COMMUNITY HERBAL MONOGRAPH ON
ELEUTHEROCOCCUS SENTICOSUS
(RUPR. ET MAXIM.) MAXIM., RADIX
1.
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended.
Eleutherococcus senticosus
(Rupr. et Maxim.)
Maxim., radix (eleutherococcus root)
i) Herbal substance
Notapplicable
ii) Herbal preparations
- Comminuted herbal substance
- Powdered herbal substance
- Liquid extract (1:1, ethanol 30-40 % v/v)
- Dry extract (13-25 : 1, ethanol 28-40 % v/v)
- Dry extract (17-30 : 1, ethanol 70 % v/v)
- Dry aqueous extract (15-17:1)
- Tincture (1:5, ethanol 40 % v/v)
Well-established use
Traditional use
Comminuted herbal substance for preparation of a
herbal tea, other herbal preparations in solid or
liquid dosage forms for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Ph. Eur. monograph (ref. 01/2008:1419 corrected 6.0)
2
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
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4.
C
LINICAL
P
ARTICULARS
4.1. Therapeuticindications
Well-established use
Traditional use
Traditional herbal medicinal product for
symptoms of asthenia such as fatigue and
weakness.
The product is a traditional herbal medicinal
product for use in specified indications
exclusively based upon long-standing use.
4.2. Posology and method of administration
Well-established use
Traditional use
Posology
Adolescents over 12 years of age, adults, elderly
Herbal preparations
Daily dose
Comminuted herbal substance 0.5-4 g
Powdered herbal substance 0.75-3 g
Liquid extract: 2-3 ml
Dry extracts (ethanol 28-70% v/v) corresponding
to 0.5-4 g dried root
Dry aqueous extract (15-17:1): 90 – 180 mg
Tincture: 10-15 ml
The daily dose may be taken in one to three doses.
The use is not recommended in children under
12 years of age (see section 4.4 Special warnings
and precautions for use).
Duration of use
Not to be taken for more than 2 months.
If the symptoms persist for more than 2 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Oral use.
Tea preparation: 0.5 to 4 g of comminuted herbal
substance for infusion in 150 ml of water.
Dosage frequency: 150 ml of tea infusion should
be divided in one to three doses taken during the
day.
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4.3. Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance
.
Arterial hypertension.
4.4. Special warnings and precautions for use.
Well-established use
Traditional use
The use in children under 12 years of age is not
recommended because sufficient experience is not
available.
If the symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
4.5. Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
4.6. Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
4.7. Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
Well-established use
Traditional use
Insomnia, irritability, tachycardia and headaches
may occur. The frequency is not known.
4.9. Overdose
Well-established use
Traditional use
No case of overdose has been reported.
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5.1
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2. Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3. Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on reproductive toxicity and carcinogenicity
have not been performed.
In vitro
experiments, using the
Salmonella
typhimurium
strains TA 100 and TA 98 assay and
the micronucleus test in mice, did not reveal any
mutagenic potential
of
aqueous and ethanolic
extracts.
6.
Well-established use
Traditional use
Not applicable.
7.
D
ATE OF
C
OMPILATION
/
LAST REVISION
8 May 2008
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Assessment Report
ASSESSMENT REPORT
FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS
THEREOF WITH TRADITIONAL USE
Eleutherococcus senticosus
(Rupr. et Maxim.) Maxim., radix
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND
16H OF DIRECTIVE 2001/83/EC AS AMENDED
Herbal substance(s) (binomial scientific name of
Eleutherococcus senticosus
(Rupr. et Maxim.)
Maxim., radix
Herbal preparation(s)
Comminuted herbal substance
Powdered herbal substance
Liquid extract (1:1, ethanol 30-40 % v/v)
Dry extract (13-25 : 1, ethanol 28-40 % v/v)
Dry extract (17-30 : 1, ethanol 70 % v/v)
Dry aqueous extract (15-17:1)
Tincture (1:5, ethanol 40 % v/v)
Pharmaceutical forms
Comminuted herbal substance for the preparation
of a herbal tea, other herbal preparations in solid
or liquid dosage forms for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
Rapporteurs
D. Pakalns
D. Kalke
1
The material complies with the Ph. Eur. monograph (ref. 01/2008: 1419 corrected 6.0)
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I.
INTRODUCTION
1.1. Description of the traditional herbal substance(s), herbal preparation(s) or
combinations thereof
This assessment report is based on the scientific literature on Eleutherococcus root (ER) that is
specified in the list of references. The most relevant articles from that list, particularly the
pharmacological and clinical data, are discussed in more detail here.
The correct binominal botanic name is
Eleutherococcus senticosus
(Rupr. et Maxim.) Maxim., syn.
Acanthopanax senticosus
(Rupr. et Maxim.) Harms (Poyarkova, 1950). Eleutherococcus was formerly
known as
Acanthopanax senticosus
(Rupr. et Maxim) Harms and this name is still widely used by
Chinese scientists (Hu,1980a, 1980b;
Li, 2005; Frodin, 2006).
In this assessment report the names “Eleutherococcus” or latin “
Eleutherococcus senticosus”
are used
although both synonyms may be found in the original articles.
Herbal substance(s)
Constituents:
Although over 35 compounds have been identified from the ER,
the search for active substances is not
finished yet.
Eleutherococcus senticosus
is characterised by the co-existence of pentacyclic and
tetracyclic triterpenoidal saponins and their prosapogenins, lignans, coumarins, phenylcarbonic acids
and xanthones (Jeljakov, 1972;
Sandberg, 1973;
Ro, 1977; Wagner, 1980; Obermeier, 1980; Shih,
1981; Hahn, 1986; Anetai, 1987, Sonnenborn, 1993). The main constituents are phenyl propane
compounds [eleutheroside B – 0.5 %, chlorogenic acid, coniferyl aldehyde and its glucoside (Slacanin,
1991), caffeic acid derivates (Wagner,1982); lignanes (eleutheroside E – 0.10 % (Ovodov, 1965,
1967; Lapchik, 1970), eleutheroside B
4
(Suprunov, 1971) – 0.023 % (Bladt, 1990; Li, 2001);
coumarins – (isofraxidin (Wagner, 1982) and its O-glucoside (Nörr, 1993)); triterpensaponines – (2-
protoprimulagenin A-glycoside – 0.125 % (Segiet-Kujawa, 1991;Evans, 2002)). Other constituents
comprise steroids, carbohydrates and immunologically active polysaccharides (heteroglycans and
eleutherans) (Xu, 1983; Fang, 1985; Wagner, 1984; Wagner, 1985a 1985b; Hikino, 1986; Shen,
1991).
Herbal preparation(s)
•
Comminuted herbal substance
•
Powdered herbal substance
•
Liquid extract (1:1, ethanol 30-40 % v/v)
•
Dry extract (13-25 : 1, ethanol 28-40 % v/v)
•
Dry extract (17-30 : 1, ethanol 70 %, v/v)
•
Dry aqueous extract (15-17:1)
•
Tincture (1:5, ethanol 40 % v/v)
Combinations of herbal substance(s) and/or herbal preparation(s)
ER and extracts are used in combinations with other herbal substances/herbal preparations (e.g.
Rhodiola rosea
L., radix;
Leuzea carthamoides
(Willd.) D.C., radix;
Schizandra chinensis
(Turcz.)
Baill., fructus etc.). Such combinations have not been assessed. This assessment report refers
exclusively to ER and preparations thereof.
2
The material complies with the Ph. Eur. monograph (ref. 01/2008: 1419 corrected 6.0)
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2.
