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Carvi aetheroleum Caraway Oil 2019

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

CARVI AETHEROLEUM Caraway Oil

2019

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 978-1-901964-65-3

Carvi aetheroleum - Caraway Oil

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 Roberta Hutchins and Simon Mills Cover photographs by H. Zell (license CC) (Carum carvi) and Martin Willoughby Cover and text design by Martin Willoughby Typeset in Optima by Roberta Hutchins

Plant illustrated on the cover: Carum carvi FOREWORD

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

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

Dr. Tankred Wegener Chair of the Board of ESCOP

PREFACE

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

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

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

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

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

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

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

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

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

Information on the member organizations and people involved in the production of ESCOP monographs and other 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 CAT catalase

CCl4 carbon tetrachloride CI confidence interval

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 nuclear factor kappa-B NO nitric oxide NOAEL no observed adverse effect level 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 PARP poly (ADP-ribose) polymerase PBMC peripheral blood mononuclear cells 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 ROS reactive oxygen species RT-PCR reverse transcription polymerase chain reaction s.c. subcutaneous SCI spinal cord injury SERM selective oestrogen receptor modulator SGOT or GOT serum glutamate oxalacetate transaminase (= ASAT or AST) SGPT or GPT serum glutamate pyruvate transaminase (= ALAT or ALT) SHBG sex hormone binding globulin SOD superoxide dismutase SSRI selective serotonin reuptake inhibitor STAI state-trait anxiety inventory t1/2 elimination half-life TBARS thiobarbituric acid reactive substances TC total cholesterol TGF-b transforming growth factor-beta TNF tumour necrosis factor TPA 12-O-tetradecanoylphorbol-13-acetate URT upper respiratory tract URTI upper respiratory tract infection UTI urinary tract infection VAS visual analogue scale VLDL very low density lipoprotein CARVI AETHEROLEUM 2019 Caraway Oil

DEFINITION

Caraway oil is obtained by steam distillation from the dry fruits of Carum carvi L.

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

CONSTITUENTS

Mainly oxygenated monoterpenes: (S)-(+)-carvone: 50 to 65%; trans-dihydro- carvone: up to 2.5%; trans-carveol: up to 2.5%; and monoterpene hydrocarbons: (R)-(+)-limonene: 30 to 45%; b-myrcene: 0.1 to 1.0% [Caraway oil; Samojlik 2010; Raal 2012].

CLINICAL PARTICULARS

Therapeutic indications

Internal use Symptomatic relief of digestive disorders such as bloating, flatulence and spasm of the gastrointestinal tract [Martindale 2014; Sticher 2015; Stahl-Biskup 2016]. Flatulent colic of infants and children [BPC 1973; Dorsch 2002; Bradley 2006, Martindale 2014].

In these indications, efficacy is plausible on the basis of human experience and long-standing use.

External use Flatulent colic of infants [Fintelmann 2009]. In this indication, efficacy is plausible on the basis of human experience and long-standing use.

Posology and method of administration

Dosage

Internal use Adults: 3 to 6 drops daily in divided doses [BPC 1973, Fintelmann 2009, Schilcher 2010].

Children Infants over 6 months: 2–3 drops concentrated caraway water (0.26 - 0.38 μL of caraway oil) [BPC 1973] for use in feeding bottles (equivalent to circa 60 mg caraway fruit) per day [Bradley 2006] Children up to 1 year: 1–2 drops daily [Dorsch 2002] Children from 1 to 4 years: 2-4 drops daily [Dorsch 2002] Children above 4 years: 3-6 drops daily [Dorsch 2002]

External use Children and adolescents: An ointment (2% w/w) to be applied once daily as a thin layer on the abdominal area after bathing in the evening. Adults: 10% in olive oil, rub 10-12 drops onto the stomach [Weiss & Fintelmann 2000].

Method of administration For oral administration or external application to the abdomen.

Duration of use If symptoms persist or worsen, use should be discontinued and medical advice sought.

Contra-indications Patients with known sensitivity to Apiaceae (Umbelliferae) should not use caraway oil and its preparations.

1 CARVI AETHEROLEUM

Special warnings and special precautions for use aureus (MIC = 0.1 µL/mL; MBC = 0.25 µL/mL), than Gram- None required. negative bacteria: Escherichia coli (MIC = 2.0 µL/mL; MBC = 4.0 µL/mL); Proteus mirabilis (MIC = 2.0 µL/mL; MBC = Interaction with other medicaments and other forms of 4.0 µL/mL); Pseudomonas tolaasii (MIC = 4.0 µL/mL; MBC = interaction 6.0 µL/mL); Salmonella enteritidis (MIC = 0.25 µL/mL; MBC None reported. = 0.5 µL/mL). Evaluation of antifungal activity against a series of micromycetes, found a concentration of 0.25 – 2.5 µL/mL Pregnancy and lactation inhibited their growth, except for Trichoderma viride when In accordance with general practice the product should not 10.0 µL/mL was effective [Simic 2008]. be used during pregnancy and lactation without medical advice. The oil displayed a high degree of antimicrobial selectivity, inhibiting the growth of potential pathogens associated with Effects on ability to drive and use machines intestinal dysbiosis at concentrations that had no effect on None known the beneficial bacteria examined (Lactobacillus acidophilus, L. plantarum). MIC for Candida albicans was 0.55% V/V and Undesirable effects 0.275% V/V for Clostridium difficile [Hawrelak 2009]. None reported. The antimicrobial activity of the oil was stronger against Overdose fungi than bacteria. The following MIC values were observed: No toxic effects reported. Aspergillus niger (0.12%); Penicillium expansum (0.12%); Saccharomyces cerevisiae (0.06%); Candida knusei (0.06%); Salmonella enteritidis (0.12%); E. coli (0.12%); S. aureus PHARMACOLOGICAL PROPERTIES (0.12%); Bacillus subtilis (0.12%). Results confirmed that the oil was more effective against Gram-positive than Gram-negative Pharmacodynamic properties bacteria [Gniewosz 2013]. Caraway oil acts as a carminative, spasmolytic, choleretic and cholagogue [Georg 2003; Mickelfield 2003]. The antimicrobial activity of caraway oil differs, depending on the genotypes, ranging from MIC = 0.16 mg/mL to 1.75 mg/ In vitro experiments mL. A significant negative correlation was found between MIC and carvone content and a positive correlation with limonene Muscle relaxant / spasmolytic activity content [Seidler-Lozykowska 2013]. Caraway oil had a relaxant effect on guinea pig tracheal muscle, decreasing the force of phasic contractions by 50% at 27 mg/L, Antioxidant activity but no antispasmodic effect was observed on electrically- The antioxidant activity of caraway oil was measured in the stimulated guinea pig ileum. Caraway oil (20 – 60 mg/L) DPPH assay. The oil reduced the DPPH in a dose-dependent produced a marked increase in resting force (i.e. contracture) of manner. Effects on lipid peroxidation were determined by the the ileal mesenteric plexus- longitudinal muscle preparation thiobarbituric acid assay (TBA) assay. In the Fe2+/ascorbate [Reiter 1985]. system the oil expressed a strong and partly dose-dependent

