COMMUNITY HERBAL MONOGRAPH ON
CASSIA SENNA
L. AND
CASSIA ANGUSTIFOLIA
VAHL, FOLIUM
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10(a) of Directive
2001/83/EC, as amended
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC, as
amended
Cassia senna
L. (
C. acutifolia
Delile) [known as
Alexandrian or Khartoum senna] or
Cassia angustifolia
Vahl [known as Tinnevelly
senna], folium (senna leaf)
•
Herbal substance
dried leaflets, standardised
•
Herbal preparation
standardised herbal preparations thereof
Well-established use
Traditional use
Standardised herbal substance or herbal
preparation for oral use in solid or liquid dosage
forms.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Herbal medicinal product for short-term use in
cases of occasional constipation.
None
2
The material complies with the Ph. Eur. monograph.
3
The declaration of the active substance(s) should be in accordance with relevant herbal quality guidance .
©
EMEA 2007
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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 15 – 30
mg hydroxyanthracene derivatives, calculated as
sennoside B, to be taken once daily at night.
Normally it is sufficient to take this medicinal
product up to two to three times a week.
Not recommended for use in children under 12
years of age (see section 4.3 Contraindications).
The pharmaceutical form must allow lower
dosages.
Method of administration
As described in the package leaflet corresponding
to the pharmaceutical form e.g. tea bag.
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.
4.3.
Contraindications
Well-established use
Traditional use
Known 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.
©
EMEA 2007
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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, adrenocorticosteroids
or liquorice root, have to consult a doctor before
taking senna leaves concomitantly.
Like all laxatives, senna leaves 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. Senna leaf 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 senna leaf 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.
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,
adrenocorticosteroids and liquorice root) may
enhance electrolyte imbalance.
©
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4.6 Pregnancy and lactation
Well-established use
Traditional use
Pregnancy
Wording for extracts specified as those
investigated (see section 5.3 Preclinical safety
data):
There are no reports of undesirable or damaging
effects during pregnancy and on the foetus when
used at the recommended dosage.
As a consequence of experimental data concerning
a genotoxic risk of several anthranoids, e.g.
emodin and aloe-emodin, the use is to be avoided
during the first trimester. Senna leaves should only
be used intermittently and if other actions like
behavioural modification, dietary changes and use
of bulk forming agents failed.
Wording for all other preparations:
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. emodin and aloe-emodin, 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.
Small amounts of active metabolites (rhein) are
excreted in breast milk. 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 (pruritus, urticaria, local
or generalised exanthema) may occur.
Senna leaves may produce abdominal pain and
spasm and passage of liquid stools, in particular in
patients with irritable colon. However, these
symptoms may also occur generally as a
consequence of individual overdose. 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 especially cause
potassium depletion, which may lead to cardiac
disorders and muscular asthenia, particularly
where cardiac glycosides, diuretics,
adrenocorticosteroids 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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5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Pharmaco-therapeutic group: contact laxatives
ATC-code: A 06 AB
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
1,8-dihydroxyanthracene derivatives possess a
laxative effect. The β-Ο-linked glycosides
(sennosides) are not absorbed in the upper gut;
they are converted by bacteria of the large
intestine into the active metabolite (rhein
anthrone).
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.
5.2. Pharmacokinetic properties
Well-established use
Traditional use
The β-Ο-linked glycosides (sennosides) are neither
absorbed in the upper gut nor split by human
digestive enzymes. They are converted by the
bacteria of the large intestine into the active
metabolite (rhein anthrone). Aglyca are absorbed
in the upper gut. Animal experiments with radio-
labeled rhein anthrone administered directly into
the caecum demonstrated absorption < 10%. In
contact with oxygen, rhein anthrone is oxidised
into rhein and sennidins, which can be found in the
blood, mainly in the form of glucuronides and
sulphates. After oral administration of sennosides,
3 - 6% of the metabolites are excreted in urine;
some are excreted in bile.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
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Most of the sennosides (ca. 90%) are excreted in
faeces as polymers (polyquinones) together with 2
- 6% of unchanged sennosides, sennidins, rhein
anthrone and rhein. In human pharmacokinetic
studies with senna pods powder (20 mg
sennosides), administered orally for 7 days, a
maximum concentration of 100 ng rhein/ml was
found in the blood. An accumulation of rhein was
not observed. Active metabolites, e.g. 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
There are no new, systematic preclinical tests for
senna leaves or preparations thereof. Data derive
from investigations with senna pods. Since the
spectrum of constituents of senna leaf and fruit is
comparable these data can be transferred to senna
leaves. Most data refer to extracts 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 isolated active
constituents, e.g. rhein or sennosides A and B. The
acute toxicity of senna pods, specified extracts
thereof, as well as of sennosides in rats and mice
was low after oral treatment.
As a result of investigations with parenteral
application in mice, extracts are supposed to
possess a higher toxicity than purified glycosides,
possibly due to the content of aglyca.
In a 90-day rat study, senna pods were
administered at dose levels from 100 mg/kg up to
1,500 mg/kg. The tested drug contained 1.83 %
sennosides A-D, 1.6 % potential rhein, 0.11 %
potential aloe-emodin and 0.014 % potential
emodin. In all groups epithelial hyperplasia of the
large intestine of minor degree was found and was
reversible within the 8-week recovery period. The
hyperplastic lesions of the forestomach epithelium
were reversible as well. Dose-dependent tubular
basophilia and epithelial hypertrophy of the
kidneys were seen at a dose of, or greater than 300
mg/kg per day without functional affection. These
changes were also reversible. Storage of a brown
tubular pigment led to a dark discoloration of the
renal surface and still remained to a lesser degree
after the recovery period. No alterations were seen
in the colonic nervous plexus. A no-observable-
effect-level (NOEL) could not be obtained in this
study.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
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A 104-week study on rats of both genders did not
reveal any carcinogenic effects with the same
senna pods preparation at oral dosages of up to
300 mg/kg.
In addition a specified senna extract given orally
for 2 years was not carcinogenic in male or female
rats. The extract investigated contained
approximately 40.8% of anthranoids from which
35% were sennosides, corresponding to about
25.2% of potential rhein, 2.3% of potential aloe-
emodin and 0.007% of potential emodin and 142
ppm free aloe-emodin and 9 ppm free emodin.
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.
Sennosides displayed no specific toxicity when
tested at doses up to 500 mg/kg in dogs for 4
weeks and up to 100 mg/kg in rats for 6 months.
There was no evidence of any embryolethal,
teratogenic or foetotoxic actions in rats or rabbits
after oral treatment with sennosides. Furthermore,
there was no effect on the postnatal development
of young rats, on rearing behaviour of dams or on
male and female fertility in rats. Data for herbal
preparations are not available.
An extract and aloe-emodin were mutagenic in
in
vitro
tests, sennoside A, B and rhein gave negative
results. Comprehensive
in vivo
examinations of a
defined extract of senna pods were negative.
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.
Well-established use
Traditional use
Not applicable.
1 March 2007
©
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Assessment Report
T
ABLE OF CONTENTS
I.
Introduction
3
II. Clinical Pharacology
3
II.1 Pharacokinetics
3
II.1.1 Phytochemical characterisation
3
II.1.2 Absorption, metabolism and excretion
4
II.1.3 Progress of action
5
II.2 Pharacodynaics
5
II.2.1 Mode of action
5
•
Laxative effect
5
II.2.2 Interactions
7
III. Clinical Efficacy
7
III.1 Dosage
7
III.2 Clinical studies
8
III.2.1 Constipation
8
III.2.2 Irritable bowel syndrome
10
III.3 Clinical studies in special populations
15
III.3.1 Use in children
15
III.3.2 Use during pregnancy and lactation
16
III.4 Traditional use
17
IV. Safety
19
IV.1 Toxic, genotoxic and cancerogenic risk
19
IV.1.1 Preclinical Data
19
IV.1.3 Conclusion
25
IV.2 Contraindications
26
IV.3 Special warnings and precautions for use
26
IV.4 Undesirable effects
27
IV.5 Interactions
28
IV.6 Overdose
28
V. Overall conclusion
30
Community herbal monograph
annex
References
annex
©EMEA 2007
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III.2.3 Bowel cleansing
11
IV.1.2 Clinical Data
23
I.
Introduction
This assessment report reviews the scientific data available for senna leaves (
Cassia senna
L. (
C.
acutifolia
Delile)
et
Cassia angustifolia
Vahl), primarily the clinical data. The core-SPC for Sennae
folium established in 1994 by the Committee for Proprietary Medicinal Products (CPMP) was taken
into consideration. This report was prepared on the basis of the expert-reports presented in 2002 for an
herbal medicinal product containing senna leaves as the active pharmaceutical ingredients. The report ,
reviews also the literature presented by the European Scientific Cooperative on Phytotherapy
(ESCOP) to support the monographs “Sennae folium (Senna Leaf)” (94), “Sennae fructus acutifoliae
(Alexandrian Senna Pods)” (95) and “Sennae fructus angustifoliae (Tinnevelley Senna Pods)” (96)
(ESCOP Monographs, second edition 2003). The report takes also into account the literature presented
by the World Health Organization (WHO) for the monographs “Folium Sennae” and “Fructus
Sennae”.
Since the spectrum of constituents of senna leaf is comparable to that of senna fruit, this report also
considers scientific data available for senna fruits (pods).
Constipation is a common complaint in 1 – 6% of the middle-aged population and 20 – 80 % of the
elderly people, and may be treated by laxatives. Constipation also tends to be more prevalent among
women. Functional constipation is the most common type without any specific aetiology (1). The most
commonly used laxatives are either stimulant preparations (containing anthracenic derivatives from
senna, frangula or cascara), lubricant laxatives (e.g mineral oils) or bulk forming agents.
Preparations based on senna plants are among the most commonly used herbal laxatives (2, 3). Senna
has been used for medicinal purposes for centuries (4). It was introduced into European medicine by
the Arabs in the 9
th
or 10
th
century. Its laxative properties were already known at that time. The leaves
and fruits of the senna plant were used to an equal extent (5).
According to the CPMP core-SPC, senna leaves are intended “for short-term use in cases of occasional
constipation”. This indication is substantiated by extensive empirical data (derived from research into
the constituents and their pharmacology) and by clinical data.
Senna leaves preparations have to be regarded as herbal medicinal products with a “well-established
medicinal use” in this indication with respect to the application of Directive 2001/83/EC of the
Parliament and of the Council on the Community code relating to medicinal products for human use as
amended.
II.
CLINICAL PHARMACOLOGY
II.1 Pharmacokinetics
II.1.1 Phytochemicalcharacterisation
Senna leaves consist of the dried leaflets of
Cassia senna
L. (
Cassia acutifolia
Delile), known as
Alexandrian or Khartoum senna, or
Cassia angustifolia
Vahl, known as Tinnevelly senna, or a mixture
of the two species. The active constituents are the anthranoids that are present in the leaf of the herbal
substance as dianthrones (75 – 80 %) and as anthrones (20 – 25 %) (6). The amount of anthranoids of
the emodin and aloe-emodin type is generally higher in the leaves than in the fruits (7).
The herbal substance contains not less than 2.5 percent of hydroxyanthracene glycosides, calculated as
sennoside B (C
42
H
38
O
20
;
M
r
863). The material complies with the European Pharmacopoiea monograph
“Senna leaf” (ref.01/2005:0206).
The herbal substance also contains small quantities of other dianthrone diglycosides,
monoanthraquinone glycosides and aglyka. The amount of aglyka increases during storage. Aglyka are
classified as toxic substances. Preparations produced with heat like teas contain aglyka whereas
preparations produced without heat like cold macerations do not contain these constituents. The
amount of aglyka is limited by specific requirements for the quality and the storage of the medicinal
©EMEA 2007
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herbal substance. Furthermore the amount of aglyka has to be determined during tests of stability.
Adverse events are caused by overdose rather than by the aglyka themselves. Therefore, a higher risk
for teas than for cold preparations cannot be postulated and the Community herbal monograph also
covers senna teas.
The naphthalene glycosides are without pharmacological significance but are important for
differentiating the two species of senna: tinnevellin glycoside is found only in
Cassia angustifolia
Vahl, and 6-hydroxymusizin glycoside only in the mature plants of
Cassia senna
L. (8, 9).
II.1.2 Absorption, metabolism and excretion
The glycosidic sennosides are not absorbed. They are hydrophilic and do not pass the gastrointestinal
tract membranes (10). Neither the gastric acid nor the α-glycosidase of the small intestine is able to
hydrolyse the β-Ο-glycosidic linkages of the sennosides. Only the β-glycosidase of the bacteria of the
large intestine is able to hydrolyse them to sennidins. These sennidins are further cleaved to the active
metabolite (rhein anthrone) by the bacteria (11). Aglyka are absorbed in the upper gut.
