Rhubarb 2018

Online Series Monographs The Scientific Foundation for Herbal Medicinal Products

Rhei radix Rhubarb 2018

www.escop.com The Scientific Foundation for Herbal Medicinal Products

RHEI RADIX Rhubarb

2018

ESCOP Monographs were first published in loose-leaf form progressively from 1996 to 1999 as Fascicules 1-6, each of 10 monographs © ESCOP 1996, 1997, 1999

Second Edition, completely revised and expanded © ESCOP 2003

Second Edition, Supplement 2009 © ESCOP 2009

ONLINE SERIES ISBN 978-1-901964-59-2

Rhei radix - Rhubarb © ESCOP 2018

Published by the European Scientific Cooperative on Phytotherapy (ESCOP) Notaries House, Chapel Street, Exeter EX1 1EZ, United Kingdom www.escop.com

All rights reserved Except for the purposes of private study, research, criticism or review no part of this text may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, without the written permission of the publisher.

Important Note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment may be required. In their efforts to provide information on the efficacy and safety of herbal drugs and herbal preparations, presented as a substantial overview together with summaries of relevant data, the authors of the material herein have consulted comprehensive sources believed to be reliable. However, in view of the possibility of human error by the authors or publisher of the work herein, or changes in medical knowledge, neither the authors nor the publisher, nor any other party involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for results obtained by the use of such information. Readers are advised to check the product information included in the package of each medicinal preparation they intend to use, to be certain that the information contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.

Edited by Simon Mills and Roberta Hutchins Cover photographs by ©Steven Foster (Rheum officinale) and Martin Willoughby Cover and text design by Martin Willoughby Typeset in Optima by Roberta Hutchins

Plant illustrated on the cover: Rheum officinale FOREWORD

It is a great pleasure for me to introduce the online era of ESCOP Monographs. Interest in herbal medicinal products continues to stimulate research on herbal substances and the body of knowledge in this field is steadily growing. ESCOP takes account of this by preparing new monographs and - as the only organisation in the field at the moment - particularly through regular revision of our published monographs. In order to provide readers and authorities with balanced compilations of scientific data as rapidly as possible, ESCOP Monographs will be published online from now on. This contemporary way of publishing adds further momentum to ESCOP’s endeavours in the harmonization of European standards for herbal medicinal products.

The Board of ESCOP wishes to express its sincere gratitude to the members of the Scientific Committee, external experts and supervising editors, and to Peter Bradley, the final editor of every monograph published up to March 2011. All have voluntarily contributed their time and scientific expertise to ensure the high standard of the monographs.

Dr. Tankred Wegener Chair of the Board of ESCOP

PREFACE

Over the 15 years since ESCOP published its first monographs, initially as loose-leaf documents then as two hardback books, ESCOP Monographs have achieved a reputation for well-researched, comprehensive yet concise summaries of available scientific data pertaining to the efficacy and safety of herbal medicinal products. The Second Edition, published in 2003 with a Supplement in 2009, covered a total of 107 herbal substances.

The monograph texts are prepared in the demanding format of the Summary of Product Characteristics (SPC), a standard document required in every application to market a medicinal product for human use within the European Union and ultimately providing information for prescribers and users of individual products.

As a change in style, literature references are now denoted by the name of the first author and year of publication instead of reference numbers; consequently, citations at the end of a monograph are now in alphabetical order. This is intended to give the reader a little more information and perspective when reading the text.

Detailed work in studying the pertinent scientific literature and compiling draft monographs relies to a large extent on the knowledge, skills and dedication of individual project leaders within ESCOP Scientific Committee, as well as invited experts. After discussion and provisional acceptance by the Committee, draft monographs are appraised by an eminent Board of Supervising Editors and all comments are taken into account before final editing and approval. In this way a wide degree of consensus is achieved, but it is a time-consuming process.

To accelerate the publication of new and revised monographs ESCOP has therefore decided to publish them as an online series only, commencing in 2011. We trust that rapid online access will prove helpful and convenient to all users of ESCOP Monographs.

As always, ESCOP is indebted to the many contributors involved in the preparation of monographs, as well as to those who provide administrative assistance and hospitality to keep the enterprise running smoothly; our grateful thanks to them all. NOTES FOR THE READER

From 2011 new and revised ESCOP Monographs are published as an online series only. Earlier monographs are available in two books, ESCOP Monographs Second Edition (2003) and the Second Edition Supplement 2009, but are not available online for copyright reasons.

