selected medicinal plants - World Health Organization

WHO monographs on 

selected 

medicinal 

plants 

Volume 3

WHO 

monographs 

on selected 

medicinal plants 

VOLUME 3

WHO Library Cataloguing-in-Publication Data 

WHO monographs on selected medicinal plants. Vol. 3. 

1. Plants, Medicinal. 2. Angiosperms. 3. Medicine, Traditional. I. WHO Consultation on Selected Medicinal 

Plants (3rd: 2001: Ottawa, Ont.) II. World Health Organization. 

ISBN 978 92 4 154702 4 (NLM classifi cation: QV 766) 

© World Health Organization 2007 

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Printed in Spain

Contents 

Acknowledgements v 

Introduction 1 

General technical notices 5 

Monographs (in alphabetical order of plant name) 

Fructus Ammi Majoris 9 

Fructus Ammi Visnagae 23 

Fructus Anethi 33 

Aetheroleum Anisi 42 

Fructus Anisi 53 

Semen Armenicae 64 

Flos Arnicae 77 

Folium Azadirachti 88 

Oleum Azadirachti 102 

Flos Carthami 114 

Stigma Croci 126 

Fructus Foeniculi 136 

Radix Gentianae Luteae 150 

Radix Gentianae Scabrae 160 

Gummi Gugguli 169 

Radix Harpagophyti 182 

Rhizoma Hydrastis 194 

Radix Ipecacuanhae 204 

Aetheroleum Lavandulae 219 

Flos Lavandulae 229 

Strobilus Lupuli 236 

Gummi Myrrha 247 

Herba Passifl orae 257 

Testa Plantiginis 268 

Radix Rehmanniae 283 

iii

Contents 

Fructus Schisandrae 296 

Radix Scutellariae 314 

Radix cum Herba Taraxaci 328 

Semen Trigonellae Foenugraeci 338 

Cortex Uncariae 349 

Fructus Zizyphi 359 

Annex 1 

Participants in the Third WHO Consultation on Selected 

Medicinal Plants, The Governmental Conference Centre, 

Ottawa, Canada, 16–19 July, 2001 370 

Annex 2 

Cumulative index (in alphabetical order of plant name) 373 

Annex 3 

Cumulative index 

(in alphabetical order of plant material of interest) 375 

iv

Acknowledgements 

Special acknowledgement is due to Professors Norman R. Farnsworth, 

Harry H.S. Fong, and Gail B. Mahady of the WHO Collaborating Centre 

for Traditional Medicine, College of Pharmacy, University of Illinois at 

Chicago, Chicago, IL, USA, for drafting and revising the monographs. 

Similarly, special acknowledgement is due to Dr Raymond Boudet- 

Dalbin of the Laboratoire de Chimie Thérapeutique, University of René 

Descartes, Paris, France, for drawing the chemical structures. The photograph 

for the front cover was kindly provided by Professor Yoshiteru Ida of 

the School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. 

WHO also acknowledges with thanks the valuable work of the 

approximately 170 experts in more than 65 countries who provided comments 

and advice on the draft texts; those who submitted comments 

through the World Self-Medication Industry (a nongovernmental organization 

in offi cial relations with WHO); and those who participated in the 

Third WHO Consultation on Selected Medicinal Plants held in Ottawa, 

Canada, in July 2001 to review the monographs (see Annex 1). 

Sincere appreciation is extended to Health Canada, who hosted the 

above-mentioned WHO Consultation with its fi nancial support, and to 

the Regional Government of Lombardy, Italy, which provided funds for 

the editing and printing of this volume. 

Finally, WHO wishes to express thanks to Mr Raymond Tsai, Boston, 

USA, and Dr Hermann Garden, Düsseldorf, Germany, for their indispensable 

assistance in fi nalizing and editing the manuscripts. 

v

Introduction 

Increasing role of the WHO monographs on selected 

medicinal plants 

Since 1999, WHO has published two volumes of the WHO monographs 

on selected medicinal plants. Volume 1 includes 28 monographs and 

volume 2 contains an additional 30 monographs. Both of these volumes 

are now available on the WHO web site http://www.who.int/medicines/ 

organization/trm/orgtrmstrat.htm). 

Despite the increasing use of herbal medicines, there is still a signifi cant 

lack of research data in this fi eld, so that the WHO monographs are playing 

an increasingly important role. For example, in the recent WHO global survey 

on national policy and regulation of herbal medicines, of the 34 countries 

reporting that they do not have their own national monographs and use 

other monographs, 13 use the WHO monographs as an authoritative reference. 

Moreover, the format of the WHO monographs continues to be commonly 

used for developing national monographs. In the same survey, of the 

46 countries that have already developed national monographs on herbal 

medicines, several countries, such as Armenia, Bhutan, Brazil, Malaysia, and 

Myanmar, reported having used the WHO format as a basis. 

In May 2002, WHO launched its Traditional Medicine Strategy covering 

the period 2002–2005. In 2003, the World Health Assembly adopted resolution 

WHA56.31 on traditional medicine, which requests WHO to seek, together 

with WHO collaborating centres, evidence-based information on the 

quality, safety and cost-effectiveness of traditional therapies. The objective 

is to provide guidance to Member States on the defi nition of products to be 

included in national directives and proposals on traditional-medicine policy 

implemented in national health systems. The continued development of the 

WHO monographs on selected medicinal plants is one of the important activities 

being undertaken to meet the demands from Member States and in the 

implementation of the WHO Traditional Medicine Strategy. 

Preparation of monographs for volume 3 

During the preparation of volume 3, more than 170 experts were involved, 

in addition to members of WHO’s Expert Advisory Panel on Traditional 

1

Introduction 

Medicine, a signifi cant expansion in comparison to the numbers involved 

in the fi rst two volumes. National drug regulatory authorities in 65 countries 

participated in the process, again a greater number than for the previous 

volumes. This global network of active players facilitated wider access 

to the available scientifi c references and information, in terms of both 

quality and quantity. This considerable level of support contributed 

greatly to the effi ciency of the preparation process. 

The Third WHO Consultation on Selected Medicinal Plants was held in 

Ottawa, Canada, in July 2001 to review and fi nalize the draft monographs. 

Thirty-two experts and drug regulatory authorities from WHO Member 

States participated (Annex 1). Following extensive discussion, 31 of the 33 

draft monographs were adopted for inclusion. 

At the subsequent tenth International Conference of Drug Regulatory 

Authorities held in China, Hong Kong Special Administrative Region in 

June 2002, the 31 draft monographs adopted for volume 3 of the WHO 

monographs on selected medicinal plants were presented. In its recommendations, 

the Conference requested WHO to publish them as soon as possible. 

Selection of medicinal plants 

The selection of medicinal plants for inclusion in the WHO monographs 

is based on worldwide use. The medicinal plants selected must meet two 

major criteria: (1) they must be in common use in at least two WHO Regions; 

and (2) there must be suffi cient scientifi c data available to satisfy 

the requirements of the various sections in the monograph format. 

The Third WHO Consultation on Selected Medicinal Plants discussed 

the selection criteria and made recommendations that will be applied 

starting with the preparation of volume 4 of the WHO monographs. 

Changes in format in volume 3 

Following intensive discussion at the Ottawa Consultation the title and 

context of the three categories included in the section Medicinal uses has 

been changed. The changes are described in the in the General technical 

notices. 

It was also decided at the Ottawa Consultation that the section on 

Adverse reactions should be moved to follow immediately after the section 

on Pharmacology, to provide a more logical progression for the subsequent 

sections on Contraindications, Warnings and Precautions. 

A description of selected sections of the monographs is given in the 

General technical notices, which refl ect the above-mentioned format 

changes. For easy reference, two cumulative indexes are provided as an- 

2

nexes. Annex 2 lists the monographs in alphabetical order of the plant 

name, while Annex 3 is according to the plant materials of interest. 

Under the section “Geographical distribution”, an attempt has been 

made to describe the geographical distribution of the plant, i.e. its natural 

distribution, where it is cultivated, and conditions of cultivation, harvesting 

and storage. This has been a challenge, owing to the lack of data based 

on established national good agricultural practices and/or good collection 

practices for medicinal plants. In 2003, WHO published the WHO guidelines 

on good agricultural and collection practices (GACP) for medicinal 

plants, which provide general technical guidance on obtaining medicinal 

plant materials of good quality for the sustainable production of herbal 

medicines in the overall context of quality assurance and control of herbal 

medicines. It is hoped that these guidelines will facilitate the development 

of GACP monographs on specifi c medicinal plants at national level, 

which in turn should bridge the current information gap in this area. 

Purpose and content of monographs 

The purpose of the monographs was clearly explained in the introduction 

to volume 1, and it is unnecessary to repeat it here. But I would like to 

emphasize again that the word “monograph” is used as a technical term 

only. It does not have the same meaning as “monograph” in any type of 

pharmacopoeia. In addition, I must reaffi rm that this publication is not 

intended to replace any offi cial compendia such as pharmacopoeias, formularies 

or legislative documents. 

It should also be emphasized that the descriptions included in the section 

on medicinal uses should not be taken as implying WHO’s offi cial 

endorsement or approval. They merely represent the systematic collection 

of scientifi c information available at the time of preparation, for the 

purpose of information exchange. 

Dr Xiaorui Zhang 

Coordinator 

Traditional Medicine 

Department of Technical Cooperation for Essential Drugs 

and Traditional Medicine 

World Health Organization 

Geneva, Switzerland 

Introduction 

3

General technical notices 

These WHO monographs are not pharmacopoeial monographs. Their 

purpose is to provide scientifi c information on the safety, effi cacy and 

quality control/quality assurance of widely used medicinal plants, in order 

to facilitate their appropriate use in WHO’s Member States; to provide 

models to assist WHO’s Member States in developing their own 

monographs or formularies for these and other herbal medicines; and to 

facilitate information exchange among WHO’s Member States. 

The format used for volume 3 essentially follows that of volume 2. 

However, to keep relevant sections together, Adverse reactions appears 

immediately after the section on Pharmacology. The titles of three categories 

under the Medicinal uses have been changed to the following: 

• Uses supported by clinical data 

• Uses described in pharmacopoeias and well established 

documents 

• Uses described in traditional medicine 

The Defi nition provides the Latin binomial name, the most important 

criterion in quality assurance. Latin binomial synonyms and vernacular 

names, listed in Synonyms and Selected vernacular names respectively, 

are names used in commerce or by local consumers. The monographs 

place outdated botanical nomenclature in the synonyms category, based 

on the International Code of Botanical Nomenclature. The vernacular 

names comprise an alphabetical list of selected names from individual 

countries worldwide, in particular from areas where the medicinal plant 

is in common use. They refer to the medicinal plant itself not the medicinal 

plant part, which is identical to the monograph name. The lists 

are not complete, but refl ect the names of the concerned medicinal plant 

appearing in the offi cial monographs and reference books consulted and 

those in the Natural Products Alert (NAPRALERT) database (a database 

of literature from around the world on ethnomedical, biological 

and chemical information on medicinal plants, fungi and marine organisms, 

located at the WHO Collaborating Centre for Traditional 

Medicine at the University of Illinois at Chicago, Chicago, IL, USA). 

While every effort has been made to delete names referring to the 

5


medicinal plant part, the relevant section of each monograph may still 

include these. 

Geographical distribution is not normally found in offi cial compendia, 

but is included here to provide additional quality assurance information. 

The detailed botanical description under Description is intended for quality 

assurance at the stages of production and collection; the description of 

the crude drug material under Plant material of interest is for the same 

purpose at the manufacturing and commerce stages. 

General identity tests, Purity tests and Chemical assays are all normal 

compendial components included under those headings in these monographs. 

Where purity tests do not specify accepted limits, those limits 

should be set in accordance with national requirements by the appropriate 

authorities of Member States. 

Each medicinal plant and the specifi c plant part used as crude drug 

material contain active or major chemical constituents with a characteristic 

profi le that can be used for chemical quality control and quality assurance. 

These constituents are described in the Major chemical constituents. 

Descriptions included in Medicinal uses should not be taken as implying 

WHO’s offi cial endorsement or approval for such uses. They merely 

represent the systematic collection of scientifi c information available at 

the time of preparation, for information exchange. 

The fi rst category, Uses supported by clinical data, includes medical 

indications that are well established in some countries and have been validated 

by clinical studies documented in the scientifi c literature. Clinical 

trials may be controlled, randomized, double-blind studies, open trials, 

cohort studies or well documented observations on therapeutic applications. 

The second category, Uses described in pharmacopoeias and well established 

documents, includes medicinal uses that are well established in 

many countries and are included in offi cial pharmacopoeias or governmental 

monographs. Uses having a pharmacologically plausible basis are 

also included, as well as information resulting from clinical studies that 

clearly need to be repeated because of confl icting results. 

The third category, Uses described in traditional medicine, refers to 

indications described in unoffi cial pharmacopoeias and other literature, 

and to traditional uses. Their appropriateness could not be assessed, because 

suffi cient data to support the claims could not be found in the literature. 

Traditional uses that address severe pathologies, such as cancer, 

AIDS, hepatitis, etc., as they relate to these modern biomedical terms, 

should only be included under the third heading if pharmacological data 

6


or robust ethnopharmacological/ethnobotanical reports are available to 

support the claims. 

The Experimental pharmacology section includes only the results of 

investigations that prove or disprove the cited medicinal uses. Abbreviated 

details of the best-performed studies have been included in this section. 

Other published experimental data that are not associated with the 

medicinal uses have not been included, to avoid confusion. 

The details included in the References have been checked against the 

original sources wherever possible. For references in languages other than 

English, except for those in Chinese and Japanese, the title is given in the 

original language, except in cases where an English summary is available. 

7

Fructus Ammi Majoris 

Defi nition 

Fructus Ammi Majoris consists of the dried ripe fruits of Ammi majus L. 

(Apiaceae) (1, 2). 

Synonyms 

Apium ammi Crantz, Selinum ammoides E.H.L. Krause (3). Apiaceae are 

also known as Umbelliferae. 

Selected vernacular names 

Aatrilal, ammi commun, bishop’s weed, bullwort, crow’s foot, cumin 

royal, devil’s carrot, gazar el-shitan, greater ammi, habab, herb william, 

hirz al-shayateen, khella shaitani, khellah shitany, mayweed, nounkha, 

qciba, rejl el-ghorab, rijl al-tair, zfenderi el maiz (1, 2, 4–6). 

Geographical distribution 

Indigenous to Egypt, and widely distributed in Europe, the Mediterranean 

region and western Asia. Cultivated in India (2). 

Description 

An annual, 0.9–1.5 m high with striated subglaucous stems. Leaves 

acutely serrulate, alternate, bipinnate, lobes oblong. Infl orescence a 

compound umbel with slender primary rays up to 5 cm long, scattered 

secondary rays 2–5 cm long, minute reticulate points; involucre of 

bracts 1.5–2.5 cm long; fl owers bisexual, polygamous, bracteate; calyx 

teeth obsolete or small; petals obovate with an infl exed point, exterior 

petals frequently longer; stamens epigynous; ovary inferior, two-locular, 

stigma capitate. Fruit laterally compressed, oblong, mericarps of 

the cremocarp separated by a carpophore. Seed small, pendulous, 

albuminous (2). 

9

WHO monographs on selected medicinal plants 

Plant material of interest: dried ripe fruits 

General appearance 

Cremocarp nearly cylindrical, usually separated into its two mericarps, 

rarely entire, with a part of the pedicel attached. Mericarp small, slightly 

concave on the commissural side, slightly tapering towards the apex; 

2.0–2.5 mm long, 0.75 mm wide, reddish-brownish to greenish-brown, 

crowned with a nectary, disc-like stylopod. Externally glabrous, rough, 

marked with fi ve broad, distinct, yellowish-brown primary ridges, alternating 

with four equally prominent, dark brown secondary ridges. 

Internally comprises a pericarp with six vittae, four in the dorsal and 

two in the commissural side, and a large orthospermous endosperm in 

which is embedded a small apical embryo. Carpophore forked, each 

branch entering at the apex of the mericarp and uniting with the 

raphe (1, 2). 

Organoleptic properties 

Odour: slightly aromatic, terebinthinate; taste: aromatic, strongly pungent, 

slightly bitter (1). 