Until now it is unclear how much of the rhein anthrone is absorbed. The absorbed rhein anthrone is
glucuronidised in the liver. One part of the glucuronides is excreted via the urine and cause the yellow
or redbrown discolouration of the urine. The other part is excreted via the bile (12).
Animal experiments with radio-labeled rhein anthrone administered directly into the caecum
demonstrated absorption < 10 % (14).
Excretion of sennosides and their known metabolites is mainly by faeces. According to different
analysing methods, sennosides are recovered from faeces in up to 92.8 % in unbound or bound
polymerised forms (15). In experimental animal studies, nearly 6 % of the amount of the oral
administered anthranoids could be found unchanged in the urine and faeces (12, 13).
Therapeutic doses of two laxatives were repeatedly administered to 10 healthy volunteers in a two-
way change-over design (16). Sennatin® contains purified sennosides 20 mg, and Agiolax® is a
combination of
Plantago ovata
seeds/husks and senna pod. Blood samples were collected up to 96 h
after the first dose, and plasma levels of total aloe-emodin and rhein were determined simultaneously
with a sensitive (lower limit of quantification: 0.5 ng aloe-emodin and 2.5 ng rhein per millilitre
plasma) and specific fluorometric HPLC method. Aloe-emodin was not detectable in any plasma
sample of any subject. Rhein concentration time courses showed highest levels of 150 – 160 ng/ml,
mean 81.8 ng/ml (Agiolax®) and 49.6 ng/ml (Sennatin®), and peak maxima at 3 – 5 h and 10 – 11 h
after dosing probably according to absorption of free rhein and rhein released from prodrugs (e.g.
sennosides) by bacterial metabolism, respectively.
Hattori M et al.
1988
(17) reported that during the course of studies on the metabolism of sennosides
by human intestinal bacteria, an enzyme which takes part in the reduction of sennosides and sennidins
could be originally isolated from
Peptostreptococcus intermedius
. This enzyme catalysed the electron
transfer from NADH (nicotinamide adenine dinucleotide) to FAD (flavin adenine dinucleotide), FMN
(riboflavine 5’phosphate) or benzyl viologen, which reduced nonenzymatically sennosides and
sennidins to 8-glycosyl-rhein anthrone and rhein anthrone, respectively.
Faber P. et al. 1988
(18) investigated the excretion of rhein in 100 breast milk samples of 20 post-
partum women after intake of a “standardised senna laxative”, which also contains
Plantago ovata
seeds/husks as bulk substances (Agiolax®). After daily doses of 5 g of the senna laxative containing
15 mg sennosides for 3 days, the rhein concentration in milk samples from every lactation during 24 h
post-dose varied between 0 and 27 ng/ml with values below 10 ng/ml in 94 %. Based on median
values, 0.007 % of the sennoside intake (calculated as rhein) was excreted in breast milk. None of the
breast-fed infants had an abnormal stool consistency. Assuming theoretically a complete metabolism
of sennosides to rhein in the mother, the amount of rhein delivered to the infant (ng/kg b.w.) is by the
factor 10
-3
below the rhein intake of the mother.
Animal experiments demonstrated that placental passage of rhein is small.
©EMEA 2007
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II.1.3 Progressofaction
Senna leaves act within 8 to 12 hours due to the time taken for transport to the colon and
metabolisation into the active compound.
II.2 Pharmacodynamics
II.2.1 Mode of action
•
Laxative effect
Constipation is said to be present when passed stools are of hard consistency and when evacuation of
faeces is too difficult, too infrequent and irregular. The physiological range for frequency of bowel
movements is wide, extending from three times daily to once every 2 to 3 days. In the pathogenesis of
constipation the colon plays a key role because this is where the contents of the gut remain for 24 – 48
hours. During this period the liquid contents from the small intestine are converted into faeces by
absorption of water and electrolytes in response to the action of bacteria. These functions are
dependent on the interplay of peristaltic processes, which mix the contents and the normal
coordination of the anorectal muscles during defaecation. A disturbance involving any of these
individual areas may lead to constipation. In this context, functional disturbances are far more
common than those of an organic origin. In addition, assessment is problematic because the symptoms
are perceived differently by the individuals affected (19, 20), due to different concepts of what normal
bowel habits are.
Senna leaves belong to the stimulant laxatives. Rhein-9-anthrone is the most important metabolite,
which is produced by the bacteria of the large intestine. The mode of action is based on two
mechanisms. Firstly, colonic motility is increased leading to a reduced transit time and reduced fluid
absorption. Secondly, an influence on secretion processes by two concomitant mechanisms, namely
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), results 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.
Ishii Y et al. 1990
(99) investigated the mechanism of action of aloe-emodin-9-anthrone in causing a
significant increase in the water content of the rat large intestine. Aloe-emodin-9-anthrone inhibited rat
colonic Na
+
/K
+
-adenosine triphosphatase (ATPase)
in vitro
, and increased the paracellular
permeability across the rat colonic mucosa
in vivo
. Therefore, it seemed that the increase in water
content of the rat large intestine produced by aloe-emodin-9-anthrone was due to both inhibition of
absorption and stimulation of secretion without stimulation of peristalsis. Since, however, pretreatment
with loperamide completely prevented the increase of paracellular permeability induced by aloe-
emodin-9-anthrone, but did not completely reduce the concomitant increase in residual fluid volume,
other multiple mechanisms of action might be involved in the increase of water content in the rat large
intestine.
Hoenig J, Rauwald HW et al. 1992
(100, 101) studied the influence of 23 anthraquinones and
anthrones on the regulatory volume decrease (RVD) which is effected in Ehrlichs ascites tumor cells
by activation of Cl
-
channels. They showed that the strongest inhibition of the Cl-channels’ activity
was caused by aloe-emodin-anthrone and aloe-emodin. These anthraquinones reduce the Cl
-
permeability of the cells, this influence being sometimes more pronounced than that of the Cl
-
channel
blocker 130B. In contrast to the investigations of Ishii Y et al. 1990 (99), both substances showed no
pronounced inhibition activity of the Na
+
/K
+
-ATPase. Rhein, frangula-emodin and other
anthraquinones with an additional phenolic hydroxyl group showed inhibition.
©EMEA 2007
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Ishii Y et al. 1994
(102) measured the charcoal transport, as an indicator of the degree of peristalsis,
and water content in the large intestine after intracaecal administration of barbaloin simultaneously in
the same rat. Charcoal transport was significantly accelerated at both 3.5 and 6.5 h after the
administration of barbaloin. At 6.5 h, diarrhoea instead of normal faeces was observed. Moreover, at
1 h before the acceleration of charcoal transport, a marked increase in water content of the large
intestine was observed. It appeared that the increase in water content of the large intestine induced by
barbaloin preceded the stimulation of peristalsis, attended by diarrhoea. The authors therefore
suggested that the increase in water content is a more important factor than the stimulation of
peristalsis in the diarrhoea induced by barbaloin.
Results of investigations of
Capasso F et al. 1983
(103) in rat isolated colon suggest that the laxative
properties of aloin and 1,8-dioxyanthraquinone may depend, at least in part, on increased
prostaglandin synthesis by the intestinal tissue.
The quantity of the laxative effect is dependent on the orocaecal transit time and colonic metabolism
of the herbal substance (21), the dosage of the herbal substance, the amount and period of
accompanying fluid intake (22, 23).
No laxative effect was seen in germ-free animals (24, 25).
Ewe K et al. 1993
(26) measured gastric emptying, small and large intestinal transit in 24 healthy
volunteers using a metal detector method. Twelve persons taking a normal diet received loperamide in
a dose sufficient to double the individual transit time. All subjects measured gastrointestinal transit
time under normal conditions and with Sennatin® containing purified sennosides 20 mg, Agiocur®
(30 g) as a fibre product containing 20 g
Plantago ovata
seeds/husks, or Agiolax® (10 g) as a
combination of 5.4 g
Plantago ovata
seeds/husks + 1.2 g senna pod with a sennoside content of
30 mg. Colonic transit was reduced by Sennatin® and by Agiolax® from 39 +/- 4 h to 17 +/- 3 h
(p<0.005). Agiocur® did not influence colonic transit (39 +/- 3 h). Loperamide prolonged colonic
transit from 27 +/- 0.7 to 72 +/- 12 h. This effect was abolished by Sennatin® (30 +/- 5 h) and
Agiolax® (27 +/- 1 h) (p<0.005), but not by Agiocur® (64 +/- 13 h). The same effects were seen when
right and left colonic transit were analysed separately. Neither gastric emptying nor small intestinal
transit was affected by either substance. All three investigated medicinal products increased stool
weight significantly (p<0.05). When stool frequency and consistency were compared, the effects were
less clear. Agiolax® caused the greatest, Agiocur® the least changes of these parameters. Oroanal
transit times measured by the metal detector and by the Hinton method using 20 radiopaque markers
were similar (43 +/- 6 and 47 +/- 6 h, respectively).
Buhmann S et al. 2005
enrolled 15 healthy individuals (8 males, 7 females, 20 to 45 years old) with
no history or present symptoms of bowel disorders in a functional cine-MRI examination at 6 a.m.
after a starving phase for at least eight hours before and after oral administration of senna tea. Two
consecutive sets of repeated measurements of the entire abdomen were performed using a 1.5T MRI
system with coronal T2-weighted HASTE sequences anatomically adjusted to the course of the large
bowel. A navigator technique was used for respiratory gating at the level of the right dorsal
diaphragm. The changes in diameter (given in cm) were measured at 5 different locations of the
ascending (AC), transverse (TC) and descending colon (DC), and assessed as parameters for the bowel
motility. The mean values as a statistical measure for large bowel relaxation were determined. Before
ingestion of senna tea, the mean diameter measured 3.41 cm (AC), 3 cm (TC) and 2.67 cm (DC). After
the ingestion of senna tea, the mean diameter increased to 3.69 cm (AC), to 3.4 cm (TC) and to 2.9 cm
(DC). A statistically significant difference was demonstrated with the Wilcoxon test (level of
confidence 0.05). For the determination of dynamic increase, the changes of the statistical scatter
amplitude to the mean value were expressed as percentage before and after the ingestion of senna tea.
Thereby, an increase in variation and dynamic range was detected for the AC (112.9 %) and DC (100
%), but a decrease in the dynamics for the TC (69 %).
This study investigated a non-invasive method for the assessment of bowel motility for the first time.
The results have therefore to be regarded with caution. Further studies have to determine whether the
results of this technique are clinical relevant (27).
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In a pharmacological study the jejunum and the colon of humans were perfused with 15 mg and 20 mg
rhein, respectively, via tube. The fluid absorption was turned into a fluid secretion. The net transport
of sodium changed and there was a loss of potassium (28).
II.2.2 Interactions
Chronic use or abuse of senna leaves may lead to hypokalaemia. 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 (105). Concomitant
use with medicinal products inducing hypokalaemia (e.g. diuretics, adrenocorticosteroids and liquorice
root) may aggravate electrolyte imbalance.
The hypokalaemia can be aggravated by thiazide diuretics and by loop diuretics, in particular, but not
by potassium-sparing diuretics such as amiloride. However, the patient cannot always differentiate
between the different kinds of diuretics. All kind of diuretics should therefore be mentioned. Because
the mechanism, which this interaction is based on, is described in the SPC, the doctor can decide
whether the concomitant use of a given diuretic is dangerous or not.
Seybold U et al. 2004
(92) reported a case of a 28-year-old woman, who presented a 2-week history
of fatigue, myalgias, epigastric pain, pyrosis, and nausea. For 2 days, she had noted yellowish eyes and
dark urine. Recently, she had been consuming 3 to 4 l of beer per week. The patient declined liver
biopsy. Ultrasonography showed only increased hepatic echogenicity. After the patient stopped
drinking alcohol, liver function levels initially decreased but, after 4 weeks, increased again. The
patient recalled that she had been found to be homozygous for the CYP2D6*4 variant while
participating in a scientific study. She also reported drinking an herbal tea containing senna leaves.
She stopped drinking the tea, and her laboratory results gradually returned to normal. Twelve months
later, a controlled tea reexposure was performed. Within 7 days, liver function levels increased
dramatically. The tea was withdrawn, and the values slowly decreased. One month later, another
increase in liver function levels was noted after moderate alcohol consumption. Without further senna
or alcohol ingestion, all laboratory values normalised after 7 more weeks. Rhein levels in stored serum
samples were as follows: 330 ng/mL after 11 months of tea consumption, 130 ng/mL 2 weeks after the
patient stopped drinking the tea, 200 ng/mL at 2 weeks after 1 week of reexposure, and less than
100 ng/ml (lower limit of quantification) 3 weeks later. Serum rhein levels in this patient 24 hours
after the last senna dose were 2 to 10 times higher than in the investigation of Krumbiegel G et al.1993
(16). The authors assumed that the toxic effects in this patient were caused by a small dose of
sennosides that would not have harmed persons with normal metaboliser status. Furthermore, the exact
amount of ingested sennosides is not given in the publication and the first duration of administration
was 11 months. The role of the alcohol consumption cannot be evaluated definitely. On the other side,
a reexposition again resulted in an increase in liver function levels. It cannot be assessed if CYP2D6*4
played a key role. This can be assessed as a signal, not more and not less. Until there are further data
available, no information referring to this publication is given in the Community herbal monograph.