After purchase of a single monograph, the specific items to be downloaded are:

Front cover Title page Verso Foreword and Preface Notes for the Reader Abbreviations The monograph text Back cover

Information on the member organizations and people involved in ESCOP’s activities can be found on the website (www.escop.com):

Members of ESCOP Board of Supervising Editors ESCOP Scientific Committee Board of Directors of ESCOP ABBREVIATIONS used in ESCOP monographs

AA arachidonic acid ABTS 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) ACE angiotensin converting enzyme ADP adenosine diphosphate ALAT or ALT alanine aminotransferase (= SGPT or GPT) ALP alkaline phosphatase anti-IgE anti-immunoglobulin E ASA acetylsalicylic acid ASAT or AST aspartate aminotransferase (= SGOT or GOT) ATP adenosine triphosphate AUC area under the concentration-time curve BMI body mass index BPH benign prostatic hyperplasia b.w. body weight cAMP cyclic adenosine monophosphate CI confidence interval

CCl4 carbon tetrachloride

Cmax maximum concentration of a substance in serum CNS central nervous system CoA coenzyme A COX cyclooxygenase CSF colony stimulating factor CVI chronic venous insufficiency CYP cytochrome P450 d day DER drug-to-extract ratio DHT dihydrotestosterone DMSO dimethyl sulfoxide DNA deoxyribonucleic acid DPPH diphenylpicrylhydrazyl DSM Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association) ECG electrocardiogram

ED50 effective dose in 50% of cases EDTA ethylenediamine tetraacetate EEG electroencephalogram EMA European Medicines Agency ENT ear, nose and throat ER oestrogen receptor ERE oestrogen-responsive element FSH follicle-stimulating hormone GABA gamma-aminobutyric acid Gal galactose GFR glomerular filtration rate GGTP gamma-glutamyl transpeptidase GOT glutamate oxalacetate transaminase (= SGOT) GPT glutamate pyruvate transaminase (= SGPT) GSH glutathione (reduced) GSSG glutathione (oxidised) HAMA Hamilton Anxiety Scale 12-HETE 12-hydroxy-5,8,10,14-eicosatetraenoic acid HDL high density lipoprotein HIV human immunodeficiency virus HMPC Committee on Herbal Medicinal Products (of the EMA) HPLC high-performance liquid chromatography 5-HT 5-hydroxytryptamine (= serotonin)

IC50 concentration leading to 50% inhibition ICD-10 International Statistical Classification of Diseases and Related Health Problems, Tenth Revision ICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICSD International Classification of Sleep Disorders IFN interferon IL interleukin i.m. intramuscular iNOS inducible nitric oxide synthase INR International Normalized Ratio, a measure of blood coagulation (clotting) tendency i.p. intraperitoneal IPSS International Prostate Symptom Score i.v. intravenous kD kiloDalton KM Index Kuppermann Menopausal Index kPa kiloPascal LC-MS liquid chromatography-mass spectrometry

LD50 the dose lethal to 50% of animals tested LDH lactate dehydrogenase LDL low density lipoprotein LH luteinizing hormone 5-LOX 5-lipoxygenase LPS lipopolysaccharide

