eucalypti
View the documentCortex Frangulae
View the documentFolium et Cortex Hamamelidis
View the documentSemen Hippocastani
View the documentHerba Hyperici
View the documentAetheroleum Melaleucae Alternifoliae
View the documentFolium Melissae
View the documentAetheroleum Menthae Piperitae
View the documentFolium Menthae Piperitae
View the documentFolium Ocimi Sancti
View the documentOleum Oenotherae Biennis
View the documentRhizoma Piperis Methystici
View the documentCortex Pruni Africanae
View the documentCortex Rhamni Purshianae
View the documentFlos Sambuci
View the documentRadix Senegae
View the documentFructus Serenoae Repentis
View the documentFructus Silybi Mariae
View the documentHerba Tanaceti Parthenii
View the documentRadix Urticae
View the documentFolium Uvae Ursi
View the documentAnnex: Participants in the Second WHO Consultation on Selected Medicinal Plants
 

Radix Eleutherococci

Definition

Radix Eleutherococci consists of the dried roots and rhizomes of Eleutherococcus senticosus (Rupr. and Maxim.) Maxim. (Araliaceae) (1-3).1

1 A 33% ethanol extract of Radix Eleutherococci is listed as Extractum Radicis et Rhizomatis Eleutherococcus in the Russian Pharmacopoeia (4, 5).


Synonyms

Acanthopanax senticosus (Rupr. et Maxim.) Harms., Hedera senticosa (1, 4, 6).

Selected vernacular names

Buisson du diable, chi wu cha, ciwujia, devil’s bush, devil’s shrub, eleuthero, eleutherococc, eleutherococoque, eleutherokokk koljucij, ezoukogi, gashi ohgap, hongmao-wujiapi, many prickle acanthopanax, pai wu cha pi, prickly eleutherococc, prickly eleutherococcus, shigoka, Siberian ginseng, Stachelkraftwurz, Stachelpanax, taiga root, Taigawurzel, thorny ginseng, thorny Russian pepperbush, touch-me-not, tsu wu cha, wild pepper, wu cha sang, wu cha seng, wu jia pi (2, 7).

Geographical distribution

Indigenous to south-east Asia, northern China, the Democratic People’s Republic of Korea, Japan and the south-eastern part of the Russian Federation (4, 5).

Description

A prickly shrub, up to 4-6 m high, usually with several mostly unbranched stems; oldest stems may be unarmed, while the youngest are densely covered with flexible prickles. Palmate leaves, on long, often reddish stalks, usually composed of 5 elliptical leaflets with serrate margins. Flowers small, polygamous, occurring toward the tips of stems in single or paired umbels that have long peduncles. Floral parts are in groups of 5, including the epigynous ovary surrounded by a nectar-secreting disc. Fruit, a drupe, contains the same number of kernels as carpels. Flower and fruit resemble those of ivy (Hedera helix) (8).

Plant material of interest: dried roots and rhizomes

Roots from the unrelated plant Periploca sepium Bunge (Asclepiadaceae) (Chinese silk vine) have been surreptitiously used as a substitute for Radix Eleutherococci in commerce. To a lesser extent, roots from the related Acanthopanax species and Kalopanax septemlobus (Thunb.) Koidz. (Araliaceae) have also been so used (9, 10).

General appearance

Roots: cylindrical, up to 0.5 cm in diameter, straight, occasionally branched, dark brown, smooth surface with bark adhering closely to the xylem. Rhizomes: up to 4 cm thick, pale brown, longitudinally wrinkled, showing root scars and traces of aerial stems; fracture somewhat fibrous; fractured surface pale yellow (1).

Organoleptic properties

Odour: faint, aromatic; taste: bitter, acrid, persistent (1).

Microscopic characteristics

Roots: rows (5-7) of brown cork cells; secondary phloem containing secretory canals in groups of 4 or 5, up to 20µm in diameter, with brown contents; phloem fibres with thick, lignified walls occurring singly or in small groups; cluster crystals of calcium oxalate in phloem parenchyma; parenchymatous cells surrounding secretory cells and the medullary ray cells containing small starch grains; xylem of reticulate and bordered, pitted vessels. Rhizomes: similar to the roots except for larger secretory canals, up to 25µm in diameter, and presence of parenchymatous pith containing starch grains (1).

Powdered plant material

Yellowish; numerous groups of thick-walled, lignified fibres; fragments of reticulate and bordered, pitted vessels with a wide lumen; groups of secretory canals, up to 20µm in diameter, with brown contents; parenchymatous cells containing cluster crystals of calcium oxalate 10-50µm in diameter; small starch grains, rounded to slightly angular in outline, single or in groups of 2 or 3 (3).