III.
CLINICAL EFFICACY
III.1 Dosage
There are no dose-finding studies available.
The recommended dosage as a laxative for adults, elderly and adolescents over 12 years of age (15 –
30 mg hydroxyanthracene derivatives only once daily at night) is supported by experts’ opinions (7)
and by clinical investigations as reported below. This recommendation is also given in consideration
of the toxicological data, which were evaluated and led to pharmacovigilance actions in Germany for
anthranoid-containing laxatives in 1996 (29). This dosage corresponds to the recommendation given in
the above-mentioned ESCOP monographs. The WHO monographs referred above (65) recommend 10
– 30 mg sennosides (calculated as sennoside B).
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Through the individual product information (especially the package leaflet), patient should be
informed that the correct individual dose is the smallest required to produce a comfortable soft-formed
motion.
It is normally sufficient to take an anthranoid-containing laxative up to two to three times a week
(104).
III.2 Clinical studies
The efficacy of senna preparations has been evaluated in clinical trials in the treatment of constipation
and for bowel cleansing before radiological investigations or colonoscopy. In the majority of the
studies, combinations of senna with fibre were investigated. For bowel cleansing high doses of a senna
preparation were tested.
III.2.1 Constipation
Pers M et al. 1983
(30) treated 20 elderly in-patients (above 60 years old) suffering from severe
constipation, once daily for 2 weeks with either Agiolax® (“2.6 g Semen plantaginis ovata, 0.11 g
Ispaghula husk and 0.62 g Sennae fructus angustifolie equivalent to 15 mg glycoside A+B per sachet
of 5 g”) or Lunelax comp® (“3.3 g Testa ispaghula ‘Tika’ and 25 mg glycoside sennae A+B per
sachet”). The patients were allocated randomly into the two treatment groups, one starting with
Agiolax®, the other with Lunelax comp®. The investigation comprised three periods. The first one
was the week prior to the treatment with either of the two preparations. During that week the patients
received the medication routinely used at the department. The second period comprised 2 weeks
treatment with one or the other of the 2 preparations. During the third period, of another 2 weeks, the
preparations were changed. The periods were strictly consecutive. The dosage was one sachet in the
evening. Nineteen patients completed the trial. In one patient diarrhoea from sources obviously not
related to the medication occurred and this patient was classified as a drop-out. The defaecation
frequency was higher during the Lunelax comp® treatment than during the Agiolax® one. This was
expected as the given dose of Lunelax comp® contained 10 mg glycosides more than that of
Agiolax®. Precise data are not given in the publication. Large differences were seen both between
individuals and for the same individual during treatment. Enemas were given to a few patients during
the first period as well as during the second and third period. There were no differences between the
two treatments. Concerning ease of administration, ease of swallowing and taste, there were also no
differences. No-side effects were seen. The authors concluded that both preparations worked well,
even if they have differences in senna glycoside content in the given dosage.
A study was conducted by
Marlett
JA
et al. 1987
(31) involving 42 adults with chronic constipation
who remained constipated after a week of single-blind placebo treatment. Qualifying patients were
than randomised to receive ispaghula husk (Metamucil ® 7.2 g/day) or psyllium plus senna (6.5 g +
1.5 g/day) for 1 week. The ingested amount of sennosides is not mentioned in the publication. Because
the psyllium and senna preparation is a granular formulation ingested with a cold liquid, and the
ispaghula husk product is a powder that must be mixed with a liquid before ingestion, no attempt was
made to blind the identity of the treatment. Both preparations significantly increased stool frequency
(p<0.001). In the ispaghula husk group stool frequency increased from 2.3 +/- 0.1 during placebo to
3.6 +/- 0.3 stools/wk during laxative ingestion and in the combination group from 2.0 to 6.8 stools/wk.
Both treatments also significantly increased mean wet and dry stool weights, although the added effect
of senna was clearly evident. Ispaghula husk treatment increased the mean wet stool weight from
254.2 g to 444.8 g/7 day and the mean dry stool weight from 75.4 g to 126.5 g/7 day. The combination
treatment increased the mean wet stool weight from 277.7 g to 982.1 g/7 day and the mean dry stool
weight from 79.9 g to 190.8 g/7 day. Overall relief of constipation was reported by 90 % of patients on
the combination therapy and by 85 % of patients on ispaghula husk alone. Interestingly, the objective
improvement in stool frequency in both groups did not attain the high level of subjective
improvement; 63 % of the combination group and 48 % of the ispaghula husk group had more than
three bowel movements during the week of treatment. Reports of gastrointestinal side effects (pain and
cramping) were predominant in the combination group (32 % versus 14 % for ispaghula husk alone).
Three of the 22 patients treated with ispaghula husk reported side effects of cramping and gas. Seven
of the 22 patients treated with the combination experienced 11 episodes of side effects, which included
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mainly cramps, uncomfortable diarrhoea, as well as bloating, gas, and nausea. After completion of the
protocol and evaluation of the data, two distinct responses to the combination therapy were evident.
These two groups were designated as normal responders and high responders. The subpopulation of
high responders was responsible for most of the increases in stool frequency and wet weight and all of
the effect on dry stool weight. All seven high responders classified their bowel movements as too
frequent. Despite significant positive results from the objective faecal parameters, including an
increase to more than 3 bowel movements per week after treatment, and despite the fact that 85 % of
patients reported relief of constipation, the authors concluded that a dose higher than 7 g psyllium per
day or a period of treatment longer than 7 days might be necessary to produce an effect in a
chronically constipated population. The single daily dose of “senna plus psyllium” had two distinct
effects; approximately one-third of the subjects had a marked response, which included
gastrointestinal side effects, while two-thirds had a mild response not significantly different from those
given by ispaghula husk alone. The authors suggested that doses of psyllium + senna be
individualised, given the higher incidence of undesirable side effects with combination therapy.
Passmore AP et al. 1993
(32, 33) compared the efficacy of a senna-fibre combination (Manevac®,
Agiolax®: ispaghula 54.2%, senna 12.4 % (m/m)) and lactulose in 77 elderly patients (average age:
82.9 years) with a history of chronic constipation in long-term hospital or nursing home care in a
randomised, double-blind, crossover study. The patients received active senna-fibre combination
10 ml daily with lactulose placebo 15 ml twice daily, or active lactulose 15 ml twice daily with senna-
fibre placebo 10 ml daily for two 14 day periods. Doses could be increased or decreased according to
response. The maximum daily dose for active or placebo senna-fibre was 20 ml (10 ml twice daily)
and for lactulose or lactulose placebo 60 ml. Before entry into the first phase, and between treatments,
subjects had a three to five day period free of laxatives. The number of stools and their consistency
and ease of evacuation, together with any other symptoms or adverse effects were noted daily. Mean
daily bowel frequency was greater with the senna-fibre combination (0.8, 95 % confidence interval 0.7
to 0.9) than with lactulose (0.6 (0.5 to 0.7); t=3.51, p< 0.001). Scores for stool consistency and ease of
evacuation were significantly higher for the senna-fibre combination than for lactulose (p< 0.005,
p=0.02 respectively). The recommended dose was exceeded more frequently with lactulose than the
senna-fibre combination. Compared with the recommended daily dose, this equates to a dose per stool
of 1.52 for lactulose and 0.97 for the senna-fibre combination. Twenty one patients had adverse effects
with lactulose: 7 cramps, 7 urgency, 8 wind or flatulence, 3 bloating, 1 headache, 4 anorexia. Twenty
four patients had adverse effects with the combination: 7 cramps, 13 urgency, 10 wind or flatulence, 2
nausea, 3 bloating, 1 anorexia. There was no difference between treatments when adverse effects were
analysed, individually or overall. The authors concluded that both treatments were effective and well
tolerated for chronic constipation in long stay elderly patients. The senna-fibre combination was
significantly more effective than lactulose at a lower cost.
Kinnunen O et al. 1993
(34) compared the efficacy of a senna-fibre combination (Agiolax®) and
lactulose (Levolac®) in 30 long stay elderly patients aged 65 – 94 years (mean 81.8 years) in the
treatment of chronic constipation. The trial was an open, randomised and controlled crossover study.
A week’s run-in without laxatives was followed by a 5-week period (I) of a daily dose of 14.8 mg (20
ml) Agiolax® or 20.1 g (30 ml) Levolac ®. “Agiolax® contains
Plantago ovata
seed 521.6 mg (bulk
forming), Fructus cassiae angustifoliae 138 mg (stimulant) and atsulen 70 μg (anti-inflammatory).”
Period I ended with a week’s wash-out, which was followed by another 5-week period with crossed
medicines (period II). If over 4 days had elapsed since the last defaecation, 10 mg bisacodyl
(Metalax®) was given per rectum. The bowel frequency, bisacodyl use and stool consistency were
recorded. In period I, 21 patients received Agiolax® and 9 patients Levolac®; in period II, 7 patients
received Agiolax® and 18 patients Levolac®. Bowel frequency/week was significantly higher on
Agiolax® treatment during both periods, mean (SD) in period I: 4.5 (2.3); period II: 4.5 (2.4),
compared to Levolac®. Bowel frequency on Levolac® treatment was in period I 2.2 (0.9) (p=0.0006)
and in period II 1.9 (0.9) (p=0.027). There was a tendency for the number of bisacodyl doses to be
greater when lactulose was used. During both periods bulk plus senna tended to produce more
frequently hard, normal or watery stools but the differences did not reach any statistical significance.
The frequency of loose stools was greater (p<0.05) during the bulk plus senna period. No
complications or such changes in laboratory parameters which could be indicated as medicinal product
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related could be found. The authors concluded that bulk laxatives plus senna was more efficient than
lactulose.
Agra Y et al. 1998
(35) enrolled 91 terminal cancer patients treated with opioids in a randomised,
open, parallel –group trial to determine treatment and cost efficiency for senna derivatives and
lactulose and to determine their efficacy at different opioid doses. Constipation is a frequent condition
in terminal cancer patients, approximately 80 % of whom need laxatives to counteract it. The period of
the study was 7 days to assess laxative efficacy on defaecation days and laxative efficacy at variable
opioid dosage and 27 days to assess the mean morphine dose at which a laxative was necessary. Both
laxative and opioid treatments were initiated simultaneously. Laxative dosage increases were
determined as a function of the patient’s intestinal rhythm, irrespective of opioid dose variation. Initial
daily intake in two doses was 0.4 ml (12 mg) for senna (no other information of the formulation are
given) and 15 ml (10 g) for lactulose, with increments of 0.4 ml and 15 ml, respectively, every 3 days,
according to clinical response. Maximum doses were 1.6 ml (48 mg) for senna and 60 ml (40 g) for
lactulose. When a patient reached the ceiling of his respective laxative and had a defaecation-free
period of 3 days, he was maintained on that dose and, in the absence of side effects, he was also given
the initial dose of the other laxative, which could then be increased at 3-day intervals until reaching the
experimental maximum. Forty three patients were assigned to senna and 48 to lactulose. Sixteen
patients dropped out during the first 4 days. By the end of the 27 days, 37 patients were lost: 21 in the
senna group and 16 in the lactulose group. Three developed vomiting, five refused to continue in the
protocol, 17 died, and 12 were hospitalised. No significant differences were found regarding the
number of defaecation-free 72-hr periods, mean number of defaecation days, or the general state of
health between the experimental groups. There were no differences in the respective defaecation-free
72-hr intervals as a function of opioid. The number of defaecation days was similar in both groups
(senna: mean 8.9 days; SD 6.6 days; lactulose: mean 10.6 days, SD 7.3 days). 37.5 % of patients
tracked until the end of the study period required both laxatives. During the first 7 days, 6 patients (3
treated with senna and 3 treated with lactulose) presented adverse effects (diarrhoea, vomiting, and
cramps) easy to manage with conventional therapy. Fifteen patients, 8 with senna and 7 with lactulose,
required laxatives from days 12 – 27 of the study. The mean morphine dose at which laxatives proved
necessary was 84.1 mg (SD 72.3 mg).
The ingested dose of hydroxyanthracene derivatives is not defined in the publication.
Conclusion
There are no recent clinical studies available, which evaluate senna leaves or fruits alone and not in
combination with other laxatives in a representative study population.
The postulated laxative effect is mainly based on the pharmacological data, experts’ opinions and
clinical experiences. The results of the studies mentioned above show a clear laxative effect
additionally to fibre intake.