Microscopic characteristics 

Epidermis of the pericarp consists of polygonal cells, with straight anticlinal 

walls and short papillae, containing cluster or prismatic crystals of 

calcium oxalate, and covered with a strongly striated cuticle; stomata, occasionally 

of the anisocytic type, but with no trichomes. Mesocarp consists 

of brownish parenchyma; traversed longitudinally by six large schizogenous 

vittae, four in the dorsal and two in the commissural side, which 

appear elliptical in transverse section, each surrounded by large, radiating 

cells; traversed in the primary ridges by vascular bundles, which appear 

oval, ovoid or rounded in transverse section, not accompanied by vittae, 

each bundle with a xylem strand and two lateral phloem strands, and accompanied 

by strongly lignifi ed fi bres and reticulate, lignifi ed cells. Innermost 

layer consists of large, polygonal, brown-walled cells, with thick, 

non-porous inner walls. Endocarp composed of narrow, tangentially 

elongated cells, many in regular arrangements in variously oriented groups 

(e.g. parquet arrangement), adhering to the brown seed coat, which is 

formed of similar but wider and shorter cells. Endosperm consists of 

polygonal, thick-walled, cellulosic parenchyma, containing fi xed oil and 

several aleurone grains, 4–12 μm in diameter, each with one or two rounded 

globoid and one or two microrosette crystals of calcium oxalate, 2– 

5 μm in diameter. Carpophore, each branch traversed by a vascular bundle 

of fi bres and spiral vessels (1, 2, 7). 

10

Powdered plant material 

Yellowish-brown and characterized by fragments of epicarp with polygonal, 

subrectangular or elongated, short, papillose cells, containing cluster 

or prismatic crystals of calcium oxalate, and covered with thick, distinctly 

striated cuticle. Also present are fragments of mesocarp with brownish 

pieces of vittae, reticulate cells, vessels and fi bres; fragments of endocarpal 

cells with a distinct parquet arrangement, usually adhering to brown cells 

of the testa; numerous fragments of the endosperm containing colourless, 

polygonal cells, numerous oil globules and several aleurone grains, 4– 

12 μm in diameter, each enclosing microrosette crystals of calcium oxalate, 

2–5 μm in diameter. Trichomes and starch grains absent (1, 2). 

General identity tests 

Macroscopic and microscopic examinations, microchemical tests (1, 2), 

and thin-layer chromatography for the presence of xanthotoxin and bergapten 

(8). 

Purity tests 

Microbiological 

Tests for specifi c microorganisms and microbial contamination limits are 

as described in the WHO guidelines on quality control methods for medicinal 

plants (9). 

Total ash 

Not more than 7% (1, 2). 

Acid-insoluble ash 

Not more than 0.04% (2). 

Water-soluble extractive 

Not less than 17% (2). 

Alcohol-soluble extractive 


Loss on drying 

Not more than 12% (1). 


Pesticide residues 

The recommended maximum limit of aldrin and dieldrin is not more than 

0.05 mg/kg (10). For other pesticides, see the European pharmacopoeia 

(10), and the WHO guidelines on quality control methods for medicinal 

plants (9) and pesticide residues (11). 

11


Heavy metals 

For maximum limits and analysis of heavy metals, consult the WHO 

guidelines on quality control methods for medicinal plants (9). 

Radioactive residues 

Where applicable, consult the WHO guidelines on quality control methods 

for medicinal plants (9) for the analysis of radioactive isotopes. 

Other purity tests 

Chemical, foreign organic matter and sulfated ash tests to be established 

in accordance with national requirements. 

Chemical assays 

Contains not less than 0.5% xanthotoxin, 0.3% imperatorin and 0.01% 

bergapten, determined by spectrophotometry (1). A high-performance liquid 

chromatography method is also available for quantitative analysis 

(12). 

Major chemical constituents 

The major constituents are furanocoumarins, the principal compounds 

being xanthotoxin (methoxsalen, 8-methoxypsoralen (8-MOP) ammoidin; 

up to 1.15%), imperatorin (ammidin; up to 0.75%) and bergapten 

(heraclin, majudin, 5-methoxypsoralen (5-MOP), up to 1.88%). Other 

coumarins of signifi cance are marmesin (up to 0.25%), isoimperatorin 

(0.01%), heraclenin (0.07%) and isopimpinellin (0.01%). Other constituents 

of interest are acetylated fl avonoids (13–17). The structures of 

xanthotoxin, imperatorin and bergapten are presented below. 

O 

Medicinal uses 

Uses supported by clinical data 

Treatment of skin disorders such as psoriasis and vitiligo (acquired leukoderma) 

(1, 5, 18–26). 

Uses described in pharmacopoeias and well established documents 

Treatment of vitiligo (1). 

12 

R2 

R1 

O 

O 

furanocoumarins 

bergapten 

imperatorin 

xanthotoxin 

R1 

OCH 3 

H 

H 

R2 

H 

O-CH 2-CH=C(CH 3) 2 

OCH 3


Uses described in traditional medicine 

As an emmenagogue to regulate menstruation, as a diuretic, and for treatment 

of leprosy, kidney stones and urinary tract infections (6). 

Pharmacology 

Experimental pharmacology 

Antimicrobial and antischistosomal activities 

A 50% dilution of an acetone or 95% ethanol extract of Fructus Ammi 

Majoris inhibited the growth of the fungus Neurospora crassa in vitro 

(27). Intragastric administration of 400.0 mg/kg body weight (bw) of a 

hot aqueous extract or 15.0 mg/kg bw of a petroleum ether extract of the 

fruits per day for 6 days reduced the Schistosoma mansoni worm burden 

in mice by 49.3–72.3% (15). 

Miscellaneous effects 

Intragastric administration of 500.0 mg/kg bw of the powdered fruits per 

day to rats for 4 weeks did not reduce the incidence of glycolic acidinduced 

kidney stones (28). 

Photosensitizing effects 

Xanthotoxin is available in synthetic form and is a known photosensitizing 

agent and antipsoriatic. The augmented sunburn reaction involves excitation 

of the drug molecule by radiation in the long-wave ultraviolet 

(UV) A range. The transfer of energy to the drug molecule produces a 

triplet electronic state. The excited molecule then binds covalently with 

cutaneous DNA, forming a cyclobutane ring with the DNA pyrimidine 

bases, within the epidermal cells of the skin. In this manner, xanthotoxin 

inhibits nuclear division and cell proliferation (21, 22, 29). 

Toxicology 

Intoxication due to the simultaneous ingestion of ergot alkaloids from 

Claviceps purpurea sclerotia and furanocoumarins from Ammi majus 

seeds was reported in pigs after ingestion of contaminated feed. Nervous 

system intoxication was fi rst observed 5–7 days after the initiation of 

feeding of the suspect rations. This was followed by cutaneous irritation, 

including snout ulcers, eyelid oedema and conjunctivitis. Ten days after 

the feeding, eight abortions were observed and, in nursing sows, udder 

oedema and teat cracking were observed. Examination of the adulterated 

feed indicated that it contained 2.2% A. majus seeds and 0.14% 

C. purpurea sclerotia. Quantitative analysis showed the presence of 3.2 g 

of xanthotoxin and 0.65 g of imperatorin per 100 g of A. majus seeds, and 

0.73 g of ergot alkaloids per 100 g of C. purpurea sclerotia (30). 

13


The median lethal doses (LD 50 ) of xanthotoxin, imperatorin and bergapten 

injected into the ventral lymph sac of toads were 13.8 mg/100 g 

bw, 14.0 mg/100 g bw and 32.0 mg/100 g bw, respectively. In rats, the intramuscular 

LD 50 values were 16.0 mg/kg bw, 33.5 mg/kg bw and 94.5 mg/ 

kg bw, respectively (31). 

After 4–8 days of administration of 2 g of A. majus seeds per day to 3- 

to 5-week-old goslings in the diet, the animals became photosensitive. 

Photosensitivity appeared after 4–5 hours of exposure to sunlight and was 

characterized by erythema, haematomas and blisters on the upper side of 

the beak (32). The photoirritant effects of fi ve constituents of A. majus 

seeds, xanthotoxin, imperatorin, isopimpinellin, bergapten and isoimperatorin, 

were evaluated in the mouse-ear assay. Isoimperatorin was the most 

irritant compound (median irritant dose (ID 50 ) 0.0072 mg after 5 days of 

treatment), while imperatorin was the least irritant (ID 50 0.3823 mg after 

6 days of treatment). The three other compounds showed minimal 

photoirritant activity (33). 

Chronic toxicity in the form of decreases in the red blood cell count 

and haemoglobin A concentration was observed in mice after administration 

of 100.0 mg/kg bw of a 95% ethanol extract of the fruits in drinkingwater 

(34). Administration of 6.2–18.9 g/kg bw of the fruits per day in the 

diet to cattle and sheep for 49 days caused photosensitization in both species 

(35). Ingestion of A. majus seeds together with exposure to sunlight 

caused mydriasis in geese and ducks (36). Chronic 7-week exposure of 

ducks and geese to the fruits (dose not specifi ed) caused severe deformities 

of the beak and footwebs, mydriasis and ventral displacement of the pupils 

(37, 38). Ophthalmological examination of the animals revealed dense pigmentation 

in the fundus (pigmentary retinopathy) and hyperplasia of the 

retinal pigment epithelium (36, 39). The iris showed varying degrees of 

atrophy of the sphincter pupillae (36). 

Intragastric administration of a single dose of 8.0 g/kg bw of the fruits 

to sheep produced cloudy cornea, conjunctivokeratitis, photophobia and 

oedema of the muzzle, ears and vulva (40). Intragastric administration of 

2.0 g/kg or 4.0 g/kg bw per day produced similar symptoms after 72– 

96 hours (40). 

Clinical pharmacology 

Numerous clinical trials have assessed the effi cacy of Fructus Ammi 

Majoris and xanthotoxin for the treatment of vitiligo, psoriasis and hypopigmentation 

tinea versicolor (18–20, 41–44). 

The powdered fruits (dose not specifi ed) were administered orally to 

leukodermic patients, who then exposed the affected patches to direct 

sunlight for 1 hour. The patients subsequently developed symptoms of 

14


itching, redness, oedema, vesiculation and oozing in the leukodermic 

patches. A few days later the affected skin gradually started to display 

deep brown pigmentation. Repigmentation usually developed within 

1 week, in a punctate or perifollicular fashion, spreading inwards from 

the margin or diffuse (5). In a small clinical trial without controls, two 

groups of eight patients with leukoderma were treated orally with 0.05 g 

of xanthotoxin three times per day or in the form of a liniment, 

1 g/100 ml, applied to the skin. The patients then exposed the leukodermic 

areas to the sun for 0.5 hour or to UV light for 2 minutes, gradually 

increasing to 10 minutes, per day. After treatment, the leukodermic skin 

areas were infl amed and vesiculated, and were treated as second-degree 

burns. When healing occurred these areas began to show normal 

pigmentation (19). 

Since 1966, over 100 clinical studies have investigated the safety and 

effi cacy of xanthotoxin for the treatment of a wide range of ailments including 

vitiligo and psoriasis, in a variety of dosage forms and routes of 

administration. The drug is now accepted as standard medical therapy for 

the symptomatic control of severe, recalcitrant, disabling psoriasis that 

does not respond to other therapy, diagnosis being supported by biopsy. 

Xanthotoxin should be administered only in conjunction with a schedule 

of controlled doses of long-wave UV radiation. It is also used with longwave 

UV radiation for repigmentation of idiopathic vitiligo (29). While a 

review of all the clinical studies is beyond the scope of this monograph, 

some of the more recent data are presented below. 

A comparative trial involving 34 patients with plaque psoriasis assessed 

the effi cacy of xanthotoxin administered by two different routes in combination 

with exposure to UV-A light. Each group of 17 patients was treated 

with the drug delivered either orally or in bath-water. Both treatments 

were effective; however, bath treatments were as effective or more effective 

than oral treatment and required less than half the dose of UV-A radiation 

required in the oral treatment group. Bath treatments also caused fewer 

side-effects (26). 

A randomized, double-blind, right-left comparison trial investigated 

the effi cacy of a combination of xanthotoxin plus UV-A radiation with 

topical calcipotriol in the treatment of vitiligo. Nineteen patients with 

bilateral symmetrical lesions were treated with an oral dose of 0.6 mg/kg 

bw of xanthotoxin 2 hours before exposure to sunlight three times per 

week. The patients were instructed to apply calcipotriol ointment at 

50 μg/g on one side of the body and placebo ointment on the other. At the 

end of 6 months, 70% of patients showed signifi cant improvement on the 

calcipotriol-treated side as compared with 35% on the placebo-treated 

15


side (P < 0.05). It was concluded that the combination of xanthotoxin and 

calcipotriol is highly effective for the photochemotherapy of vitiligo (25). 

A randomized comparison trial assessed the effi cacy of xanthotoxin plus 

exposure to either UV-A or UV-B radiation for the treatment of plaque 

psoriasis in 100 patients. Both treatments were effective in reducing the 

number of plaques; no signifi cant difference between the treatments was 

observed (24). 

The effi cacy of two UV-A radiation dosage regimens for treatment with 

oral administration of 0.6 mg/kg bw of xanthotoxin plus UV-A photochemotherapy 

for moderate–severe chronic plaque psoriasis was assessed 

using a half-body comparison. The high- and low-dose UV-A treatments 

were administered twice per week and symmetrical plaques were scored to 

determine the rate of resolution for each treatment. Patients were reviewed 

monthly for 1 year and 33 patients completed the study. Both regimens were 

effective and well tolerated; 42% of patients were clear 1 year after treatment 

and, for those whose psoriasis had recurred, there was no signifi cant 

difference between the regimens in the number of days of remission (23). 

In a clinical trial without controls, the effi cacy of xanthotoxin in 

10-mg capsules was assessed for the treatment of psoriasis, vitiligo and tinea 

versicolor (43). Fifty-three patients were treated orally with 0.25 mg/kg bw 

of xanthotoxin and then exposed to UV-A light for varying periods of time. 

In 87% of psoriasis patients, remission occurred after 30 treatments with 

xanthotoxin and UV-A, 85% of patients with vitiligo had acceptable repigmentation 

after 70 treatments, and 100% of patients with hypopigmentation 

tinea versicolor showed complete repigmentation after 

12 treatments (43). 

Exposure to Fructus Ammi Majoris or xanthotoxin in combination with 

exposure to UV-A light elicits a cutaneous infl ammation, including erythema, 

oedema and bullae. The infl ammatory processes culminate after 72 hours 

and hyperpigmentation appears after 1–2 weeks, lasting for several months. 

The mechanism of repigmentation is still a matter of debate. Affected cells 

may include keratinocytes, Langerhans cells and melanocytes in the epidermis 

as well as mononuclear and endothelial cells in the upper dermis. Epidermal 

changes include dyskeratosis, mild spongiosis and intracellular oedema 

at 24 hours, increasing at 72 hours. After 72 hours there is an increased 

mitotic activity in melanocytes and an increased number of functional melanocytes, 

with rises in the production of melanosomes and tyrosinase activity 

(45). Hyperpigmentation is due to the increased number of melanin 

granules in the epidermis, both in the Malpighian stratum and in the hyperkeratotic 

stratum corneum (46, 47). 

16


Adverse reactions 

One case of phototoxic dermatitis was reported in a patient with vitiligo 

after ingestion of Fructus Ammi Majoris (48). One case of allergic rhinitis 

and contact urticaria due to exposure to the fruits was reported (49). Phototoxic 

reactions were reported in subjects who handled the fruits and 

were subsequently exposed to sunlight. Erythema developed within 48– 

72 hours and persisted for several days. Skin that had been protected from 

sunlight for 30 days after exposure still had many erythematous areas and 

became irritated again when re-exposed to the sun. Small areas of darker 

pigmentation developed in the skin of some subjects (35). Prolonged use 

or overdose may cause nausea, vertigo, constipation, lack of appetite, 

headache, allergic symptoms and sleeplessness (50). 

Photochemotherapy combining administration or application of xanthotoxin 

with UV-light treatment can be repeated many times (four times 

a week), and after about 14 days of therapy, a clear dilution of the epidermis 

results, cornifi cation normalizes and the infl ammation fades away. 

However, overdosage may result in severe erythema and blistering. This 

can partly be prevented through the application of β-carotene (51). 

A 5-year prospective study of ophthalmological fi ndings in 1299 patients 

treated with oral xanthotoxin plus UV photochemotherapy for 

psoriasis failed to demonstrate a signifi cant dose-dependent increase in 

the risk of developing cataracts (52). 

Other adverse reactions reported after treatment with xanthotoxin include 

itching, nausea, oedema, hypotension, nervousness, vertigo, depression, 

painful blistering, burning and peeling of the skin, pruritus, freckling, 

hypopigmentation, rash, cheilitis and erythema (29). 

