Salviae trilobae foliumSage Leaf, Three-lobed

MonographsThe Scientific Foundation for Herbal Medicinal Products

2014

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The Scientific Foundation for Herbal Medicinal Products

SALVIAE TRILOBAE FOLIUMSage Leaf, Three-lobed

2014

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 978-1-901964-14-1

Salviae trilobae folium - Sage Leaf, Three-lobed

© ESCOP 2014

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 photograph by Professor Salvador Cañigueral Folcara (Salvia fruticosa)

Cover and text design by Martin WilloughbyTypeset in Optima by Roberta Hutchins

Plant illustrated on the cover: Salvia fruticosa

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.

Liselotte KrennChair 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 intervalCmax 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 dihydrotestosteroneDNA 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 synthaseINR International Normalized Ratio, a measure of blood coagulation (clotting) tendency

i.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 EPHA 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 substancesTGF-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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Sage Leaf, Three-lobed

DEFINITION

Three-lobed sage leaf consists of the whole or cut, dried leaves of Salvia fruticosa Mill. [syn. S. triloba L.fil.]. It contains not less than 18 ml/kg of essential oil in the whole drug, and not less than 12 ml/kg of essential oil in the cut drug, both calculated with reference to the dried material.

The material complies with the monograph of the European Pharmacopoeia [Sage leaf, three-lobed].

CONSTITUENTS

1.5-3.5% of essential oil consisting mainly of terpenes with cineole (40-67%), a- and b-thujone (2-6%), camphor (1-24%), camphene (0.3-5%), borneol (1%), b-caryophyllene, a- and b-pinene, bornyl acetate, limonene, linalyl acetate and viridoflorol [Länger 1996; Stahl-Biskup 2008; Pitarokili 2003; Brand 2008; Papageorgiou 2008].

Other characteristic constituents include phenolic acids (1-4%) such as 3,4-dihydroxybenzoic, rosmarinic and caffeic acids [Brand 2008; Papageorgiou 2008]; flavonoids such as salvigenin, glucosides and glucuronides of apigenin, chrysoeriol, hispidulin, luteolin, 6-methoxyluteolin and jaceosidin [Abdalla 1983; Brand 2008]; diterpenes such as carnosol and triterpenes such as ursolic and oleanolic acids (< 8%) [Stahl-Biskup 2008; Brand 2008].

CLINICAL PARTICULARS

Therapeutic indications

Inflammations and infections of the mouth and throat such as stomatitis, gingivitis and pharyngitis [Stahl-Biskup 2008; Benedum 2006]; digestive disorders such as dyspepsia [Benedum 2006].

Efficacy for these indications is plausible on the basis of human experience and long-standing use.

Posology and method of administration

Dosage Topical useAdult daily dose: An infusion of 3 g of dried drug in 125 ml of water as a mouthwash or gargle [Stahl-Biskup 2008; Böhme 2010].

Oral useAdult dose: 1-1.5 g of dried drug as an infusion in 150 ml of water, once or several times daily [Stahl-Biskup 2008; Böhme 2010].

Method of administrationFor oral administration.

Duration of administrationNo restriction. If symptoms persist or worsen, medical advice should be sought.

ContraindicationsNone known.

Special warnings and special precautions for useNone required.

Interaction with other medicaments and other forms of interactionNone reported [Williamson 2009].

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Pregnancy and lactationNo data available. In accordance with normal medical practice, three-lobed sage leaf should not be used during pregnancy and lactation without medical advice.

Effects on ability to drive and use machinesNone known.

Undesirable effectsNone reported.

OverdoseNo toxic effects reported.

PHARMACOLOGICAL PROPERTIES

Data relating to the essential oil and lipophilic extracts are included below for completeness, although their components are present to only a minor extent in aqueous preparations such as those recommended under Dosage.

Pharmacodynamic properties

In vitro experiments Antioxidant and radical-scavenging activityAn aqueous extract (0.25 g/10 ml, 1.4% polyphenols) showed antioxidant activity of 53.5 µmol trolox equivalents per g of dry plant material and an 80% methanolic extract (0.25 g/10 ml, 2.4% polyphenols) 175 µmol trolox equivalents per g of dry plant material in the 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical cation decolourisation test [Tawaha 2007].

In the deoxyribose assay an infusion (1 g/25 ml) exhibited antioxidant activity in the presence or absence of digestive enzymes and bile salts. The amount of total dialysable iron was increased compared to the Fe(III) control under simulated gastric conditions [Matsingou 2000].