III.2.2 Irritable bowel syndrome
Moser EH and Hübner WD 2002/2003
(36, 37) enrolled 284 patients between 19 and 70 years
suffering from irritable bowel syndrome (IBS) in a 12-week double blind, controlled, randomised,
multicentre 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 rhubarb extract”) 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 Eucarbon® group. After the 12-week treatment period, 262 patients were available for intention-
to-treat (ITT) analysis and 144 for per-protocol (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 visual analogue scale (VAS) (0%-100%) to score the
severity of pain, distension, bowel dysfunction, and quality of life/global well-being) as the primary
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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 package
leaflet obtained from the chemical-pharmaceutical factory F. Trenka, Vienna, Austria, indicates an
amount of 2.65 – 3.95 mg anthraquinone per tablet.
Conclusion
This study cannot prove the efficacy of senna leaves in irritable bowel syndrome. The study treatment
was a combination product and the differences between the groups concerning the primary efficacy
parameter were not statistically significant. Based on the results of this study, it is not possible to
recommend the specific indication “irritable bowel syndrome”.
III.2.3 Bowel cleansing
Most of these studies were conducted with X-Prep®, a senna fruit dry extract preparation
corresponding to 150 mg hydroxyanthracene glycosides, calculated as sennoside B, per single dose.
In the sixties, seventies and eighties, several studies were conducted with X-Prep® alone or in
comparison with other cleansing methods.
From the eighties onwards, studies compared X-Prep® with the newly developed electrolyte solutions.
The more recent studies are presented.
Frigerio G et al. 1996
(39) compared to doses of senna (X-Prep®, a senna fruit dry extract
preparation corresponding to 150 mg hydroxyanthracene glycosides, calculated as sennoside B, per
single dose) for colon cleansing. 473 patients (225 males and 248 females with a mean age of 59.7
years, range 14 – 96 years) referred for colonoscopy participated in the randomised, single-blind
study. 250 patients (group A) received a dose of the solution equivalent to 150 mg sennosides in a
single administration the evening before the examination. 223 patients (group B) received two doses,
one at mid-day and one on the evening prior to the examination, equivalent to 300 mg sennosides. All
patients were advised to consume liquids orally according to need, and no enema was given. At the
end of the colonoscopy the following scores were attributed: 0 = perfect examination, possible to
observe the entire colon mucosa; 1 = acceptable examination, capable of responding to the diagnostic
problem but with insufficient observation of some areas; 2 = examination impossible, requiring
repetition. Colonoscopy was impossible (and had to be repeated) in 44 patients (M/F = 22/22), 38 of
these (15.2%) belonged to group A (150 mg) and 6 (2.7%) belonged to group B. The observed
difference was highly significant (p=0.000006). The examination was acceptable in 148 patients (M/F
= 79/69), 85 (34.0%) belonging to group A and 63 (28.3%) to group B (p=0.02). A perfect
examination could be carried out in 281 patients, 127 patients (51%) belonging to group A and 154
patients (69%) belonging to group B. 48 patients (M/F = 22/26), 23 (9.2%) belonging to group A and
25 (11.2%) to group B (p=0.568 NS) complained of side effects: group A: abdominal pain 19, nausea
2, fainting 3; group B: abdominal pain 17, nausea 5, fainting 1, headache 1. The authors concluded
that 300 mg of senna was more efficacious than 150 mg and that both doses were well tolerated.
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Krakamp B et al. 1996
(40) tested three different colonoscopy preparation methods in 150 out-
patients, who received colonoscopies, 50 in each group, in a randomised simple-blind study. The
original Golytely-recepture (polyethylene glycol 3350 and electrolytes for oral solution) with 3 litres
of liquid between 5 and 8 a.m. on the day of colonoscopy (group 1) was tested against Klean Prep
®,
which was dissolved in four litres of liquid and administered between 3 and 7 p.m. on the day before
colonoscopy (group 2). Both receptures had the same isotonic salt solutions. The third group was a
method with the laxative X-Prep® (a senna fruit dry extract preparation corresponding to 150 mg
hydroxyanthracene glycosides, calculated as sennoside B, per single dose) administered at 1 p.m. on
the day before colonoscopy including eating restriction lasting three days (for 3 days diet easy to
digest, the day before colonoscopy clear liquid diet) and an enema one hour before colonoscopy. The
mean age was 57 +/- 19 years in group 1, 55 +/- 15 years in group 2 and 57 +/- 17 years in group 3.
The judgement criteria were the cleanliness of the bowel by a 4-stage score (‘excellent’ to
‘colonoscopy not possible’), the formation of foam by a 4-stage score (‘no foam’ to ’examination
strongly restricted’) and the subjective sensitivity of the patient during the preparation phase. The
preparation with the three bags containing 3 litres of Golytely solution according to the original
recepture proved to be the least troublesome for the patients and was the most efficient method when it
came to cleanliness and the formation of foam. The costs of this preparation method were lower than
those of the other methods.
Valverde A et al. 1999
(41) included 523 patients with colonic or rectal carcinoma or sigmoid
diverticular disease, undergoing elective colonic or rectal resection followed by immediate
anastomosis in a prospective, randomised, observer-blind, parallel, multicentre study. 262 patients
received senna (sennosides A + B 120 mg or 240 mg in obese patients, X-Prep Sarget®) in the
evening before surgery. 261 patients received polyethylene glycol (PEG) (2 packages diluted in 2 – 3 l
of water, ColoPeg®) in the evening before surgery. All patients received 5% povidone iodine
antiseptic enemas (2 l) the evening and the morning before surgery. Criteria of evaluation were the
surgeons’ assessment of bowel cleanliness by a 3-stage score according to Hollender et al. (0 = no
faecal matter, + = small amount of faecal matter, ++ = faecal matter bothersome to the surgery). Other
criteria were consistency of faecal matter, rate and magnitude of intraoperative faecal soiling, rate of
abdominal infective complications and patient tolerance. Colonic cleanliness was better (p=0.006),
faecal matter in the colonic lumen was less fluid (p=0.001), and the risk for moderate or large
intraoperative faecal soiling was lower (p=0.11) with senna. Overall, clinical tolerance did not differ
significantly between groups, but 20 patients receiving PEG (vs 16 with senna) had to interrupt their
preparation. Adverse reactions with senna were reported as follows: discomfort 55 patients (21%),
vomiting 12 (4.6%), abdominal pain 35 (13.4%), distension 8 (3%), malaise 23 (8.8%). In the other
group the following adverse reactions were reported: discomfort 55 patients (21.1%), vomiting 7
(2.7%), abdominal pain 30 (11.5%), distension 15 (5.7%), malaise 15 (5.7%). Senna was better
tolerated (p=0.03) in the presence of stenosis. There was no statistically significant difference found in
the number of patients with postoperative infective complications (14.7% vs 17.7%) or anastomotic
leakage (5.3% vs 5.7%) with senna and PEG, respectively. The authors concluded that mechanical
preparation before colonic or rectal resection with senna is better and easier than with PEG. An
analysis of the subgroups receiving either 120 mg or 240 mg sennosides is not given. All patients
additionally received two enemas.
Bokemeyer B 2000
(42) compared in an open prospective study different colonoscopy preparations in
more than 300 outpatient colonoscopies. Endoscopists assessed the bowel cleanliness by a score 1
(best) – 6 (worse). Patients assessed the tolerance and acceptance by a score 1 (best) – 6 (worse).
Following colonoscopy preparation with Golytely (Klean-Prep®, 2 l on the day before colonoscopy
and 2 l on the day of colonoscopy p.o), Golytely-RSS (Endofalk®, 3 l on the day of colonoscopy p.o.)
and Phospho-Soda (Fleet®, 45 ml on the day before and 45 ml on the day of colonoscopy p.o.) mainly
good or excellent cleansing results were found: score for Golytely 2.1, for Golytely-RSS 2.1 and for
Phospho-Soda 1.9. Colonoscopy preparation with a smaller volume of PEG-lavage solution in
combination with a laxative (X-Prep®, a senna fruit dry extract preparation corresponding to 150 mg
hydroxyanthracene glycosides, calculated as sennoside B, per single dose, and an enema and 2 l
Golytely on the day before colonoscopy p.o. and an enema in the morning before colonoscopy)
produced significantly worse results: score 3.0. The questioning of the patients before and after
endoscopy demonstrated the sufficient tolerance of colonoscopy preparation and colonoscopy overall.
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Problems resulted from a relative large volume of remaining fluid in the bowel especially after 1-day
preparation with PEG-lavage solutions. By using an additional dose of cisaprid (Propulsin®) the
remaining fluid could be reduced and the cleansing result was better. In patients prepared with
Phospho-Soda, disturbing bubbles were found more often and in most cases significant changes were
observed in serum electrolyte levels (97.6%).
Arezzo A 2000
(43) compared a randomised observer-blind, parallel study effectiveness and tolerance
of different bowel preparations. 300 patients were randomised into three groups, to be administered
either a senna compound (group 1; 12 tablets each containing 12 mg sennosides A+B at 10 a.m. and
magnesium sulfate 15 g at 5 p.m. on the day before colonoscopy p.o.), a PEG lavage (group 2; 4 l at 4
p.m. on the day before colonoscopy p.o.), or an oral sodium phosphate solution (group 3; Fleet®, 40
ml at 6 p.m. on the day before and 40 ml at 6 a.m. on the day of colonoscopy). After each
colonoscopy, the endoscopist blindly scored cleansing for each bowel segment (‘good’, ‘medium’,
‘scarce’) and defined the quality of the examination as ‘optimal’, ‘acceptable’ or ‘to be repeated’.
Bowel cleanliness was scored as ‘good’ in 38 (group 1), 50 (2), 68 (3) patients. Bowel cleanliness was
scored as ‘good’ or ‘medium’ in 73 (group 1), 77 (2) and 95 (3) patients. Bowel cleanliness was scored
as ‘scarce’ in 27 (group 1), 23 (2) and 5 (3) patients. Significant more patients in group 3 (68%)
achieved a good cleansing compared with group 2 (50%) (p<0.0001) and group 1 (38%) (p<0.005).
Significant more patients in group 3 achieved a ‘good’ or ‘medium’ cleansing compared with group 2
and group 1. 63% of constipated patients obtained a good preparation in group 3, which was
significantly higher than in group 1 (28%, p<0.05) and than in group 2 (42%, p<0.02). Feasibility of
the examination was considered ‘optimal’ significantly more in group 3 (80 patients) than in group 2
(62 patients, p<0.005)) and in group 1 (59 patients, p<0.005). There was however no difference
between the groups when ‘optimal’ and ‘acceptable’ examinations were considered together (96
patients group 1, 96 patients group 2 and 100 patients group 3). There was no statistically significant
difference between the three groups with regard to patient tolerance. Eighty seven patients (group 1),
85 patients (2) and 93 patients (3) rated the preparation as ‘good’ (no symptoms), 10 patients (group
1), 10 patients (2) and 5 patients (3) as ‘medium’ (nausea, mild abdominal pain) and 3 patients (group
1), 5 patients (2) and 2 patients (3) as ‘scarce’ (vomiting, severe abdominal pain, severe diarrhoea).
The author believed that the sodium phosphate
solution should be the standard preparation for elective
colonoscopy.
Chilton AP et al. 2000
(44) compared in a randomised, observer-blind, parallel study a novel low-
dose, low-volume triple regimen with Fleet® Phospho-soda. A blinded, experienced colonoscopist
examined 132 consecutive patients randomly allocated to receive i) either a triple regimen consisting
of 75 mg sennoside A+B at 10 a.m. + sodium picosulphate 10 mg (Picolax®) at 2 p.m. + Golytely 1 l
at 6 p.m. on the day before colonoscopy when colonoscopy took place before 12 a.m. or 75 mg
sennosides A+B at 2 p.m. + sodium picosulphate 10 mg (Picolax®) at 6 p.m. + Golytely 1 l at 7 a.m.
on the day of colonoscopy when colonoscopy took place after 12 a.m. (n=81), ii) or sodium phosphate
solution (Fleet® Phospho-soda) 45 ml at 8 a.m. and 45 ml at 8 p.m. on the day before colonoscopy
when colonoscopy took place before 12 a.m. or sodium phosphate solution (Fleet® Phospho-soda)
45 ml at 8 p.m. and at 8 a.m. in the morning of the colonoscopy when colonoscopy took place after 12
a.m. (n=51). Endoscopists assessed bowel cleanliness by a 4-stage score (excellent, good,
intermediate, poor). Further on time taken to reach the caecum and completeness of examination were
assessed. In the triple regimen group, 73% of the patients were scored ‘excellent’ or ‘good’ compared
with 57% in the other group (p=0.037 Mann-Whitney U-test). Examination of the caecum was
achieved in 95% of patients of the triple regimen group and in 89 % of the other group. Among those
examined as far as the caecum, the time to reach the caecum was 11 minutes (range 5 – 50 min) in the
triple regimen group compared with 16 minutes (range 5 – 65 min) in the other group (p=0.08, Mann-
Whitney U-test). Patient tolerability was not assessed in this study. The authors concluded that this
novel triple regimen produces a cleaner colon than Fleet® Phospho-soda, is associated with a trend
towards a quicker and more efficient colonic examination, and is also 30% cheaper per patient.
