Rheum – Rhubarb (Rhei radix)
|Latin name of the genus:||Rheum|
|Latin name of herbal substance:||Rhei radix|
|Botanical name of plant:||Rheum palmatum l.; rheum officinale baillon|
|English common name of herbal substance:||Rhubarb|
Latin name of the genus: Rheum
Latin name of herbal substance: Rhei radix
Botanical name of plant: Rheum palmatum L.; Rheum officinale Baillon
English common name of herbal substance: Rhubarb
- TABLE OF CONTENTS
- II. ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS THEREOF WITH WELL-ESTABLISHED USE AND/OR TRADITIONAL USE 4
- REGULATORY STATUS OVERVIEW1
- II.ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS THEREOF WITH WELL-ESTABLISHED USE AND/OR TRADITIONAL USE
- BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
- (WELL-ESTABLISHED USE)
- BASED ON ARTICLE 16 D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
- (TRADITIONAL USE)
- II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- Primary pharmacodynamics
- Secondary pharmacodynamics
- Safety pharmacology
- Pharmacodynamic interactions
- II.2.1.2 Assessor’s overall conclusions on pharmacology
- II.2.2 Pharmacokinetics
- II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- Absorption, distribution, metabolism, elimination
- Pharmacokinetic interactions
- II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
- II.2.3 Toxicology
- II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- II.2.3.2 Assessor’s overall conclusions on toxicology
- II.3.1 Clinical Pharmacology
- II.3.1.1 Pharmacodynamics
- II.188.8.131.52 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.3.1.2 Pharmacokinetics
- II.184.108.40.206 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.3.1.3 Assessor’s overall conclusions on pharmacodynamics and pharmacokinetics
- II.3.2 Clinical Efficacy3
- II.3.2.1 Dose response studies
- II.3.2.2 Clinical studies (case studies and clinical trials) Laxative effect
- Fotiades P et al. 1976
- Bauer H 1977
- Borgia M et al. 1985
- Moser EH and Hübner WD 2002/2003
- Other effects
- II.3.2.3 Clinical studies in special populations (e.g. elderly and children) Use in children
- II.3.2.4 Assessor’s overall conclusions on clinical efficacy
- II.3.3 Clinical Safety/Pharmacovigilance
- II.3.3.1 Contraindications
- II.3.3.2 Special warning/precautions for use
- II.3.3.3 Adverse events
- II.3.3.6 Safety in special populations and situations
- II.220.127.116.11 Drug interactions
- II.18.104.22.168 Use in pregnancy and lactation
TABLE OF CONTENTS
II. ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS THEREOF WITH
WELL-ESTABLISHED USE AND/OR TRADITIONAL USE 4
REGULATORY STATUS OVERVIEW1
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ’Not Known’
1This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
2Not mandatory field
II.ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS THEREOF WITH
WELL-ESTABLISHED USE AND/OR TRADITIONAL USE
RHUBARB (RHEI RADIX) AND HERBAL PREPARATION(S) THEREOF WITH WELL-
ESTABLISHED USE AND/OR TRADITIONAL USE
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
BASED ON ARTICLE 16 D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Rhubarb belongs to the
Chirikdjian JJ et al. 1983 isolated physcion diglycoside from rhubarb roots and showed that this compound had a laxative activity similar to physcion monoglycoside in mice, orally administered, although with physcion diglycoside the onset of the purgative effect was observed 2 hours later than with physcion monoglycoside. Physcion itself showed no remarkable effect. Only higher doses (300 and 450 mg/kg b.w.) slightly increased the number of defaecations. Stool consistency did not change (7).
Harima S et al. 1994 measured sennoside A content in
Yagi T et al. 1997 tried to explore the mechanism involved in the synergistic purgative action of
achieve net secretion, at ½ dose. The mixture significantly decreased net water absorption and reversed it into net secretion at this dose. These anthrones did not stimulate mucus secretion in the colon lower than ½ dose. The authors conclude that the synergistic purgative effect of
Yagi T et al. 1999 investigated the purgative effects of intracaecally administered rhein anthrone and anthraquinones such as
Rhubarb acts within 8 to 12 hours due to the time taken for transport to the colon and metabolisation into the active compounds (4). The content of tannin agents may possibly counteract the laxative effect of the anthraquinones , and rhubarb is therefore considered to be a milder laxative than other anthraquinones.
Due to the content of tannin agents rhubarb preparations were used for diarrhoea, for gastritis and enteritis, and as a styptic (3, 4).