Contraindications 

Fructus Ammi Majoris is contraindicated in diseases associated with 

photosensitivity, cataract, invasive squamous-cell cancer, known sensitivity 

to xanthotoxin (psoralens), and in children under the age of 

12 years (29). The fruits are also contraindicated in pregnancy, nursing, 

tuberculosis, liver and kidney diseases, human immunodefi ciency virus 

(HIV) infections and other autoimmune diseases (22). 

Warnings 

Care should be taken where there is a familial history of sunlight allergy 

or chronic infections; lotions should be applied only under direct supervision 

of a physician and should not be dispensed to the patient; for use 

only if response to other forms of therapy is inadequate. Serious burns 

17


may result from exposure to UV-A light or sunlight, even through glass, 

if the correct dose and exposure schedule is not maintained. 

If burning, blistering or intractable pruritus occurs, discontinue therapy 

until side-effects subside. Do not sunbathe for at least 24 hours prior 

to therapy and 48 hours after. Avoid direct and indirect sunlight for up to 

8 hours after oral and 12–48 hours after topical treatment. If sunlight cannot 

be avoided, protective clothing and/or sunscreen must be worn. Following 

oral therapy, sunglasses must be worn for 24 hours. Avoid the ingestion 

of foods that contain furanocoumarins, such as limes, fi gs, parsley, 

celery, cloves, lemons, mustard and carrots (29). 

Precautions 

Drug interactions 

The toxicity of Fructus Ammi Majoris may be increased when the fruits 

are administered with other photosensitizing agents such as coal tar, dithranol, 

griseofulvin, nalidixic acid, phenothiazines, sulfanilamides, tetracyclines 

and thiazides (22, 29). 

Carcinogenesis, mutagenesis, impairment of fertility 

A 95% ethanol extract of Fructus Ammi Majoris, 10.0 mg/plate, was not 

mutagenic in the Salmonella/microsome assay using S. typhimurium 

strains TA98 and TA102. Furthermore, an infusion of the fruits (concentration 

not specifi ed) had antimutagenic effects against ethyl methanesulfonate- 

or 2-amino-anthracene-induced mutagenicity in S. typhimurium 

strains TA98 and TA100 (53). 

A study of 4799 Swedish patients who received xanthotoxin/UV-A 

photochemotherapy in the period 1974–1985 showed a dose-dependent 

increase in the risk of squamous-cell cancer of the skin. Male patients who 

had received more than 200 treatments had over 30 times the incidence of 

squamous-cell cancer compared with the general population. Increases in 

the incidence of respiratory cancer, pancreatic cancer and colon cancer 

were also found (54). 

Pregnancy: non-teratogenic effects 

See Contraindications. 

Nursing mothers 


Paediatric use 


18


Other precautions 

No information available on general precautions or precautions concerning 

drug and laboratory test interactions; or teratogenic effects in pregnancy. 

Dosage forms 

Powdered dried fruits for oral use (1). Store in a tightly sealed container 

away from heat and light. 

Posology 

(Unless otherwise indicated) 

Average daily dose: Fructus Ammi Majoris 0.02–0.04 g orally in divided 

doses (dosage schedule not specifi ed) (1); xanthotoxin 0.25–0.7 mg/kg bw 

(18, 20, 43). Clinical treatment requires management by a health-care provider. 

References 

1. Egyptian pharmacopoeia. Vol. 2, 3rd ed. Cairo, General Organization for 

Government Printing, 1972. 

2. Central Council for Research in Unani Medicine. Standardisation of single 

drugs of Unani medicine – Part I. New Delhi, Ministry of Health and Family 

Welfare, 1987. 

3. Flora reipublicae popularis sinicae. Tomus 55. China, Science Press, 1985. 

4. Trabut L. Flore du nord de l’Afrique. [Flora of North Africa.] Algiers, Imprimeries 

La Typo-Lyto et Jules Carbonel Réunis, 1935. 

5. Hakim RE. Rediscovery of a treatment for vitiligo. Clio medica, 1969, 4:277– 

289. 

6. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of 

Illinois at Chicago, 9 February 2001 production (an online database available 

directly through the University of Illinois at Chicago or through the Scientifi 

c and Technical Network (STN) of Chemical Abstracts Services). 

7. Saber AH. Practical pharmacognosy, 2nd ed. Cairo, Al-Etemad Press, 1946. 

8. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas, 

2nd ed. Berlin, Springer, 1996. 

9. Quality control methods for medicinal plant materials. Geneva, World Health 

Organization, 1998. 

10. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996. 

11. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. 

Geneva, World Health Organization, 1997 (WHO/FSF/FOS/97.7; available 

from Food Safety, World Health Organization, 1211 Geneva 27, Switzerland). 

12. Ekiert H, Gomólka E. Coumarin compounds in Ammi majus L. callus cultures. 

Pharmazie, 2000, 55:684–687 

19


13. Abu-Mustafa EA, Fayez MBE. Natural coumarins. I. Marmesin and marmesinin, 

further products from the fruits of Ammi majus L. Journal of Organic 

Chemistry, 1961, 26:161–166. 

14. Hilal SH, Haggag MY. A thin-layer chromatography (TLC)-colorimetric assay 

of furocoumarins. Egyptian Journal of Pharmaceutical Sciences, 1975, 

16:495–499. 

15. Abdulla WA et al. Preliminary studies on the anti-schistosomal effect of 

Ammi majus L. Egyptian Journal of Bilharziasis, 1978, 4:19–26. 

16. Ivie GW. Linear furocoumarins (psoralens) from the seed of Texas Ammi 

majus L. (bishop’s weed). Journal of Agricultural and Food Chemistry, 1978, 

26:1394–1403. 

17. Singab ANB. Acetylated fl avonol triglycosides from Ammi majus L. Phytochemistry, 

1998, 49:2177–2180. 

18. El-Mofty AM. A preliminary clinical report on the treatment of leucodermia 

with Ammi majus Linn. Journal of the Royal Egyptian Medical Association, 

1948, 31:651–665. 

19. Fahmy IR, Abu-Shady H. The isolation and properties of ammoidin, ammidin 

and majudin, and their effect in the treatment of leukodermia. Quarterly 

Journal of Pharmacy and Pharmacology, 1948, 21:499–503. 

20. El-Mofty AM. Further study on treatment of leucodermia with Ammi majus 

Linn. Journal of the Royal Egyptian Medical Association, 1952, 35:1–19. 

21. Pathak MA, Worden LR, Kaufman KD. Effect of structural alterations on 

the photosensitizing potency of furocoumarins (psoralens) and related compounds. 

Journal of Investigative Dermatology, 1967, 48:103–118. 

22. Wagner H, Wisenauer M. Phytotherapie. [Phytotherapy.] Stuttgart, Gustav 

Fisher, 1995. 

23. Collins P et al. 8-MOP PUVA for psoriasis: a comparison of minimal phototoxic 

dose-based regimen with a skin-type approach. British Journal of Dermatology, 

1996, 135:248–254. 

24. De Berker DA et al. Comparison of psoralen-UVB and psoralen UVA photochemotherapy 

in the treatment of psoriasis. Journal of the American Academy 

of Dermatology, 1997, 36:577–581. 

25. Parsad D, Saini R, Verma N. Combination of PUVAsol and topical calcipotriol 

in vitiligo. Dermatology, 1998, 197:167–170. 

26. Cooper EJ et al. A comparison of bathwater and oral delivery of 8-methoxypsoralen 

in PUVA therapy for plaque psoriasis. Clinical and Experimental 

Dermatology, 2000, 25:111–114. 

27. Kubas J. Investigations on known or potential antitumoral plants by means 

of microbiological tests. Part III. Biological activity of some cultivated 

plant species in Neurospora crassa test. Acta Biologica Cracoviensa, Series 

Botanica, 1972, 15:87–100. 

28. Ahsan SK et al. Effect of Trigonella foenum-graecum and Ammi majus on 

calcium oxalate urolithiasis in rats. Journal of Ethnopharmacology, 1989, 

26:249–254. 

20


29. Lacy C et al. Drug Information Handbook, 6th ed. Hudson, OH, Lexicomp, 

2000. 

30. Lopez TA et al. Ergotism and photosensitization in swine produced by the 

combined ingestion of Claviceps purpurea sclerotia and Ammi majus seeds. 

Journal of Veterinary Diagnosis and Investigation, 1997, 9:68–71. 

31. Rastogi RR, Mehrota BN, eds. Compendium of Indian medicinal plants. Vol. 

I 1960–1969. Lucknow, Central Drug Research Institute and New Delhi, Publications 

and Information Directorate, 1991. 

32. Shlosberg A, Egyed MN, Eilat A. Comparative photosensitizing properties 

of Ammi majus and Ammi visnaga in goslings. Avian Diseases, 1974, 18:544– 

550. 

33. Saeed MA, Khan FZ. Studies on the contact dermatitic properties of indigenous 

Pakistani medicinal plants. Part V. Dermal irritating properties of Ammi 

majus seed constituents. Journal of the Faculty of Pharmacy, Gazi University, 

1994, 11:17–24. 

34. Shah AH et al. Toxicity studies on six plants used in the traditional Arab 

system of medicine. Phytotherapy Research, 1989, 3:25–29. 

35. Dollahite JW, Younger RL, Hoffman GO. Photosensitization in cattle and 

sheep caused by feeding Ammi majus (greater Ammi; bishop’s weed). American 

Journal of Veterinary Research, 1978, 39:193–197. 

36. Barishak YR et al. Histology of the iris in geese and ducks photosensitized 

by ingestion of Ammi majus seeds. Acta Ophthalmologica (Copenhagen), 

1975, 53:585–590. 

37. Egyed MN et al. Chronic lesions in geese photosensitized by Ammi majus. 

Avian Diseases, 1975, 19:822–826. 

38. Egyed MN et al. Acute and chronic manifestations of Ammi majus-induced 

photosensitisation in ducks. Veterinary Record, 1975, 97:193–199. 

39. Singer L et al. Methoxsalen-induced ocular lesions in ducks. Ophthalmic Research, 

1976, 8:329–334. 

40. Witzel DA, Dollahite JW, Jones LP. Photosensitization in sheep fed Ammi 

majus (bishop’s weed) seed. American Journal of Veterinary Research 1978, 

39:319–320. 

41. Parrish JA et al. Photochemotherapy of psoriasis with oral methoxsalen and 

longwave ultraviolet light. New England Journal of Medicine, 1974, 291:1207– 

1211. 

42. El-Mofty AM, El-Mofty M. Psoralen photochemotherapy in contrast to 

chemotherapy of psoriasis. Medical Journal of Cairo University, 1980, 48:71–83. 

43. El-Mofty AM, El-Sawalhy H, El-Mofty M. Clinical study of a new preparation 

of 8-methoxypsoralen in photochemotherapy. International Journal of 

Dermatology, 1994, 33:588–592. 

44. El-Mofty AM, El-Sawalhy H, El-Mofty M. Photochemotherapy in the treatment 

of post tinea versicolor hypopigmentation. Medical Journal of Cairo 

University, 1995. 

45. Kavli G, Volden G. Phytophotodermatitis. Photodermatology, 1984, 1:65– 

75. 

21


46. Becker SW. Psoralen phototherapeutic agents. Journal of the American Medical 

Association, 1967, 202:422–424. 

47. Rosario R. In Fitzpatrick TB et al., eds. Dermatology in general medicine, 

2nd ed. New York, NY, McGraw-Hill, 1979. 

48. Ossenkoppele PM, van der Sluis WG, van Vloten WA. Fototoxische dermatatis 

door het gebruik van de Ammi majus-vrucht bij vitiligo. [Phototoxic 

dermatitis following the use of Ammi majus fruit for vitiligo.] Nederlands 

Tijdschrift voor Geneeskunde, 1991, 135:478–480. 

49. Kiistala R et al. Occupational allergic rhinitis and contact urticaria caused by 

bishop’s weed (Ammi majus). Allergy, 1999, 54:635–639. 

50. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC 

Press, 1994. 

51. Bethea D et al. Psoralen photobiology and photochemotherapy: 50 years of 

science and medicine. Journal of Dermatological Science, 1999, 19:78–88. 

52. Stern RS, Parrish JA, Fitzpatrick TB. Ocular fi ndings in patients treated with 

PUVA. Journal of Investigative Dermatology, 1985, 85:269–273. 

53. Mahmoud I, Alkofahi A, Abdelaziz A. Mutagenic and toxic activities of several 

spices and some Jordanian medicinal plants. International Journal of 

Pharmacognosy, 1992, 30:81–85. 

54. Lindelof B et al. PUVA and cancer: a large-scale epidemiological study. 

Lancet, 1991, 338:91–93. 

22

Fructus Ammi Visnagae 

Defi nition 

Fructus Ammi Visnagae consists of the dried ripe fruits of Ammi visnaga 

(L.) Lam. (Apiaceae) (1–3). 

Synonyms 

Daucus visnaga L., Selinum visnaga E.H.L. Krause, Sium visnaga Stokes, 

Visnaga daucoides Gaertn. (2, 4). Apiaceae are also known as Umbelliferae. 


Ammi, besnika, bisagna, bishop’s weed, herbe aux cure-dents, herbe aux 

gencives, kella, kella balady, khelâl dandâne, khella, nunha, owoc keli, 

Spanish carrot, viznaga, Zahnstocherkraut (2, 5–8). 


Indigenous to the Mediterranean region. Cultivated in North America 

and in Argentina, Chile, Egypt, India, Islamic Republic of Iran, Mexico, 

Tunisia and Russian Federation (2, 5–7). 

Description 

An annual or biennial herb, up to 1.0 m high. Leaves dentate, in strips. 

Stems erect, highly branched. Infl orescence umbellate; rays, highly swollen 

at the base, become woody and are used as toothpicks. Fruits as described 

below (2, 6). 



Cremocarp usually separated into its mericarps; rarely, occurs entire with a 

part of the pedicel attached. Mericarp small, ovoid, about 2 mm long, 1 m 

wide, brownish to greenish-brown, with a violet tinge. Externally glabrous, 

marked with fi ve distinct, pale brownish, broad primary ridges, four inconspicuous, 

dark secondary ridges, and a disc-like stylopod at the apex. Internally 

comprises a pericarp with six vittae, four in the dorsal and two in the 

23


commissural side, a large oily orthospermous endosperm and a small apical 

embryo. Carpophore single, passing into the raphe of each mericarp (1, 2). 


Odour: slightly aromatic; taste: aromatic, bitter, slightly pungent (1, 2). 


Epidermis of the pericarp consists of polygonal cells, elongated on the ridges, 

with occasional crystals of calcium oxalate and fi nely striated cuticle, but 

no hairs. Mesocarp consists of parenchyma, traversed longitudinally by 

large, schizogenous vittae, each surrounded by large, slightly-radiating cells, 

and in the ridges by vascular bundles, each forming a crescent around a comparatively 

large lacuna and accompanied by fi bres and reticulate, lignifi ed 

cells. Innermost layer consists of large, polygonal, brown-walled cells, with 

thick, porous inner walls. Endocarp composed of narrow tangentially elongated 

cells, some of which are in regular arrangements in variously oriented 

groups, adhering to the brown seed coat, which is formed of similar but 

wider, shorter cells. Endosperm consists of polygonal, thick-walled, cellulosic 

parenchyma containing fi xed oil and numerous small, oval aleurone 

grains, each enclosing a minute, rounded globoid and a microrosette crystal 

of calcium oxalate. Carpophore, passing at the apex into the raphe of each 

mericarp, traversed by a vascular bundle of fi bres and spiral vessels (1, 2). 


Brown and characterized by fragments of pericarp with some brownish 

pieces of vittae, reticulate cells, vessels and fi bres. Also present are fragments 

with inner porous mesocarp cells crossed by and intimately mixed with 

variously oriented groups of endocarpal cells; and numerous fragments of 

endosperm. Other fragments show cells of the brown seed coat and aleurone 

grains 4–10 μm in diameter, containing microrosette crystals of calcium oxalate 

2–5 μm in diameter. Hairs and starch grains absent (1, 2). 


Macroscopic and microscopic examinations, microchemical tests (1–3), and 

thin-layer chromatography for the presence of khellin and visnagin (3, 6, 9). 

Purity tests 





24

Foreign organic matter 


Total ash 












Heavy metals 







Chemical, sulfated ash, water-soluble extractive and alcohol-soluble extractive 

tests to be established in accordance with national requirements. 


