Butcher's Broom 2017

Online Series Monographs The Scientific Foundation for Herbal Medicinal Products

Rusci rhizoma Butcher's Broom 2017

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

RUSCI RHIZOMA Butcher's Broom

2017

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 978-1-901964-51-6

Rusci rhizoma - Butcher's Broom

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 Fritz Geller-Grimm and Felix Grimm [CC BY-SA 3.0], via Wikimedia Commons (Ruscus aculeatus) and Martin Willoughby Cover and text design by Martin Willoughby Typeset in Optima by Roberta Hutchins

Plant illustrated on the cover: Ruscus aculeatus 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.

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 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 RUSCI RHIZOMA 2017 Butcher's Broom

DEFINITION

Butcher’s Broom consists of the dried, whole or fragmented underground parts of Ruscus aculeatus L. It contains not less than 1.0 per cent of total sapogenins,

expressed as ruscogenins [a mixture of neoruscogenin (C27H40O4; Mr 428.6) and ruscogenin (C27M42O4; Mr 430.6)] and calculated with reference to the dried drug.

The material complies with the monograph of the European Pharmacopoeia [Butcher`s Broom].

CONSTITUENTS

The characteristic constituents are steroidal saponins based upon (25R)- spirost-5-ene-1b,3b-diol (ruscogenin) and spirosta-5,25(27)-diene-10,3b-diol (neoruscogenin), such as ruscoside, ruscin, deglucoruscoside and deglucoruscin. Minor constituents include flavonoids, anthraquinones, benzofurans, the coumarin esculin, essential oil (mainly monoterpenes) and sterols [Rauwald 1988; Schneider 1990; Mimaki 1998a, 1998b; Mari 2012; Barbic 2013; Sticher 2015].

CLINICAL PARTICULARS

Therapeutic indications Supportive therapy for symptoms of chronic venous insufficiency, such as painful, tired and heavy legs, tingling and swelling [Vanscheidt 2002; Boyle 2003; Aguilar Peralta 2007; Lascasas Proto 2009; Guex 2010]. Supportive therapy for symptoms of haemorrhoids, such as itching and burning [Anger 1981; Willuhn 2009; Abascal 2005].

Posology and method of administration

Dosage Adult daily dose: Solid or liquid extracts in amounts corresponding to 7-11 mg of total ruscogenins [Willuhn 2009].

Method of administration For oral administration.

Duration of administration No restriction; long-term administration may be advisable. If symptoms persist or worsen, medical advice should be sought.

Contraindications None known.

Special warnings and special precautions for use None required.

Interaction with other medicaments and other forms of interaction None reported.

Pregnancy and lactation In accordance with general medical practice, the product should not be used during pregnancy and lactation without medical advice.

No adverse effects have been reported in mothers or newborn babies when used in late pregnancy [Anger 1981; Baudet 1991].

Effects on ability to drive and use machines None known.

Undesirable effects Contact allergy to ruscogenins might occur in rare cases [Elbadir 1998].

1 RUSCI RHIZOMA

Overdose 11 female, 3 male). The threshold dose ranged between 0.01 No toxic effects reported. and 0.1 mg/mL. Contractions of the varicose tributaries were about two-fold greater than those of saphenous veins from the

same patients. In veins from varicose patients, a2-blockade with PHARMACOLOGICAL PROPERTIES rauwolscine was more effective than a1-blockade with prazosin in reducing contractions induced by butcher’s broom in rings Pharmacodynamic properties with and without endothelium [Miller 2000].

In some studies, combinations have been used, consisting Maximal contractions induced by an extract (not further of an extract (not further specified) plus hesperidin methyl specified; 1 mg/mL) in veins taken from women undergoing chalcone as well as in some cases ascorbic acid. In the text, varicectomy were independent from the oestrogen level during these preparations are indicated by the term “a combination”. the menstrual cycle. Comparable effects were seen in veins from menopausal women [Marcelon 1988a]. In vitro experiments A water-soluble extract (not further specified; 0.01, 0.1 and 1 Vasoconstriction mg/mL) caused dose-dependent reduction of noradrenaline In rings of saphenous vein from ovariectomized female rabbits, accumulation in isolated normal and varicose human saphenous an extract (prepared using DMSO with further dilution in veins. The highest concentration caused a reduction of about distilled water) (0.001-1 mg/mL) induced dose-dependent 50% in the normal vein and reduced the formation of all contractions. This effect was insensitive to blockade by either metabolites of noradrenaline [Branco 1988]. prazosin (3 x 10-7 M) or rauwolscine (10-7 M), but was partially inhibited by both substances in rings isolated from oestradiol- Saponin mixtures and ruscogenin provoked remarkable vaso- treated animals [Harker 1988]. constrictive effects in the isolated rabbit ear. The ED50 of ruscogenin was 20-25 fold lower than for the saponins [Capra 1972]. A hydroalcoholic extract (not further specified) caused dose- dependent contraction in segments of isolated canine saphenous Effects on permeability veins (effective dose: 30 µg/mL and higher). The maximal Damage to isolated pig ear vein induced by ethacrynic acid contraction caused by the extract averaged 80 ± 12% of the was diminished by pre-incubation with an extract (not further response to 10-4 M noradrenaline. Prazosin and rauwolscine specified; 0.05%). This effect was related to reduced permeability given alone decreased, and the presence of both substances to both water and protein [Hönig 1989]. eliminated, the response to the extract (0.1-1 mg/mL, n = 5 each concentration). Cocaine reduced the contraction evoked by Vasoprotection butcher’s broom extract suggesting also an indirect sympatho- In the presence of an extract (not further specified), the viability mimetic effect of the extract. The contractile response to the of human umbilical vein endothelial cells exposed to hypoxia extract was also depressed by phentolamine, adenosine, increased by up to 60%. A pronounced effect was observed verapamil and by sympathectomy with 6 hydroxydopamine. when cells under hypoxia were incubated for 48 hours with Tetrodotoxin, atropine, methysergide and indometacin did not concentrations above 330 µg/mL [Baurain 1994]. The extract at significantly influence the effect of butcher’s broom extract; 0.05 µg/mL provided only slight protection from the hypoxia- acetylcholine enhanced the increase in tension [Marcelon induced decrease in ATP, while 50 µg/mL totally prevented 1983,1984,1988]. the effect of hypoxia (n=9 for each concentration). Inhibition of phospholipase A2 activation by 50%, observed with the Femoral vein rings and coronary arterial rings were isolated from extract at 0.05 µg/mL, increased only slightly with higher adult female mongrel dogs. An extract (not further specified; concentrations (0.5 µg/mL, 5 µg/mL and 50 µg/mL). The extract 0.001-1 mg/mL) induced dose-dependent contractions of the also dose-dependently inhibited hypoxia-induced adherence vein preparations. The effect was modulated by the integrity of neutrophils to the endothelial cells: 0% at 0.05 µg/mL and of the endothelial cells and the hormonal status of the 88% at 50 µg/mL [Bouaziz 1999]. animals. Treatment with prazosin plus rauwolscine reduced the contractions evoked by the extract following progesterone Effects on lymphatic vessels treatment; inhibition of a-adrenergic receptors in veins from Noradrenaline (10–8 to 10–4 M) and a combination (0.01-1 mg/ oestrogen-treated animals augmented the contractions evoked mL) caused dose-dependent contractions in isolated canine by the combination [Miller 1991a,b]. In both the venous and lymphatic thoracic duct. The activity of the combination was arterial rings with endothelium, the extract (4-6 g/mL) relaxed partially inhibited by prazosin and rauwolscine, whereas contractions induced by noradrenaline (veins) or prostaglandin phentolamine completely eliminated the contractile response F2a (PGF2a; arteries) in a dose-dependent manner. The relaxing [Marcelon 1988b]. effect was inhibited by atropine and by inactivation of the endothelial relaxing factors [Miller 1991a]. Addition of an extract (not further specified; 30 µg/mL) increased the contraction frequency caused by electrical field stimulation An extract (not further specified; 0.001-1 mg/mL) induced dose- in isolated bovine mesenteric lymphatic vessels (n = 8) by about dependent contractions in rings from greater saphenous veins and 50%. Noradrenaline blocked the response to the field stimul- varicose tributaries of patients (3 male, 17 female), who underwent ation (n = 6) [McHale 1991]. vein stripping for primary varicosity (n = 5-7 for each experiment). Blocking of a- and b-adrenergic receptors with phentolamine and Antioxidant effect propranolol reduced the maximal tonus induced by butcher’s Ruscogenin showed antioxidative effects against Formyl-Met- broom extract in each type of vein [Miller 1994]. Leu-Phe (FMLP)-induced extra- and intracellular superoxide

