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Rheum (Rhei radix)

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Authorisation details
Latin name of the genus: Rheum
Latin name of herbal substance: Rhei radix
Botanical name of plant: Rheum palmatum L.; Rheum officinale Baillon
English common name of herbal substance: Rhubarb
Status: F: Final positive opinion adopted
Date added to the inventory: 23/11/2005
Date added to priority list: 23/11/2005
Outcome of European Assessment: Community herbal monograph
Additional Information:





Product Characteristics
COMMUNITY HERBAL MONOGRAPH ON RHEUM PALMATUM L. AND
RHEUM OFFICINALE BAILLON, RADIX
1. N AME OF THE MEDICINAL PRODUCT
To be specified for the individual finished product.
2. Q UALITATIVE AND QUANTITATIVE COMPOSITION 1 , 2
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10(a) of Directive
2001/83/EC as amended
Rheum palmatum L. or Rheum officinale Baillon
or their hybrids or a mixture of these two species
and/or their hybrids, radix (rhubarb)
i) Herbal substance
whole or cut, dried underground parts,
standardised
ii) Herbal preparations
standardised herbal preparations thereof
3. PHARMACEUTICAL FORM
Well-established use
Traditional use
Standardised herbal substance or herbal
preparation 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. 01/2005:0291).
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 PARTICULARS
4.1. Therapeutic indications
Well-established use
Traditional use
Herbal medicinal product for short-term use in
cases of occasional constipation.
4.2. Posology and method of administration
Well-established use
Traditional use
Posology
The maximum daily dose of hydroxyanthracene
glycosides is 30 mg. This is equivalent to ....(dose
of the preparation).
The correct individual dose is the smallest
required to produce a comfortable soft-formed
motion.
Adolescents over 12 years of age, adults, elderly
Herbal substance/preparation equivalent to
20 - 30 mg hydroxyanthracene derivatives,
calculated as rhein, to be taken once daily at
night. Normally it is sufficient to take this
medicinal product up to two to three times a
week.
The pharmaceutical form must allow lower
dosages.
The use in children under 12 years of age is
contraindicated
(see
section
4.3
Contraindications).
Duration of use
Use for more than 1 - 2 weeks requires medical
supervision.
If the symptoms persist during the use of the
medicinal product, a doctor or a pharmacist
should be consulted.
See also section 4.4 Special warnings and
precautions for use.
Method of administration
As described in the package leaflet corresponding
to the pharmaceutical form.
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4.3. Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Cases of intestinal obstructions and stenosis,
atony, appendicitis, inflammatory colon diseases
(e.g. Crohn’s disease, ulcerative colitis);
abdominal pain of unknown origin; severe
dehydration state with water and electrolyte
depletion.
Children under 12 years of age.
4.4. Special warnings and precautions for use
Well-established use
Traditional use
Patients taking cardiac glycosides, antiarrhythmic
medicinal products, medicinal products inducing
QT-prolongation, diuretics, corticosteroids or
liquorice root, have to consult a doctor before
taking rhubarb concomitantly.
Like all laxatives, rhubarb should not be taken by
patients suffering from faecal impaction and
undiagnosed, acute or persistent gastro-intestinal
complaints, e.g. abdominal pain, nausea and
vomiting unless advised by a doctor because these
symptoms can be signs of potential or existing
intestinal blockage (ileus).
If laxatives are needed every day the cause of the
constipation should be investigated. Long-term
use of laxatives should be avoided.
If stimulant laxatives are taken for longer than a
brief period of treatment, this may lead to
impaired function of the intestine and dependence
on laxatives. Rhubarb preparations should only be
used if a therapeutic effect cannot be achieved by
a change of diet or the administration of bulk
forming agents.
When rhubarb preparations are administered to
incontinent adults, pads should be changed more
frequently to prevent extended skin contact with
faeces.
Patients with kidney disorders should be aware of
possible electrolyte imbalance.
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4.5. Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
Hypokalaemia (resulting from long-term laxative
abuse) potentiates the action of cardiac glycosides
and interacts with antiarrhythmic medicinal
products, with medicinal products, which induce
reversion to sinus rhythm (e.g. quinidine) and
with medicinal products inducing QT-
prolongation. Concomitant use with other
medicinal products inducing hypokalaemia
(e.g. diuretics, corticosteroids and liquorice root)
may enhance electrolyte imbalance.
4.6. Pregnancy and lactation
Well-established use
Traditional use
Pregnancy
There are no reports of undesirable or damaging
effects during pregnancy and on the foetus when
used at the recommended dosage.
However, as a consequence of experimental data
concerning a genotoxic risk of several
anthranoids, e.g. aloe-emodin, emodin, frangulin,
chrysophanol and physcion, use is not
recommended during pregnancy.
Lactation
Use during breastfeeding is not recommended as
there are insufficient data on the excretion of
metabolites in breast milk.
After administration of other anthranoids, active
metabolites, such as rhein, are excreted in breast
milk in small amounts. A laxative effect in breast
fed babies has not been reported.
4.7. Effects on ability to drive and use machines
Well-established use
Traditional use
Not relevant.
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4.8. Undesirable effects
Well-established use
Traditional use
Hypersensitivity reactions may occur.
Rhubarb may produce abdominal pain and spasm
and passage of liquid stools, in particular in
patients with irritable colon. The frequency is not
known. However, these symptoms may also occur
generally as a consequence of individual
overdosage. In such cases dose reduction is
necessary.
Chronic use may lead to disorders in water
equilibrium and electrolyte metabolism and may
result in albuminuria and haematuria.
Furthermore, chronic use may cause pigmentation
of the intestinal mucosa (pseudomelanosis coli),
which usually recedes when the patient stops
taking the preparation.
Yellow or red-brown (pH dependent)
discolouration of urine by metabolites, which is
not clinically significant, may occur during the
treatment.
If other adverse reactions not mentioned above
occur, a doctor or a pharmacist should be
consulted.
4.9. Overdose
Well-established use
Traditional use
The major symptoms of overdose/abuse are
griping pain and severe diarrhoea with
consequent losses of fluid and electrolytes, which
should be replaced. Diarrhoea may cause
potassium depletion, in particular. Potassium
depletion may lead to cardiac disorders and
muscular asthenia, particularly where cardiac
glycosides, diuretics, corticosteroids or liquorice
root are being taken at the same time. Treatment
should be supportive with generous amounts of
fluid. Electrolytes, especially potassium, should
be monitored. This is especially important in the
elderly.
Chronic ingested overdoses of anthranoid
containing medicinal products may lead to toxic
hepatitis.
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5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Well-established use
Traditional use
Pharmacotherapeutic group: contact laxatives
ATC code: A 06 AB
1,8-dihydroxyanthracene derivatives possess a
laxative effect.
The β-0-linked glycosides e.g. sennosides are not
absorbed in the upper gut; they are converted by
bacteria of the large intestine into the active
metabolites, the anthrones.
There are two different mechanisms of action:
1. stimulation of the motility of the large intestine
resulting in accelerated colonic transit.
2. influence on secretion processes by two
concomitant mechanisms viz . inhibition of
absorption of water and electrolytes (Na + ,Cl - ) into
the colonic epithelial cells (antiabsorptive effect)
and increase of the leakiness of the tight junctions
and stimulation of secretion of water and
electrolytes into the lumen of the colon
(secretagogue effect) resulting in enhanced
concentrations of fluid and electrolytes in the
lumen of the colon.
Defaecation takes place after a delay of
8 - 12 hours due to the time taken for transport to
the colon and metabolisation into the active
compound.
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5.2. Pharmacokinetic properties
Well-established use
Traditional use
The β-0-linked glycosides are not split by human
digestive enzymes and therefore not absorbed in
the upper gut to a large extent. They are
converted by the bacteria of the large intestine
into the active metabolites. The absorbed
anthraquinone aglycones are transformed into
their corresponding glucuronides and sulphate
derivatives.
It is not known to what extent anthrones are
absorbed. However, in the case of senna, animal
experiments with radio-labeled rhein-anthrone
administered directly into the caecum show that
only a very small proportion (less than 10%) of
rhein-anthrone is absorbed.
After administration of other anthranoids, active
metabolites, such as rhein, pass in small amounts
into breast milk. Animal experiments
demonstrated that placental-passage of rhein is
low.
5.3. Preclinical safety data
Well-established use
Traditional use
Total rhubarb (rhizomes of Rheum palmatum L.)
anthraquinones (TRAs) were orally administered
for 13 weeks to Sprague Dawley rats at a dose of
0, 140, 794, 4,500 mg/kg bw. In the highest dose
group, nephrotoxicity was discernible at
13 weeks.
In the Salmonella /microsome assay an ethanolic
root extract of Rheum officinale Baillon was
weakly mutagenic in strain TA 1537 with and
without metabolic activation.
No further toxicological data are available for
rhubarb itself or preparations thereof.
Experimental data, mainly in vitro tests showed a
genotoxic risk of several anthranoids in the
Salmonella/microsome assay, aloe-emodin,
emodin, chrysophanol and physcion were weakly
mutagenic. No mutagenic effects were observed
in the V79-HGPRT mutation assay and in the
unscheduled DNA synthesis (UDS) assay for
chrysophanol and physcion. Emodin was highly
mutagenic in the V79-HGPRT mutation assay. In
the UDS assay emodin was a string inducer of
UDS in primary hepatocytes. Aloe-emodin
showed a significant increase in net
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grains/nucleus. Emodin was also tested with
respect to its transforming activity in C3H/M2
mouse fibroblasts in vitro . In the in vitro
Salmonella /microsome mutagen test and the
deoxyribonucleic acid (DNA) repair test of
primary rat hepatocytes emodin and frangulin
showed a dose-dependent increase in the mutation
rate or the induction of DNA repair.
However, in vivo studies of other anthranoid-
containing herbal substance (senna) in rat
hepatocytes (chromosome aberration test, mouse
spot test, in vivo / in vitro UDS (unscheduled DNA
synthesis) showed no evidence of any genetic
effects.
In in vivo studies (micronucleus assay in bone
marrow cells of NMRI mice; chromosome
aberration assay in bone marrow cells of Wistar
rats; mouse spot test [DBA/2J x NMRI]) no
indication of a mutagenic activity of aloe emodin
was found.
Sennoside B and rhein did not induce significant
numbers of chromosomal aberrations or aberrant
cells in bone marrow cells of Swiss mice.
Further 2-year studies on male and female rats
and mice with emodin gave no evidence of
carcinogenic activity for male rats and female
mice, and equivocal evidence for female rats and
male mice.
A long-term study over 2 years on male and
female rats with a senna pods preparation
(anthranoid-containing herbal substance as well)
gave no evidence of carcinogenic activity.
Chronic laxative use as a risk factor in colorectal
cancer (CRC) was investigated in some clinical
trials. Some studies revealed a risk for CRC
associated with the use of anthraquinone-
containing laxatives, some studies did not.
However, a risk was also revealed for
constipation itself and underlying dietary habits.
Further investigations are needed to assess the
carcinogenic risk definitely.
The short-term use of rheum as recommended can
be regarded as safe.
6. PHARMACEUTICAL PARTICULARS
Well-established use
Traditional use
Not applicable.
7. DATE OF COMPILATION / LAST REVISION
31 October 2007
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Assessment Report
TABLE OF CONTENTS
I. REGULATORY STATUS OVERVIEW 3
I.
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REGULATORY STATUS OVERVIEW 1
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ’Not Known’
Member State
Regulatory Status
Comments 2
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify:
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
1 This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in
the MSs concerned.
2 Not mandatory field
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II.
ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
PREPARATION(S) OR COMBINATIONS THEREOF WITH WELL-ESTABLISHED
USE AND/OR TRADITIONAL USE
RHUBARB (RHEI RADIX) AND HERBAL PREPARATION(S) THEREOF WITH WELL-
ESTABLISHED USE AND/OR TRADITIONAL USE
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
(WELL-ESTABLISHED USE)
BASED ON ARTICLE 16 D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
(TRADITIONAL USE)
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
The whole or cut, dried underground parts of
Rheum palmatum L. or of Rheum officinale
Baillon or of hybrids of these two species or of a
mixture
Herbal preparation(s)
Standardised herbal preparations thereof
Pharmaceutical forms
Herbal substance or preparation for oral use
Rapporteur
Dr Werner Knöss
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II.1
I NTRODUCTION
II.1.1
Description of the herbal substance(s) or herbal preparation(s) thereof
Rhubarb belongs to the stimulating laxatives containing hydroxyanthracene derivatives and is
intended “for short-term use in cases of occasional constipation”. Therefore we refer to the
assessment reports for senna, aloe, frangulae cortex and cascara.
Constipation is a common complaint in 1-6 % middle-aged and 20-80 % of the elderly
people, which is treated by laxatives. Constipation also tends to be more prevalent among
women. The functional constipation is the most common type without any specific etiology
(59). Among the most commonly used laxatives are either preparations containing
stimulating hydroxyanthracene derivatives or lubricating laxatives (vegetable or mineral oils)
or bulk forming agents.
