Rhamnus (Frangulae cortex)

COMMUNITY HERBAL MONOGRAPH ON

RHAMNUS FRANGULA L., CORTEX

1. N AME OF THE MEDICINAL PRODUCT

To be specified for the individual finished product.

2. Q UALITATIVE AND QUANTITATIVE COMPOSITION 2 , 3

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

Rhamnus frangula L. ( Frangula alnus Miller),

cortex (frangula bark)

• Herbal substance

dried, whole or fragmented bark of the

stems and branches, standardised

• Herbal preparation

standardised herbal preparations thereof

3. PHARMACEUTICAL FORM

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. C LINICAL PARTICULARS

4.1. Therapeutic indications

Well-established use

Traditional use

Herbal medicinal product for short-term use in

cases of occasional constipation.

2 The material complies with the Ph. Eur. monographs.

3 The declaration of the active substance(s) should be in accordance with relevant herbal quality guidance.

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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 10 – 30

mg hydroxyanthracene derivatives, calculated as

glucofrangulin A, 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.

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.

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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 frangula bark concomitantly.

Like all laxatives, frangula bark 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. Frangula bark preparation should

only be used if a therapeutic effect cannot be

achieved by a change of diet or the administration

of bulk forming agents.

When frangula bark 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

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, frangulin, chrysophanol and

physcion, use is not recommended during

pregnancy.

Lactation

Use during breastfeeding is not recommended as

there are insufficient data on the excretion of

metabolites in breast milk.

After administration of other anthranoids, active

metabolites, such as rhein, are excreted in breast

milk in small amounts. A laxative effect in breast

fed babies has not been reported.

4.7. Effects on ability to drive and use machines

Well-established use

Traditional use

Not relevant.

4.8. Undesirable effects

Well-established use

Traditional use

Hypersensitivity reactions may occur.

Frangula bark 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 overdosage. In such

cases dose reduction is necessary.

Chronic use may lead to disorders in water

equilibrium and electrolyte metabolism and may

result in albuminuria and haematuria.

Furthermore, chronic use may cause pigmentation

of the intestinal mucosa (pseudomelanosis coli),

which usually recedes when the patient stops

taking the preparation.

Yellow or red-brown (pH dependent)

discolouration of urine by metabolites, which is

not clinically significant, may occur during the

treatment.

If other adverse reactions not mentioned above

occur, a doctor or a pharmacist should be

consulted.

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4.9. Overdose

Well-established use

Traditional use

The major symptoms of overdose/abuse are

griping pain and severe diarrhoea with consequent

losses of fluid and electrolytes, which should be

replaced. Diarrhoea may cause potassium

depletion, in particular. Potassium depletion may

lead to cardiac disorders and muscular asthenia,

particularly where cardiac glycosides, diuretics,

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.

5. PHARMACOLOGICAL PROPERTIES

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.

Glucofrangulins and frangulins are respectively 0-

diglycosides and 0-monoglycosides, which are

largely (all β-0-glycosides) not split by human

digestive enzymes in the upper gut and therefore

not absorbed to a large extent. They are converted

by the bacteria of the large intestine into the active

metabolites (emodin-9-anthrone).

There are two different mechanisms of action:

1. stimulation of the motility of the large intestine

resulting in accelerated colonic transit.

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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. The motility effects are

mediated by direct stimulation of colonic

neurons and possibly by prostaglandins.

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-0-linked glycosides are not split by human

digestive enzymes and therefore not absorbed in

the upper gut to a large extent. They are converted

by the bacteria of the large intestine into the active

metabolite (emodin-9-anthrone). Mainly

anthraquinone aglycones are absorbed and

transformed into their corresponding glucuronides

and sulphate derivatives. After oral administration

of frangula bark extract, rhein, emodin and traces

of chrysophanol are found in human urine.

Not required as per Article 16c(1)(a)(iii) of

Directive 2001/83/EC as amended.

After administration of other anthranoids, active

metabolites, such as rhein, pass in small amounts

into breast milk. Animal experiments

demonstrated that placental-passage of rhein is

low.

5.3 Preclinical safety data

Well-established use

Traditional use

There are no studies on single dose toxicity, on

repeated dose toxicity, on reproductive toxicity or

on carcinogenicity.

Experimental data, mainly in vitro tests showed a

genotoxic risk of several anthranoids in the

Salmonella microsome assay, emodin,

chrysophanol and physcion were weakly

mutagenic. No mutagenic effects were observed in

the V79-HGPRT mutation assay and in the

unscheduled DNA synthesis (UDS) assay for

chrysophanol and physcion. Emodin was highly

mutagenic in the V79-HGPRT mutation assay. In

the UDS assay emodin was a string inducer of

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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UDS in primary hepatocytes. Emodin was also

tested with respect to its transforming activity in

C3H/M2 mouse fibroblasts in vitro . In the in vitro

salmonella/microsome mutagen test and the

deoxyribonucleic acid (DNA) repair test of

primary rat hepatocytes emodin and frangulin, an

alcoholic extract of “Rhamnus frangula”, and a

commercial frangula bark preparation showed a

dose-dependent increase in the mutation rate or the

induction of DNA repair.

However, in vivo studies of other anthranoid-

containing herbal substance (senna) in rat

hepatocytes (chromosome aberration test, mouse

spot test, in vivo / in vitro UDS (unscheduled DNA

synthesis) showed no evidence of any genetic

effects.

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.

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.

6. PHARMACEUTICAL PARTICULARS

Well-established use

Traditional use

Not applicable.

7. DATE OF COMPILATION / LAST REVISION

26 October 2006

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Assessment Report

T ABLE OF CONTENTS

I. Introduction

II. Clinical Pharacology

II.1 Pharacokinetics

II.1.1 Phytochemical characterisation

II.1.2 Absorption, metabolism and excretion

II.2 Pharacodynaics

II.2.1 Mode of action

• Laxative effect

• Other effects

II.2.2 Interactions

III. Clinical Efficacy

III.1 Dosage

III.2 Clinical studies

III.2.1 Constipation

III.2.2 Other studies

III.3 Clinical studies in special populations

III.3.1 Use in children

III.3.2 Use during pregnancy and lactation

III.4 Traditional use

IV. Safety

IV.1 Genotoxic and carcinogenic risk

IV.1.1 Preclinical Data

IV.1.3 Conclusion

IV.2 Toxicity

IV.3 Contraindications

IV.4 Special warnings and precautions for use

IV.5 Undesirable effects

IV.6 Interactions

IV.7 Overdose

V. Overall conclusion

Community herbal monograph

annex

References

annex

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III.2.3 Conclusion

IV.1.2 Clinical Data

INTRODUCTION

This assessment report reviews the scientific data available on frangula bark ( Rhamnus frangula L.

( Frangula alnus Miller)), primarily the clinical data. The core-SPC for Frangulae cortex established

in 1994 by the Committee for Proprietary Medicinal Products (CPMP) the German monograph of the

Commission E “Frangulae cortex” (1) and the German pharmacovigilance actions for anthranoid-

containing laxatives of 21 June 1996 (2) were taken into consideration. Due to the lack of specific

clinical data, results of investigations in animals are also referred to. The report also takes into account

the literature presented by the European Scientific Cooperative on Phytotherapy (ESCOP) to support

the monograph “Frangulae cortex (Frangula bark)” (ESCOP Monographs, second edition 2003) (3).

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 (4). The most

commonly used laxatives are either stimulant preparations (containing anthracenic derivatives),

lubricant laxatives (e.g. mineral oils) or bulk forming agents.

Frangula preparations of the dried bark belong to the stimulant laxatives containing

hydroxyanthracene derivatives. According to the CPMP core-SPC, they are intended “for short-term

use in cases of occasional constipation”. This indication is substantiated by empirical data derived

from research into the constituents of frangula bark and their pharmacology and those of other

anthranoid-containing herbal substances. There are only limited clinical data available.