An acidic aqueous methanolic dry extract (30% V/V, 3.4-5.2:1) had an IC50 value of 0.021-0.046 g/litre in the DPPH assay and was also active in the ABTS cation decolourisation assay. The free radical scavenging activity in both assays was correlated with the total phenolic content (6.4-14.4%) determined by a colorimetric method [Papageorgiou 2008].

An ethanolic dry extract (1.6:1) and an acetone dry extract (4.2:1) reduced DPPH by 98.5% and 97.6% respectively. Antioxidant activity of these extracts was also observed in the phosphatidylcholine liposome assay. The protective effect of the extracts against oxidation of sunflower oil under accelerated conditions (120°C) was evaluated in a Rancimat apparatus using 0.02% (w/w) of extract in bulk oil; the ethanolic and acetone extracts protected the oil by factors of 1.7 and 2.2 compared to a blank control [Exarchou 2002]. In another study using the Rancimat method a methanolic dry extract (3.8:1) protected sunflower oil from oxidation by a factor of 1.08 at 0.02% and 3.03 at 1% [Bozan 2002].

Free radical scavenging activity of the essential oil of three-lobed sage leaf harvested during different seasons, and some of its components, was determined in the DPPH assay. IC50 values of the essential oils were between 2.4 and 5.2 g/litre, while that of b-caryophyllene was 18.6 g/litre, and 1,8-cineole and a-pinene were inactive; IC50 values of the positive controls, ascorbic acid and butylated hydroxytoluene, were 0.06 g/litre and 0.08 g/litre respectively. A positive correlation was found

between free radical scavenging activity and concentrations of oxygenated sesqui- and diterpenes [Papageorgiou 2008].

Acetyl- and butyrylcholinesterase inhibitory activityA dichloromethane dry extract (13.4:1) inhibited acetylcholin-esterase activity by 27% at 25 µg/ml and 51% at 100 µg/ml [Senol 2010].

In another study, a 75%-hydroethanolic dry extract (1 g/60 ml; 1% total phenols) inhibited acetylcholinesterase activity with an IC50 of 0.71 mg/ml [Orhan 2009].

An ethyl acetate dry extract (1 g/20 ml) slightly inhibited acetyl-cholinesterase activity, by 28% at 1.0 mg/ml and 11% at 0.25 mg/ml, while a dry aqueous extract (1 g/20 ml) was inactive [Salah 2005].

In an assessment of the inhibition of human cholinesterases by three-lobed sage leaf essential oil, contradictory results were obtained in the case of butyrylcholinesterase, whereas IC50 values of 0.04-0.06 mg/ml were reported for inhibition of acetylcholinesterase. The most pronounced acetylcholin-esterase inhibition by individual components of the oil was observed for 1,8-cineole (IC50: 0.06 mg/ml), b-caryophyllene (IC50: 0.03 mg/ml), a-pinene (IC50: 0.1 mg/ml) and b-pinene (IC50: 0.2 mg/ml); a-thujone and camphor at 0.5 mg/ml inhibited the enzyme by 37% and 13% respectively. No or only low butyrylcholinesterase inhibition was observed with all tested compounds [Savelev 2004].

Cytotoxic activityAn aqueous dry extract (2 g/150 ml, 71.5 µg/ml rosmarinic acid, 28.6 µg/ml 6-hydroxyluteolin-7-glucoside, 29.4 µg/ml other phenolic compounds, lyophilised) at 50 µg/ml significantly inhibited cell proliferation in the human colon cancer cell line HCT15 (from 26.2% in the control to 4.7%, p ≤ 0.001). No significant effect was observed in CO115 cells; rosmarinic acid at 10-100 µg/ml was inactive in both cell lines. The extract and rosmarinic acid induced apoptosis in a concentration-dependent manner. In HCT15 cells the extract increased the proportion of apoptotic cells from 0.4% in the control to 6.6% at 50 µg/ml, rosmarinic acid increased numbers to 2.5% (p ≤ 0.001). In CO115 cells, the proportion of apoptotic cells increased from 1.8% in the control to 6.8% after treatment with the extract and to 3.6% by rosmarinic acid at the same concentrations. No cleaved caspase-9 and caspase-3 were observed 24 hours after treatment.