Rhubarb consists of the whole or cut, dried underground parts of Rheum palmatum L. or of
Rheum officinale Baillon or of hybrids of these two species or of a mixture. The underground
parts are often divided; the stem and most the bark with the rootlets are removed. It contains
not less than 2.2 per cent of hydroxyanthracene derivatives, expressed as rhein (C 15 H 8 O 6 , M r
284.2), calculated with reference to the dried herbal substance. This complies with the
European Pharmacopoeia (1, 2).
Herbal preparations thereof have to be standardised to their amount of hydroxyanthracene
derivatives, calculated as rhein.
Rhubarb contains a complex mixture of different hydroxanthracene derivatives. The amount
is 3 to 12 % depending on the method of determination. These hydroxanthracene derivatives
mainly (60 – 80 %) consist of mono- and diglycosides of 1,8-dihydroxyanthrachinons
aloeemodin, chrysophanol, emodin, physcion and rhein (6), and only small amounts of the
respective aglycones. Dianthrone glycosides (sennosides) are also present (10 - 25 %). Oshio
H et al. 1974 (15) isolated sennosides E and F besides the sennosides A, B and C from the
rhizome of Rheum palmatum L. Small amounts of anthrone glycosides depending on the time
of harvesting and the conditions of drying are also found. The level of the oxidized forms is
maximal in the summer and almost nil in the winter (3, 4, 5).
Rhubarb also contains tannin agents like gallotannins (ca. 5 %) (3, 4).
Chemotaxonomical investigations have shown that the underground parts of Rheum
palmatum L. or of Rheum officinale Baillon do not contain stilbenes like rhaponticin (74).
Other analytical investigations discovered several different stilbenes. Kubo I et al. 1991 (20)
isolated two stilbene glycosides, 4’-O-methylpiceid and rhapontin, from a methanolic extract
of the root of Rheum palmatum , which was purchased at a marketplace in Indonesia. Further
investigations are necessary to clarify the analytic and the kind of herbal substances
investigated whether these were not any falsifications (3). According to the European
Pharmacopoeia it has to be shown that the herbal substance does not contain rhaponticin.
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
II.2
N ON -C LINICAL D ATA
II.2.1
Pharmacology
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II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
Primary pharmacodynamics
Laxative effect
Rhubarb belongs to the anthranoid-containing laxatives. 1,8-dihydroxanthracene derivatives
possess a laxative effect (28). The mode of action is based on two mechanisms. Firstly,
colonic motility is increased leading to a reduced transit time and reduced fluid absorption,
and secondly, an influence on secretion processes by two concomitant mechanisms viz.
inhibition of absorption of water and electrolytes (Na+,Cl-) into the colonic epithelial cells
(antiabsorptive effect) and increase of the leakiness of the tight junctions and stimulation of
secretion of water and electrolytes into the lumen of the colon (secretagogue effect) resulting
in enhanced concentrations of fluid and electrolytes in the lumen of the colon. These findings
are based on investigations with different anthrones deriving also from other anthranoid-
containing herbal substances, but the results of these investigations are not always consistent.
Chirikdjian JJ et al. 1983 isolated physcion diglycoside from rhubarb roots and showed that
this compound had a laxative activity similar to physcion monoglycoside in mice, orally
administered, although with physcion diglycoside the onset of the purgative effect was
observed 2 hours later than with physcion monoglycoside. Physcion itself showed no
remarkable effect. Only higher doses (300 and 450 mg/kg b.w.) slightly increased the number
of defaecations. Stool consistency did not change (7).
Leng-Peschlow E 1986 measured quantity and consistency of the faecal output, large
intestine transit time, and colonic net absorption in rats after oral administration of sennoside
A + B (12.5 – 200 mg/kg). The release of normal faecal pellets was accelerated 3-4 h after
drug administration. Excretion of soft faeces reached its maximum 5-7 h after administration.
Large intestine transit time was dose- and time-dependently influenced. Net fluid absorption
in the colon was inhibited. The increase in fluid volume due to net fluid secretion is delayed
compared with the acceleration of large intestine transit. The author concluded that the
laxative effect of the sennosides consists of changes in colon motility as well as in colonic
fluid absorption, but motility may be an earlier and more sensitive parameter than net
absorption (29).
Leng-Peschlow E 1989 administered bisacodyl or sennosides A + B (10-100 mg/kg each)
orally and intracaecally to rats. Similar quantity of soft faeces within 24 h and a similar
acceleration of large intestine transit time were induced, but in each case bisacodyl had a
prolonged action. Net fluid absorption in the perfused rat colon was reduced by rhein (10 -3
mol/l), an active metabolite of sennosides, comparable to the effect of bisacodyl, however
recovery was delayed after bisacodyl (30).
Harima S et al. 1994 measured sennoside A content in hot-water extracts from 17 varieties of
rhubarb obtained from the Japanese market. The contents are between 0.4 and
18.8 mg/extract g. The authors also examined the respective cathartic effects of the different
varieties in mice. A positive correlation was confirmed between the sennoside A content and
the cathartic effects (8).
Yagi T et al. 1997 tried to explore the mechanism involved in the synergistic purgative action
of aloe-emodin anthrone and rhein anthrone, the active metabolite of sennoside C, a purgative
constituent of rhubarb and senna. Aloe-emodin anthrone and rhein anthrone, and their
equimolar mixture, induced excretion of an approximately equal number of faeces by
intracaecal administration at a dose of 23.2 µmol/kg in mice (standard dose). The number of
wet faeces induced by aloe-emodin anthrone was less than those of rhein anthrone and the
mixture. At the same dose, rhein anthrone and the mixture significantly stimulated large
intestinal propulsion, though aloe-emodin anthrone had little stimulatory effect. Aloe-emodin
anthrone and rhein anthrone decreased net water absorption, but could not reverse it to
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achieve net secretion, at ½ dose. The mixture significantly decreased net water absorption
and reversed it into net secretion at this dose. These anthrones did not stimulate mucus
secretion in the colon lower than ½ dose. The authors conclude that the synergistic purgative
effect of aloe-emodin anthrone and rhein anthrone in mice results from synergistic
stimulation of large intestinal transit and large intestinal water secretion (9).
Yagi T et al. 1999 investigated the purgative effects of intracaecally administered rhein
anthrone and anthraquinones such as aloe-emodin and chrysophanol, isolated from rhubarb,
emodin and rhein, and the possible synergistic effects of the anthraquinones with rhein
anthrone in mice. The anthraquinones were less potent purgatives than rhein anthrone, but the
equimolar mixture of aloe-emodin and rhein anthrone had synergistic potentiating effects. An
equimolar mixture of other anthraquinones and rhein anthrone tended to potentiate the
purgative action (10).
Rhubarb acts within 8 to 12 hours due to the time taken for transport to the colon and
metabolisation into the active compounds (4). The content of tannin agents may possibly
counteract the laxative effect of the anthraquinones , and rhubarb is therefore considered to
be a milder laxative than other anthraquinones.
Secondary pharmacodynamics
Due to the content of tannin agents rhubarb preparations were used for diarrhoea, for gastritis
and enteritis, and as a styptic (3, 4).
Bae EA et al. 1998 tested different herbal substances for their inhibitory effect on
Helicobacter pylori (HP) and on the HP urease in vitro. HP was isolated from the gastric
antrum of chronic gastric patients. HP also produces a vacuolating toxin and its toxicity may
be potentiated by urease-mediated ammonia production. HP urease is considered to play
critical roles in the pathogenesis of gastric and peptic ulcer. Therefore, eradication of this
bacteria and inhibition of the HP urease seems to be important for the treatment. The water
extract of Rheum palmatum very strongly inhibited the growth of HP at 1 mg/ml, but it has
no inhibitory effect on the urease activity (11).
Sydikes RJ et al. 1991 tested the virucidal effects of hot glycerine extracts from Rheum
officinale, Aloe barbadensis, Rhamnus frangula, Rhamnus purshianus , and Cassia
angustifolia against herpes simplex virus type 1. All the plant extract inactivated the virus.
The active components in these plants were separated by thin-layer chromatography and
identified as anthraquinones. Anthraquinone-glycosides should be ineffective. A purified
sample of aloe-emodin was prepared from aloin, and its effects on the infectivity of herpes
simplex virus type 1 and type 2, varicella-zoster virus, pseudorabies virus, influenza virus,
adenovirus, and rhinovirus were tested by mixing virus with dilutions of aloe-emodin for 15
min at 37 degrees C, immediately diluting the sample, and assaying the amount of infectious
virus remaining in the sample. The results showed that aloe-emodin inactivated all of the
viruses tested except adenovirus and rhinovirus. Electron examination of anthraquinone-
treated herpes simplex virus demonstrated that the envelopes were partially disrupted. These
results show that anthraquinones extract from a variety of plants are directly virucidal to
enveloped viruses (67).
Hsinag CY et al. 2001 screened 31 herbs in 5 different preparations (cold aqueous, hot
aqueous, ethanolic, acidic ethanolic, and methanolic) for their antiviral activities. 7 extracts,
which showed significant antiviral activities, were further investigated for their antiviral
mechanisms in vitro. Ethanolic extract of Rheum officinale prevented the process of Herpes
simplex attachment and penetration (12).
Blaszczyk T et al. 2000 screened 56 dried Chinese plants for their antimycotic properties in
vitro. They used 10 % aqueous extracts. The extract of Rheum palmatum L. (radix et
rhizoma) showed antimycotic activity against Aspergillus fumigatus and Candida albicans
comparable to that of nystatin. The growth of Geotrichum candidum and Rhodotorula rubra
was also inhibited, but to a lesser extent (13).
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Cyong JC et al. 1987 screened in vitro 178 Chinese herbs for their antibacterial activity
against Bacteroides fragilis , a major anaerobic microorganism in the intestinal flora in
humans. Only rhubarb root ( Rheum officinale ) was found to have significant activity and the
purified active substance was identified as rhein. Rhein also has potent activity against
Candida albicans and weak activity against Escherichia coli and Bacillus subtilis . Negligible
or no activity was shown against e.g. Enterobacter aerogenes , Pseudomonas aeruginosa ,
Salmonella typhimurium , and Staphylococcus aureus (14).
Several in vivo animal investigations deal with renal failure.
Yokozawa T et al. 1984 (16), 1985 (21), 1986 (17) and 1987 (22) examined the effect of
orally administered aqueous extract of roots of Rheum officinale Baillon in rats with chronic
renal failure induced by an adenine diet. The herbal preparation caused a marked decrease of
blood urea nitrogen and creatinine, and a decrease of methylguanidine and guanidinsuccinic
acid levels. Hypocalcaemia, hyperphosphataemia, and free amino acid patterns were also
improved.
Yokozawa T et al. 1997 administered an aqueous dry extract of rhubarb ( Rheum officinale
Baillon) 125 mg/kg b.w./day orally to rats with diabetic nephropathy induced by subtotal
nephrectomy and injection of streptozotocin for 80 consecutive days. High blood and urinary
glucose levels were ameliorated. Furthermore, improvement of hyperlipidaemia, and
accelerated excretion of urinary urea nitrogen and creatinine were observed. The changes
were significant compared to untreated controls (18).
Zhang G et al. 1996 studied the effect of orally administered aqueous extract of dry roots of
Rheum palmatum (150 mg/day from day 30 to day 120 in drinking water) on the course of
chronic renal failure in rats submitted to subtotal nephrectomy. Rhubarb treatment had no
effect on the systemic hypertension. Rhubarb-treated rats had significantly less proteinuria
when compared to the untreated group. Renal function was comparable in both groups, but
the severity of glomerulosclerosis was significantly reduced in the treated group (19).
Kosuge T et al. 1985 tried to identify the anticoagulative principle of Rheum palmatum L. by
a combination of partition, fractional precipitation and column chromatography on silica gel
and plasma recalcification time in mice, because the herb is used as an anticoagulant and
haemostatic agent in Chinese medicine. D-catechin was identified as the anticoagulative
principle. D-catechin has been also isolated from Sanguisorba and Hypericum species,
although these herbs are commonly used as haemostatics in Chinese medicine (23). The
clinical relevance concerning efficacy and safety has to be proven. Up to now no adverse
event dealing with a bleeding event has been reported during short-term use in cases of
occasional constipation.
Several investigations deal with the possible anticancer effect of Rheum palmatum , especially
with emodin isolated from the root.
An extract of Rheum palmatum L. increased the sensitivity to paclitaxel at a concentration of
10 µg/ml and 50 µg/ml significantly, not to 5-fluorouracil in HeLa cells (human cervical
carcinoma cell line). Paclitaxel is a MDR1 substrate whereas 5-fluorouracil is not such a
substrate. Rhodamine123 was used to evaluate the MDR1-mediated transport. Rhodamine123
uptake by HeLa cells was significantly increased by the presence of rhubarb at 100 µg/ml.
The authors concluded that the effect is mediated by an inhibition of MDR1 function in
tumour cells and that the combination of anticancer drugs with some herbal extracts
contributes to the enhancement of clinical outcomes in cancer chemotherapy (36). (see also
pharmacokinetic interactions)
A cytotoxic anthraquinone glycoside, pulmatin, 1,8-dihydroxy-3-methyl-anthraquinone-1-O-
ß-d-glycoside, and its congeners, chrysophanein and physcionin, have been isolated as minor
components from a methanolic extract of the root of Rheum palmatum . These anthranquinone
glycosides exhibited moderate cytotoxic activity against several types of carcinoma cells
(HeLa epithelioid carcinoma cells, BT-20 human breast carcinoma cells). The authors also
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isolated two stilbene glycosides, 4’-O-methylpiceid and rhapontin. Therefore falsifications of
the herbal substance cannot be ruled out (40).