LTB 4 leukotriene B4 M molar (concentration) MAO monoamine oxidase MBC minimum bactericidal concentration MDA malondialdehyde MFC minimum fungicidal concentration MIC minimum inhibitory concentration Mr molecular MRS Menopause Rating Scale MRSA methicillin-resistant Staphylococcus aureus MTD maximum tolerated dose MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MW molecular weight NBT nitro blue tetrazolium NF-kB necrosis factor kappa-B NO nitric oxide NOS nitric oxide synthase n.s. not significant NSAID non-steroidal anti-inflammatory drug ovx ovariectomy or ovariectomized ORAC oxygen radical absorbance capacity PA pyrrolizidine alkaloid PAF platelet activating factor PCR polymerase chain reaction PEG polyethylene glycol PGE prostaglandin E Pgp P-glycoprotein PHA phythaemagglutinin p.o. per os POMS profile of mood states PVPP polyvinylpolypyrrolidone RANKL receptor activator of nuclear factor kappa-B ligand RNA ribonucleic acid RT-PCR reverse transcription polymerase chain reaction s.c. subcutaneous SCI spinal cord injury SERM selective oestrogen receptor modulator SGOT or GOT serum glutamate oxalacetate transaminase (= ASAT or AST) SGPT or GPT serum glutamate pyruvate transaminase (= ALAT or ALT) SHBG sex hormone binding globulin SOD superoxide dismutase SSRI selective serotonin reuptake inhibitor STAI state-trait anxiety inventory t1/2 elimination half-life TBARS thiobarbituric acid reactive substances TC total cholesterol TGF-b transforming growth factor-beta TNF tumour necrosis factor TPA 12-O-tetradecanoylphorbol-13-acetate URT upper respiratory tract URTI upper respiratory tract infection UTI urinary tract infection VAS visual analogue scale VLDL very low density lipoprotein RHEI RADIX 2018 Rhubarb

DEFINITION

Rhubarb consists of the whole or cut, dried underground parts of Rheum palmatum L. or of Rheum officinale Baillon or of hybrids of these two species or of a mixture. The underground parts are often divided; the stem and most of the bark with the rootlets are removed. It contains not less than 2.2% of

hydroxyanthracene derivatives, expressed as rhein (C15H806; Mr 284.2), calculated with reference to the dried drug.

The material complies with the monograph of the European Pharmacopoeia [Rhubarb].

CONSTITUENTS

The main characteristic constituents are hydroxyanthracene derivatives (3- 12%, depending on the method of determination) consisting mainly (60-80%) of mono- and diglucosides of rhein, chrysophanol, aloe-emodin, physcion and emodin, and only small amounts of the respective aglycones. Dianthrone glycosides (sennosides) are also present and small amounts of anthrone glycosides depending on the time of harvesting and the conditions of drying [van Os 1976; Chirikdjian 1983; Engelshowe 1985; Hänsel 1994, 1999].

Other constituents include gallotannins (ca. 5%) [Engelshowe 1985; Weiß 1990; Hänsel 1994, 1999], chromones, phenylbutanones and traces of volatile oil [Hänsel 1994, 1999; Miyazawa 1996].

CLINICAL PARTICULARS

Therapeutic indications For short-term use in cases of occasional constipation [Weiß 1990; Reynolds 1996; Wichtl 1997; Schilcher 2000].

Although no published clinical data is currently available, the laxative effect of rhubarb is well-known, and is comparable to the other anthranoid containing laxatives.

Posology and method of administration

Dosage

The correct individual dose is the smallest required to produce a comfortable soft-formed motion.

Adults and children over 12 years: drug or preparations equivalent to 15-50 mg of hydroxyanthracene derivatives (calculated as rhein) daily, preferably taken in one dose at night [Hänsel 1994; Wichtl 1997; Schilcher 2000].

Not recommended for use in children under 12 years of age.

The pharmaceutical form must allow lower dosages.

Method of administration For oral administration.

Duration of use Stimulant laxatives should not be used for periods of more than 2 weeks without medical advice.

Contraindications Pregnancy and lactation; children under 10 years of age [Hänsel 1994].

Not to be used in cases of intestinal obstruction and stenosis, atony, inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), appendicitis, abdominal

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pain of unknown origin [Hänsel 1994]; severe dehydration urine by metabolites, which is not clinically significant [Cooke states with electrolyte depletion. 1977; Tedesco 1985; Ewe 1986].

Special warnings and precautions for use Overdose As for all laxatives, rhubarb should not be given when any The major symptoms are griping and severe diarrhoea with undiagnosed acute or persistent abdominal symptoms are consequent losses of fluid and electrolytes, which should be present. replaced.