antioxidant capacity (IC50 of <2.5 µL/mL), with the highest The oil administered to isolated rat uterus inhibited the tonic inhibition (68.1%) at 5 µL/mL [Samojlik 2010]. contraction to KCl (80 mM) and the phasic contraction to ACh (320 nM) in a concentration-dependent manner [Sadraei Other effects 2003]. Foam height of simulated gastric juice was reduced by caraway oil at concentrations of 0.025 - 0.1% [Harries 1978]. (S)-(+)-carvone and (R)-(+)-limonene produced relaxation in isolated guinea-pig ileum but were less potent than (R)-(-)- De-sheathed sciatic nerves isolated from male Wistar rats carvone [de Sousa 2008]. were used to evaluate the effects of R-(-)- and S-(+)-carvone on inhibition of the compound action potential (CAP). Using Smooth muscle contractility was evaluated using longitudinal a modified single sucrose-gap technique both enantiomers (at strips isolated from the gastric fundus and duodenum of 10 mM) reduced peripheral nerve conduction (VCAP) compared ++ mice. Under Ca -free conditions, (S)-(+)-carvone (600 µM) to control. S-(+)-Carvone produced an IC50 of 8.7+0.1mM. significantly (p<0.05) inhibited both the phasic and tonic phases After 30 min of incubation S-(+)-carvone inhibited the CAP of carbachol (1 µM) - induced contractions and contractions amplitude to about 25% of control reducing from 39.4+ 2.0 caused by electrical field stimulation, indicating muscle relaxant mV to 9.8+3.0 mV (p<0.05) and then reverted to 29.9+1.6 and antispasmodic effects. Effects were more pronounced in mV after 30 min nerve washing with the vehicle. Carvone may duodenal tissues where 100 µM concentrations were also decrease nerve excitability by blocking voltage-gated sodium active [Silva 2015]. channels in a reversible manner. (+)-limonene (10mM) had no CAP-blocking effect [Goncalves 2010]. Antimicrobial activity The MIC of caraway oil against Helicobacter pylori was found The effect of (+)-carvone on glutamatergic spontaneous excitatory to be 0.03 % V/V (273.1 µg/mL) with an MBC of 0.06-0.125 % postsynaptic currents (sEPSCs) was examined in substantia V/V (546.1-1092.2 µg/mL) in comparison with amoxicillin (MIC: gelatinosa (SG) neurons of adult rat spinal cord slices by using 0.02 µg/mL), ampicillin (MIC: 0.064 µg/mL) and levofloxacin the whole-cell patch-clamp technique. The stereoisomers (+)- (MIC: 0.39 µg/mL) [Weseler 2005]. and (-)-carvone were found to activate different types of TRP channels. The (+)-carvone (1mM) activity was inhibited by the The oil was found to have antibacterial and antifungal activities. TRPA1 antagonist HC-030031, indicating activation of TRPA1 Gram-positive bacteria in general were more sensitive: Bacillus channels, resulting in an increase in spontaneous L-glutamate cereus (MIC = 0.5 µL/mL; MBC = 1.0 µL/mL); Micrococcus release into SG neurons. The EC50 value for this activation was luteus (MIC = 1.0 µL/mL; MBC = 1.0 µL/mL); Staphylococcus 0.72 mM [Kang 2015].

2 CARVI AETHEROLEUM

In vivo experiments when compared to vehicle (control, 59.2%), but higher than the positive control loperamide (29.1%). Both enantiomers Anti-colitic activity also significantly (p<0.05) delayed intestinal transit when the Caraway oil was given to groups (n=6) of male Wistar rats liquid test meal was injected directly into the duodenum, with orally (100, 200, 400 µL/kg) or intraperitoneally (100, 400 effects being comparable to that produced by the positive µL/kg) 6 hours after induction of trinitrobenzene sulfonic control (loperamide). Spontaneous and rhythmic intragastric acid (TBNS)-induced colitis and daily for 5 consecutive days. mean amplitudes of pressure waves were significantly (p<0.05) Colon tissue lesions (ulcer areas) and colitis indices were decreased by (R)-(-)-carvone (13.2 mmHg) and (S)-(+)-carvone significantly reduced (p<0.001) in all cases in comparison to (10.7 mmHg) when compared to vehicle alone (24.6 mmHg), control groups, irrespective of dose and route of administration but higher than loperamide (6.9 mmHg) [Silva 2015]. [Keshavarz 2013]. Other effects Anti-carcinogenic activity Male albino rats (n = 30) were divided into 3 groups: control Premalignant lesions were induced in rat colon by administration (A), diabetic positive control (B) receiving 60 mg/kg s.c. of 1,2-dimethylhydrazine (DMH; 20 mg/kg b.w. for 5 weeks). streptozotocin (STZ) for 3 days and the experimental group Rats given caraway oil (0.01 and 0.1% in the diet) for 16 weeks (C) receiving 60 mg/kg STZ s.c. for 3 days followed by 10 mg/ showed a suppression of DMH-induced lesions (72–87%) when kg/day p.o. caraway oil. After 22 days rats in group B showed compared to controls. Results indicated that long-term feeding an increase in serum glucose and a decrease in glutathione of caraway oil altered colonic CYP1A1 and GST activities and peroxidase. Caraway oil reduced these changes in rats of group the expression of b-catenin (a dual-function protein, which C. Examination of the kidneys of group C rats showed minor regulates the coordination of cell–cell adhesion and gene pathological changes compared with group B rats where kidneys transcription) [Dadkhah 2011; Allameh 2013]. In a further showed glomerular and tubular degeneration, with haemorrhage experiment with DMH-treated rats given caraway oil (0.2% and deformed renal tissue architecture [Abou El-Soud 2014]. in the diet), a significant inhibition of colonic b-catenin was shown. A 65% inhibition (p<0.05) of aberrant crypt foci (ACF) To assess hepatoprotective activity against CCl4, 2 groups of formation was also reported. In addition, a significant reduction NMRI mice (n=6 each) were pre-treated daily for 5 days p.o. of hepatic CYP450 activity (p<0.05) and increase of GST with saline (control) or caraway oil (0.13 g/kg). 20 h before