An in vitro investigation shows that emodin, selectively inhibits casein kinase II (CKII), a
Ser/Thr kinase, as a competitive inhibitor (24).In human lung adenocarcinoma cells emodin
induces apoptosis through a reactive oxygen species-dependent mitochondrial signaling
pathway (25).In various human cancer cell lines (breast cancer, hepatocarcinoma, skin
squamous carcinoma) emodin significantly inhibits epidermal growth factor (EGF)-induced
migration which is one of the underlying mechanisms in cancer invasion and metastasis (26).
Furthermore emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by
blocking receptor-2 (KDR/Flk-1) phosphorylation (27).
Kazuhiro S et al. 2000 reported about phytoestrogen properties of emodin isolated of an
aqueous extract of the rhizome of Rheum palmatum for the first time. Emodin binds to the
estrogen receptor and activates transcription through estrogen responsive elements (ERE).
However, the exact mechanism is still unclear. The inhibition of casein kinase II (CKII) by
emodin may play a role because this kinase phosphorylates serine-167 on the human estrogen
receptor, which results in increased estrogen response element binding and transcriptional
activation (37).
Several Chinese plant extracts were tested to screen pharmacological activities that could be
relevant to the treatment of cognitive disorders. A simple and rapid enzyme essay on thin
layer chromatography (TLC) plates has been developed for the screening of
acetylcholinesterase and butyrylcholinesterase inhibition in plant extracts. The hexane extract
of Rheum officinale Baillon showed a clear activity whereas the methanolic and the
chloroform extract showed no activity (38).
Safety pharmacology
There are no special investigations available.
Pharmacodynamic interactions
Chronic use or abuse of rhubarb preparations may lead to hypokalaemia like the abuse of all
anthranoid-containing laxatives. This hypokalaemia and the increased loss of potassium may
increase the activity of cardiac glycosides and interfere with the action of antiarrythmic
agents (interaction with antiarrhythmic medicinal products, which induce reversion to sinus
rhythm, e.g. quinidine) and medicinal products inducing QT-prolongation. Concomitant use
with medicinal products inducing hypokalaemia (e.g. diuretics, corticosteroids and liquorice
root) may aggravate electrolyte imbalance.
II.2.1.2
Assessor’s overall conclusions on pharmacology
The postulated laxative effect is supported by the pharmacological data, even if the most data
derive from investigations with isolated constituents of rhubarb and not with the preparation
or the herbal substance itself. Pharmacological data obtained from other anthranoid-
containing laxatives complete these scientific findings.
In Asia (China, Japan) rhubarb is used as an anticancer agent among others. Therefore
several investigations try to clarify the underlying pharmacodynamic actions. Up to now the
clinical relevance of the findings is doubtful.
The phytoestrogen properties of emodin need to be confirmed and to elucidated by further
investigations.
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II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
Absorption, distribution, metabolism, elimination
No pharmacokinetic data obtained with rhubarb or its preparations are available.
According to Witte P and Lemli L 1990 (31) anthrone-glycosides are carried, unabsorbed, to
the large intestine, where the active aglykon is released by bacterial hydrolysis of the sugar.
The intestinal bacterial flora also accounts for the reduction of anthraquinone aglyka to the
corresponding anthrones. After absorption, the anthranoids are transformed mainly to their
corresponding glucuronide and sulfate derivatives, which appear in urine and bile.
In the case of senna, animal experiments with radio-labeled rhein-anthrone administered
directly into the caecum demonstrated absorption < 10 % (32).
Experiments with radiochemical anthranoids showed a significant clearance of tissue-bound
activity of all organs, except the kidneys, which exhibited a pronounced retention of
anthranoid equivalents.
After oral administration of 4.5 mg/kg 14C-aloe-emodin (AE) to rats 20 – 30 % of the dose
was excreted in urine and the rest in faeces. Aloe-emodin was quickly meatobolised to rhein,
to an unknown metabolite and to conjugates of all three. In the plasma about 10% of 14C-
activity was identified as free aloe-emodin. Maximum plasma values were reached
1.5 – 3 h p.a. with 248 (male) and 441 (female) ng equivalents aleo-emodin/ml. Maximum
concentrations in plasma were about 3 times higher than those in ovaries and 10 times higher
than those in testes. Because of the low activity concentrations in the reproductive organs
TLC analysis was not possible. But if the metabolic profile of these organs is assumed to be
the same as in plasma, concentrations of free aloe-emodin can be calculated to be maximally
about 2-4 ng/g in testes and 8-10 ng/g in ovaries after an oral dose of 4.5 mg/kg. Only liver,
kidney and intestinal tract showed higher concentrations than plasma. Terminal half-life (for
radioactivity) in blood was about 50 h (33).
Emodin was admininstered to rabbits by i.v. bolus. The AUC of emodin was 518 µg.min/ml,
clearance was 72.3 ml/min, and elimination half life was 227 min. Oral administration at
10 mg/kg b.w. resulted in a very low serum concentration (approximately 2.5 µg/ml).
Emodin was found to be highly bound (99.6%) to serum protein, investigated by the
equilibrium dialysis method (34).
Müller SO et al. 1998 (35) presented studies which were designed to elucidate the enzymes
involved in the biotransformation of naturally occurring 1,8-dihydroxyanthraquinones and to
investigate whether biotransformation of 1,8 dihydroxyanthraquinones may represent a
bioactivation pathway. First the metabolism of emodin was studied. With rat liver
microsomes, the formation of two emodin metabolites, omega-hydroxemodin and
2-hydroxyemodin, was observed. The rates of formation of omega-hydroxyemodin were not
different with microsomes from rats that had been pretreated with inducers for different
cytochrome P450 enzymes. Thus, the formation of omega-hydroxyemodin seems to be
catalysed by several cytochrome P450 enzymes at low rates. The formation of
2-hydroxemodin was increased in liver microsomes from 3-methylcholanthracene-pretreated
rats and was inhibited by alpha-naphthoflavone, by an anti-rat cytochrome P450 1A1/2
antibody, and to a lesser degree, by anti-rat cytochrome P450 1A1 antibody. These data
suggest the involvement of cytochrome P450 1A2 in the formation of this metabolite.
However, other cytochrome P450 enzymes also seem to catalyse this reaction. The
anthraquinone chrysophanol is transformed, in a cytochrome P450-dependent oxidation, to
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aloe-emodin as the major product formed. Further on Müller SO et al. compared the
mutagenicity of the parent dihydroxyanthraquinones and their metabolites in the in vitro
micronucleus test in mouse lymphoma L5178Y cells. 2-hydroxyemodin induced much higher
micronucleus frequencies, compared with emodin. Omega-hydroxyemodin induced lower
micronucleus frequencies, compared with emodin. Aloe-emodin induced significantly higher
micronucleus frequencies than did chrysophanol. These data indicate that the cytochrome
P450-dependent biotransformation of emodin and chrysophanol may represent bioactivation
pathways for these compounds.
Pharmacokinetic interactions
Takara K et al. 2005 (36) concluded an inhibition of MDR1 function in tumour cells by a
rhubarb extract from their in-vitro investigations (see secondary pharmacodynamics).
However, rhodamine123, the substrate used is also transported by transporters for organic
cations, and therefore it is not a selective substrate. It is not known whether the HeLa cell line
expressed MDR1-gene in a constant way.
This might be a hint that rhubarb influences this transport system in some way but up to now
this hint is too weak to draw some conclusion concerning possible interactions.
A recherche in the database XMEDALL with the keywords “rhubarb (Rheum)” and “MDR”
or “PGP (glycoprotein)” did not show any further publications. There are no reports of
clinical relevant pharmacokinetic interactions available. We also take into account that
rhubarb is only used for short term.
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics
Anthrone-glycosides are carried, unabsorbed, to the large intestine. They are converted by the
bacteria of the large intestine into the aglycones and subsequently to the active compounds,
the anthrones. Absorption seems to be low.
The data available concerning some pharmacokinetics interactions are too weak to draw
some conclusions.
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
No specific data are available for single dose toxicity and reproductive toxicity for rhubarb or
the preparations thereof.
The study of Yan M et al. 2006 focuses on the toxicity of total rhubarb (rhizomes of Rheum
palmatum L.) anthraquinones (TRAs) on Sprague Dawley rats. TRAs were orally
administered for 13 weeks. 20 animals were randomly allocated into four groups. TRAs were
dissolved in 0.5% sodium carboxymethylcellulose solution and each group was administered
per os once daily for 13 weeks a dose of 0, 140, 794, 4500 mg/kg b.w. After that, rats were
sacrificed under halothane anesthesia and all main organs and glands were taken for
pathohistology studies. In the highest dose group, nephrotoxicity were discernible at
13 weeks. There was no clear morphologic change in the kidney of the control group, while
in TRAs tested group, swelled and denatured renal tubule epithelial cells were observed. The
results of gene differential expression study indicated the TRAs affect mostly at oxidative
stress pathway, cell cycles, nutrients metabolism, thus caused renal tubule epithelial cells
swelled and denatured in histopathology study. CYP1A1, which is regarded as a carcinogen-
metabolising enzyme, was dramatically up-regulated and may account to genotoxicity.
Mitogen-activated protein kinase (MAPK) kinase 6 was identified to be the target gene which
cause cell cycle arrest and proliferation inhibition and contributes to the nephrotoxicity on
rats. However, the discernible nephrotoxicity was only observed at the high dose group.
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According to the authors therapeutic dosage of TRAs is 420 mg/day, 7 mg/kg b.w.
respectively, if one person weighs 60 kg. The dosage used in the experiment is 642 times
ordinary clinical dose (39).
Paneitz et al. 1999 compared ethanolic extracts of different Rheum species with respect to
their mutagenicity in the Salmonella /microsome assay with strains TA 98, TA 100 and TA
1537. The root extract of Rheum officinale Baillon was weakly mutagenic in strain TA 1537
even without metabolic activation at a dosage of 300 µg/plate and the effect is enhanced by
addition of S9-mix, already at dosage of 30 µg/plate. The authors concluded that the positive
effect without metabolic activation might be due to the content of aloe-emodin, which is the
only direct-acting mutagenic anthraquinone present in Rheum species, whereas the
enhancement of the mutagenic potency after addition of S9-mix is probably related to emodin
(41).
In a dose 5 mg/plate, an aqueous extract (1:6) of Rhei radix (no further specification is given)
had a mutagenic effect on Salmonella typhimurium TA 98 following metabolic activation
with S9-mixture. However, this effect was not obtained with Salmonella typhimurium TA
100. In a rec-assay with Bacillus subtilis for DNA-damage the same extract (6 mg/plate) gave
a positive result. A methanolic (1:6) extract gave no response in the same tests. Sennoside B
and rhein did not induce significant numbers of chromosomal aberrations or aberrant cells in
bone marrow cells of Swiss mice (53).
Further data exist for different hydroxanthraquinones and other anthranoid-containing herbal
substances like senna.
Older toxicological data indicate that the two hydroxyanthraquinones, emodin and aloe-
emodin might represent a genotoxic or carcinogenic risk (Mori 1990 (42), Siegers 1992 (43),
Brusick 1997 (44)). While most studies gave negative responses, results from some of the
studies suggest a genotoxic activity by both (Wölfle 1990 (45), Westendorf 1990 (46),
Westendorf 1993 (47)). These were Ames tests showing an interaction with Salmonella DNA
resulting in the production of frameshift mutations (Westendorf 1990 (46), Sandnes 1992
(48), Heidemann 1993 (49)). Other sennosides and rhein were mostly negative in the
respective tests. In three in vivo studies the crude senna herbal substance at a concentration of
1 or 1.5 g/kg body weight showed no evidence of any genetic effects (Heidemann 1993 (49)).
In vitro assays overestimate the potential hazard from exposure and must be reevaluated by in
vivo experiments.
Westendorf et al. 1990 (46) reported that in the Ames test aloe-emodin was mutagenic in
S . typhimurium strain TA1537 and furthermore active against TA98, TA1538 and TA97 (all
frameshift mutant sites). The activity was independent of metabolic activations; in fact, the
addition of S9 mix tends to suppress the mutagenicity. In the Mammalian Cell Mutation Test
Westendorf et al. reported that aloe-emodin was mutagenic to V79 cells. However, other
scientists question this conclusion. The highest concentration employed was 30 µg/ml and
did not show much, if any toxicity (see publication). This indicates the possibility of a
problem, since mutagenic effects in this assay are typically associated with toxicity. The
apparent positive response was based on a very low spontaneous mutant frequency.