Bae EA et al. 1998 tested different herbal substances for their inhibitory effect on Helicobacter pylori (HP) and on the HP urease in vitro. HP was isolated from the gastric antrum of chronic gastric patients. HP also produces a vacuolating toxin and its toxicity may be potentiated by
Sydikes RJ et al. 1991 tested the virucidal effects of hot glycerine extracts from Rheum officinale, Aloe barbadensis, Rhamnus frangula, Rhamnus purshianus, and Cassia angustifolia against herpes simplex virus type 1. All the plant extract inactivated the virus. The active components in these plants were separated by
Hsinag CY et al. 2001 screened 31 herbs in 5 different preparations (cold aqueous, hot aqueous, ethanolic, acidic ethanolic, and methanolic) for their antiviral activities. 7 extracts, which showed significant antiviral activities, were further investigated for their antiviral mechanisms in vitro. Ethanolic extract of Rheum officinale prevented the process of Herpes simplex attachment and penetration (12).
Blaszczyk T et al. 2000 screened 56 dried Chinese plants for their antimycotic properties in vitro. They used 10 % aqueous extracts. The extract of Rheum palmatum L. (radix et rhizoma) showed antimycotic activity against Aspergillus fumigatus and Candida albicans comparable to that of nystatin. The growth of Geotrichum candidum and Rhodotorula rubra was also inhibited, but to a lesser extent (13).
Cyong JC et al. 1987 screened in vitro 178 Chinese herbs for their antibacterial activity against Bacteroides fragilis, a major anaerobic microorganism in the intestinal flora in humans. Only rhubarb root (Rheum officinale) was found to have significant activity and the purified active substance was identified as rhein. Rhein also has potent activity against
Candida albicans and weak activity against Escherichia coli and Bacillus subtilis. Negligible or no activity was shown against e.g. Enterobacter aerogenes, Pseudomonas aeruginosa, Salmonella typhimurium, and Staphylococcus aureus (14).
Several in vivo animal investigations deal with renal failure.
Yokozawa T et al. 1984 (16), 1985 (21), 1986 (17) and 1987 (22) examined the effect of orally administered aqueous extract of roots of Rheum officinale Baillon in rats with chronic renal failure induced by an adenine diet. The herbal preparation caused a marked decrease of blood urea nitrogen and creatinine, and a decrease of methylguanidine and guanidinsuccinic acid levels. Hypocalcaemia, hyperphosphataemia, and free amino acid patterns were also improved.
Yokozawa T et al. 1997 administered an aqueous dry extract of rhubarb (Rheum officinale Baillon) 125 mg/kg b.w./day orally to rats with diabetic nephropathy induced by subtotal nephrectomy and injection of streptozotocin for 80 consecutive days. High blood and urinary glucose levels were ameliorated. Furthermore, improvement of hyperlipidaemia, and accelerated excretion of urinary urea nitrogen and creatinine were observed. The changes were significant compared to untreated controls (18).
Zhang G et al. 1996 studied the effect of orally administered aqueous extract of dry roots of Rheum palmatum (150 mg/day from day 30 to day 120 in drinking water) on the course of chronic renal failure in rats submitted to subtotal nephrectomy. Rhubarb treatment had no effect on the systemic hypertension.
Kosuge T et al. 1985 tried to identify the anticoagulative principle of Rheum palmatum L. by a combination of partition, fractional precipitation and column chromatography on silica gel and plasma recalcification time in mice, because the herb is used as an anticoagulant and haemostatic agent in Chinese medicine.
Several investigations deal with the possible anticancer effect of Rheum palmatum, especially with emodin isolated from the root.
An extract of Rheum palmatum L. increased the sensitivity to paclitaxel at a concentration of 10 µg/ml and 50 µg/ml significantly, not to
A cytotoxic anthraquinone glycoside, pulmatin,
isolated two stilbene glycosides,
An in vitro investigation shows that emodin, selectively inhibits casein kinase II (CKII), a Ser/Thr kinase, as a competitive inhibitor (24).In human lung adenocarcinoma cells emodin induces apoptosis through a reactive oxygen
Kazuhiro S et al. 2000 reported about phytoestrogen properties of emodin isolated of an aqueous extract of the rhizome of Rheum palmatum for the first time. Emodin binds to the estrogen receptor and activates transcription through estrogen responsive elements (ERE). However, the exact mechanism is still unclear. The inhibition of casein kinase II (CKII) by emodin may play a role because this kinase phosphorylates
Several Chinese plant extracts were tested to screen pharmacological activities that could be relevant to the treatment of cognitive disorders. A simple and rapid enzyme essay on thin layer chromatography (TLC) plates has been developed for the screening of acetylcholinesterase and butyrylcholinesterase inhibition in plant extracts. The hexane extract of Rheum officinale Baillon showed a clear activity whereas the methanolic and the chloroform extract showed no activity (38).
There are no special investigations available.
Chronic use or abuse of rhubarb preparations may lead to hypokalaemia like the abuse of all
II.2.1.2 Assessor’s overall conclusions on pharmacology
The postulated laxative effect is supported by the pharmacological data, even if the most data derive from investigations with isolated constituents of rhubarb and not with the preparation or the herbal substance itself. Pharmacological data obtained from other anthranoid- containing laxatives complete these scientific findings.