(p<0.05) in DMH-treated rats were shown, when compared to sacrifice animals were administered i.p. a single dose of CCl4 the DMH-treated control group [Dadkhah 2014]. in olive oil (1:1; 2 mL/kg), 4 h after the last dose of caraway oil. Pre-treatment with caraway oil prevented a pro-oxidative Effects on central nervous system effect in liver tissue homogenate, despite increased peroxidase The effect of chirality on locomotor activity (LA) was evalu- activity, while xanthine oxidase activity showed a statistically ated in mice pre-treated with analeptics (amphetamine, significant decrease (p<0.05 vs control). The oil pre-treated methamphetamine, caffeine) and sedatives (diazepam, pheno- group given CCl4 showed significant (p<0.05) increases in barbital). Results were dependent on the chirality of the terpene glutathione peroxidase (oil+CCl4: 1.76 vs CCl4:1.08 nmol/mg and the circadian rhythm of mice. Inhalation of (S)-(+)-carvone of protein/min). Plasma aspartate transaminase activity (U/L) by ‘morning’ mice (i.e. ‘highly-active’) produced a stimulating rose significantly (p<0.05) compared to the saline control effect with phenobarbital-treatment (p<0.05) but a decreased LA (oil+CCL4:173 U/L vs CCl4:229 U/L vs control 89 U/L). In spite in over-stimulated animals (with caffeine p<0.05) [Buchbauer of the CCl4 potential to form lipid peroxidation products (LPx), 2005]. the LPx remained unchanged in the oil-treated group compared

to both control and CCl4 groups [Samojlik 2010]. (S)-(+)-carvone (200 mg/kg i.p.) given to mice produced a depressant effect in the CNS and had anticonvulsant-like activity Carvone or limonene, both isolated from caraway oil, given [De Sousa 2007]. by oral administration (3 times over 6 days) to mice (20 mg/ animal) significantly increased (p<0.05 to p<0.005) glutathione Mice treated with methylphenidate (5 mg/kg i.p.) or sleep- S-transferase (GST) activity in the liver, forestomach, small deprived for 24 h exhibited an increase in locomotor activity. intestinal mucosa and colon. Limonene was less effective Single dose acute pre-treatment and chronic treatment once daily [Zheng 1992]. for 3 weeks with 100 mg/kg i.p. of (S)-(+)-carvone significantly (p<0.05) reduced methylphenidate-induced hyperlocomotion Pharmacological studies in humans compared to a saline control group. Lithium (100 mg/kg), used as a positive control, showed significant activity with Antispasmodic effect chronic treatment. Acute pre-treatment with (S)-(+)-carvone Healthy volunteers (n=12) took a capsule containing caraway and lithium at the same doses significantly (p<0.001) blocked oil (50 mg) on an empty stomach, followed 15 mins later by sleep deprivation-induced hyperlocomotion. Spontaneous loco- a non-fat test drink (400 mL apple juice + 1 mL lactulose). motor activity was not significantly altered by (S)-(+)-carvone Sonographic measurements showed that the gall bladder (50 or 100 mg/kg) or lithium (100 g/kg) in the first experiment; emptied in response to the drink. On refilling the gall bladder in the sleep deprivation experiment a non-sleep deprived showed a volume increase of 90% (from initial) compared to control group given (S)-(+)-carvone (100 mg/kg) did exhibit 40% in the controls (test drink only) indicating that caraway oil a significant (p<0.05) reduction in spontaneous locomotion had a relaxing effect on the gall-bladder without significantly [Nogoceke 2016]. prolonging orocaecal transit time [Goerg 2003].

Effects on gastrointestinal motility The effect of an intraduodenal administration of caraway oil (50 The effects of (R)-(-)- and (S)-(+)-carvone (100 mg/kg dissolved mg) on gastroduodenal motility was studied in healthy volunteers in vehicle) on gut motility were evaluated in ‘awake’ mice by (n = 7). Results showed significant reductions in contraction measuring gastric dye emptying and the rate of intestinal transit. amplitudes of the duodenum (p = 0.025) as well as reduced Intragastric pressure was also monitored. Gastric emptying contraction duration and amplitudes in the gastric corpus and (expressed as % of dye) was significantly lower (p<0.05) in mice antrum (p = 0.028), indicating smooth-muscle relaxing effects treated with (R)-(-)-carvone (32.1%) and (S)-(+)-carvone (41.9%), of the oil [Mickelfield 2003].

