Rhei radixRhubarb

MonographsThe Scientific Foundation for Herbal Medicinal Products

2018

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The Scientific Foundation for Herbal Medicinal Products

RHEI RADIXRhubarb

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 SERIESISBN 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 reservedExcept 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 HutchinsCover photographs by ©Steven Foster (Rheum officinale) and Martin Willoughby

Cover and text design by Martin WilloughbyTypeset 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 WegenerChair 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 acidABTS 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)ACE angiotensin converting enzymeADP adenosine diphosphateALAT or ALT alanine aminotransferase (= SGPT or GPT)ALP alkaline phosphataseanti-IgE anti-immunoglobulin EASA acetylsalicylic acidASAT or AST aspartate aminotransferase (= SGOT or GOT)ATP adenosine triphosphateAUC area under the concentration-time curveBMI body mass indexBPH benign prostatic hyperplasiab.w. body weightcAMP cyclic adenosine monophosphateCI confidence intervalCCl4 carbon tetrachlorideCmax maximum concentration of a substance in serumCNS central nervous systemCoA coenzyme ACOX cyclooxygenaseCSF colony stimulating factorCVI chronic venous insufficiencyCYP cytochrome P450d dayDER drug-to-extract ratioDHT dihydrotestosteroneDMSO dimethyl sulfoxideDNA deoxyribonucleic acidDPPH diphenylpicrylhydrazylDSM Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association)ECG electrocardiogramED50 effective dose in 50% of casesEDTA ethylenediamine tetraacetateEEG electroencephalogramEMA European Medicines AgencyENT ear, nose and throatER oestrogen receptorERE oestrogen-responsive elementFSH follicle-stimulating hormoneGABA gamma-aminobutyric acidGal galactoseGFR glomerular filtration rateGGTP gamma-glutamyl transpeptidaseGOT glutamate oxalacetate transaminase (= SGOT)GPT glutamate pyruvate transaminase (= SGPT)GSH glutathione (reduced)GSSG glutathione (oxidised)HAMA Hamilton Anxiety Scale12-HETE 12-hydroxy-5,8,10,14-eicosatetraenoic acidHDL high density lipoproteinHIV human immunodeficiency virusHMPC Committee on Herbal Medicinal Products (of the EMA)HPLC high-performance liquid chromatography 5-HT 5-hydroxytryptamine (= serotonin)IC50 concentration leading to 50% inhibitionICD-10 International Statistical Classification of Diseases and Related Health Problems, Tenth RevisionICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human UseICSD International Classification of Sleep DisordersIFN interferonIL interleukini.m. intramusculariNOS inducible nitric oxide synthase

INR International Normalized Ratio, a measure of blood coagulation (clotting) tendencyi.p. intraperitonealIPSS International Prostate Symptom Scorei.v. intravenouskD kiloDaltonKM Index Kuppermann Menopausal IndexkPa kiloPascalLC-MS liquid chromatography-mass spectrometryLD50 the dose lethal to 50% of animals tested LDH lactate dehydrogenaseLDL low density lipoproteinLH luteinizing hormone5-LOX 5-lipoxygenaseLPS lipopolysaccharideLTB4 leukotriene B4M molar (concentration)MAO monoamine oxidaseMBC minimum bactericidal concentrationMDA malondialdehydeMFC minimum fungicidal concentrationMIC minimum inhibitory concentrationMr molecularMRS Menopause Rating ScaleMRSA methicillin-resistant Staphylococcus aureusMTD maximum tolerated doseMTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideMW molecular weightNBT nitro blue tetrazoliumNF-kB necrosis factor kappa-BNO nitric oxide NOS nitric oxide synthasen.s. not significantNSAID non-steroidal anti-inflammatory drugovx ovariectomy or ovariectomizedORAC oxygen radical absorbance capacityPA pyrrolizidine alkaloidPAF platelet activating factorPCR polymerase chain reactionPEG polyethylene glycolPGE prostaglandin EPgp P-glycoproteinPHA phythaemagglutininp.o. per osPOMS profile of mood statesPVPP polyvinylpolypyrrolidoneRANKL receptor activator of nuclear factor kappa-B ligandRNA ribonucleic acidRT-PCR reverse transcription polymerase chain reactions.c. subcutaneousSCI spinal cord injury SERM selective oestrogen receptor modulatorSGOT or GOT serum glutamate oxalacetate transaminase (= ASAT or AST)SGPT or GPT serum glutamate pyruvate transaminase (= ALAT or ALT)SHBG sex hormone binding globulinSOD superoxide dismutaseSSRI selective serotonin reuptake inhibitorSTAI state-trait anxiety inventoryt1/2 elimination half-lifeTBARS thiobarbituric acid reactive substancesTC total cholesterolTGF-b transforming growth factor-betaTNF tumour necrosis factorTPA 12-O-tetradecanoylphorbol-13-acetateURT upper respiratory tractURTI upper respiratory tract infectionUTI urinary tract infectionVAS visual analogue scaleVLDL very low density lipoprotein