In Asia (China, Japan) rhubarb is used as an anticancer agent among others. Therefore several investigations try to clarify the underlying pharmacodynamic actions. Up to now the clinical relevance of the findings is doubtful.
The phytoestrogen properties of emodin need to be confirmed and to elucidated by further investigations.
II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Absorption, distribution, metabolism, elimination
No pharmacokinetic data obtained with rhubarb or its preparations are available.
According to Witte P and Lemli L 1990 (31)
In the case of senna, animal experiments with
Experiments with radiochemical anthranoids showed a significant clearance of
After oral administration of 4.5 mg/kg
Emodin was admininstered to rabbits by i.v. bolus. The AUC of emodin was 518 µg.min/ml, clearance was 72.3 ml/min, and elimination half life was 227 min. Oral administration at 10 mg/kg b.w. resulted in a very low serum concentration (approximately 2.5 µg/ml). Emodin was found to be highly bound (99.6%) to serum protein, investigated by the equilibrium dialysis method (34).
Müller SO et al. 1998 (35) presented studies which were designed to elucidate the enzymes involved in the biotransformation of naturally occurring
Takara K et al. 2005 (36) concluded an inhibition of MDR1 function in tumour cells by a rhubarb extract from their
This might be a hint that rhubarb influences this transport system in some way but up to now this hint is too weak to draw some conclusion concerning possible interactions.
A recherche in the database XMEDALL with the keywords “rhubarb (Rheum)” and “MDR” or “PGP (glycoprotein)” did not show any further publications. There are no reports of clinical relevant pharmacokinetic interactions available. We also take into account that rhubarb is only used for short term.
II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
The data available concerning some pharmacokinetics interactions are too weak to draw some conclusions.
II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
No specific data are available for single dose toxicity and reproductive toxicity for rhubarb or the preparations thereof.
The study of Yan M et al. 2006 focuses on the toxicity of total rhubarb (rhizomes of Rheum palmatum L.) anthraquinones (TRAs) on Sprague Dawley rats. TRAs were orally administered for 13 weeks. 20 animals were randomly allocated into four groups. TRAs were dissolved in 0.5% sodium carboxymethylcellulose solution and each group was administered per os once daily for 13 weeks a dose of 0, 140, 794, 4500 mg/kg b.w. After that, rats were sacrificed under halothane anesthesia and all main organs and glands were taken for pathohistology studies. In the highest dose group, nephrotoxicity were discernible at 13 weeks. There was no clear morphologic change in the kidney of the control group, while in TRAs tested group, swelled and denatured renal tubule epithelial cells were observed. The results of gene differential expression study indicated the TRAs affect mostly at oxidative stress pathway, cell cycles, nutrients metabolism, thus caused renal tubule epithelial cells swelled and denatured in histopathology study. CYP1A1, which is regarded as a carcinogen- metabolising enzyme, was dramatically
According to the authors therapeutic dosage of TRAs is 420 mg/day, 7 mg/kg b.w. respectively, if one person weighs 60 kg. The dosage used in the experiment is 642 times ordinary clinical dose (39).
Paneitz et al. 1999 compared ethanolic extracts of different Rheum species with respect to their mutagenicity in the Salmonella/microsome assay with strains TA 98, TA 100 and TA 1537. The root extract of Rheum officinale Baillon was weakly mutagenic in strain TA 1537 even without metabolic activation at a dosage of 300 µg/plate and the effect is enhanced by addition of
In a dose 5 mg/plate, an aqueous extract (1:6) of Rhei radix (no further specification is given) had a mutagenic effect on Salmonella typhimurium TA 98 following metabolic activation with
Further data exist for different hydroxanthraquinones and other
Older toxicological data indicate that the two hydroxyanthraquinones, emodin and aloe- emodin might represent a genotoxic or carcinogenic risk (Mori 1990 (42), Siegers 1992 (43), Brusick 1997 (44)). While most studies gave negative responses, results from some of the studies suggest a genotoxic activity by both (Wölfle 1990 (45), Westendorf 1990 (46), Westendorf 1993 (47)). These were Ames tests showing an interaction with Salmonella DNA resulting in the production of frameshift mutations (Westendorf 1990 (46), Sandnes 1992 (48), Heidemann 1993 (49)). Other sennosides and rhein were mostly negative in the respective tests. In three in vivo studies the crude senna herbal substance at a concentration of 1 or 1.5 g/kg body weight showed no evidence of any genetic effects (Heidemann 1993 (49)). In vitro assays overestimate the potential hazard from exposure and must be reevaluated by in vivo experiments.