Frangula 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.

Anthraquinone laxatives such as aloe and senna preparations share a tricyclic anthracene nucleus

modified with hydroxyl, methyl, or carboxyl groups to form monoanthrones (54). This report on the

assessment of frangula bark therefore refers also to the assessment report on senna leaves and fruits

and to the assessment report on aloe.

II.

CLINICAL PHARMACOLOGY

II.1

Pharmacokinetics

II.1.1 Phytochemical characterisation

Frangula bark consists of the dried, whole or fragmented bark of the stems and branches of Rhamnus

frangula L. ( Frangula alnus Miller). It contains not less than 7.0 per cent of glucofrangulins,

expressed as glucofrangulin A (C 27 H 30 O 14 ; M r 578.5) and calculated with reference to the dried herbal

substance. The material complies with the European Pharmacopoeia monograph “Frangula bark” (ref.

01/2005:0025).

The constituents with known therapeutic activity of frangula bark are emodin-di- and mono-glycosides

viz . the diglycosides glucofrangulin A (emodin-6-0-α-L-rhamnosyl-8-0-β-D-glucoside) and

glucofrangulin B (emodin-6-0-β-D-apiosyl-8-0-β-D-glucoside) and the monoglycosides frangulins A,

B, C (emodin-6-0-α-L-rhamnoside, emodin-6-0-β-D-apioside, emodin-6-0-β-D-xyloside) and emodin-

8-0-β-D-glucoside.

The herbal substance also contains small quantities of other anthraquinone glycosides, dianthrones and

the aglycones emodin and emodin-9-anthrone (3).

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Lemli J 1965 (5) confirmed the presence of chrysophanol, emodin and emodin dianthrone in the fresh

bark of Rhamnus frangula . In addition he identified the heterodianthrone palmidin C. In the fresh bark,

the glucofrangulins are available in reduced form, in the stored bark in oxidised form. With this

oxidisation a saccharolytic process occurs and the stored bark therefore contains a higher amount of

frangulin and frangulin-emodin.

The anthrone O-glycosides (reduced form) are supposedly responsible for serious side effects seen in

the stomach after oral administration (6). Therefore, the bark should not be used before at least 1 year,

so that oxidation of the anthrones can take place.

II.1.2 Absorption, metabolism and excretion

We refer to the assessment report on “ Cassia senna L. et Cassa angustiolia Vahl, folium”.

Glucofrangulin A and B are the main constituents of frangula bark with known therapeutic activity,

and they belong to the anthraquinone O-glycosides. For glucofrangulin, Longo R 1980 (7) has shown

that the aglyka moieties are set free in the gut through bacterial β-glycosidases. Mainly anthraquinones

aglyka are absorbed.

In comparison to anthrones, anthraquinones are absorbed to a much larger extent (8). This was shown

in studies with [ 14 C]rhein anthraquinone and [ 14 C] emodin. Rhein anthraquinone was absorbed to at

least 37% of the injected dose after intracecal administration and to 50 – 60 % of an oral dose in rats.

[ 14 C] emodin showed the same absorption. The author explains the great difference between rhein

anthraquinone and rhein anthrone in terms of chemical stability and reactivity. Rhein anthraquinone

does not react with unabsorbable substances present in the intestinal mass and is not degraded to

polyphenols. The amount of time which rhein anthrone spends in the intestinal tract is more limited

than for rhein anthraquinone. The absorption of rhein anthraquinone is slowly limited by the

continuous bacterial reduction. After absorption, the aglyka are distributed over the different organs

and tissues of the body. Exact data are missing. The aglyka are excreted in urine (causing the yellow

or redbrown discolouration of the urine) and bile as glucuronides and sulphates. With three substances

(rhein anthrone, rhein and emodin) a fast body clearance was shown.

After oral administration of 600 mg or 400 mg of a powdered frangula extract in 2 volunteers, rhein,

emodin and traces of chrysophanol were found in human urine (67).

Frangula bark acts within 8 to 12 hours due to the time taken for transport to the colon and

metabolisation into the active compounds (3).

II.2

Pharmacodynamics

We also refer to the assessment report on “ Cassia senna L. and Cassa angustiolia Vahl, folium” and

to the assessment report on “ Aloe barbadensis Miller and Aloe (various species, mainly Aloe ferox

Miller and its hybrids)”.

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 defaecation 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

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are perceived differently by the individuals affected (9, 10), due to different concepts of what normal

bowel habits are.

Frangula bark belongs to the stimulant laxatives. Emodin-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. 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 (see the assessment report on “ C assia senna L. et Cassia angustifolia Vahl, folium”).

Results of investigations of Capasso F et al. 1983 (55) in rat isolated colon suggest that the laxative

properties of aloin and 1,8-dihydroxyanthraquinone may depend, at least in part, on increased

prostaglandin synthesis by the intestinal tissue.

Frangula bark predominantly contains the anthranoids as anthraquinones. Therefore it is supposed that

the influence of frangula bark on fluid absorption and on secretion processes is lower than the

influence of other anthranoid-containing herbal substances. Data of a direct clinical comparison of the

effects are missing (8).

Cressari A et al. 1966 (11) investigated different constituents of the frangula bark to evaluate the

laxative effect in comparison to a standard senna leaves extract (amount of anthranoids not mentioned)

in mice. Glucofrangulin and frangulin only showed a laxative effect after oral administration. This

effect was nearly 4 to 5 times stronger than the effect of the senna extract. The effect of emodin was

comparable with the effect of the senna extract. Physcion and chrysophanol had no noteworthy effect.

The administration of a methanolic extract of frangula bark (17.5 % anthranoid glycosides calculated

as 1,8-dihydroxyanthraquinon-glycoside) in mice resulted in a dose dependent decrease of the

intestinal transit time. After oral administration of 50 mg/kg body weight defaecation after 4 h took

place in 20 % of the mice, after oral administration of 100 mg/kg body weight in 40 %. The ED 50 was

mentioned with 121.5 mg/kg body weight (12, 13).

A methanolic extract of frangula bark (23 % glucofrangulin, 2 % frangulin, 0.5 % aglyka) had a

laxative effect in mice with a weight of 20 g after oral administration. The ED 50 was 3.66 mg/20 g

body weight. The ED 50 of another frangula extract with 25 % glucofrangulin, 1.5 % frangulin and 0.5

% aglyka was 2.45 mg; the ED 50 of pure glucofrangulin A was 7.97 mg, of pure frangulin A 2.37 mg

and of pure emodin 4.67 mg /20 g body weight (7).

The administration of an aqueous suspension of 0.6 g pulverised bark (12 mg anthranoids

(glucofrangulin and frangulin) had a laxative effect in humans after 6 to 24 h (12, 14).

• Other effects

¾ Antifungal effect

An alcoholic extract of frangula bark (500 mg dried bark) completely prevented the germination of

spores from Aspergillus fumigatus , Penicillium digitatum and Fusarium oxysporum in the agar

dilution test (15).