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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 indicationsFor 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 administrationFor oral administration.

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

ContraindicationsPregnancy 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 states with electrolyte depletion.

Special warnings and precautions for useAs for all laxatives, rhubarb should not be given when any undiagnosed acute or persistent abdominal symptoms are present.

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 2 weeks requires medical super-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 electrolytes, may cause [Leng-Peschlow 1992]: dependence with possible need for increased dosages; disturbance of the water and electrolyte (mainly hypokalaemia) balance; an atonic colon with impaired function. Intake of anthranoid-containing laxatives for more than a short period of time may result in aggravation of constipation. Hypokalaemia can result in cardiac and neuromuscular dysfunction, especially if cardiac glycosides, diuretics or corticosteroids are taken. Chronic use may result in albuminuria and haematuria.

In chronic constipation, stimulant laxatives are not an acceptable alternative to a change in diet.

Note: A detailed text with advice concerning changes in dietary habits, physical activities and training for normal bowel evacuation should be included on the package leaflet. An example is given in the booklet “Médicaments à base de plantes” published by the French health authority (Paris: Agence du Médicament).

Interaction with other medicinal products and other forms of interactionHypokalaemia (resulting from long term laxative abuse) potentiates the action of cardiac glycosides and interacts with anti-arrhythmic drugs or with drugs which induce reversion to sinus rhythm (e.g. quinidine). Concomitant use with other drugs inducing hypokalaemia (e.g. thiazide diuretics, adreno-corticosteroids and liquorice root) may aggravate electrolyte imbalance.

Pregnancy and lactation

PregnancyNot recommended during pregnancy.There are no reports of undesirable or damaging effects during pregnancy or on the foetus when used in accordance with the recommended dosage schedule. However, experimental data concerning a genotoxic risk from several anthranoids (e.g. emodin) are not counterbalanced by sufficient studies to eliminate a possible risk.

LactationBreast-feeding is not recommended as there are insufficient data on the excretion of metabolites in breast milk. Excretion of active principles in breast milk has not been investigated. However, small amounts of active metabolites (e.g. rhein) are known to be excreted in breast milk. A laxative effect in breast-fed babies has not been reported [Faber 1988].

Effects on ability to drive and use machinesNone known.

Undesirable effectsAbdominal spasms and pain, in particular in patients with irritable colon; yellow or red-brown (pH dependent) discoloration of

urine by metabolites, which is not clinically significant [Cooke 1977; Tedesco 1985; Ewe 1986].

OverdoseThe major symptoms are griping and severe diarrhoea with consequent losses of fluid and electrolytes, which should be replaced.

Treatment should be supportive with generous amounts of fluid. Electrolytes, especially potassium, should be monitored; this is particularly important in the elderly and the young.

PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties

1,8-dihydroxyanthracene derivatives possess a laxative effect [Fairbairn 1970; Leng-Peschlow 1992]. The b-linked glucosides in rhubarb are not absorbed in the upper gut; they are converted by the bacteria of the large intestine into active metabolites (anthrones).