Westendorf et al. 1990 (46) reported that in the Ames test
assay for chrysophanol and physcion. Emodin was highly mutagenic in the
Sandnes D et al. 1992 (48) investigated the mutagenicity of senna glycosides and extracts of senna folium and senna fructus in the Salmonella typhimurium reversion assay. Senna glycosides were inactive in all strains, except for a slight, but significant increase in mutant frequency in TA102 in the absence and presence of liver microsomes. Extracts of senna fructus and senna folium demonstrated weak activity in TA97a, TA100 and TA102 in the presence of liver microsomes, and in TA97a and TA102 in the absence of liver microsomes. A strong increase in mutant frequency (3- to
Helmholz H et al. 1993 (114) investigated the mutagenic and genotoxic activities of the glycosides emodin and frangulin, and of an alcoholic extract of frangula bark, and of a commercial frangula bark preparation Sanurtin N® with the aid of the in vitro Ssalmonella/microsome mutagen test and the deoxyribonucleic acid (DNA) repair test of primary rat hepatocytes. 1 g of the alcoholic extract contained 50.76 mg glucofrangulin, 86.84 mg frangulin, 30.88 mg emodin, 10.3 mg pyscion, and 14.32 mg chrysophanol. One coated tablet of Sanurtin N® contained 8.28 mg glucofrangulin, 0.21 mg frangulin, <0.1 mg emodin, and physcion and chrysophanol only in traces. The tests provided evidence of a
The three in vivo studies by Heidemann 1993 (49) which showed no evidence of any genetic effects, were the Chromosome Aberration Test, the Mouse Spot Test, and the in vivo/in vitro UDS (unscheduled DNA synthesis) in rat hepatocytes.
Mengs U et al. 1997 (54) investigated the potential of emodin to induce micronuclei in polychromatic erythrocytes (PCEs). Mice of both genders received a single oral dose of 2000 mg emodin/kg and were killed 24 and 48 h later. Bone marrow cells were collected from 5 males and 5 females and 2000 PCEs per animal were scored for the presence of micronuclei. There was no enhancement in the frequency of micronuclei at both preparation intervals when compared to the negative controls. Blood level examination confirmed the systemic availability of emodin. Plasma levels of up to 190 µg emodin/ml represented concentrations being in the concentration range that induced positive responses in several genotoxicity cell culture assays.
Jahnke GD et al.2004 (55) evaluated emodin for potential effects on pregnancy outcome. Emodin was administered in feed to
maternal body weight and weight gain was decreased at the high dose. Prenatal mortality, live litter size, fetal sex ratio, and morphological development were unaffected in both rats and mice. At the high dose, rat average fetal body weight per litter was unaffecte, but was significantly reduced in mice.
The rat maternal lowest observed adverse effect level (LOAEL) was 1700 ppm; the no observed adverse effect level (NOAEL) was 850 ppm. The rat developmental toxicity NOAEL was +/- 1700 ppm. A LOAEL was not established.
2001 the National Toxicology Programm (NTP) of the U.S. Department of Health and Human Services published a technical report on toxicology and carcinogenesis studies of emodin (50).
Groups of 5 male and 5 female rats were fed diets containing 0, 600, 2000, 5,500, 17,000, or 50,000ppm emodin. This corresponds in males to average daily doses of approximately 50, 170, 480, 1,400, or 3,700 mg emodin/kg bw and in females to 50, 160, 460, 1,250, or 2,000 mg/kg bw. 3 female rats died before the end of the study. Mean body weights of males and females exposed to 5,500 ppm and greater were signifcantly less than those of the controls. Feed consumption by males and females receiving 17,000 or 50,000 ppm was decreased throughout the study. Macroscopic lesions were present in the kidney of rats exposed to 17,000 or 50,000 ppm.
The size of the groups and the administered concentrations were the same as described above. The concentrations correspond in males to average daily doses of approximately 120, 400, 1,200 or 3,800 mg/kg bw and in females to 140, 530, 1,600 or 5,000 mg/kg bw. 50,000 ppm equivalents were not calculated due to high mortality. All mice exposed to 50,000 ppm died before the end of the study. Mice in the 17,000 ppm groups lost weight during the study. Feed consumption by 5,500 ppm was greater than by the controls. Macroscopic lesions were present in the gallbladder and kidney exposed to 17,000 ppm.
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 to males and 60, 130, 240, 500, or 1,100 mg/kg to females. Relative kidney weights of male mice exposed to 1,250 ppm or greater, relative lung weights of males exposed to 625 ppm or greater, and relative liver weights of female mice exposed to 625 ppm or greater were increased. The incidences and severities of nephropathy were increased in males and females exposed to 1,250 ppm or greater. The incidences of renal tubule pigmentation were significantly increased in males exposed to 1,250 ppm or greater.
Groups of 65 male and 65 female rats were fed diets containing 0, 280, 830, or 2,500 ppm emodin (equivalent to average daily doses of approximately 110, 320, or 1,000 mg/kg to males and 120, 370, or 1,100 mg/kg to females).