Schanz S et al. 2003
(45)
compared different bowel cleansing modalities referring to tolerability
(primary aim), cleanliness and acceptance (secondary aims). 355 consecutive out-patients between 18
and 75 years undergoing colonoscopy were randomised to 3 groups (A, B, C). Group A received a
sodium phosphate solution (Fleet® Phospho-soda). Group B received a sodium phosphate solution and
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sennosides (X-Prep®, a senna fruit dry extract preparation corresponding to 150 mg
hydroxyanthracene glycosides, calculated as sennoside B, per single dose). Group C received PEG-
ELS (Klean-Prep®) and sennosides (X-Prep®). Gastroenterologists performing colonoscopy were
blinded to the type of preparation. All patients documented tolerance and adverse events. Vital signs,
premedication, completeness, discomfort and complications during the procedure were recorded. A
quality score (0 – 4) of cleanliness was generated: 0 = excellent to 4 = repeated examination necessary.
The 3 groups (A = 128, B = 133, C = 94) were similar with regard to age, sex, Body Mass Index
(BMI), indication for colonoscopy and comorbidity. Drinking volumes (L) (A = 4.33+1.2, B =
4.56+1.18, C = 4.93+1.71) were different (p=0.005). Discomfort from ingested fluid was recorded in
A = 39.8% (vs. C: p=0.015), B = 46.6% (vs. C: p=0.147) and C = 54.6%. No differences in adverse
events and the cleanliness effects occurred in the three groups (p=0.113). Tolerability in group A was
bad in 6.4%, moderate in 21.6% and good in 72%, in group B 7.5%, 20.3% and 72.2%, respectively,
in group C 5.4%, 10.9% and 83.7%, respectively. The cleanliness quality scores 0 – 2 were calculated
in A: 77.7%, B: 86.7% and C: 85.2%. Acceptance between the 3 groups was not different: refusal for
repeated equal preparation procedure reported in A: 14.8%, B: 18.5% and C: 17% (p=0.737).
Alternative bowel preparation would prefer in A: 30.2%, B: 30%, C: 37.2% (n.s.). These data do not
demonstrate significant differences in tolerability, preparation quality and acceptance between the 3
types of bowel preparation for colonoscopy. Cleansing with the sodium phosphate solution was not
superior to PEG-ELS.
Tasci I et al. 2003
(46) conducted a prospective randomised trial to assess the cleansing ability and
tolerance of bowel preparations for colonoscopy in a group of 953 patients. Of the 1021 patients
enrolled, 68 were excluded from analysis because of intolerance to the solutions or medicinal
products, improper use of the regimen, electrolyte imbalance, cardiac disorders or vomiting. The
bowel cleansing methods were: i) sennoside calcium (300 ml of a 1 mg/ml solution (X-M, Yenisehir
Ilac) given 2 days prior to colonoscopy), ii) PEG lavage (3 l given 1 day prior to colonoscopy), iii)
oral sodium phosphate solution (Fleet ® Phosphosoda) in one 90 ml-dose 1 day prior to colonoscopy,
iv) oral sodium phosphate solution in 2 doses (90 ml 1 day prior to colonoscopy + 45 ml 5 h prior to
colonoscopy), v) oral sodium phosphate solution
in 2 doses (45 ml + 90 ml), vi) oral sodium
phosphate solution in 2 doses (45 ml + 90 ml) plus 10 mg cisapride, and vii) oral sodium phosphate
solution in 2 doses (45 ml + 90 ml) plus 10 ml domperidone. All patients were recommended to take
clear liquid diet one day before starting the bowel cleansing regimen. Sodium phosphate enema was
applied to the patients on the morning of colonoscopy. The efficiency of the different procedures was
evaluated according to a 5-point scale. The cisapride-containing procedure was abandoned partially
through the study because of its adverse effects. Overall, bowel cleansing was effective in 890 (93%)
patients. Procedures using sodium phosphate solution and either cisapride or domperidone were
effective in all patients, while the other 5 protocols led to insufficient bowel preparation in some
patients (p<0.05). Among these first 5 protocols, those using 2 doses of sodium phosphate solution
were superior to the single treatments of the first 3 groups (p<0.05). Tolerance to sennoside calcium
and PEG lavage in comparison to other groups was significantly worse (p<0.05). Of the patients who
received sodium phosphate-based treatments, 72%-78% stated that they would undergo the procedure
again if necessary, while only 21% of patients in the sennoside calcium group and 11% in the PEG
group were so willing (p<0.05). The authors concluded that 2 doses of the sodium phosphate solution
(45 ml +90 ml) plus domperidone for colon cleansing is a safe, effective, rapid, inexpensive and well
tolerated procedure.
In an uncontrolled study
Iida Y et al. 1992
(93) already investigated a colon cleansing preparation
regimen in which examinees had to drink 2 l of Golytely on the day of examination by taking 36 mg of
sennosides (no further information of the formulation) orally in the evening before colonoscopy.
Bowel preparation was carried out in 297 examinees (219 male and 78 female; mean age 57 years). No
special diet was recommended. 97 % of the patients were able to drink the total dose of 2 l Golytely.
Bowel cleanliness was assessed as ‘excellent’ or ‘good’ in 90% to 97% of the patients at all sites in the
colon and rectum. There was a tendency for better irrigation to be achieved in the proximal colon
compared with the distal colon. With regards to foam and peristalsis, there were no problems in 85%
respectively 92% of the patients. No severe adverse reactions were noted. During the drinking of
Golytely, 1% of patients complained of abdominal pain, 10% of chills or nausea and 24% of
abdominal fullness. 54% of patients had no adverse reactions.
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Conclusion
The more recent studies do not unequivocally prove that bowel cleansing with high doses of senna is
superior to other preparations like a polyethylene glycol lavage or an oral sodium phosphate solution.
An adequate bowel cleansing can be achieved by other preparation methods than with a high dose of
senna with a less favourable benefit-risk-ratio. In particular, if different methods are combined, lower
doses of senna seem to be effective enough. But up to now there is no clear evidence to recommend a
specific dose nor a specific combination of different bowel cleansing methods. No recommendation
concerning the use of senna for bowel cleansing is therefore made in the Community herbal
monograph, even not for a special patient group, who is not able to ingest high amounts of fluid, e.g.
patients suffering from cardiac insufficiency.
III.3 Clinical studies in special populations
III.3.1 Use in children
In an open controlled trial
Nolan T et al. 1991
(47) randomly allocated 169 children with encopresis
and evidence of stool on plain abdominal radiograph to receive multimodal (MM) therapy (laxatives
plus behaviour modification; n=83) or behaviour modification only (BM; n=86). The protocol for the
MM group used laxative therapy in two phases. The initial disimpaction phase consisted of 3-day
cycles of 5 ml Microlax ® (sodium citrate 90 mg, sodium lauryl sulphoacetate 9 mg, sorbic acid 5 mg,
glycerol, sorbitol, distilled water) on day 1, one 5 mg bisacodyl suppository after school and one in the
evening on day 2, and a 5 mg bisacodyl tablet after school and one in the evening on day 3. Up to 4
cycles (12 days) were undertaken. Further cycles were prescribed if there was later evidence of stool
reaccumulation. The subsequent maintenance phase consisted of Agarol® (liquid paraffin,
phenolphthalein, benzoic acid, sorbic acid) 5-30 ml once or twice each day, senna granules, and/or
bisacodyl tablets. Doses were adjusted to maintain at least daily defaecation and were increased if
there was persistent or recurrent stool retention. By 12 months follow-up 42 (51%) of the MM group
and 31 (36%) of the BM group (p=0.079) had achieved remission (at least one 4 week period with no
soiling episodes) and 52 (63%) vs 37 (43%) (p=0.016) had achieved at least partial remission (soiling
no more than once a week). MM subjects achieved remission significantly sooner than BM subjects.
The authors concluded that this study shows a clear advantage overall for the use of laxative
medication, although the benefit may not be as great for children, who are able to maintain regular
bowel habits.
Only poor information concerning senna is given in the publication. No evaluation of the efficacy nor
of the safety or tolerability is possible. Furthermore, this is a special study population, which cannot be
compared with constipated children.
Bliesener JA et al. 1978
(48)
reported his experiences with X-Prep® in children. 111 patients
between 0.5 and 15 years undergoing bowel cleansing before radiological examination were enrolled
and 107 completed this prospective uncontrolled study (44 patients between 0.5 – 5 years; 47 between
6 – 10; 20 between 11 – 15). They received 1 ml = 2 mg/kg body weight of X-Prep® (150 mg/75 ml
sennosides A+B) at 7 p.m. in the evening prior to radiological examination. According to the authors,
the preparation method was well accepted even by the younger (
<
5 years) children. Excellent
radiographic visualisation was obtained in most patients (87%) and diagnosis was possible in all
patients. The preparation method was well tolerated.
Dahshan A et al. 1999
(49) performed a prospective, randomised, single-blind study in children
undergoing colonoscopy to evaluate the acceptance and efficacy of three different bowel preparations.
70 patients (ages 3 – 20 years, 38 male) were randomly assigned to one of the three study
preparations: Group A: Magnesium citrate with X-Prep® and clear liquid diet for 2 days. Group B:
Dulcolax® (bisacodyl) for 2 days and Fleet
®
enema without dietary restriction. Group C: Golytely
20 ml/kg (up to 1 l) per hour for 4 h with clear liquid diet for 1 day. Endoscopists blinded to bowel
preparation graded the adequacy of colon cleansing. The preparations were rated by patients for
tolerance, willingness to retake them, adverse effects, and compliance. Data analysis using Fisher
exact test and trend test showed that colon cleansing in groups A and C was superior to that in group B
(p<0.0001) and better in group C than A (p<0.075). Overall tolerance and compliance were
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significantly better for groups A and B than group C (p<0.003), but not different between A and B.
More of group B patients were willing to retake the preparation than in group C (p<0.002) and group
A (p<0.05), but this was not different between groups A and C. Adverse effects were reported more
frequently by patients in group C than in groups A and B (p<0.01). The authors concluded that
although the least well tolerated, Golytely provided the best cleansing. Dulcolax® without dietary
restriction provided unsatisfactory colon cleansing. Magnesium citrate with X-Prep® was acceptable
and provided good cleansing.
This investigation cannot prove the efficacy of senna because it was given in combination with
magnesium citrate and the study groups were very small.
There are several reports of local intolerance of X-Prep® on skin in children wearing napkins. These
skin irritations were bullous and comparable with skin irritations caused by scalds (51).
Conclusion
First of all, change of nutrition is recommended in constipated children with an increase in daily fibre
intake. According to the recommendations from a conference on dietary fibre in childhood, children
older than 2 years of age should increase their intake of dietary fibre (increased consumption of a
variety of fruits, vegetables, cereal and other grain product) to an amount equal or greater than their
age plus 5 g (e.g. 8 g/day at age 3) (50). Change in nutrition should be accompanied with behaviour
modification, e.g. increased physical exercise.
The data mentioned above are not sufficient to show the efficacy and safety of senna leaves to treat
constipated children, if change of nutrition and increase of daily fibre intake is not effective (see
chapter IV.2 Contraindications).
They do not represent strong evidence supporting a recommendation for bowel cleansing for
colonoscopy in children.
According to the ‘Note for guidance on clinical investigation of medicinal products in the paediatric
population’ (CPMP/ICH/2711/99) of 27 July 2000, the age limit between ‘children’ and ‘adolescents’
is set to 12 years of age.
III.3.2 Use during pregnancy and lactation
There are no recent investigations available.
Up to now there are no reports of undesirable or damaging effects during pregnancy or on the foetus
associated with senna preparations when used in accordance to the recommended dosage schedule.
Bauer H 1977
(106) administered Laxariston® to 95 pregnant women suffering from 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. Fourteen pregnant women were in the
first trimester, 15 in the second one, and 66 women in the third trimester. 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 trimesters. 4 patients (4.2%)
complained about adverse reactions.
Twelve 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. This
investigation cannot prove the safe use of senna preparations in general in pregnancy.
There are also no new, systematic preclinical tests for senna leaves or preparations thereof. There are
some preclinical data that refer to an 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. This
extract is one of the ingredients of Agiolax®, a combination of
Plantago ovata
seeds/husks and senna
pods. The following
in vivo
studies were conducted using this extract:
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Chromosome Aberration Assay in Bone Marrow Cells of the Rat, Micronucleus Test in Rats, Mouse
Spot Test. No cytotoxic, toxic, embryotoxic or genotoxic effect could be found.