Numerous laboratories have recognised that the spontaneous background for HGPRT-
mutants (hypoxanthine-guanine phosphoribosyl transferase) is quite variable and increase of
at least 3-5 fold are required in duplicate tests to confirm an effect. In the in vitro UDS assay,
also conducted by Westendorf et al. 1990, aloe-emodin was associated with a significant
increase in net grains/nucleus. 2 trials were reported. The concentrations range in both
covered 6.3 µg/ml to 100 µg/ml. At a concentration of 25 µg/ml the net grains/nucleus
reached the criteria to call the response positive. In the Salmonella / microsome assay emodin,
chrysophanol and physcion were weakly mutagenic in strain TA1537 in the presence of
S9 mix only. Chrysophanol was also weakly mutagenic in strain T102 without and with
exogenous metabolic activation for induction of mutagenicity. No mutagenic effects were
observed in the V79-HGPRT mutation assay and in the unscheduled DNA synthesis (UDS)
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assay for chrysophanol and physcion. Emodin was highly mutagenic in the V79-HGPRT
mutation assay. In the UDS assay emodin was a string inducer of UDS in primary
hepatocytes. Emodin was also tested with respect to its transforming activity in C3H/M2
mouse fibroblasts in vitro. Emodin was clearly active in this in this assay.
Sandnes D et al. 1992 (48) investigated the mutagenicity of senna glycosides and extracts of
senna folium and senna fructus in the Salmonella typhimurium reversion assay. Senna
glycosides were inactive in all strains, except for a slight, but significant increase in mutant
frequency in TA102 in the absence and presence of liver microsomes. Extracts of senna
fructus and senna folium demonstrated weak activity in TA97a, TA100 and TA102 in the
presence of liver microsomes, and in TA97a and TA102 in the absence of liver microsomes.
A strong increase in mutant frequency (3- to 5-fold above background frequency) was
observed with all extracts in TA98 in the presence of liver microsomes. This activity
increased further following enzymatic hydrolysis with hesperidinase of extracts of senna
fructus from one source, and could be correlated to the release of the flavonol aglyka
kaempferol and quercetin.
Helmholz H et al. 1993 (114) investigated the mutagenic and genotoxic activities of the
glycosides emodin and frangulin, and of an alcoholic extract of frangula bark, and of a
commercial frangula bark preparation Sanurtin N® with the aid of the in vitro
Ssalmonella /microsome mutagen test and the deoxyribonucleic acid (DNA) repair test of
primary rat hepatocytes. 1 g of the alcoholic extract contained 50.76 mg glucofrangulin,
86.84 mg frangulin, 30.88 mg emodin, 10.3 mg pyscion, and 14.32 mg chrysophanol. One
coated tablet of Sanurtin N® contained 8.28 mg glucofrangulin, 0.21 mg frangulin, <0.1 mg
emodin, and physcion and chrysophanol only in traces. The tests provided evidence of a
dose-dependent increase in the mutation rate or the induction of DNA repair, for the
glycosides, the extract of the crude herbal substance and the commercial preparation. The
mutagenic potency was larger for emodin than for the alcoholic extract than for frangulin
than for Sanurtin N®. The authors concluded that phytotherapeuticals based on frangula bark
can cause genotoxic effects and are potential tumour promoters.
The three in vivo studies by Heidemann 1993 (49) which showed no evidence of any genetic
effects, were the Chromosome Aberration Test, the Mouse Spot Test, and the in vivo/in vitro
UDS (unscheduled DNA synthesis) in rat hepatocytes.
Mengs U et al. 1997 (54) investigated the potential of emodin to induce micronuclei in
polychromatic erythrocytes (PCEs). Mice of both genders received a single oral dose of
2000 mg emodin/kg and were killed 24 and 48 h later. Bone marrow cells were collected
from 5 males and 5 females and 2000 PCEs per animal were scored for the presence of
micronuclei. There was no enhancement in the frequency of micronuclei at both preparation
intervals when compared to the negative controls. Blood level examination confirmed the
systemic availability of emodin. Plasma levels of up to 190 µg emodin/ml represented
concentrations being in the concentration range that induced positive responses in several
genotoxicity cell culture assays.
Jahnke GD et al.2004 (55) evaluated emodin for potential effects on pregnancy outcome.
Emodin was administered in feed to timed-mated Sprague-Dawley (CD) rats (0, 425, 850,
and 1700 ppm; gestational day (GD) 6-20), and Swiss Albino (CD-1) mice (0, 600, 2500 or
6000 ppm; GD 6-17). Ingested dose was 0, 31, 57, and ~80-144 mg emodin/kg/day (rats) and
0, 94, 391, and 1005 mg emodin/kg/day (mice). Timed-mated animals (23-25/group) were
monitored for body weight, feed/water consumption, and clinical signs. At termination (rats:
GD 20; mice: GD 17), confirmed pregnant dams (21-25/group) were evaluated for clinical
signs: body, liver, kidney, and gravid uterine weights, uterine contents, and number of
corpora lutea. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal
malformations/variations. There were no maternal deaths. In rats, maternal body weight,
weight gain during treatment, and corrected weight exhibited a decreasing trend. Maternal
body weight gain during treatment was significantly reduced at the high dose. In mice,
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maternal body weight and weight gain was decreased at the high dose. Prenatal mortality,
live litter size, fetal sex ratio, and morphological development were unaffected in both rats
and mice. At the high dose, rat average fetal body weight per litter was unaffecte, but was
significantly reduced in mice.
The rat maternal lowest observed adverse effect level (LOAEL) was 1700 ppm; the no
observed adverse effect level (NOAEL) was 850 ppm. The rat developmental toxicity
NOAEL was +/- 1700 ppm. A LOAEL was not established.
2001 the National Toxicology Programm (NTP) of the U.S. Department of Health and
Human Services published a technical report on toxicology and carcinogenesis studies of
emodin (50).
16-day study in F344/N rats
Groups of 5 male and 5 female rats were fed diets containing 0, 600, 2000, 5,500, 17,000, or
50,000ppm emodin. This corresponds in males to average daily doses of approximately
50, 170, 480, 1,400, or 3,700 mg emodin/kg bw and in females to 50, 160, 460, 1,250, or
2,000 mg/kg bw. 3 female rats died before the end of the study. Mean body weights of males
and females exposed to 5,500 ppm and greater were signifcantly less than those of the
controls. Feed consumption by males and females receiving 17,000 or 50,000 ppm was
decreased throughout the study. Macroscopic lesions were present in the kidney of rats
exposed to 17,000 or 50,000 ppm.
16-day study in B6C3F 1 mice
The size of the groups and the administered concentrations were the same as described above.
The concentrations correspond in males to average daily doses of approximately 120, 400,
1,200 or 3,800 mg/kg bw and in females to 140, 530, 1,600 or 5,000 mg/kg bw. 50,000 ppm
equivalents were not calculated due to high mortality. All mice exposed to 50,000 ppm died
before the end of the study. Mice in the 17,000 ppm groups lost weight during the study.
Feed consumption by 5,500 ppm was greater than by the controls. Macroscopic lesions were
present in the gallbladder and kidney exposed to 17,000 ppm.
14-week study in rats
Groups of 10 male and 10 female rats were fed diets with 0, 312.5, 625, 1,250, 2,500 or
5,000 ppm emodin. This corresponds to average daily doses of approximately 20, 40, 80,
170, or 300 mg/kg bw in males and females. Among others relative kidney weights of rats
exposed to 1,250 ppm or greater and relative lung weights of rats exposed to 625 ppm or
greater were significantly increased compared to the control groups. Relative liver weights
were increased in females exposed to 625 ppm or greater. The estrous cycle length was
significantly increased in females exposed to 1,250 or 5,000 ppm. All male rats exposed to
1,250 ppm or greater and all exposed female rats had pigment in the renal tubules; and the
severity of pigmentation generally increased with increasing exposure concentration. The
incidences of hyaline droplets in the cortical epithelial cytoplasm were increased in all groups
of exposed males and in females exposed to 312.5, 625, or 1,250 ppm.
14-week study in mice
The size of the groups and the administered concentrations were the same as described above.
This corresponds to average daily doses of approximately 50, 100, 190, 400, or 800 mg/kg to
males and 60, 130, 240, 500, or 1,100 mg/kg to females. Relative kidney weights of male
mice exposed to 1,250 ppm or greater, relative lung weights of males exposed to 625 ppm or
greater, and relative liver weights of female mice exposed to 625 ppm or greater were
increased. The incidences and severities of nephropathy were increased in males and females
exposed to 1,250 ppm or greater. The incidences of renal tubule pigmentation were
significantly increased in males exposed to 1,250 ppm or greater.
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2-year (105 weeks) study in rats
Groups of 65 male and 65 female rats were fed diets containing 0, 280, 830, or 2,500 ppm
emodin (equivalent to average daily doses of approximately 110, 320, or 1,000 mg/kg to
males and 120, 370, or 1,100 mg/kg to females).
3 Zymbal’s gland carcinomas were observed in female rats exposed to 2,500 ppm. This
incidence exceeded the range observed for current historical controls and was considered an
equivocal finding. At the 6- and 12-month interim evaluations and at 2 years, emodin-related
increases in the incidences of renal tubule hyaline droplets occurred in all exposed groups.
The incidences of renal tubule pigmentation were significantly increased of all exposed
groups of males at 2 years. There were negative trends in the incidences of mononuclear cell
leukaemia in male and female rats, and the incidences in the 2,500 ppm groups were
significantly decreased. In females exposed to 2,500 ppm, the incidence was below the
historical control range; the incidence in males exposed to 2,500 ppm was at the lower end of
the historical control range.
2-year study in mice
Groups 0f 60 male mice were fed diets containing 0, 160, 312, or 625 ppm emodin
(equivalent to average daily doses of approximately 15, 35, or 70 mg/kg) and groups of
60 female mice were fed diets containing 0, 312, 625, or 1,250 ppm emodin (equivalent to
average daily doses of approximately 30, 60, or 120 mg/kg). Low incidences of renal tubule
adenoma and carcinoma occurred in exposed male mice; these incidences included one
carcinoma each in the 312 and 625 ppm groups. Renal tubule neoplasms are rare in male
mice, and their presence in these groups suggested a possible association with emodin
exposure. At the 12-month interim evaluation, the severity of nephropathy was slightly
increased in males exposed to 625 ppm. Also at 12 months, the severity of nephropathy
increased from minimal in the lower exposure groups to mild in females exposed to
1,250 ppm; the incidence in this group was significantly increased compared to the control
group. At 2 years, the severities of nephropathy were slightly increased in males exposed to
625 ppm and females exposed to 1,250 ppm. The incidences of nephropathy were
significantly increased in all exposed groups of females. At the 12-month interim evaluation,
the incidences of renal tubule pigmentation were significantly increased in all exposed groups
of males and in females exposed to 625 or 1,250 ppm. The severities increased with
increasing concentration of exposure. At 2-years, the incidences of renal tubule pigmentation
were significantly increased in all exposed groups; severities also gained with increasing
concentration of exposure.
Genetic toxicology
Emodin was mutagenic in Salmonella typhimurium strain TA100 in the presence of
S9 activation; no mutagenicity was detected in strain TA98, with or without
S9. Chromosomal aberrations were induced in cultured Chinese hamster ovary cells treated
with emodin, with and without S9. Three separate in vivo micronucleus tests were performed
with emodin. A male rate bone marrow micronucleus test, with emodin administerd by
3 intraperitoneal injections, gave negative results. Results of acute-exposure (intraperitoneal
injection) micronucleus tests in bone marrow and peripheral blood erythrocytes of male and
female mice were negative. In a peripheral blood micronucleus test on mice from the
14-week study, negative results were seen in male mice, but a weekly positive response was
observed in similarly exposed females.
Conclusion by the “National Toxicology Program’s Board of Scientific Counselors’
Technical Reports Review Subcommittee”:
-
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The studies give no evidence of carcinogenic activity for male rats and female mice,
and equivocal evidence for female rats and male mice.
- In view of conflicting results on genotoxicity, it was noted the first pass effect and
need for metabolic activation suggesting a metabolite as the genotoxic form. The
metabolite 2-hydroxyemodin acts as the genotoxin (51).
2002 the American Herbal Products Association submitted a review of the data from the
National Toxicology Program and relevant to the status of Cascara sagrada ingredients (52).
All of the NTP oral feeding studies were of durations which exceed the duration of human
exposure. The studies that are nearest the human exposure are the 16 day studies in mice and
rats. The most conservative no adverse level (NOAEL) reported for these studies, is
160 mg/kg in female rats and 400 mg/kg in male mice. Assuming that an adult of 70 kg body
weight consumes 21 – 100 mg hydroxanthracenes daily (0.3 – 1.43 mg per kg body weight),
the association calculated a standard conservative 100-fold margin of safety.
Based on the maximal daily dose of 30 mg hydroxyanthracene recommended in the HMPC
monograph of rhubarb (0.43 mg per kg body weight) a standard conservative 370-fold
margin of safety can be calculated.
Concerning the evaluation of carcinogenicity the association concluded that the equivocal
evidence of carcinogenicity in female rats in the 2-year feed study is clearly not relevant to
humans because humans do not have a Zymbal’s gland and there was no additional data on
which the finding of equivocal evidence was made. The equivocal evidence of carcinogenic
activity of emodin in male mice based on a single occurrence of uncommon renal tubule
neoplasm in each of the highest doses (i.e., at 35 and at 70 mg/kg body weight) but not in the
low dose (15 mg/kg body weight). Because of the short-term duration of exposure to cascara
this finding would be of questionable relevance to human exposure, just as the sex-specific
differences.