TRADITIONAL MEDICINAL USE
2.1.
Information on period of medicinal use in the Community regarding the specified
indication
References are going back at least until 1960 (Brekhman, 1960a). In fact ER has been used in
medicine for many decades. ER is in medicinal use in France (Pharm. Franc, 10), in Germany (Aicher,
1998), in Russia (Ross Ph XI, Mashkowsky, 1997), in UK (British Herbal Pharmacopoeia) and in
China (Pharmacopoeia of the People's Republic of China, 2005, Tang, 1992) The first English name,
created in the USA for Eleutherococcus, was “Eleuthero” (Lucas, 1973; Baranov, 1979). "Siberian
Ginseng" has been used in the USA as a second name since 1971, but the name has been banned by
the Ginseng Labelling Act of 2002. (Soejarto, 1978; Farnsworth, 1986; Israelsen, 1993).15 names that
are based on the abbreviated Latin generic name “Eleuthero” are currently used in various EU official
languages; in 4 languages variants from name “Siberian Ginseng”, in 4 languages – variants from
“Russian root” or “Russian ginseng root”, and in German and in Hungarian variants from
“Taiga root” - “Taigawurzel” and “tajga gyökér” are used.
Since the first article was published by Brekhman in 1960, over 1,000 articles have appeared.
Preparations from Eleutherococcus root, including powdered root, have been in medicinal use in
Germany prior to January 1978 when corresponding medicinal products were notified to the German
agency.
ER is now widely offered in pharmacies, health food stores and as food supplements in the United
States and in Europe, though not always as a product that conforms to pharmacopoeial requirements
(Barna, 1985). Based on the information found in literature and information provided by Member
States, a period of at least 30 years of medical use as requested by Directive 2004/24 EC for
qualification as a traditional herbal medicinal product is documented for the preparations included in
the monograph and in the list entry.
2.2. Type of tradition, where relevant
In Chinese traditional medicine as “Ci-wu-jia” (Hübotter, 1957; Foster, 1996; Stöger, 1996; Winston,
2007); traditional of the Far East (Schroeter, 1975).
Duke (1985) reported that the plant was used in the North-eastern city of Harbin, China, as a folk
remedy for bronchitis, heart ailments, and rheumatism. Referring to representatives from the China
National Native Produce Corporation, Duke also reported that regular use of the plant is thought to
help to restore vigour, improve general health, restore memory, promote good appetite and to increase
longevity, basically serving as a preventive medicine and general tonic.
Lin (2000) has reported that Eleutherococcus is a popular folk medicine used in patients with hepatitis
and cancer in Taiwan.
Reviews of studies performed in the former Soviet Union: Grinewicz, 1966;
Brekhman, 1968a;
Dardymov, 1976a; Halstead, 1984; Farnsworth, 1985; European traditional uses: Wikman, 1980,
1981b; Sonnenborn, 1993; Wagner, 1994; Aicher, 1998; Blumenthal, 1998; WHO monograph
,
2002;
ESCOP monograph, 2003.
2.3.
Bibliographic/expert evidence on the medicinal use
There are pharmacological and clinical studies and reviews published in medical, pharmacological
Journals, starting 1957.
In 1962 an ER extract was approved by the former Soviet Union Pharmacological Committee for
clinical use as a "stimulant". In 1966 ER was recommended for use in the Soviet space program
(Belay, 1966). In 1968 Brekhman published the first book on the subject entitled “Eleutherococcus”.
After that, results of many tests which have been performed in Russia have been verified by
researchers all over the world. (Fulder,1980).
This assessment report is based on the summary of the most relevant scientific literature which
includes more than 300 articles. Hundreds of other articles related to research work are summarized in
various monographs and reviews (Brekhman, 1968a; Brekhman et al, 1968c, 1969c; Dardimov,
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1976a;
Halstead, 1984; Farnsworth, 1985; Collisson, 1991; Sonnenborn, 1993; Aicher, 1998; WHO
monographs on selected medicinal plants, 2002; ESCOP monographs,
2003). These texts were also
used in preparing this assessment report.
2.3.1. Evidence regarding the indication/traditional use
Herbal medicinal products with ER are traditionally used to improve general health.
The following indications have been reported for ER:
•
As a tonic in case of decreased performance such as fatigue and sensation of weakness,
exhaustion, tiredness and loss of concentration (Brekhman, 1968a; Halstead, 1984; Duke, 1985;
Aicher, 1998; Blumenthal, 1998; Szolomicki, 2000; ESCOP monograph,
2003, Hartz, 2004);
•
As a prophylactic and restorative tonic for enhancement of mental and physical position for
functional asthenia, strengthening and normalizing, as well as convalescence (Golikov, 1963;
Zotova, 1966; Batin, 1981; Berdyshev, 1977, 1981a, 1981b; Farnsworth, 1985; Asano, 1986b;
Turbina, 1986; Novikov, 1987; Obolentseva, 1988; Karnaukh, 1990; Wagner, 1992; Winther,
1997; Blumenthal, 1998;
ESCOP monograph, 2003; Goulet, 2005);
•
As adaptogen, to increase body resistance to such stressful exposures as heat, cold, physical
exhaustion, viruses, bacteria, chemicals, extreme working conditions, noise, pollution
(Korobkov, 1962; Kolotlin, 1963; Baburin, 1966a, 1966b, 1976; Dardymov, 1966b; Berdyshev,
1970, 1977, 1995; Lucas, 1973; Brekhman, 1965a, 1965b, 1966, 1968a, 1976, 1977, 1980a,
1980b,1982b; Brekhman, 1971a, 1971b; Schezin, 1977, 1981; Demin, 1977; Gagarin, 1977;
Galanova, 1977; Kalashnikov, 1977, 1986; Bulanov, 1981; Lindendbraten, 1981; Shornikov,
1981a 1981b; Wikman, 1981a, 1981b, 1981c; Marochko, 1982; Sosnova, 1984; Sosnova, 1986;
Shadrin, 1986; Yaremenko, 1990; Collinsson, 1991; Williams, 1995; Dowling, 1996; Azizov,
1997; Glatthaar-Saalmülle, 2001; Webb, 2001; Arushanian, 2003; Arushanian, 2004).
•
ER was commonly used in Russia in oncology hospital departments to increase the tolerance of
the patients to the adverse effects of chemotherapy and radiation therapy (Gvamichava, 1966;
Khatiashvili, 1964, 1966; Kupin, 1986a, 1986b).
The pharmacological effects of ER preparations have been investigated by many researchers.
However, the mechanism of action and the active compound(s) have not yet been fully identified.
Many clinical studies have been published. However, most of the publications are not of appropriate
quality and do not provide sufficient information. The data are not sufficient to prove the efficacy of
ER preparations in a well-defined clinical condition. The lack of complete data may be in part
explained by the fact that ER preparations were tested in 1960-1970 with the view to support
members of Soviet Union army and sportsmen and some information has been disclosed for this
reason. Nevertheless efficacy of adaptogens has been reported by many groups of investigators. The
extensive studies on
ER have contributed much to the beginning of an understanding of the
adaptogenic response. Modern clinical studies on adaptogens that were started only in recent years
may provide a better insight in future (Makarov, 2007).
Therefore herbal medicinal products made of ER, can be only considered as a plausible traditional
herbal medicinal product and not a "well-established" one.
Based on the available literature and the information provided by Member States on traditional use,
the following indication is recommended:
Traditional herbal medicinal product for symptoms of asthenia such as fatigue and weakness. The
product is a traditional herbal medicinal product for use in specified indications exclusively based
upon long-standing use.