Contains not less than 1% γ-pyrones (furanochromone derivatives) calculated 

as khellin, determined by spectrophotometry (1–3). A number of 

high-performance liquid chromatography methods are also available for 

quantitative analysis (13–17). 


The major constituents are γ-pyrones (furanochromone derivatives; up to 

4%), the principal compounds being khellin (0.3–1.2%) and visnagin 

(0.05–0.30%). Other γ-pyrones of signifi cance are khellinol, ammiol, 

khellol and its glucoside khellinin (0.3–1.0%). A second group of major 

constituents are the coumarins (0.2–0.5%), the main one being the 

25


pyranocoumarin visnadin (0.3%). Essential oil contains camphor, 

α-terpineol and linalool, among others, and also fi xed oil (up to 18%) 

(6, 8, 13–15, 18, 19). Representative structures are presented below. 



None. 


As an antispasmodic, muscle relaxant and vasodilator (1). 


Treatment of mild anginal symptoms. Supportive treatment of mild obstruction 

of the respiratory tract in asthma, bronchial asthma or spastic 

bronchitis, and postoperative treatment of conditions associated with the 

presence of urinary calculi. Treatment of gastrointestinal cramps and 

painful menstruation (6). Internally as an emmenagogue to regulate menstruation, 

as a diuretic, and for treatment of vertigo, diabetes and kidney 

stones (8). 

Pharmacology 


Antimicrobial activities 

A 50% acetone, 50% aqueous or 95% ethanol extract of Fructus Ammi 

Visnagae inhibited the growth of the fungus Neurospora crassa in vitro 

26 

O 

H 3 C 

H 

R3 

R1 

H3C H3C O 

O 

CH3 O 

O 

H 

H 

R2 

visnadin 

O 

O CH 3 

O O O 

ammiol 

khellin 

khellinin 

khellinol 

khellol 

visnagin 

R1 R2 R3 

OCH3 OCH3 OCH 3 

OH 

H 

OCH3 O-Glc 

OH H 

OCH 3 

OH 

H 

OCH3 OCH3 H 

OCH 3 

H 

H 

Glc = 

HO 

HO 

OH 

O 

OH 

β-D-glucopyranosyl


(20). A 95% ethanol extract of the fruits inhibited the growth of Mycobacterium 

tuberculosis H37RVTMC 102 at a dilution of 1:40 in vitro (21). 

An aqueous extract of the fruits, 2–10 mg/ml inhibited growth and afl atoxin 

production by Aspergillus fl avus; the effects were dose-dependent 

(22). 

Antispasmodic effects 

A methanol extract of the fruits, 1.0 mg/ml, inhibited potassium chlorideinduced 

contractions in rabbit aorta in vitro (23). A chloroform extract of 

the fruits (concentration not specifi ed) inhibited potassium chlorideinduced 

contractions in guinea-pig aorta in vitro (24). Visnadin inhibited 

carbaminoylcholine- and atropine-induced contractions in isolated 

guinea-pig ileum at concentrations of 8.8 μmol/l and 0.02 μmol/l, respectively 

(25). Visnagin, 1.0 μmol/l, inhibited the contractile responses in rat 

aortic rings induced by potassium chloride, norepinephrine and phorbol 

12-myristate 13-acetate, and spontaneous myogenic contractions of rat 

portal veins. Visnagin appears to inhibit only contractions mediated by 

calcium entry through pathways with low sensitivity to classical calcium 

channel blockers (26, 27). 

Cardiovascular effects 

Visnadin, 60.0 μg/ml or 120.0 μg/ml, increased coronary blood fl ow in 

isolated guinea-pig hearts by 46% and 57% and blood fl ow in a Laewan- 

Trendelenburg frog vascular preparation by 78% and 147%, respectively 

(25). Interarterial administration of 10.0 mg/kg body weight (bw) of visnadin 

to anaesthetized dogs increased blood fl ow by 30–100%, the effect 

lasting for 20 minutes after administration (25). Six compounds isolated 

from the fruits were tested for their ability to dilate coronary blood vessels 

in rabbits. Coronary vasospasm and myocardial ischaemia were induced 

by daily intramuscular injections of vasopressin tannate. All compounds 

were administered at 4.7 mg/kg bw per day by intramuscular 

injection for 7 days. Visnadin, dihydrosamidin, khellin and samidin effectively 

normalized the electrocardiogram, while visnagin and khellol 

glucoside were inactive (28). Positive inotropic effects were observed in 

dogs treated with intramuscular injections of samidin and khellol glucoside. 

No effects were observed for visnadin, dihydrosamidin, khellin and 

visnagin at varying doses (28). 

Toxicology 

In mice, the oral and subcutaneous median lethal doses (LD 50 ) of the fruits 

were 2.24 g/kg bw and > 370.0 mg/kg bw, respectively (25). In rats, the 

oral LD 50 was > 4.0 g/kg bw, and in rabbits, the intravenous LD 50 was 

27


50.0 mg/kg bw. In dogs, the oral and intravenous LD 50 values were 

20.0 mg/kg bw and 200.0 mg/kg bw, respectively. 

Subchronic oral administration of visnadin to mice, rats and rabbits at 

doses of up to 2.2 g/kg bw, up to 600.0 mg/kg bw and 6.0 mg/kg bw, 

respectively, produced no pronounced toxicity (25). In dogs, daily intramuscular 

injections of isolated chemical constituents of the fruits at ten 

times the therapeutic concentration for 90 days produced toxic effects 

characterized by increases in the serum glutamic-pyruvic and glutamicoxaloacetic 

transaminases, increases in plasma urea, haematological 

changes and, in some cases, death. Of the six compounds tested, samidin 

was the most toxic, dihydrosamidin was the least toxic and khellin, visnagin, 

visnadin and khellol glucoside were of intermediate toxicity (29). The 

acute toxicities of khellin, visnagin, visnadin and samidin were assessed in 

mice and rats after intramuscular injection of doses of 0.316–3.16 mg/kg 

bw. The LD 50 values were: khellin, 83.0 mg/kg bw in mice and 309.0 mg/ 

kg bw in rats; visnagin, 123.0 mg/kg bw and 831.0 mg/kg bw; visnadin, 

831.8 mg/kg bw and 1.213 g/kg bw; and samidin, 467.7 mg/kg bw and 

1.469 g/kg bw (30). 

Administration of Ammi visnaga seeds at 1.25–3% in the diet for 

14 days had no toxic effects on turkeys or ducks. However, in chickens, 

the 3% dose produced mild signs of photosensitization within 6–8 days 

(31). Administration of 2.0 g/day for 4–8 days to goslings at age 3–5 weeks 

induced photosensitivity in the form of erythema, haematomas and blisters 

on the upper side of the beak (32). 

The chemical constituents responsible for the induction of contact 

dermatitis in the mouse-ear assay were khellol, visnagin and khellinol, 

median irritant doses 0.125 μg/5 μl, 1.02 μg/5 μl and 0.772 μg/5 μl, respectively 

(33). 


A placebo-controlled study assessed the effects of oral administration of 

50 mg of khellin four times per day for 4 weeks on the plasma lipids of 20 

non-obese, normolipaemic male subjects. Plasma lipids were measured 

every week during treatment and 1 week after cessation. Plasma total 

cholesterol and triglyceride concentrations remained unchanged, while 

high-density-lipoprotein cholesterol concentrations were signifi cantly elevated, 

the effect lasting until 1 week after cessation of treatment (34). 


Pseudoallergic reactions and reversible cholestatic jaundice have been reported 

(35). High oral doses of khellin (100.0 mg/day) reversibly elevated 

28

the activities of liver transaminases and γ-glutamyltransferase (35). Prolonged 

use or overdose may cause nausea, vertigo, constipation, lack of 

appetite, headache and sleeplessness (6). 


Fructus Ammi Visnagae is used in traditional systems of medicine as an 

emmenagogue (8), and its safety during pregnancy has not been established. 

Therefore, in accordance with standard medical practice, the 

fruits should not be used during pregnancy. 

Warnings 

No information available. 

Precautions 

General 

Exposure to sun or other sources of ultraviolet light should be avoided 

during treatment because khellin causes photosensitivity (35). 


No drug interactions have been reported. However, khellin is reported to 

inhibit microsomal cytochrome P450 subenzymes, and may therefore decrease 

the serum concentrations of drugs metabolized via this pathway, 

such as ciclosporin, warfarin, estrogens and protease inhibitors (36). 


A 95% ethanol extract of Fructus Ammi Visnagae, 10.0 mg/plate, was not 


strains TA98 and TA102. Furthermore, an infusion of the fruits had antimutagenic 

effects against ethyl methanesulfonate- or 2-amino-anthraceneinduced 

mutagenicity in S. typhimurium strains TA98 and TA100 (37). 

Khellin also inhibited the mutagenicity of promutagens such as benzopyrene, 

2-aminofl uorene and 2-aminoanthracene in S. typhimurium TA98. 

However, there was no effect on direct-acting mutagens, such as 2-nitrofl 

uorene, 4-nitro-o-phenylenediamine, in S. typhimurium TA100 (36). 

Pregnancy: teratogenic effects 

Intragastric administration of up to 600.0 mg/kg bw of visnadin to rats on 

days 8–12 of pregnancy produced no toxic effects (25). 




29



Owing to the lack of safety data, Fructus Ammi Visnagae should be taken 

internally only under the supervision of a health-care provider. 


Owing to the lack of safety data, Fructus Ammi Visnagae should be taken 



No information available on precautions concerning drug and laboratory 

test interactions. 

Dosage forms 

Dried fruits, infusions, extracts and other galenical preparations (35). 

Store fully dried fruits in well closed containers in a cool and dry place 

protected from light (1). 

Posology 


Average daily dose: Fructus Ammi Visnaga 0.05–0.15 g (1). 

References 



2. African pharmacopoeia. Vol. 1. Lagos, Organization of African Unity, Scientifi 

c, Technical and Research Commission, 1985. 

3. Homöopathisches Arzneibuch 2000. [Homoeopathic pharmacopoeia 2000.] 

Stuttgart, Deutscher Apotheker Verlag, 2000. 

4. Flora reipublicae popularis sinicae, Tomus 55. China, Science Press, 1985. 

5. Zargari A. [Medical plants, Vol. 2.], 4th ed. Tehran, Tehran University, 1989 

(Tehran University Publications, No. 181012) [in Farsi]. 


Press, 1994. 

7. Physician’s desk reference for herbal medicine. Montvale, NJ, Medical 

Economics Co., 1998. 







30








13. Martelli P et al. Rapid separation and quantitative determination of khellin 

and visnagin in Ammi visnaga (L.) Lam. fruits by high-performance liquid 

chromatography. Journal of Chromatography, 1984, 301:297–302. 

14. Franchi GG et al. High-performance liquid chromatography analysis of the 

furanochromones khellin and visnagin in various organs of Ammi visnaga 

(L.) Lam. at different developmental stages. Journal of Ethnopharmacology, 

1985, 14:203–212. 

15. El-Domiaty MM. Improved high-performance liquid chromatographic 

determination of khellin and visnagin in Ammi visnaga fruits and pharmaceutical 

formulations. Journal of Pharmaceutical Sciences, 1992, 81:475–478. 

16. Ganzera M, Sturm S, Stuppner H. HPLC-MS and MECC analysis of 

coumarins. Chromatographia, 1997, 46:197–203. 

17. Zgórka G et al. Determination of furanochromones and pyranocoumarins in 

drugs and Ammi visnaga fruits by combined solid-phase extraction-highperformance 

liquid chromatography and thin-layer chromatography-highperformance 

liquid chromatography. Journal of Chromato graphy A, 1998, 

797:305–309. 

18. Abou-Mustafa EA et al. A further contribution to the γ-pyrone constituents 

of Ammi visnaga fruits. Planta Medica, 1990, 56:134. 

19. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier, 

1995. 

20. Kubas J. Investigations on known or potential antitumoural plants by means 

of microbiological tests. Part III. Biological activity of some cultivated plant 

species in Neurospora crassa test. Acta Biologica Cracoviensia, Series Botanica, 

1972, 15:87–100. 

21. Grange JM, Davey RW. Detection of antituberculous activity in plant 

extracts. Journal of Applied Bacteriology, 1990, 68:587–591. 

22. Mahmoud A-LE. Inhibition of growth and afl atoxin biosynthesis of 

Aspergillus fl avus by extracts of some Egyptian plants. Letters in Applied 

Microbiology, 1999, 29:334–336. 

23. Rauwald HW, Brehm H, Odenthal KP. Screening of nine vasoactive medicinal 

plants for their possible calcium antagonist activity. Strategy of selection 

and isolation for the active principles of Olea europaea and Peucedanaum 

ostruthium. Phytotherapy Research, 1994, 8:135–140. 

24. Rauwald HW, Brehm H, Odenthal KP. The involvement of Ca 2+ channel 

blocking mode of action in the pharmacology of Ammi visnaga fruits. Planta 

Medica, 1994, 60:101–105. 

31


25. Erbring H, Uebel H, Vogel G. Zur Chemie, Pharmakologie und Toxicologie 

von Visnadin. [Chemistry, pharmacology, and toxicology of visnadine.] Arzneimittelforschung, 

1967, 17:283–287. 

26. Duarte J et al. Vasodilator effects of visnagin in isolated rat vascular smooth 

muscle. European Journal of Pharmacology, 1995, 286:115–122. 

27. Duarte J et al. Effects of visnadine on rat isolated vascular smooth muscles. 

Planta Medica, 1997, 63:233–236. 

28. Galal EE, Kandil A, Latif MA. Evaluation of cardiac inotropism of Ammi 

visnaga principles by the intra-ventricular technique. Journal of Drug Research 

of Egypt, 1975, 7:45–57. 

29. Kandil A, Galal EE. Short-term chronic toxicity of Ammi visnaga principles. 

Journal of Drug Research, 1975, 7:109–122. 

30. Galal EE, Kandil A, Latif MA. Acute toxicity of Ammi visnaga principles. 

Journal of Drug Research of Egypt, 1975, 7:1–7. 

31. Egyed MN, Shlosberg A, Eilat A. The susceptibility of young chickens, 

ducks and turkeys to the photosensitizing effect of Ammi visnaga seeds. 

Avian Diseases, 1975, 19:830–833. 

32. Shlosberg A, Egyed MN, Eilat A. Comparative photosensitizing properties 

of Ammi majus and Ammi visnaga in goslings. Avian Diseases, 1974, 18:544– 

550. 

33. Saeed MA, Khan FZ, Sattar A. Studies on the contact dermatitic properties of 

indigenous Pakistani medicinal plants. Part III. Irritant principles of Ammi 

visnaga L. seeds. Journal of the Faculty of Pharmacy, Gazi University, 1993, 

10:15–23. 

34. Harvengt C, Desager JP. HDL-cholesterol increase in normolipaemic subjects 

on khellin: a pilot study. International Journal of Clinical Pharmacology 

Research, 1983, 3:363–366. 

35. Blumenthal M et al., eds. The complete German Commission E monographs. 

Austin, TX, American Botanical Council, 1998. 

36. Schimmer O, Rauch P. Inhibition of metabolic activation of the promutagens, 

benzo[α]pyrene, 2-aminofl uorene and 2-aminoanthracene by furanochromones 

in Salmonella typhimurium. Mutagenesis, 1998, 13:385–389. 




32

Fructus Anethi 

Defi nition 

Fructus Anethi consists of the dried ripe fruits of Anethum graveolens L. 

(Apiaceae) (1, 2). 

Synonyms 

Pastinaca anethum Spreng., Peucedanum graveolens Benth. & Hook., 

Selinum anethum Roth (1, 3). Apiaceae are also known as Umbelliferae. 


Aneth, anethum, bo-baluntshep, dill, Dill-Fenchel, eneldo, faux anis 

aneth, fenouil bâtard, fenouil puant, garden dill, Gartendill, hinan, inondo, 

jirashi, kapor, kerwiya amya, koper, sadapa, sadhab el barr, satakuppa, 

satakuppi, sathukuppa, satpushpa, shabat, shabath, shatapuspi, shebet, 

shebid, sheved, shevid, shi ra ja, shibth, sibt, slulpha, soolpha, sova, sowa, 

s-sebt, suva, sulpha, sutopsha, thian ta takkataen, zira (1, 4–9). 


Indigenous to southern Europe. Cultivated widely throughout the world 

(1, 4, 5, 8, 10, 11). 