Heidemann A et al. 1996 (56) undertook in vitro and in vivo experiments to clarify the
genotoxic potential of the hydroxyanthraquinone aloe-emodin. The results confirmed that
aloe-emodin is able to induce mutagenic effects in vitro. In in vivo studies (micronucleus
assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow
cells of Wistar rats; mouse spot test [DBA/2J x NMRI]) no indication of a mutagenic activity
of aloe emodin was found. Information about a possible reaction of aloe-emodin with DNA
was derived from an in vivo unscheduled DNA synthesis (UDS) assay. Hepatocytes of aloe-
emodin treated male Wistar rats did not show DNA damage via repair synthesis. These data
suggest that aloe-emodin is able to interact with DNA under certain in vitro conditions.
However, in vivo the results did not indicate a genotoxic potential. Therefore the authors
assume that a genotoxic risk for man might be unlikely.
The aim of the study of Schörkhuber M et al. 1998 (57) was to demonstrate the effect of the
1,8-dihydroxyanthraquinone (DHA)-laxatives, danthrone, rhein, aloe-emodin and sennidine,
on colorectal tumour cells because the available information is still inconclusive. In SW480
carcinoma cultures, dose-dependent induction of urokinase secretion into the medium was the
predominant effect. Simultaneously, cell numbers were decreased by DHA-aglyka, but not by
sennoside or the biphenylic laxative bisacodyl. DNA synthesis was not similarly reduced:
0.4-4 microM danthrone and sennidine even stimulated 5-bromo-2’-desoxyuridine (BrdU)
uptake into DNA. When uptake was normalised to cell number, danthrone and sennidine
doubled BrdU uptake/10(6) cells, 18 microM rhein and 0.7 microM aloe-emodin induced
increases of 37 and 50%, respectively. This may at least partially be due to selective
resistance of S-phase cells to DHA-caused cell loss. In VACO235 adenoma cells, sennidine
and aloe-emodin did not affect urokinase secretion, but stimulated growth. Both cell numbers
and DNA synthesis were increased. In contrast to SW480 carcinoma cells, VACO235 cells
were also sensitive to sennoside and bisacodyl. No effects of DHA were observed in normal
colorectal epithelial cells. The biological effects were preceeded by specific phosphorylation
of cellular proteins with molecular weights of 110, 78, 63, 57 kCa, indicating the specific
induction of a cellular signalling cascade by the laxatives.
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Mitchell JM, Mengs U et al. 2006 (115) conducted an oral carcinogenicity and toxicity study
of senna in rats. The administered senna preparation were powdered Tinnevelly senna pods
containing 1.829% of sennosides A-D, 1.596 % of potential rhein, 0.111% of potential aloe-
emodin, 0.014% of total emodin, and 0.004% of total chrysophanol (sum of potential
hydroxyanthraquinones 1.725%). Senna was administered by gavage to Sprague Dawley rats
once daily at dose levels of 0, 25, 100 and 300 mg/kg/day for up to 104 consecutive weeks.
Based upon clinical signs related to laxation effect of senna, the highest dose
(300 mg/kg/day) was considered to be a maximum tolerated dose. The primary treatment-
related clinical observation was mucoid faeces seen at 300 mg/kg/day. In the highest dose
group animals had slightly reduced body weights, increased water consumption and notable
electrolyte changes in serum and urine. At necropsy, dark discolouration of the kidneys was
observed in all treated groups. Histological changes were seen in the kidneys of animals of all
treated groups and included slight to moderate tubular basophilia and tubular pigment
deposits like already described above. For all treated groups, minimal to slight hyperplasia
was evident in the colon and caecum. Under the conditions of the study there were no
alteration seen in the colonic nervous plexus. Even in the highest dose group, there was no
indication of any pigment deposits in the mucous membranes of the large intestine. No
treatment-related neoplastic changes were observed in any of the examined organs. The
authors concluded that senna did not reveal any evidence of carcinogenicity in this study.
II.2.3.2
Assessor’s overall conclusions on toxicology
Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids. Most
of the in-vivo studies showed no effect or only equivocal effects.
Mueller SO et al. 1999 concluded in their publication “Occurrence of emodin, chrysophanol
and physcion in vegetables, herbs and liquors. Genotoxicity and anti-genotoxcity of the
anthraquinones and of whole plants” (58), although three common vegetables have been
shown to contain anthraquinones, data on their genotoxicity alone should not be used to
derive a human risk. The authors analysed vegetables, herbs and herbal-flavoured liquids for
the quantitative determination of the content of the aglycosidic anthraquinones emodin,
chrysophanol and physicion. For example emodin, chrysophanol and physcion were found in
lettuce and beans, and emodin and physcion in peas. For emodin the authors had shown
unequivocal genotoxic potency in mammalian cells. On the contrary, chrysophanol and
physcion showed borderline effects, and physcion was cytotoxic at higher concentrations.
The lyophilisates of these vegetables were tested in the micronucleus test in lymphoma cells,
alone and in combination with the known genotoxic and carcinogenic anthraquinone
danthrone. None of the lyophilisates increased the frequency of micronuclei. Surprisingly, the
genotoxicity of danthron was reduced significantly by addition of the vegetables
lyophilisates. The authors concluded that the vegetables as a whole contain numerous other
constituents some of which might also have protective effects and therefore for evaluation of
a putative human health risk from dietary mutagens, the assessment should not be based on
measured concentrations of mutagens.
This is also to be considered in anthranoid-containing herbal substances like rhubarb which
also are combinations of numerous constituents.
Nephrotoxicity observed in mice occurred after administration during 13 weeks and with a
642 times higher dose than the ordinary clinical dose according to the authors.
Pharmacovigilance actions were initiated in Germany in 1996 (60) to minimise a possible
risk. The maximal dose and the duration of use were limited.
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II.3
C LINICAL D ATA
II.3.1
Clinical Pharmacology
II.3.1.1
Pharmacodynamics
II.3.1.1.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
There exist several investigations with different Chinese and Japanese herbal preparations
which are not specified exactly. We mainly mention the investigations with Rheum palmatum
L. or Rheum officinale Baillon
Mitsuma T et al. 1998 investigated the differences in cathartic actions of three different types
of rhubarb: rhubarb A (produced in the Province of Sichuan, China), rhubarb B (Rheum
coreanum, cultivated and processed in Japan), rhubarb C (tablets manufactured with the
processed rhizome of Rheum palmatum from the Province of Qing-Hai, China). These three
types were administered to 12 healthy volunteers for 3 days. Pharmacological effects were
evaluated in terms of the number of bowel movements, bowel sounds, urinary volume and
various blood chemical parameters. From the results, the authors concluded that the
processed rhubarb (C), with a weaker cathartic action, was suitable for therapeutic use in
patients with chronic renal failure (63).
II.3.1.2
Pharmacokinetics
II.3.1.2.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Vyth A et al. 1979 (61) isolated rhein, aloe-emodin, emodin, physcion and chrysophanol
from powdered root of rhubarb (no further specification is given) after oxidative hydrolysis.
After oral administration of 65 mg or 200 mg of powdered root of rhubarb in 2 volunteers,
rhein was found in human urine. The sample collected in the morning contained more
anthraquinones than those collected noon.
Zhu W et al. (62) compared the pharmacokinetic parameters of rhein administered by
retention enemas with those conventional oral dosing of rhubarb extract (aqueous extract of
Rheum officinalis Baillon). The amounts of rhein, emodin, aloe-emodin, chrysophanol,
physcion on the extract were 12.308, 1.337, 1.594, 1.204, 1.615 mg/g, respectively. Eight
healthy male volunteers were enrolled in a prospective crossover study. All subjects received
a single dose of rhubarb extract (50 mg/kg corresponding to about 54 mg hydroxyanthracene
derivatives, body weight 60 kg) on two separate occasions, once orally, once by a retention
enema. Rhein plasma concentration was measured by HPLC. The plasma rhein levels rose
rapidly after oral administration and then declined slowly. The curve fitted a two-
compartment model well. Concerning the retention enema administration, the distribution of
rhein reached its C max at 53.46 +/- 33.10 minutes after a rapid ascent, characteristic of fast
absorption. The distribution and elimination of the plasma rhein followed a one-
compartement model. The C max , AUC 0-∞ , AUMC (area under the first moment of plasma
concentration-time curve) were significantly higher in oral administration, while V d (volume
of distribution) of rhein after oral administration was significantly lower. However, no
statistically significant differences between the two treatments were observed for any other
pharmacokinetic parameters like T max , t 1/2 , MRT 0-∞ (mean residue time), CL (body
clearance).Two subjects reported mild to moderate diarrhoea, which resolved without
treatment. No clinically meaningful changes in examinations findings or vital signs were
observed.
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II.3.1.3
Assessor’s overall conclusions on pharmacodynamics and pharmacokinetics
There are only limited human pharmacological data available. Based on animals experiments
and experiences with other anthranoid-containing herbal substances it is assumed that the
laxative effect in humans is also caused by the two mechanisms described in chapter II.2.1.1.
Rhubarb acts within 8 to 12 hours due to the time taken for transport to the colon and
metabolisation into the active compounds.
II.3.2
Clinical Efficacy 3
II.3.2.1
Dose response studies
There are no dose response studies available.
The German monograph of Rhei radix (2) indicates a daily dose of 20 – 30 mg
hydroxyanthracene derivatives calculated as rhein, but recommends that the pharmaceutical
form must allow lower dosages than the usual daily dose.
The ESCOP monograph for “RHEI RADIX”, 2nd edition, (4) recommends 15 – 50 mg
hydroxyanthracene derivatives.
The WHO monograph on Rhizoma Rhei (5) recommends 10 – 30 mg hydroxyanthracene
derivatives.
The recommendation in the German pharmacovigilance actions for anthranoid-containing
laxatives of 21 June 1996 (2) only determines a daily maximum limit of 30 mg
hydroxyanthracene derivatives in consideration of the toxicological data. The patient has to
be informed that the correct individual dose is the smallest required to produce a comfortable
soft-formed motion.
Taken into account that rhubarb also contains tannin agents which may possibly counteract
the laxative effect of the anthraquinones and according to the German pharmacovigilance
actions we recommend a dose range from 20 – 30 mg hydroxyanthracene derivatives
calculated as rhein like the German monograph.
Normally it is sufficient to take an anthranoid-containing laxative up to two to three times a
week (64).
II.3.2.2 Clinical studies (case studies and clinical trials)
Laxative effect
Fotiades P et al. 1976 (68) investigated the efficacy of Laxariston® in the treatment of
constipation. 3 g of this preparation contain 0.9 g methyl cellulose, 0.3 g frangula bark
(13.5 mg hydroxyanthracene derivatives), 0.3 g senna leaves (7.5 mg hydroxyanthracene
derivatives), 0,15 g rhubarb root (6.75 mg hydroxyanthracene derivatives) and 0.015 g
achillea extract. Laxariston® was given to 61 inpatients with mainly arthritic illness
(3 g daily for 26.1 days on average) and to 33 outpatients mainly after abdominal surgery
(7.6 g daily for 88.9 days). 31 patients of the whole study population had acute complaints,
20 patients suffered from chronic constipation and 41 patients from “functional” constipation.
Special complaints are not mentioned in the publication. The time until disappearance of
complaints was evaluated as follows: 0-2 days: very good efficacy; 3 – 14 days: good
efficacy; 15 – 28 days: sufficient efficacy; more than 28 days: insufficient efficacy.
Laxariston® had a very good efficacy in 71 patients (77.2%), a good efficacy in 19 patients
(20.7%) and a satisfactory efficacy in 2 patients (2.1%). In the group with acute complaints
the efficacy was very good in 77.4% and good in 22.6%. In the group with chronic
complaints the efficacy was very good in 35%, good in 55% and satisfactory in 10 %. In the
group with functional complaints the efficacy was very good in 97.6% and good in 2.4%. The
3 In case of traditional use the long-standing use and experience should be assessed.
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tolerance of the preparation was good in all these patients. The efficacy in 2 patients was not
evaluated because these patients developed abdominal pain.
Bauer H 1977 (69) administered Laxariston® (specification see above) to 73 patients with
gynaecological diseases and to 95 pregnant women suffering from constipation. Special
complaints are not mentioned in the publication.
The first group consisted of 30 patients with laparotomy in the past, of whom 15 patients
additionally took oestrogens, 6 patients with oestrogens and conservative gynaecological
diseases, 7 patients with oestrogens and other medicinal products which influence the
intestine motility, 13 patients with pathological-anatomic alteration in the pelvis minor, and
7 patients with constipation not caused by the gynaecological diseases. On average the
women took this medicinal product for 47.2 days and the complaints disappeared in 5.3 days
with a daily dose of 5.3 g. The time until disappearance of constipation complaints was
assessed as follows: 0-3 days: very good efficacy; 4-5 days: good efficacy; 6-7 days:
satisfactory efficacy; >7 days: insufficient efficacy. Efficacy was very good in 41 patients,
good in 20 patients and satisfactory in 11 patients. One patient dropped out (reason not
given). 6 patients (8.2%) complained about adverse reactions (spasms, tenesms, and nausea).