Based on experimental studies and studies in humans with Tinnevelly senna pods and isolated sennosides, two distinct mechanisms of action are assumed [Leng-Peschlow 1986]:

i. an influence on the motility of the large intestine (stimulation of peristaltic contractions and inhibition of local contractions) resulting in accelerated colonic transit, thus reducing fluid absorption [Garcia-Villar 1980; Bueno 1980], and

ii. an influence on secretion processes (stimulation of mucus and active chloride secretion) resulting in enhanced fluid secretion [Leng-Peschlow 1986, 1989].

Defecation takes place after a delay of 8-12 hours due to the time taken for transport to the colon and metabolic conversion of hydroxyanthracene glycosides to the active compounds.

In vitro experiments

Antimicrobial activityIn an agar plate assay, strong inhibition of Helicobacter pylori was observed with a water extract (MIC < 1 mg) [Bae 1998]. An ethanolic extract inhibited Helicobacter pylori growth with a MIC of 17.24 µg/ml; in this test the MICs of anthraquinone compounds isolated from rhubarb were 0.40 µg/ml (emodin), 0.60 µg/ml (rhein), 0.78 µg/ml (chrysophanol) and 0.85 µg/ml (aloe-emodin) [Gou 1997].

Rhein, in combination with ampicillin or oxacillin, had syner-gistic or partial synergistic effects against methicillin-resistant Staphylococcus aureus strains (MRSA). The MIC of the respective antimicrobial agent in combination with rhein, compared to the antimicrobial agent alone, ranged 0.28-1 for ampicillin and 0.18-1 for oxacicillin [Joung 2012].

An ethanolic extract exhibited antiviral activity against Herpes simplex by preventing virus attachment and penetration [Hsiang 2001].

The antimycotic activity of an aqueous extract against Aspergillus fumigatus and Candida albicans was comparable to that of nystatin. The growth of Geotrichum candidum and Rhodotorula rubra was inhibited to a lesser extent [Blaszcyk 2000].

Rhein isolated from rhubarb showed strong antimicrobial activity against Candida albicans and Bacteroides fragilis [Cyong 1987].

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Anti-proliferative activityA dried aqueous extract (8:1) had significant (p<0.001) dose- and time-dependent growth inhibitory effects on both human lung adenocarcinoma cells and human breast cancer cells with IC50 values of 620 ±12.7 and 515 ±10.1 µg/ml respect-ively [Li 2009].

Rhein inhibited growth of three cancer cell lines in a dose dependent manner. The IC50 values against human cervical cancer cells, breast adenocarcinoma cells (MCF-7) and hepatocellular carcinoma cells (HepG2) were 54.28 ± 0.17, 49.35 ± 0.23 and 36.34 ± 0.14 µMol respectively (p<0.05) [Al-Fatlawi 2014].

Aloe-emodin induced apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway [Lin 2010].

Emodin exhibited antiproliferative, antimetastatic and apop-totic effects in human chronic myelocytic leukemia K562 cells, pancreatic cancer cells, cervical cancer hela cells, hepatoma cells, neuroblastoma cells and tongue squamous cancer cells [Chun-Guang 2010, Liu 2011, Yaoxian 2013, Hsu 2010, Huang 2013, Lin 2009].

Several phenolic compounds from rhubarb showed cytotoxicity against human oral squamous cell carcinoma and salivary gland tumour cell lines as well as human gingival fibroblasts [Shi 2001]. Aloe-emodin induced apoptotic cell death in human lung squamous cell carcinoma [Lee 2001].

Bioassay-guided fractionation of an ethyl acetate extract showed emodin to be a selective inhibitor of casein kinase II with an IC50 of 2 µM [Yim 1999].

However, methanolic extracts from Rheum palmatum and Rheum officinalis rhizomes were found to significantly (p<0.01) enhance proliferation of the oestrogen-sensitive MCF-7 cell line at concentrations of 100 and 30 µg/ml, respectively. This effect was mainly attributed to emodin and emodin-8-O-b-D-glucoside, which bound to human oestrogen receptors a and b [Matsuda 2001].