3 CARVI AETHEROLEUM

Effects on the central nervous system Pharmacokinetics in animals The effects of chirality on the human autonomic nervous system were studied in healthy volunteers (n = 20). Inhalation Absorption, distribution, metabolism and elimination of R-(+)-limonene increased systolic blood pressure, subjective The absorption rate of a caraway fruit extract (1:3, ethanol alertness and restlessness, while S-(+)-carvone increased levels 30%) determined as carvone, was carried out using the mouse of both systolic and diastolic blood pressure [Heuberger 2001]. everted gut sac technique. Incubation time was 30 min and extract concentrations were 10, 25, 50 and 100 µL/mL. Data Clinical studies indicate a fast uptake of carvone linearly correlated to the mucosal concentration [Kelber 2006]. Irritable bowel syndrome In a monocentric, randomized, open-label, cross-over trial, 48 In rabbits, (S)-(+)- and (R)-(-)-carvone is reduced to yield carveol patients with Irritable Bowel Syndrome (IBS) were randomly which is converted to the glucuronic acid conjugate and excreted assigned to one of 6 groups. Each group received, in different in the urine [Ishida 1989]. orders, three interventions: (i) hot caraway oil-containing poultice (2% solution in olive oil; CarO); (ii) hot olive oil The main route of elimination of (R)-(+)-limonene administered poultice (OliveH) as control and (iii) cold olive oil (OliveC). orally was via the urine in animals and man, 75-95% of the Patients applied each intervention to their abdominal area administered radioactivity being excreted in the urine during daily for 3 weeks. By means of patient questionnaires symptom 2-3 days. Faecal excretion accounted for less than 10% of the severity was measured using the IBS-symptom severity scale dose in animals during 2-3 days. In addition to six metabolites, [Francis 1997]. A significant difference (p = 0.033) was found namely p-mentha-1,8-dien- 10-ol (M-I), p-menth-1-ene-8,9-diol for symptom severity in favour of CarO compared to OliveC, (M-II), perillic acid (M-III), perillic acid-8,9-diol (M-IV), p-mentha- but not compared to OliveH [Lauche 2015]. 1,8-dien-10-yl-beta-D-glucopyranosiduronic acid (M-V) and 8-hydroxy-p-meth-1-en-9-yl-beta-D-glucopyranosiduronic acid Pharmacokinetic properties (M-VI) isolated from rabbit urine previously, five new metabolites have been isolated from dog and rat urine, and which were Pharmacokinetics in vitro characterized as 2-hydroxy-p-menth-8-en-7-oic acid (M-VII), A membrane diffusion model was used to study the transfer of perillylglycine (M-VIII), perillyl-beta-D-glucopyranosiduronic caraway oil (0.5 g) from a buffer solution pH 1.1 (= stomach) acid (M-IX), p-mentha-1,8-dien-6-ol (M-X) and probably and pH 6.5 (= intestine) to pH 7.5 (= plasma). Only very low p-menth-1-ene-6,8,9-triol (M-XI). The major metabolite of (R)- concentrations of carvone, d-limonene and other components (+)-limonene in the urine was M-IV in rat and rabbit, M-IX in (no amounts given) were transferred through the membrane hamster, M-II in dog and M-VI in guinea pig [Kodama 1976]. [Lado 2005]. Pharmacokinetics in humans Gastrointestinal absorption Oral administration of an immediate-release preparation The absorption of carvone from a caraway fruit extract (1:3, containing peppermint oil (180 mg) and caraway oil (100 mg) ethanol 30% V/V) was tested in everted intestinal sacs prepared to healthy male volunteers (n=15) yielded a mean Cmax for from male adult rats. After 30 minutes, the uptake from an carvone of 12.57 ng/mL, a mean Tmax of 1.24 h and mean t1/2 extract concentration of 11.7µg/mL was about 3 µg/cm2 carvone of 2.0 h [Mascher 2001]. [Kelber 2000]. (S)-(+)-Carvone Percutaneous absorption Caraway oil increased permeation of salicylic acid by 48% Percutaneous absorption when evaluated using goat skin [Kaza 2006]. To determine whether an enantioselective difference in the metabolism of topically applied R-(-)- and S-(+)-carvone could After a single topical application to an area of the lower be observed in man, the metabolism and pharmacokinetics abdomen (376 cm2) of healthy subjects (n=4), S-(+)-carvone of R-(-)- and S-(+)-carvone was investigated in four healthy

(300 mg in 1.5 g arachis oil) was rapidly absorbed (Tmax (min) subjects. Following separate topical applications at a dose -1 32.4), resulting in a Cmax of 88 ng mL and distribution half-life of 300 mg, R-(-)- and S-(+)-carvone were rapidly absorbed, (t1/2a) of 19.4 min [Jäger 2001]. resulting in significantly higher Cmax levels for (S)-(+)-carvone (88.0 vs 23.9 ng/mL) and longer distribution half-lives (t(1/2a); Using human abdominal skin, (R)-(+)-limonene (5% V/V) was 19.4 vs 7.8 min), resulting in 3.4-fold higher areas under the found to improve the permeability of haloperidol (2.5 mg/mL) blood concentration-time curves (5420 vs 1611 ng x min/mL). by 26.5 times (p<0.05) and reduce the lag time from 14.1 to The biotransformation products for both enantiomers in plasma 9.2 h (p<0.05), compared to control [Lim 2006]. were below detection limit. Analysis of control- and beta- glucuronidase pre-treated urine samples, however, revealed a A terpene-based hydroxypropyl cellulose gel drug reservoir system stereoselective metabolism of R-(-)-carvone to 4R,6S-(-)-carveol was used to study the transdermal permeation of ondansetron and 4R,6S-(-)-carveol glucuronide. No metabolites could be hydrochloride through prepared rat epidermis. Carvone (8% m/m) found in urine samples after (S)-(+)-carvone application. These produced an optimal permeation of 87.4 mg/cm2.h (p<0.001) data indicate that stereoselectivity in phase-I and phase-II and limonene (3% m/m) of 181.9 mg/cm2.h (p<0.01). The metabolism has significant effects on R-(-)- and S-(+)-carvone enhancement ratio in drug permeability was 10.8 with carvone pharmacokinetics and could explain the increased blood levels and 22.5 with limonene, when compared with 1.0, i.e. that of (S)-(+)-carvone [Jäger 2001]. obtained without a terpene-enhancer (control) [Krishnaiah 2008]. Metabolism Biotransformation Using the Metabolism Ingestion-Correlated Amounts (MICA) R-(-)- and S-(+)-carvone are stereoselectively biotransformed by approach, volunteers (n=6) receiving a controlled diet were human liver microsomes to 4(R),6(S)-(-)- and 4(R),6(S)-(+)-carveol given a single dose of (S)-(+)- or (R)-(-)- carvone (0.5 mmol; ~ respectively and 4(R),6(S)-(-)-carveol is further glucuronidated 1 mg/kg b.w.) ingested as a solution in full-fat milk (500 mL). [Jäger 2000]. 24-hour urine samples were collected before (control) and after