Description 

An aromatic annual or biennial herb, 40–120 cm high, with an erect hollow 

green stem, branching above. Leaves glaucous, tripinnate, with linear 

leafl ets. Infl orescence umbellate with 15–30 rays; bracts and bracteoles 

absent; fl owers yellow. Fruits deep brown, fl attened, oval, with protruding 

clear back ribs with sharp edges (1, 5, 11–13). 



Mericarps separate, broadly oval, chocolate-brown, each dorsally compressed, 

3–4 mm long, 2–3 mm wide and 1 mm thick, the ratio of length 

33


to width being approximately 1.6:1.0; two ventral ridges prolonged into 

wide yellowish membranous wings; three dorsal ridges, brown, inconspicuous. 

Transversely cut surface of the fruit surface shows six vittae, 

four in the dorsal and two in the commissural side; fi ve vascular bundles, 

three in the ridges and two in the wings, those in the wings being wider 

than those in the ridges (1, 4, 5). 


Odour: characteristic, aromatic; taste: characteristic, pleasant (1, 4, 5). 


Mericarp has four vittae in the dorsal and two in the commissural side. 

Outer epidermis has a striated cuticle. Mesocarp contains lignifi ed, reticulate 

parenchyma. Inner epidermis composed of tabular cells frequently 

with wavy walls, tabular cells all parallel (e.g. parquet arrangement). 

Thick-walled parenchyma of the endosperm contains fi xed oil, aleurone 

grains and microrosette crystals of calcium oxalate (1, 4, 14, 15). 


Greyish-brown powder characterized by fragments of pericarp with a 

few brownish pieces of vittae. Outer epidermis has striated cuticle. Mesocarp 

fragments show lignifi ed reticulate parenchyma, inner epidermis, 

tabular cells frequently wavy walled, numerous fragments of endosperm; 

aleurone grains, fi xed oil and microrosette crystals of calcium oxalate (1). 


Macroscopic and microscopic examinations (1, 2), and thin-layer chromatography 

(2). 

Purity tests 





Chemical 

Not less than 3.0% essential oil (2). 



34

Total ash 





Not less than 15.0% (2). 









Heavy metals 







Loss on drying test to be established in accordance with national requirements. 


Contains not less than 2.0% essential oil (1). Gas chromatography (19) 

and gas chromatography–mass spectrometry (20) methods for essential 

oil constituents are also available. 


Contains 2–5% essential oil, the major constituent of which is carvone 

(20–60%) (11, 21, 22). The carvone content in plants cultivated in India is 

reported to be 6% less than in those cultivated in Europe (9). Other characteristic 

terpenoid essential oil constituents include dihydrocarvone, 

1,8-cineole, p-cymene, limonene, α-phellandrene, α-pinene and α-terpinene. 

The fl avonoids present include kaempferol-glucuronide (22, 23). 

35


Dillapiol is found in the essential oil obtained from plants cultivated in 

Egypt, India and Japan (24). Representative structures are presented below. 

H 2 C 

H 3 C 

H 3 C 



None. 


Treatment of dyspepsia (25), gastritis and fl atulence (1, 26), and stomach 

ache (27). 


As an aphrodisiac, analgesic, antipyretic, diuretic, emmenagogue, galactagogue, 

appetite stimulant and vaginal contraceptive. Treatment of diarrhoea, 

asthma, neuralgia, dysuria, dysmenorrhoea, gallbladder disease, 

insomnia, hiatus hernia and kidney stones (9, 26–29). 

Pharmacology 


Antispasmodic and carminative activities 

A 50% ethanol extract of Fructus Anethi inhibited acetylcholine- and histamine-induced 

contractions of guinea-pig ileum in vitro (30). The essential 

oil, 50 mg/ml, reduced contractions of rabbit intestine (31). The essential 

oil (containing the monoterpenes and phenylpropanes: dillapiol, 

myristicin and isomyristicin) (concentration not specifi ed) acted as a mild 

carminative and stomachic (32). The essential oil had carminative activity 

and reduced foaming in vitro, median effective concentration 2.0% (33). 

Anti-infl ammatory and analgesic activities 

A single topical application of an ethanol extract of the fruits, at a dose 

corresponding to 1.0 mg/20 μl of a 10.0-mg dried methanol extract dissolved 

in 200.0 μl of ethanol, to the inner and outer surface of the ear of 

36 

H 

C H 3 

O 

C H 3 

a n d e n a n t i o m e r 

c a r v o n e 

C H 3 

H 2 C 

H 3 C 

H 

C H 3 

C H 3 

O 

C H 3 

C H 3 

1 , 8 - c i n e o l e 

H 3 C 

H 3 C 

H 

H 2 C 

H 3 C 

H 

O 

C H H 

3 H 3 C 

H 3 C 

H 

C H 3 

d i h y d r o c a r v o n e 

a n d e n a n t i o m e r 

C H 3 

a n d e n a n t i o m e r H 3 C 

p-cymene (+)-limonene (-)-α-phellandrene α-pinene α-terpinene 

H 

C H 3 

C H 3

mice inhibited ear infl ammation induced by 12-O-tetradecanoylphorbol- 

13 acetate by 60% (34). Ethyl acetate and hexane extracts of the fruits 

(concentration not specifi ed) were inactive in this assay. A 10% aqueous 

extract of the fruits and a 5% aqueous solution of the essential oil had 

analgesic effects in mice as assessed in the hot plate and acetic acid writhing 

tests. The action of the fruits at 1.0 g/kg body weight (bw) was comparable 

with that of acetylsalicyclic acid at 200.0 mg/kg bw (35). 

Miscellaneous effects 

Intravenous administration of 12.5 mg/kg bw of a 70% dried ethanol extract 

of the fruits, dissolved in normal saline, to dogs had a diuretic effect, 

with a 2.2-fold increase in urine output. Intravenous administration of 

25.0 mg/kg bw of a 70% ethanol extract to dogs reduced blood pressure. 

Intravenous administration of 4.0 μl/kg bw of the essential oil induced 

diuresis in dogs lasting 80 minutes, with increased sodium and calcium ion 

excretion (36). Intravenous administration of 5.0–10.0 mg/kg bw of a 5% 

seed oil in saline to cats increased respiration volume and lowered blood 

pressure; intraperitoneal administration of 35.0 mg/kg bw of the seed oil 

to guinea-pigs induced anaphylactic shock (11). A single intragastric dose 

of 250.0 mg/kg bw of a 50% ethanol extract of the fruits to fasted rats reduced 

blood glucose levels by 30% compared with controls (30). 

Toxicology 

In a report by a national regulatory authority “generally regarded as safe 

status” was granted to Fructus Anethi as a fl avouring agent in 1976 (37). 




Allergic reactions to Fructus Anethi including oral pruritus, tongue and 

throat swelling and urticaria, as well as vomiting and diarrhoea were reported 

in one patient with a history of allergic rhinitis (38). 


Traditionally, extracts of fruits (seeds) have been used as a contraceptive 

and to induce labour (4). Furthermore, extracts of the fruits may have 

teratogenic effects (39). Therefore, the use of Fructus Anethi during pregnancy 

and nursing is not recommended. 

Warnings 



37


Precautions 


A chloroform–methanol (2:1) extract of the fruits was not mutagenic in 

concentrations up to 100.0 mg/plate in the Salmonella/microsome assay 

using S. typhimurium strains TA98 and TA100, with or without metabolic 

activation. A 95% ethanol extract was also without mutagenic activity 

in the same test system (40). 

An essential oil prepared from the fruits was cytotoxic to human lymphocytes 

in vitro, and was active in the chromosome aberration and sister 

chromatid exchange tests in the same system. The oil was inactive in the 

Drosophila melanogaster somatic mutation and recombination test in vivo 

(41). 







drug interactions; drug and laboratory test interactions; teratogenic 

effects during pregnancy; or paediatric use. 

Dosage forms 

Dried fruits for teas, essential oil and other galenical preparations for internal 

applications. Store in a tightly sealed container away from heat and 

light. 

Posology 


Average daily dose: Fructus Anethi 3 g; essential oil 0.1–0.3 g; or equivalent 

for other preparations (25). 

References 



2. The Ayurvedic pharmacopoeia of India. Part I. Vol. II. New Delhi, Ministry 

of Health and Family Welfare, Department of Indian System of Medicine 

and Homeopathy, 1999. 

38


3. Issa A. Dictionnaire des noms des plantes en latin, français, anglais et arabe. 

[Dictionary of plant names in Latin, French, English and Arabic.] Beirut, 

Dar al-Raed al-Arabi, 1991. 

4. Trease GE. A text-book of pharmacognosy, 3rd ed. Baltimore, MD, Williams 

and Wilkins, 1939. 

5. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA, 

Blakiston, 1950. 

6. Zahedi E. Botanical dictionary. Scientifi c names of plants in English, French, 

German, Arabic and Persian languages. Tehran, Tehran University Publications, 

1959. 

7. Schlimmer JL. Terminologie médico-pharmaceutique et française-persane, 

2nd ed. [French-Persian medico-pharmaceutical terminology, 2nd ed.] 

Tehran, University of Tehran Publications, 1979. 

8. Namba T. The encyclopedia of Wakan-Yaku (Traditional Sino-Japanese 

medicines) with color pictures. Vol. II. Tokyo, Hoikusha Publishing, 1994. 


Illinois at Chicago, 10 January 2001 production (an online database available 

directly through the University of Illinois at Chicago or through the 

Scientifi c and Technical Network (STN) of Chemical Abstracts 

Services). 

10. Wren RC. Potter’s new cyclopedia of botanical drugs and preparations. Saffron 

Walden, CW Daniel, 1988. 

11. Leung AY, Foster S. Encyclopedia of common natural ingredients used in 

food, drugs and cosmetics. New York, NY, John Wiley and Sons, 1996. 

12. Launert E. Edible and medicinal plants of Britain and Northern Europe. 

London, Hamlyn Publishing Group, 1989. 




15. Wallis TE. Textbook of pharmacognosy, 4th ed. London, J & A Churchill, 

1960. 







19. Pino JA et al. Evaluation of fl avor characteristic compounds in dill herb 

essential oil by sensory analysis and gas chromatography. Journal of Agricultural 

and Food Chemistry, 1995, 43:1307–1309. 

20. Mahran GH et al. GC/MS analysis of volatile oil of fruits of Anethum 

graveolens. International Journal of Pharmacognosy, 1992, 30:139–144. 

21. Rao BS, Sudborough JJ, Watson HE. Notes on some Indian essential oils. 

Journal of the Indian Institute of Science, Series A, 1925, 8:143–188. 

39


22. Hodisan V, Pepescu H, Fagarasan E. [Studies on Anethum graveolens. I. II. 

Chemical composition of essential oil from fruits.] Contributii Botanice, 

Universitatea Babes-Bolyai, Cluj-Napoca [Botanical Contributions, Babes- 

Bolyai University, Cluj-Napoca], 1980, 1980:263–266 [in Romanian]. 

23. Racz G, Racz-Kotilla E, Szabo LG. Gyógynövényismeret – fi toterápia 

alapjai. [Pharmacognosy – basic elements of phytotherapy.] Budapest, 

Sanitas, 1992. 

24. Khafagy SM, Mnajed HK. Phytochemical investigation of the fruit of 

Egyptian Anethum graveolens. I. Examination of the volatile oil and isolation 

of dillapiole. Acta Pharmaceutica Suecica, 1968, 5:155–162. 



26. Singh VP, Sharma SK, Khare VS. Medicinal plants from Ujjain District 

Madhya Pradesh – part II. Indian Drugs and Pharmaceuticals Industry, 1980, 

5:7–12. 

27. Mokkhasmit M et al. Pharmacological evaluation of Thai medicinal plants. 

Journal of the Medical Association of Thailand, 1971, 54:490–504. 

28. Brückner C. In Mitteleuropa genützte Heilpfl anzen mit milchsekretionsfördernder 

Wirkung (Galactagoga). [The use of medicinal plants with 

lactation-stimulating activity (galactagogues) in Central Europe.] Gleditschia, 

1989, 17:189–201. 

29. Heinrich M, Rimpler H, Barrera NA. Indigenous phytotherapy of gastrointestinal 

disorders in a lowland Mixe community (Oaxaca, Mexico): ethnopharmacologic 

evaluation. Journal of Ethnopharmacology, 1992, 36:63– 

80. 

30. Dhar ML et al. Screening of Indian plants for biological activity: part I. 

Indian Journal of Experimental Biology, 1968, 6:232–247. 

31. Shipochliev T. [Pharmacological investigation into several essential oils. I. 

Effect on the smooth musculature.] Veterinarno-Meditsinski Nauki, 1968, 

5:63–69 [in Bulgarian]. 

32. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 4, 

Drogen A–D, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 4, 

Drugs A–D, 5th ed.] Berlin, Springer, 1992. 

33. Harries N, James KC, Pugh WK. Antifoaming and carminative actions of 

volatile oils. Journal of Clinical Pharmacology, 1978, 2:171–177. 

34. Okuyama T et al. Studies on cancer bio-chemoprevention of natural 

resources. X. Inhibitory effect of spices on TPA-enhanced 3 H-choline incorporation 

in phospholipids of C3H10T1/2 cells and TPA-induced mouse ear 

edema. Zhonghua Yaoxue Zazhi, 1995, 47:421–430. 

35. Racz-Kotilla E, Rotaru G, Racz G et al. Anti-nociceptive effect of dill 

(Anethum graveolens L.). Fitoterapia, 1995, 2:80–81. 

36. Mahran GH et al. Investigation of diuretic drug plants. 1. Phytochemical 

screening and pharmacological evaluation of Anethum graveolens L., 

Apium graveolens L., Daucus carota L. and Eruca sativa Mill. Phytotherapy 

Research, 1991, 5:169–172. 

40


37. GRAS status of foods and food additives. Federal Register, 1976, 41:38644. 

38. Chui AM, Zacharisen MC. Anaphylaxis to dill. Annals of Allergy, Asthma 

and Immunology, 2000, 84:559–560. 

39. Nath D et al. Commonly used Indian abortifacient plants with special reference 

to their teratologic effect in rats. Journal of Ethnopharmacology, 1992, 

36:147–154. 

40. Rockwell P, Raw I. A mutagenic screening of various herbs, spices, and food 

additives. Nutrition and Cancer, 1979, 1:10–15. 

41. Lazutka JR et al. Genotoxicity of dill (Anethum graveolens L.), peppermint 

(Mentha piperita L.) and pine (Pinus sylvestris L.) essential oils in human 

lymphocytes and Drosophila melanogaster. Food and Chemical Toxicology, 

2001, 39:485–492. 

41

42 

Aetheroleum Anisi 

Defi nition 

Aetheroleum Anisi consists of the essential oil obtained by steam distillation 

from the dry ripe fruits of Pimpinella anisum L. (Apiaceae) (1–5). 1 

Synonyms 

Anisum offi cinarum Moench, A. vulgare Gaertn., Apium anisum (L.) 

Crantz, Carum anisum (L.) Baill., Pimpinella anisum cultum Alef., P. aromatica 

Bieb., Selinum anisum (L.) E.H.L. Krause, Sison anisum Spreng., 

Tragium anisum Link (1, 6–8). Apiaceae are also known as Umbelliferae. 


Anacio, Änes, Aneis, anice, anice verde, Anis, anisbibernelle, anis verde, 

anis vert, anise, anisoon, anisum, ánizs, anizsolaj, annsella, badian, badian 

rumi, boucage, boucage anis, Grüner Anis, habbat hlawa, jintan manis, 

jinten manis, petit anis, pimpinelle, razianag, razianaj, roomy, saunf, sweet 

cumin, yansoon (1, 6–10). 


Indigenous to the eastern Mediterranean region, western Asia and Europe. 

Cultivated in southern Europe and northern Africa, and in Argentina, 

Bulgaria, Chile, China, India, Islamic Republic of Iran, Japan, Mexico, 

Romania, Russian Federation and Turkey (8). 

Description 

An aromatic annual herb, up to 60 cm high with an erect, cylindrical, 

striated, smooth stem. Leaves alternate below, opposite above, the lower 

being long-petioled, ovate–orbicular, dentate, the upper with short dilated 

petioles, pinnatifi d or ternately pinnate with long, entire or cut cuneate 

segments. Infl orescence long-stalked, compound umbel with 8–14 rays; 

fl owers small, white, each on a long hairy pedicel. Fruit comprises a 

1 The European pharmacopoeia (5) permits the inclusion of the essential oil of Illicium verum Hook.

mouse-shaped cremocarp with a small stylopod and two minutely pubescent 

mericarps that do not readily separate from the carpophore (6, 11). 