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2.3.2. Evidence regarding the specified strength
Not relevant.
2.3.3. Evidence regarding the specified posology
Adolescents over 12 years of age, adults, elderly
The dosages used in studies to determine prophylactic use of the ER fluid extract ranged from as little
as 0.5 ml every other day to as much as 22 ml per day. In experiments with healthy persons, stress-
mitigating effects have been reported by giving single doses from 2.0 up to 16.0 ml of the extract
(p.o.). The usual dose employed ranged from 0.5 to 6.0 ml. given one to three times a day for a period
of up to 35 days. Additional courses of ER extract therapy were sometimes employed up to a series of
eight courses. At the end of each course there has been a rest period of two to three weeks, during this
period no extract was administered.
It is reported that patients should start on a low dose, i.e. 500 mg of powdered root, or its equivalent,
three times a day; if no effect has been noted after two weeks, the dose can be increased to 1 g
(Collinson, 1991).
Other posologies that were reported in literature are: 2-3 g per day of comminuted ER for teas for up
to three months, as well as aqueous alcoholic extracts for internal use. A repeated course is feasible.
Internally: as a rule ethanol fluid extract of ER is given 20 to 40 drops two to three times daily before
meals (daily dose to 80 drops). The cure lasts 25 to 30 days; then it is repeated with one to 2-week
breaks two to three times. If necessary, cures can be carried out without interruption for several years.
Infusion: 2-3 g in 150 ml of water; fluid extract 1:1 (g/ml): 2-3 ml; tincture 1:5 (g/ml): 10-15 ml
(Brekhman, 1968a).
Dosage – from ESCOP
(2003)
:
Adults 1-2 ml of fluid extract (1 : 1, ethanol 40 % v/v) one to three
times daily (Aicher, 1998; Farnsworth, 1985).
65-195 mg of dry extract (14-25 : 1, ethanol 40 % v/v)
daily (Strokina,1967).
Other preparations corresponding to 2-3 g of dried root daily (Aicher, 1998; Farnsworth, 1985).
For oral administration.
Dosage for powdered herbal substance that are present on the German market for more than 30 years:
single dose 0.25 - 1 g, daily dose 0.75-3 g;
Dosage and recommended dosage forms – from WHO and others:
Powdered crude drug or
extracts in capsules, tablets, teas, syrups, fluid extracts (Sonnenborn, 1993).
Daily dosage: 2-3 g powdered crude drug or equivalent preparations (Blumenthal, 1998).
Dry roots: 0.6-3 g daily (Newal., 1996).
0.2-1 g of dried root equivalent, three times a day (Mills, 1985).
Daily dose 2-3 g (as powdered drug, cut drug for tea infusions or aqueous-alcoholic extracts
(Bradley, 1992).
Can be taken daily in the amount of 0.6 to 4 g of crude drug (herb) or an equivalent dose of an extract-
based preparation. (Dew, 2002).
Posology in children
:
Only a few
studies have tested the effect of ER in children.
Effect of ER on respiratory viral infectious morbidity in children in organised collectives has been
studied by Barkan (1980).
Sheparev (1986) investigated the effect of preventive administration of ER extract on the health of
children under school age. The morbidity rate is reported to have decreased by 30-40 %.
Vereshchagin (1978) and Vereshchagin (1982)
have studied the effect of adaptogens on antibiotic
therapy in children aged 0-14 years suffering from dysentery and Proteus infections.
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No clear information on posologies in children of different age groups can be taken from these studies.
The use of ER is generally not recommended in children below the age of 12 years.
Elderly:
Since ER has been reported to increase the feeling of strength and wellbeing, Schmidt (1984) has
speculated upon the danger that older, weakened, and convalescent patients might overstrain
themselves, when taking herbal medicinal products with ER. However, clinical studies or case reports
about such an effect of ER intake are not available and no restrictions are known on the use of
preparations of ER
.
Turkewicz (1966a, 1966b, 1969) analysed the results with ER or Eleutherococcus leaves extracts in
the treatment of patients with psychosis in the elderly and atherosclerotic psychoses. Patients at the
age between 65 and 90 years were given 5-15-20 drops daily 30 minutes before food, the treatment
lasted 1 month, then it was repeated, after a 10 days break, 2 to three times. It is reported that the
number of patients with psychopathological symptoms: asthenia, depression, tension, mental
deficiency, had been reduced and that biochemical parameters were improved. Normalization of all
biochemical parameters did coincide with improved clinical symptoms.
Davydov, (2000) reported that ER improves self-reported quality of life in elderly, without affecting
their blood pressure control. Similar results were described in young healthy adults (Asano, 1986b).
The aim of studies by Cicero (2004) was to test the effect of a middle term ER administration on
elderly, health related quality of life (HRQOL). 20 elderly hypertensive and digitalized volunteers
(age >/= 65 years) were randomized in a double-blind manner to ER dry extract 300 mg/day (n = 10)
or placebo (n = 10) for 8 weeks. After 4 weeks of therapy, higher scores in social functioning
(p = 0.02) scales were observed in patients randomized to ER; these differences did not persist until
the end of the study at 8-weeks. No adverse event has been observed in both groups of patients.
No significant difference in both blood pressure control and digitalemia was observed in both
treatment groups. Persons given ER have received more active therapy than persons given placebo
(20 p.c., p < 0.05). The authors conclude that ER safely improves some aspects of mental health and
social functioning after 4 weeks of therapy, although these differences attenuate with continued use.
On the basis the literature and information provided by Member States the following posology is
proposed:
Adolescents over 12 years of age, adults, elderly
Herbal preparations
Daily dose
0.5-4 g per day as comminuted herbal substance as herbal tea.
Powdered herbal substance: 0.75-3 g
Liquid extract: 2-3 ml
Dry extracts (ethanol 28-70% v/v) corresponding to 0.5-4 g dried root
Dry aqueous extract (15-17:1): 90 – 180 mg
Tincture: 10-15 ml
The daily dose can be taken in one to three doses.
The use is not recommended in children under 12 years of age.
2.3.4. Evidence regarding the route of administration
The oral administration is the only route of administration for ER preparations in the recommended
traditional indication. HMPC decided to provide specific information on the preparation of the tea:
Tea preparation: 0.5 to 4 g of comminuted herbal substance for decoction in 150 ml of water.
Dosage frequency: 150 ml should be divided in one to three doses taken during the day.
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2.3.5. Evidence regarding the duration of use
Some authors recommend that ER should not to be taken for more than 2 months. For chronic
conditions such as fatigue, preparations have been used for three months. Most authors recommend
that, if a course is repeated, the next course should start after a 10-14 days break.
In a more recent study, the effect did not persist after 4 weeks of use (Cicero, 2004). As traditional
herbal medicinal products can only be accepted if they can be used without medical advice for
diagnosis and as the symptoms, should they persist for more than 2 weeks, might be a signal for a
serious disease that needs medical advice, the HMPC decided to limit the duration of use to 2 month
and to refer the patient to medical advice in case of persistent symptoms.
Duration of use
Not to be taken for more than 2 months.
If the symptoms persist for more than 2 weeks during the use of the medicinal product, a doctor or a
qualified health care practitioner should be consulted.
2.4.
Assessor’s overall conclusion on the traditional medicinal use
Preparations from ER have been traditionally used as a tonic for the relief of symptoms in case of
decreased performance such as fatigue and sensation of weakness, exhaustion, tiredness and loss of
concentration, also as a prophylactic and restorative tonic for enhancement of mental and physical
position, and as adaptogen to increase body resistance to such stressful exposures for many decades.