General identity tests

Macroscopic and microscopic examinations (1-3), thin-layer chromatography (2, 3) and high-performance liquid chromatography (11-13).

Purity tests

Microbiological

Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for medicinal plants (14).

Foreign organic matter

Not more than 3% (3). Must be free of Periploca sepium and other foreign plant materials.

Total ash

Not more than 6% (1).

Acid-insoluble ash

Not more than 1.5% (1).

Water-soluble extractive

Not less than 4% (1).

Alcohol-soluble extractive

Not less than 6% using 75% ethanol (3).

Loss on drying

Not more than 10% (3).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (15). For other pesticides, see the European pharmacopoeia (15), and the WHO guidelines on quality control methods for medicinal plants (14) and pesticide residues (16).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (14).

Radioactive residues

Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (14) for the analysis of radioactive isotopes.

Other purity tests

Chemical tests to be established in accordance with national requirements.

Chemical assays

Several methods based on high-performance liquid chromatography are available for quantitative determination of syringaresinol-diglucoside (eleutheroside E) and syringin (eleutheroside B) (11-13).

Major chemical constituents

The constituents responsible for the characteristic biological effects of Radix Eleutherococci appear to be a complex mixture of phenylpropane derivatives of diverse structure, and various sugar polymers (4, 6, 11). The principal components of the former group are the lignans, (+)-sesamin (eleutheroside B4), (+)-syringaresinol and its monoglucoside (eleutheroside E1) and diglucoside (eleutherosides D and E); the simple phenylpropanes, syringenin and its monoglucoside (eleutheroside B); and the coumarins isofraxidin and its monoglucoside (eleutheroside B1). An immunostimulant polysaccharide complex and a glycan series (eleutherans A-G) have also been isolated from the drug (17). β-Sitosterol and daucosterol (eleutheroside A) are the major sterols. Eleutheroside E has been found in all samples regardless of geographical origin, whereas eleutheroside B is present in all samples, except those from plants grown in the Democratic People’s Republic of Korea (11, 12). The structures of the representative constituents are presented below.


(+)-sesamin

eleutheroside D
1-epi = eleutheroside E

(+)-syringaresinol R = H
eleutheroside E1 R = Glc

syringenin R = H
eleutheroside B R = Glc

isofraxidin R = H
eleutheroside B1 R = Glc


β-D-glucopyranosyl

daucosterol R = Glc
β-sitosterol R = H


eleutheroside C

Medicinal uses

Uses supported by clinical data

As a prophylactic and restorative tonic for enhancement of mental and physical capacities in cases of weakness, exhaustion and tiredness, and during convalescence (4, 18-20).

Uses described in pharmacopoeias and in traditional systems of medicine

Treatment of rheumatoid arthritis, insomnia and dream-disturbed sleep (2).

Uses described in folk medicine, not supported by experimental or clinical data

As a carminative in the treatment of acute and chronic gastritis, as a diuretic, to treat impotence and to regulate blood pressure (7).

Pharmacology

Experimental pharmacology

Adaptogenic/antistress activity

The mechanism of the antistress or adaptogenic activities of Radix Eleutherococci appears to be threefold. Extracts of the roots have an adaptogenic effect that produces a non-specific increase in the body’s defence against exogenous stress factors and noxious chemicals (4, 21, 22). The roots also stimulate the immune system, and promote an overall improvement in physical and mental performance (4).

Numerous in vivo studies have demonstrated the pharmacological activity of a 33% ethanol extract of the roots in a variety of animal models (4, 23-29). Most of these investigations were designed to analyse the adaptogenic response to a variety of adverse conditions (stress, immobilization or chemical challenge) (4, 24, 25, 28, 30). An increase in the resistance of rats to the toxic effects of noxious chemicals such as alloxan, cyclophosphan, ethymidine and benzo-tepa was observed after oral administration of a 33% ethanol extract of the roots (1-5 ml/kg body weight) (24, 25, 28). Intragastric administration of a 33% ethanol extract of the roots to mice (10 ml/kg body weight) decreased the toxicity of diethylglycolic acid, but did not reduce the severity of electroshockinduced convulsions (31). Administration of a 10% decoction of the roots to frogs’ ventral lymph sac (0.1 ml) protected them against injection of lethal doses of cardiac glycosides (32). Intragastric administration of a 33% ethanol extract of the roots (1.0 ml/kg body weight) daily for 21-23 days increased the resistance of rats to the toxic effects of alloxan, but did not lower alloxan-induced hyperglycaemia (33). Intragastric administration of a freeze-dried extract of the roots (80 or 320 mg/kg body weight) daily for 3 days decreased blood glucose levels of mice by 35% and 60%, respectively, compared with placebo treatment (34). Reduction of blood glucose levels may be due partially to enhanced synthesis of glycogen and high-energy phosphate compounds (35).