Plant material of interest: essential oil 


A clear, colourless or pale yellow liquid, solidifying on cooling, practically 

insoluble in water, miscible with alcohol, ether, light petroleum or 

methylene chloride (1, 5). 


Odour: characteristic, aromatic; taste: sweet, strongly aromatic (1). 


Not applicable. 





Thin-layer chromatography for the presence of anethole, anisaldehyde 

and linalool. A gas chromatography method is also available (5). 

Purity tests 





Chemical 

Soluble in three parts ethanol (90%) at 20 o C (4). Relative density 0.978– 

0.994 (5). Refractive index 1.552–1.561 (5). Freezing-point 15–19 o C (5). 

Acid value not more than 1.0 (5). 



0.05 mg/kg (5). For other pesticides, see the European pharmacopoeia (5), 

and the WHO guidelines on quality control methods for medicinal plants 

(12) and pesticide residues (13). 

Heavy metals 



43






Tests for foreign organic matter, total ash, acid-insoluble ash, water-soluble 

extractive, alcohol-soluble extractive and loss on drying not applicable. 


Contains 0.1–1.5% linalool, 0.5–6.0% methylchavicol, 0.1–1.5% α-terpineol, 

< 0.5% cis-anethole, 84–93% trans-anethole, 0.1–3.5% p-anisaldehyde 

(5). 


The major constituents are trans-anethole (84–93%), cis-anethole (< 0.5%), 

methylchavicol (estragole, isoanethole; 0.5–6.0%), linalool (0.1–1.5%) and 

p-anisaldehyde (0.1–3.5%) (5). The structures of trans-anethole, methylchavicol, 

β-linalool and p-anisaldehyde are presented below. 

H 3 CO 



None. 


Treatment of dyspepsia and mild infl ammation of the respiratory tract 

(14, 15). 


As an aphrodisiac, carminative, emmenagogue, galactagogue and insecticide. 

Treatment of chronic bronchitis (8, 10). 

Pharmacology 


Antimicrobial activity 

Aetheroleum Anisi, 500 mg/l, inhibited the growth of Alternaria alternata, 

Alternaria tenuissima, Aspergillus spp., Botryodiplodia spp., Clado- 

44 

trans-anethole 

CH 3 

H 3 CO 

methylchavicol 

CH 2 

H 3C 

CH3 H OH 

and enantiomer 

CH 2 

H3CO 

CHO 

β-linalool p-anisaldehyde


sporium herbarum, Cladosporium werneckii, Colletotrichum capsici, Curvularia 

lunata, Curvularia pallescens, Fusarium moniliforme, F. oxysporum, 

Mucor spinescens, Penicillium chrysogenum, P. citrinum and Rhizopus nigricans 

(16). The oil (concentration not specifi ed) inhibited the growth of 

Aspergillus fl avus, A. niger, Fusarium oxysporum and Penicillium spp. in 

vitro (17). The oil, 1.0 ml/plate, inhibited the growth of Rhizoctonia solani 

and Sclerotinia sclerotiorum, but was inactive against Fusarium moniliforme 

and Phytophthora capsici in vitro (18). The oil (concentration 

not specifi ed) did not inhibit the growth of Bacillus cereus, Escherichia 

coli, Pseudomonas aeruginosa or Staphylococcus aureus but did inhibit 

that of Aspergillus aegyptiacus, Penicillium cyclopium and Trichoderma 

viride in vitro (19). The oil (concentration not specifi ed) was active against 

Bacillus subtilis, Escherichia coli, Lentinus lepideus, Pseudomonas aeruginosa 

and Staphylococcus aureus (20). The oil inhibited the growth of Candida 

albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, 

Microsporum gypseum, Rhodotorula rubra and Saccharomyces cerevisiae, 

minimum inhibitory concentration (MIC) 0.097%, and Geotrichum spp., 

MIC 1.562% (21). 

Anticonvulsant activity 

Intraperitoneal administration of 1.0 ml/kg body weight (bw) of the oil to 

mice suppressed tonic convulsions induced by pentylenetetrazole or 

maximal electroshock (22). Intraperitoneal administration of 2.5 g/kg bw 

of linalool to rodents provided protection against convulsions induced by 

pentylene tetrazole, picrotoxin and electroshock (23, 24). Intraperitoneal 

administration of 2.5 g/kg bw of linalool to mice interfered with glutamate 

function and delayed convulsions induced by N-methyl-d-aspartate 

(25). Linalool acts as a competitive antagonist of [ 3 H]-glutamate 

binding and as a non-competitive antagonist of [ 3 H]-dizocilpine binding 

in mouse cortical membranes. The effects of linalool were investigated on 

[ 3 H]-glutamate uptake and release in mouse cortical synaptosomes. Linalool, 

1.0 mmol/l, reduced potassium-stimulated glutamate release (26). 

These data suggest that linalool interferes with elements of the excitatory 

glutamatergic transmission system. 

Anti-infl ammatory activity 

Anethole is a potent inhibitor of tumour necrosis factor (TNF)-induced 

nuclear factor (NF)-κβ activation, inhibitor-κβα phosphorylation and 

degradation, and NF-κβ reporter gene expression in vitro, demonstrating 

that anethole suppresses infl ammation by inhibiting TNF-induced cellular 

responses (27). 

45


Antispasmodic activity 

The oil inhibited the phasic contractions of ileal myenteric plexus-longitudinal 

muscle preparations isolated from guinea-pigs in vitro, median effective 

dose 60 mg/l (28). The oil, 1:20 000, decreased the rate and extent 

of contractions in intestinal smooth muscle isolated from rats, cats or rabbits 

in vitro, and antagonized the stimulant activity of acetylcholine, barium 

chloride, pilocarpine and physostigmine (29). Anethole, 0.05–1.00 mg/ 

ml, blocked twitching induced by acetylcholine and caffeine in toad rectus 

abdominis and sartorius muscles, but had no effect on skeletal muscle 

twitching induced by nerve stimulation in isolated rat diaphragm (30). 

Bronchodilatory activity 

The oil, 1.0 mmol/l, had relaxant effects in precontracted, isolated guineapig 

tracheal chains indicating a bronchodilatory effect. It also induced a 

parallel rightwards shift in the methacholine-response curve (methacholine 

is a muscarinic receptor antagonist), indicating that the bronchodilatory 

activity may be due to an inhibitory effect of the oil on the 

muscarinic receptors (31). 

Estrogenic activity 

Subcutaneous administration of 0.1 ml of the oil to ovariectomized rats 

had an estrogenic effect equivalent to that of 0.1 μg of estradiol (32). Intraperitoneal 

administration of 0.1 ml of the oil had a uterine relaxation effect 

in female rats (32). Anethole is thought to be the estrogenic component 

of the oil; polymers of this compound, such as dianethole and 

photoanethole, have also been suggested (33). 

Expectorant activity 

Intragastric administration of 10.0–50.0 mg/kg bw of the oil to guineapigs 

increased bronchial secretions, demonstrating an expectorant effect 

(34). Intragastric administration of two drops of the oil as an emulsion 

with gummi arabicum to cats induced hypersecretion of the respiratory 

tract (35). However, other researchers have demonstrated that administration 

of the oil to cats by steam inhalation had no effect on respiratory 

tract fl uid except when given in toxic doses, which increased the output 

(36). Administration of the oil by inhalation to anaesthetized rabbits did 

not appreciably affect respiratory tract fl uids until doses of 720.0 mg/kg 

bw and over were used in a vaporizer (36, 37). At this dose, 20% of the 

animals died and there was local irritation of the lining of the respiratory 

tract, which appeared as congestion at 6 hours and progressed to leukocytic 

infi ltration and destruction of the ciliated mucosa at 24 hours (36). 

Inhalation of 1 ml/kg bw of anisaldehyde in anaesthetized rabbits signifi - 

46


cantly increased (P < 0.05) the volume of respiratory fl uid collected for 

4–6 hours after treatment and decreased the specifi c gravity of the fl uid in 

treated animals compared with untreated controls (38). 

Liver effects 

Subcutaneous administration of 100.0 mg/kg bw of the oil per day for 

7 days stimulated liver regeneration in partially hepatectomized rats (39). 

Toxicology 

The oral median lethal dose (LD 50 ) of anisaldehyde in rats was 1.51 g/kg 

bw, with death occurring within 4–18 hours following depression of the 

central nervous system (40). The oral LD 50 in guinea-pigs was 1.26 g/kg 

bw, death occurring after 1–3 days (40). 

The safety and metabolism of trans-anethole were evaluated in rats as 

a model for assessing the potential for hepatotoxicity in humans exposed 

to the compound as a fl avouring agent. In chronic dietary studies in rats, 

hepatotoxicity was observed when the estimated daily hepatic production 

of anethole epoxide exceeded 30 mg/kg bw. Chronic hepatotoxicity and a 

low incidence of liver tumours were observed at a dietary intake of transanethole 

of 550.0 mg/kg bw per day (41). The effects of trans-anethole on 

drug metabolizing enzymes were assessed in rats; intragastric administration 

of 125.0 mg/kg or 250.0 mg/kg bw per day for 10 days had no effect 

on total cyctochrome P450 content in liver microsomes (42). In a chronic 

feeding study, trans-anethole was administered to rats in the diet at concentrations 

of 0, 0.25%, 0.5% and 1.0% for 117–121 weeks, giving an average 

dose of 105–550.0 mg/kg bw per day. No abnormalities related to 

treatment were observed with the exception of a very low incidence of 

hepatocarcinomas in female animals treated with the 1.0% dose (43). 

The acute oral LD 50 of anethole in rats was 2090.0 mg/kg bw; repeated 

doses of 695.0 mg/kg bw caused mild liver lesions consisting of slight discoloration, 

mottling and blunting of the lobe edges (33). 


The absorption of anethole from the gastrointestinal tract was assessed in 

healthy volunteers. The drug was rapidly absorbed from the gastrointestinal 

tract and rapidly eliminated in the urine (54–69%) and through 

the lungs (13–17%). The principal metabolite was 4-methoxyhippuric 

acid (approximately 56%); other metabolites were 4-methoxybenzoic 

acid and three other unidentifi ed compounds (44, 45). Increases in drug 

dose did not alter the pattern of metabolite distribution in humans, contrary 

to fi ndings in animal models (46). 

47



Contact dermatitis was reported in a cake factory worker after external 

exposure to a 5% concentration of Aetheroleum Anisi (47). Occasional 

allergic reactions to the oil affecting the skin, respiratory tract and gastrointestinal 

tract are reported (15). Inhalation of powdered Fructus Anisi 

induced an allergic effect in one subject with asthma. Skin-prick tests 

showed a positive reaction to the fruits and the patient had high specifi c 

anti-aniseed immunoglobulin E antibodies in his blood (48). Anethole 

toxicity in infants has been reported, and presents clinically with symptoms 

of hypertonia, continued crying, atypical ocular movements, twitching, 

cyanosis, vomiting and lack of appetite (7, 49). Ingestion of 1.0–5.0 ml 

of the oil can result in nausea, vomiting, seizures and pulmonary oedema 

(50). In cases of overdose (> 50 mg/kg), the ingestion of milk and alcohol 

is contraindicated owing to increased resorption. 


Aetheroleum Anisi is contraindicated in cases of known allergy to aniseed 

and anethole (48). Owing to the traditional use of the oil as an emmenagogue 

and to induce labour, its experimental estrogenic and potential mutagenic effects, 

and reports of anethole toxicity in infants (7, 49), use of the oil in pregnancy 

and nursing, and in children under the age of 12 years is contraindicated. 

Warnings 

Applications of Aetheroleum Anisi should be limited to inhalation therapy 

(51). 

Precautions 


Inconsistent results have been reported concerning the mutagenicity of 

trans-anethole in the Salmonella/microsome assay. One group showed 

that anethole was mutagenic (52), another that it was very weakly mutagenic 

in S. typhimurium strains TA1535, TA100 and TA98 (53). In a further 

study, trans-anethole (concentrations not specifi ed) did not increase 

the mutant frequency in the Salmonella/microsome assay, but did increase 

mutant frequency in the L5178Y mouse-lymphoma TK+/- assay in a 

dose-dependent manner, with metabolic activation (49). Trans-anethole 

did not induce chromosome aberrations in vitro in the Chinese hamster 

ovary cell assay (49). Trans-anethole was weakly hepatocarcinogenic in 

female rats when administered at a dose of 1% in the diet for 121 weeks; 

48

however, this effect is not mediated by a genotoxic event (54). Trans-anethole 

was investigated for its antifertility activity in rats, after intragastric 

administration of doses of 50.0 mg/kg bw, 70.0 mg/kg bw and 80.0 mg/kg 

bw (55). Anti-implantation activity of 100% was observed in animals 

treated with the highest dose. The compound has been reported to show 

estrogenic, antiprogestational, androgenic and antiandrogenic activities 

(55). 









No information available on general precautions or on precautions concerning 

drug interactions; drug and laboratory test interactions; and teratogenic 

effects in pregnancy. 

Dosage forms 

Essential oil. Preparations containing 5–10% essential oil for inhalation 

are also available. Store in a well-fi lled, tightly sealed container, protected 

from light and heat (5). 

Posology 


Average daily dose for internal use: essential oil 0.3 g; equivalent for other 

preparations (15). 

References 

1. Egyptian pharmacopoeia, 3rd ed. Cairo, General Organization for Government 

Printing, 1972. 

2. Hungarian pharmacopoeia, 7th ed. Budapest, Medicina Könyvhiadó, 1986. 

3. Thai pharmacopoeia. Vol. 1. Bangkok, Department of Medical Sciences, 

Ministry of Public Health, 1987. 

4. Farmakope Indonesia, 4th ed. Jakarta, Departmen Kesehatan, 1995. 




49



Drogen P–Z, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 6, 

Drugs P–Z, 5th ed.] Berlin, Springer, 1994. 

8. de Guzman CC, Siemonsma JS, eds. Plant resources of South-East Asia, 

No. 13. Spices. Bogor, PROSEA, 1999. 

9. Halmai J, Novak I. Farmakognózia. [Pharmacognosy] Budapest, Medicina 

Könyvhiadó, 1963. 












14. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association, 

1996. 



16. Shukla HS, Tripathi SC. Antifungal substance in the essential oil of 

anise (Pimpinella anisum L.). Agricultural and Biological Chemistry, 1987, 

51:1991–1993. 

17. Gangrade SK et al. In vitro antifungal effect of the essential oils. Indian 

Perfumer, 1991, 35:46–48. 

18. Müller-Riebau F, Berger B, Yegen O. Chemical composition and fungitoxic 

properties to phytopathogenic fungi of essential oils of selected aromatic 

plants growing wild in Turkey. Journal of Agricultural and Food Chemistry, 

1995, 43:2262–2266. 

19. El-Keltawi NEM, Megalla SE, Ross SA. Antimicrobial activity of some 

Egyptian aromatic plants. Herba polonica, 1980, 26:245–250. 

20. Janssen AM et al. Screening for antimicrobial activity of some essential oils 

by the agar overlay technique. Pharmazeutisch Weekblad (Scientifi c Edition), 

1986, 8:289–292. 

21. Pepeljnjak S et al. Antimycotic activities of Pimpinella anisum L. fruit and 

essential oil. In: Ethnopharmacology 2000: challenges for the new millennium, 

Zurich, Switzerland, 4–7 September, 2000. Zurich, 2000:75 (P2A). 

22. Pourgholami MH et al. The fruit essential oil of Pimpinella anisum exerts 

anticonvulsant effects in mice. Journal of Ethnopharmacology, 1999, 66:211– 

215. 

23. Elisabetsky E et al. Sedative properties of linalool. Fitoterapia, 1995, 66:407– 

414. 

50


24. Elisabetsky E, Silva Brum LF, Souza DO. Anticonvulsant properties of 

linalool in glutamate-related seizure models. Phytomedicine, 1999, 6:107–113. 

25. Silva Brum LF, Elisabetsky E, Souza DO. Effects of linalool on [ 3 H] MK801 

and [ 3 H] muscimol binding in mouse cortical membranes. Phytotherapy 

Research, 2001, 15:422–425. 

26. Silva Brum LF et al. Effects of linalool on glutamate release and uptake in 

mouse cortical synaptosomes. Neurochemical Research, 2001, 26:191–194. 

27. Chainy GBN et al. Anethole blocks both early and late cellular responses 

transduced by tumor necrosis factor: effect on NF-κB, AP-1, JNK, MAPKK 

and apoptosis. Oncogene, 2000, 19:2943–2950. 