Both the extract and rosmarinic acid inhibited the mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) pathway in HCT15 cells by 50% (p ≤ 0.001) and had no effects in CO115 cells. No inhibition on Akt (a serine/threonine kinase) phosphorylation was observed. Both pathways are commonly altered in colorectal carcinoma, and lead to increased proliferation and inhibition of apoptosis [Xavier 2009].

Three-lobed sage leaf essential oil and its main components exhibited cytotoxic activity against African green monkey kidney (Vero) cells. The essential oil caused complete cell death within 24 hours of exposure at a dilution of 1/500 (V/V) and within 48 hours at 1/1000. At 1/2000 a transient decrease in cell viability was initially observed, but this had been overcome after 48 hours. Among the main components at dilutions of 1/1000 (i.e. 0.10%), thujone was the most cytotoxic causing 95% reduction in viability, and camphor showed moderate activity (40% reduction), whereas 1,8-cineole was less active (5% reduction) [Sivropoulou 1997].

In another evaluation of cytotoxic activity, the IC50 values for

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an undefined dichloromethane-methanol dry extract were 180 µg/ml in mouse fibrosarcoma cells, 250 µg/ml in a benign human breast carcinoma cell line and 290 µg/ml in a metastatic human breast carcinoma cell line [Kaileh 2007].

Spasmolytic activityA decoction and an infusion from three-lobed sage leaf, and corresponding fractions obtained by partitioning these between benzene and water, as well as a fluid extract (1:2, 70% ethanol), had varying effects on the tone and phasic contractile activity of isolated segments from guinea pig ileum. The decoction, and the aqueous fraction of the infusion, caused contraction of the smooth muscle preparation without affecting phasic contractions, the aqueous fraction of the decoction decreased the tone and caused relaxation, while the fluid extract potentiated phasic activity but did not affect the tone. The infusion caused contraction of the intestinal segments and intensified phasic contractions. All the extracts inhibited contractions induced by acetylcholine (10-7 M), barium chloride (10-4 M), histamine (10-5 M) and serotonin (10-5 M) by 20-90% [Todorov 1984].

Antimicrobial and antiviral activity of the essential oilThe essential oil of three-lobed sage leaf exhibited slight inhibitory activity against growth of Fusarium moniliforme, Rhizoctonia solani, Phytophthora capsici [Müller-Riebau 1997], Botrytis cinerea, Fusarium solani var. coeruleum [Daferera 2003], Trichophyton rubrum and Trichosporon beigelii [Adam 1998]. In tests of the antifungal activity of the essential oil, 1,8-cineole and camphor against 13 other fungal species (type cultures and isolates), such as Aspergillus sp., Penicillium sp., Phomopsis, Alternaria, Microsporum and Epidermophyton sp., minimium inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC) respectively were found to be: 5.0-15.0 µl/ml and 5.0-20.0 µl/ml for the essential oil, 4.0-9.0 µl/ml and 5.0-15.0 µl/ml for 1,8-cineole, and 3.0-5.0 µl/ml and 3.0-10.0 µl/ml for camphor [Sokovic 2002].

Three-lobed sage leaf essential oil exhibited low activity against Erwinia herbicola (MIC: 2 mg/ml) and was inactive against Pseudomonas syringae, whereas leaf surface phenolics extracted with dichloromethane inhibited both bacterial strains. Camphor, with an MIC and MBC (minimum bactericidal concentration) of 2 mg/ml, was more effective than 1,8-cineole (both values ≥ 2 mg/ml) [Karamanoli 2000].

Essential oil of three-lobed sage leaf cultivated in Brazil inhibited the growth of Escherichia coli, Proteus mirabilis, Salmonella typhimurium, Aeromonas sp., Klebsiella oxytoca, Citrobacter sp., Serratia marcescens, Bacillus sp., Pseudomonas sp. and Staphylococcus sp. The MICs (0.1 to 10 mg/ml) and MBCs (0.1 to >10 mg/ml) indicated that the essential oil of Salvia triloba was generally more effective than that of S. officinalis against these bacterial strains. The activity was more pronounced against Gram-negative bacteria [Delamare 2007].

In the disk diffusion assay the essential oil, 1,8-cineole and thujone showed moderate activity against a selection of eight bacteria, Salmonella typhimurium being the most resistant and Pseudomonas aeruginosa being the most sensitive, while camphor was almost inactive. The essential oil was bactericidal against Staphylococcus aureus at 1/4000 dilution, while dilutions up to 1/10000 caused a considerable decrease in bacterial growth rates [Sivropoulou 1997].