4 CARVI AETHEROLEUM

ingestion of carvone. Carvonic acid, dihydrocarvonic acid, and an isomer of perillic acid. Both isomers of perillic acid, carveol, dihydrocarveol and uroterpenolone were identified and cis- and trans- isomers of dihydroperillic acid were in as the metabolites in humans. 10-Hydroxycarvone was not urine hydrolysates. Intratumoural levels of (R)-(+)-limonene and detected, indicating either concentration effects or interspecies uroterpenol exceeded the corresponding plasma levels. Other differences. No differences in metabolism between (S)-(+)- and metabolites were trace constituents in tissue [Vigushin 1998]. (R)-(-)-carvone were detected [Engel 2001]. Preclinical safety data Lactation/Breast milk Lactating women (n=18) were each given 100 mg of (S)-(+)- Allergenicity carvone mixed with lactose and talc in a capsule on 3 test days. In a 24-hour closed-patch test in humans a 4% concentration of Milk samples were collected every 2 hours for 8 hours starting caraway oil in petroleum jelly produced no irritation [Opdyke 1973]. at the time of ingestion. Carvone was detected in milk at all times, with the average concentrations of 1.3 µg/L at 0 hours, The Scientific Committee on Consumer Safety [SCCS] on reaching a maximum of 7.2 µg/L at 2 hours, 5.6 µg/L at 4 hours, fragrance allergens in cosmetic products has listed carvone 4.3 µg/L at 6 hours and 2.7 µg/L at 8 hours. The average peak among the established contact allergens (skin sensitisers) in carvone concentration in milk was 10.5 µg/L. It is considered humans [EFSA 2014]. that lipophilic flavour compounds are transported from blood into milk via passive diffusion [Hausner 2008]. Although the non-oxidized R-(+)-limonene itself is not allergenic, it easily forms allergenic autoxidation products. A limonene In another study, 20 mothers consumed 30 mg of (S)-(+)- hydroperoxide fraction proved to be the most important allergen carvone in 75 grams of hummus every third day for 28 days of the oxidation mixture, showing positive reactions in around (10 exposures) at about 2 hours before a "usual" nursing time. 60% of the limonene-allergic patients. Testing limonene oxide Breastmilk samples were obtained 2 hours after ingestion on and carvone separately resulted in very few positive reactions. the first and last days of carvone intake. Carvone was detectable In Europe, R-(+)-limonene containing oxidation products are in the milk of 18 mothers. Average carvone concentrations in classified as a skin sensitizer in animals and humans [Matura breastmilk were 2.5 µg/L and 3.8 µg/L on the first and last days 2002; 2003; Kim 2013]. of sampling, respectively. However, these values did not differ statistically and the combined average carvone concentration Acute toxicity was 3.2 µg/L. A control group of 20 women who did not ingest The oral LD50 for caraway oil in rats is 3.5 mL/kg b.w. corres- (S)-(+)-carvone had no detectable carvone in their breastmilk ponding to 3720 mg/kg b.w. [EMEA 1998] and 3500 mg/kg; LD50 [Hausner 2010]. for rabbit skin 1780 mg/kg [Lewis 1996].

(R)-(+)-Limonene LD50 value for (S)-(+)-carvone in mice was 484.2 mg/kg [De About 25-30% of an oral dose of (R)-(+)-limonene in humans was Sousa 2007]. found in urine as (R)-(+)-limonene-8,9-diol and its glucuronide; about 7-11% was eliminated as perillic acid and its metabolites The EFSA Scientific Committee established an Accepted Daily [Kodama 1976]. Intake (ADI) for (S)-(+)-carvone of 0.6 mg/kg b.w./day, based

on the BMDL10 of 60 mg/kg b.w./day for an increase in relative Healthy human volunteers (n=7) ingested 100 mg/kg limonene. liver weight in the rat, 90-day studies and an uncertainty factor Blood was drawn at 0 and 24 h for chemistry-panel analysis of 100 [EFSA 2014]. and at 0, 4, and 24 h for limonene-metabolite analysis. At least five compounds were present at 4 h that were not present at The oral LD50 for R-(+)-limonene in male and female mice is time zero. Two major peaks were identified as dihydroperillic reported to be 5.6 and 6.6 g/kg b.w. respectively, and 4.4 and acid and perillic acid, and two minor peaks were found to 5.1 g/kg b.w. in male and female rats respectively [IARC 1999]. be the respective methyl esters of these acids. A third major peak was identified as limonene-1,2-diol. Limonene was a Administration to rats and mice of R-(+)-limonene at doses minor component. At a dose of 100 mg/kg, limonene caused ranging from 413 - 6,600 mg/kg/day for 5 days/week for 3 no gradable toxicity [Crowell 1994]. weeks, resulted in no signs of compound-related toxicity at doses <1,650 mg/kg daily [NTP 1990b]. In a single centre, open-label pharmacokinetic study, healthy male volunteers (n=24) were given a single dose of 300 mg The dose-response for R-(+)-limonene has shown NOEL of 3.6 (R)-(+)-limonene with 240 mL water. The maximum plasma mg/kg/day in the development of hyaline-droplet nephropathy in concentration of (R)-(+)-limonene ranged from 40.1 to 327.4 male rats and no development of kidney tumours are expected ng/mL. Tmax values ranged from 0.75 to 3.0 h and oral clearance to occur in male rats below this NOEL. Neither female rats nor ranged from 53.7 to 312.1L/h [Wang 2007]. mice developed tumours or hyaline-droplet nephropathy, which is associated with elevated alpha2u-globulin as found in male Patients (n=32) with refractory solid tumours completed 99 rats. R-(+)-limonene is stated as not posing a risk to humans for courses of (R)-(+)-limonene 0.5 to 12 g/m2 per day administered the formation of renal neoplasms [Whysner 1996]. orally in 21-day cycles. Additional breast cancer patients (n=10) received 15 cycles of (R)-(+)-limonene at 8 g/m2 per Subchronic and chronic toxicity day. One partial response in a breast cancer patient on 8 g/ A study in rats demonstrated that 0.1% carvone in their diet m2 per day was maintained for 11 months; three patients with for 28 weeks and 0.25% for one year had no effects, while colorectal carcinoma had prolonged stable disease. There were 1% of (S)-(+)-carvone in the diet for 16 weeks caused growth no responses in the phase II study. Peak plasma concentration retardation and testicular atrophy [EMEA 1998; Hagan 1967].