28. Reiter M, Brandt W. Relaxant effects on tracheal and ileal smooth muscles of 

the guinea pig. Arzneimittelforschung, 1985, 35:408–414. 

29. Gunn JWC. The carminative action of volatile oils. Journal of Pharmacology 

and Experimental Therapeutics, 1920, 16:39–47. 

30. Albuquerque AA, Sorenson AL, Leal-Cardoso JH. Effects of essential oil of 

Croton zehntneri, and of anethole and estragole on skeletal muscles. Journal 

of Ethnopharmacology, 1995, 49:41–49. 

31. Boskabady MH, Ramazani-Assari M. Relaxant effect of Pimpinella anisum 

on isolated guinea pig tracheal chains and its possible mechanism(s). Journal 


32. Sharaf G, Goma N. Phytoestrogens and their antagonism to progesterone 

and testosterone. Journal of Endocrinology, 1965, 31:289–290. 

33. Albert-Puleo M. Fennel and anise as estrogenic agents. Journal of Ethnopharmacology, 

1980, 2:337–344. 

34. Boyd EM, Pearson GL. On the expectorant action of volatile oils. American 

Journal of the Medical Sciences, 1946, 211:602–610. 

35. Van Dongen K, Leusink H. The action of opium-alkaloids and expectorants 

on the ciliary movements in the air passages. Archives of International 

Pharmacodynamics, 1953, 93:261–276. 

36. Boyd EM, Sheppard EP. Effect of steam inhalation of volatile oils on the 

output and composition of respiratory tract fl uid. Journal of Pharmacology 

and Experimental Therapeutics, 1968, 163:250–256. 

37. Boyd EM. A review of studies on the pharmacology of the expectorants and 

inhalants. International Journal of Clinical Pharmacology, 1970, 3:55–60. 

38. Boyd EM, Sheppard EP. Inhaled anisaldehyde and respiratory tract fl uid. 

Pharmacology, 1970, 3:345–352. 

39. Gershbein LL. Regeneration of rat liver in the presence of essential oils and 

their components. Food and Cosmetics Toxicology, 1977, 15:173–181. 

40. Jenner P et al. Food fl avourings and compounds of related structure. I. Acute 

oral toxicity. Food and Cosmetics Toxicology, 1964, 2:327–343. 

41. Newberne P et al. The FEMA GRAS assessment of trans-anethole used as a 

fl avouring substance. Food and Chemical Toxicology, 1999, 37:789–811. 

42. Rompelberg CJ, Verhagen H, Van Bladeren PJ. Effects of the naturally occurring 

alkenylbenzenes eugenol and trans-anethole on drug-metabolizing 

enzymes in the rat liver. Food and Chemical Toxicology, 1993, 31:637–645. 

51


43. Truhaut R et al. Chronic toxicity/carcinogenicity study of trans-anethole in 

rats. Food and Chemical Toxicology, 1989, 27:11–20. 

44. Sangster SA, Caldwell J, Hutt AJ et al. The metabolic dispostion of 

[methoxy 14 C]-labelled trans-anethole, estragole, and p-propylanisole in human 

volunteers. Xenobiotica, 1987, 17:1223–1232. 

45. Caldwell J, Sutton JD. Infl uence of dose size on the disposition of trans-[methoxy-14C] 

anethole in human volunteers. Food and Chemical Toxicology, 

1988, 26:87–91. 

46. Sangster SA, Caldwell J, Smith RL. Metabolism of anethole. II. Infl uence of 

dose size on the route of metabolism of trans-anethole in the rat and mouse. 

Food and Chemical Toxicology, 1984, 22:707–713. 

47. Garcia-Bravo B et al. Occupational contact dermatitis from anethole in food 

handlers. Contact Dermatitis, 1997, 37:38–39. 

48. Fraj J et al. Occupational asthma induced by aniseed. Allergy, 1996, 51:337– 

339. 

49. Gorelick NJ. Genotoxicity of trans-anethole in vitro. Mutation Research, 

1995, 326:199–209. 

50. Chandler RF, Hawkes D. Aniseed – a spice, a fl avor, a drug. Canadian Pharmaceutical 

Journal, 1984, 117:28–29. 


Press, 1994. 

52. Sekizawa J, Shibamoto T. Genotoxicity of safrole-related chemicals in microbial 

test systems. Mutation Research, 1982, 101:127–140. 

53. Swanson AB et al. The mutagenicities of safrole, estragole, eugenol, transanethole, 

and some of their known or possible metabolites for Salmonella 

typhimurium mutants. Mutation Research, 1979, 60:143–153. 

54. Marshall AD, Caldwell J. Lack of infl uence of modulators of epoxide metabolism 

on the genotoxicity of trans-anethole in freshly isolated rat hepatocytes 

assessed with the unscheduled DNA synthesis assay. Food and Chemical 

Toxicology, 1996, 34:337–345. 

55. Dhar SK. Anti-fertility activity and hormonal profi le of trans-anethole in 

rats. Indian Journal of Physiology and Pharmacology, 1995, 39:63–67. 

52

Fructus Anisi 

Defi nition 

Fructus Anisi consists of the dried fruits of Pimpinella anisum L. 

(Apiaceae) (1–3). 

Synonyms 

Anisum offi cinarum Moench, A. vulgare Gaertn., Apium anisum (L.) 

Crantz, Carum anisum (L.) Baill., Pimpinella anisum cultum Alef., P. aromatica 

Bieb., Selinum anisum (L.) E.H.L. Krause, Sison anisum Spreng., 

Tragium anisum Link (1, 2, 4, 5). Apiaceae are also known as Umbelliferae. 


Anacio, Änes, Aneis, anice, anice verde, Anis, anisbibernelle, anis verde, 

anis vert, anise, anisoon, anisum, ánizs, anizsolaj, annsella, badian, badian 

rumi, boucage, boucage anis, Grüner Anis, habbat hlawa, jintan manis, 

jinten manis, petit anis, pimpinelle, razianag, razianaj, roomy saunf, sweet 

cumin, yansoon (1, 2, 4–7). 


Indigenous to the eastern Mediterranean region, western Asia and 

Europe. Cultivated in southern Europe and northern Africa, and in 

Argentina, Bulgaria, Chile, China, India, Islamic Republic of Iran, Japan, 

Mexico, Romania, Russian Federation and Turkey (5, 8). 

Description 

An aromatic annual herb, up to 60 cm high, with an erect, cylindrical, 

striated, smooth stem. Leaves alternate below, opposite above, the lower 

being long-petioled, ovate–orbicular, dentate, the upper with short, dilated 

petioles, pinnatifi d or ternately pinnate with long, entire or cut cuneate 

segments. Infl orescence long-stalked, compound umbel with 8–14 

rays; fl owers small, white, each on a long hairy pedicel. Fruit comprises a 

mouse-shaped cremocarp with a small stylopod and two minutely pubescent 

mericarps that do not readily separate from the carpophore (2, 9). 

53




Cremocarp, partly separated into its mericarps, often entire, remaining 

attached to a slender pedicel 2–12 mm long; pear-shaped, 3–6 mm long 

and 2–3 mm wide, enlarged at the base and tapering at the apex, somewhat 

laterally compressed, crowned with a disc-like nectary; stylopod 

ends with the remains of two diverging styles; greyish or greenish-grey, 

seldom greyish-brown. Mericarp externally rough to the touch owing to 

the presence of numerous very short, stiff hairs; marked with fi ve very 

slightly raised, fi liform, pale-brown primary ridges; commissural surface, 

nearly fl at, with two dark brownish, longitudinal areas, containing 

vittae, separated by a middle paler area; internally comprises a pericarp 

with numerous branched vittae in the dorsal side and usually only two 

large ones in the commissural side, a large white oily endosperm, not 

deeply grooved on the commissural side, and a small apical embryo. 

Carpophore forked, passing at the apex into the raphe of each pericarp 

(1, 2). 


Odour: characteristic, aromatic; taste: sweet, strongly aromatic (1, 2). 


Pericarp epidermis consists of cells with striated cuticle, many of which 

project into short, conical, curved, thick-walled, unicellular, sometimes 

bicellular, non-glandular hairs, with bluntly pointed apex and fi nely 

warty cuticles. Mesocarp formed of thin-walled parenchyma, traversed 

longitudinally by numerous schizogenous vittae, with brown epithelial 

cells and, in each primary ridge, by a small vascular bundle, accompanied 

by a few fi bres; also a patch of porous or reticulate lignifi ed cells in the 

middle of the commissural side, but not in the ridges. Endocarp composed 

of narrow, tangentially elongated, thin-walled cells, except when 

adjacent to the reticulate cells in the mesocarp, where it is formed of porous, 

lignifi ed and reticulately thickened cells. Testa consists of one layer 

of tangentially elongated cells with yellowish-brown walls, closely adhering 

to the endocarp except along the commissural surface, where 

separated by a large cavity. Endosperm formed of polygonal thick-walled 

cellulosic cells containing fi xed oil and many aleurone grains, each enclosing 

one globoid and one or two microrosette crystals of calcium 

oxalate with dark centres. Carpophore traversed by a vascular bundle of 

fi bres and spiral vessels (1, 2). 

54


Grey, greenish-brown or yellowish-brown, characterized by numerous, 

almost colourless fragments of endosperm; abundant minute oil globules; 

numerous warty simple hairs 25–100 μm long and 10–15 μm wide. Fragments 

of pericarp with yellowish-brown, comparatively narrow, branching 

vittae, usually crossed by the cells of the endocarp, the ratio of the 

width of these cells to that of the vittae varying from 1:7 to 1:5. Few fi bres 

and very scanty pitted lignifi ed parenchyma; aleurone grains 2–15 μm in 

diameter. Microrosette crystals of calcium oxalate 2–10 μm in diameter, 

each containing a minute air bubble (1, 2). 



for the presence of anethole (3). 

Purity tests 







Total ash 



Not more than 2.5% (1, 3). 



Fructus Anisi 






Heavy metals 



55






Chemical, water-soluble extractive and alcohol-soluble extractive tests to 

be established in accordance with national requirements. 


Contains not less than 2% (v/w) essential oil (3). A high-performance 

liquid chromatography method for the analysis of phenylpropanoid constituents 

is available (12). 


Contains 1.5–5.0% essential oil, the major constituents of which are 

linalool (0.1–1.5%), methylchavicol (estragole, isoanethole; 0.5–6.0%), αterpineol 

(0.1–1.5%), cis-anethole (< 0.5%), trans-anethole (84–93%), panisaldehyde 

(0.1–3.5%) (3). The structures of trans-anethole, methylchavicol, 

β-linalool and p-anisaldehyde are presented below. 

H 3 CO 





Treatment of dyspepsia and mild infl ammation of the respiratory tract 

(13, 14). 


As an aphrodisiac, carminative, emmenagogue, galactagogue and tonic, 

and for treatment of asthma, bronchitis, diarrhoea, fever, spasmodic 

cough, fl atulent colic and urinary tract infections (5, 7, 15). 

Pharmacology 


Analgesic and central nervous system activity 

Intraperitoneal or intragastric administration of a dried ether extract of 

the fruits dissolved in normal saline did not potentiate barbiturate- 

56 

trans-anethole 

CH 3 

H 3 CO 

methylchavicol 

CH 2 

H 3C 

CH3 H OH 


CH 2 

H3CO 

CHO 

β-linalool p-anisaldehyde

Fructus Anisi 

induced sleeping time when administered to mice in doses of up to 

200.0 mg/kg body weight (bw) (16). 


A 95% ethanol extract of the fruits, 50 μl/plate, inhibited the growth of 

Staphylococcus aureus in vitro (17). A dried methanol extract of the fruits 

inhibited the growth of Helicobacter pylori in vitro, minimum inhibitory 

concentration (MIC) 100.0 μg/ml (18). A decoction of the fruits did not 

inhibit the growth of Aspergillus niger, Escherichia coli, Pseudomonas aeruginosa, 

Salmonella typhi or Staphylococcus aureus in vitro at concentrations 

of up to 62.5 mg/ml (19). An ethanol extract of the fruits inhibited 

the growth of Candida albicans, C. krusei, C. parapsilosis, C. tropicalis, 

Microsporum gypseum, Rhodotorula rubra and Saccharomyces cerevisiae, 

MIC 0.097%, and Geotrichum spp., MIC 1.562% (20). 

Anticonvulsant activity 

Intraperitoneal administration of 4.0 mg/kg bw of a dried 95% ethanol 

extract of the fruits dissolved in normal saline to mice inhibited convulsions 

induced by supramaximal electroshock. At the same dose, the extract 

was ineffective against convulsions induced by pentylenetetrazole 

and strychnine (21). 

Intraperitoneal administration of 2.5 g/kg bw of linalool to rodents provided 

protection against convulsions induced by pentylenetetrazole, picrotoxin, 

and electroshock (22, 23). Intraperitoneal administration of 2.5 g/kg 

bw of linalool to mice interfered with glutamate function and delayed Nmethyl-d-aspartate-induced 

convulsions (24). Linalool acts as a competitive 

antagonist of [ 3 H]-glutamate binding and as a non-competitive antagonist 

of [ 3 H]-dizocilpine binding in mouse cortical membranes. The effects 

of linalool on [ 3 H]-glutamate uptake and release in mouse cortical synaptosomes 

were investigated. Linalool, 1.0 mmol/l, reduced potassium-stimulated 

glutamate release (25). These data suggest that linalool interferes with 

elements of the excitatory glutamatergic transmission system. 


External application of 2.0 mg of a methanol extract of the fruits inhibited 

ear infl ammation induced by 12-O-tetradecanoyl phorbol-13-acetate in 

mice (26). External application of 20.0 μl of an ethyl acetate or hexane 

extract of the fruits did not inhibit ear infl ammation induced by 

O-tetradecanoyl phorbol-13-acetate in mice; application of 20.0 μl of a 

methanol extract was weakly active in the same assay (27). Anethole is a 

potent inhibitor of tumour necrosis factor (TNF)-induced nuclear factor 

(NF)-κβ activation, inhibitor-κβα phosphorylation and degradation, and 

57


NF-κβ reporter gene expression in vitro, demonstrating that anethole suppresses 

infl ammation by inhibiting TNF-induced cellular responses (28). 

Bronchodilatory activity 

The fruits, 1.0 mmol/l, had signifi cant (P < 0.05) relaxant effects in precontracted, 

isolated guinea-pig tracheal chains in vitro, indicating a bronchodilatory 

effect. At the same dose, the fruits induced a parallel rightwards 

shift in the methacholine-response curve, indicating that the 

bronchodilatory activity may be due to an inhibitory effect on the muscarinic 

receptors (29). 

Hypotensive activity 

Intravenous administration of 50.0 mg/kg bw of a dried 50% ethanol extract 

of the fruits dissolved in normal saline to dogs decreased blood pressure 

(30). Intragastric administration of an aqueous extract of the fruits 

reduced atropine-induced hypertension at a dose of 10.0% (no further 

information available) (31). Administration of an unspecifi ed extract of 

the fruits had a diuretic effect in rabbits, which was blocked by pretreatment 

with morphine (32). 

Platelet aggregation inhibition 

A methanol extract of the fruits, 500.0 μg/ml, inhibited collagen-induced 

platelet aggregation in human platelets (33). 

Smooth muscle stimulant activity 

An aqueous extract of the fruits, 10.0% in the bath medium, stimulated 

contractions of isolated frog rectus abdominis muscle and rat jejunum 

strips (31). Anethole, 0.05–1.00 mg/ml, blocked twitching induced by 

acetylcholine and caffeine in toad rectus abdominis and sartorius muscles, 

but had no effect on skeletal muscle twitching in isolated rat diaphragm 

induced by electrical nerve stimulation (34). 

Toxicity 

For intraperitoneal injection of a dried 50% ethanol extract of the fruits 

dissolved in normal saline in mice, the maximum tolerated dose was 

500.0 mg/kg bw, median lethal dose (LD 50 ) 750.0 mg/kg (30). 