If laxatives are needed every day the cause of the constipation Treatment should be supportive with generous amounts of fluid. should be investigated. Long term use of laxatives should be Electrolytes, especially potassium, should be monitored; this is avoided. Use for more than 2 weeks requires medical super- particularly important in the elderly and the young. vision. Chronic use may cause pigmentation of the colon (pseudomelanosis coli) which is harmless and reversible after drug discontinuation. Abuse, resulting in loss of fluid and PHARMACOLOGICAL PROPERTIES electrolytes, may cause [Leng-Peschlow 1992]: dependence with possible need for increased dosages; disturbance of the Pharmacodynamic properties water and electrolyte (mainly hypokalaemia) balance; an atonic colon with impaired function. Intake of anthranoid-containing 1,8-dihydroxyanthracene derivatives possess a laxative effect laxatives for more than a short period of time may result in [Fairbairn 1970; Leng-Peschlow 1992]. The b-linked glucosides aggravation of constipation. Hypokalaemia can result in cardiac in rhubarb are not absorbed in the upper gut; they are converted and neuromuscular dysfunction, especially if cardiac glycosides, by the bacteria of the large intestine into active metabolites diuretics or corticosteroids are taken. Chronic use may result (anthrones). in albuminuria and haematuria. Based on experimental studies and studies in humans with In chronic constipation, stimulant laxatives are not an acceptable Tinnevelly senna pods and isolated sennosides, two distinct alternative to a change in diet. mechanisms of action are assumed [Leng-Peschlow 1986]:

Note: A detailed text with advice concerning changes in i. an influence on the motility of the large intestine (stimulation dietary habits, physical activities and training for normal of peristaltic contractions and inhibition of local contractions) bowel evacuation should be included on the package leaflet. resulting in accelerated colonic transit, thus reducing An example is given in the booklet “Médicaments à base de fluid absorption [Garcia-Villar 1980; Bueno 1980], and plantes” published by the French health authority (Paris: Agence du Médicament). ii. an influence on secretion processes (stimulation of mucus and active chloride secretion) resulting in enhanced fluid Interaction with other medicinal products and other forms secretion [Leng-Peschlow 1986, 1989]. of interaction Hypokalaemia (resulting from long term laxative abuse) Defecation takes place after a delay of 8-12 hours due to the potentiates the action of cardiac glycosides and interacts with time taken for transport to the colon and metabolic conversion anti-arrhythmic drugs or with drugs which induce reversion of hydroxyanthracene glycosides to the active compounds. to sinus rhythm (e.g. quinidine). Concomitant use with other drugs inducing hypokalaemia (e.g. thiazide diuretics, adreno- In vitro experiments corticosteroids and liquorice root) may aggravate electrolyte imbalance. Antimicrobial activity In an agar plate assay, strong inhibition of Helicobacter pylori Pregnancy and lactation was observed with a water extract (MIC < 1 mg) [Bae 1998]. An ethanolic extract inhibited Helicobacter pylori growth with Pregnancy a MIC of 17.24 µg/ml; in this test the MICs of anthraquinone Not recommended during pregnancy. compounds isolated from rhubarb were 0.40 µg/ml (emodin), There are no reports of undesirable or damaging effects during 0.60 µg/ml (rhein), 0.78 µg/ml (chrysophanol) and 0.85 µg/ml pregnancy or on the foetus when used in accordance with (aloe-emodin) [Gou 1997]. the recommended dosage schedule. However, experimental data concerning a genotoxic risk from several anthranoids Rhein, in combination with ampicillin or oxacillin, had syner- (e.g. emodin) are not counterbalanced by sufficient studies to gistic or partial synergistic effects against methicillin-resistant eliminate a possible risk. Staphylococcus aureus strains (MRSA). The MIC of the respective antimicrobial agent in combination with rhein, compared to Lactation the antimicrobial agent alone, ranged 0.28-1 for ampicillin and Breast-feeding is not recommended as there are insufficient 0.18-1 for oxacicillin [Joung 2012]. data on the excretion of metabolites in breast milk. Excretion of active principles in breast milk has not been investigated. An ethanolic extract exhibited antiviral activity against Herpes However, small amounts of active metabolites (e.g. rhein) are simplex by preventing virus attachment and penetration [Hsiang known to be excreted in breast milk. A laxative effect in breast- 2001]. fed babies has not been reported [Faber 1988]. The antimycotic activity of an aqueous extract against Aspergillus Effects on ability to drive and use machines fumigatus and Candida albicans was comparable to that of None known. nystatin. The growth of Geotrichum candidum and Rhodotorula rubra was inhibited to a lesser extent [Blaszcyk 2000]. Undesirable effects Abdominal spasms and pain, in particular in patients with irritable Rhein isolated from rhubarb showed strong antimicrobial activity colon; yellow or red-brown (pH dependent) discoloration of against Candida albicans and Bacteroides fragilis [Cyong 1987].

