Rhamnus – Frangula bark (Frangulae cortex)
|Latin name of the genus:||Rhamnus|
|Latin name of herbal substance:||Frangulae cortex|
|Botanical name of plant:||Rhamnus frangula l.|
|English common name of herbal substance:||Frangula bark|
Latin name of the genus: Rhamnus
Latin name of herbal substance: Frangulae cortex
Botanical name of plant: Rhamnus frangula L.
English common name of herbal substance: Frangula bark
This assessment report reviews the scientific data available on frangula bark (Rhamnus frangula L. (Frangula alnus Miller)), primarily the clinical data. The
Constipation is a common complaint in 1 – 6% of the
Frangula preparations of the dried bark belong to the stimulant laxatives containing hydroxyanthracene derivatives. According to the CPMP
Frangula preparations have to be regarded as herbal medicinal products with a
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.1.1 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 (C27H30O14; Mr 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
The herbal substance also contains small quantities of other anthraquinone glycosides, dianthrones and the aglycones emodin and
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
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
Longo R 1980 (7) has shown that the aglyka moieties are set free in the gut through bacterial
In comparison to anthrones, anthraquinones are absorbed to a much larger extent (8). This was shown in studies with [14C]rhein anthraquinone and [14C] 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. [14C] 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).
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
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.
These findings are based on investigations with different anthrones deriving also from other
Results of investigations of
Capasso F et al. 1983 (55) in rat isolated colon suggest that the laxative properties of aloin and
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
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
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 ED50 was 3.66 mg/20 g body weight. The ED50 of another frangula extract with 25 % glucofrangulin, 1.5 % frangulin and 0.5 % aglyka was 2.45 mg; the ED50 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).
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
antifungal activity of the
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
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
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
Wei BL et al. 2001 (18) assessed in vitro the
¾ Anticancer effect
Zhang L et al. 1995 (62 and 63) reported on results, obtained with human breast cancer
Zhang L and Hung MC 1996 (64) also investigated the effect of emodin in human
Zhang L et al. 1999 (65) examined whether emodin can inhibit the growth of
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
Chronic use or abuse of frangula preparations may lead to hypokalaemia like the abuse of all
III. Clinical Efficacy
There are no
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
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
It is normally sufficient to take an
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.
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
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
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
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
The composition of one coated tablet Bilicura® was the following: 30mg Extr.
The composition of one coated tablet
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’.
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
The postulated laxative effect of frangula bark is mainly based on pharmacological data, experts’ opinions (CPMP
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.
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
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
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
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
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
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
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
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.
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).
Since the 14th 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
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.
Martindale 1967 (40) frangula bark is described as a mild purgative with properties similar to those of cascara sagrada.
The use of frangula bark as a laxative is mentioned in nearly all
Rarely the external use of the fresh bark is mentioned. The use in skin affections is surprising because other
Furthermore the possible risks described in chapter IV have to be taken into account.
None of the
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
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).
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.
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.
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.
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.
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
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
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
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
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
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
Sonnenberg A and Müller AD 1993 (45) performed a
components, such as fat, meat, alcohol, and
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
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
Nusko G et al. 2000 (47) performed a prospective case control study at the University of Erlangen to investigate the risk of
Willems M et al. 2003 (48) described a case of melanosis coli, which occurred in a
Roberts MC et al. 2003 (71) conducted a
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
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
Because of the possible genotoxic or tumourigenic risk in experimental investigations and the results of Siegers 1993, pharmacovigilance actions for
The results of the most recent studies are inconsistent and the question of a possible carcinogenic risk of
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
In “Goodman & Gilman’s The Pharmacological Basis of Therapeutics” (11th 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
Taking all available data in consideration, the conditions determined in the
Acute toxicity data are available for emodin in mice. The intraperitoneal LD50 (dimethylsulfoxide solvent) is 35 mg/kg; the oral LD50 (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)).
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
Furthermore, like all
The following warnings and precautions for use are recommended:
Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products inducing
Like all laxatives, frangula bark should not be taken by patients suffering from faecal impaction and undiagnosed, acute or persistent
If laxatives are needed every day the cause of the constipation should be investigated. Long- term use of laxatives should be avoided.
Use for more than 1 – 2 weeks requires medical supervision as outlined in the posology section of the Community herbal monograph.
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.
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
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).
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
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).
See chapter II.2.2
Like for all
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
Beuers U et al. 1991 (80) reported a case of toxic hepatitis related to abuse of senna glycosides in a
Vanderperren B et al. 2005 (81) reported a case of a
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
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
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
The current level of evidence1 of the available scientific data for “the
The conditions determined in the pharmacovigilance actions for
The use in children under 12 years of age is contraindicated and use during pregnancy and lactation is not recommended.
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
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