(Cmax) for (R)-(+)-limonene ranged from 10.8+6.7 to 20.5+11.2 mM. Predominant circulating metabolites were perillic acid Based on short-term and long-term toxicity studies in rodents,

(Cmax 20.7+13.2 to 71+29.3 mM), dihydroperillic acid (Cmax including a NOEL of 93 mg/kg b.w./day in rats, the World Health 16.6+7.9 to 28.1+3.1 mM), limonene-1,2-diol (Cmax 10.1+8 to Organization established the ADI for (S)-(+)-carvone of 0-1 mg/ 20.7+8.6 mM), uroterpenol (Cmax 14.3+1.5 to 45.1+1.8 mM), kg b.w. per day [WHO 1999].

5 CARVI AETHEROLEUM

For (S)-(+)-carvone a daily intake of 1 mg/kg b.w. was considered R-(+)-Limonene has been found to be safe, when 100 mg/kg harmless. For a 60 kg person this corresponds to a dose of 60 (equivalent to about 7 g for an average adult male) was ingested. mg, approx. equivalent to 120 mg caraway oil (corresponding Only mild eruction for 1-4 h, mild satiety for 10 h and mild to approx. 6 drops) [EMEA 1998]. fatigue for 4 h were reported [Crowell 1994].

Mutagenicity and carcinogenicity In a dose-escalation study in patients (n=32) with refractory solid (S)-(+)-Carvone was not mutagenic in Salmonella typhimurium tumours, R-(+)-limonene (0.5 – 12 g/m2/day) was given orally strains TA 98, TA 100, TA 1535 and TA 1537, with and without for 21 days. The maximum tolerated oral dose was 8 g/m2/day metabolic activation [EMA 1998]. (15 g /day). Nausea, vomiting and diarrhoea were observed and effects were dose-dependent. R-(+)-Limonene was considered (S)-(+)-Carvone was reported to be non-carcinogenic in a 103- to have low toxicity after single and repeated doses for up to week study in mice dosed with oral doses of 375 and 750 mg/ one year [Vigushin 1998]. kg b.w., 5 days per week [NTP 1990a; EMA 1998; EFSA 2009].

R-(+)-Limonene was not mutagenic in four strains of S. REFERENCES typhimurium (TA98, TA100, TA1535, or TA1537), did not significantly increase the number of trifluorothymidine (Tft)-resistant Caraway Oil – Carvi aetheroleum. European Pharmacopoeia, Council cells in the mouse L5178Y/TK± assay and did not induce of Europe chromosomal aberrations or sister chromatid exchanges (SCEs) in cultured CHO cells [NTP 1990b]. Caraway Water, Concentrated. In: British Pharmaceutical Codex 1973, London: Pharmaceutical Press, 1973:825 R-(+)-Limonene was administered by gavage to F344/N male rats for 5 days per week for 103 weeks at doses of 0, 75 or 150 Caraway Oil. In: British Pharmaceutical Codex 1973, London: mg/kg, and female F344/N rats at doses of 0, 300 or 600 mg/kg. Pharmaceutical Press, 1973:74-75 There was no evidence of carcinogenic activity of R-(+)-limonene for the female rats that received 300 or 600 mg/kg. Evidence Abou El-Soud NH, El-Lithy NA, El-Saeed G, Wahby MS, Khalil MY, Morsy F, Shaffie N. Renoprotective effects of Caraway (Carum carvi of carcinogenic activity was found only in male F344/N rats L.) essential oil in streptozotocin induced as shown by increased incidences of tubular cell hyperplasia, diabetic rats. J Applied Pharm Sci. 2014;4:27-33. adenomas and adenocarcinomas of the kidney [NTP 1990b]. Similarly there was no evidence of carcinogenic activity of Allameh A, Dadkhah A, Rahbarizadeh F, Ashrafi-Helan J, Fatemi F. limonene for male B6C3F1 mice that received 250 or 500 Effect of dietary caraway essential oils on expression of b-catenin mg/kg or female B6C3F1 mice that received 500 or 1,000 mg/ during 1,2-dimethylhydrazine-induced colonic carcinogenesis. J Nat kg [NTP 1990b]. Renal toxicity of limonene results from the Medicines. 2013;67(4):690-697. accumulation in male rat kidney proximal tubule lysosomes of https://doi.org/10.1007/s11418-012-0650-2 alpha-2u-globulin, a protein synthesized exclusively by adult male rats [Whysner 1996]. Bradley P (ed.) Caraway Fruit. British Herbal Compendium: Vol 2. British Herbal Medicine Association, Bournemouth, 2006:91-5 Male Big Blue TM rats were given limonene (525 mg/kg) as part (1%) of their diet for 10 consecutive days. The rat carcinogen Buchbauer G, Jager W, Gruber A, Dietrich H. R-(+)- and S-(-)-carvone: 4-aminophenyl was used as positive control. Limonene failed to influence of chirality on locomotion activity in mice. Flav Fragr J. increase the mutant frequency in the rat liver or kidney, results 2005;20:686-689 https://doi.org/10.1002/ffj.1600 consistent with a non-genotoxic mechanism of carcinogenic action [Turner 2001]. Crowell PL, Elson CE, Bailey HH, Elegbede A, Haag JD, Gould MN. 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Nutr Cancer 2011;63(1):46-54. https://doi.org/10.1080/01635581.2010.516473 Safety of a standardized preparation of enteric coated capsules Dadkhah A, Fooladvand M, Fatemi F, Ashrafi-Helan J.Chemopreventive containing 90 mg peppermint oil and 50 mg caraway oil per effects of caraway powder and oils to suppress 1,2-dimethylhydrazine- capsule was studied in a double-blind, placebo-controlled induced colon carcinogenesis. Turk J. Biochem 2014;39:260-269. multicentre trial in patients with non-ulcer dyspepsia. The test https://doi.org/10.5505/tjb.2014.17362 preparation was well tolerated, even over a 4-week period [May 1996; Madish 1999]. De Sousa SP, De Nobrega FF, De Almeida RN. Influence of the chirality of (R)-(-)-carvone and (S)-(+)-carvone in the central nervous system: a A second double-blind, randomized, parallel-group evaluation comparative study. Chirality 2007;19:264-268. https://doi.org/10.1002/ of the fixed peppermint oil/caraway oil combination vs chir.20379 placebo was carried out in patients suffering from functional dyspepsia (n=96). Patients received one capsule twice daily of De Sousa DP, Júnior GA, Andrade LN, Calasans FR, Nunes XP, Barbosa- the combination or placebo for 28 days. No side effects were Filho JM, et al. Structure and spasmolytic activity relationships of reported by patients receiving the verum [May 2000]. monoterpene analogues found in many aromatic plants. Z Naturforsch C. 2008;63:808-12 https://doi.org/10.1515/znc-2008-11-1205 In further randomized, placebo-controlled, double-blind clinical trials with the same combination (2 x 1 capsule daily), the test Dorsch W, Loew D, Meyer-Buchtela E, Schilcher H. In: Kinderdosierungen preparation did not show any adverse events [Holtmann 2001; von Phytopharmaka; 2002Hrsg.: Kooperation Phytopharmaka GbR, Holtmann 2003]. Bonn. p51