Hydrosols of three-lobed sage leaf (the aqueous phases obtained by 1 hour of steam distillation) were inactive against fifteen bacterial strains such as E. coli or S. aureus [Sagdic 2003].

The virucidal activity of three-lobed sage leaf essential oil and its

main components was evaluated against HSV-1, an ubiquitous human pathogen. At a concentration of 0.2% the essential oil inactivated 80% of infectious virus within 30 minutes and thujone at 0.1% inactivated 95%, whereas 1,8-cineole and camphor at 0.1% inactivated 35% and 0% respectively [Sivropoulou 1997].

Other effectsPretreatment of murine fibrosarcoma cells with a dichloro-methane-methanol dry extract at 62.5 µg/ml revealed a weak inhibitory effect on the IL-6 promoter and the recombinant NFkB promoter construct [Kaileh 2007].

An ethanolic extract showed moderate binding affinity at the GABAA-benzodiazepine receptor site [Salah 2005].

In vivo experiments

Antidiabetic activityThe hypoglycaemic activity of a 10% infusion was evaluated in normoglycaemic rabbits and rabbits with alloxan-induced diabetes. A single oral dose of 2.5 ml/kg b.w. (corresponding to 0.25 g/kg of dried leaf) had no acute effect on blood glucose levels in either group. Repeated oral administration at 2.5 ml/kg/day over a period of 7 days produced a significant reduction of blood glucose levels in hyperglycaemic rabbits but had no effect in normoglycaemic animals. Compared to hyperglycaemic control animals, blood glucose levels in treated hyperglycaemic rabbits were 20.2% lower 60 minutes after the last administ-ration of infusion (p<0.05), 24.9% lower after 90 minutes (p<0.01) and 25.7% lower after 120 minutes (p<0.01).

After oral glucose loading at 1 g/kg, administration of a single oral dose of the infusion at 0.25 ml/kg significantly reduced blood glucose levels in both normo- and hyperglycaemic animals, the effect being more evident in the latter. In treated hyperglycaemic rabbits the increase in blood glucose was only 19.2% (p<0.05), 7.8% (p<0.01) and 7.1% (p<0.01) after 60, 90 and 120 minutes, compared to 78.2%, 73.1% and 55.5% in hyperglycaemic control animals receiving water only.

A single oral administration of the infusion had no significant effects on plasma insulin levels in any group of rabbits following oral glucose loading, nor on blood glucose levels in normo-glycaemic animals after intravenous glucose loading. The results suggested that three-lobed sage leaf does not influence glucose metabolism; the hypoglycaemic activity might be due to inhibition of intestinal absorption of glucose [Perfumi 1991].

In another study, the effect of an infusion (5:1) in streptozotocin (STZ)-induced diabetic rats was investigated. One week after i.p. injection of a single dose of 45 mg/kg b.w. STZ, the glucose level was 311 ± 25 mg/dL in diabetic rats (n=12) compared to 119 ± 4 mg/dL in healthy rats (n=12). In water drinking STZ-diabetic animals (n=6), plasma glucose levels continued to increase throughout the 14-day experimental period but remained stable in STZ-diabetic animals (n=6) drinking the infusion (0.28% w/v, ad libidum) (p<0.01 on day 14). In non-diabetic animals glucose levels were not influenced by drinking the infusion (n=6). The administration of the infusion did not significantly change the liver glycogen content or induce liver toxicity or increase the regeneration of b-cell mass. The increase in intestinal Na+/glucose cotransporter-1 (SGLT1), localized to the enterocyte brush-border membrane, was significantly abrogated by treatment with the infusion (30% compared to untreated animals, p<0.01) without changes in total cellular transporter protein levels. Comparable results were obtained in rats with high carbohydrate diet-induced diabetes (n=6) drinking the infusion (32%, p<0.05) when compared to a water drinking group (n=6). Rosmarinic acid (0.58 mg/mL) in the drinking water inhibited SGTL1 to 50% (p<0.01). No effects

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were observed on glucose transporter 2, Na+/K+-ATPase or glucagon-like peptide-1 levels by the treatment [Azevedo 2011].

Antihypertensive activity A dry decoction, administered intraperitoneally to nembutal-anaesthetized, spontaneously hypertensive rats as a single dose of 50 mg/kg b.w., reduced blood pressure by 31% compared to saline controls after 120 minutes [Todorov 1984].