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Anti-proliferative activity In vivo experiments A dried aqueous extract (8:1) had significant (p<0.001) dose- In rats with adenine-induced chronic renal failure a hot water and time-dependent growth inhibitory effects on both human extract decreased levels of serum urea nitrogen and creatinine, lung adenocarcinoma cells and human breast cancer cells as well as the hepatic urea concentration, in a dose-dependent with IC50 values of 620 ±12.7 and 515 ±10.1 µg/ml respect- manner. The effects were significant at doses of 15 and 35 ively [Li 2009]. mg/rat/day (p<0.01 to p<0.05) and 55 mg/rat/day (p<0.001). Hypocalcaemia, hyperphosphataemia and the concentrations Rhein inhibited growth of three cancer cell lines in a dose of guanidino compounds in the serum, liver and kidney were dependent manner. The IC50 values against human cervical improved. Proanthocyanidin oligomers were shown to be the cancer cells, breast adenocarcinoma cells (MCF-7) and active substances [Yokozawa 1984, 1986]. hepatocellular carcinoma cells (HepG2) were 54.28 ± 0.17, 49.35 ± 0.23 and 36.34 ± 0.14 µMol respectively (p<0.05) Rats with streptozotocin-induced diabetic nephropathy were [Al-Fatlawi 2014]. treated orally with 125 mg/kg b.w./day of a hot water extract (drug to extract ratio 4:1) over a period of 80 days. At the end Aloe-emodin induced apoptosis of human nasopharyngeal of the experimental period treated animals showed decreases in carcinoma cells via caspase-8-mediated activation of the blood glucose levels, serum triglycerides and total cholesterol, mitochondrial death pathway [Lin 2010]. and increases in urinary excretion of urea nitrogen and creatinine. All the changes were significant (p<0.01) compared to Emodin exhibited antiproliferative, antimetastatic and apop- untreated controls [Yokozawa 1997]. totic effects in human chronic myelocytic leukemia K562 cells, pancreatic cancer cells, cervical cancer hela cells, hepatoma A hot water extract was administered orally to rats after subtotal cells, neuroblastoma cells and tongue squamous cancer cells nephrectomy (SN) at a dose of 150 mg/day from day 30 to [Chun-Guang 2010, Liu 2011, Yaoxian 2013, Hsu 2010, Huang day 120. The treated animals had significantly less proteinuria 2013, Lin 2009]. (p<0.05) compared to untreated SN controls on days 90 and 120 after SN. Renal function was similar in the two groups, Several phenolic compounds from rhubarb showed cytotoxicity but the severity of glomerulosclerosis was significantly (p<0.5) against human oral squamous cell carcinoma and salivary gland reduced by the treatment [Zhang 1996]. tumour cell lines as well as human gingival fibroblasts [Shi 2001]. Aloe-emodin induced apoptotic cell death in human Anti-inflammatory activity of rhubarb was demonstrated in lung squamous cell carcinoma [Lee 2001]. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear oedema. After single or multiple topical applications of Bioassay-guided fractionation of an ethyl acetate extract showed TPA, an extract (50% ethanol, drug to extract ratio 3:1) applied emodin to be a selective inhibitor of casein kinase II with an topically at 0.5 mg/ear led to significant inhibition of oedema