Since the clinical documentation is not fully satisfactory and no controlled clinical studies in well
defined clinical conditions are available, the use of ER preparations has to be regarded as traditional.
The indication given in the monograph and in the list entry reflects the consistent traditional use in EU
Member States and it is plausible on the basis of the available studies.
2.5.
Bibliographic review of safety data of the traditional herbal medicinal substances
2.5.1. Patient exposure
No exact data on patient exposure are available. In clinical investigations of more than 20,000 patients
and test persons no signs of acute toxicity have been observed (Fulder, 1980). On the basis of the
wide-spread use in some Member States over a period of more than 30 years a significant exposure
can be expected.
2.5.2
Adverse events
Information on adverse events is inconsistent.
In general, only minimal adverse events have been reported. Systematic studies that were designed to
detect adverse events are absent. Case reports and general evidence point to the following effects: ER
may cause
insomnia
in some people if taken too close to bedtime. In two studies involving
atherosclerotic patients, some cases of insomnia, shifts in heart rhythm, tachycardia, extrasystoles, and
hypertonia were reported (Golikov PP, 1966a 1966b). Another study involving 55 patients with
rheumatic heart disease (Mikunis et al, 1966a 1966b), showed that 2 of the patients (at high dose
levels of the extract) reported headaches, pericardial pain, palpitations, and elevated blood pressure.
Another study (Koshkareva, 1966), involving 11 patients diagnosed as hypochondriacs, reported that
the ER extract was well tolerated at dose levels of 2.5-3.0 ml three times daily for 60 days, but some
patients often presented insomnia, irritability, melancholy and anxiety at dose levels of 4.5-6.0 ml.
2.5.3
Serious events and deaths
None known for ER preparations administrated orally.
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2.5.4.1 Intrinsic (including elderly and children)/extrinsic factors
None known
2.5.4.2 Drug-drug interactions and other interactions
None reported
2.5.4.3 Use in pregnancy and lactation
Effects on fertility or effects during lactation have not been reported for humans (Sonnenborn, 1993).
In a therapy accompanying investigation in 619 pregnant women with a high risk for a prenatal
dystrophy no teratogenic or embryo-toxic effects (Bolkhovitinova, 1981) were observed with a
prophylactic interval therapy about 3 weeks three times daily by 20 to 30 drops of the fluid extract of
ER. Bolkhovitinova (1986) investigated the influence of ER on pregnancy termination for mother, on
the fetus and on experimental clinical investigation.
However, safety during pregnancy and lactation has not been fully established. In accordance with
general medical practice and in absence of sufficient data, ER should not be used during pregnancy
and lactation without medical advice (ESCOP, 2003).
2.5.4.4 Overdose
No case of overdose has been reported.
2.5.4.5 Drugabuse
None known
2.5.4.6 Withdrawal and rebound
None known
2.5.4.7
Effects on ability to drive or operate machinery
None known (ESCOP, 2003) No studies have been performed.
2.5.4.8
Contraindications (hypersensitivity and allergic potential to be both covered)
Known hypersensitivity to the active substance or to Araliaceae (WHO monographs, 2002)
.
Literature
that points to the occurrence of a general hypersensitivity to Araliacea has not been found.
Arterial hypertension (Blumenthal, 1998).
2.5.5 Non-clinical safety data
2.5.5.1 Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
The toxicity of ER extracts is reported to be extremely low (Brekhman, 1969b; Curtze, 1980;
Owen, 1981; Vogt, 1981; Halstead, 1984; Farnsworth, 1985; Baldwin, 1986; Hirosue, 1986;
Sonnenborn, 1993). In clinical investigations of more than 20,000 patients and test persons no signs of
acute toxicity have been observed (Fulder, 1980).
Single-Dose toxicity
The oral acute LD
50
of powdered ER in mice is reported to be in the range of about 30.0 g/kg
(Brekhman, 1968a; Farnsworth,1985; Baldwin, 1986). The oral LD
50
value of the 33 % ethanolic
extract was about 14.5 g/kg body weight in mice (Brekhman,1960b, 1961, 1968a; Farnsworth,1985).
Toxic effects at very high dosages (sedation, ataxia, tremor, or vomiting) are thought to be more
readily due to the alcohol content of the extract than to a toxic effect of the ER compounds themselves
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(Curtze, 1980). Medon (1981) reported that a single dose of 3 g freeze-dried root extract did not cause
death in mice.
Repeat-Dose toxicity
Preparations of the ER are reported to be non-toxic when administered over a long period of time.
In clinical investigations of more than 6,000 patients and test persons no signs for toxicity have been
observed. ER is reported to be free from a cumulative toxicity (Steinmann, 2001). In 29 patients that
have been taken fluid extract of ER for more than 5 years there no signs of toxic effects have been
reported (Wikman,1986).
Genotoxicity
In
in vitro
experiments, using the AMES assay with
Salmonella typhimurium
strains TA 100 and TA
98 and in the micronucleus test in mice, no mutagenic potential
of
ER aqueous and ethanolic extracts
has been found (Hirosue, 1986). A "desmutagenic effect" has been observed in
Drosophila
(Sakharova
et al, 1985, 1986).
Carcinogenicity
Studies of carcinogenicity that would allow a reliable assessment have not been performed. In rats no
carcinogenic potential of ER was detected (Hirosue, 1986). Anticancer effects were noted in
experimental animals with transplanted tumours (Monakhov, 1965, 1967a, 1967b; Sakharova, 1985,
1986; Stukov, 1965, 1966, 1967).
Reproductive and Developmental Toxicity
No teratogenic or other effects have been observed in studies on pregnant animals (Brekhman, 1982a,
1982 b). Dardymov et al (1972d) reported the absence of teratogenic effects in offspring from male
and female Wistar rats given 10.0 mg/kg of total eleutherosides from ER daily for 16 days.
Gordeichuk (1986, 1993) have studied preventive administration of ER extract during prenatal and
pre-embryonic periods of development. The extract prevented embryotoxic effect of subsequent
treatment of pregnant rats with ethanol and sodium salicylate. ER abolished embryotoxic and
teratogenic effects of ethanol manifested against the background of experimental syndrome of iron
deficit in pregnant females. Mechanism of its antiteratogenic action is supposed to be based on
stimulation of cell detoxification mechanisms. ER decreased embryotoxicant activity (P=0.01) and
completely eliminated of different teratogenes in rats (Chebotar, 1981).
Curtze
(1980) reported that teratogenicity studies on rats (13.5 ml of the fluid extract per kilogram
body weight during the sixth to fifteenth day of pregnancy) did not reveal any negative effects on
dams or foetuses.
Local Tolerance
Not applicable.
Contraindications /application restrictions
The German Commission E notes that people with high blood pressure should avoid ER preparations,
but there is limited general evidence and very limited information from studies to support this
contraindication. In two of the studies, it was recommended that the extract should not be given to
subjects having blood pressure in excess of 180/90 mm Hg (Dalinger, 1966b; Lapchik, 1967).
The literature refers on isolated and controversially discussed reports on possible contraindications:
acute myocardial infarction, heart rhythm disturbances, paroxysmal hypertension and hypertension in
the stage II and III, acute period of infection illnesses (in particular bacterial infections) and other
states are characterized by raised excitability (Brekhman, 1980b; Baldwin at al, 1986; Baranov, 1982).
Golikov PP (1966b) mentioned that insomnia, tachycardia, extrasystoles and hypertonicity were
relative contraindications against employment of the preparation of ER.