(7). Therefore use during pregnancy can only be recommended for such a specified extract but with
the advice that the use is to be avoided during the first trimester, because of the experimental data
concerning a genotoxic risk of several anthranoids. Senna leaves should only be used intermittently
and if other actions like behavioural modification, dietary changes and use of bulk forming agents
have failed (53).
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 (11).
Garcia Villar R 1988
(54) evaluated the effects of sennosides on uterine motility in the pregnant ewe. Repeated intracolonic
administration of laxative doses of sennosides A+B (60mg/kg) between the 70
th
and 120
th
day of the
pregnancy had no effect on cervical motility but significantly reduced uterine motility in some ewes.
Pregnancy maintenance was normal (11).
Shelton MG 1980
(55) reported that successful treatment of constipation in the immediate postpartum
period in 93% of white patients and 96% of coloured patients was achieved in a clinical randomised
controlled trial of “standardised senna tablets” (Senokot®). The time of the first spontaneous normal
bowel action was taken as the criterion. If this occurred within the first 24 hours after delivery or on
the following day (i.e. within 48 hours of delivery) the response was regarded as successful. This
result was significantly better than the success rates of 51% and 59% in white and coloured patient
controls treated with placebo. Minor abdominal cramps occurred in some 13% of the patients treated
with senna and in 4% of the controls given the placebo. Furthermore the author reported that there was
no evidence to suggest that standardised senna had any effect whatsoever on a breast-fed baby if taken
by the mother.
Faber P et al. 1988
(18) (see also chapter II.1.2 Absorption, metabolism and excretion) reported that
based on median values, 0.007 % of the mothers’ sennoside intake (calculated as rhein) was excreted
in breast milk. None of the breast-fed infants had an abnormal stool consistency.
Conclusion
Use during lactation is not recommended as there are insufficient data on the excretion of metabolites
in breast milk. Small amounts of active metabolites (rhein) are excreted in breast milk. A laxative
effect in breast fed babies has not been reported.
III.4 Traditional use
As already mentioned in chapter I Introduction, senna has been used for medicinal purposes for
centuries (4). It was introduced into European medicine by the Arabs in the 9
th
or 10
th
century.
Tabernaemontanus 1625
(56) mentions “Kassie” (Cassis alata). Different parts and preparations of
the plant were used: “CASSIA FISTULA” or “CASSIA FISTULATIS”, MEDULLA CASSIAE,
FLORES CASSIAE and CASSIA EXTRACTUM CUM FOLIIS SENNAE. The last one was an
electuary (a medicine composed of powders, or other ingredients, incorporated with some conserve,
honey, or syrup, a soft solid) which was prepared from MEDULLA CASSIAE and different other
herbs and senna leaves. This extract was used as a clysma. Tabernaemontanus also mentioned the use
as a purgative, which was administered in case of fever or heat.
In the “American Materia Medica, Therapeutics and Pharmacognosy” of
Finley Ellingwood 1919
(57) “Alexandria Senna” is described as an efficient remedy, mild, kindly, certain and uniform in its
action. It is a constituent of the larger number of the proprietary laxative or cathartic compounds,
syrups, cordials or elixirs. It is used in all cases of temporary constipation, however induced.
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Hager 1927
(58) also mentions the use of an electuary of senna as a laxative which was sometimes
used as a klysma. Combination preparations with senna are used for purification the blood, to treat
obesity and gallstones. “Sennatin”, an extract of senna leaves, was administered subcutaneous or
intramuscular to treat constipation.
Thoms 1927
(59)
describes the use of senna in teas for purification of blood and as a laxative. He also
mentioned “Sennatin” like Hager 1927.
Madaus 1938
(60) gives a review of the use of senna. Paracelsus already indicated the use as a
purgative, as well Hecker 1814. Lonicerus 1564, Bock 1565, Matthiolus 1626 and Clarus 1860
described the use as a laxative. Matthiolus also cured lues venerea (syphilis) with senna. Other
described indications are as an emmenagogue agent and in acidosis in diabetics, in congestion by
night, in fever and scurf and in lung and liver diseases.
Hoppe 1949
(119) mentions senna leaves as a laxative in cases of acute and chronic constipation.
In
Martindale 1967
(61) senna is described as a purgative for the treatment of constipation.
The
Austrian Pharmacopoeia 1812
(120) lists senna leaves as “infusum laxativum”.
In his “Manual of Materia Medica and Pharmacology”
Culbreth 1927
(62) described the use of
“Cassia senna” as follows: “The Arabians used it in skin affections”; the herbal substance is “now
employed for habitual constipation, haemorrhoids, fissura ani, fevers”. But “its smell, taste, tendency
to nauseate, injurious effects in hemorrhoids, intestinal hemorrhage, and inflammation, all lessen its
popularity.”
In Hungary, combinations with senna preparations are used traditionally as cholagoga. Two
prescriptions can be found in Hungarian Pharmacopoiea (in Edition VI. 1967) and some in the
Formulae Normales (the officinal compendium of prescriptions, Edition V. 1967) and there are some
paramedicines with this indication also. But the pharmacological data available for senna do not
support such use; taking into consideration the benefit-risk ratio for senna, this use cannot be accepted.
In Hungary, the use for slimming cure is also described in paramedicines. The Hungarian competent
authority limited the quantities of anthranoids in such products to 15 mg/day and the duration of use
was limited to maximum one month. The use of either an anthranoid-containing laxative or any other
laxative during a slimming cure must be regarded as obsolete. An effective and lasting body weight
reduction cannot be reached with such substances. They do not reduce adipose tissue.
In India, senna leaves are also used in loss of appetite, abdominal pain, liver disease, splenetic
extension, hepatitis, anaemia, leprosy, foul smelling breath, bronchitis and tumours (
Kirtikar KR et
al. 1975
(63)). In his “Indian materia medica”
Nadkarni KM 1976
(121) describes senna leaves and
pods as purgatives. Therapeutical doses stimulate intestinal peristalsis. Furthermore externally
powdered leaves mixed with vinegar and made into a plaster are applied locally in certain skin
diseases. Senna leaves combined with Henna are also used as a hair-dye to make the hair black.
As
Koenen 1977
(64) described, senna was used in South Africa in grippe (influenza) and as
secretolytic ointment. In Central Africa, senna was used in digestive complaints and to treat wounds,
burns and furuncles.
The WHO monograph “Folium Sennae” (65) mentions the following uses described in folk medicine,
not supported by experimental or clinical data: as an expectorant, a wound dressing, an antidysenteric,
a carminative agent; and for the treatment of gonorrhoea, skin diseases, dyspepsia, fever, and
haemorrhoids.
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Conclusion
Besides the use in occasional constipation in Europe and America, senna was used for purification of
the blood, bowel and other organs. In former times such a purification was often the first step to treat a
lot of diseases. Such a procedure is now obsolete. Furthermore there are no plausible pharmacological
data for the purification of the blood and other organs than the bowel, as well as for the use as
cholagoga.
The other indications described for India and Arabia are not traditional one for Europe. The use in skin
affections is surprising because senna can cause skin irritations by itself.
Furthermore the possible risks as described in chapter IV have to be taken into account.
None of the above-mentioned uses can therefore be accepted for inclusion in the ‘Community list of
herbal substances, preparations and combinations thereof for use in traditional herbal medicinal
products’.
IV.
SAFETY
IV.1 Toxic, genotoxic and cancerogenic risk
IV.1.1 Preclinical Data
Toxicological data indicate that two hydroxyanthraquinones, emodin and aloe-emodin, present as
minors component in senna, might represent a genotoxic or carcinogenic risk (
Mori H 1990
(66),
Siegers CP 1992
(67),
Brusick D 1997
(68)). While most studies gave negative responses, results
from some studies suggest a genotoxic activity by both (
Wölfle D 1990
(69),
Westendorf J et al.
1990
(70),
Westendorf J 1993
(71)). These were Ames tests showing an interaction with Salmonella
DNA resulting in the production of frameshift mutations (Westendorf J et al. 1990 (70),
Sandnes D et
al. 1992
(72),
Heidemann A 1993
(73)). 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 A 1993 (73)).
In vitro
assays overestimate the potential hazard from exposure and must be reevaluated by
in vivo
experiments.
Westendorf J et al. 1990 (70) 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
tended to suppress the mutagenicity.
In the Mammalian Cell Mutation Test, Westendorf J 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
unscheduled DNA synthesis (UDS) assay, also conducted by Westendorf J et al. 1990,
aloe-emodin was associated with a significant increase in net grains/nucleus. Two 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.
Sandnes D et al. (72) 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
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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.
The three
in vivo
studies by Heidemann A 1993 (73) which showed no evidence of any genetic effects,
were the
Chromosome Aberration Test, the Mouse Spot Test, and the
in vivo/in vitro
UDS test in rat
hepatocytes.
Chromosome Aberration Test
Each of NMRI mice or Wistar rats, conventionally housed, received the test substances orally via
stomach tube. They were suspended in either 0.3 – 0.5% tragacanth in aqua dest. or aqua dest. The
volume administered was 15 ml/kg. 2.5 h prior to sacrifice the animals were injected intraperitoneally
with the spindle inhibitor Colcemid (2 mg/kg) to arrest cells in metaphase. The preparation intervals
were 6, 24 and 48 h after treatment. After flushing out of the bone marrow from the femora with
hypotonic potassium chloride solution the cells were fixed, spread by flame drying and stained with
Giemsa solution. The mitotic index from 1,000 cells was determined in each experimental group, and
scoring of chromosomal aberrations was done in 50 metaphases per animal on coded slides of each 5
males and females per group. A test substance was classified positive if it induced either a dose-related
increase in the number of structural chromosomal aberrations or a statistically significant (Mann-
Whitney test) positive response for at least one of the test points.
Mouse Spot Test
Housing of the animals and treatment with the test substances were as described above. In the spot test
embryos were exposed to the test substances at an appropriate stage of development, mostly day 9, and
allowed to grow up. The target cells in the developing embryos were melanoblasts, and target genes
were those which control the pigmentation of the coat hairs. The embryos were heterozygous for three
coat colour genes. A mutation in or loss of the dominant allele of such genes resulted in the expression
of the recessive genotype forming a spot of altered colour in the black coat of the F
1
mouse. The F
1
offspring were examined for coat colour spots 3 weeks after birth. Brownish or greyish pigmented
spots and non-midventral white spots were regarded to have genetic relevance. A test substance was
classified as positive if it induced either a dose-related increase in the frequency of genetically relevant
spots or a statistically significant (exact Fisher Yates test) positive response for at least one of the test
points.
In vivo/in vitro
UDS Test in Rat Hepatocytes
Housing of the animals and treatment with the test substances were as described above. After a
treatment period of 4 and 16 h, the animals were anaesthetised and sacrificed during liver perfusion.
Primary hepatocyte cultures were set up and exposed for 4 h to
3
H-thymidine, which is incorporated
into the DNA if UDS occurs. The uptake of
3
H-thymidine by the hepatocytes was determined by
autoradiography. For each test group hepatocytes from 3 animals were assessed for the occurrence of
UDS. The number of silver grains above the nuclear area was counted using Artek 880 or 982 counter.
In addition, the number of grains of one nuclear-sized cytoplasmic area adjacent to the nucleus was
counted. At least two slides per animal and 50 cells per slide were evaluated. A test substance was
classified as positive if it induced either a dose-related increase in
3
H-thymidine incorporation
expressed as grains per nuclear area (=nucleus) or a statistically significant (Mann-Whitney test)
positive response for at least one of the test points.
A carcinogenicity study was done by
Lyden-Sokolowski A et al. 1993
(74) in rats receiving for 2
years a purified senna extract, that contained approximately 40.8% anthranoids, of which 35.7% were
total sennosides, corresponding to approximately 25.2% calculated potential total rhein, 2.3% potential
aloe-emodin and 0.007% potential emodin. Besides the control group, 3 dosages groups (5, 15 and
25 mg/kg) were tested, which showed clinical signs of chronic electrolyte loss, mostly in the high-
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dosage 25 mg/kg group. No treatment-related increase in tumours of the gastro-intestinal tract, liver or
kidneys could be found. The highest dose level was approximately 20-25 times the recommended
clinical dose.
Mereto E et al.1996
(75) found that senna glycosides acted as weak promoters of rat colon
carcinogenesis. The doses used were considerably above those taken by humans and which are usually
used in therapy.
Mascolo N et al. 1999
(76) investigated the influence of senna extract on the growth and initiation of
malignant tumours in rat colon. In the dose of 10 mg of extract/kg, which just produced a slight
laxative effect, no carcinogenic or tumourigenic effects were observed. Only the second dose level of
100 mg/kg given for 13 – 28 weeks together with azoxymethane produced a higher rate of tumours
compared to the control group (only given azoxymethane). The authors concluded that, under
therapeutic dosage, senna extracts have no carcinogenic effects whatever. The dose of 100 mg/kg led
to permanent diarrhoea in the animals for 3 months and was thus clearly too high and of no therapeutic
relevance.