IC50 of 2 µM [Yim 1999]. (p<0.01). Increased myeloperoxidase activity in the tissue after multiple applications of TPA was significantly reduced by the However, methanolic extracts from Rheum palmatum and extract (p<0.01) [Cuéllar 2001]. Rheum officinalis rhizomes were found to significantly (p<0.01) enhance proliferation of the oestrogen-sensitive MCF-7 cell Mice with streptozocin-induced diabetes were treated with line at concentrations of 100 and 30 µg/ml, respectively. This emodin at 1.5 mg/kg i.p., daily for 3 weeks. The serum glucose effect was mainly attributed to emodin and emodin-8-O-b-D- level in the emodin-treated group was significantly (p<0.01) glucoside, which bound to human oestrogen receptors a and lowered compared to the diabetic control group. After 3 weeks b [Matsuda 2001]. glucose tolerance and insulin sensitivity in the emodin group were significantly (p<0.05) improved compared to control Other effects [Xue 2010]. Methanolic extracts from Rheum palmatum and Rheum officinale showed radical scavenging activity, reducing 40 In db/db mice treated daily for 2 weeks with either 100 mg/kg µM a,a-diphenyl-b-picrylhydrazyl (DPPH) radical by 50% at b.w. of rhein or emodin by oral gavage, total fat weight was concentrations of 5.2 and 3.3 µg/ml respectively. IC50 values significantly (p<0.05) decreased in the rhein group compared on superoxide anion radical in the xanthine/xanthine oxidase to an untreated control, whereas no effects were observed in system were 5.0 and 3.8 µg/ml [Matsuda 2001]. Pyrogallol the emodin group. In a further test, obesity was induced in autoxidation and hydroxyl radicals generated via the Fenton C57BL/6 mice using a high fat diet. Mice were fed for 8 weeks reaction were inhibited by anthraquinones from rhubarb with either a high fat diet mixed with 0.1% rhein or a high fat [Yuan 1997]. diet alone. At the end of treatment, body weight of the rhein- treated mice was significantly lower (p<0.01) than that of the A hot water extract inhibited rat squalene epoxidase, an enzyme high fat diet control group, indicating that rhein could block that catalyzes a rate-limiting step of cholesterol biosynthesis, by weight gain despite the amount of food intake in both groups 70% at a concentration of 50 µg/ml; several galloyl compounds being similar [Zhang 2012]. isolated from rhubarb were found to be potent inhibitors of the enzyme [Abe 2000]. In mice on a high fat diet treated with rhein at 150 mg/kg b.w. by oral gavage, daily for 4 weeks, the expression of liver X target A 90% hydroethanolic dried extract (3.4:1) was administered genes related to adipogenesis in white adipose tissue (regulating intragastrically to normal and CCl4-treated rats daily for 12 cholesterol homeostasis, lipid and energy metabolism) was weeks at dosage levels equivalent to 2, 5.4, 14.69 and 40g significantly (p<0.05) suppressed compared to a high fat diet crude drug/kg b.w. A decrease in the extent of cellular injury control [Sheng 2012]. was observed in the two lowest dosage groups of CCl4-treated rats. However, a significant increase in fibrosis indicating Three groups of mice (n=10 each) were injected i.p. with rhubarb-induced liver damage was observed in both normal myelomonocytic leukemia WEHI-3-cells and 2 weeks later rats at all dosage levels and CCl4-treated rats at the two highest began treatment for 14 days with a daily oral gavage of either dosage levels [Wang 2011]. 5 mg/kg or 10 mg/kg of emodin in olive oil or olive oil vehicle

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only. Two further groups (n= 10 each) served as control (no observed in male rats. A marginal increase in the incidence treatment) or negative control (olive oil administration only). In of Zymbal’s gland carcinoma occurred in female rats treated comparison to the olive oil only treated leukemia mice group, with the high dosage but was interpreted as questionable [NIH CD19 and CD11b levels were significantly (p<0.05) increased in Publication 1999]. the 10 mg/kg and 5 mg/kg emodin groups respectively, whereas levels of CD3 were unaffected. The activity of peritoneal cavity In a further 2-year study, on B6C3F1 mice, males were exposed phagocytes was significantly increased in the 5 mg/g emodin to 160, 312 or 625 ppm of emodin (corresponding to an average group (p<0.05) and in the 10 mg/kg emodin group (p<0.001) daily dose of 15, 35 or 70 mg/kg b.w.) and females to 312, 625 [Chang 2011]. or 1250 ppm of emodin (corresponding to an average daily dose of 30, 60 or 120 mg/kg b.w.). There was no evidence of Three weeks after transfection of nude mice with SW1990 carcinogenic activity in female mice. A low incidence of renal pancreatic tumour cells, four groups (n=12 each) received ten tubule neoplasms in exposed males was not considered relevant i.p. injections (every three days) of either emodin (40 mg/kg), [NIH Publication 1999]. gemcitabine (125 mg/kg), emodin (40 mg/kg) plus gemcitabine (80 mg/kg) or isotonic saline. One week after the final injection A 90% hydroethanolic dried extract (3.4:1) was administered