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2.5.6
Assessor’s overall conclusions on safe use
The oral administration of ER preparations can be regarded as safe under the conditions of use that are
described in the monograph/list entry. Preparations of ER
have been used in humans for many decades
without any indication of serious risks.
3.
3.1.
Overview of pharmacological effects of herbal substance(s), herbal preparation(s) and
relevant constituents thereof on the basis of long-standing use and experience
3.1.1. The Adaptogenic concept.
Reference is made to the HMPC reflection paper on the adaptogenic concept
(EMEA/HMPC/102655/2007).
3.1.2. Pharmacological studies in connection with the term adaptogen
The concept of “adaptogens” is not well-known to Western medicine. When more than 50 years ago
physicians of West Europe used this type of medicines terms such as a “roborants” (strengthening
substances), “tonics” (which restore normal tone to tissue) and “alteratives” (which cause favourable
changes in the processes of nutrition and repair) were used. In 1958 the term “resistogen” or
“adaptogen” was introduced by Soviet scientists with the view to describe the actions of ER.
The heterogenicity of pharmacological studies relates to the general concept that ER is expected to
increase unspecific resistance to various "stressors". ER is often described as having a "stimulating
and tonic effect" on the body. Stimulating action refers to the ability of medicinal substances to
increase the work capacity of the organism after a single dose of the preparation. The tonic effect of a
substance refers to the results obtained after prolonged doses of the medicament. This effect is
reported to be manifested by an increase in work capacity, not only during the time period that the
substance is being used, but for a sustained period of time thereafter (Dardymov, 1966a, 1972a, 1982).
Only a few studies on pharmacology of purified compounds from ER have been carried out so far
(Hahn, 1986; Ro, 1977; Fang, 1985; Wagner, 1985b; Zhu, 1982; Yun-Choi, 1987; Anisimov, 1972;
Brekhman, 1969c; Yang, 1984). These studies do not deliver a clear indication with respect to
substances that may be responsible for he clinical effects. The pharmacology of ER reflects the
synergistic effects of its combined phytochemical constituents, especially those effects produced by
the glycosides (eleutherosides) which are present.
3.1.2.1. In vitro experiments
Several
in vitro
studies have been reported for ER extracts.
ER extracts are reported to inhibit the growth of a variety of viruses, bacteria and fungi:
An ethanolic fluid extract inhibited the replication of human rhinovirus, respiratory syncytial virus and
influenza A virus in cell cultures (Wacker, 1978; Wacker, 1983; Wacker, 1986; Glatthaar-Saalmüller,
2001). The EC
50
of the extract was a 1/120 dilution in the case of rhinovirus and influenza A virus and
1/2240 in the case of respiratory syncytial virus. The effect of the fluid extract was affected neither by
heat stress nor by conversion to a dry extract preparation (Glatthaar-Saalmüller, 2001; from ESCOP,
2003).
According to Wildfeuer (1994), the fluid extract of ER increased the
in vitro
phagocytosis of
Candida
albicans
by granulocytes and monocytes from healthy donors by 30-45 %. Preparations did not induce
in vitro
transformation of lymphocytes and had no effect in either direction on intracellular killing of
bacteria or yeasts.
When ER liquid extract (100 µg, after removal of ethanol) and a suspension of vesicular stomatitis
virus were simultaneously introduced into mouse fibroblast culture, the growth of virus was not
inhibited (Wacker 1978). However, when the extract was introduced into the mouse fibroblast culture
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before contact with the virus, the cells became resistant to the virus. The duration of this effect,
however, was only about 6 hours.
Parenteral administration of a 33 % ethanolic extract of the ER for 15 days prior to induced infection
(dose not specified) increased the resistance of mice and rabbits to listeriosis, an infection caused by
Listeria monocytogenes,
capable of producing meningitis in man and animals (Cherkashin,
1966,1968).
However, administration of the extract simultaneously with the bacteria increased the
severity of the infection (Cherkashin, 1966).
Wikman (1980) has reported experiments performed in 1963 and 1965 by Pichurina and Bronnikov
who investigated the protective action of ER towards infections and other harmful influences. In one
experiment rabbits were contaminated with a cultivation of dysentery microbes (
Shigella flexneri
,
10
9
microbes per rabbit). One hour before the test, one group had been given 0.1 ml of ER extract per
20 g of body weight. The control group remained untreated.
Seventy-two hours later 36 % of the
animals in the control group were still alive whereas 74 % of the animals in the ER group survived.
The antiviral activity of an ER ethanolic fluid extract was evaluated in experimental influenza
infection. The virus and the extract were simultaneously administered intranasally to mice. The titre of
influenza virus in the lungs of the animals was recorded over 6 days. On the 5
th
and the 6
th
day after
infection marked virus titres were measured in the lungs of control animals, whereas no virus titre was
found in the animals treated with ER extract (Protasova, 1986, from ESCOP, 2003).
3.1.2.2. Immunomodulating activity
The stimulating effect of ER preparations is thought to involve the activation of T-lymphocytes by the
eleutherosides. There may also be an indirect immunoenhancing effect mediated via the glycosides'
more non-specific antistressor activity – as stress may decrease the activity of the immune system,
particularly that of natural killer T-cells (Collisson, 1991; Li, 1991). ER is reported to act as an
effective γ-interferon inducer, immunomodulator and anti-viral agent (Zykov, 1986; Kupin, 1986b;
Wacker, 1978; Wacker, 1983; 1986; Barenboim, 1986).
A study on the immunomodulatory activity of the ethanol extract of ER administered orally to healthy
volunteers for 4 weeks, reported an increase in the absolute number of immune competent cells,
especially T lymphocytes. No side effects were observed within 6 months (Bohn, 1987, 1988).
In vitro
the polysaccharides caused a five- to tenfold increase in interferon titre in S 801 and S 7811
leukemic cell cultures (Yangl 1984).
ER extract have been shown to exhibit cytoprotective effects
in vitro
and antagonistic effects against
different toxins in experimental animals (Brekhman, 1969b; Anetai, 1987; Monakhov, 1965;
Sakharova, 1985). In addition, antistress properties and an antifatigue effect of the drug have been
described by Kaznachejev, 1977; Kirillov, 1977; Baranov, 1982; Farnsworth, 1985; Hahn, 1986;
Fulder, 1980, 1981; Gvamichava, 1966; Dalinger, 1966a, 1966b. The actions of ER
may be partially
explained by its antioxidant (Mikaelyan, 1986), or by its immuno-modulatory activities (Fang, 1985;
Wagner, 1985a, 1985b; Barenboim, 1984, 1986; Barkan, 1980; Kupin, 1986a, 1986b; Bohn,
1987 – from Sonnenborn, 1993).
Although it has been reported that ER performs anti-fatigue and anti-stress actions, these actions still
need to be further investigated. The same applies to the action on the immune system, especially
natural killer (NK) activity and the endocrine system (corticosterone level).
3.1.2.3.
In vivo
experiments.
Many studies have been published relating to the pharmacological testing of ER extracts prepared with
ethanol/water in animals. Most of these studies involve experiments designed to demonstrate the
"adaptogenic" or "normalizing" effect of ER to a variety of adverse conditions (stress, immobilization,
chemical challenge, etc.), or to elucidate the mechanism for these effects (Farnsworth, 1985).
There are studies that demonstrate that ER extract counteract the effect of different noxious substances
or agents. Positive results have been described in application of ER for reducing toxicity of biological
toxins, physical factors, chemical compounds, including drugs, and ionizing radiation as well as for its
ability to increase human's resistance (Maianskii, 1962; Voskresensky, 1977; Voskresensky, 1986;
Yonezawa, 1989; Collisson, 1991).