Anti-inflammatory activity Three-lobed sage leaf was successively extracted with chloroform (dry yield: 6.75%), ethanol (4%), butanol (1%) and water (> 20%, viscous extract). Oral administration of the chloroform fraction at 25 mg/kg b.w. significantly inhibited carrageenan-induced rat paw oedema by 17% (p<0.01) compared to 47% by diclofenac at 10 mg/kg as positive control (p<0.01); the other fractions were less effective. In the cotton pellet granuloma assay the chloroform fraction inhibited chronic mean gain in pellet weight by 18 mg compared to 29 mg by diclofenac (p<0.01) [El-Sayed 2006].

Central effectsA dry decoction and the dry benzene fraction from an infusion, administered subcutaneously to mice at 100 mg/kg b.w. 10 minutes before administration of hexobarbital (80 mg/kg b.w.), delayed the onset of sleep [Todorov 1984].

In another study, a 75%-hydroethanolic dry extract (1g/60 ml; total phenolic content: 10.9 mg/g, expressed as gallic acid equivalent) exerted dose-dependent anti-amnesic activity in mice. A passive avoidance apparatus (step-through type) was used to investigate long-term memory; amnesia was induced by scopolamine (1 mg/kg, given intraperitoneally 30 minutes after oral administration of the extract) and donezepil was used as a positive control. The extract had a relative memory-enhancing effect of 57.1 and 71.4% at 200 and 400 mg/kg b.w. respectively (control group 0%, donezepil group set to 100%) [Orhan 2009].

Clinical studiesNo clinical studies have been published on mono-preparations of three-lobed sage leaf.

Pharmacokinetic propertiesNo data available.

Preclinical safety data

MutagenicityAn aqueous dry extract (1 g/100 ml, extracted at 50°C) at 40 and 80 µg per plate showed no mutagenic potential in the Ames test using Salmonella typhimurium strains TA98 and TA100 with and without metabolic activation. In the alkaline single cell gel electrophoresis (COMET) assay in human lymphocytes treatment with 40 µg of the aqueous dry extract produced a significant increase in COMET tail moments when compared to the positive control, 4 mM hydrogen peroxide (22.0 vs 13.2, p<0.01) [Basaran 1996].

Essential oil of three-lobed sage leaf at concentrations of 250-2000 ppm did not exhibit any mutagenic activity in the Ames test using S. typhimurium strains TA97, TA98, TA100 and TA102 in [Adam 1998].

Effects on fertilityIngestion of an aqueous dry extract by female rats at 200, 400 and 800 mg/kg b.w. from days 1 to day 6 of pregnancy had no significant effects on the number of pregnancies, implantations, viable fetuses or resorptions when compared to the control. Intragastric administration of a 95%-ethanolic dry extract at

400 mg/kg also had no effect on the number of pregnancies or implantations; however, the number of viable fetuses de-creased (p<0.005) and the number of resorptions increased (p<0.005).

In contrast, intragastric administration of the aqueous dry extract at 800 mg/kg or the ethanolic dry extract at 400 mg/kg to adult female rats for 30 consecutive days had no effect on the occurrence of pregnancy, but the number of implantations (p<0.05) and viable fetuses (p<0.01) decreased and the number of resorptions increased (p<0.01 for aqueous dry extract, p<0.005 for ethanolic dry extract). Ingestion of the same extracts at the same dosage levels for 30 consecutive days by adult male rats had no effect on the final proportion of pregnant females impregnated by these males; however the number of implantations and viable fetuses were reduced in such females (p<0.01 for aqueous dry extract, p<0.001 for ethanolic dry extract), whereas the number of resorptions increased (p<0.005). Prenatal exposure of male and female rat offspring to the ethanolic dry extract at 400 mg/kg had no effect on the timing of testicular descent or vaginal opening [Al-Hamood 1998].

UlcerogenicityThree-lobed sage leaf was successively extracted with chloroform (dry yield: 6.75%), ethanol (4%), butanol (1%) and water (> 20%, viscous extract), and each fraction was orally administered to rats at 25 mg/kg b.w. The ulcer indices were 0 for the ethanol fraction, 1.2 for the water fraction (p<0.01) and 1.3 for the chloroform fraction (p<0.01), compared to 12.3 for acetylsalicylic acid at 1 mg/kg (p<0.01) [El-Sayed 2006].