generation in mouse bone marrow neutrophils, with IC50 An extract (not further specified) caused comparable and values of 1.07 ± 0.32 μM and 1.77 ± 0.46 μM respectively. moderate contraction of human saphenous veins with and Phorbol myristate acetate (PMA)-elicited extra- and intracellular without endothelium isolated from healthy volunteers (n = 8; 3 superoxide generation were also suppressed by ruscogenin, females, 5 males) and patients with primary varicosity (n = 14; with IC50 values of 1.56 ± 0.46 μM and 1.29 ± 0.49 μM

2 RUSCI RHIZOMA

respectively. Furthermore, it inhibited the membrane trans- anaesthetized young adult cats. Following intra-arterial location of p47phox and p67phox and reduced FMLP-induced administration of 0.4 mg/min/kg b.w., arterial, arteriolar and phosphorylation of cytosolic phospholipase A2 (cPLA2) venular resistance increased by 30-35% within 90 seconds, and p21-activated kinase (PAK). The cAMP levels and PKA while higher doses (0.8 mg/min/kg and 3 mg/min/kg) produced expression were increased by ruscogenin. Ruscogenin inhibited sustained dilator effects. This pattern of response was consistent phosphorylation of protein kinase B (Akt), p38 mitogen-activated in all experiments (n = 24). Intravenous administration of protein kinase (p38MAPK), extracellular signal-regulated the extract at 1-9 mg/min/kg resulted in a dose-dependent kinase 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK). venoconstrictive response (n = 10) [Mellander 1991]. The inhibitory effects of ruscogenin on superoxide production and the phosphorylation of Akt, p38MAPK, and ERK1/2 were In dogs (n = 4), constant infusion of an extract (not further reversed by PKA inhibitor (H89) [Lin 2015]. specified) at 50 µg/hour/kg b.w. for 5 days (total doses: 60-84 mg) had beneficial effects on alterations caused by denervation Anti-inflammatory effect of the lateral saphenous vein segments, with the increase in Ruscogenin significantly suppressed zymosan A-evoked smooth muscle cell diameter being completely prevented. The peritoneal total leukocyte migration in mice in a dose-dependent extract increased the O-methylating capacity of the denervated manner (1 and 3 mg/kg), while these concentrations had no effect and the non-denervated tissues [Teixeira 1988]. on PGE2 content in peritoneal exudate. At a concentration of 1µM, ruscogenin also inhibited TNFa-induced over-expression Effect on permeability of ICAM-1 both at mRNA and protein levels and considerably Topical application of an extract (not further specified; 0.002- suppressed NF-kB activation by decreasing NF-kB p65 2.0 mg/mL/min) to male hamster cheek pouch preparations translocation and DNA binding activity [Huang 2008]. dose-dependently inhibited the increase in macromolecular permeability caused by histamine. A concentration of 0.2 Elastase activity mg/mL/min elicited 50% inhibition of the histamine-induced Ruscogenins inhibited the activity of porcine pancreatic elastase permeability. This effect was blocked by prazosin and by

(IC50: 119 µM; competitive inhibition) [Maffei Facino 1995]. diltiazem, but not by rauwolscine (all applied topically) [Bouskela1994b]. Antimicrobial effect A dry extract (70% methanol) was active against 8 bacteria and An intravenously administered extract (not further specified) 5 fungi (MIC between 0.2 and 1.00 mg/mL). The antifungal at 5 mg/kg b.w. showed protective effects against leakage of activity against Trichoderma viride exceeded the one of the dextran in the hamster cheek pouch after topical administration positive controls, ketoconazole [Hadžifejzović 2013]. of various permeability-increasing substances such as brady-

kinin, leukotriene B4 or histamine [Bouskela 1993]. In vivo experiments Two isolated saponins and esculin were tested for their activity Vasoconstriction against hyperpermeability in endothelial cells induced by An extract (not further specified) was added to the superfusion thrombin. The saponins reduced permeability to 41.9% and solution applied to cheek pouch preparations of male hamsters. 42.6% whereas esculin reduced it to 53.3% [Barbic 2013]. The venules constricted with doses above 0.05 mg/mL/min, while arterioles remained unchanged. Venular constriction evoked by Oedema-protective effect the extract at 0.2 mg/mL/min was blocked by prazosin (10-9 M), The oedema-protective effects of an extract (containing 2.5% of by diltiazem (10-9 M) and by high concentrations of rauwolscine ruscogenin) and ruscogenin were demonstrated in a perfusion (10-6 M) [Bouskela 1994a]. model of the hindleg of anaesthetized cats. Oedema was induced by perfusion with 0.1% of ethacrynic acid for 10 minutes. The The vasoconstrictive effects of an extract (not further specified) extract (200 or 400 mg/kg b.w.) or ruscogenin (20 or 80 mg/kg applied topically to hamster cheek pouch preparations were b.w.) were administered orally 4 hours before induction of oed- found to be temperature-dependent. At 25°C venules and ema. Alternatively, the extract at 10 or 20 mg/kg or ruscogenin arterioles dilated. At 36.5°C venules constricted, whereas at 4 mg/kg were administered intravenously 1 hour prior to arterioles either dilated with extract concentrations of up oedema induction. Each treatment group comprised 5 or 6 to 0.05 mg/mL or remained unchanged even with higher animals and 16 animals served as controls. After an additional concentrations of the extract. At 40°C constriction of venules 45-minute perfusion with 0.9 % sodium chloride solution, the was more pronounced than at the lower temperatures, whereas blood, protein and water contents in the oedema of the skin arterioles only constricted with higher concentrations of the and muscle were measured. The optimal protective dose of the extract (above 0.01 mg/mL) [Bouskela 1991]. extract was 20 mg/kg b.w. when administered intravenously, whereas an oral dose 10- to 20-fold higher was necessary. An Intravenous administration of an extract (not further specified) intravenous dose of ruscogenin at 4 mg/kg b.w. was as effective at 5 mg/kg b.w. caused venular constriction in the cheek pouch as an oral dose of 20 mg/kg [Felix 1983]. of male hamsters, but did not affect the arteriolar diameter. Mean arterial pressure was not affected at this dose level Anti-inflammatory effect [Bouskela 1991]. An extract (not further specified) showed anti-inflammatory activity in rats when administered by the intraperitoneal (100, Oral administration of a solution of an extract (not further 200 or 300 mg/kg b.w.) or the rectal route (suppositories, 275 specified) at 150 mg/kg b.w. for 28 days resulted in constriction mg/kg b.w.). The effect of 300 mg/kg of the extract (i.p.) was of the venules by 30% and dilatation of the arterioles by 37% equivalent to 72% of the activity of phenylbutazone (165 mg/ in the hamster cheek pouch (n = 6) compared to water-treated kg i.p). Two other purified extracts with higher concentrations controls (n = 6). Arteriolar and venular side branches were not of ruscogenins were effective at lower doses [Chevillard 1965]. affected [Bouskela 1991]. In rats oedema was induced by injection of dextran, histamine, The vasoconstrictive effects of an extract (not further specified) serotonin or hyaluronidase. Intraperitoneal administration of were investigated in lower leg muscle preparations of 12 purified sapogenins from butcher’s broom at 20, 40 or 80 mg/