(day 37), the tumour growth inhibition rate (difference of mean intragastrically to normal and CCl4-treated rats daily for 12 weeks tumour volume between end and start of treatment in the at dosage levels equivalent to 2, 5.4, 14.69 and 40g crude drug/ treatment group divided by the respective difference in control kg b.w. Although a decrease in the extent of cellular injury was group) was found to be high in the emodin and gemcitabine observed in the two lowest dosage groups of CCl4-treated rats, groups at 71.3 and 83.3% respectively, but highest in the a significant increase in fibrosis indicating rhubarb-induced combination group at 103.7% [Wei 2011]. liver damage was observed in both normal rats at all dosage

levels and CCl4-treated rats at the two highest dosage levels Five groups of nude mice (n=5 each) were transfected with [Wang 2011]. transplantable tumours induced by chronic myeloid leukemia K562 cells. After 12 days the groups were treated for 12 days Clinical safety data with either 25, 50 or 100 mg/kg emodin, or 120 mg/kg hydroxy Despite a lack of formal preclinical data on rhubarb, epi- carbamide as positive control and isotonic saline as negative demiological studies suggest that there is no carcinogenic risk control. Tumour weight was reduced in the emodin groups, to humans from the use of anthranoid laxatives [Siegers 1993; by 61.4% at 50 mg/kg (p<0.05) and by 75.6% at 100 mg/kg Nusko 1993; Sonnenberg 1993; Kune 1993, 1996; Loew (p<0.01) and also in the positive control group by 78.3% (p<0.01) 1996, 1997]. when compared to the negative control [Chun-Guang 2010].

Studies in humans REFERENCES Although no published clinical data is currently available, the laxative effect of rhubarb is well-known, and is comparable to Al-Fatlawi AA, Al-Fatlawi AA, Zafaryab MD, Irshad MD, Ahmad I, Kazim the other anthranoid containing laxatives. Z, Ahmad A et al. Rhein induced cell death and apoptosis through caspase dependent and associated with modulation of p53, BCL-2/ Pharmacokinetic properties bax ratio in human cell lines. Int J Pharmacy Pharm Sci 2014;6:515-9. No systematic data are available on rhubarb. It is assumed that aglycones present in the drug are absorbed in the upper gut, Abe I, Seki T, Noguchi H, Kashiwada Y. Galloyl esters from rhubarb are and that (by analogy with sennosides from senna) the b-linked potent inhibitors of squalene epoxidase, a key enzyme in cholesterol glucosides are neither absorbed in the upper gut nor split by biosynthesis. Planta Med 2000;66:753-6. human digestive enzymes. They are converted by the bacteria https://doi.org/10.1055/s-2000-9781 of the large intestine into aglycones and subsequently to the active compounds, the anthrones [Kobashi 1980]. Bae EA, Han MJ, Kim NJ, Kim DH. Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull 1998;21:990-2. In rat liver microsomes emodin was metabolized to 6-hydroxy- https://doi.org/10.1248/bpb.21.990 aloe-emodin and 2-hydroxyemodin, and chrysophanol was converted to aloe-emodin [Mueller 1998]. Blaszczyk T, Krzyzanowska J, Lamer-Zarawska E. Screening for antimycotic properties of 56 traditional Chinese drugs. Phytother Res Preclinical safety data 2000;14:210-2. There are no studies on single dose toxicity, repeated dose https://doi.org/10.1002/(SICI)1099-1573(200005)14:3<210::AID- toxicity, reproductive toxicity or in vivo tests on carcinogenicity PTR591>3.0.CO;2-7 of rhubarb or preparations from it. In the Salmonella micro- some assay an ethanolic extract showed mutagenic effects Bruggeman IM, van der Hoeven JCM. Lack of activity of the bacterial against S. typhimurium strain TA 1537 [Paneitz 1999]. Some mutagen emodin in HGPRT and SCE assay with V79 Chinese hamster isolated anthraquinones (aloe-emodin, emodin, physcion and cells. Mutat Res 1984;138:219-24. https://doi.org/10.1016/0165-1218(84)90047-8 chrysophanol) gave positive results in in vitro genotoxicity studies [Bruggemann 1984; Westendorf 1990; Heidemann Bueno L, Fioramonti J, Frexinos J, Ruckebusch Y. Colonic myoelectrical 1993, 1996]. All in vivo genotoxicity studies were negative activity in diarrhea and constipation. Hepato-Gastroenterology [Heidemann 1993, 1996; Mengs 1997]. Sennosides A and B and 1980;27:381-9. rhein gave negative results in in vitro and in vivo mutagenicity tests [Heidemann 1993; Mengs 1993]. Chang YC, Lai TY, Yu CS, Chen HY, Yang JS, Chueh FS, Lu CC et al. Emodin induces apoptotic death in murine myelomonocytic leukemia In a 2-year study, male and female F344/N rats were exposed WEHI-3 cells in vitro and enhances phagocytosis in leukemia mice to 280, 830 or 2500 ppm of emodin in the diet, corresponding in vivo. Evid Based Complement Alternat Med 2011;2011:523596. to an average daily dose of emodin of 110, 320 or 1000 mg/kg https://doi.org/10.1155/2011/523596 b.w. in male rats and 120, 370 or 1100 mg/kg b.w. in female rats. No evidence of carcinogenic activity of emodin was Chirikdjian JJ, Kopp B, Beran H. Über die laxative Wirkung eines neuen