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Gniewosz M, Krasniewska K, Woreta M, Kosakowska O. Antimicrobial Kang Q, Jiang C-Y, Fujita T, Kumamoto E. Spontaneous L-glutamate activity of a pullulan-caraway essential oil coating on reduction release enhancement in rat substantia gelatinosa neurons by (-)-carvone of food microorganisms and quality of baby carrot. J Food Sci. and (+)-carvone which activate different types of TRP channel. Biochem 2013;78:M1242-M1248. https://doi.org/10.1111/1750-3841.12217 Biophys Res Comm. 2015;459:498-503. https://doi.org/10.1016/j.bbrc.2015.02.135 Goerg KJ, Spilker TH. Effect of peppermint oil and caraway oil on gastrointestinal motility in healthy volunteers: a pharmacodynamic study Kaza R, Pitchaimani R. Formulation of transdermal delivery system, using simultaneous determination of gastric and gall-bladder emptying matrix type and selection of polymer: their evaluation. Current Drug and orocaecal transit time. Aliment Pharmacol Ther. 2003;17:445-451 Discovery Technologies. 2006;3:279-285. https://doi.org/10.1046/j.1365-2036.2003.01421.x https://doi.org/10.2174/157016306780368135

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Holtmann G, Haag S, Adam B, Funk P, Wieland K, Heydenreich C-J. Lauche R, Janzen A, Lüdtke R, Cramer H, Dobos G, Langhorst J.

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Efficacy of caraway oil poultices in treating Irritable Bowel Syndrome Raal A, Arak E, Oravb A. The content and composition of the essential – A randomized controlled cross-over trial. Digestion 2015;92:22-31. oil found in Carum carvi L. commercial fruits obtained from different https://doi.org/10.1159/000398790 countries. J Essential Oil Res. 2012;24:53-59. https://doi.org/10.1080/10412905.2012.646016 Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. Regulation (EC) No 1223/2009 of the European Parliament and of 650 the Council of 30 November 2009 on cosmetic products, OJ L 342, 22.12.2009 Lim PFC, Liu XY, Kang L., Ho PCL, Chan YW, Chan SY. Limonene GP1/PG organogel as a vehicle in transdermal delivery of haloperidol. Int J Pharm Reiter M, Brandt W. Relaxant effects on tracheal and ileal smooth 2006;311:157-164. https://doi.org/10.1016/j.ijpharm.2005.12.042 muscles of the guinea pig. Arzneim.-Forsch./Drug Res. 1985;35:408- 414 Madisch A, Heydenreich C-J, Wieland V, Hufnagel R, Hotz J. Treatment of functional dyspepsia with a fixed peppermint oil and caraway oil Sadraei H, Ghannadi A, Takei-Bavani M. Effects of Zataria multiflora combination preparation as compared to cisapride. Arzneim.-Forsch./ and Carum carvi essential oils and hydroalcoholic extracts of Passiflora Drug Res. 1999;49:925-932. https://doi.org/10.1055/s-0031-1300528 incarnata, Berberis integerrima and Crocus sativus on rat isolated uterus. Int J Aromatherapy 2003;13:121-127 Martindale The Royal Pharmaceutical Society of Great Britain 2014 https://doi.org/10.1016/S0962-4562(03)00092-4 (through Micromedex® 2.0)014 Samojlik I, Lakic N, Mimica-Dukic N, Dakovic-Svajcer K, Bozin B. Mascher H, Kikuta C, Schiel H. Pharmacokinetics of menthol and carvone Antioxidant and hepatoprotective potential of essential oils of coriander after administration of an enteric formulation containing peppermint (Coriandrum sativum L.) and caraway (Carum carvi L.) (Apiaceae). J oil and caraway oil. Arzneim.-Forsch./Drug Res. 2001;51:465-469. Agric Food Chem. 2010:58:8848-8853. https://doi.org/10.1055/s-0031-1300064 https://doi.org/10.1021/jf101645n