3 Zymbal’s gland carcinomas were observed in female rats exposed to 2,500 ppm. This incidence exceeded the range observed for current historical controls and was considered an equivocal finding. At the 6- and
Groups 0f 60 male mice were fed diets containing 0, 160, 312, or 625 ppm emodin (equivalent to average daily doses of approximately 15, 35, or 70 mg/kg) and groups of 60 female mice were fed diets containing 0, 312, 625, or 1,250 ppm emodin (equivalent to average daily doses of approximately 30, 60, or 120 mg/kg). Low incidences of renal tubule adenoma and carcinoma occurred in exposed male mice; these incidences included one carcinoma each in the 312 and 625 ppm groups. Renal tubule neoplasms are rare in male mice, and their presence in these groups suggested a possible association with emodin exposure. At the
S9. Chromosomal aberrations were induced in cultured Chinese hamster ovary cells treated with emodin, with and without S9. Three separate in vivo micronucleus tests were performed with emodin. A male rate bone marrow micronucleus test, with emodin administerd by 3 intraperitoneal injections, gave negative results. Results of
Conclusion by the “National Toxicology Program’s Board of Scientific Counselors’ Technical Reports Review Subcommittee”:
–The studies give no evidence of carcinogenic activity for male rats and female mice, and equivocal evidence for female rats and male mice.
–In view of conflicting results on genotoxicity, it was noted the first pass effect and need for metabolic activation suggesting a metabolite as the genotoxic form. The metabolite
2002 the American Herbal Products Association submitted a review of the data from the National Toxicology Program and relevant to the status of Cascara sagrada ingredients (52). All of the NTP oral feeding studies were of durations which exceed the duration of human exposure. The studies that are nearest the human exposure are the 16 day studies in mice and rats. The most conservative no adverse level (NOAEL) reported for these studies, is 160 mg/kg in female rats and 400 mg/kg in male mice. Assuming that an adult of 70 kg body weight consumes 21 – 100 mg hydroxanthracenes daily (0.3 – 1.43 mg per kg body weight), the association calculated a standard conservative
Based on the maximal daily dose of 30 mg hydroxyanthracene recommended in the HMPC monograph of rhubarb (0.43 mg per kg body weight) a standard conservative
Concerning the evaluation of carcinogenicity the association concluded that the equivocal evidence of carcinogenicity in female rats in the
Heidemann A et al. 1996 (56) undertook in vitro and in vivo experiments to clarify the genotoxic potential of the hydroxyanthraquinone
The aim of the study of Schörkhuber M et al. 1998 (57) was to demonstrate the effect of the
Mitchell JM, Mengs U et al. 2006 (115) conducted an oral carcinogenicity and toxicity study of senna in rats. The administered senna preparation were powdered Tinnevelly senna pods containing 1.829% of sennosides
II.2.3.2 Assessor’s overall conclusions on toxicology
Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids. Most of the
Mueller SO et al. 1999 concluded in their publication “Occurrence of emodin, chrysophanol and physcion in vegetables, herbs and liquors. Genotoxicity and
This is also to be considered in
Nephrotoxicity observed in mice occurred after administration during 13 weeks and with a 642 times higher dose than the ordinary clinical dose according to the authors.
Pharmacovigilance actions were initiated in Germany in 1996 (60) to minimise a possible risk. The maximal dose and the duration of use were limited.
II.3.1 Clinical Pharmacology
II.22.214.171.124 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
There exist several investigations with different Chinese and Japanese herbal preparations which are not specified exactly. We mainly mention the investigations with Rheum palmatum
L. or Rheum officinale Baillon
Mitsuma T et al. 1998 investigated the differences in cathartic actions of three different types of rhubarb: rhubarb A (produced in the Province of Sichuan, China), rhubarb B (Rheum coreanum, cultivated and processed in Japan), rhubarb C (tablets manufactured with the processed rhizome of Rheum palmatum from the Province of
II.126.96.36.199 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
Vyth A et al. 1979 (61) isolated rhein,
Zhu W et al. (62) compared the pharmacokinetic parameters of rhein administered by retention enemas with those conventional oral dosing of rhubarb extract (aqueous extract of Rheum officinalis Baillon). The amounts of rhein, emodin,
II.3.1.3 Assessor’s overall conclusions on pharmacodynamics and pharmacokinetics
There are only limited human pharmacological data available. Based on animals experiments and experiences with other
II.3.2 Clinical Efficacy3
II.3.2.1 Dose response studies
There are no dose response studies available.
The German monograph of Rhei radix (2) indicates a daily dose of 20 – 30 mg hydroxyanthracene derivatives calculated as rhein, but recommends that the pharmaceutical form must allow lower dosages than the usual daily dose.
The ESCOP monograph for “RHEI RADIX”, 2nd edition, (4) recommends 15 – 50 mg hydroxyanthracene derivatives.
The WHO monograph on Rhizoma Rhei (5) recommends 10 – 30 mg hydroxyanthracene derivatives.