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Anthrachinonglykosides aus Radix Rhei. Planta Med 1983;48:34-7. Joung DK, Joung H, Yang DW, Kwon DY, Choi JG, Woo S, Shin DY et al. https://doi.org/10.1055/s-2007-969874 Synergistic effect of rhein in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Exp Ther Med Chun-Guang W, Jun-Qing Y, Bei-Zhong L, Dan-Ting J, Chong W, 2012;3:608-12. https://doi.org/10.3892/etm.2012.459 Liang Z, Dan Z et al. Anti-tumor activity of emodin against human myelocytic leukemia K562 cell lines in vitro and in vivo. Eur J Pharmacol Kobashi K, Nishimura T, Kusaka M, Hattori M, Namba T. Metabolism of 2010;627:33-41. https://doi.org/10.1016/j.ejphar.2009.10.035 sennosides by human intestinal bacteria. Planta Med 1980;40:225-36. https://doi.org/10.1055/s-2008-1074963 Cooke WT. Laxative abuse. Clin Gastroenterol 1977;6:659-73. Kune GA. Laxative use not a risk for colorectal cancer: data from the Cuéllar MJ, Giner RM, Recio MC, Mánez S, Ríos JL. Topical anti- Melbourne colorectal cancer study. Z Gastroenterol 1993;31:140-3. inflammatory activity of some Asian medicinal plants used in dermatological disorders. Fitoterapia 2001;72:221-9. Kune GA. Causes and control of colorectal cancer. Boston-Dordrecht- https://doi.org/10.1016/S0367-326X(00)00305-1 London: Kluwer Academic, 1996:179-90. https://doi.org/10.1007/978-1-4613-1273-4_11 Cyong J-C, Matsumoto T, Arakawa K, Kiyohara H, Yamada H, Otsuka Y. Anti-Bacteroides fragilis substance from rhubarb. J Ethnopharmacol Lee H-Z, Hsu S-L, Liu M-C, Wu C-H. Effects and mechanisms of aloe- 1987;19:279-83. https://doi.org/10.1016/0378-8741(87)90005-5 emodin on cell death in human lung squamous cell carcinoma. Eur J Pharmacol 2001;431:287-95. Engelshowe R. Rhabarber: eine alte Droge - noch immer aktuell. Pharm https://doi.org/10.1016/S0014-2999(01)01467-4 unserer Zeit 1985;14:40-9. https://doi.org/10.1002/pauz.19850140203 Leng-Peschlow E. Dual effect of orally administered sennosides on Ewe K, Karbach U. Factitious diarrhoea. Clin Gastroenterol 1986;15: large intestine transit and fluid absorption in the rat. J Pharm Pharmacol 723-40. 1986;38:606-10. https://doi.org/10.1111/j.2042-7158.1986.tb03089.x

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The second edition of ESCOP Monographs, published as a hardback book in 2003 with a Supplement in 2009, has been widely acclaimed for its authoritative information on the therapeutic uses of herbal medicines. Monographs covering a total of 107 herbal substances include extensive summaries of pharmacological, clinical and toxicological data, and copious references to scientific literature form an important part of each text.

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