Investigations to elucidate the adaptogenic effect on the lymphatic system assessed the ability of root extracts to inhibit cortisone-induced weight decreases of the thymus and spleen in rats (4). Intraperitoneal administration of a 33% ethanol extract of the roots (1.0 ml/kg body weight) daily for 8 days prevented a decrease in spleen and thymus weight due to cortisone administration (22). A 33% ethanol root extract had normalizing effects on experimentally induced hypothermia when administered intragastrically to rats and mice (0.1 or 1.0 ml/kg body weight) daily for 12-14 days (36). Intragastric administration of a 33% ethanol extract of the roots to rats and mice normalized experimentally induced hypothermia, and acted as a sedative (37).

Intragastric administration of an aqueous extract of the roots to mice (500 mg/kg body weight) decreased stress-induced enlargement of the adrenal gland, normalized a decrease in rectal temperature due to chronic stress, and enhanced sexual behaviour (26). Intragastric administration of an aqueous extract of the roots (500 mg/kg body weight) daily for 15 days prolonged the swimming times of rats (38). Intragastric administration of an aqueous or butanol extract of the roots to rats (500 mg/kg body weight) suppressed gastric ulcer formation induced by stress (immersion in cold water) (39). Intragastric administration of an aqueous extract of the roots (500mg/kg body weight) to rats suppressed the decrease in locomotor activity induced by exposure to light, indicating a reduction in the anxiety levels of the animals (40).

The antistress or adaptogenic effects of Radix Eleutherococci are produced through metabolic regulation of energy, nucleic acids and proteins of the tissues. Under stress, a β-lipoprotein-glucocorticoid complex is generated in the blood. This complex inhibits permeation of cell membranes by sugars and also inhibits hexokinase activity in vivo and in vitro (4). The root extracts increase the formation of glucose-6-phosphate, which in turn decreases the competition between the different pathways of its utilization. In animal tissues deficient in ATP, glucose-6-phosphate is oxidized via the pentose phosphate pathway, yielding substrates for the biosynthesis of nucleic acids and proteins (4). The constituents syringin (eleutheroside B) and (-)-syringaresinol-4,4'-O-β-Ddiglucoside (eleutheroside E) are thought to be responsible for the adaptogenic activity (21). Intraperitoneal administration of total eleutherosides isolated from the roots to rats (5.0 mg/kg body weight) partially reversed the decrease in the levels of muscle ATP, glycogen, creatine phosphate, lactic acid and pyruvic acid induced by 2 hours of swimming. The same treatment also increased the work capacity of mice (41). Intraperitoneal administration of total eleutherosides to rats (15 mg/kg body weight), 1 hour prior to 15 minutes of forced swimming, delayed the inhibition of RNA polymerase. The same treatment also increased the activity of this enzyme during rest periods (42). Intragastric administration of a butanol extract of the roots to mice (170mg/kg body weight, daily, 6 days a week for 6 weeks) enhanced the activities of oxidative enzymes and superoxide dismutase in skeletal muscle, resulting in improved aerobic metabolic rates (43). Intragastric administration of an aqueous extract of the roots to mice (170 mg/kg body weight, daily for 9 weeks) increased the activity of succinate dehydrogenase and malate dehydrogenase in skeletal muscle (44).

Intraperitoneal administration of an aqueous root extract to mice (40-320mg/kg body weight) increased sleeping times up to 228% compared to controls treated with hexobarbital, and decreased sleep latency when given in conjunction with hexobarbital (45).

Intraperitoneal administration of an aqueous extract of the roots to rats (3 mg/kg body weight) caused a significant increase in corticosterone levels 3 hours after injection, whereas adrenocorticotropic hormone levels remained unchanged (40). Intraperitoneal administration of a fluidextract of the roots (1.0 ml/kg body weight) increased anabolic activity in male rats (46). Oral administration of a glycoside fraction isolated from an ethanol root extract to rats (5.0 mg/kg body weight) increased the body weight and RNA content of the prostate and seminal vesicles, and inhibited atrophy of the prostate and seminal vesicles in castrated animals (47). A 30% ethanol extract of the roots was shown to bind in vitro to the estrogen receptor in rat uterus, and the glucocorticoid and mineralocorticoid receptors in rat kidney, but not to the androgen receptor in rat kidney (48).