3 RUSCI RHIZOMA

kg b.w. reduced limb oedema; this antiphlogistic activity was chronic venous insufficiency included 20 randomised, placebo- suppressed by adrenalectomy. Slight anti-inflammatory activity controlled, double blind studies, 5 randomised studies against was observed against granulomas induced by subcutaneous a positive control, and 6 single arm studies (without placebo) implantation of cotton pellets. When the purified sapogenins including a total of 10,246 patients. In all studies the response to were administered orally neither antiphlogistic nor anti- the preparation was compared to baseline values. On a 4 point inflammatory activity was observed [Cahn 1965]. symptom severity scale, where 0 corresponds to no symptoms and 3 to severe symptoms, the combination significantly reduced Saponins and ruscogenins isolated from butcher’s broom showed the severity of pain by 0.44 points (p = 0.02), cramps by 0.26 anti-inflammatory activity in carrageenan- and brewer’s yeast- (p = 0.025), heaviness by 0.53 (p = 0.001) and paraesthesia induced rat paw oedema when administered intraperitoneally by 0.29 points (p = 0.031) compared to placebo. There was or intravenously. In the rabbit, only the ruscogenins (80 mg/ also a significant (p = 0.014) reduction in venous capacity of kg b.w. i.p.) decreased capillary permeability significantly (p 0.7 ml/100 ml with the combination compared to placebo. = 0.05). These substances were not active against capillary Non-significant decreases in calf and ankle circumference fragility [Capra 1972]. (0.72 and 1.17 cm respectively) and in the severity of oedema (0.43 points), were found in the treated patients compared to Effect on lymph vessels placebo [Boyle 2003]. Intravenous administration of a water-soluble extract (not further specified) at 1, 2 or 5 mg/kg b.w. dose-dependently The efficacy of an orally administered dry extract (15-20:1; enhanced flow duration and intensity in isolated lymph vessels methanol 60%) was evaluated in a randomized, double-blind, of anaesthetized dogs. A similar effect was seen in the veins. placebo-controlled study involving 166 women suffering from The activity of the extract was not influenced by injection of chronic venous insufficiency (Widmer grades I and II; CEAP nifedipine [Pouget 1991]. 3-4). After a placebo run-in period of 2 weeks, the patients were randomly assigned to either 72-75 mg of the extract or Pharmacological studies in humans placebo daily for 12 weeks. Data relating to 148 patients (30- In a randomized, double-blind, crossover, 4-armed study, 20 89 years, 150-182 cm height, 49-97 kg weight), with mean healthy volunteers (11 men and 9 women aged between 20 and disease durations of 14.6 years in the extract group (n = 77) 43 years) took a single oral dose of four different treatments, and 15.1 years in the placebo group (n = 71), were eligible for separated by 1-week wash-out periods: 450 mg of an extract, efficacy analysis. Significant differences in favour of the verum 450 mg of trimethylhesperidin chalcone (TMHC), a combination treatment were found for reductions in lower leg volume and of both substances, or a placebo. Venous function, capillary ankle circumference after 8 and 12 weeks (p<0.001), and in filtration rate, tissue and blood volume were monitored before leg circumference (p<0.001) and the main subjective symptoms intake and after 50, 70, 90, 120 and 150 minutes. Compared (p<0.05) after 12 weeks. There was a clear relationship between to placebo, butcher’s broom extract significantly decreased the changes in lower leg volume and the subjective symptoms venous capacity (p<0.01), reduced the blood pool in the lower “tired, heavy legs”, “sensation of tension” and “tingling leg (p< 0.05) and reduced tissue volumes in the foot and ankle sensation” (p<0.05). Global assessment by the investigators (p<0.01). TMHC did not influence venous capacity and its also confirmed the superiority of the extract treatment (p<0.05) influence on tissue volume was about 3 times weaker than that compared to placebo [Vanscheidt 2002]. of the extract [Rudofsky 1989]. In a prospective, multicentre, open clinical study, an oral In a double-blind, placebo-controlled study the influence of combination was tested for 8 weeks in 124 patients suffering venous stasis on several microrheological factors and the effects from chronic venous insufficiency. Initial reports of intensity were of taking a combination for 30 days were investigated in 25 79% for pain, 85% for heaviness, 74% for cramps and 82% for patients suffering from chronic venous insufficiency (13 verum, oedema, decreasing within two weeks to 20%, 12%, 8% and 12 placebo). All parameters were also measured in 20 untreated 14% respectively. The authors state that symptoms were absent healthy controls. In patients treated with the combination, at the end of treatment. Capillaroscopy changes at treatment haematocrit values after stasis did not increase, while they completion were: 98% to 20% inter-capillary fluid decrease; rose in the placebo group. The combination prevented an 80% to 20% efferent loop thickening; 5% to 2% peri-capillary increase in plasma viscosity after stasis and improved red cell bed, and 5% to 4% mega-capillaries [Aguilar Peralta 2007]. deformability. The red blood cell aggregation index after stasis was similar to that of control subjects, while it increased after Fifty-two female chronic venous disorder (CVD) patients were stasis in the placebo group [Le Devehat 1991]. allocated consecutively to one of three groups: a combination, elastic compression stockings and no treatment. After 4-weeks Application of 4-6 g of a cream containing 1.6 % of an extract treatment, the combination significantly decreased venous twice daily to the legs of healthy volunteers (n=18) led to diameters (popliteal vein parameters: right p< 0.04 and left constriction of the femoral vein, demonstrated by a decrease p<0.01) and great saphenous vein diameters (bilaterally p<0.01) in diameter in 8 out of 10 of the verum group by 0.5-3 mm compared pre-treatment, effects which were comparable to (median=1.25), compared to no change or a dilatation by 0.5 compression stockings [Lascasas Porto 2009]. mm (median) in 7 out of 8 of the placebo group (significant between group difference: p = 0.0139). In a group of 9 women In an observational, single arm, multicentre, prospective trial, 192 suffering from pregnancy-related varicosis, application of the patients suffering from CVD were treated with a combination. preparation to 3 of the women demonstrated that increases in Patient profiles, risk factors, clinical symptomatology and quality the femoral vein diameter of the painful leg were significantly of life (QoL) assessed by SF-12 and CIVIQ questionnaires were (p = 0.047) lower with treatment with the cream compared to evaluated at inclusion and after 12 weeks of treatment. Clinical without, and pain in the leg was reduced [Berg 1991]. symptoms such as feeling of heaviness, pain, swelling of the lower limbs and cramps improved with treatment and ankle Clinical studies circumferences significantly (p<0.001) decreased over time. The physical and psychological dimensions of the SF-12 score Chronic venous insufficiency, varicosis as well as the CIVIQ score significantly (p<0.001) improved A meta-analysis of studies using an oral combination to treat over time [Guex 2010].