Manojlovic NT et al. 2005 (23) reported the results of a preliminary antifungal screening of the

methanol extracts and the major anthraquinone aglyka, alizarin (1,2-dihydroxyanthracene) and emodin

(1,8-dihydroxyanthracene), of Rubia tinctorum and Rhamnus frangula in comparison with the

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antifungal activity of the anthraquinone-containing lichen Caloplaca cerina and its main secondary

metabolite parietin. The methanol extracts were significantly active against the fungi tested:

Trichoderma viride , Doratomyces stemonitis , Aspergillus niger , Penicillium verrucosum , Alternaria

alternata , Aueobasidium pullulans , Mucor mucedo . All three extracts contain anthraquinone

derivatives as major secondary metabolites. However, the major isolated anthraquinone aglyka from

Rubia tinctorum (alizarin), from Rhamnus frangula (emodin) and from Caloplaca cerina (parietin)

were less active against fungi than the corresponding extracts. The Rhamnus frangula extract and

emodin showed an inhibition as follows: Trichoderma viride 63% and 31% respectively; Doratomyces

stemonitis 45% and 41%; Aspergillus niger 41% and 41%; Penicillium verrucosum 25% and18%;

Alternaria alternata 39% and 56%; Aueobasidium pullulans 46% and 41%; Mucor mucedo 68% and

48%.

¾ Antiviral effect

Sydiskis RJ et al. 1991 (16) tested the virucidal effects of hot glycerine extracts from Rheum

officinale, Aloe barbadensis, Rhamnus frangula, Rhamnus purshianus , and Cassia angustifolia against

herpes simplex virus type 1. All the plant extract inactivated the virus. The active components in these

plants were separated by thin-layer chromatography and identified as anthraquinones. Anthraquinone-

glycosides should be ineffective. The extract of Rhamnus frangula was completely virucidal after 15

min incubation with herpes simplex virus type 1. The ID 50 was 0.35µg/mL whilst 0.75µg/ml inhibited

the replication to an amount of 90%. A 90% higher concentration was not cytotoxic against WI-38-

cells and renal cells of monkeys. A purified sample of aloe emodin was prepared from aloin, and its

effects on the infectivity of herpes simplex virus type 1 and type 2, varicella-zoster virus, pseudorabies

virus, influenza virus, adenovirus, and rhinovirus were tested by mixing virus with dilutions of aloe

emodin for 15 min at 37˚C, immediately diluting the sample, and assaying the amount of infectious

virus remaining in the sample. The results showed that aloe emodin inactivated all of the viruses tested

except adenovirus and rhinovirus. Electron microscopic examination of anthraquinone-treated herpes

simplex virus demonstrated that the envelopes were partially disrupted. These results showed that

anthraquinones extracted from a variety of plants are directly virucidal to enveloped viruses.

¾ Antibacterial effect

Wang HH and Chung JG 1997 (61) reported on studies, which were conducted to examine the dose

effects of emodin on inhibition of growth versus DNA damage events in Helicobacter pylori from

patients who had peptic ulcer disease. Inhibition of growth study from H. pylori demonstrated that

emodin caused a dose-dependent growth inhibition in H. pylori cultures. S1 nuclease sensitivity

analysis studies revealed that emodin induced dose-dependent DNA damage in H. pylori . The authors

concluded that these results suggest that there was a possible relationship between the dose response to

emodin and the inhibition of growth and DNA damage in H. pylori .

¾ Effect on platelet aggregation

Teng CM et al. 1993 (17) isolated emodin and frangulin B from the plant Rhamnus formosana .

Emodin inhibited the aggregation of rabbit platelets induced by arachidonic acid and collagen, without

affecting that by ADP (adenosine diphosphat) or PAF (platelet-activating factor), while emodin

acetate had no antiplatelet effect. Frangulin B inhibited selectively and concentration-dependently

collagen-induced aggregation and ATP release in rabbit platelets, without affecting those induced by

arachidonic acid, ADP, PAF and thrombin. Frangulin B also inhibited the platelet aggregation induced

by trimucytin which was reported to be a collagen receptor agonist isolated from Trimeresurus

muscrosquamatus snake venom. The aggregability of platelets inhibited by frangulin B could be

recovered after washing the platelets. Frangulin B also selectively suppressed the thromboxane B2

formation caused by collagen, but not those by arachidonic acid and thrombin. Similarly, the

formation of inositol phosphate caused by collagen was also suppressed by frangulin B, while that of

PAF or thrombin was not affected. In the presence of PGE 1 , frangulin B also decreased Mg(2+)-

dependent platelet adhesion to collagen. The authors concluded that frangulin B may be an antagonist

of collagen receptor in platelet membrane.

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¾ Anti-inflammatory effect

Wei BL et al. 2001 (18) assessed in vitro the anti-inflammatory activities of the isolated

anthraquinone, frangulin B, of Rhamnus formosana by determining its inhibitory effects on the

chemical mediators released from mast cells, neutrophils, macrophages, and microglial cells.

Frangulin B showed potent inhibitory effects on TNF-alpha formation in LPS/IFN-gamma (interferon-

gamma)-stimulated murine microglial cell lines N9.

¾ Anticancer effect

Zhang L et al. 1995 (62 and 63) reported on results, obtained with human breast cancer MDA-MB453

cells, which indicated that emodin inhibits HER-2/neu tyrosine kinase activity and preferentially

suppresses growth and induces differentiation of HER-2/neu -overexpressing cancer cells. The HER-

2/neu proto-oncogene encodes the tyrosine kinase receptor p185neu. Amplification and

overexpression of the gene have frequently been observed in human breast cancer and are correlated

with poor prognosis. The authors concluded that the results may have chemotherapeutic implications

for using emodin to target HER-2/neu overexpressing cancer cells.

Zhang L and Hung MC 1996 (64) also investigated the effect of emodin in human non-small cell

lung cancer (NSCLC) cells in which overexpression of the HER-2/neu proto-oncogene has been also

observed. Emodin decreased tyrosine phosphorylation of HER-2/neu and preferentially suppressed

proliferation of HER-2/neu -overexpressing NSCLC cells. Furthermore, the combination of emodin

with cisplatin, doxorubicin or etoposide (VP16) synergistically inhibited the proliferation of HER-

2/neu -overexpressing lung cancer cells, whereas low doses of emodin, cisplatin, doxorubicin or VP16

alone had only minimal antiproliferative effects on these cells.

Zhang L et al. 1999 (65) examined whether emodin can inhibit the growth of HER-2/neu -

overexpressing tumours in mice and whether emodin can sensitize these tumours to paclitaxel, a

commonly used chemotherapeutic agent for breast cancer patients. Special human breast cancer cells

were injected s.c. into the flanks of female nu/nu (athymic) mice. Three weeks later, when the solid

tumours were palpable, the mice were given either placebo, emodin (40 mg/kg bw), paclitaxel (10

mg/kg bw), or emodin plus paclitaxel by i.p. injection twice a week for 8 weeks. The authors reported

that emodin enhanced the effects of paclitaxel on growth and transformation of HER-2/neu -

overexpressing human breast cancer cells and significantly inhibited tumour growth and prolonged

survival of these mice.

Fenig E et al. 2004 (66) conducted a study to determinate if members of the anthraquinone family

could be used as adjuncts to increase the growth inhibiting effect of anticancer agents in Merkel cell

carcinoma (MCC). An adherent variant of MCC was derived from a previously established MCC cell

line suspension. Emodin and aloe-emodin inhibited proliferation of the adherent MCC cells, with a

slight advantage of aloe-emodin over emodin. Aloin had no effect on cell proliferation. The

chemotherapeutic agents, cis-platinol (abiplastin), doxorubicin (adriablastin), and 5-fluorouracil, and

the tyrosine kinase inhibitor STI 571, all independently inhibited the proliferation of adherent MCC

cells. The addition of aloe-emodin potentiated their inhibitory effect, especially when low

concentrations of the anticancer compounds were used. The addition of emodin was not investigated.

II.2.2 Interactions

Chronic use or abuse of frangula preparations may lead to hypokalaemia like the abuse of all

anthranoid-containing laxatives. This hypokalaemia and the increased loss of potassium may increase

the activity of cardiac glycosides and interfere with the action of antiarrythmic agents (interaction with

antiarrhythmic medicinal products, which induce reversion to sinus rhythm, e.g. quinidine) and

medicinal products inducing QT-prolongation (68). Concomitant use with medicinal products

inducing hypokalaemia (e.g. diuretics, adrenocorticosteroids and liquorice root) may aggravate

electrolyte imbalance.