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However, one
in vivo
experiment that evaluated the effect of ER on stamina and longevity found no
significant difference between mice given ER and control mice (Lewis, 1983).
It has been reported by Elkin (1970) that ER extract shortens the duration of the sleep induced in mice
by hexobarbital, chloralhydrate, sodium barbital and ether.
Brekhman (1982b) reported that ER extract raises the sensitivity threshold of test animals to narcotics
(ether, chloralhydrate or sodium barbital) and to ethanol. A median lethal dose of 35 % ethanol for
mice was doubled as a result of single administration of ER, while the prophylactic use of ER for a
period of 30 days caused a 2.5-fold increase of the DL
50
value. These results point to the effect that
ER extract may enhance ethanol tolerance in test animals. In another experiment on rats Brekhman
(1982b) confirmed this hypothesis.
It has been found that intraperitoneal injection of ER in irradiated (X-ray) mice, at a dosage of 3.5
ml/kg for seven days, exerts a moderate radioprotective action. (Collisson, 1991). Irradiated (X-ray)
mice treated with ER extract are reported to survive five times longer than controls (Brekhman et al,
1970b, 1970c).
Kirillov, (1966) has reported that ER given daily to rats under various types of stress normalized the
weights of the thyroid and adrenal glands (usually shrunken by stress) and eliminated any evidence of
stress upon the functions of these glands. It has been proposed (Panossian et al, 2007) that nitric oxide
and cortisol may be used as appropriate stress markers that can be employed in the evaluation of the
anti-stress effects of stress-protectors and adaptogens.
The total eleutherosides had no effect on oxygen utilization by rat liver mitochondria with succinate,
glutamate, or tetramethylphenyl substrates (Dardymov, 1972b), but did increase oxygen uptake in
whole rat liver homogenates. The eleutherosides are reported to potentiate the effect of insulin on
glucose consumption
in vitro
, using the rat diaphragm (Dardymov, 1972c).
Glucocorticoids are major mediators of the stress response and directly suppress the natural killer
(NK) activity. Thus, the response for body the stress is complex, involving metabolic, inflammatory,
neuroendocrine, and immunological aspects. It has been speculated that the extracts of
ER may have
stress-reducing actions and consequently, may act on the reduction of NK activity and blood
corticosterone elevations induced by stress (Fujikawa et al, 2002).
In support of reports of the glucocorticoidlike effects
in vivo
for ER, Pearce (1982) reported that
30 % ethanol extract of ER did bind to the estrogen receptor in rat uterus, mineralocorticoid, and
glucocorticoid receptors in rat kidney
in vitro
, but not to the androgen receptor in rat kidney
.
Bykhovtsova (1966) have reviewed the results of studies of the effect of ER on certain metabolic
processes. Intraperitoneal administration of an aqueous extract of the ER to rats (3mg/kg body weight)
caused a significant increase in corticosterone levels 3 hours after injection, whereas
adrenocorticotropic hormone levels remained unchanged (Winterhoff, 1993)
.
Belonosov (1966)
administered ER extract
in a dosage of 4 ml daily to blood donors for a period of one month.
As a summary of their experiences, the author came to the opinion that the anabolic activity may be
due to the action of ER on carbohydrate and protein metabolism. Nitrogen metabolism in normal and
stressed rats has been reported to be normalized by s.c. 1.0 mL/kg ER extract (Feoktistova, 1966;
Revina, 1966; Sal'nik, 1966). Anisimov, (1972) tested the effect of compounds isolated from
Araliaceae
family plants on the biosynthesis of protein
in vitro.
Lin (2000) evaluated the antioxidant activity of the ER crude extract and the hepatoprotective
activities on CCl
4
or acetaminophen-induced toxicity in the rat liver. Results suggest that ER may
exert some antioxidant effects.
The working capacity of mice was assessed by forcing them to climb along an endless cord until
complete exhaustion. ER was administered one hour before the experiment. At a dose of 2.5 ml/kg the
animals' running time was significantly increased to 72 minutes; controls could only endure
52 minutes, representing an increase of 38 %. At a dose of 5 ml/kg the time increased to 76 minutes
(45 %). However, a further increase in dosage to 7.5 ml/kg did not further increase the animals'
working capacity (Collisson, 1991).
Kimura (2004) compared the effects of water extracts of
Eleutherococcus senticosus
bark on the
swimming time, natural killer and blood corticosterone level using forced swimming stressed mice.
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It was concluded that eleutheroside E may contribute to the anti-fatigue action and to the inhibition of
elevation of corticosterone induced by swimming stress.
The results of pharmacological investigations of Eleutherococcus have been summarized by
Dardymov, (1993). The authors postulate multiple effects on the human body, which involve:
•
energy-mobilizing impact, primarily through intensified utilization of glucose;
•
stress-protective effect conditioned by change in regulating the central nervous system and
hormonal regulation;
•
the action on the effects of hormones and their mediators, including changes in the contents of
cyclic nucleotides and prostaglandins.
3.1.2.4.
Clinical studies.
The main activity that is expected from an adaptogen is to enable an organism to adapt to and cope
with unfavourable conditions, such as physical and psychological stress, infections, environmental
pollutants, radiation and extreme climatic conditions. Since the early 1960’s ER was extensively used
in the former Soviet Union by athletes, particularly of Soviet Olympic Team, (Brunner, 1990),
cosmonauts, physical labour workers, as well as it was administered to divers, sailors, miners and it
had also been used to prevent stress-related illnesses.
Numerous clinical studies, designed to measure the adaptogenic effects of ER, have been
performed in Soviet Union during the 1960s and 1970s (reviewed in Farnsworth, 1985: Afanasiev,
1973; Baburin, 1966a, 1966b, 1970a, 1970b, , 1972; 1976a, 1976b Berdyshev, 1970, 1977; Blokhin,
1966a, 1966b; Brandis, 1962, 1966a, 1966b; Dalinger, 1966a, 1966b; Dardymov, 1966b; Egorov,
1966; Gagarin, 1977; Golikov 1963; Korobkov, 1962; Medvedev, 1963; Oleinychenko, 1966). In 35
clinical trials without controls, involving over 2,100 healthy subjects (4-1,000 per study), oral
administration of a 33 % ethanol root extract (2.0-20.0 ml, daily for up to 60 days) has been reported
to improved physical and mental work performance under stress conditions, and reduced auditory
disorders and the incidence of illness (Farnsworth., 1985, Halstead,1984 ). A statistical evaluation of
the results was not carried out; control groups were absent.
Effects on the psychophysical one and the cognitive efficiency were examined in a placebo-controlled
study of 190 pilots, co-pilots and flight engineers in different partial groups (Gubchenko, 1986a). The
test persons received 1 ml liquid extract or placebo solution (controls) over more than 10 days twice
daily. The psychophysical measurements were performed before the treatment and during the 10 days
of treatment in the Arctic (Collisson, 1991). In the study on 655 flight crew members (including pilots,
navigators, and radio operators), adaptogens are reported to have improved the recovery following
long flight schedules, allowing physiological state to be significantly restored within three hours
compared to a one day recovery that was needed in typical, non-treated cases (Brekhman, 1976).
Kolomievsky (1986) studied
reactions in 147 cardiologic patients with hypertension, coronary heart
disease and atherosclerosis induced by 30 drops of ER fluid extract over 7-10 days. The author reports
an improvement of different blood count parameters (among them Lymphocytes) as compared to
42 untreated controls. A statistical evaluation of the results was not carried out.