4 RUSCI RHIZOMA

Haemorrhoids about 20% compared to absorption after oral administration. In observational studies more than 1800 patients (including 26 Maximum urinary excretion occurred after about 7.5 hours and pregnant women) suffering from haemorrhoids and anorectal sapogenins were identified as the major urinary metabolites. complaints have been treated topically with isolated ruscogenins A considerable proportion of the radioactivity was excreted in in suppositories (each containing 8 mg) and/or creams (0.8%) for urine (26%, 20% and 4% respectively) and faeces (6.5%, 23% 2 days to 13 weeks. Improvements were reported with respect and 9% respectively) within 24 hours after i.v., oral or topical to symptoms and objective evaluation by the physicians. The administration [Bernard 1985]. efficacy of treatment was estimated as very good or good in 85-93% of cases [Salzmann 1977; Bärmig 1978; Anger 1981]. Pharmacokinetics in humans The presence of butcher’s broom saponins in the blood Retinopathy was clearly demonstrated after oral administration of 1 g of In 60 type 2 diabetic patients, oral treatment for 3 months butcher’s broom extract in three volunteers. Plasma levels of with 37.5 mg of an extract (15-20:1; methanol 60%) twice a the spirostanol glycosides degluconeoruscin and deglucoruscin day showed an increased amplitude of oscillating potentials were measured by HPLC for 4 hours at 30-minute intervals. by 15% and an increase in visual acuity from 0.83 to 0.93 The Tmax for degluconeoruscin was 90-120 minutes after dosing, (not statistically significant results). Furthermore, it led to with a Cmax of 2.5 µg/mL [Rauwald 1991]. improvement of the fundus of the eyeball in 23% of the patients (n=20) and prevented progression of retinopathy in all cases Preclinical safety data [Archimowicz-Cyryłowska 1996]. Acute toxicity Pharmacokinetic properties The acute toxicity of an ethanolic extract (not further specified) was investigated in dogs and guinea pigs. In 6 male and female Pharmacokinetics in animals dogs death occurred within 1 hour following intravenous The pharmacokinetic characteristics of a radiolabelled extract infusion of the extract at doses between 0.83 and 1.8 g/kg. By (not further specified) were investigated in two male Wistar rats. the intraperitoneal route no toxic signs were found in guinea The activity of the extract was 2.8 mCi/mg, with 94% of the pigs at doses lower than 1.5 g/kg b.w.; animals receiving total radioactivity bound to saponins. Each animal received 1 doses of 2 g/kg b.w. and above died. Toxic and subtoxic doses mL of extract orally. Radioactivity was detected in the blood affected the respiratory function, and lethal doses resulted in 15 minutes after administration. After 2 hours, 39% of the hyperventilation followed by fatal apnoea [Moscarella 1953; radioactivity was found in the blood samples. After 3.5 hours, Caujolle 1953]. in 10 mL samples of blood a maximum radioactivity of 0.41% and 0.45% was observed and was maintained until the end Estimation of the oral and intraperitoneal LD50 values of a fluid of the 24-hour observation period. The extract was eliminated extract (ethanol 50% V/V) in rats and mice revealed differences mainly in the faeces but also renally in a ratio of 2:1, 46% of depending on the harvest time of the plant, the route of the administered radioactivity being excreted within 96 hours. administration and the use of roots or rhizomes. The oral LD50 Biliary excretion within 24 hours was 8.5 and 10.8% [Chanal of the rhizome extracts was 2.07-2.39 mL/kg b.w. in rats and 1978]. 24.69-33.73 mL/kg in mice; after intraperitoneal administration the toxicity was 10-20 fold higher. Root extract was found to The bioavailability of a 3H-labelled extract (not further specified) be more toxic than rhizome extract (1.4-1.8 fold in rats and after oral, topical and intravenous administration was studied 4-5 fold in mice). The observed symptoms of intoxication were in rats. Male Wistar rats were treated orally with 1 mL of an convulsion, paralysis and gastro-intestinal inflammation with aqueous solution containing 0.1 mL of a fluid extract (2% dysentery. Animals died following respiratory failure. Autopsies saponins, 70 µCi). Male Atrichi rats were treated topically with revealed pronounced irritation of the mucosa and strong visceral 250 mg of a combination of labelled butcher’s broom extract, congestion [Boucard 1967]. melilotus extract and dextran sulphate, corresponding to 25µCi.

By the intravenous route, male Wistar rats received 0.5 mL of an Oral LD50 values of ruscogenin and Ruscus saponins were aqueous solution containing 50 mg of the extract (56 µCi). Based estimated to be greater than 3g/kg b.w. in mice and rats [Capra on radioactivity in the blood and urine, absorption by the oral 1972]. route was estimated at 65% and by the local route at 25%. After intravenous administration the existence of an enterohepatic Repeated dose toxicity cycle was demonstrated and one-third of the radioactivity An extract (not further specified) was given to male rabbits in was eliminated via the faeces. Following oral administration their diet for 26 weeks, 17 animals received 2g/kg b.w., 19 maximum radioactivity was found in the blood after 2 hours received 5g/kg and 16 animals served as controls. Body weights and was maintained for 24 hours. In similar experiments with and blood counts did not reveal any differences between treated orally-treated Atrichi rats 80% of the radioactivity was eliminated animals and controls [Roux 1969]. within 72 hours, with 35% of the dose being detected in the urine [Chanal 1981]. Rats were treated with 300 mg/kg of ruscogenin or Ruscus saponins by gavage daily for 8 weeks (10 animals per group, with Macaca monkeys (3 females, 3 males) were treated with a 10 untreated rats as controls). No toxic signs or differences in tritiated extract (not further specified; 1.5 mCi/kg b.w.) by oral body and organ weight were observed. Histological examination (n = 4) or intravenous (n = 1) routes, or topically in a fixed did not reveal any pathological changes in any group. Blood combination (n = 1). Thin layer chromatography showed that glucose and liver function did not differ significantly between 80-83% of the labelling was fixed in the sapogenin fraction the groups. An increase in diuresis and excretion of electrolytes of the extract. Most of the radioactivity was found in the bile, was observed in the ruscogenin group but not in animals treated the digestive tract and the urinary tract 2 hours after oral with saponins [Capra 1972]. administration, with less in the liver and kidneys. After 7 hours, radioactivity had further increased only in the urinary tract, the Reproductive toxicity bile and the faeces. Radioactivity after 24 hours was markedly Reproductive toxicity was studied with a combination containing lower in all measured tissues. Percutaneous absorption was an ethanolic extract (10%), TMHC, citric acid, methyl-4-esculetol