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The above-mentioned investigations of Teng CM et al. 1993 (17) showed an antagonistic effect of

frangulin B to collagen receptor in platelet membrane. This effect resulted in an inhibition of the

platelet aggregation. Clinical studies in humans are not available. It is unknown whether these

investigations have relevance for the concomitant use with other medicinal products, which inhibit the

thrombocyte aggregation. Until now, data are too poor to give special information on such

concomitant use in the HMPC 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 (20 – 30 mg

hydroxyanthracene derivatives only once daily at night) is supported by experts’ opinions and by

clinical investigations with other anthranoid-containing laxatives like senna preparations. We refer to

the assessment report on “ Cassia senna L. et Cassa angustiolia Vahl, folium”.

The German Commission E monograph “Frangulae cortex” (1) indicates a daily dose of 20 – 30 mg

hydroxyanthracene derivatives calculated as glucofrangulin A, but it recommends that the

pharmaceutical form must allow lower dosages than the usual daily dose.

The ESCOP monograph “Frangulae cortex” (3) also recommends 20 – 30 mg hydroxyanthracene

derivates daily.

The recommendation in the pharmacovigilance actions taken in Germany in 1996 for anthranoid-

containing laxatives after consideration of the toxicological data (2) only determines a daily maximum

limit of 30 mg hydroxyanthracene derivatives.

Through the individual product information (especially the package leaflet), patients should be

informed that the correct individual dose is the smallest required to produce a comfortable soft-formed

motion. It is therefore preferable to recommend a larger range of 10 – 30 mg hydroxyanthracene

derivatives daily.

It is normally sufficient to take an anthranoid-containing laxative up to two to three times a week (69).

III.2

Clinical studies

III.2.1 Constipation

The only available clinical investigations of frangula bark evaluate its efficacy in combination

preparations. There are no controlled clinical studies available.

Fotiades P et al. 1976 (19) investigated the efficacy of Laxariston® in the treatment of constipation; 3

g of this preparation contain 0.9 g methyl cellulose, 0.3 g frangula bark (13.5 mg hydroxyanthracene

derivatives), 0.3 g senna leaves (7.5 mg hydroxyanthracene derivatives), 0.15 g rhubarb root (6.75 mg

hydroxyanthracene derivatives) and 0.015 g achillea extract. Laxariston® was given to 61 inpatients

with mainly arthritic illness (3 g daily for 26.1 days on average) and to 33 outpatients mainly after

abdominal surgery (7.6 g daily for 88.9 days). 31 patients of the whole study population had acute

complaints, 20 patients suffered from chronic constipation and 41 patients from “functional”

constipation. Special complaints are not mentioned in the publication. The time until disappearance of

complaints was evaluated as follows: 0 – 2 days: very good efficacy; 3 – 14 days: good efficacy; 15 –

28 days: satisfactory efficacy; more than 28 days: insufficient efficacy. Laxariston® had a very good

efficacy in 71 patients (77.2%), a good efficacy in 19 patients (20.7%) and a satisfactory efficacy in 2

patients (2.1%). In the group with acute complaints, the efficacy was very good in 77.4% and good in

22.6%. In the group with chronic complaints, the efficacy was very good in 35%, good in 55% and

satisfactory in 10 %. In the group with functional complaints, the efficacy was very good in 97.6% and

good in 2.4%. The tolerance of the preparation was good in all these patients. The efficacy in 2

patients was not evaluated because these patients developed abdominal pain.

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Bauer H 1977 (20) administered Laxariston® (specification defined above) to 73 patients with

gynaecological diseases and to 95 pregnant women suffering from constipation. Special complaints

are not mentioned in the publication.

The first group consisted of 30 patients who underwent a laparotomy in the past, of whom 15 patients

additionally took oestrogens, 6 patients with conservative gynaecological diseases and under

oestrogenic treatment, 7 patients who took oestrogens and other medicinal products, which influence

the intestine motility, 13 patients with pathological-anatomic alteration in the pelvis minor, and 7

patients with constipation not caused by the gynaecological diseases. On average, the women took this

medicinal product for 47.2 days and the complaints disappeared in 5.3 days with a daily dose of 5.3 g.

The time until disappearance of constipation complaints was assessed as follows: 0-3 days: very good

efficacy; 4-5 days: good efficacy; 6-7 days: satisfactory efficacy; >7 days: insufficient efficacy.

Efficacy was very good in 41 patients, good in 20 patients and satisfactory in 11 patients. One patient

dropped out (reason not given). Six patients (8.2%) complained about adverse reactions (spasms,

tenesmus, and nausea) whilst 21 patients (28.8%) reported about positive reactions like weight

reduction, decrease of haemorrhoidal complaints, and decrease of flatulence.

In the second group, 14 pregnant women were in the first 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. Four patients (4.2%) complained about adverse

reactions whilst 29 patients (30.5%) reported about positive 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.

It is worth noting that 3 g of Laxariston® contain 27.75 mg hydroxyanthracene derivatives, of which

nearly 50% derive from frangula bark. A contribution to the efficacy of Laxariston® by frangula bark

is therefore supposable. However, Laxariston® also contains the bulk forming agent methyl cellulose,

which also has a laxative effect.

III.2.2 Other studies

Feldman H et al. 1971 (25) conducted a double-blind trial to evaluate Caved-S tablets in 47 patients

with active duodenal ulcer. Caved-S tablets contained 380 mg deglycyrrhizinated powdered block

liquorice, 100 mg bismuth subnitrate, 100 mg aluminium hydroxide gel, 200 mg magnesium

carbonate, 100 mg sodium bicarbonate and 30 mg powdered frangula bark. The content of

hydroxyanthracene derivatives is not mentioned. Patients received 2 tablets 3 times daily after meals

for 30 days. Tablets were chewed before swallowing. A placebo was administered to 24 patients and

23 patients received Caved-S tablets. Clinical results were similar in both groups. No advantages of

Caved-S over placebo were found. No side effects were observed.

Gracza L et al. 1977 (21) described therapeutic results following the use of Bilicura® in 61

outpatients (22 male, 39 female, 21 – 83 years old) with diseases of the hepatocholegastroenteral

system, and of Spasmo-Bilicura® in 73 outpatients (18 male, 55 female, 28 – 78 years old).

The composition of one coated tablet Bilicura® was the following: 30mg Extr. Kava-Kava sicc. e

rhiz., 40 mg Extr. Cynarae scol. sicc. e fol. recent., 50 mg Extr. Cardui Mariae sicc. e fruct., 20 mg

Extr. Aloes, 20 mg Extr. Frangulae sicc. e cort., 30 mg Fel tauri, 5 mg Oleum Menthae pip., and 0.5

mg guajazulene. The content of hydroxyanthracene derivatives was not mentioned. On average the

patients took 1 – 2 coated tablets three times daily for 2 weeks. The complaints disappeared in 11

patients, considerably decreased in 20 patients, decreased in 18 patients, and remained unchanged in 4

patients. Two patients discontinued because of diarrhoea, and in 6 cases, there were no data available.

A positive efficacy was reported by 80.3 % of the practitioners, and a negative efficacy by 9.9 %.

Adverse reactions occurred in 8 patients, with 6 reports of diarrhoea and 2 reports of headache. The

tolerance was assessed by 12 patients as ‘excellent’, by 45 as ‘good’.