ER is reported to improve the adaptation of sailors in the tropics and influence positively body
functions and the work capacity of sailors on a cruise (Berdyshev, 1970, 1977, 1981a, 1981b;
Wikman, 1981b), to help adaptation to high altitudes (Kalashnikov, 1977) and in the Arctic
(Gagarin, 1977; Brekhman, 1977; Kalashnikov, 1977, 1986). During long-term navigation in the
tropics, where high temperature and humidity substantially restrict working capacity, seamen were
given either extract of ER or a placebo. It was found that ER reduces mental disturbances, such as
depression, excitability, insomnia etc. ER is reported to have improved asthenia and depression,
calmed excitability and normalized sleep. Novikov (1987) studied the influence of ER on the body
resistance in sailors and Elizarov, (1977)
reported about the effect of ER on physical exercises and on
lipid metabolism in crew members of a submarine.
Korobkov (1962) and Brekhman (1968a) carried out experiments on more than 1,500 sportsmen.
No adverse effects were observed except for an occasional feeling of sleepiness after administration of
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the extract. This condition has been associated with a hypoglycemic condition. During one series of
tests in 1961 and 1962 by Shkurdoda and Korobkov, as reported by Brekhman in 1968, 30 male and
female Olympic athletes took the extract in a dose of 2 ml 30 minutes before sleep and 4 ml one hour
before training. The control group received a placebo. The group of Olympic athletes was given the
extract, included sprinters, high-jumpers, decathlon contestants, 5 and 10 kilometer runners, and
marathon runners. For all of them an increased endurance and the preparedness to repeat the exercises
soon after completion have been reported. The control group was less active, and the restoration of
pulse, arterial blood pressure, and regain of tonicity of muscles required a greater period of time.
Asano (1986) has investigated the effects of a preparation of
ER
on physical performance and
resources in maximal and submaximal work. 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-capacity tests using a bicycle ergometer were performed on 3 consecutive days
prior to treatment, and two tests were carried out after treatment with either 2ml extract (containing
0.53mg syringin (eleutheroside B) and 0.12mg syringaresinol-4,-4¢-O-b-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.
Several experiments carried out in the Soviet Union during the 1970s appear to demonstrate that ER
extract, given prophylactically, can reduce the overall disease incidence by up to 35 %. (Galanova,
1977; Schezin, 1977; Kalashnikov, 1977; Sheparev, 1981). An in-depth analysis of clinical studies on
ER has been presented by Farnsworth et al (1985), reviewing the data available up to 1985. The
effects of a 33 % ethanol extract of the roots were assessed in 35 clinical trials without controls in
2,200 patients at the age between 19 and 72 years (5-1,200 per study) with various disorders, such as
arteriosclerosis (Golikov,1966b; Shekhtman, 1966); acute cranio-cerebral trauma, Sandler, 1970a,
1970b, 1972a, 1972b), hypertensive and hypotensive patients (Lyubomudrov et al, 1970), neurotic
patients and neurasthenia (Strokina, Mukho, 1966a, Strokina 1966bc, 1967); stressed drivers and
factory workers (Galanova, 1977); chronic bronchitis and pneumoconiosis (Lyubomudrov 1971,
1972), and rheumatic heart disease (Mikunis, 1966a, 1966b). Andreev (1976)
investigated the
influence of ER extract on secretion, as well as on fermentative and motor functions in 18-25 years old
patients with chronic gastritis.
ER is reported to enhance vision and hearing.
Stschichenkov (1963)
performed 60 trials to determine
the influence of ER on adaptation in darkness and acuteness of vision; Tikhomirova (1977) analysed
vision in seamen given adaptogens during long-term navigation. Sosnova (1969) determined the effect
of ER on the colour discrimination function in persons with normal trichromatic vision
.
In a more recent study, Sosnova (1984) investigated to effect of ER in women performing visual
control during a regime involving working with semi-conductor devices. The women were suffering
from visual fatigue, followed by a significant and sharp reduction in productivity. A 40-day intake of
ER and Schisandra are reported to have a favourable effect on the colour discrimination capacity, to
reduce fatigue, reduce the time needed for performing the main operations and to improve the quality
of work and to result in a higher productivity.
In other experiment Sosnova (1986) has examined also a visual performance in a placebo-controlled
study involving the group of healthy 232 volunteers (locomotive engineers and assistants aged 24 to
45 years). All persons had normal colour perception and visual acuity. Spectral sensitivity, colour
contrast sensitivity and stability of colour perception were determined at baseline of experiment and
on days 1, 5, 20 and 40 and then 2-2.5 month after the course to determine duration of the tonic effect.
The treated group received 2 ml of fluid extract per day. The contrast sensitivity and the sensitivity for
red, green and blue light was increased with a maximum after 5 days of treatment. After 40 days a
2.5 to 4.5 fold increase, as compared to the pre-treatment results, is reported. The effect persisted after
2.5 months. No improvement has been observed in the placebo group.
Arushanyan (2003) studied the effect of ER on short-term memory and visual perception in healthy
humans. It was reported that acute administration of liquid extract significantly improves short-term
memory in healthy humans.
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Hartz (2004) conducted a
2-month, randomized, blinded, controlled trial of
ER in patients with
chronic fatigue. Ninety-six subjects were randomized to treatment groups, and 76 provided
information at 2 months of follow-up. Fatigue among subjects assigned to either placebo or ER,
was substantially reduced during the study, but differences between treatment groups were not
statistically significant. It was concluded that overall efficacy was not demonstrated. However, the
findings of possible efficacy in a subgroup of patients with moderate fatigue suggest that further
research may be of value.
In a double-blind, placebo-controlled study, 93 patients were treated orally with 400 mg of ER dry
extract or placebo daily for 6 months as a prophylactic treatment to recurrent episodes of
Herpes
simplex type
II infections. Based on questionnaires (covering the 6 months before treatment and after
6 months of treatment), 75 % of patients in the ER group reported an improvement in the frequency,
severity and duration of outbreaks compared to 34 % in the placebo group; the results were significant
in favour of the verum group (p = 0.0002 to 0.0007) (Williams,1995).
In most of the studies, results were generally reported to be positive: e.g. blood pressure was
normalized, serum prothrombin and cholesterol levels were reduced, and overall wellbeing and
physical work performance improved (Farnsworth, 1985). However, these trials lacked good
methodology (for example, very few patients were involved, lacked proper controls and
randomization, experiments were not double-blind etc.). The clinical data have a number of
shortcomings such as deficiencies in the description of inclusion and exclusion criteria, description of
the medication, diagnosis, study design, analysis etc. There is a wide range of clinical conditions that
have been investigated and in some studies the number of patients was very small. None of the studies
would be sufficient to substantiate efficacy of ER preparations in a clearly defined clinical condition,
although, in total, the data available are sufficient to justify further research into the concept of
adaptogens.
Assessors overall conclusions on studies in connection with the term adaptogen
Brekhman (1968a) has coined the term “adaptogen” to designate substances which in a non-specific
way: increase protein biosynthesis; raise antibody titre at immunisation; elevate the body’s metabolic
capacity by means of general endocrine stimulation; enhance mental work capacity; uplift physical
work capacity along with performance and endurance; quench free radicals; improve senses such as
eyesight, colour perception, hearing and vestibular functions; offer beneficial effects in cardiovascular
and respiratory systems; promote longevity; heighten the body’s non-specific resistance to various
stressors such as toxins, excess cooling, overheating, altered barometric pressure, ultraviolet, ionizing
radiation. Adaptogens must present a non-specific effect (raising the power of resistance to toxins of a
physical, chemical or biological nature); must be harmless and disturb the body functions as little as
possible. Accordingly, adaptogens are expected to strengthen the non-specific powers of resistance to
non-infectious stresses, raise the general performance capacity during stress situations, and thereby
prevent diseases that could develop as a result of over-stressing the organism.