5 and ascorbic acid; 5 mL of the preparation contained 0.5 Anger H, Nietsch P. Ruscorectal bei Analerkrankungen. Med Welt mL of the butcher’s broom extract. Twenty female Wistar rats 1981;33:1450-2. received a daily dose of 2.4 mL of the preparation, equivalent to 25 times the recommended dose for humans; 20 untreated Archimowicz-Cyrylowska B, Adamek B, Drozdzik M, Samochowiec animals served as controls. Treatment started one week before L, Wójcicki J. Clinical effect of buckwheat herb, Ruscus extract and conception and continued until delivery. The animals tolerated Troxerutin on retinopathy and lipids in diabetic patients. Phytotherapy the drug without any signs of intoxication. The fertility of Research 1996;10:659-662. females in the treatment group was comparable to that in the http://dx.doi.org/10.1002/(SICI)1099-1573(199612)10:8<659::AID- control group, and the offspring did not show any teratogenic PTR930>3.3.CO;2-L signs [Labie 1984]. Barbic M, Willer EA, Rothenhofer M, Heilmann J, Fürst R, Jürgenliemk G. Spirostanol saponins and esculin from Rusci rhizoma reduce the Clinical safety data thrombin-induced hyperpermeability of endothelial cells. Phyto- A dry extract (15-20:1, methanol 60%) taken orally by 77 women chemistry 2013;90:106-13. at a dosage of 72-75 mg daily for 12 weeks was well tolerated. http://dx.doi.org/10.1016/j.phytochem.2013.02.004 Overall tolerability was assessed as very good by 76.8% and good by 23.2% of the patients and was comparable to that of Bärmig H. Ruscorectal - ein neues anorektales Therapeutikum. placebo treatment. Laboratory data, comparison of vital signs Therapiewoche 1978;28:7279-80. and physical examination before and after treatment did not reveal any treatment-related changes [Vanscheidt 2002]. Baudet JH, Collet D, Aubard Y, Renaudie P. Therapeutic test of Ruscus extract in pregnant women: evaluation of the fetal tolerance applying An early report stated that contact allergy to ruscogenins is a rare the pulse Doppler’s method of the cord. In: adverse effect [Elbadir 1998]. However, this was not confirmed Baurain R, Dom G, Trouet A. Protecting effect of Cyclo 3 Fort and its in more recent studies using preparations of ruscogenins, apart constituents for human endothelial cells under hypoxia. Clin Hemorheol from one report of a case of contact dermatitis in a patient using 1994;14:S15-S21. a topical preparation (not further specified) for haemorrhoidal disease. Patch testing revealed positive results for ruscogenins Beaugerie L, Luboinski J, Brousse N, Cosnes J, Chatelet FP, Gendre JP, [Ramirez-Hernandez 2006]. Quintrec YL. Drug induced lymphocytic colitis. Gut 1994;35:426-8. http://dx.doi.org/10.1136/gut.35.3.426 In a case report, the development of ketoacidosis in a diabetic patient after consumption of an extract (not further specified) Berg D. First results with Ruscus extract in the treatment of pregnancy was described. A causal relationship could not be established related varicose veins. In: Vanhoutte P, editor. Return circulation and [Sadarmin 2013]. norepinephrine: an update. Paris: John Libbey Eurotext, 1991:55-61.

Combination preparations Bernard P, Cousse H, Rico AG, Fauran F. Etude autoradiographique de la distribution du tritium chez des singes macaques traité par un extrait Placebo-controlled and open studies with combinations de Ruscus tritié. Ann Pharm Fr 1985;43:573-84. containing butcher’s broom extracts have not revealed any specific side effects. Moderate gastric complaints were observed Bouaziz N, Michiels C, Janssens D, Berna N, Eliaers F, Panconi E, Remacle [Monteil-Seurin 1991; Parrodo 1999]. J. Effect of Ruscus extract and hesperidin methylchalcone on hypoxia- induced activation of endothelial cells. Int Angiol 1999;18:306-12. Single cases of diarrhoea and lymphocytic colitis have been reported following the use of combinations containing butcher’s Boucard M, Beaulaton IS, Reboul C. Étude de la toxicité aiguë de divers broom extract [Beaugerie 1994; Maechel 1992; Rassiat 2001]. extraits fluides de fragon épineux (Ruscus aculeatus L.). Travaux Soc Pharm Montpellier 1967;27:187-91. In a prospective, multicentre, open study in 124 patients who were treated with a combination containing 300 mg of an Bouskela E, Cyrino FZGA, Marcelon G. Inhibitory effect of the Ruscus extract (not further specified) for 8 weeks, mild headache and extract and of the flavonoid hesperidine methylchalcone on increased vertigo were reported in 24% of the patients during the first microvascular permeability induced by various agents in the hamster week which disappeared in the second week. Mild transient cheek pouch. J Cardiovasc Pharmacol 1993;22:225-30. epigastric complaints were reported in 19% of the patients in http://dx.doi.org/10.1097/00005344-199308000-00009 the fourth week [Aguilar Peralta 2007]. Bouskela E, Cyrino FZGA, Marcelon G. Possible mechanism for the Reproductive toxicity venular constriction elicited by Ruscus extract on hamster cheek pouch. Ruscogenin-containing suppositories were well tolerated by 30 J Cardiovasc Pharmacol 1994a;24:165-70. pregnant women without any apparent effects on the newborn http://dx.doi.org/10.1097/00005344-199407000-00025 babies [Anger 1981]. Bouskela E, Cyrino FZGA. Possible mechanisms for the effects of Ruscus extract on microvascular permeability and diameter. Clin Hemorheol 1994b;14:S23-S36. REFERENCES Bouskela E. Microcirculatory responses to Ruscus extract in the Abascal K, Yarnall E. Botanical treatments for Hemorrhoids. Alternative hamster cheek pouch. In : Vanhoutte PM, editor. Return circulation and and complementary therapies 2005;285-289. norepinephrine: an update. Paris: John Libbey Eurotext, 1991:207-18. http://dx.doi.org/10.1089/act.2005.11.285 Boyle P, Diehm C, Robertson C. Meta-analysis of clinical trials of Aguilar Peralta GR, Arévalo Gardoqui J, Llamas Macias FJ, Navarro Cyclo 3 Fort in the treatment of chronic venous insufficiency. Int Angiol Ceja VH, Mendoza Cisneros SA, Martinez Macias CG. Clinical 2003;22:250-62. and capillaroscopic evaluation in the treatment of chronic venous insufficiency with Ruscus aculeatus, hesperidin methyl chalcone and Branco D, Osswald W. The influence of Ruscus extract on the uptake ascorbic acid in venous insufficiency treatment of ambulatory patients. and metabolism of noradrenaline in the normal and varicose human Int Angiol 2007;26:378-84. saphenous vein. Phlebology 1988;3(Suppl 1):33-9. RUSCI RHIZOMA