Antimicrobial activity

Parenteral administration of a 33% ethanol extract of the roots (dose not speci- fied) increased the resistance of mice and rabbits to listeriosis when administered for 15 days prior to infection (49, 50). However, administration of the extract simultaneously with the bacteria increased the severity of the infection (49). Intragastric administration of the same extract (1 ml daily) for 15 days stimulated specific antiviral immunity in guinea-pigs and mice (51). A polysaccharide fraction of the roots (0.01 mg/ml) increased the activities of lymphokine-activated killer (LAK) cells and enhanced the activities of interleukin 2-stimulated LAK cells in vitro (52). A 95% ethanol extract of the roots (1 ml daily) increased phagocytosis of Candida albicans by human granulocytes and monocytes in vitro by 30-45% (53). Intraperitoneal administration of a polysaccharide fraction isolated from an aqueous root extract (10mg/kg body weight) had immunostimulant activity in mice, as demonstrated by the colloidal carbon clearance test (17). A pyrogen-free polysaccharide fraction of the roots stimulated lymphocyte phagocytosis and T-cell-dependent functions of B-cells in vitro, as determined by plaque-forming cell stimulation assays and the production of anti-bovine serum albumin antibodies. Intraperitoneal administration of the same polysaccharide fraction to mice (100mg/kg body weight daily for 7 days) significantly increased plaque-forming cell counts, antibovine serum albumin antibody levels and the phagocytic activity of lymphocytes (54). Intraperitoneal administration of a polysaccharide fraction of an aqueous extract of the roots to mice (125mg/kg body weight) markedly increased the serum levels of anti-bovine serum albumin IgA and total antibovine serum albumin immunoglobulins, but not total IgA (55).

Inhibition of platelet aggregation

A 100% methanol extract of the root inhibited ADP-induced platelet aggregation in blood samples from rats and humans in vitro (56).

Clinical pharmacology

Adaptogenic/antistress activity

Numerous clinical studies, designed to measure the adaptogenic effects of Radix Eleutherococci, were performed in Russia during the 1960s and 1970s (reviewed in Farnsworth et al., 1985 [4]). In 35 clinical trials without controls, involving over 2100 healthy subjects (4-1000 per study), oral administration of a 33% ethanol root extract (2.0-20.0 ml, daily for up to 60 days) improved physical and mental work performance under stress conditions, and reduced auditory disorders and the incidence of illness (4, 30).

In another 35 clinical trials without controls, the effects of a 33% ethanol extract of the roots were assessed in 2200 patients (5-1200 per study) with various disorders, such as arteriosclerosis, acute pyelonephritis, diabetes, hypertension, hypotension, chronic bronchitis and rheumatic heart disease. Patients received 0.5-6.0 ml extract orally 1-3 times daily for up to eight courses of 35 days each, each course being separated by 2-3 weeks without treatment. The overall results were generally positive: for example, blood pressure was normalized, serum prothrombin and cholesterol levels were reduced, and overall well-being and physical work performance improved (4). It should be noted, however, that these trials lacked good methodology (for example, they used only a small number of patients, lacked proper controls and randomization, and were not double-blind).