The composition of one coated tablet Spasmo-Bilicura® was the following: 30mg Extr. Kava-Kava

sicc. e rhiz., 40 mg Extr. Cynarae scol. sicc. e fol. recent., 50 mg Extr. Cardui Mariae sicc. e fruct., 10

mg Extr. Aloes, 10 mg Extr. Frangulae sicc. e cort. c. Meth. parat., 30 mg Fel tauri, 5 mg Oleum

Menthae pip., 0.5 mg guajazulene, 0.5 mg L-scopolamine-N-methylbromide, and 10 mg Ethaverin-

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hydrochloride. The content of hydroxyanthracene derivatives was not mentioned. On average the

patients took 1 – 2 coated tablets three times daily for 2 weeks. The complaints disappeared in 23

patients, considerably improved in 30 patients, improved in 9 patients, and remained unchanged in 2

patients. Two patients discontinued because of diarrhoea. Seventeen patients reported immediate

analgesia and 45 patients after 3.2 day on average. In 11 cases there were no data available. A positive

efficacy was reported by 85 % of the practitioners, and a negative efficacy by 5.4 %. Adverse

reactions occurred in 6 patients, with 4 reports of diarrhoea, 1 report of stomach ache and 1 report of

xerostomia. The tolerance was assessed by 9 patients as ‘excellent’, by 22 as ‘good’. No data were

available for 42 patients.

The contribution of each constituent of the preparation cannot be assessed by this investigation. Data

on the amount of hydroxyanthracene derivatives were lacking. The investigated population did not

suffer from constipation.

Arndt EM 1982 (22) observed the effectiveness of the product Cefakliman® when taken orally

during climacteric deficiency symptoms, over a period of one to four months, in four groups of

patients: 1) women in preclimacteric stage; 2) women in the climacterium after prior hormonal

therapy; 3) women in the climacterium without prior hormone therapy; and 4) women in the post

menopause. In each case, 15 patients from these four groups were treated with Cefakliman® drops,

and after the observation period were asked about the subjective improvement of their complaints.

Cefakliman® is a combination preparation containing 5 g Ferrum phosphoricum D8, 1 g Lachesis D6,

10 mg Kalium phosphoricum UT, 1 g Aqua silicata, 7.5 g extract of alchemilla and 12.5 g extract of

frangula bark. The best results were obtained with women in the post menopause with lighter

deficiency symptoms (group 4). Nine women described the treatment success as ‘very good’, 4 women

as ‘good’ and 2 women as ‘satisfactory to adequate’. The success with women in the climacterium

without prior hormonal therapy (group 3) was almost the same. Here 8 women replied with ‘very

good’, 5 women with ‘good’ and 2 women with ‘satisfactory to adequate’. None of the patients from

both these groups assessed the therapeutic success as being ‘inadequate’. The results with women in

the preclimacteric stage (group 1) were almost as good. Eight women were very satisfied, 4 women

described the improvement in their complaints as ‘good’, and 3 women as ‘adequate’. The lowest

therapeutic success was obtained with group 2. No improvement was reported by 6 women, ‘adequate

to satisfactory’ improvement was reported also by 6 women, and only 3 women assessed the

therapeutic success with ‘good’.

III.2.3 Conclusion

There are no recent clinical investigations available, which evaluate frangula bark alone i.e. not in

combination with other laxatives, in a representative study population. Two non-controlled

investigations of the seventies assessed the efficacy of a combination preparation in patients with

constipation; 3 g of this preparation contain 27.75 mg hydroxyanthracene derivatives, of which nearly

50% derive from frangula bark, and 0.9 g of the bulk forming agent methyl cellulose. The daily dose

was 3 to 7.6 g on average. A contribution of frangula bark to the efficacy of the investigated product is

supposable.

The postulated laxative effect of frangula bark is mainly based on pharmacological data, experts’

opinions (CPMP core-SPC, German Commission E monograph, ESCOP monograph) and clinical

experiences. Clinical and pharmacological data obtained on other anthranoid-containing laxatives

(please refer to the assessment report on “ Cassia senna L. and Cassa angustiolia Vahl, folium”) and

the 2 above-mentioned non-controlled investigations with Laxariston® support the efficacy of this

anthranoid-containing herbal substance for short-term use in cases of occasional constipation.

The investigations concerning effectsother than the laxative effect are insufficient to support further

indications. The other effects mentioned in chapter II.2.1 have indeed only been investigated in

experimental studies. Adequate clinical trials are not available.

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III.3

Clinical studies in special populations

III.3.1 Use in children

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 products) to an amount equal or greater than their

age plus 5 g (e.g. 8 g/day at age 3) (24). Change in nutrition should be accompanied with behaviour

modification, e.g. increased physical exercise.

There are no available systematic clinical data, which evaluate the use of frangula bark as a laxative in

children.

According to the ESCOP monograph, the use in children under 10 years of age cannot be

recommended.

According to the “Note for guidance on clinical investigation of medicinal products in the paediatric

population” (CPMP/ICH/2711/99) of 27 July 2000, 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.

As reported above (20), 95 pregnant women suffering from constipation were treated with a

combination preparation containing frangula bark. Most of them were in the third trimester. Twelve

women were gynaecologically treated because of a threatening abortion. Only one of these women

miscarried. No information about the state of the new-borns was given in the publication.

In theory, it is possible that reflex stimulation might occur, involving not only the colon but also

uterine muscles and then might lead to the development of hyperaemia in the pelvic region and to

miscarriage as a result of neuromuscular stimulation of uterine muscles. This explains why this herbal

substance had been misused as an abortifacient agent (12).

Animal experiments demonstrated that placental passage of rhein is small.

Bruggemann IM et al. (26) studied genotoxicity of emodin in the Salmonella/microsome assay, the

sisterchromatid exchange (SCE) assay and the hypoxanthine-guanine-phosphoribosyltransferase

(HGPRT) forward mutation assay with V79 Chinese hamster cells. In the Salmonella/microsome

assay, emodin was found to be positive in TA97, TA100 and TA1537 in the presence of liver

homogenate. In TA1537 a weak direct mutagenicity was also observed. In both mammalian test

systems, no genotoxicity was found either with or without metabolic activation.

Westendorf et al. 1990 (27) reported on the genotoxicity of several structurally related

hydroxyanthraquinones. Frangula bark contains chrysophanol and physcion, albeit in small amounts,

and emodin. In the Salmonella microsome assay, emodin, chrysophanol and physcion were weakly

mutagenic in strain TA1537 in the presence of S9 mix only. Chrysophanol was also weakly mutagenic

in strain T102 without and with exogenous metabolic activation for induction of mutagenicity. No

mutagenic effects were observed in the V79-HGPRT mutation assay and in the unscheduled DNA

synthesis (UDS) assay for chrysophanol and physcion. Emodin was highly mutagenic in the V79-

HGPRT mutation assay. In the UDS assay, emodin was a string inducer of UDS in primary

hepatocytes. Emodin was also tested with respect to its transforming activity in C3H/M2 mouse

fibroblasts in vitro . Emodin was clearly active in this assay.

Helmholz H et al. 1993 (28) investigated the mutagenic and genotoxic activities of the glycosides

emodin and frangulin, of an alcoholic extract of “ Rhamnus frangula ”, and of a commercial frangula

bark preparation Sanurtin N®, using the in vitro salmonella/microsome mutagen test and the

deoxyribonucleic acid (DNA) repair test of primary rat hepatocytes. The anthranoid content of 1 g of

the alcoholic extract was the following: 50.76 mg glucofrangulin, 86.84 mg frangulin, 30.88 mg

emodin, 10.3 mg physcion, and 14.32 mg chrysophanol. One coated tablet of Sanurtin N® contained

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8.28 mg glucofrangulin, 0.21 mg frangulin, <0.1 mg emodin, and physcion and chrysophanol only in

traces. The tests provided evidence of a dose-dependent increase in the mutation rate or the induction

of DNA repair, for the glycosides, the extract of the crude herbal substance and the commercial

preparation. The mutagenic potency was larger for emodin than for the alcoholic extract than for

frangulin than for Sanurtin N®. The authors concluded that phytotherapeuticals based on “ Rhamnus

frangula ” can cause genotoxic effects and are potential tumour promoters.