The recommendation in the German pharmacovigilance actions for
Taken into account that rhubarb also contains tannin agents which may possibly counteract the laxative effect of the anthraquinones and according to the German pharmacovigilance actions we recommend a dose range from 20 – 30 mg hydroxyanthracene derivatives calculated as rhein like the German monograph.
Normally it is sufficient to take an
II.3.2.2 Clinical studies (case studies and clinical trials)
Fotiades P et al. 1976 (68) investigated the efficacy of Laxariston® in the treatment of constipation. 3 g of this preparation contain 0.9 g methyl cellulose, 0.3 g frangula bark (13.5 mg hydroxyanthracene derivatives), 0.3 g senna leaves (7.5 mg hydroxyanthracene derivatives), 0,15 g rhubarb root (6.75 mg hydroxyanthracene derivatives) and 0.015 g achillea extract. Laxariston® was given to 61 inpatients with mainly arthritic illness (3 g daily for 26.1 days on average) and to 33 outpatients mainly after abdominal surgery (7.6 g daily for 88.9 days). 31 patients of the whole study population had acute complaints, 20 patients suffered from chronic constipation and 41 patients from “functional” constipation. Special complaints are not mentioned in the publication. The time until disappearance of complaints was evaluated as follows:
3 In case of traditional use 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 (69) administered Laxariston® (specification see above) to 73 patients with gynaecological diseases and to 95 pregnant women suffering from constipation. Special complaints are not mentioned in the publication.
The first group consisted of 30 patients with laparotomy in the past, of whom 15 patients additionally took oestrogens, 6 patients with oestrogens and conservative gynaecological diseases, 7 patients with oestrogens and other medicinal products which influence the intestine motility, 13 patients with
In the second group 14 pregnant women were in the first trimenon, 15 in the second, and 66 women in the third trimenon. On average Laxariston® was administered for 61.4 days and the complaints disappeared in 3.9 days with a daily dose of 3.9 g. Efficacy was very good in 55 patients, good in 31 patients, satisfactory in 7 patients and insufficient in 2 patients. This result was not analysed with regard to the different trimenons. 4 patients (4.2%) complained about adverse reactions. 29 patients (30.5%) reported about positive reactions. 12 women in the second group were gynaecologically treated because of a threatening abortion. One of these women only miscarried.There is no information about the state of the
3 g of Laxariston® already contains 27.75 mg hydroxyanthracene derivatives, nearly 25% derive from rhubarb.
Borgia M et al. 1985 (70) carried out a
Moser EH and Hübner WD 2002/2003 (65, 66) enrolled 284 patients between 19 and 70 years suffering from irritable bowel syndrome (IBS) in a
Eucarbon® group. After the
The ingested dose of hydroxyanthracene derivatives is not mentioned in the publication. The leaflet of the
From 1989 to 1992, 151 chronic renal failure (CRF) patients with initial serum creatinine level of 328 +/- 92 mmol/l (3.7 mg/dL) were enrolled to compare the clinical effectiveness of rhubarb (Rheum palmatum L.), an ACE inhibitor as well as a combined regimen of rhubarb and ACE inhibitor, captopril, in a prospective
462 patients with upper gastrointestinal bleeding took Rheum palmatum L. (Dahunag) up to a maximum of 15.4 g herbal substance. Blood was not found any more in the faeces after 1.5 days in 97 % of the patients. The data are limited because the original Chinese publication is not available (3).
Zhou H et al. 1990 have studied alcoholic extracted tablets of rhubarb for 10 years. 312 patients with gastric and duodenal ulcer bleeding were divided into three groups, namely,
Rheum officinale Baillon, Rheum palmatum L, and Rheum tanguticum Maxim ex Balf. By using
Saller R et al. investigated the efficacy of a combined topical preparation with 23mg/g rhubarb (standardised dried
rhein) and 23 mg/g sage (aqueous extract from the leaves of Salvia officinales), of a single- agent preparation with sage extract and of a reference treatment Zovirax® Creme (50 mg acyclovir/g) for topical treatment of Herpes labialis in a
II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
Use in children
First of all change of nutrition is recommended in constipated children with an increase in daily fibre intake. It is recommended that children older than 2 years of age should increase their intake of dietary fibre to an amount equal or greater than their age plus 5 g (77). The behaviour has to modify additionally, e.g. increased physical exercise.
There are no systematic clinical data available which evaluate the use of rhubarb as a laxative in children.
In China herbal treatment of neonatal jaundice (NNL) has been practiced for a long time. Even
There are several reports of local intolerance of a high dose senna preparation on skin in children wearing napkins. These skin irritations were bullous and comparable with skin irritations caused by scalds (78).
According to the ESCOP and WHO monographs the use for children less than 10 years cannot be recommended. According to the “NOTE FOR GUIDANCE ON CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE PAEDIATRIC POPULATION” (CPMP/ICH/2711//99) of 27 July 2000 and other monographs age limit for children should be determined to “12 years of age”.