21 patients (28.8%) reported about positive reactions like weight reduction, decrease of
haemorrhoidal complaints, and decrease of flatulence.
In the second group 14 pregnant women were in the first trimenon, 15 in the second, and
66 women in the third trimenon. On average Laxariston® was administered for 61.4 days and
the complaints disappeared in 3.9 days with a daily dose of 3.9 g. Efficacy was very good in
55 patients, good in 31 patients, satisfactory in 7 patients and insufficient in 2 patients. This
result was not analysed with regard to the different trimenons. 4 patients (4.2%) complained
about adverse reactions. 29 patients (30.5%) reported about positive reactions.
12 women in the second group were gynaecologically treated because of a threatening
abortion. One of these women only miscarried.There is no information about the state of the
new-borns.
3 g of Laxariston® already contains 27.75 mg hydroxyanthracene derivatives, nearly 25%
derive from rhubarb.
Borgia M et al. 1985 (70) carried out a double-blind controlled trial in 4 centers. 359 patients
with slight or moderate functional disorders of the gastrointestinal tract were included. The
effect of a combination of herbs with rhubarb, gentian, boldus and cascara (91 patients) was
compared with the effect of placebo (90 patients), the effect of a combination with rhubarb
and gentian (90 patients), and the effect of a combination with boldus and cascara
(88 patients). The amount of anthranoides is not specified. The test preparation with rhubarb,
gentian, boldus and cascara was more effective than the inert control excluding the
disturbances not related to the pharmacological activities of the components. Combinations
of the components “rhubarb + gentian” and “boldus + cascara” tested as active controls,
showed significant favourable effects on disturbances of appetite and digestion and on
constipation respectively.
Moser EH and Hübner WD 2002/2003 (65, 66) enrolled 284 patients between 19 and
70 years suffering from irritable bowel syndrome (IBS) in a 12-week double blind,
controlled, randomised, multi-centre and prospective clinical trial to compare the efficacy as
well as the tolerance of Eucarbon® tablets (containing as active ingredients “180 mg Carbo
ligni”, i.e. vegetable, non-activated charcoal, “105 mg Fol. Sennae, 25 mg Extr. Rhei”) to
Carbo ligni (CL) containing tablets. Men and women who met the Rome criteria for IBS (all
forms) for at least 3 months were eligible. 145 patients received Eucarbon® and 139 patients
Carbo ligni. During the first 4 weeks, the physician was allowed to adapt the dosage to a
patient’s individual needs, from one to eight tablets per day. No dosage changes were
allowed after the fourth week. The number of tablets prescribed daily (1-3, 4-6, or >6) was
similar between groups, although a tendency to use fewer tablets was evident in the
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Eucarbon® group. After the 12-week treatment period, 262 patients were available for ITT
analysis and 144 for PP-analysis whereby changes of the disease were evaluated with scores
based on the Francis IBS system (38) modified with an open upper boundary (a patient-
administered questionnaire that uses a VAS (0%-100%) to score the severity of pain,
distension, bowel dysfunction, and quality of life/global well-being) as the primary efficacy
parameter. Scores on the VAS for overall well-being decreased in the PP population from
48 with Eucarbon® and 46 with CL before treatment (ITT, 47 and 47) to 18 and 20 after 12-
week treatment (ITT, 19 and 22). This translates to an amelioration of symptoms in the PP
population by 62.5% with Eucarbon® and 56.5% with CL; respective values in the ITT
population were 59.6% and 53.2%. The relative gain in efficacy with Eucarbon® compared
with its basic component (charcoal) was therefore only about 8% to 9% without statistical
significance. Differences in the Francis score became more prominent in some subgroups
selected for exploratory analysis. The patients who described “often normal stools” at
baseline achieved significantly greater overall well-being after treatment with Eucarbon®
(p=0.038, Wilcoxon test, PP population). Similar improvement in the subgroup admitting to
“movements often hard” was more pronounced with Eucarbon® than with CL (not
statistically significant). Both treatments were well tolerated, adverse events occurred with
similar frequency in both groups (22% of patients treated with Eucarbon® vs. 17% treated
with CL). In most cases, it was not possible to distinguish the event from symptoms of IBS.
The ingested dose of hydroxyanthracene derivatives is not mentioned in the publication. The
leaflet of the chemical-pharmaceutical factory F. Trenka, Vienna, Austria, indicates an
amount of 2.65 – 3.95 mg anthraquinone per tablet.
Other effects
From 1989 to 1992, 151 chronic renal failure (CRF) patients with initial serum creatinine
level of 328 +/- 92 mmol/l (3.7 mg/dL) were enrolled to compare the clinical effectiveness of
rhubarb ( Rheum palmatum L.), an ACE inhibitor as well as a combined regimen of rhubarb
and ACE inhibitor, captopril, in a prospective open-label trial. All patients were also kept on
a low-protein (0.6 g/kg/day) and low-phosphorus (10 mg/kg/day) diet. After follow up of an
average of 32.5 months (range, 15 to 62), uraemic symptoms of nausea and anorexia
improved in most of the treated patients. The frequency of reaching a serum creatinine
greater than or equal to 8 mg/dL was 54.3 % for the captopril group, 25.9 % for the rhubarb-
treated group, and 13.1 % for those receiving the combined regimen. The slope of the
reciprocal serum creatinine versus time in months suggests that the progression rate of renal
failure was slowed down in the groups of patients treated with rhubarb. Rhubarb also lowered
the cholesterol and triglyceride levels of CRF patients. The authors concluded that this effect
might be helpful in preventing the development of glomerulosclerosis (72, 73, 113).
462 patients with upper gastrointestinal bleeding took Rheum palmatum L. (Dahunag) up to a
maximum of 15.4 g herbal substance. Blood was not found any more in the faeces after
1.5 days in 97 % of the patients. The data are limited because the original Chinese
publication is not available (3).
Zhou H et al. 1990 have studied alcoholic extracted tablets of rhubarb for 10 years.
312 patients with gastric and duodenal ulcer bleeding were divided into three groups, namely,
Rheum officinale Baillon, Rheum palmatum L, and Rheum tanguticum Maxim ex Balf. By
using double-blind measurement of effect, the efficiencies of the groups appeared to be
90.7 %, 93.7 %, and 92.8 % respectively. The time taken for the stool occult blood changing
from positive into negative was 57.1, 53.4 and 56 hours respectively. The differences were
not significant (p > 0.05). The data are also limited because the language of the original
publication is Chinese and we can only focus on the English abstract (75).
Saller R et al. investigated the efficacy of a combined topical preparation with 23mg/g
rhubarb (standardised dried aqueous-ethanolic extract from the roots of Rheum palmatum L.
and Rheum officinale Baillon with 4.0 – 6.0 % hydroxyanthracene derivatives, calculated as
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rhein) and 23 mg/g sage (aqueous extract from the leaves of Salvia officinales ), of a single-
agent preparation with sage extract and of a reference treatment Zovirax® Creme
(50 mg acyclovir/g) for topical treatment of Herpes labialis in a double-blind, comparative,
randomised trial. Out of 149 patients 145 patients (111 female, 34 male) could be evaluated
by intention-to-treat analysis. 64 patients received the combination, 40 the sage cream, and
41 Zovirax cream. The mean time to crust formation in all cured patients was 7.2 days,
7.8 days, and 6.6 days respectively. The mean time to healing was 6.7 days, 7.6 days and
6.5 days respectively. No statistically significant differences could be found. There were
statistically significant differences in the course of the symptoms. For the parameter
“swelling”, at the first follow-up visit there was a significant advantage for Zovirax cream
compared to the sage cream, and for the parameter “pain”, at the 2 nd follow-up visit there was
a significant difference in favour of the combination compared to the sage cream. No
significant differences were found between the Zovirax treated and the sage treated group.
The authors concluded that the combination was as effective as Zovirax and tended to be
more active than the sage cream (76).
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
Use in children
First of all change of nutrition is recommended in constipated children with an increase in
daily fibre intake. It is recommended that children older than 2 years of age should increase
their intake of dietary fibre to an amount equal or greater than their age plus 5 g (77). The
behaviour has to modify additionally, e.g. increased physical exercise.
There are no systematic clinical data available which evaluate the use of rhubarb as a laxative
in children.
In China herbal treatment of neonatal jaundice (NNL) has been practiced for a long time.
Even to-date, a variety of herbals, including Rheum officinale (Da-huang), are still being
prescribed to jaundiced infants, often in combination with modern treatment such as
phototherapy and exchange transfusion. Their efficacy and their safety have, however, not
been tested systematically. No data are available of the exact preparation, the dose
administered and the positive and negative outcomes (78).
There are several reports of local intolerance of a high dose senna preparation on skin in
children wearing napkins. These skin irritations were bullous and comparable with skin
irritations caused by scalds (78).
According to the ESCOP and WHO monographs the use for children less than 10 years
cannot be recommended. According to the “NOTE FOR GUIDANCE ON CLINICAL
INVESTIGATION OF MEDICINAL PRODUCTS IN THE PAEDIATRIC POPULATION”
(CPMP/ICH/2711//99) of 27 July 2000 and other monographs age limit for children should
be determined to “12 years of age”.
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
There are no recent clinical investigations available, which evaluate rhubarb alone and not in
combination with other laxatives in a representative study population. 2 non-controlled
investigations of the seventies assessed the efficacy of a combination preparation in patients
with constipation. 3 g of this preparation contain 27.75 mg hydroxyanthracene derivatives,
nearly 25 % derive from rhubarb, and 0.9 g of the bulk forming agent methyl cellulose. The
daily dose was 3 to 7.6 g on average. A contribution of rhubarb to the efficacy of the
investigated product is supposable.
Two double-blinded controlled trials were also conducted with combinations which showed
positive effects if different functional disorders of the gastrointestinal tract. The ingested
doses of hydroxyanthracene derivatives derived from rhubarb are not mentioned. The
contribution of rhubarb to the efficacy cannot be assessed.
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The postulated laxative effect is mainly based on the pharmacological data, experts’ opinions
(German monograph, ESCOP monograph, WHO monograph etc.) and clinical experiences.
Clinical and pharmacological data obtained from other anthranoid-containing laxatives (we
refer to the assessment report of Cassia senna L. et Cassia angustiolia Vahl, folium) and the
2 non-controlled investigations with Laxariston® support the efficacy of this also anthranoid-
containing herbal substance for short term use in cases of occasional constipation. The
current level of evidence for “the short term use of occasional constipation” can be identified
as III.
The investigations concerning other indications than occasional constipation are insufficient
to support further indications.
Use for topical treatment of Herpes labialis in a combination with sage needs further
investigation whether the part of rhubarb is essential for the efficacy or not.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Contraindications
Rhubarb preparations should not be used by patients with hypersensitivity to rhubarb.
Furthermore rhubarb containing medicinal products should not be used in cases of intestinal
obstructions and stenosis, atony, appendicitis, inflammatory colon diseases (e.g. Crohn’s
disease, ulcerative colitis); abdominal pain of unknown origin; severe dehydration states with
water and electrolyte depletion like all anthranoid-containing laxatives.
II.3.3.2
Special warning/precautions for use
Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products
inducing QT-prolongation, diuretics, corticosteroids or liquorice root, have to consult a
doctor before taking rhubarb preparations concomitantly.
Like all laxatives, rhubarb containing medicinal products should not be taken by patients
suffering from faecal impaction and undiagnosed, acute or persistent gastro-intestinal
complaints, e.g. abdominal pain, nausea and vomiting unless advised by a doctor because
these symptoms can be signs of potential or existing intestinal blockage (ileus).
If laxatives are needed every day the cause of the constipation should be investigated. Long-
term use of stimulating laxatives should be avoided.
Use for more than 1 - 2 weeks requires medical supervision. Rhubarb preparations should
only be used if a therapeutic effect cannot be achieved by a change of diet or the
administration of bulk forming agents.
See also point 3.3.5 drug abuse.
II.3.3.3
Adverse events
Like all anthranoid-containing laxatives rhubarb preparations may produce abdominal pain
and colicky gastrointestinal symptoms and passage of liquid stools, in particular in patients
with irritable colon. However, these symptoms may also occur generally as a consequence of
individual overdosage. In such cases dose reduction is necessary. The correct individual dose
is the smallest required to produce a comfortable soft-formed motion (60).
Like mentioned above hypersensitive reactions may occur.
Chronic use may lead to disorders in water equilibrium and electrolyte metabolism.
Chronic use may result in albuminuria and haematuria.
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Furthermore, use over a long period may lead to pigmentation of the intestinal mucosa
(pseudomelanosis coli), which usually recedes when the patient stops taking the preparation.
Yellow or red-brown (pH dependent) discolouration of urine by metabolites, which is not
clinically significant, may occur during the treatment.
1 case of development of generalised flush 2 h after drinking a 10% aqueous solution of radix
e rhizome rhei for constipation is described (80).
II.3.3.4
Overdose
Like for all anthranoid-containing laxatives the major symptoms of overdose / abuse are
griping and severe diarrhoea with consequent losses of fluid and electrolyte, which should be
replaced. Diarrhoea may cause potassium depletion, in particular. Potassium depletion may
lead to cardiac disorders and muscular asthenia, particularly where cardiac glycosides,
diuretics or corticosteroids are being taken at the same time.