Toxicity of thujoneAlthough a-thujone is present in the essential oil of three-lobed sage leaf, the proportion is far less than in essential oils of Salvia officinalis or Artemisia absinthium; aqueous preparations are unlikely to contain toxic amounts of a-thujone.

Clinical safety data No data available.

REFERENCES

Abdalla MF, Saleh NAM, Gabr S, Abu-Eyta AM, El-Said H. Flavone glycosides of Salvia triloba. Phytochemistry 1983;22:1057-60. http://dx.doi.org/10.1016/0031-9422(83)80044-2

Adam K, Sivropoulou A, Kokkini S, Lanaras T, Arsenakis M. Antifungal activities of Origanum vulgare subsp. hirsutum, Mentha spicata, Lavandula angustifolia and Salvia fruticosa essential oils against human pathogenic fungi. J Agric Food Chem 1998;46:1739-45.http://dx.doi.org/10.1021/jf9708296

Al-Hamood MH, Elbetieha A, Alkofahi A, Bataineh H. Reproductive toxicity potentials of Salvia fruticosa (Labiatae) in rats. J Ethnopharmacol 1998;61:67-74. Erratum: ibid. 1998;63:265.

Azevedo MF, Lima CF, Fernandes-Ferreira M, Almeida MJ, Wilson JM, Pereira-Wilson C. Rosmarinic acid, major phenolic constituent of Greek sage herbal tea, modulates rat intestinal SGTL1 levels with effects on blood glucose. Mol Nutr Food Res 2011;55:S15-S25. http://dx.doi.org/10.1002/mnfr.201000472

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Daferera DJ, Ziogas BN, Polissiou MG. The effectiveness of plant essential oils on the growth of Botrytis cinerea, Fusarium sp. and Clavibacter michiganensis subsp. michiganensis. Crop Protection 2003;22:39-44. http://dx.doi.org/10.1016/S0261-2194(02)00095-9

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Exarchou V, Nenadis N, Tsimidou M, Gerothanassis IP, Troganis A, Boskou D. Antioxidant and phenolic composition of extracts from Greek oregano, Greek sage and summer savory. J Agric Food Chem 2002;50:5294-9. http://dx.doi.org/10.1021/jf020408a

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Karamanoli K, Vokou D, Menkissoglu U, Constantinidou HI. Bacterial colonization of phyllosphere of Mediterranean aromatic plants. J Chem Ecol 2000;26:2035-48. http://dx.doi.org/10.1023/A:100555601 3314

Länger R, Mechtler C, Jurenitsch J. Composition of the essential oils of commercial samples of Salvia officinalis L. and S. fruticosa Miller: a comparison of oils obtained by extraction and steam distillation. Phytochem Anal 1996;7:289-93. http://dx.doi.org/10.1002/(SICI)1099-1565(199611)7:6<289::AID-PCA318> 3.0.CO;2-7

Matsingou TC, Kapsokefalou M, Salifoglou A. In vitro antioxidant activity of black tea and Mediterranean herb infusions toward iron under simulated gastrointestinal conditions. J Food Sci 2000;65:1060-5. http://dx.doi.org/ 10.1111/j.1365-2621.2000.tb09418.x

Müller-Riebau F, Berger BM, Yegen O, Cakir C. Seasonal variation in the chemical compositions of essential oils of selected aromatic plants growing wild in Turkey. J Agric Food Chem 1997;45:4821-5. http://dx.doi.org/10.1021/jf970110y

Orhan I, Aslan M. Appraisal of scopolamine-induced antiamnesic effect in mice and in vitro antiacetylcholinesterase and antioxidant activities of some traditionally used Lamiaceae plants. J Ethnopharmacol 2009;122:327-32. http://dx.doi.org/10.1016/j.jep.2008.12.026

Papageorgiou V, Gardeli C, Mallouchos A, Papaioannou M, Komaitis M. Variation of the chemical profile and antioxidant behaviour of Rosmarinus officinalis L. and Salvia fruticosa Miller grown in Greece. J Agric Food Chem 2008;56:7254-64. http://dx.doi.org/10.1021/jf800802t

Perfumi M, Arnold N, Tacconi R. Hypoglycemic activity of Salvia fruticosa Mill. from Cyprus. J Ethnopharmacol 1991;34:135-40. http://dx.doi.org/10.1016/0378-8741(91)90030-H

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

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 978-1-901964-14-1

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