Mengs U et al.
2004 (97) conducted a toxicity study on senna in male and female 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, 100, 300, 750 or 1,500
mg/kg for up to 13 consecutive weeks followed by an 8-week recovery period for selected animals.
There was a dose-dependent laxative effect at 300 mg/kg per day and above. Animals receiving 750 or
1,500 mg/kg per day had significantly reduced body weight gain (males only) and, related to the
laxative properties of senna, increased water consumption and notable electrolyte changes in blood
and urine. At both the terminal and recovery phase necropsy, an increase in absolute and relative
kidney weights was seen for male and female animals receiving 750 and/or 1,500 mg/kg per day. A
dark discolouration of the kidneys was observed at necropsy along with histopathological changes
(slight to moderate tubular basophilia and pigment deposits) at 300 mg/kg and above. Although the
pigmentation decreased towards the end of the recovery period, it still remained to a lesser degree.
However, there were no indications in laboratory parameters of any renal dysfunction. In addition, for
all treated groups, minimal to slight hyperplasia was recorded in the forestomach and large intestine,
which was reversible within the 8-week recovery period. The histological changes were considered a
physiological adaptation to the laxative substance. 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. The authors concluded that
senna did not cause any notable target organ toxicity up to the highest dose tested. A no-observable-
effect-level (NOEL) could not be obtained, but the changes seen were considered to represent a
physiological adaptation to treatment and not a true toxic response.
Mitchell JM, Mengs U et al. 2006
(98) conducted an oral carcinogenicity and toxicity study of senna
in rats. The administered senna preparation was the same preparation described above. 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 the 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.
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Emodin
In 2001 the National Toxicology Program (NTP) of the U.S. Department of Health and Human
Services published a technical report on toxicology and carcinogenesis studies of emodin (107).
¾
16-day study in F344/N rats
Groups of 5 male and 5 female rats were fed diets containing 0, 600, 2,000, 5,500, 17,000, or 50,000
ppm 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. Three female
rats died before the end of the study. Mean body weights of males and females exposed to 5,500 ppm
or greater were significantly 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.
¾
16-day study in B6C3F1 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 females
was greater than that by the controls. Macroscopic lesions were present in the gallbladder and kidney
of mice exposed to 17,000 ppm.
¾
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.
¾
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 625 ppm or greater and
in females exposed to 1,250 ppm or greater.
¾
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).
Three 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 in 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,
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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.
¾
2-year (105 weeks) study in mice
Groups of 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). 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 exposure concentration. At 2-years, the incidences of renal tubule pigmentation were
significantly increased in all exposed groups; severities also raised with increasing exposure
concentration.
¾
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 weakly positive response was
observed in similarly exposed females.
Conclusion by the “National Toxicology Program’s Board of Scientific Counselors’ Technical Reports
Review Subcommittee”:
•
The studies give no evidence of carcinogenic activity of emodin in male rats and female mice,
and equivocal evidence in 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 (108).
IV.1.2 Clinical Data
Siegers C-P et al. 1993
(77) reported about a retrospective study of 3,049 patients, who underwent
diagnostic colorectal endoscopy. The incidence of pseudomelanosis coli, which is regarded as a
reliable indicator of chronic anthranoid laxative abuse (use for more than nine to 12 months), 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% for patients
with no abnormality seen on endoscopy, 9.8% (p=0.068) for patients with adenomas and 18.6% for
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 chronic anthranoid laxative abuse.
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Kune GA et al. 1988
(78) and
Kune GA 1993
(79) reported about 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 etiologic 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) with the risk of colorectal cancer
was found 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
(80) tested whether in these patients laxative use or the endoscopically 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.
Jacobs EJ et White E 1998
(109) examined the associations of colon cancer with constipation and
use of commercial laxatives in a case control study among men and women aged 30 – 62 years (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.
Van Gorkom B et al. 2000
(81) performed a controlled study to evaluate the effects of a highly
purified senna extract (X-Prep®, 2 mg/ml sennoside A and B) on cell proliferation and crypt length in
the entire colon and to clarify the mechanism of the suggested cancer-promoting effects of long-term
senna ingestion. 171 outpatients were randomised into 2 groups. 84 patients received 1 ml/kg (max.
75 ml) X-Prep® taken orally 18 h before colonoscopy. This was followed 3 h later by the oral intake
of 2 litres lavage solution containing polyethylene glycol and electrolytes (Klean-Prep®). Another 1 –
3 litres of this lavage solution were given on the morning of the colonoscopy. The same bowel
preparation, but without senna, was given to 87 patients. From 32 randomised patients (15 with senna,
17 without senna) biopsies were taken. A massive acute loss of cells was found in the senna group
(presumably due to induced, uninhibited apoptosis), with a shortening in the crypts and an increase in
cell proliferation. The authors interpreted these effects as possible signs of a carcinogenic effect, but
also pointed out that in this study patients were treated with a single high dose of senna extract, which
is normally not used for repeated treatment. Furthermore the study population was very small. Others
found no such effects (Hallmann F 2000 (82)).
In his review
Hallmann F 2000
(82) summarises toxicological data of stimulant laxatives and other
freely available compounds such as lactulose. He reported on possible connections between the
increased incidence of (colon) cancer and the use of senna preparations. In retrospective studies, only
a relationship with long-term use of the laxative could be demonstrated.
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Nusko G et al. 2000
(83) performed a prospective case control study at the University of Erlangen to
investigate the risk of anthranoid laxative use for the development of colorectal adenomas or
carcinomas. A total of 202 patients with newly diagnosed colorectal carcinomas, 114 patients with
adenomatous polyps, 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
(84) described 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. Since there had been preliminary reports suggesting a possible role of anthranoid-containing
laxatives in the development of colorectal adenomas and cancer, the authors discouraged their use.
Roberts MC et al. 2003
(110) conducted a population-based, case control study with equal
representation by white and black men and women aged 40 – 80 years. Constipation, defined as fewer
than three reported bowel movements per week, was associated with a greater than two-fold risk of
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
association with laxative use (OR 0.88; 95% CI = 0.69-1.11). The authors did not explicitly mention
anthraquinone-containing laxatives. They mentioned the group “stimulants, fibers, natural remedies,
stool softeners, oils, osmotic agents, enemas, suppositories, and unknown”. They mentioned in
particular phenolphthalein and magnesium.
Ewing CA et al. 2004
(85) reported the case of an 83-year old man, who underwent a left
hemicolectomy for colonic adenocarcinoma and was found incidentally to have melanosis coli
associated with long-term use of the herbal laxative Swiss Kriss®, a senna leaves preparation, not only
in his colonic mucosa, but also in the colonic submucosa and in his pericolonic lymph nodes. Four
more cases were described in the literature (86) in which spindle-shaped, yellow-brown bodies were
seen in the mesentric lymph nodes of patients with melanosis coli. The authors concluded that this
implies that the melanosis pigment-laden macrophages formed in the lamina propria of the colon pass
to the regional lymph nodes and may explain the observation of similar pigment-laden macrophages in
other sites. In addition the authors require further studies to determine whether there is a relation
between the prolonged use of this herbal laxative and colonic adenocarcinoma.
Nilsson SE et al. 2004
(87) 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 secondary to reduced supply of folate and cobolamine might indicate an
increased risk of cancer, and cardiovascular and neurological diseases. The homocysteine level
depends on the supply of folate and cobalamine, which constipation and/or laxative treatment might
compromise. 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 substances. 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.
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IV.1.3 Conclusion
Because of the possible genotoxic or tumourigenic risk in experimental investigations and the results
of Siegers 1993, pharmacovigilance actions for anthranoid-containing laxatives (52) were initiated in
Germany in 1996. The daily dose and the duration of administration were limited. Use in children and
nursing mothers was contraindicated. Use during pregnancy was linked to special conditions (see
chapter III.3 Clinical studies in special populations).
Results of toxicity and carcinogenicity studies in 2004 and 2005 in rats did not reveal any evidence of
carcinogenicity and did not show any notable toxicity. But rats as well as mice and dogs do not
develop a pseudomelanosis coli like humans and guinea pigs and it is therefore questionable if these
results can be extrapolated to humans.
The results of the more recent clinical studies are inconsistent and the question of a possible
carcinogenic risk of long-term use of anthranoid-containing laxatives is still open (90). 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 determine the carcinogenic risk definitely. Therefore the
conditions determined in the pharmacovigilance actions for anthranoid-containing laxatives have to be
maintained for the moment.
Long-term administration of anthranoid-containing medicinal products leads to the development over
a period of 4 – 13 months of 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 anthraquinone-
containing laxatives. This finding disappears 6 – 12 months after stopping chronic laxative
administration (5).
IV.2 Contraindications
During processing steps such as drying, cutting, weighing and filling, senna occasionally causes an
inhalation allergy involving the mucous membranes of the respiratory organs (88). Isolated instances
of various anaphylactic reactions have also been reported in connection with senna administration
(89). Senna leaves should therefore not be used by patients with known hypersensitivity to senna
leaves.
Furthermore, senna leaves 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 (7, 52).
Finally, senna leaves preparations are contraindicated in children under 12 years of age.
IV.3 Special warnings and precautions for use
The following warnings and precautions for use are recommended:
Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products
inducing QT-prolongation, diuretics, adrenocorticosteroids or liquorice root, have to consult a
doctor before taking senna leaves concomitantly (see chapter II.2.2 Interactions).
Like all laxatives, senna leaves 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 a potential or
existing intestinal blockage (ileus).
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If laxatives are needed every day the cause of the constipation should be investigated. Long-term
use of laxatives should be avoided.
Use for more than 1 - 2 weeks requires medical supervision, as outlined in the posology section of
the Community herbal monograph.
Senna leaves preparation should only be used if a therapeutic effect cannot be achieved by a
change of diet or the administration of bulk forming agents (7).
It cannot be assessed definitely if a longer than a brief period of treatment with stimulant laxatives
leads to dependence requiring increasing quantities of the medicinal product, to an atonic colon with
impaired function and to aggravation of the constipation.
Müller-Lissner SA 2005
(111) concluded in his review 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, in contrast, the investigations that do not support such damage are well done.
The studies in the cited references (Smith B 1968 (112); Riemann JF et al. 1980 (113) and 1982 (114);
Berkelhammer C et al. 2002 (115); Meisel JL et al. 1977 (116); Pockros PJ et al. 1985 (117)) showed
abnormalities observed in humans (damage to enteric nerves, smooth muscle atrophy; distension or
ballooning of axons, reduction of nerve-specific cell structures and increase in lysosomes, and
sometimes a total degeneration of whole nerve fibers; short-lived superficial damage to the mucosa).
These were uncontrolled observations and the author therefore concluded that the cause of these
damages can also be the constipation itself or pre-existing changes of unknown aetiology.
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
(118)) did not support the hypothesis that anthraquinone-
containing laxatives are able to provoke relevant degenerative changes in the colonic nerve tissue. But
this investigation was conducted in 11 matched pairs only.
In the light of existing safety concerns, further warnings and precautions for use are recommended:
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.
Patients with kidney disorders should be aware of possible electrolyte imbalance.
When senna leaves preparations are administered to incontinent adults, pads should be changed
more frequently to prevent extended skin contact with faeces (see chapter III.3.1 Use in children).
IV.4 Undesirable effects
Senna leaves may produce abdominal pain and colickly 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 (7, 52).
As mentioned above, hypersensitive reactions (pruritus, urticaria, local or generalised exanthema) may
occur (see chapter IV.2 Contraindications).
Chronic use may lead to disorders in water equilibrium and electrolyte metabolism, and may result in
albuminuria and haematuria.
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 (see chapter II.1.2 Absorption, metabolism and excretion).
Farah MH et al. 2000
(89) published a review article where they presented details of reported adverse
events with herbal medicines received at the Uppsala Monitoring Center of the WHO during the
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period from 1968 – 1997 (8985 individual reports). 101 cases were reported in connection with senna
products. The symptoms listed were epileptic seizures (5 times), circulatory disorders (4), death (3),
intestinal perforation (4), vomiting (6), facial oedema (3), hypertension (3), apnoea (2), hepatitis (2),
bloody stools (2), anaphylactic reaction/shock (2), diarrhoea (11), abdominal pain (9), nausea (8),
pruritus (7), erythema (7), skin rash (5), syncope (5), urticaria (5), vesicular eruption (4).
Due to poor information the data do not permit any meaningful analysis. It is not clear whether these
adverse events occurred with mono-preparations or with combination products; furthermore the
combination partners are not known. A further problem in analysing the database arises from the use
of incomplete or incorrect names for the herbal medicines. In addition, the review article provides no
information about dosage and the patients’ medical history. Adverse events like abdominal pain,
nausea and allergic reactions are known (see above).