Treatment should be supportive with generous amounts of fluid. Electrolytes, especially
potassium, should be monitored. This is especially important in the elderly. Furthermore
chronic ingested overdoses of anthranoid containing medicinal products may lead to toxic
hepatitis (we refer to the assessment report of senna and cascara).
Yuen MF et al. 2006 studied the clinical outcome of traditional Chinese medicine (TCM)-
induced hepatotoxicity in chronic hepatitis B patients. 45 chronic hepatitis B patients in 2004
with liver dysfunction requiring hospitalisation in the Queen Mary Hospital, The University
of Hong Kong, Hong Kong, were screened prospectively for traditional Chinese medicine
intake. The inclusion criteria were HBsAg positivity, intake of TCM within 6 months prior to
admission, elevated bilirubin levels of more than two times upper limit of normal or elevated
level of at least one of the liver enzymes. Patients with other possible cause for
hepatotoxicity, e.g. any other virus hepatitis, alcohol intake, hepatotoxic medication were
excluded. Seven patients had liver derangement attributable to the intake of TCM. Possibly
hepatotoxic components were identified by extensive literature research. Rheum palmatum L.
and Cassia obtusifolia L. were identified to be one of the hepatotoxic components, though
these components were taken together with more than ten other Chinese herbal substances.
From our point of view the causality cannot be assessed definitely (81).
II.3.3.5
Drug abuse
It cannot be assessed definitely, if a longer than a brief period of treatment with stimulating
laxatives leads to dependence requiring increasing quantities of the medicinal product, an
atonic colon with impaired function and aggravation of the constipation.
Müller-Lissner 2005 (82) concludes that the arguments in favour of laxative-induced damage
to the autonomous nervous system of the colon are based on poorly documented experiments
and that the investigations that do not support such damage are well done. The cited
references (Smith B 1968 (83); Riemann JF et al. 1980 (84) and 1982 (85); Berkelhammer C
et al. 2002 (86); Meisel JL et al. 1977 (87); Pockros PJ et al. 1985 (88)) show abnormalities
observed in humans (damage to enteric nerves, smooth muscle atrophy; distension or
ballooning of axons, reduction of nerv-specific cell structures and increase in lysosomes, and
sometimes a total degeneration of whole nerve fibers; short-lived superficial damage to the
mucosa). They are uncontrolled observations and therefore the author concludes that the
cause of these damages can also be the constipation itself or pre-existing changes of unknown
etiology.
The only study comparing the morphology of the autonomous nervous system of constipated
patients taking anthraquinones (aloe) to that of an appropriate control group of constipated
patients without laxative intake (Riecken EO et al. 1990 (89)) does not support the hypothesis
that anthraquinone containing laxatives are able to provoke relevant degenerative changes in
the colonic nerve tissue. But this investigation was only conducted in 11 matched pairs only.
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For safety concerns we inform the patients that if stimulating laxatives are taken for longer
than a brief period of treatment, this may lead to impaired function of the intestine and
dependence on laxatives.
Controversial discussion is done whether chronic use of anthranoid-containing laxatives
promotes the development of colorectal carcinomas.
Siegers C-P et al. 1993 (90) reported about a retrospective study of 3,049 patients who
underwent diagnostic colorectal endoscopy. The incidence of pseudomelanosis coli was
3.13% in patients without pathological changes. In those with colorectal adenomas, the
incidence increased to 8.64% (p<0.01), and in those with colorectal carcinomas it was 3.29%.
This lower rate was probably caused by incomplete documentation of pseudomelanosis coli
in those with carcinoma. In a prospective study of 1,095 patients, the incidence of
pseudomelanosis coli was 6.9% in patients with no abnormality seen on endoscopy, 9.8%
(p=0.068) in patients with adenomas and 18.6% in patients with colorectal carcinomas. From
these data a relative risk of 3.04 (1.18, 4.9; 95% confidence interval) can be calculated for
colorectal cancer as a result of anthranoid laxative abuse if the pseudomelanosis coli in
patients with no abnormality is calculated with 1 %.
Kune GA et al. 1988 (91) and Kune GA 1993 (92) reported of the “Melbourne Colorectal
Cancer Study”. Commercial laxative use as a risk factor in colorectal cancer was investigated
as one part of this large population based epidemiological study of colorectal incidence,
aetiology and survival. Commercial laxative use was similar in 685 colorectal cancer patients
and 723 age/sex matched community based controls. Also, when laxatives were subdivided
into various groups containing anthraquinones, phenolphthalein, mineral salts and others,
previous laxative intake was similar between cases and controls. Previous use of
anthraquinone laxatives and of phenolphthalein containing laxatives was not associated with
the risk of colorectal cancer. Furthermore the results of this study suggest that chronic
constipation, diarrhoea, and the frequency and consistency of bowel motions are unlikely to
be aetiologic factors in the development of colorectal cancer. They indicate that it is the diet
and not the constipation that is associated with the risk of large-bowel cancer. Additionally, a
highly statistically significant association (p=0.02) was found with the risk of colorectal
cancer in those who reported constipation and also had a high fat intake.
In a retrospective study a cohort of 2,277 patients was defined by colonoscopy. Among other
factors Nusko G et al. 1993 (93) tested whether in these patients laxative use or the
endoscopially diagnosed presence of melanosis coli were risk factors related to colorectal
neoplasm. In comparison to patients taking no laxatives there was no significant increase in
colorectal cancer rate either in laxatives users or in patients with melanosis coli. However,
there was a statistically significant association between the occurrence of colorectal
adenomas and laxative use (relative risk of all patients exposed to laxatives = 1.72; of
patients exposed to laxatives without melanosis coli = 1.47). The relative risk of adenoma
development in patients with melanosis coli was 2.19. Taking into account that polyps can be
diagnosed in the dark mucosa of melanosis coli patients more easily, the authors concluded
that even this relative risk of 2.19 seems to be related to a generally enhanced risk of laxative
intake rather than to a special group of (anthranoid containing) laxatives.
Sonnenberg A and Muller AD 1993 (94) performed a meta-analysis, since individual case-
control studies have failed to resolve the question whether constipation and use of cathartics
represent significant risk factors of colorectal cancer. The analysis of 14 previously (from
1954 to 1988) published case-control studies revealed statistically significant risks for
colorectal cancer associated with both constipation and use of cathartics, the pooled odds
ratios and their 95 percent confidence intervals being 1.48 (1.32-1.66) and 1.46 (1.33-1.61),
respectively. The increased risk applied similarly to both sexes, it was higher in cancer of the
colon than rectum. Since constipation and cathartics are associated with much lower odds
ratio than various dietary components, such as fat, meat, alcohol, and low-vegetable or low-
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residue diets, the authors concluded that their risks reflects the confounding influence of
underlying dietary habits.
Loew D et al. 1994 (95) conducted a comparative study involving 423 patients with
colorectal neoplasms and 522 patients with benign proctologic disorders who were regular
users of laxatives for bowel regulation. A pseudomelanosis coli (PMC) test was used as an
indicator of exposure to anthranoid-containing laxatives to determine if these preparations
were potential colorectal carcinogenics. Results indicated no significant difference of the
PMC rates between carcinoma (6.1%) and the control groups (4.2%) (p</=0.197).
Jacobs EJ et White E 1998 (96) examined the associations of colon cancer with constipation
and use of commercial laxatives in a case-control study (424 incident cases and 414 random-
digital-dial controls). Constipation was defined by “feeling constipated to the point of having
to take something”. The adjusted relative risk (RR) was 2.0 [95% confidence interval (CI) =
1.2-3.6] for constipation 12-51 times per year, and 4.4 (95%CI = 2.1-8.9) for constipation 52
or more times a year. Cumulative lifetime use of commercial laxatives was also associated
with increased risk of colon cancer. When adjusted for constipation, commercial laxative use
was no longer associated with increased risk (RR = 0.3, 95%CI = 0.1-0.9 for less than
350 uses; RR = 0.9, 95% CI = 0.4-2.3 for 350 or more uses). The association with
constipation remained. In this study no subject reported use of anthranoid-containing
laxatives.
Nusko G et al. 2000 (97) performed a prospective case control study at the University of
Erlangen to investigate the risk of anthranoid-containing laxative use for the development of
colorectal adenomas or carcinomas. A total of 202 patients with newly diagnosed colorectal
carcinomas, 114 patients with adenomatous polyp, and 238 patients (controls) with no
colorectal neoplasm who had been referred for total colonoscopy were studied. The use of
anthranoid preparations was assessed by standardised interview, and endoscopically visible
or microscopic melanosis coli was studied by histopathological examination. There was no
statistically significant risk of anthranoid use for the development of colorectal adenomas
(unadjusted odds ratio 1.0; 95% CI 0.5-1.9) or carcinomas (unadjusted odds ratio 1.0; 95% CI
0.6-1.8). Even after adjustment for the risk factors age, sex, and blood in the stools by logistic
regression analysis the odds ratio for adenomas was 0.84 (95% CI 0.4-1.7) and for
carcinomas 0.93 (95% CI 0.5-1.7). Also, there were no differences between the patient and
control groups for duration of intake. Macroscopic and high grade microscopic melanosis coli
were not significant risk factors for the development of adenomas or carcinomas.
Willems M et al. 2003 (71) describe a case of melanosis coli, which occurred in a 39-year-old
liver transplant patient who took an over-the-counter product containing aloe, rheum and
frangula. The typical brownish pigmentation of the colonic mucosa developed in a period of
ten months. The anthranoid medication was stopped and follow-up colonoscopy one year
later showed normal looking mucosa once more. However, in contrast to previous
examinations, a sessile polypoid lesion was found in the transverse colon. Histology showed
tubulovillous adenoma with extensive low-grade dysplasia. From a practical point of view,
the authors discourage from use of anthranoid-containing laxatives, although they stated that
“the role of the short-term use of the laxative in the development of this patient’s adenoma is
highly speculative” because he clearly was at risk for developing colonic neoplasm
considering his long-standing ulcerative colitis in association with primary sclerosing
cholangitis and the use of immunosuppressive medication after liver transplantation.
Furthermore it would remain controversial whether melanosis coli is associated with an
increased risk for colorectal cancer because of controversial results of several investigations.
Roberts MC et al. 2003 (98) conducted a population-based, case-control study with equal
representation by blacks. Constipation, defined as fewer than three reported bowel
movements per week, was associated with a greater than two-fold risk for colon cancer (OR
2.36; 95% CI = 1.41-3.93) adjusted for age, race, sex, and relevant confounders. The OR for
constipation was slightly higher for distal than for proximal colon cancers. There was no
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association with laxative use (OR 0.88; 95% CI = 0.69-1.11). The authors do not explicitly
mention anthraquinone-containing laxatives. They mentioned the group “stimulants, fibers,
natural remedies, stool softeners, oils, osmotic agents, enemas, suppositories, and unknown”.
unknown”. In particular they mention phenolphthalein and magnesium.
Nilsson SE et al. 2004 (99) examined the impact of constipation and laxative treatment on the
blood levels of homocysteine, folate and cobalamine in a population-based sample of aged
people. Elevated plasma homocysteine might indicate an increased risk of cancer, and
cardiovascular and neurological diseases. The homocysteine level depends on the supply of
folate and cobalamine, and constipation and/or laxative treatment might compromise this
supply. The study was based on biochemical tests in 341 females and 183 males aged 82
years and older. The concentrations of homocysteine (plasma), folate, cobalamine and urea
(serum) were measured in subjects with and without ongoing treatment with laxative
products. Values were adjusted for age, gender and frailty, as well as for clinical diagnoses
and medicinal therapies known to affect homocysteine levels. Homocysteine levels were
increased and those of folate reduced in aged subjects on laxatives. Homocysteine remained
elevated after adjusting for frailty and various neurological disorders. There was no
significant effect on homocysteine and folate in constipated subjects without laxatives.
Jae Sik Joo et al. 1998 (100) investigated changes occurring on barium enema in patients
ingesting stimulant laxatives. The study consisted of two parts. In part 1, a retrospective
review of consecutive barium enemas performed on two groups of patients with chronic
constipation (group 1, stimulant laxative use (n=29); group 2, no stimulant laxative use
(n=26)) was presented to a radiologist who was blinded to the patient group. A data sheet
containing classic descriptions of cathartic colon (historic term for the anatomic alteration of
the colon secondary to chronic stimulant laxative use) was completed for each study. Chronic
stimulant laxative use was defined as stimulant ingestion more than three times per week for
1 year or longer. To confirm the findings of the retrospective study, 18 consecutive patients
who were chronic stimulant laxative users underwent barium enema examination, and data
sheets for cathartic colon were completed by another radiologist (part 2). Colonic redundancy
(group 1, 34.5%; group 2, 19.2%) and dilatation (group 1, 44.8%; group 2, 23.1 %) were
frequent radiographic findings in both patient groups and were not significantly different in
the two groups. Loss of haustral folds, however, was a common finding in group 1 (27.6%)
but was not seen in group 2 (p<0.005). Loss of haustral markings occurred in 15 (40.5%) of
the total stimulant laxative users in the two parts of the study and was seen in the left colon of
6 (40%) patients, in the right colon of 2 (13.3%) patients, in the transverse colon of 5 (33.3%)
patients, and in the entire colon of 2 (13.3%) patients. Loss of haustra was seen in patients
chronically ingesting bisacodyl, phenolphthalein, senna, and casanthranol. The authors
conclude that long-term stimulant laxative use results in anatomic changes in the colon
characterised by loss of haustral folds, a finding that suggest neuronal injury or damage to
colonic longitudinal musculature caused by these agents.