A single-blind, placebo-controlled clinical trial in six baseball players assessed the effects of a 33% ethanol root extract on maximal work capacity. Three maximal work tests using a bicycle ergometer were performed on 3 consecutive days prior to treatment, and two tests were carried out after treatment with either 2 ml extract (containing 0.53 mg syringin (eleutheroside B) and 0.12 mg syringaresinol-4,-4'-O-β-diglucoside (identified here as eleutheroside D)) or placebo orally twice daily for 8 days. After each work test, maximal oxygen uptake, oxygen pulse, total work time and exhaustion time were measured. A significant improvement in all four parameters was observed in subjects treated with the extract (P < 0.01), including a 23.3% increase in total work time as compared with only a 7.5% increase following placebo treatment (18). A randomized, double-blind, placebo-controlled study measured the effect of an ethanol extract of the roots (standardized to contain 0.2% w/v syringin) on the immune system, using quantitative multiparameter flow cytometry with monoclonal antibodies directed against specific surface markers of human lymphocyte subsets to determine cellular immune status. Thirty-six healthy subjects were treated orally with either 10 ml extract or placebo three times daily for 4 weeks. Subjects treated with the extract had a significant increase in the total number of immunocompetent cells (P < 0.0001), including lymphocytes (predominantly T-cells, T-helper/inducer cells and natural killer cells). A significant increase in activated T-cells was also observed (P < 0.01) (19). A randomized, double-blind, placebo-controlled study examined the effect of the crude drug on submaximal and maximal exercise performance. Twenty highly trained distance runners received either a 30-34% ethanol extract of the roots (3.4 ml) or placebo daily for 8 weeks, during which they completed five trials of both 10 minute and maximal treadmill tests. Heart rate, oxygen consumption, expired minute volume, ventilatory equivalent for oxygen, respiratory exchange ratio and rating of perceived exertion were measured during both tests. Serum lactate levels were analysed in blood samples. No significant differences were observed in any of the measured parameters between the placebo and treatment groups (57). A randomized, placebo-controlled, crossover study of 30 healthy volunteers compared the effects of Radix Eleutherococci, Panax ginseng and placebo on maximal oxygen uptake, using a bicycle ergometer. After 6 weeks of treatment, maximal oxygen uptake increased significantly only in subjects who had received P. ginseng (58). A comparative study assessed the ability of tinctures of Radix Eleutherococci and Leuzea carthamoides (containing eleutherosides and ecdysones, respectively) to decrease blood coagulation in highly trained athletes. Athletes treated with a 20-day course of the Radix Eleutherococci tincture showed a decrease in blood coagulation, and the activity of blood coagulation factors induced by intensive training (59).

Contraindications

Radix Eleutherococci should not be used during pregnancy or lactation, or by patients with blood pressure in excess of 180/90mmHg (24/12kPa) (4). Radix Eleutherococci is also contraindicated in cases of known allergy to plants of the Araliaceae family.

Warnings

No information available.

Precautions

Drug interactions

There is one case report of an increased level of serum digoxin due to the concomitant use of digoxin and Radix Eleutherococci (60). However, the identity of the plant material as Eleutherococcus senticosus was not established, and it is believed that it may have been Periploca sepium, which contains cardiac glycosides (9, 10).

Carcinogenesis, mutagenesis, impairment of fertility

No carcinogenicity was observed in rats (61). No mutagenic activities were observed in the Salmonella/microsome assay using S. typhimurium strains TA100 and TA98, in the mouse bone marrow micronucleus test, or in rats in vivo (61). Desmutagenic effects were observed in Drosophila (62, 63).

Pregnancy: teratogenic effects

No teratogenic effects were observed in the offspring of rats administered total eleutherosides intragastrically (10 mg/kg body weight) daily for 16 days, or in pregnant rats given 13.5 ml/kg body weight fluidextract of Radix Eleutherococci daily during days 6-15 of gestation (64, 65). No teratogenic effects were observed in the offspring of sheep or mink when an ethanol extract of the roots was added to the diet (4). (See also Contraindications.)

Pregnancy: non-teratogenic effects

See Contraindications.

Nursing mothers

See Contraindications.

Other precautions

No information available on general precautions or precautions concerning drug and laboratory test interactions or paediatric use. Therefore, Radix Eleutherococci should not be used in children without medical supervision.

Adverse reactions

A few cases of insomnia, arrhythmia (including tachycardia), extrasystole and hypertonia were reported in a clinical study involving 64 patients with atherosclerosis, who received a 33% ethanol extract of the crude drug at a dose of 4.5-6.0 ml daily for 6-8 cycles of treatment (lasting 25-35 days) (66). In another study of 55 patients with rheumatic heart lesions, two patients experienced hypertension, pericardial pain and palpitations, and pressure headaches after ingesting 3 ml of a 33% ethanol extract of the roots daily for 28 days (67). Insomnia has also been reported as a side-effect in other clinical trials (4). In one case report, neonatal androgenization was tentatively associated with the ingestion of Radix Eleutherococci tablets during pregnancy (68, 69). However, analysis of the raw materials used in the preparation of the tablets indicated that they were probably from Periploca sepium (70). Furthermore, intragastric administration of either Radix Eleutherococci or P. sepium to rats (1.5 g/kg body weight) did not demonstrate any androgenization potential, indicating that the neonatal androgenization was probably not due to the plant material (71).

Dosage forms

Powdered crude drug or extracts in capsules, tablets, teas, syrups, fluidextracts (63). Store in a well-closed container, protected from light (3).

Posology

(Unless otherwise indicated)
Daily dosage: 2-3 g powdered crude drug or equivalent preparations (20).

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