II.3.2.4 Assessor’s overall conclusions on clinical efficacy
There are no recent clinical investigations available, which evaluate rhubarb alone and not in combination with other laxatives in a representative study population. 2
The postulated laxative effect is mainly based on the pharmacological data, experts’ opinions (German monograph, ESCOP monograph, WHO monograph etc.) and clinical experiences. Clinical and pharmacological data obtained from other
The investigations concerning other indications than occasional constipation are insufficient to support further indications.
Use for topical treatment of Herpes labialis in a combination with sage needs further investigation whether the part of rhubarb is essential for the efficacy or not.
II.3.3 Clinical Safety/Pharmacovigilance
Rhubarb preparations should not be used by patients with hypersensitivity to rhubarb.
Furthermore rhubarb containing medicinal products should not be used in cases of intestinal obstructions and stenosis, atony, appendicitis, inflammatory colon diseases (e.g. Crohn’s disease, ulcerative colitis); abdominal pain of unknown origin; severe dehydration states with water and electrolyte depletion like all
II.3.3.2 Special warning/precautions for use
Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products inducing
Like all laxatives, rhubarb containing medicinal products 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 stimulating laxatives should be avoided.
Use for more than 1 – 2 weeks requires medical supervision. Rhubarb preparations should only be used if a therapeutic effect cannot be achieved by a change of diet or the administration of bulk forming agents.
See also point 3.3.5 drug abuse.
II.3.3.3 Adverse events
Like mentioned above hypersensitive reactions may occur.
Chronic use may lead to disorders in water equilibrium and electrolyte metabolism. Chronic use may result in albuminuria and haematuria.
The only study comparing the morphology of the autonomous nervous system of constipated patients taking anthraquinones (aloe) to that of an appropriate control group of constipated patients without laxative intake (Riecken EO et al. 1990 (89)) does not support the hypothesis that anthraquinone containing laxatives are able to provoke relevant degenerative changes in the colonic nerve tissue. But this investigation was only conducted in 11 matched pairs only.
For safety concerns we inform the patients that if stimulating laxatives are taken for longer than a brief period of treatment, this may lead to impaired function of the intestine and dependence on laxatives.
Controversial discussion is done whether chronic use of
Kune GA et al. 1988 (91) and Kune GA 1993 (92) reported of the “Melbourne Colorectal Cancer Study”. Commercial laxative use as a risk factor in colorectal cancer was investigated as one part of this large population based epidemiological study of colorectal incidence, aetiology and survival. Commercial laxative use was similar in 685 colorectal cancer patients and 723 age/sex matched community based controls. Also, when laxatives were subdivided into various groups containing anthraquinones, phenolphthalein, mineral salts and others, previous laxative intake was similar between cases and controls. Previous use of anthraquinone laxatives and of phenolphthalein containing laxatives was not associated with the risk of colorectal cancer. Furthermore the results of this study suggest that chronic constipation, diarrhoea, and the frequency and consistency of bowel motions are unlikely to be aetiologic factors in the development of colorectal cancer. They indicate that it is the diet and not the constipation that is associated with the risk of
In a retrospective study a cohort of 2,277 patients was defined by colonoscopy. Among other factors Nusko G et al. 1993 (93) tested whether in these patients laxative use or the endoscopially diagnosed presence of melanosis coli were risk factors related to colorectal neoplasm. In comparison to patients taking no laxatives there was no significant increase in colorectal cancer rate either in laxatives users or in patients with melanosis coli. However, there was a statistically significant association between the occurrence of colorectal adenomas and laxative use (relative risk of all patients exposed to laxatives = 1.72; of patients exposed to laxatives without melanosis coli = 1.47). The relative risk of adenoma development in patients with melanosis coli was 2.19. Taking into account that polyps can be diagnosed in the dark mucosa of melanosis coli patients more easily, the authors concluded that even this relative risk of 2.19 seems to be related to a generally enhanced risk of laxative intake rather than to a special group of (anthranoid containing) laxatives.
Sonnenberg A and Muller AD 1993 (94) performed a
residue diets, the authors concluded that their risks reflects the confounding influence of underlying dietary habits.