Butcher’s Broom - Rusci rhizoma. European Pharmacopoeia, Council Lin YN, Jia R, Liu YH, Gao Y, Wang LL, Kou JP, Yu BY. Ruscogenin of Europe. suppresses mouse neutrophil activation: Involvement of protein kinase A pathway. J Ster Biochem Mol Biol 2015;154:85-93. Cahn J, Herold M, Senault B. Antiphlogistic and anti-inflammatory activity of F191 (purified sapogenins of Ruscus aculeatus). Proc Int Maechel H. Diarrhée chronique secondaire au Cirkan®. Gastroenterol Symposium on non-steroidal anti-inflammatory drugs. Mailand, 8-10 Clin Biol 1992;16:373. Sept 1964. Amsterdam 1965:293-8. Maffei Facino R, Carini M, Stefani R, Aldini G, Saibene L. Anti-elastase Capra C. Studio farmacologico e tossicologico di componenti del and anti-hyaluronidase activities of saponins and sapogenins from Ruscus aculeatus L. Fitoterapia 1972;43:99-113. Hedera helix, Aesculus hippocastanum and Ruscus aculeatus: factors contributing to their efficacy in the treatment of venous insufficiency. Caujolle F, Mériel P, Stanislas E. Sur les propriétés pharmacologiques Arch Pharm (Weinheim) 1995;328:720-4. de l’extrait de Ruscus aculeatus. Ann Pharm Fr 1953;11:109-20. http://dx.doi.org/10.1002/ardp.19953281006

Chanal JL, Cousse H, Sicart MT, Derocq JM. Étude cinétique de Marcelon G, Pouget G, Tisne-Versailles J. Effect of Ruscus on the l’absorption d’un extrait de Ruscus radiomarqué. Travaux Soc Pharm adrenoceptors of the canine lymphatic thoracic duct. Phlebology Montpellier 1978;38:43-8. 1988b;3(Suppl 1):109-112.

Chanal JL, MBatchi B, Sicart MT, Cousse H, Fauran F. Comparaison de Marcelon G, Vanhoutte PM. Mechanism of action of Ruscus extract. la biodisponibilité d’extrait de Ruscus tritié chez le rat en fonction de la Int Angiol 1984;3:74-6. voie d’administration. Travaux Soc Pharm Montpellier 1981;41:263-72. Marcelon G, Vanhoutte PM. Venotonic effect of Ruscus under variable Chevillard L, Ranson M, Senault B. Activité anti-inflammatoire d’extraits temperature conditions in vitro. Phlebology 1988;3(Suppl 1):51-4. de fragon épineux (Ruscus aculeatus L.). Med Pharmacol 1965;12:109- 14. http://dx.doi.org/10.1159/000135535 Marcelon G, Verbeuren TJ, Lauressergues H, Vanhoutte PM. Effect of Ruscus aculeatus on isolated canine cutaneous veins. Gen Pharmacol Elbadir S, El Sayed F, Renaud F, Bazex J. L’allergie de contact aux 1983;14:103-6. http://dx.doi.org/10.1016/0306-3623(83)90074-5 ruscogénines. Revue Franc. d’Allergologie et d’Immunologie Clinique 1998;38:37-40. Marcelon G, Vieu S, Pouget G, Tisne-Versailles J. Oestrogenous impregnation and Ruscus action on the human vein in vitro, depending Felix W, Nieberle J, Schmidt G. Protektive Wirkung von on preliminary results. Phlebology 1988a;3(Suppl 1):83-5. Trimethylhesperidinchalkon und Ruscus aculeatus gegenüber dem Etacrynsäureödem am Hinterlauf der narkotisierten Katze. Phlebol Mari A, Napolitano A, Perrone A, Pizza C, Piacente S. An analytical Proktol 1983;12:209-18. approach to profile steroidal saponins in food supplements: The case of Ruscus aculeatus. Food Chemistry 134 (2012) 461-68. Guex JJ, Avril L, Enrici E, Enriquez E, Lis C, Taieb C. Quality of life http://dx.doi.org/10.1016/j.foodchem.2012.02.099 improvement in Latin American patients suffering from chronic venous disorder using a combination of Ruscus aculeatus and hesperidin methyl- McHale NG. Mechanism of noradrenaline action in lymphatic vessels. chalcone and ascorbic acid. Int Angiol 2010; 29:525-32. In: Vanhoutte PM, editor. Return circulation and norepinephrine: an update. Paris: John Libbey Eurotext 1991:73-88. Hadžifejzović N, Kukić-Marković J, Petrović S, Soković M, Glamočlija J, Stojkovič D, Nahrstedt A. Bioactivity of the extracts and compounds Mellander S, Maspers M, Ekelund U. Sympathetic nervous control of of Ruscus aculeatus L. and Ruscus hypoglossum L. Industrial Crops tonus in large bore arterial vessels, arterioles and veins, and of capillary and Products 2013;49: 407-11. pressure and fluid exchange in cat skeletal muscle (comparative effects http://dx.doi.org/10.1016/j.indcrop.2013.05.036 evoked by Ruscus aculeatus extract). In: Vanhoutte PM, editor. Return circulation and norepinephrine: an update. Paris: John Libbey Eurotext, Harker CT, Marcelon G, Vanhoutte PM. Temperature, oestrogens 1991:181-96. and contractions of venous smooth muscle of the rabbit. Phlebology 1988;3(Suppl 1):77-82. Melzig M, Hiller K, Loew D. Rusci rhizoma - Mäusedornwurzelstock. In: Blaschek W, editor. Wichtl - Teedrogen und Phytopharmaka. 6th ed. Hönig I, Felix W. Effect on the permeability of the isolated ear vein of the Stuttgart: Wissenschaftliche Verlagsgesellschaft, 2016:569-71. pig; a comparison between flavonoid and saponins. In: Davy A, Stemmer R, editors. Phlébologie. Paris: John Libbey Eurotext, 1989:680-2. Miller VM, Marcelon G, Vanhoutte PM. Progesterone augments the venoconstrictor effect of Ruscus without altering adrenergic reactivity. Huang Y-L, Kou J-P, Ma L, Song J-X, Yu B-J. Possible mechanism of the Phlebology 1991b;6:261-8. anti-inflammatory actitity of ruscogenin: Role of intercellular adhesion molecule-1 and nuclear factor-kB. J Pharmacol Sci 2008;108:198-205. Miller VM, Marcelon G, Vanhoutte PM. Ruscus extract releases endothelium-derived relaxing factor in arteries and veins. In: Vanhoutte Labie C. Gutachten über die teratogene Wirkung des Präparates “Cyclo PM, editor. Return circulation and norepinephrine: an update. Paris: 3” (Unpublished). John Libbey Eurotext 1991a:31-42.