Mengs U et al. 1997 (59) investigated the potential of emodin to induce micronuclei in polychromatic

erythrocytes (PCEs). Mice of both genders received a single oral dose of 2,000 mg emodin/kg and

were killed 24 and 48 h later. Bone marrow cells were collected from 5 males and 5 females and 2,000

PCEs per animal were scored for the presence of micronuclei. There was no enhancement in the

frequency of micronuclei at both preparation intervals when compared to the negative controls. Blood

level examinations confirmed the systemic availability of emodin. Plasma levels of up to 190 µg

emodin/ml represented concentrations being in the concentration range that induced positive responses

in several genotoxicity cell culture assays.

Jahnke GD et al. 2004 (56) evaluated emodin for potential effects on pregnancy outcome. Emodin

was administered in feed to timed-mated Sprague-Dawley (CD) rats (0, 425, 850, and 1,700 ppm;

gestational day (GD) 6-20), and Swiss Albino (CD-1) mice (0, 600, 2,500 or 6,000 ppm; GD 6-17).

Ingested dose was 0, 31, 57, and ~80-144 mg emodin/kg/day (rats) and 0, 94, 391, and 1005 mg

emodin/kg/day (mice). Timed-mated animals (23-25/group) were monitored for body weight,

feed/water consumption, and clinical signs. At termination (rats: GD 20; mice: GD 17), confirmed

pregnant dams (21-25/group) were evaluated for clinical signs: body, liver, kidney, and gravid uterine

weights, uterine contents, and number of corpora lutea. Fetuses were weighed, sexed, and examined

for external, visceral, and skeletal malformations/variations. There were no maternal deaths. In rats,

maternal body weight, weight gain during treatment, and corrected weight exhibited a decreasing

trend. Maternal body weight gain during treatment was significantly reduced at the high dose. In mice,

maternal body weight and weight gain was decreased at the high dose. Prenatal mortality, live litter

size, fetal sex ratio, and morphological development were unaffected in both rats and mice. At the

high dose, rat average fetal body weight per litter was unaffected, but was significantly reduced in

mice.

The rat maternal lowest observed adverse effect level (LOAEL) was 1,700 ppm; the no observed

adverse effect level (NOAEL) was 850 ppm. The rat developmental toxicity NOAEL was ≥ 1,700

ppm. A LOAEL was not established.

In mice, the maternal toxicity LOAEL was 6000 ppm and the NOAEL was 2,500 ppm. The

developmental toxicity LOAEL was 6,000 ppm (reduced fetal body weight) and the NOAEL was

2,500 ppm.

No in vivo study on reproductive toxicity of frangula bark or frangula bark preparations is available

(3).

Conclusion

Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids (e.g. emodin,

chrysophanol, and physcion). However, in vivo studies of the crude senna herbal substance (please see

the assessment report on “ Cassia senna L. and Cassia angustifolia Vahl, folium”: Chromosome

Aberration Test, Mouse Spot Test, in vivo / in vitro UDS Test in rat hepatocytes ) showed no evidence

of any genetic effects ( Heidemann A et al. 1993 (29)). In vitro assays overestimate the potential

hazard from exposure and must be reevaluated by in vivo experiments.

The NOAELs for emodin defined by Jahnke GD are twice the decimal power and above the maximum

daily dose of hydroxyanthracene derivatives (30 mg).

However, data on frangula bark and its preparations are insufficient and results of available

investigations are not consistent. Use during pregnancy cannot therefore be recommended.

Furthermore, other actions like behavioural modification, dietary changes and use of bulk forming

agents should be the first actions taken during pregnancy to treat constipation.

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Use during lactation is not recommended as there are insufficient data on the excretion of metabolites

in breast milk. Investigations with a “standardised senna laxative” (Agiolax®), which also contains

Plantago ovata seeds/husks as bulk substances, showed that small amounts of active metabolites

(rhein) are excreted in breast milk. No laxative effect in breast fed babies has been reported (30).

III.4 Traditional use

Since the 14 th century frangula has been used as a medicinal plant. The dried bark has been mostly

used as a laxative. Because of its purgative properties, this herbal substance was also used for other

diseases like diseases of the liver, gallbladder and spleen, and for dropsy and scabies.

Madaus 1938 (31) describes that in 1556 Hieronymus Bock mentioned frangula bark in his

“Kreutterbuch” to cure scurf and affected teeth, but did not mention the laxative properties. He

indicates that, in his New-Kreuterbuch in 1626, Matthiolus compared the laxative effect of frangula

bark with the effect of rhubarb and that V. Haller in 1755 recommended the use for dropsy.

Furthermore Madaus mentionsd the use for diseases of the liver, gallbladder and spleen, for scabies

and as antihelminthic. Frangula bark was also an ingredient in teas used for purification of the blood.

The British Pharmaceutical Codex 1911 (32), the Dispensatory of the United States of America

1918 (33) and the Ecletic Materia Medica, Pharmacology and Therapeutics, 1922 (34) mention

frangula bark as a purgative.

In his “Manual of Materia Medica and Pharmacology” Culbreth 1927 (35) mentions the use as a

purgative, tonic and diuretic. The effect resembles that of rhubarb and senna, although milder. Further

indications are dropsy, costiveness, constipation during pregnancy and, as an ointment of fresh bark,

for parasitic skin affection, itch etc.

Hager 1927 (36) refers to frangula bark as a ‘cheap and effective laxative’. Frangula bark is indicated

as also effective for complaints of haemorrhoids and for liver diseases, as a decoction often together

with sodium sulphate. Intoxication causes colics, and the fresh bark causes vomiting.

Thoms 1931 (37) also describes the use a mild effective laxative.

Fischer 1966 (38) mentions the use for constipation and all diseases, which can be associated with

constipation like liver damage, gallbladder complaints, but even headache and decrease of intellectual

power, dizziness, decrease of the ability to see and to concentrate, and heart palpitation.

Dragendorff 1967 (39) describes the emetic effect of fresh bark and the laxative effect of dried bark.

Additionally, there is a mention that the bark is externally used for scabies. He does not specify the

preparation used.

In Martindale 1967 (40) frangula bark is described as a mild purgative with properties similar to

those of cascara sagrada.

Conclusion

The use of frangula bark as a laxative is mentioned in nearly all above-mentioned references. Due to

its laxative properties, the herbal substance was also used as a detoxifier for the blood and other

viscera (liver, gallbladder and spleen). In former times such purification was often the first step to treat

a lot of diseases. Such a procedure is obsolete now. Furthermore there are no plausible

pharmacological data for the purification of the blood and other organs than the bowel.

Rarely the external use of the fresh bark is mentioned. The use in skin affections is surprising because

other anthranoid-containing herbal substances, e.g. senna leaves/pods, can cause skin irritations by

themselves.

Furthermore the possible risks described in chapter IV have to be taken into account.

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None of the above-mentioned uses can therefore be accepted for frangula bark for inclusion in the

‘Community list of herbal substances, preparations and combinations thereof for use traditional herbal

medicinal products’.

IV.

SAFETY

IV.1

Genotoxic and carcinogenic risk

IV.1.1 Preclinical Data

In vivo studies of frangula bark on single dose toxicity, repeated dose toxicity, reproductive toxicity or

on carcinogenicity are not available (3).