Other effectsMethanolic extracts from Rheum palmatum and Rheum officinale showed radical scavenging activity, reducing 40 µM a,a-diphenyl-b-picrylhydrazyl (DPPH) radical by 50% at concentrations of 5.2 and 3.3 µg/ml respectively. IC50 values on superoxide anion radical in the xanthine/xanthine oxidase system were 5.0 and 3.8 µg/ml [Matsuda 2001]. Pyrogallol autoxidation and hydroxyl radicals generated via the Fenton reaction were inhibited by anthraquinones from rhubarb [Yuan 1997].

A hot water extract inhibited rat squalene epoxidase, an enzyme that catalyzes a rate-limiting step of cholesterol biosynthesis, by 70% at a concentration of 50 µg/ml; several galloyl compounds isolated from rhubarb were found to be potent inhibitors of the enzyme [Abe 2000].

A 90% hydroethanolic dried extract (3.4:1) was administered intragastrically to normal and CCl4-treated rats daily for 12 weeks at dosage levels equivalent to 2, 5.4, 14.69 and 40g crude drug/kg b.w. A decrease in the extent of cellular injury was observed in the two lowest dosage groups of CCl4-treated rats. However, a significant increase in fibrosis indicating rhubarb-induced liver damage was observed in both normal rats at all dosage levels and CCl4-treated rats at the two highest dosage levels [Wang 2011].

In vivo experimentsIn rats with adenine-induced chronic renal failure a hot water extract decreased levels of serum urea nitrogen and creatinine, as well as the hepatic urea concentration, in a dose-dependent manner. The effects were significant at doses of 15 and 35 mg/rat/day (p<0.01 to p<0.05) and 55 mg/rat/day (p<0.001). Hypocalcaemia, hyperphosphataemia and the concentrations of guanidino compounds in the serum, liver and kidney were improved. Proanthocyanidin oligomers were shown to be the active substances [Yokozawa 1984, 1986].

Rats with streptozotocin-induced diabetic nephropathy were 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 of the experimental period treated animals showed decreases in blood glucose levels, serum triglycerides and total cholesterol, and increases in urinary excretion of urea nitrogen and creat-inine. All the changes were significant (p<0.01) compared to untreated controls [Yokozawa 1997].

A hot water extract was administered orally to rats after subtotal nephrectomy (SN) at a dose of 150 mg/day from day 30 to day 120. The treated animals had significantly less proteinuria (p<0.05) compared to untreated SN controls on days 90 and 120 after SN. Renal function was similar in the two groups, but the severity of glomerulosclerosis was significantly (p<0.5) reduced by the treatment [Zhang 1996]. Anti-inflammatory activity of rhubarb was demonstrated in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear oedema. After single or multiple topical applications of TPA, an extract (50% ethanol, drug to extract ratio 3:1) applied topically at 0.5 mg/ear led to significant inhibition of oedema (p<0.01). Increased myeloperoxidase activity in the tissue after multiple applications of TPA was significantly reduced by the extract (p<0.01) [Cuéllar 2001].

Mice with streptozocin-induced diabetes were treated with emodin at 1.5 mg/kg i.p., daily for 3 weeks. The serum glucose level in the emodin-treated group was significantly (p<0.01) lowered compared to the diabetic control group. After 3 weeks glucose tolerance and insulin sensitivity in the emodin group were significantly (p<0.05) improved compared to control [Xue 2010].

In db/db mice treated daily for 2 weeks with either 100 mg/kg b.w. of rhein or emodin by oral gavage, total fat weight was significantly (p<0.05) decreased in the rhein group compared to an untreated control, whereas no effects were observed in the emodin group. In a further test, obesity was induced in C57BL/6 mice using a high fat diet. Mice were fed for 8 weeks with either a high fat diet mixed with 0.1% rhein or a high fat diet alone. At the end of treatment, body weight of the rhein-treated mice was significantly lower (p<0.01) than that of the high fat diet control group, indicating that rhein could block weight gain despite the amount of food intake in both groups being similar [Zhang 2012].

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 genes related to adipogenesis in white adipose tissue (regulating cholesterol homeostasis, lipid and energy metabolism) was significantly (p<0.05) suppressed compared to a high fat diet control [Sheng 2012].