Lascasas Porto CL, Milhomens ALM, Pires CE, Salles Xavier S, Sicuro F, Miller VM, Rud K, Gloviczki P. Interactions of Ruscus extract with Bottino DA, Bouskela E. Changes on venous diameter and leg perimeter endothelin-receptors in human varicose veins. Clin Hemorheol 1994; with different clinical treatments for moderate chronic venous disease: 14:S37-S45. Evaluation using Duplex scanning and perimeter measurements. Int Angiol 2009;28:222-31. Miller VM, Rud KS, Gloviczki. Pharmacological assessment of adrenergic receptors in human varicose veins. Int Angiol 2000;19:176-183. Le Devehat C, Khodabandehlou T, Vimeux M, Bondoux G. Hemorheological concepts in venous insufficiency and implications Mimaki Y, Kuroda M, Kameyama A, Yokosuka A, Sashida Y. New steroidal for treatment with Ruscus extract. In: Vanhoutte PM, editor. Return constituents of the underground parts of Ruscus aculeatus and their circulation and norepinephrine: an update. Paris: John Libbey Eurotext, cytostatic activity on HL-60 cells. Chem Pharm Bull 1998a;46:298-303. 1991:225-36. http://dx.doi.org/10.1248/cpb.46.298

7 RUSCI RHIZOMA

Mimaki Y, Kuroda M, Kameyama A, Yokosuka A, Sashida Y. Steroidal Roux G. Toxikologisches Gutachten für Ruscus aculeatus. Faculté Med saponins from the underground parts of Ruscus aculeatus and their Pharm, Université de Toulouse, 1969 (Unpublished). cytostatic activity on HL-60 cells. Phytochemistry 1998b;48:485-93. http://dx.doi.org/10.1016/S0031-9422(98)00157-5 Rubanyi, F, Marcelon G, Vanhoutte PM. Effect of temperature on the responsiveness of cutaneous veins to the extract of Ruscus aculeatus. Monteil-Seurin J, Ladure P. Efficacy of Ruscus extract in the treatment of Gen Pharmacol 1994;15:431-4. the premenstrual syndrome. In: Vanhoutte PM, editor. Return circulation http://dx.doi.org/10.1016/0306-3623(84)90045-4 and norepinephrine: an update. Paris: John Libbey Eurotext, 1991:43-53. Rudofsky G. Venentonisierung und Kapillarabdichtung. Fortschr Med Moscarella C. Contribution a l’étude pharmacodynamique du Ruscus 1989;107:430-4. aculeatus L. [Thesis]. Université de Toulouse, 1953. Sadarmin PP, Timperley J. An unusual case of Butcher’s Broom Parrodo F, Buzzi A. A study of the efficacy and tolerability of a preparation precipitating diabetic ketoacidosis. The Journal of Emergency Medicine containing Ruscus aculeatus in the treatment of chronic venous 2013;45:63–5. insufficiency of the lower limbs. Clin Drug Invest 1999;18:255-61. http://dx.doi.org/10.1016/j.jemermed.2012.11.087 http://dx.doi.org/10.2165/00044011-199918040-00001 Salzmann P, Ehresmann U, Adler U. Ruscus aculeatus L. - der Mäusedorn: Pouget G, Ducros L, Marcelon G. Effect of Ruscus extract on peripheral ein Therapeutikum in der Proktologie. Fortschr Med 1977;95:1419-22. lymphatic vessel pressure and flow. In: Vanhoutte PM, editor. Return circulation and norepinephrine: an update. Paris: John Libbey Eurotext, Schneider G. Saponine. In: Arzneidrogen. Mannheim-Wien-Zürich: 1991:89-95. BI-Wiss.-Verlag, 1990:153-62.

Ramirez-Hernandez M. Allergie contact dermatis to ruscogenins. Sticher O. Mäusedornwurzelstock. In: Hänsel R, Sticher O. Contact Dermatis 2006;54:60. Pharmakognosie - Phytopharmazie, 10th ed. Stuttgart: Wissenschaftliche http://dx.doi.org/10.1111/j.0105-1873.2006.0729b.x Verlagsgesellschaft, 2015:634-7.

Rassiat E, Michiels C, Piard F, Faivre J. Colite lymphocytaire chez une Teixeira AA, Oswald W. Effects of Ruscus aculeatus extract on the femme ayant une maladie de Biermer et traitée par Cirkan®. La Presse structural and functional alterations caused by sympathetic denervation Medicale 2001;30:970. of the saphenous vein. Phlebology 1988;3(Suppl 1):27-31.

Rauwald HW, Grünwidl J. Ruscus aculeatus extract: unambiguous proof Vanhoutte PM, editor. Return circulation and norepinephrine: an update. of the absorption of spirostanol glycosides in human plasma after oral Paris: John Libbey Eurotext 1991:63-71. administration. Planta Med 1991;57(Suppl 2):A75-A76. http://dx.doi.org/10.1055/s-2006-960344 Vanscheidt W, Jost V, Wolna P, Lücker PW, Müller M, Theurer C, et al. Efficacy and safety of a butcher’s broom preparation (Ruscus aculeatus L . Rauwald HW, Janßen B. Desglucoruscin und Desglucoruscosid als Leitstoffe extract) compared to placebo in patients suffering from chronic venous des Ruscus aculeatus-Wurzelstock. Pharm Ztg Wiss 1988;133/1:61-8. insufficiency. Arzneim-Forsch/Drug Res 2002;52:243-50.