As mentioned in chapter III.3 Clinical studies in special populations, toxicological data from in vitro

investigations indicate that several hydroxyanthraquinones might represent a genotoxic risk. However,

in vivo studies of anthranoid-containing herbal substances (senna) showed no evidence of any genetic

effects.

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 (57).

¾ 16-day study in F344/N rats

Groups of 5 male and 5 female rats were fed diets containing 0, 600, 2000, 5,500, 17,000, or 50,000

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 B6C3F 1 mice

The size of the groups and the administered concentrations were the same as described above. The

concentrations correspond in males to average daily doses of approximately 120, 400, 1,200 or 3,800

mg/kg bw and in females to 140, 530, 1,600 or 5,000 mg/kg bw. 50,000 ppm equivalents were not

calculated due to high mortality. All mice exposed to 50,000 ppm died before the end of the study.

Mice in the 17,000 ppm groups lost weight during the study. Feed consumption by 5,500 ppm females

was greater than that by the controls throughout the study. 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.

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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 in males and 60,

130, 240, 500, or 1,100 mg/kg in females. Relative kidney weights of male mice exposed to 1,250

ppm or greater, relative lung weights of males exposed to 625 ppm or greater, and relative liver

weights of female mice exposed to 625 ppm or greater were increased. The incidences and severities

of nephropathy were increased in males and females exposed to 1,250 ppm or greater. The incidences

of renal tubule pigmentation were significantly increased in males exposed to 1,250 ppm or greater.

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 in males and 120, 370,

or 1,100 mg/kg in 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 of all exposed groups of males at 2 years. There were

negative trends in the incidences of mononuclear cell leukaemia in male and female rats, and the

incidences in the 2,500 ppm groups were significantly decreased. In females exposed to 2,500 ppm,

the incidence was below the historical control range; the incidence in males exposed to 2,500 ppm was

at the lower end of the historical control range.

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 administered 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.

©EMEA 2007

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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 (60).

IV.1.2 Clinical Data

Siegers C-P et al. 1993 (41) reported about a retrospective study of 3,049 patients, who underwent

diagnostic colorectal endoscopy. The incidence of pseudomelanosis coli was 3.13% in patients without

pathological changes. In those with colorectal adenomas, the incidence increased to 8.64% (p<0.01),

and in those with colorectal carcinomas it was 3.29%. This lower rate was probably caused by

incomplete documentation of pseudomelanosis coli in those with carcinoma. In a prospective study of

1,095 patients, the incidence of pseudomelanosis coli was 6.9% in patients with no abnormality seen

on endoscopy, 9.8% (p=0.068) in patients with adenomas and 18.6% in patients with colorectal

carcinomas. From these data a relative risk of 3.04 (1.18, 4.9; 95% confidence interval) can be

calculated for colorectal cancer as a result of anthranoid laxative abuse if the pseudomelanosis coli in

patients with no abnormality is calculated with 1 %.

Kune GA et al. 1988 (42) and Kune GA 1993 (43) 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 (44) 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.

Sonnenberg A and Müller AD 1993 (45) performed a meta-analysis, since individual case control

studies have failed to resolve the question whether constipation and use of cathartics (purgatives)

represent significant risk factors of colorectal cancer. The analysis of 14 previously published (from

1954 to 1988) case control studies revealed statistically significant risks for colorectal cancer

associated with both constipation and use of cathartics, the pooled odds ratios (OR) and their 95

percent confidence intervals being 1.48 (1.32-1.66) and 1.46 (1.33-1.61), respectively. The increased

risk applied similarly to both sexes, it was higher in cancer of the colon than rectum. Since

constipation and cathartics are associated with much lower odds ratios than various dietary

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components, such as fat, meat, alcohol, and low-vegetable or low-residue diets, the authors concluded

that their risk reflects the confounding influence of underlying dietary habits.

Loew D et al. 1994 (46) conducted a comparative study involving 423 patients with colorectal

neoplasms and 522 patients with benign proctologic disorders who were regular users of laxatives for

bowel regulation. A pseudomelanosis coli (PMC) test was used as an indicator of exposure to

anthranoid-containing laxatives to determine if these preparations were potential colorectal

carcinogenics. Results indicated no significant difference of the PMC rates between carcinoma (6.1%)

and the control groups (4.2%) (p≤0.197).

Jacobs EJ et White E 1998 (70) 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.

Nusko G et al. 2000 (47) performed a prospective case control study at the University of Erlangen to

investigate the risk of anthranoid-containing laxative use for the development of colorectal adenomas

or carcinomas. A total of 202 patients with newly diagnosed colorectal carcinomas, 114 patients with

adenomatous polyp, and 238 patients (controls) with no colorectal neoplasm who had been referred for

total colonoscopy were studied. The use of anthranoid preparations was assessed by standardised

interview, and endoscopically visible or microscopic melanosis coli was studied by histopathological

examination. There was no statistically significant risk of anthranoid use for the development of

colorectal adenomas (unadjusted odds ratio 1.0; 95% CI 0.5-1.9) or carcinomas (unadjusted odds ratio

1.0; 95% CI 0.6-1.8). Even after adjustment for the risk factors age, sex, and blood in the stools by

logistic regression analysis the odds ratio for adenomas was 0.84 (95% CI 0.4-1.7) and for carcinomas

0.93 (95% CI 0.5-1.7). Also, there were no differences between the patient and control groups for

duration of intake. Macroscopic and high grade microscopic melanosis coli were not significant risk

factors for the development of adenomas or carcinomas.

Willems M et al. 2003 (48) 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. From a practical point of view, the authors discouraged the use of anthranoid-containing

laxatives, although they stated that “the role of the short-term use of the laxative in the development of

this patient’s adenoma is highly speculative” because he “clearly was at risk for developing colonic

neoplasm considering his long-standing ulcerative colitis in association with primary sclerosing

cholangitis and the use of immunosuppressive medication after liver transplantation”. The authors

stated that it remains controversial whether melanosis coli is associated with an increased risk for

colorectal cancer because of controversial results of several investigations.

Roberts MC et al. 2003 (71) 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,

©EMEA 2007

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stool softeners, oils, osmotic agents, enemas, suppositories, and unknown”. They mentioned in

particular phenolphthalein and magnesium.

Nilsson SE et al. 2004 (49) 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 cobalamine, 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 products. Values were adjusted

for age, gender and frailty, as well as for clinical diagnoses and medicinal therapies known to affect

homocysteine levels. Homocysteine levels were increased and those of folate reduced in aged subjects

on laxatives. Homocysteine remained elevated after adjusting for frailty and various neurological

disorders. There was no significant effect on homocysteine and folate in constipated subjects without

laxatives.

Jae Sik Joo et al. 1998 (50) investigated changes occurring on barium enema in patients ingesting

stimulant laxatives. The study consisted of two parts. In part 1, a retrospective review of consecutive

barium enemas performed on two groups of patients with chronic constipation (group 1, stimulant

laxative use (n=29); group 2, no stimulant laxative use (n=26)) was presented to a radiologist, who

was blinded to the patient group. A data sheet containing classic descriptions of cathartic colon

(historic term for the anatomic alteration of the colon secondary to chronic stimulant laxative use) was

completed for each study. Chronic stimulant laxative use was defined as stimulant laxative ingestion

more than three times per week for 1 year or longer. To confirm the findings of the retrospective

study, 18 consecutive patients, who were chronic stimulant laxative users underwent barium enema

examination, and data sheets for cathartic colon were completed by another radiologist (part 2).