Three groups of mice (n=10 each) were injected i.p. with myelomonocytic leukemia WEHI-3-cells and 2 weeks later began treatment for 14 days with a daily oral gavage of either 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 treatment) or negative control (olive oil administration only). In comparison to the olive oil only treated leukemia mice group, CD19 and CD11b levels were significantly (p<0.05) increased in the 10 mg/kg and 5 mg/kg emodin groups respectively, whereas levels of CD3 were unaffected. The activity of peritoneal cavity phagocytes was significantly increased in the 5 mg/g emodin group (p<0.05) and in the 10 mg/kg emodin group (p<0.001) [Chang 2011].

Three weeks after transfection of nude mice with SW1990 pancreatic tumour cells, four groups (n=12 each) received ten i.p. injections (every three days) of either emodin (40 mg/kg), gemcitabine (125 mg/kg), emodin (40 mg/kg) plus gemcitabine (80 mg/kg) or isotonic saline. One week after the final injection (day 37), the tumour growth inhibition rate (difference of mean tumour volume between end and start of treatment in the treatment group divided by the respective difference in control group) was found to be high in the emodin and gemcitabine groups at 71.3 and 83.3% respectively, but highest in the combination group at 103.7% [Wei 2011].

Five groups of nude mice (n=5 each) were transfected with transplantable tumours induced by chronic myeloid leukemia K562 cells. After 12 days the groups were treated for 12 days with either 25, 50 or 100 mg/kg emodin, or 120 mg/kg hydroxy carbamide as positive control and isotonic saline as negative control. Tumour weight was reduced in the emodin groups, by 61.4% at 50 mg/kg (p<0.05) and by 75.6% at 100 mg/kg (p<0.01) and also in the positive control group by 78.3% (p<0.01) when compared to the negative control [Chun-Guang 2010].

Studies in humansAlthough no published clinical data is currently available, the laxative effect of rhubarb is well-known, and is comparable to the other anthranoid containing laxatives. Pharmacokinetic propertiesNo systematic data are available on rhubarb. It is assumed that aglycones present in the drug are absorbed in the upper gut, and that (by analogy with sennosides from senna) the b-linked glucosides are neither absorbed in the upper gut nor split by human digestive enzymes. They are converted by the bacteria of the large intestine into aglycones and subsequently to the active compounds, the anthrones [Kobashi 1980].

In rat liver microsomes emodin was metabolized to 6-hydroxy-aloe-emodin and 2-hydroxyemodin, and chrysophanol was converted to aloe-emodin [Mueller 1998].

Preclinical safety data There are no studies on single dose toxicity, repeated dose toxicity, reproductive toxicity or in vivo tests on carcinogenicity of rhubarb or preparations from it. In the Salmonella micro-some assay an ethanolic extract showed mutagenic effects against S. typhimurium strain TA 1537 [Paneitz 1999]. Some isolated anthraquinones (aloe-emodin, emodin, physcion and chrysophanol) gave positive results in in vitro genotoxicity studies [Bruggemann 1984; Westendorf 1990; Heidemann 1993, 1996]. All in vivo genotoxicity studies were negative [Heidemann 1993, 1996; Mengs 1997]. Sennosides A and B and rhein gave negative results in in vitro and in vivo mutagenicity tests [Heidemann 1993; Mengs 1993].

In a 2-year study, male and female F344/N rats were exposed to 280, 830 or 2500 ppm of emodin in the diet, corresponding to an average daily dose of emodin of 110, 320 or 1000 mg/kg 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

observed in male rats. A marginal increase in the incidence of Zymbal’s gland carcinoma occurred in female rats treated with the high dosage but was interpreted as questionable [NIH Publication 1999].

In a further 2-year study, on B6C3F1 mice, males were exposed to 160, 312 or 625 ppm of emodin (corresponding to an average daily dose of 15, 35 or 70 mg/kg b.w.) and females to 312, 625 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 carcinogenic activity in female mice. A low incidence of renal tubule neoplasms in exposed males was not considered relevant [NIH Publication 1999].