8 MOST RECENT VERSIONS

Title Common name Publication

ABSINTHII HERBA Wormwood Second Edition, 2003 AGNI CASTI FRUCTUS Agnus Castus Second Edition, 2003 AGRIMONIAE HERBA Agrimony Supplement 2009 ALCHEMILLAE HERBA Lady's Mantle Online Series, 2013 ALLII SATIVI BULBUS Garlic Second Edition, 2003 ALOE BARBADENSIS Barbados Aloes Online Series, 2014 ALOE CAPENSIS Cape Aloes Online Series, 2014 ALTHAEAE RADIX Marshmallow Root Second Edition, 2003 ANGELICAE RADIX Angelica Root Supplement 2009 ANISI FRUCTUS Aniseed Online Series, 2014 ARNICAE FLOS Arnica Flower Second Edition, 2003 ARCTII RADIX Burdock Root Online Series, 2016 BALLOTAE NIGRAE HERBA Black Horehound Online Series, 2015 BETULAE FOLIUM Birch Leaf Online Series, 2015 BOLDI FOLIUM Boldo Leaf Second Edition, 2003 CALENDULAE FLOS Calendula Flower Second Edition, 2003 CAPSICI FRUCTUS Capsicum Supplement 2009 CARVI FRUCTUS Caraway Fruit Second Edition, 2003 CARYOPHYLLI AETHEROLEUM Clove Oil Online Series, 2014 CENTAURII HERBA Centaury Online Series, 2015 CENTELLAE ASIATICAE HERBA Centella Supplement 2009 CHELIDONII HERBA Greater Celandine Second Edition, 2003 CIMICIFUGAE RHIZOMA Black Cohosh Online Series, 2011 CINNAMOMI CORTEX Cinnamon Second Edition, 2003 COLAE SEMEN Cola Online Series, 2014 CRATAEGI FOLIUM CUM FLORE Hawthorn Leaf and Flower Second Edition, 2003 CRATAEGI FRUCTUS Hawthorn Berries Supplement 2009 CUCURBITAE SEMEN Pumpkin Seed Supplement 2009 CURCUMAE LONGAE RHIZOMA Turmeric Second Edition, 2003 CURCUMAE XANTHORRHIZAE RHIZOMA Javanese Turmeric Supplement 2009 CYNARAE FOLIUM Artichoke Leaf Supplement 2009 ECHINACEAE ANGUSTIFOLIAE RADIX Narrow-leaved Coneflower Root Supplement 2009 ECHINACEAE PALLIDAE RADIX Pale Coneflower Root Supplement 2009 ECHINACEAE PURPUREAE HERBA Purple Coneflower Herb Supplement 2009 ECHINACEAE PURPUREAE RADIX Purple Coneflower Root Supplement 2009 ELEUTHEROCOCCI RADIX Eleutherococcus Supplement 2009 EUCALYPTI AETHEROLEUM Eucalyptus Oil Second Edition, 2003 FILIPENDULAE ULMARIAE HERBA Meadowsweet Online Series, 2015 FOENICULI FRUCTUS Fennel Second Edition, 2003 FRANGULAE CORTEX Frangula Bark Online Series, 2017 FUMARIAE HERBA Fumitory Supplement 2009 GENTIANAE RADIX Gentian Root Online Series, 2014 GINKGO FOLIUM Ginkgo Leaf Second Edition, 2003 GINSENG RADIX Ginseng Second Edition, 2003 GRAMINIS RHIZOMA Couch Grass Rhizome Online Series, 2016 GRINDELIAE HERBA Grindelia Online Series, 2015 HAMAMELIDIS AQUA Hamamelis Water Online Series, 2012 HAMAMELIDIS CORTEX Hamamelis Bark Online Series, 2012 HAMAMELIDIS FOLIUM Hamamelis Leaf Online Series, 2012 HARPAGOPHYTI RADIX Devil’s Claw Root Supplement 2009 HEDERAE HELICIS FOLIUM Ivy Leaf Second Edition, 2003 HIPPOCASTANI SEMEN Horse-chestnut Seed Second Edition, 2003 HYDRASTIS RHIZOMA Goldenseal rhizome Online Series, 2013 HYPERICI HERBA St. John’s Wort Second Edition, 2003 JUNIPERI PSEUDO-FRUCTUS Juniper Second Edition, 2003 LAVANDULAE FLOS/AETHEROLEUM Lavender Flower/Oil Supplement 2009 LICHEN ISLANDICUS Iceland Moss Second Edition, 2003 LINI SEMEN Linseed Online Series, 2017 LIQUIRITIAE RADIX Liquorice Root Second Edition, 2003 LUPULI FLOS Hop Strobile Second Edition, 2003 MALVAE FLOS Mallow Flower Online Series, 2016 MARRUBII HERBA White horehound Online Series, 2013 MATRICARIAE FLOS Matricaria Flower Second Edition, 2003 MELALEUCAE AETHEROLEUM Tea Tree Oil Supplement 2009 MELILOTI HERBA Melilot Second Edition, 2003 MELISSAE FOLIUM Melissa Leaf Online Series, 2013 MENTHAE PIPERITAE AETHEROLEUM Peppermint Oil Second Edition, 2003 MENTHAE PIPERITAE FOLIUM Peppermint Leaf Second Edition, 2003 MENYANTHIDIS TRIFOLIATAE FOLIUM Bogbean Leaf Online Series, 2013 MILLEFOLII HERBA Yarrow Supplement 2009 MYRRHA Myrrh Online Series, 2014 MYRTILLI FRUCTUS Bilberry Fruit Online Series, 2014 OLIBANUM INDICUM Indian Frankincense Supplement 2009 ONONIDIS RADIX Restharrow Root Online Series, 2015 ORTHOSIPHONIS FOLIUM Java Tea Online Series, 2014 PASSIFLORAE HERBA Passion Flower Second Edition, 2003 PAULLINIAE SEMEN Guarana Seed Supplement 2009 PELARGONII RADIX Pelargonium Root Online Series, 2015 PIPERIS METHYSTICI RHIZOMA Kava-Kava Second Edition, 2003 PLANTAGINIS LANCEOLATAE FOLIUM/HERBA Ribwort Plantain Leaf/Herb Online Series, 2013 PLANTAGINIS OVATAE SEMEN Ispaghula Seed Second Edition, 2003 PLANTAGINIS OVATAE TESTA Ispaghula Husk Online Series, 2016 POLYGALAE RADIX Senega Root Second Edition, 2003 PRIMULAE RADIX Primula Root Second Edition, 2003 PRUNI AFRICANAE CORTEX Pygeum Bark Supplement 2009 PSYLLII SEMEN Psyllium Seed Online Series, 2017 RATANHIAE RADIX Rhatany Root Online Series, 2017 RHAMNI PURSHIANI CORTEX Cascara Online Series, 2015 RHEI RADIX Rhubarb Second Edition, 2003 RIBIS NIGRI FOLIUM Blackcurrant Leaf Online Series, 2017 ROSAE PSEUDO-FRUCTUS Dog Rose Hip Supplement 2009 ROSMARINI FOLIUM Rosemary Leaf Second Edition, 2003 RUSCI RHIZOMA Butcher’s Broom Online Series, 2017 SALICIS CORTEX Willow Bark Online Series, 2017 SAMBUCI FLOS Elder flower Online Series, 2013 SALVIAE OFFICINALIS FOLIUM Sage Leaf Second Edition, 2003 SALVIA TRILOBAE FOLIUM Sage Leaf, Three-lobed Online Series, 2014 SENNAE FOLIUM Senna Leaf Second Edition, 2003 SENNAE FRUCTUS ACUTIFOLIAE Alexandrian Senna Pods Second Edition, 2003 SENNAE FRUCTUS ANGUSTIFOLIAE Tinnevelly Senna Pods Second Edition, 2003 SERENOAE REPENTIS FRUCTUS (SABAL FRUCTUS) Saw Palmetto Fruit Second Edition, 2003 SERPYLLI HERBA Wild Thyme Online Series, 2014 SOLIDAGINIS VIRGAUREAE HERBA European Golden Rod Second Edition, 2003 SILYBI MARIANI FRUCTUS Milk Thistle Fruit Supplement 2009 SYMPHYTI RADIX Comfrey Root Online Series, 2012 TANACETI PARTHENII HERBA Feverfew Online Series, 2014 TARAXACI FOLIUM Dandelion Leaf Second Edition, 2003 TARAXACI RADIX Dandelion Root Second Edition, 2003 THYMI HERBA Thyme Second Edition, 2003 TORMENTILLAE RHIZOMA Tormentil Online Series, 2013 TRIGONELLAE FOENUGRAECI SEMEN Fenugreek Second Edition, 2003 URTICAE FOLIUM/HERBA Nettle Leaf/Herb Second Edition, 2003 URTICAE RADIX Nettle Root Online Series, 2015 UVAE URSI FOLIUM Bearberry Leaf Online Series, 2012 VACCINII MACROCARPI FRUCTUS Cranberry Supplement 2009 VALERIANAE RADIX Valerian Root Supplement 2009 VERBASCI FLOS Mullein Flower Online Series, 2014 VIOLAE HERBA CUM FLORE Wild Pansy Online Series, 2015 VITIS VINIFERAE FOLIUM Red Vine Leaf Supplement 2009 ZINGIBERIS RHIZOMA Ginger Supplement 2009 Online Series Monographs The Scientific Foundation for Herbal Medicinal Products

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.