Colonic redundancy (group 1, 34.5%; group 2, 19.2%) and dilatation (group 1, 44.8%; group 2, 23.1

%) were frequent radiographic findings in both patient groups and were not significantly different in

the two groups. Loss of haustral folds, however, was a common finding in group 1 (27.6%) but was

not seen in group 2 (p<0.005). Loss of haustral markings occurred in 15 (40.5%) of the total stimulant

laxative users in the two parts of the study and was seen in the left colon of 6 (40%) patients, in the

right colon of 2 (13.3%) patients, in the transverse colon of 5 (33.3%) patients, and in the entire colon

of 2 (13.3%) patients. Loss of haustra was seen in patients chronically ingesting bisacodyl,

phenolphthalein, senna, and casanthranol. The authors concluded that long-term stimulant laxative use

results in anatomic changes in the colon characterised by loss of haustral folds, a finding that suggests

neuronal injury or damage to colonic longitudinal musculature caused by these agents.

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 (2) were initiated in

Germany in 1996 : the daily dose and the duration of administration were limited and children,

pregnant women and nursing mothers were excluded from the application of frangula bark containing

laxatives.

The results of the most recent studies are inconsistent and the question of a possible carcinogenic risk

of long-term use of anthranoid-containing laxatives is still open. 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.

There are also data available suggesting an antitumourigenic effect of emodin, but only to specific

cancer cells (see chapter II.2.1 Mode of action).

In his review article Van Gorkom BA 1999 (51) concluded that although the short-term use of

anthranoid laxatives is generally safe, long-term use cannot be recommended.

©EMEA 2007

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In “Goodman & Gilman’s The Pharmacological Basis of Therapeutics” (11 th edition 2006) (54) the

following conclusion is drawn about anthraquinone laxatives: “Regardless of whether a definitive

causal relationship can be demonstrated between the use of these agents and colonic pathology, they

should not be recommended for chronic or long-term use.”

Taking all available data in consideration, the conditions determined in the above-mentioned

pharmacovigilance actions for anthranoid-containing laxatives (2) 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 anthranoid-containing

laxatives. This finding disappears 6 – 12 months after stopping chronic laxative administration.

Long-term stimulant laxative use may result in anatomic changes in the colon characterised by loss of

haustral folds.

IV.2

Toxicity

Acute toxicity data are available for emodin in mice. The intraperitoneal LD 50 (dimethylsulfoxide

solvent) is 35 mg/kg; the oral LD 50 (dimethylsulfoxide solvent) is greater than 1,000 mg/kg (58).

Repeated dose toxicity studies with emodin was conducted by the National Toxicology Program of the

United States of America (see above (57)).

IV.3

Contraindications

Frangula bark preparations should not be used by patients with known hypersensitivity to frangula.

The German Health Authority has received one report of an adverse event concerning allergic

reactions. After administration of lactulose and frangula extract for constipation, a 74-year old woman

developed urticaria the same day and collapsed the next day. She was treated with Hygroton®

(hypertension), Rohypnol® (sleep disturbance) and Lexotanil® (nervousness) for a long time. Both

medicinal products, lactulose and frangula extract, were regarded as suspect. No further information is

available.

Furthermore, like all anthranoid-containing laxatives, frangula bark-containing medicinal products

should not be used in cases of intestinal obstructions and stenosis, atony, appendicitis, inflammatory

colon diseases (e.g. Crohn’s disease, ulcerative colitis), abdominal pain of unknown origin, severe

dehydration states with water and electrolyte depletion.

IV.4

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 frangula bark concomitantly (see chapter II.2.2 Interactions).

Like all laxatives, frangula bark 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.

©EMEA 2007

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Use for more than 1 - 2 weeks requires medical supervision as outlined in the posology section

of the Community herbal monograph.

Frangula bark preparations should only be used if a therapeutic effect cannot be achieved by a

change of diet or the administration of bulk forming agents.

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 (72) 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 (73); Riemann JF et al. 1980 (74) and 1982 (75);

Berkelhammer C et al. 2002 (76); Meisel JL et al. 1977 (77); Pockros PJ et al. 1985 (78)) 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).

They 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 (79)) 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 stimulating laxatives are taken for longer than a brief period of treatment, this may lead to

impaired function of the intestine and dependence on laxatives.

Patients with kidney disorders should be aware of possible electrolyte imbalance.

When frangula bark preparations are administered to incontinent adults, pads should be changed

more frequently to prevent extended skin contact with faeces (52).

IV.5 Undesirable effects

Like all anthranoid-containing laxatives, frangula bark preparations 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 (2).

As mentioned above, hypersensitive reactions may occur.

Chronic use may lead to disorders in water equilibrium and electrolyte metabolism.

Dahlmann W et al. 1977 (53) reported the case of a 39-year old woman, who developed

hypokalaemia (1.5 mmol/l) with generalised paralysis, reversible organic brain syndrome, and cardiac

dysrhythmias after 15 years of laxative use (Tirgon®, a combination preparation of 5 mg bisacodyl,

30 mg Extr. Cort. Frangulae spir. Sicc., 4 mg Extr. Rhei, 1.5 mg Ol. Carvi, 1.5 mg Ol. Menth. pip.).

Under continuous and cautious administration of potassium the cardiac rhythm became normal within

four days and two days later the paralysis and organic brain syndrome almost disappeared. The cause

of the psychiatric symptoms is thought to be cerebral potassium deficiency and an abnormal

sodium/potassium equilibrium.

©EMEA 2007

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Chronic use 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 (see

chapter IV.1.3 Conclusion).

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).

IV.6

Interactions

See chapter II.2.2

IV.7

Overdose

Like for all anthranoid-containing laxatives, 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 (80) 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 (81) 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.

According to the Rucam score ( Roussel UCLAF causality assessment method - for detailed

information, please see the assessment report on “ Cassia senna L. and Cassia angustifolia Vahl,

folium”), these hepatotoxic cases are related to the chronic ingestion of overdoses. Rhamnus frangula

L., cortex being an anthranoid-containing herbal substance, the possibility of toxic hepatic reactions is

referred to in the section ‘Overdose’ of the Community herbal monograph on frangula bark.

OVERALL CONCLUSION

Well-established use: short term use in cases of occasional constipation

There are no recent clinical investigations available, which evaluate frangula bark alone, i.e. not in

combination with other laxatives, in a representative study population. Two non-controlled

investigations of the seventies assessed the efficacy of a combination preparation in patients with

constipation. This preparation contains 27.75 mg hydroxyanthracene derivatives, of which nearly 50%

derive from frangula bark, and the bulk forming agent methyl cellulose. A contribution of frangula

bark to the efficacy of the investigated preparation is deducible.

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The postulated laxative effect of frangula bark is mainly based on pharmacological data, experts’

opinions and clinical experiences. Clinical and pharmacological data obtained on other anthranoid-

containing laxatives (primarily senna leaf preparations) and the 2 non-controlled investigations with

Laxariston® support the efficacy of this anthranoid-containing herbal substance for short-term use in

cases of occasional constipation.

The current level of evidence 1 of the available scientific data for “the short-term use of occasional

constipation” can be identified as level III to IV because well-designed studies with mono-

preparations of frangula bark are missing, but 2 uncontrolled investigations are available.

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 pregnancy and lactation is

not recommended.

Traditional use

Due to its laxative properties, frangula bark was used as a detoxifier for the blood and other viscera. 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 related to the purification of the blood and

other organs than the bowel.

External use of frangula bark was rare and preparations used are not described exactly. The use in skin

affections is actually surprising because anthranoid-containing laxatives can cause skin irritations.

In view of existing possible risks, such traditional uses cannot be recommended and referred to in the

‘Community list of herbal substances, preparations and combinations thereof for use traditional herbal

medicinal products’. This is in accordance with the German pharmacovigilance actions for anthranoid-

containing laxatives.

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)

©EMEA 2007

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Source: European Medicines Agency

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Herbal Medicines for Human Use

Herbal Medicines
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