Reports of adverse events of epileptic seizures, circulatory disorders and anaphylactic reactions/shocks
were also received by the German Health Authority. These adverse reactions only occurred after
ingestion of high doses of senna preparations for bowel cleansing.
Since 1990 the German Health Authority received 41 reports of adverse events concerning mono-
preparations and 4 reports concerning combination products of senna leaves and fruits.
- Twenty three reports concern ingestion of high dose of senna preparations for bowel cleansing. In 6
reports, where the senna preparation was administered without co-medication, hypersensitive reactions
(angiooedema, skin irritations, dyspnoea) occurred. Hypersensitive reactions are not depending on the
administered dose in principle, These adverse reactions have therefore to be also mentioned in case of
low dose as administered for short-term use in cases of occasional constipation.
- The remaining 22 reports concern the use for constipation. In 19 cases co-medication was
administered and an objective evaluation is therefore not possible. The other 3 reports concern laxative
abuse: albuminuria and haematuria (nephrolithiasis known), vomiting (gastrointestinal infection was
diagnosed later on), abdominal pain (suspicion of ileus, colonoscopy showed melanosis coli).
IV.5 Interactions
See chapter II.2.2
IV.6 Overdose
The major symptoms of overdose/abuse are griping pain 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 adrenocorticosteroids 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 ingestion of overdoses of anthranoid-containing medicinal products may lead to
toxic hepatitis (see below).
Hepatitis
Beuers U et al. 1991
(91) reported a case of toxic hepatitis related to abuse of senna glycosides in a
26-year old female, who had taken an extract of senna fruits corresponding to 100 mg of sennoside B
daily in addition to the usual dose of 10 g senna leaves twice a week in a laxative tea. When the patient
stopped taking senna, aminotransferases fell by 70% within a week and ranged from 20 – 40 U/l
subsequently. When the patient took senna alkaloids again, 2 months later, liver function rapidly
deteriorated and improved once more when the product was stopped.
Vanderperren B et al. 2005
(122) reported a case of a 52-year old woman, who had ingested, for
more than 3 years, one litre of an herbal tea each day made from a bag containing 70 g of dry senna
fruits. She developed renal impairment and acute hepatic failure with increase in prothrombin time
(international normalised ratio > 7) and development of encephalopathy. The patient recovered with
supportive therapy. Surprisingly, large amounts of cadmium were transiently recovered in the urine.
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To asses these two cases of liver impairment, the Roussel UCLAF causality assessment method was
used. In 1993, an international group of experts published the so-called Rucam score to evaluate cases
of hepatotoxicity (
Danan G et al. 1993
(123)). The score was validated and the results published
(
Benichou C et al. 1993
(124)).
Assessment
- Beuers U et al. 1991
Rucam Score +10 highly probable:
Patient had an hepatocellular type hepatitis. One month before
the first signs of hepatitis, the patient had increased the dose of senna alkaloids by taking an extract
of senna fruits corresponding to 100mg sennoside B daily on top of her usual dose of 10 g folia
sennae twice a week in a laxative tea. At this time she was taking 10 times the recommended dose.
When she stopped taking senna, ALT decreased by 70 % within a week. When she took senna again
2 months later, ALT again increased (> 280 U/l; normal range
<
19 U/l). ALT decreased once more
when the drug was again stopped. No concomitant use of other medication could be detected. There
was no evidence for viral, autoimmune, or metabolic disease (rated with +2 points within the Rucam
Score). The histological picture suggested toxic damage.
- Vanderperren B et al. 2005
Rucam Score +4 possible:
Although the value of alkaline phosphatase (AP) is not given, it is
assumed that it was an hepatocellular type of hepatitis (ALT = 9160 IU/l; normal range 14 – 63
IU/l). ALT decreased
>
50 % within 8 days. The authors were unable to document chronic
hepatotoxicity prior to this episode because the patient had never consulted a physician and had no
laboratory workup. The patient regularly took vitamin supplements. Common causes of acute
hepatitis were ruled out by laboratory investigations (no special information). Interpretation is that
the non-drug related causes of the first group were ruled out (rated with +1 point within the Rucam
Score).
According to the Rucam score, the hepatotoxic cases are related to the chronic ingested overdoses.
Nephritis
Nephritis as a response to large doses of anthraquinones is mentioned by
Brunton LL 1996
(125)
without any further information or references.
As mentioned above, Vanderperren B et al. 2005 (122) reported one case with acute liver failure and
renal impairment related to the abuse of senna anthraquinone glycosides. The renal dysfunction in this
patient had the characteristics of secondary mixed proximal and distal renal tubular acidosis. It is
caused by an impairment of bicarbonate reabsorption in the proximal tube. This defect is either
hereditary or secondary to administration of drugs or toxin e.g. cadmium. The tubular defect in this
case is transient. Significant amounts of cadmium were found in the patient’s urine. In the present case
the source of cadmium remained unknown. The authors did not identify metals in a sample of the
herbal tea drunken by the patient. The relationship between this abuse of senna and the renal
impairment is too weak to be mentioned in the Community herbal monograph.
Finger clubbing
Silk DBA et al. 1975
(126) reported a case of a 26-year old female, who was investigated for severe
diarrhoea, which occurred after laparotomy with division of the ligament of Treitz because of a
duodenal ileus and a second laparotomy with a duodenojejunostomy because of persisting vomiting.
No organic cause could be revealed. During the course of her illness the patient had developed finger
clubbing. During a recent hospitalisation more than 2,000 tablets of Senokot® (standardised senna
concentrate; each tablet contains 8.6 mg sennosides) were found in her bedside locker, and a
subsequent analysis of her urine showed that high concentrations of anthranquinone excretion products
were present. After this finding the psychiatric assessment revealed that the patient exhibited many
features typically associated with anorexia nervosa. On stopping the purgatives, her diarrhoea
improved and her finger clubbing regressed. But vomiting and diarrhoea recurred and she admitted to
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take 100 to 200 Senokot® tablets a day. Her finger clubbing also returned 2 to 3 months after she
admitted to reingesting purgatives.
Prior J et al. 1978
(127) reported on a 24-year old woman with anorexia nervosa. Over the past 4
years she was taking increasing quantities of senna (up to 50 tablets daily) to produce a regular stool.
She denied diarrhoea. The patient was thin. She had scoliosis and the fingers and toes were clubbed.
She presented tetany, probably caused by a combination of hypokaliaemia and hyperventilation. The
patient refused to cease laxative abuse.
Malmquist J et al. 1980
(128) reported the case of a young woman with a previous history of
anorexia nervosa (body weight minimum 26 kg, height 1.56 m) and of abuse of alcohol and sedatives
presented with severe finger clubbing. Urine samples intermittently contained significant amounts of
aspartylglucosamine. Liver biopsy showed abnormal cytoplasmic inclusions in phagocytic cells. The
patient reluctantly admitted the daily intake of 2 to 5 tablets of a senna preparation (Pursennid®,
containing 12 mg senna glycoside per tablet) continuously for 10 years. Although she was strongly
advised to discontinue, she could not because attempts to do so cause severe constipation according to
what the patient said.
Levine D et al. 1981
(129) reported the case of a 64-year old woman, who had lost more than 45% of
her healthy weight loss. She had had repeated urinary infections with renal stones over many years,
but diarrhoea had been the chief symptom since 1972. Finger clubbing and hypokaliaemia were
observed in 1975. Hypogammaglobulinaemia and a B-cell deficit were diagnosed. When hospitalised
over 200 Senokot® tablets were found in her locker. Stopping ingestion of senna and increasing food
intake with enteral proprietary supplements led to rapid weight gain. Serum levels of immunoglobulins
rose and a repeat lymphocyte analysis showed B cells in normal numbers. In an interview with a
clinical psychologist, she gave a history of probable anorexia nervosa in early adult life, since when
she had apparently retained the idea that a low bodyweight was desirable.
Armstrong RD et al. 1981
(130) presented a case of a 21-year old woman with a 9-month history of
painful swelling of both ankles followed by painful swelling and morning stiffness affecting proximal
and distal interphalangeal joints of both hands without rheumatic family history. She had intermittent
diarrhoea of three years’ duration. On examination she weighed 49.1 kg. There was clubbing of
fingers and toes with pronounced periungual erythema. Both ankles were swollen, red, and tender, and
there was tenderness of interphalangeal joints of fingers. Radiographs of knees and ankles showed
striking symmetrical bilateral periosteal new bone formation, affecting particularly the ends of the
long bones. The patient confessed to habitually taking at least 3 senna (Senokot®) tablets daily to
control her weight. She also admitted to a period of secondary amenorrhoea of several months’
duration a year before. Her weight subsequently increased to 57.2 kg when she stopped taking the
laxatives. Within 6 months the clubbing had disappeared. Her rheumatic symptoms were less severe
and controlled by NSAID, though the radiological bone abnormalities did not regress.
Assessment
These cases only show symptoms of an overdose and abuse. But all these reported cases have in
common a history of anorexia nervosa with an abuse of senna to control weight. The causality of the
finger clubbing and all other disturbances with this misuse seems to be dubious. The main disease is
anorexia nervosa, which can cause life-threatening disturbances. At this moment, available data are
not strong enough and these effects are not introduced in the Community herbal monograph.
V.
Overall conclusion
Well-established use: short-term use in cases of occasional constipation
The efficacy of senna preparations has been evaluated in clinical trials in the treatment of constipation
and for bowel cleansing before radiological investigations or colonoscopy. In the majority of the
studies combinations of senna with fibre were investigated. For bowel cleansing high doses of a senna
preparation were tested.
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There is no well-designed non-experimental descriptive study with a mono-preparation of senna
available which investigates the short-term use of occasional constipation. Evidence is obtained from
experts’ reports and opinions and extensive clinical experiences.
Well-designed clinical studies are available for combination products for occasional constipation and
for high doses of senna preparations for bowel cleansing and they clarify the pharmacodynamics.
Furthermore pharmacological studies in humans are available (26, 27, 28), even if they show some
shortcomings, e.g. a not validated technique (27). The studies with combination products clearly
identify the additional effect of the senna fraction in the combination products.
Therefore in consideration of all these data the current level of evidence
1
of the available scientific
data for “the short-term use in cases of occasional constipation” can be identified as level III. The
results of the studies with combination preparations show a clear laxative effect additionally to fibre
intake.
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 most recent studies are inconsistent. However, a risk was also revealed for
constipation itself and underlying dietary habits.
The use in children under 12 years of age is contraindicated and use during lactation is not
recommended.
During pregnancy only a specified extract (as described above) can be regarded as safe, but with the
advice that the use is to be avoided during the first trimester. Senna leaves should only be used
intermittently and if other actions like behavioural modification, dietary changes and use of bulk
forming agents failed.
Provided that the correct dose and duration of administration and the advices given in the SPC are
followed, senna can be regarded as a safe and effective medicinal plant for the short-term use in cases
of occasional constipation. In this indication the benefit/risk ratio is positive.
The data available on use for bowel cleansing in a high dose are not consistent. An adequate bowel
cleansing can be achieved as well by other preparation methods than with a high dose of senna with a
less favourable benefit-risk-ratio. In particular if different methods are combined, lower doses of senna
seem to be effective enough. Use at a high dose cannot therefore be recommended.
In an unpublished multicentre, prospective, controlled, randomised, two-parallel-group, observer-blind
study in 133 patients, which was presented in the application procedure of a senna preparation
(150 mg hydoxyanthracene glycosides, calculated as sennoside B) for bowel cleansing a statistically
significant non-inferiority of this preparation in combination with 2 l PEG-ELS could not be shown in
comparison to 4 l PEG-ELS. The descriptive evaluation shows a better bowel cleansing in the rectum,
colon descendens, colon transversum and flexura coli dextra for 4 l PEG-ELS and an equivalent
cleansing for both preparations in the colon sigmoideum , colon ascendens and caecum.
Up to now there is no clear evidence to recommend a specific dose nor a specific combination of
different bowel cleansing methods. No recommendation concerning the use of senna for bowel
cleansing is therefore made in the Community herbal monograph, even not for a special patient group,
who is not able to ingest high amounts of fluid, e.g. patients suffering from cardiac insufficiency.
Traditional use
Senna was traditionally used for purification the blood, bowel and other organs in many diseases. In
former times, such a purification was often the first step to treat a lot of diseases. Such a procedure is
now obsolete. There are no plausible pharmacological data available for the purification of the blood
1
As referred to in the HMPC ‘Guideline on the assessment of clinical safety and efficacy in the preparation of
Community herbal monographs for well-established and of Community herbal monographs/entries to the
Community list for traditional herbal products/substances/preparations’ (EMEA/HMPC/104613/2005)
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and other organs than the bowel, or for use as a cholagogum. In view of possible risks, such traditional
uses cannot be recommended. This is in accordance with the German pharmacovigilance actions for
anthranoid-containing laxatives.
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Source: European Medicines Agency
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