Matura M, Goossens A, Bordalo O, Garcia-Bravo B, Magnusson K, Seidler-Lozykowska K, Kedzia B, Karpinska E, Bocianowski J. Wrangsjo K, Karlberg AT. Oxidized citrus oil (R-limonene): a frequent Microbiological activity of caraway (Carum carvi L.) essential oil obtained skin sensitizer in Europe. J Am Acad Dermatol. 2002:47: 709-714. from different origin. Acta Sci-Agron. 2013;35:495-500. https://doi.org/10.1067/mjd.2002.124817 Schilcher H, Kammerer S, Wegener T. Leitfaden Phytotherapie, 4. Matura M, Goossens A, Bordalo O, Garcia-Bravo B, Magnusson K, Auflage, Elsevier, Urban Wrangsjö, K. et al. Patch testing with oxidized R-(+)-limonene and its hydroperoxide fraction. Contact Dermatitis 2003;49:15-21. Silva CM, Wanderley CW, Lima-Junior FJ, de Sousa DP, Lima JT, et al., https://doi.org/10.1111/j.0105-1873.2003.00135.x Carvone (R)-(-) and (S)-(+) enantiomers inhibits upper gastrointestinal motility in mice. Flavour Fragr J. 2015;30:439-444. May B, Kuntz H-D, Kieser M, Köhler S. Efficacy of a fixed peppermint https://doi.org/10.1002/ffj.3267 oil/caraway oil combination in non-ulcer dyspepsia. Arzneim Forsch/ Drug Res. 1996;46:1149-1153 Simic A, Rancic A, Sokovic MD, Ristic M, Grujic-Jovanovic S, Vukojevic J, Marin PD. Essential oil composition of Cymbopogon winterianus May B, Köhler S, Schneider B. Efficacy and tolerability of a fixed and Carum carvi and their antimicrobial activities. Pharm Biol combination of peppermint oil and carawy oil in patients suffering from 2008;46(6):437-441. https://doi.org/10.1080/13880200802055917 functional dyspepsia. Aliment Pharmacol Ther. 2000;14:1671-1677. https://doi.org/10.1046/j.1365-2036.2000.00873.x Stahl-Biskup E, Hiller K, Loew D. Kümmel – Carvi fructus. In: Blaschek W, ed. Wichtl – Teedrogen und Phytopharmaka. 6th ed. Stuttgart: Micklefield G, Jung O, Greving I, May B. Effects of Intraduodenal Wissenschaftliche Verlagsgesellschaft, 2016:153-155 application of Peppermint Oil (WSR 1340) and Caraway Oil (WSR 1520) on Gastroduodenal Motility in Healthy Volunteers. Phytother Sticher O, Heilman J, Zundorf I (eds). In: Hänsel / Sticher Pharmakognosie Res. 2003;17:135-140. https://doi.org/10.1002/ptr.1089 Phytopharmazie, 10 Auflage. Wissenschaftliche Verlagsgesellschaft, Stuttgart, 2015:705 National Toxicology Program (NTP) 1990a. Toxicology and carcinogenesis studies of d-Carvone (CAS No. 2244-16-8) in B6C3F1 mice Sun J. D-Limonene: safety and clinical applications. Alt Med (gavage studies). NTP TR Series 381. National Institutes of Health. NIH Rev.2007;12:259-264 Publication No. 90-2836 Turner SD, Tinwell H, Piegorsch W, Schmezer P, Ashby J. The male rat National Toxicology Program (NTP) 1990b. Toxicology and carcinogens limonene and sodium saccharin are not mutagenic to Big Carcinogenesis Studies of d-Limonene (CAS No. 5989-27-5) in F344/N BlueTM rats. Mutagenesis 2001;16:329-332. Rats and B6C3F1 Mice (Gavage studies). NTP TR 347. US Department of https://doi.org/10.1093/mutage/16.4.329 Health and Human Services, Public Health Service, National Institutes of Health. NIH Publication No. 90-2802 Vigushin DM, Poon GK, Boddy A, English J, Halbert GW, Pagonis C, Jarman M, Coombes RC. Phase I and pharmacokinetic study of Nogoceke F, Barcaro I, De Sousa D, Andreatini R. Antimanic-like D-limonene in patients with advanced cancer. Cancer Research effects of (R)-(-)-carvone and (S)-(-)-carvone in mice. Neurosci Lett Campaign Phase I/II Clinical Trials Committee. Cancer Chemother 2016;619:43-48. https://doi.org/10.1016/j.neulet.2016.03.013 Pharmacol. 1998;42(2):111-7 https://doi.org/10.1007/s002800050793 Opdyke DLJ. Monographs on fragrance raw materials: Caraway oil. Food Cosmet Toxicol 1973;11:10510 https://doi.org/10.1016/S0015- Wang S, Chen Y, Gao Z, Xiong M, Zhong Z, Ye L. Gas chromatographic- 6264(73)80370-0 mass spectrometric analysis of d-limonene in human plasma. J Pharm and Biomed Anal. 2007;44:1095-1099. Ottillinger B, Storr M, Malfertheiner P, Allescher HD. STW 5 https://doi.org/10.1016/j.jpba.2007.04.018 (IberogastTM) – a safe and effective standard in the treatment of functional gastrintestinal disorders. Wien Med Wochenschrift. Dec 2012. Weiss R, Fintelmann V. In: Herbal Medicine (2nd Edition), Georg Thieme https://doi.org/10.1007/s10354-012-0169-x Verlag, Stuttgart, New York, 2000: 74-75

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9 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 Online Series, 2019 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 AETHEROLEUM Caraway Oil Online Series, 2019 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 Online Series, 2019 ECHINACEAE PALLIDAE RADIX Pale Coneflower Root Online Series, 2018 ECHINACEAE PURPUREAE HERBA Purple Coneflower Herb Supplement 2009 ECHINACEAE PURPUREAE RADIX Purple Coneflower Root Supplement 2009 ELEUTHEROCOCCI RADIX Eleutherococcus Supplement 2009 EQUISETI HERBA Equisetum stem Online Series, 2018 EUCALYPTI AETHEROLEUM Eucalyptus Oil Second Edition, 2003 FILIPENDULAE ULMARIAE HERBA Meadowsweet Online Series, 2015 FOENICULI AETHEROLEUM Fennel Oil Online Series, 2019 FOENICULI FRUCTUS Fennel Fruit Online Series, 2019 FRANGULAE CORTEX Frangula Bark Online Series, 2017 FUMARIAE HERBA Fumitory Online Series, 2018 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 Online Series, 2018 JUNIPERI PSEUDO-FRUCTUS Juniper Second Edition, 2003

10 LAVANDULAE FLOS/AETHEROLEUM Lavender Flower/Oil Supplement 2009 LEONURI CARDIACAE HERBA Motherwort Online Series, 2019 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 Online Series, 2019 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 Online Series, 2019 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 Online Series, 2018 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 UNCARIAE TOMENTOSAE CORTEX Cat's Claw Bark Online Series, 2018 URTICAE FOLIUM/HERBA Nettle Leaf/Herb Online Series, 2018 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 11 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.