A 90% hydroethanolic dried extract (3.4:1) was administered intragastrically to normal and CCl4-treated rats daily for 12 weeks at dosage levels equivalent to 2, 5.4, 14.69 and 40g crude drug/kg b.w. Although a decrease in the extent of cellular injury was observed in the two lowest dosage groups of CCl4-treated rats, a significant increase in fibrosis indicating rhubarb-induced liver damage was observed in both normal rats at all dosage levels and CCl4-treated rats at the two highest dosage levels [Wang 2011].

Clinical safety dataDespite a lack of formal preclinical data on rhubarb, epi-demiological studies suggest that there is no carcinogenic risk to humans from the use of anthranoid laxatives [Siegers 1993; Nusko 1993; Sonnenberg 1993; Kune 1993, 1996; Loew 1996, 1997].

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Al-Fatlawi AA, Al-Fatlawi AA, Zafaryab MD, Irshad MD, Ahmad I, Kazim Z, Ahmad A et al. Rhein induced cell death and apoptosis through caspase dependent and associated with modulation of p53, BCL-2/bax ratio in human cell lines. Int J Pharmacy Pharm Sci 2014;6:515-9.

Abe I, Seki T, Noguchi H, Kashiwada Y. Galloyl esters from rhubarb are potent inhibitors of squalene epoxidase, a key enzyme in cholesterol biosynthesis. Planta Med 2000;66:753-6. https://doi.org/10.1055/s-2000-9781

Bae EA, Han MJ, Kim NJ, Kim DH. Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull 1998;21:990-2. https://doi.org/10.1248/bpb.21.990

Blaszczyk T, Krzyzanowska J, Lamer-Zarawska E. Screening for antimycotic properties of 56 traditional Chinese drugs. Phytother Res 2000;14:210-2. https://doi.org/10.1002/(SICI)1099-1573(200005)14:3<210::AID-PTR591>3.0.CO;2-7

Bruggeman IM, van der Hoeven JCM. Lack of activity of the bacterial mutagen emodin in HGPRT and SCE assay with V79 Chinese hamster cells. Mutat Res 1984;138:219-24. https://doi.org/10.1016/0165-1218(84)90047-8

Bueno L, Fioramonti J, Frexinos J, Ruckebusch Y. Colonic myoelectrical activity in diarrhea and constipation. Hepato-Gastroenterology 1980;27:381-9.

Chang YC, Lai TY, Yu CS, Chen HY, Yang JS, Chueh FS, Lu CC et al. Emodin induces apoptotic death in murine myelomonocytic leukemia WEHI-3 cells in vitro and enhances phagocytosis in leukemia mice in vivo. Evid Based Complement Alternat Med 2011;2011:523596. https://doi.org/10.1155/2011/523596

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Chun-Guang W, Jun-Qing Y, Bei-Zhong L, Dan-Ting J, Chong W, 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 2010;627:33-41. https://doi.org/10.1016/j.ejphar.2009.10.035

Cooke WT. Laxative abuse. Clin Gastroenterol 1977;6:659-73.

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9

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.

Although publication in the form of books was convenient in the past, ESCOP recognizes that online publication now offers a number of advantages, not least in facilitating rapid publication of individual monographs as soon as all stages of preparation have been completed. Commencing from 2011, therefore, new and revised monographs will be published online only.

The European legislative framework for herbal medicines has advanced considerably over the past decade. Directive 2004/24/EC introduced a simplified registration procedure for traditional herbal medicinal products in EU member states and imposed a 2011 deadline for the registration of certain products on the market. The Committee on Herbal Medicinal Products (HMPC), established in 2004 as part of the European Medicines Agency, has made substantial progress in the preparation of Community Herbal Monographs and associated documentation to provide a more harmonized approach to the scientific assessment of herbal medicinal products throughout the European Community

Whether the evaluation of a herbal medicine is based on evidence of clinical efficacy (well-established use) or on experience and historical use of that product (traditional use) those involved at all levels of the regulatory process need access to detailed, reliable and structured summaries of the available efficacy and safety data. ESCOP monographs meet that requirement and offer an invaluable source of scientific information on herbal medicines to regulators, manufacturers, academics, researchers, health professionals and numerous others.

MonographsThe Scientific Foundation for Herbal Medicinal Products

www.escop.com ISBN 978-1-901964-59-2

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