Loew D et al. 1994 (95) conducted a comparative study involving 423 patients with colorectal neoplasms and 522 patients with benign proctologic disorders who were regular users of laxatives for bowel regulation. A pseudomelanosis coli (PMC) test was used as an indicator of exposure to
Jacobs EJ et White E 1998 (96) examined the associations of colon cancer with constipation and use of commercial laxatives in a
Nusko G et al. 2000 (97) performed a prospective case control study at the University of Erlangen to investigate the risk of
Willems M et al. 2003 (71) describe a case of melanosis coli, which occurred in a
Roberts MC et al. 2003 (98) conducted a
association with laxative use (OR 0.88; 95% CI =
Nilsson SE et al. 2004 (99) examined the impact of constipation and laxative treatment on the blood levels of homocysteine, folate and cobalamine in a
Jae Sik Joo et al. 1998 (100) investigated changes occurring on barium enema in patients ingesting stimulant laxatives. The study consisted of two parts. In part 1, a retrospective review of consecutive barium enemas performed on two groups of patients with chronic constipation (group 1, stimulant laxative use (n=29); group 2, no stimulant laxative use (n=26)) was presented to a radiologist who was blinded to the patient group. A data sheet containing classic descriptions of cathartic colon (historic term for the anatomic alteration of the colon secondary to chronic stimulant laxative use) was completed for each study. Chronic stimulant laxative use was defined as stimulant ingestion more than three times per week for 1 year or longer. To confirm the findings of the retrospective study, 18 consecutive patients who were chronic stimulant laxative users underwent barium enema examination, and data sheets for cathartic colon were completed by another radiologist (part 2). Colonic redundancy (group 1, 34.5%; group 2, 19.2%) and dilatation (group 1, 44.8%; group 2, 23.1 %) were frequent radiographic findings in both patient groups and were not significantly different in the two groups. Loss of haustral folds, however, was a common finding in group 1 (27.6%) but was not seen in group 2 (p<0.005). Loss of haustral markings occurred in 15 (40.5%) of the total stimulant laxative users in the two parts of the study and was seen in the left colon of 6 (40%) patients, in the right colon of 2 (13.3%) patients, in the transverse colon of 5 (33.3%) patients, and in the entire colon of 2 (13.3%) patients. Loss of haustra was seen in patients chronically ingesting bisacodyl, phenolphthalein, senna, and casanthranol. The authors conclude that
II.3.3.6 Safety in special populations and situations
When rhubarb preparations are administered to incontinent adults, pads should be changed more frequently to prevent extended skin contact with faeces because of the experiences in children wearing napkins.
Patients with kidney disorders should be aware of possible electrolyte balance.
II.188.8.131.52 Drug interactions
Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products inducing
Chronic use or abuse of rhubarb preparations may lead to hypokalaemia like the abuse of all
interfere with cardiac glycosides, antiarrhythmic medicinal products, and medicinal products inducing
II.184.108.40.206 Use in pregnancy and lactation
There are no recent investigations available.
Like mentioned above (69), 95 pregnant women suffering from constipation were treated with a combination preparation containing rhubarb. Most of them were in the third trimenon. 12 women were gynaecologically treated because of a threatening abortion. Only one of these women miscarried. No information about the state of the
In theory, it is possible that reflex stimulation might occur, involving not only the colon but also uterine muscles and then might lead to the development of hyperaemia in the pelvic region and to miscarriage as a result of neuromuscular stimulation of uterine muscles. Therefore
Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids (e.g. emodin, chrysophanol, and physcion). In vitro assays overestimate the potential hazard from exposure and must be reevaluated by in vivo experiments. The NOAELs for emodin defined by Jahnke GD are twice the decimal power and above the maximum daily dose of hydroxyanthracene derivatives (30 mg).
In vivo studies of the crude senna herbal substance in rat hepatocytes (chromosome aberration test, mouse spot test, in vivo/in vitro UDS (unscheduled DNA synthesis); showed no evidence of any genetic effects (Heidemann 1993 (49)).
Rhubarb and also senna mainly contain
On the other hand there only exist older preclinical data which refer to a special extract of senna pods containing 1.4 to 3.5 % of anthranoids, corresponding to 0.9 to 2.3 % of potential rhein, 0.05 to 0.15% of potential
Such data are not available for rhubarb or any preparation thereof. Therefore use during pregnancy cannot be recommended. Furthermore other actions like behavioural modification, dietary changes and use of bulk forming agents should be the first actions taken during pregnancy to treat constipation.
Use during lactation is not recommended, as there are insufficient data on the excretion of metabolites in breast milk, too. Investigations with a “standardised senna laxative” (Agiolax®), which also contains Plantago ovata seeds/husks as bulk substances, showed that
The investigations concerning other indications than occasional constipation are insufficient to support further indications.
There are two investigations dealing with the treatment of gastrointestinal bleeding. The data available are limited and cannot be assessed definitely. A
Use for topical treatment of Herpes labialis in a combination with sage needs further investigation whether the part of rhubarb is essential for the efficacy or not. Furthermore such a use does not fulfil the criteria for
Due to the possible risks traditional use as described above cannot be accepted.
The conditions determined in the pharmacovigilance actions for
The use in children below the age of 12 years and during pregnancy and lactation is not recommended.
In consideration of the recommendations in the monograph the
4According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal products’ (EMEA/HMPC/182320/2005 Rev.2)
5According to the ‘Procedure for the preparation of Community monographs for herbal medicinal products with
6According to the ‘Structure of the Community list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products’ (EMEA/HMPC/100824/2005 Rev.2)