There are numerous studies intended to support the adaptogenic nature of ER extracts in both animal
models and humans. Although many clinical studies have been published, most of them are not of
appropriate quality and does not prove the efficacy of the ER in a well-defined clinical condition. This
may be linked to the fact, that the main intention has been to prove the adaptogenic concept and not
the effect in the prevention or treatment of a well-defined disease. Whereas the term "adaptogen" is
widely used and generally accepted in some countries, it is completely unknown or badly understood
in many others. The term is absent from standard (western) handbooks such as Goodman and Gilman's
The Pharmacological Basis of Therapeutics or Harrinson's Principles of Internal Medicine.
Despite the great number of studies, ER preparations do not reach the level of WEU/scientific
evidence that would be sufficient to grant a marketing authorisation. However, the studies provide a
solid basis for plausibility of the traditional use. Please refer to the HMPC reflection paper on the
adaptogenic concept for an in depth discussion.
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4.
PHARMACOKINETIC PROPERTIES
No specific data are available on the pharmacokinetics of ER.
ANNEX INFORMATION ABOUT THE LEGAL STATUS OF PRODUCT CONTAINING
ELEUTHEROCOCCUS SENTICOSUS
,
RADIX
, IN MEMBER STATES
Germany
Well-established use
Traditional use
a) Eleutherococcus radix dry extract (15-18:1);
ethanol 36%(V/V)
b) Eleutherococcus radix fluid extract (1:1);
ethanol 34%(V/V)
c) Eleutherococcus radix (17-25:1); ethanol 30%
(V/V)
d) Eleutherococcus radix powder
e) Eleutherococcus radix extract (1:11,3); sweet
wine
f) Eleutherococcus radix (15-18:1); ethanol 28%
(V/V)
g) Eleutherococcus radix dry extract (15-17:1);
aqueous
a) Eleutherococcus radix extract (1:20); sweet
wine, aromatic with absinthe herba
b) Eleutherococcus dry extract (16-24:1); ethanol
35% (V/V)
c) Eleutherococcus radix fluid (1:1); ethanol 30%
(V/V)
Indications
:
As a tonic for invigoration in fatigue and
impairment, in decreasing capability and power
of concentration as well as in reconvalescence.
Indications
:
Herbal medicinal product traditionally used to
improve general condition. The product is a
traditional herbal medicinal product for use in
specified indications exclusively based on long-
standing use.
ad a) soft capsule
ad b) oral liquid
ad c) coated tablet
ad d) powder
ad e) oral liquid
ad f) hard capsule
ad g) lozenge
Posology
:
ad a) 2 x daily 1 soft capsule with 100 mg extract
ad b) 3 x daily 5 ml liquid with 20g fluid extract
ad c) 3 x daily 1 coated tablet with 42.mg extract
ad d) 3 x daily 0,25 - 1 g powder
ad e) 3 x daily 10 ml (1/2 cup) oral liquid with
100 g extract
ad f) 1 x daily 1 hard capsule with 140 mg extract
ad g) 2 x daily 1-2 lozenge with 45 mg extract
Posology
:
ad a) 3-4 x daily 1 cup (20 ml) with 20,6 mg
extract
ad b) 3 x daily 1 coated tablet with 10 mg dry
extract
ad c) 2 x daily 1 cup (5 ml) with 10 g fluid extract
On the market prior to 1978
On the market prior to 1978
©
EMEA 2008
17/19
Sweden
Herbal substance: Rysk root -
Eleuthrococcus senticosus,
radix
Herbal preparations: 35 products including mono- and combination products were notified. Some of
the combination products contained multivitamins and minerals
Pharmaceutical forms: Tablet, mixture, capsule
Indication: Traditionally used as a mild stimulant and tonic, to increase physical and mental stamina,
strengthening and normalizing, adaptogen, tonic during reconvalescence, to increase body resistance
to signs of stress such as general fatigue and temporary mild tension”
Posology: Daily dosage range (of 35 products): extract corresponding to 0.2- 2g root, divided in 1 – 3
doses. Not recommended for children < 8 yrs.
Belgium
Eleutherococcus radix as powdered root in hard capsules, 250 mg per capsule is authorised since 2005.
Posology: 2 capsules two times a day, up to 6 capsules per day.
There are number of food supplements on the market as capsules, tablets, ampoules, pearls, solution.
Denmark
well-established use
a) Eleutherococcus senticosus extractum radix (10:1)
0,6 gram/100 ml oral solution
b) Eleutherococcus senticosus extractum radix (10:1), corresponding to 1 gram dry root, tablets,
coated
c) Eleutherococcus senticosus extractum radix , 7,2 mg corresponding to 120 mg dry root, tablets
d) Eleutherococcus senticosus, powdered root 250 mg/capsule
Posology
:
ad a) Adults: 15 ml daily, eventually 30 ml in a short period when needed.
Not to be used daily for more than 2-3 months.
ad b) 1 tablet daily, eventually 2 tablets daily in a short period when needed. Not to be used for more
than 2-3 months.
ad c) 4 tablets 3 times daily. Not to be used for more than 2-3 months.
ad d) 2 capsules in the morning and 2 capsules in the middle of the day. Dosage may be increased to
3x2 capsules. Not to be taken for more than 3 months.
ad a-d) Not to be used by children below 12 years.
Indications:
ad a) Herbal medicinal product against tiredness and in periods of reconvalescence.
ad b) Herbal medicinal product against tiredness and in periods of reconvalescence.
ad c) herbal medicinal product for the relief of symptoms of cold. Herbal medicinal product against
tiredness and in periods of reconvalescence.
ad d) Herbal medicinal product against tiredness and in periods of reconvalescence.
There are combination products with Rhodiola rosea radix, Andrographis paniculata herba, Schisandra
chinensis fruit.
There are number of products containing ER which may also be sold as food supplements.
Italy
No herbal or conventional medicinal products containing Eleutherococcus radix or its preparation as
an active substance are currently authorized or registered in Italy.
In fact there are number of food supplements on the market.
As for the products containing
Eleutherococcus radix
food supplements, the following information
has been found:
Pharmaceutical forms:
tablets, capsules, liquid extract (hydroalcoholic solution), herb tea
Part of plant used
: root, root (dry extract), root (powder), root (dry extract – powder – freeze dried),
root (hydro-alcoholic solution), root (freeze-dried extract), root (bark), bark.
©
EMEA 2008
18/19
Indications:
Physiological tonic-adaptive effect, it may support body's adaptive response to psychological and
physical stress.
Poland
On the market from 2001, generally over 30 years.
a) Eleutherococci radicis extractum fluidum (1:2), ethanol 60º - oral drops
b) Eleutherococci radicis extractum siccum (13-25:1) – coated tablets
Posology
: a - 1 teaspoon daily
b) 1 tablet 3 times daily
Indications
: States of tiredness, weakness, in convalescence. Supplementary in prophylaxis of
atherosclerosis.
Iceland
Eleutherococcus has been on the market in Iceland as adaptogen for many years, sometimes under the
name Siberian Ginseng. However, since the products are classified as food supplement but not as
herbal medicinal products IMCA does not have any information about the products.
EU Member States without any products containing ER:
•
The Netherlands
•
Finland
•
Czech Republic
•
Ireland
•
United Kingdom
©
EMEA 2008
19/19
Source: European Medicines Agency
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