II.3.3.6
Safety in special populations and situations
When rhubarb preparations are administered to incontinent adults, pads should be changed
more frequently to prevent extended skin contact with faeces because of the experiences in
children wearing napkins.
Patients with kidney disorders should be aware of possible electrolyte balance.
II.3.3.6.1 Drug interactions
Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products
inducing QT-prolongation, diuretics, corticosteroids or liquorice root, have to consult a
doctor before taking rhubarb preparations concomitantly.
Chronic use or abuse of rhubarb preparations may lead to hypokalaemia like the abuse of all
anthranoid-containing laxatives. This hypokalaemia and the increased loss of potassium may
© EMEA 2008
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interfere with cardiac glycosides, antiarrhythmic medicinal products, and medicinal products
inducing QT-prolongation. Concomitant use with diuretics, corticosteroids and liquorice root
may aggravate electrolyte imbalance.
II.3.3.6.2 Use in pregnancy and lactation
There are no recent investigations available.
Like mentioned above (69), 95 pregnant women suffering from constipation were treated
with a combination preparation containing rhubarb. Most of them were in the third trimenon.
12 women were gynaecologically treated because of a threatening abortion. Only one of these
women miscarried. No information about the state of the new-borns is given in the
publication.
In theory, it is possible that reflex stimulation might occur, involving not only the colon but
also uterine muscles and then might lead to the development of hyperaemia in the pelvic
region and to miscarriage as a result of neuromuscular stimulation of uterine muscles.
Therefore anthranoid-containing laxatives were misused as an abortifacient agent. Animal
experiments demonstrated that placental passage of rhein is small.
Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids (e.g.
emodin, chrysophanol, and physcion). In vitro assays overestimate the potential hazard from
exposure and must be reevaluated by in vivo experiments. The NOAELs for emodin defined
by Jahnke GD are twice the decimal power and above the maximum daily dose of
hydroxyanthracene derivatives (30 mg).
In vivo studies of the crude senna herbal substance in rat hepatocytes (chromosome
aberration test, mouse spot test, in vivo/in vitro UDS (unscheduled DNA synthesis); showed
no evidence of any genetic effects (Heidemann 1993 (49)).
Rhubarb and also senna mainly contain dianthron-glycosides, cascara and also frangula and
aloe mainly contain 10-glycosyl-anthrones, anthrachinon- and anthron-glycosides. The risk of
hydrolysis in aglycones and consequently systemic absorption in the gastrointestinal tract is
higher for the anthrachinon- and anthron-glycosides than for the dianthron-glycosides due to
the different chemical structures. The amount of aglycones represents the possible genotoxic
risk. Even for this reason cascara, frangula and aloe seem to be less appropriate for sensitive
patient groups like pregnant women than senna and rhubarb (103).
On the other hand there only exist older preclinical data which refer to a special extract of
senna pods containing 1.4 to 3.5 % of anthranoids, corresponding to 0.9 to 2.3 % of potential
rhein, 0.05 to 0.15% of potential aloe-emodin and 0.001 to 0.006% of potential emodin or to
isolated active constituents, rhein or sennosides A and B. No cytotoxic, toxic, embryotoxic or
genotoxic effect could be found in Chromosome Aberration Assay in Bone Marrow Cells of
the Rat, Micronucleus Test in Rats, Mouse Spot Test. Therefore the monographs on senna
recommend for such a specified senna extract that the use is to be avoided just during the first
trimester but with the advice that the further use during pregnancy should only be an
intermittent and just if other actions like behavioural modification, dietary changes and use of
bulk forming agents fail. Use in pregnancy cannot be recommended for all other senna
preparations (we refer to the senna assessment report).
Such data are not available for rhubarb or any preparation thereof. Therefore use during
pregnancy cannot be recommended. Furthermore other actions like behavioural modification,
dietary changes and use of bulk forming agents should be the first actions taken during
pregnancy to treat constipation.
Use during lactation is not recommended, as there are insufficient data on the excretion of
metabolites in breast milk, too. Investigations with a “standardised senna laxative”
(Agiolax®), which also contains Plantago ovata seeds/husks as bulk substances, showed that
© EMEA 2008
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small amounts of active metabolites (rhein) are excreted in breast milk. A laxative effect in
breast fed babies has not been reported (104).
Bright E et al. 1970 reported when rhubarb was taken by lactating mothers, the amount
excreted in the milk was too small to affect the baby (105). There is no detailed information
available.
II.3.3.7
Assessor’s overall conclusions on clinical safety
Because of the possible genotoxic or tumourigenic risk in experimental investigations and the
results of Siegers 1993 a pharmacovigilance actions for anthranoid-containing laxatives (60)
were initiated in Germany 1996. The daily dose and the duration of administration were
limited. Children, pregnant women and nursing mothers were excluded from the application
of rhubarb containing laxatives.
The results of the more recent studies are inconsistent and the possibility of a carcinogenic
risk of long-term use of anthranoid-containing laxatives cannot be assessed definitely. Some
studies revealed a risk for colorectal cancer associated with the use of anthraquinone-
containing laxatives, some studies did not. However, a risk was also revealed for constipation
itself and underlying dietary habits. Further investigations are needed to assess the
carcinogenic risk definitely.
In his review article van Gorkom BA 1999 (101) concluded that although the short-term use
of anthranoid laxatives is generally safe, long-term use cannot be recommended.
In “Goodman & Gilman’s The Pharmacological Basis of Therapeutics” (11 th edition 2006)
(102) the following conclusion is drawn: “Regardless of whether a definitive causal
relationship can be demonstrated between the use of anthraquinone laxatives and colonic
pathology, these agents should not be recommended for chronic or long-term use.”
Taking all available data in consideration, the conditions determined in the German
pharmacovigilance actions for anthranoid-containing laxatives (60) have to be maintained for
the moment.
Within a period of 4 – 13 months long-term administration of anthranoid-containing
medicinal products leads to pseudomelanosis coli – pigmentation of the gut wall in the
caecum and colon. This condition is produced by the accumulation of macrophages that have
stored a brown pigment from the breakdown products of anthranoid (probably lipofuscin) and
consequently cause the mucosa to appear brown to blackish-brown in colour. Prevalence
among patients with chronic constipation is reported to be 12 – 31%, and 62% following
chronic ingestion of anthranoid-containing laxatives. This finding disappears 6 – 12 months
after halting laxative administration.
Long-term stimulant laxative use may result in anatomic changes in the colon. For safety
concerns we inform the patients that if stimulating laxatives are taken for longer than a brief
period of treatment, this may lead to impaired function of the intestine and dependence on
laxatives.
II.4
T RADITIONAL USE
Rhubarb was medically used in China long time ago. Rhubarb is already mentioned in an
herbal book of the 27 th century BC (106). The Chinese Materia Medica of 1998 (112)
described the traditional use as follows: “Purging heat and loosing the bowels, used for
retention of the feces and abdominal pain, fever with constipation and dysentery with
inadequate discharge of the bowels; reducing heat in the blood and counteracting toxicity,
used for hematemesis and epistaxis, inflammation of the eyes and swelling of the throat and
gum due to heat in the blood; jaundice caused by damp-heat. Externally used for scalds and
burns; eliminating blood stasis, traumatic injuries, hemorrhage from the upper
gastrointestinal tract, appendicitis with abdominal pain, boils, sores and abscess.”
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In Europe Pedanios Dioskurides, a Greek physician and pharmacologist of the 1 st century BC,
mentioned the use of Rheum rhaponticum in his
‘Materia Medica” for several gastrointestinal and urogenital disorders, for periodic fever and
for bites of poisonous animals (107).
Paracelsus (1494 – 1541) used rhubarb as a laxative and as a purgative for the gall. Lonicerus
also indicated the use as a purgative of the liver and for fever in his herbal book from 1564.
The purgative effects were also described by Bock (1565) and Matthiolus (1626). Matthiolus
also used rhubarb for dysentery with bloody diarrhoea, haematemesis and for
hypermenorrhoea. The use as a laxative and purgative, but also the use as an antidiarrhoeal
agent was confirmed by von Haller (1755) and by Weinmann (1745). Weimann also used
rhubarb as a tonic (106).
Hecker (1814) favoured the use for diarrhoea more than for constipation. He also used
rhubarb as a tonic and a styptic.The antidiarrhoeal and styptic effects are only achieved by
small doses (0.1 -0.3 g), which shall inhibit fermentation process, gastric acid and mucus
secretion and improve appetite (106). This is confirmed by Weiss 1974 (109) and Martindale
1967 and 1977, but the recommended dose in Martindale is 0.2 – 1 g: “Rhubarb is a mild
anthraquinone purgative. It differs from other anthraquinone purgatives in that it exerts an
adstringent action after purgation; with small doses the adstringent action predominates and
rhubarb is therefore used as an adstringent bitter and occasionally in the treatment of
diarrhoea.” (110, 108)
Clarus (1860) (106) and Weiss 1974 (109) ascribed choleric properties to rhubarb.
Hager 1927 (111) indicated that rhubarb has a laxative effect when administered in repeated
or in higher doses. Rhubarb is also used as a stomachic and to improve appetite, for
gastrointestinal catarrh and liver and spleen diseases.
According to Madaus (106) rhubarb was used as a laxative, a stomachic and for liver and
spleen diseases in Denmark. The bark of the root was used for cough and cold in Lithuania.
In Austria rhubarb was used as a laxative and purgative and in Hungary also a laxative.
II.4.1.1
Assessor’s overall conclusions on traditional use
The use of rhubarb as a laxative is mentioned in nearly all references. In consequence of the
laxative properties the herbal substance was also used as a purgative. The use as a laxative is
accepted as a well established use.
In former times purification often was the first step to treat a lot of diseases. Such a procedure
is obsolete now. Furthermore there are no plausible pharmacological data for the purification
of other organs than the bowel.
Due to the content of tannin agents rhubarb was also used for diarrhoea and dysentery and as
a styptic. The dose administered shall be smaller than for the use as laxative but the data are
not consistent.
Due to the possible risks traditional use cannot be accepted.
II.5
A SSESSOR S O VERALL C ONCLUSIONS
The postulated laxative effect is mainly based on the pharmacological data, experts’ opinions
(German monograph, ESCOP monograph, WHO monograph etc.) and clinical experiences.
Clinical and pharmacological data obtained from other anthranoid-containing laxatives (we
refer to the assessment report of Cassia senna L. et Cassia angustiolia Vahl, folium) and the
2 non-controlled investigations with Laxariston® support the efficacy of this also anthranoid-
containing herbal substance for short term use in cases of occasional constipation. The
current level of evidence for “the short term use of occasional constipation” can be identified
as III.
© EMEA 2008
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The investigations concerning other indications than occasional constipation are insufficient
to support further indications.
There are two investigations dealing with the treatment of gastrointestinal bleeding. The data
available are limited and cannot be assessed definitely. A well-established use cannot be
granted.
Use for topical treatment of Herpes labialis in a combination with sage needs further
investigation whether the part of rhubarb is essential for the efficacy or not. Furthermore such
a use does not fulfil the criteria for well-established use according to the Directive
2001/83/EC. This must be regarded as a new indication and all documents for a full
application have to be submitted.
Due to the possible risks traditional use as described above cannot be accepted.
The conditions determined in the pharmacovigilance actions for anthranoid-containing
laxatives have to be maintained for the moment because further investigations are needed to
clarify the carcinogenic risk. The results of the more recent studies are inconsistent.
However, a risk was also revealed for constipation itself and underlying dietary habits.
The use in children below the age of 12 years and during pregnancy and lactation is not
recommended.
In consideration of the recommendations in the monograph the benefit-risk-ratio is positive
and the short term use of occasional constipation can be regarded as safe.
III.
ANNEXES
III.1
P ROPOSED C OMMUNITY H ERBAL M ONOGRAPHS FOR <N AME OF H ERBAL
S UBSTANCE ( S ), H ERBAL P REPARATION ( S ) OR C OMBINATIONS THEREOF 4 5 >
III.2
P ROPOSAL FOR L IST E NTRY ON <H ERBAL S UBSTANCE ( S ), H ERBAL P REPARATION ( S ) OR
C OMBINATIONS T HEREOF WITH T RADITIONAL U SE > 6
III.3
L ITERATURE R EFERENCES
4 According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2)
5 According to the ‘Procedure for the preparation of Community monographs for herbal medicinal products with
well-established medicinal use’ (EMEA/HMPC/182352/2005 Rev.2)
6 According to the ‘Structure of the Community list of herbal substances, preparations and combinations thereof
for use in traditional herbal medicinal products’ (EMEA/HMPC/100824/2005 Rev.2)
© EMEA 2008
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Source: European Medicines Agency



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