The safety and metabolism of trans-anethole were evaluated in rats as a 

model for assessing the potential for hepatotoxicity in humans exposed to 

the compound as a fl avouring agent. In chronic dietary studies in rats, 

hepatotoxicity was observed when the estimated daily hepatic production 

of anethole epoxide exceeded 30.0 mg/kg bw. Chronic hepatotoxicity and 

a low incidence of liver tumours were observed at a dietary intake of transanethole 

of 550.0 mg/kg bw per day (35). The effects of trans-anethole on 

58

drug-metabolizing enzymes were assessed in rats; intragastric administration 

of 125.0 mg/kg bw or 250.0 mg/kg bw per day for 10 days had no 

effect on total cyctochrome P450 content in liver microsomes (36). In a 

chronic feeding study, trans-anethole was administered to rats in the diet 

at concentrations of 0, 0.25%, 0.5% and 1.0% for 117–121 weeks, giving 

an average dose of 105–550.0 mg/kg bw per day. No abnormalities related 

to treatment were observed, with the exception of a very low incidence of 

hepatocarcinomas in female animals treated with the 1.0% dose (37). 

The acute oral LD 50 for anethole in rats was 2.09 g/kg bw; repeated 

oral doses of 695.0 mg/kg bw caused mild liver lesions consisting of slight 

discoloration, mottling, and blunting of the lobe edges (38). 




Occasional allergic reactions to Fructus Anisi affecting the skin, respiratory 

tract and gastrointestinal tract have been reported (14). Inhalation of 

powdered fruits induced an allergic effect in one subject with asthma. 

Skin-prick tests showed a positive reaction and the patient had a high 

level of specifi c anti-aniseed immunoglobulin E antibodies in his blood 

(39). Anethole toxicity in infants has been reported, and presents clinically 

with symptoms of hypertonia, continued crying, atypical ocular 

movements, twitching, cyanosis, vomiting and lack of appetite (4, 40). 


Fructus Anisi is contraindicated in cases of known allergy to aniseed and 

anethole (14, 39). Owing to the traditional use of the oil as an emmenagogue 

and to induce labour, its experimental estrogenic and potential mutagenic 

effects, and reports of anethole toxicity in infants (4, 40), use of 

the dried fruits in pregnancy and nursing, and in children under the age of 

12 years is contraindicated. 

Warnings 


Fructus Anisi 

Precautions 


A 95% ethanol extract of Fructus Anisi, 10.0 mg/plate, was inactive in the 

Salmonella/microsome assay in S. typhimurium TA102 (41). Inconsistent 

59


results have been reported concerning the mutagenicity of anethole in this 

assay. One group showed that it was mutagenic (42), another that it was 

not mutagenic in S. typhimurium strains TA1535, TA100 and TA98 (43). 

In a further study, trans-anethole (concentration not specifi ed) did not 

increase the mutant frequency in the Salmonella/microsome assay, but 

did increase mutant frequency in the L5178Y mouse-lymphoma TK+/- 

assay in a dose-dependent manner, with metabolic activation (40). Transanethole 

did not induce chromosome aberrations in vitro in the Chinese 

hamster ovary cell assay (40). Trans-anethole was weakly hepatocarcinogenic 

in female rats when administered at a dose of 1% in the diet for 

121 weeks; however, this effect is not mediated by a genotoxic event (44). 

Trans-anethole was investigated for its antifertility activity in rats, after 

intragastric administration of doses of 50.0 mg/kg bw, 70.0 mg/kg bw and 

80.0 mg/kg bw (45). Anti-implantation activity of 100% was observed in 

animals treated with the highest dose. The compound has been reported 

to show estrogenic, antiprogestational, androgenic and antiandrogenic 

activities (45). 









drug interactions; drug and laboratory test interactions; or teratogenic 


Dosage forms 

Powdered dried fruits for oral infusions and other galenical preparations 

for internal use or inhalation (14). Store in a well-closed container, protected 

from heat and light. 

Posology 


Average oral daily dose for internal use: Fructus Anisi 3.0 g; equivalent 

for other preparations (14). 

60

Fructus Anisi 

References 



2. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African 

Unity, Scientifi c, Technical and Research Commission, 1985. 





5. de Guzman CC, Siemonsma JS, eds. Plant resources of South-east Asia, No. 13. 

Spices. Bogor, PROSEA, 1999. 

6. Halmai J, Novak I. Farmakognózia. [Pharmacognosy.] Budapest, Medicina 

Könyuhiadó, 1963. 





8. Wichtl M, ed. Teedrogen, 2nd ed. [Drugs used for infusion, 2nd ed.] Stuttgart, 

Wissenschaftliche Verlagsgesellschaft, 1989. 








12. Gracza L. Bestimmung von Phenylpropanderivaten in Arzneistoffen und 

Arnzeizubereitung durch HPLC. [Determination of phenylpropane derivatives 

in pharmaceuticals and pharmaceutical ingredients by HPLC.] Deutsche 

Apotheker Zeitung, 1980, 120:1859–1863. 


1996. 



15. Newall CA, Anderson LA, Phillipson JD. Herbal medicines. A guide for 

health-care professionals. London, The Pharmaceutical Press, 1996. 

16. Han YB, Shin KH, Woo WS. Effect of spices on hepatic microsomal enzyme 

function in mice. Archives of Pharmacal Research, 1984, 7:53–56. 

17. Perez C, Anesini C. Antibacterial activity of alimentary plants against Staphylococcus 

aureus growth. American Journal of Chinese Medicine, 1994, 

22:169–174. 

18. Mahady GB et al. In vitro susceptibility of Helicobacter pylori to botanicals 

used traditionally for the treatment of gastrointestinal disorders. Phytomedicine, 

2000, 7(Suppl. II):79. 

61


19. Anesini C, Perez C. Screening of plants used in Argentine folk medicine for 

antimicrobial activity. Journal of Ethnopharmacology, 1993, 39:119–128. 

20. Pepeljnjak S et al. Antimycotic activities of Pimpinella anisum L. fruit and 

essential oil. In: Ethnopharmacology 2000: challenges for the new millennium, 

Zurich, Switzerland, 4–7 September, 2000. Zurich, 2000:75 (P2A). 

21. Athanassova-Shopova S, Roussinov K. Pharmacological studies of Bulgarian 

plants with a view to their anticonvulsive effect. Comptes rendus de l’Académie 

Bulgare des Sciences, 1965, 18:691–694. 


414. 

23. Elisabetsky E, Silva Brum LF, Souza DO. Anticonvulsant properties of linalool 

in glutamate-related seizure models. Phytomedicine, 1999, 6:107–113. 

24. Silva Brum LF, Elisabetsky E, Souza DO. Effects of linalool on [ 3 H] MK801 

and [ 3 H] muscimol binding in mouse cortical membranes. Phytotherapy 

Research, 2001, 15:422–425. 



26. Yasukawa K et al. Inhibitory effect of edible plant extracts on 12-O-tetradecanoylphorbol-13-acetate-induced 

ear oedema in mice. Phytotherapy 

Research, 1993, 7:185–189. 

27. Okuyama T et al. Studies on cancer bio-chemoprevention of natural resources. 

X. Inhibitory effect of spices on TPA-enhanced 3 H-choline incorporation 

in phospholipids of C3H10T1/2 cells and on TPA-induced mouse ear edema. 

Zhonghua Yaoxue Zazhi, 1995, 47:421–430. 

28. Chainy GBN et al. Anethole blocks both early and late cellular responses 

transduced by tumor necrosis factor: effect on NF-κB, AP-1, JNK, MAPKK 

and apoptosis. Oncogene, 2000, 19:2943–2950. 

29. Boskabady MH, Ramazani-Assari M. Relaxant effect of Pimpinella anisum 

on isolated guinea pig tracheal chains and its possible mechanism(s). Journal 


30. Dhar ML et al. Screening of Indian plants for biological activity: part I. 


31. Haranath PSRK, Akther MH, Sharif SI. Acetylcholine and choline in 

common spices. Phytotherapy Research, 1987, 1:91–92. 

32. Skovronskii VA. [The effect of caraway, anise, and of sweet fennel on urine 

elimination.] Sbornik nauchnikh trudov l’vovskogo veterinarno-zootekhnicheskogo 

instituta, 1953, 6:275–283 [in Russian]. 

33. Okazaki K et al. Antiaggregant effects on human platelets of culinary herbs. 

Phytotherapy Research, 1998, 12:603–605. 

34. Albuquerque AA, Sorenson AL, Leal-Cardoso JH. Effects of essential oil of 

Croton zehntneri, and of anethole and estragole on skeletal muscles. Journal 




62

Fructus Anisi 

36. Rompelberg CJ, Verhagen H, Van Bladeren PJ. Effects of the naturally occurring 

alkenylbenzenes eugenol and trans-anethole on drug-metabolizing 

enzymes in the rat liver. Food and Chemical Toxicology, 1993, 31:637–645. 




1980, 2:337–344. 

39. Fraj J et al. Occupational asthma induced by aniseed. European Journal of 

Allergy and Clinical Immunology, 1996, 51:337–339. 

40. Gorelick NJ. Genotoxicity of trans-anethole in vitro. Mutation Research, 

1995, 326:199–209. 




42. Sekizawa J, Shibamoto T. Genotoxicity of safrole-related chemicals in 

microbial test systems. Mutation Research, 1982, 101:127–140. 

43. Swanson AB et al. The mutagenicities of safrole, estragole, eugenol, 

trans-anethole, and some of their known or possible metabolites for Salmonella 

typhimurium mutants. Mutation Research, 1979, 60:143–153. 

44. Marshall AD, Caldwell J. Lack of infl uence of modulators of epoxide 

metabolism on the genotoxicity of trans-anethole in freshly isolated rat 

hepatocytes assessed with the unscheduled DNA synthesis assay. Food and 

Chemical Toxicology, 1996, 34:337–345. 



63

64 

Semen Armeniacae 

Defi nition 

Semen Armeniacae consists of the dried ripe seeds of Prunus armeniaca 

L., Prunus armeniaca L. var. ansu Maxim. or allied species (Rosaceae) 

(1–4). 

Synonyms 

Armeniaca vulgaris Lam. (5). 


Abricotier, anzu, apricot, Aprikose, Aprikosenbaum, barqouq, bitter 

apricot, chuli, cuari, culu, elk mesmas, haeng-in, Himalayan wild apricot, 

hsing, ku-xinggren, kurbani, maó, michmich, mouchmouch, ó mai, 

sal-goo, touffah armani, wild apricot, xing ren, zardalou, zardalu (3, 5–8). 


Indigenous to the Korean peninsula and to China, India and Japan (9, 10). 

Cultivated in Asia, North Africa and United States of America (11). 

Description 

A medium-sized, deciduous tree, with reddish bark and glabrous twigs. 

Leaves convoluted in bud, blade broadly ovate, 5–7 cm long, 4–5 cm wide, 

acuminate, crenate-glandular, hairy on the veins of the underside when 

young, glabrous when mature, except for the axils of the underside veins. 

Petiole approximately 2.5 cm long, glandular; stipules, lanceolate, glandular 

on the margins. Flowers appearing before the leaves, bisexual, pinkish 

to white, solitary or fascicled, pedicels very short; calyx-tube campanulate, 

puberulent, 5 mm long; surrounding lobes, pubescent, half the length 

of the tube; petals suborbicular, 7–13 mm long; stamens inserted with the 

petals at the mouth of the calyx-tube; ovary and base of the style hairy. 

Fruit a downy or glabrous, yellow-tinged, red drupe with a fl eshy outer 

layer surrounding a hard stone containing the seed (9, 10).

Plant material of interest: dried ripe seeds 


Flattened, cordate, 1.1–1.9 cm long, 0.8–1.5 cm wide, 0.4–0.8 cm thick, 

acute at one end, plump, unsymmetrical, rounded at the other. Seed coat 

yellowish-brown to deep brown; short linear hilum situated at the acute 

end; chalaza at the rounded end, with numerous, deep-brown veins radiating 

upwards. Testa, thin; two cotyledons (1, 3, 4). 


Odourless; taste: bitter (1, 3, 4). 



Epidermal surface has stone cells, 60–90 μm in diameter, on veins protruded 

by vascular bundles, which appear as angular circles–ellipses, approximately 

uniform in shape, with uniformly thickened walls. In lateral 

view, stone cells appear obtusely triangular, walls extremely thickened at 

the apex (1, 2). 


See characteristic features under Microscopic characteristics (1, 2). 


Macroscopic and microscopic examinations, and microchemical tests 

(1, 2, 4). 

Purity tests 










Heavy metals 



65






Chemical, foreign organic matter, total ash, acid-insoluble ash, sulfated 

ash, alcohol-soluble extractive, water-soluble extractive and loss on drying 



Contains not less than 3.0% amygdalin determined by titrimetric assay 

with silver nitrate (4). A high-performance liquid chromatography 

method is also available (15). 


The major constituent is amygdalin (up to 4.9%), a cyanogenic glycoside 

(a plant compound that contains sugar and produces cyanide). Other cyanogenic 

compounds present are prunasin and mandelonitrile. Also present 

are the amygdalin-hydrolysing enzyme, emulsin, and fatty acids and 

sitosterols (8, 16). The structure of amygdalin is presented below. 



None. 


Internally as a decoction, after processing by dipping in boiling water and 

stir-frying until yellow (4), for symptomatic treatment of asthma, cough 

with profuse expectoration and fever. The seed oil is used for treatment of 

constipation (3, 4). 


Treatment of gynaecological disorders, skin hyperpigmentation, headache 

and rheumatic pain (8). The seed oil is used in the form of eardrops 

for infl ammation and tinnitus, and for treatment of skin diseases (17). 

66 

amygdalin 

HO 

HO 

OH 

O O 

OH 

HO 

HO 

O O 

OH 

H 

CN


Pharmacology 


Analgesic and antipyretic activity 

Intragastric administration of 46.32 mg/kg body weight (bw) of amygdalin 

to rats induced a small increase in body temperature, and prevented 

ephedrine-induced hyperthermia (18). In the hot plate and acetic acidinduced 

writhing tests in mice, the analgesic median effective doses (ED 50 ) 

were 457.0 mg/kg and 288.0 mg/kg bw, respectively. However, at these 

doses, amygdalin could not substitute for morphine in morphine-addicted 

rats in relieving withdrawal syndrome. No anti-infl ammatory effects 

were observed in the animals treated with amygdalin (19). 

Antitumour activity 

Intragastric administration of 200.0 mg/kg–2.0 g/kg bw of amygdalin to 

mice with P388 lymphocytic leukaemia or P815 mast-cell leukaemia on 

days 1 and 5, or days 1, 5 and 9. Despite treatment with high doses of 

amygdalin there was no prolongation in the lifespan of mice in either 

group (20). 

Antitussive activity 

Amygdalin, 30.0 mg, had antitussive effects in the sulfur dioxide gasinduced 

cough model in mice (21, 22). The enzymes amygdalase and 

prunase, along with gastric juice, hydrolyse amygdalin to form small 

amounts of hydrocyanic acid, thereby stimulating the respiratory refl ex 

and producing antitussive and antiasthmatic effects (19). 

Metabolism and pharmacokinetics 

After intragastric administration of 30.0 mg of amygdalin or prunasin to 

rats, capacity for hydrolysing these compounds was greatest in the organs 

of 15-day-old animals, most of the activity being concentrated in the tissues 

of the small and large intestines. The activity decreased with age. In 

adult rats, hydrolysis of prunasin was greater than that of amygdalin and 

was concentrated in the spleen, large intestine and kidney (35.0 μg, 15.0 μg 

and 8.9 μg of prunasin hydrolysed per hour per gram of tissue, respectively). 

Minced liver, spleen, kidney and stomach tissue had a greater hydrolytic 

capability than the homogenate of these organs, while the reverse 

was the case with the small and large intestines. Following oral administration 

of 30.0 mg of amygdalin to adult rats, distribution after the fi rst 

hour was as follows: stomach 0.89 mg, small intestine 0.78 mg, spleen 

0.36 mg, large intestine 0.30 mg, kidney 0.19 mg, liver 0.10 mg and serum 

5.6 μg/ml. At the end of the second hour, the highest amygdalin content, 

0.79 mg, was found in the large intestine (23, 24). 

67


Toxicology 

Intragastric administration of 125.0 mg/kg bw of powdered defatted Semen 

Armeniacae per day for 7 days to mice or rabbits produced no behavioural, 

histological or microscopic toxic effects (25). Intragastric administration 

of 250.0 mg/kg bw of an aqueous suspension of the powdered 

defatted seeds to mice had no toxic effects within a 24-hour period (25). 

The median lethal dose (LD 50 ) of amygdalin in rats was 880.0 mg/kg bw 

after intragastric administration. However, when a dose of 600.0 mg/kg 

bw was administered by the same route, together with β-glucosidase, all 

animals died. Total and magnesium adenosine triphosphatase activities in 

the heart decreased with increasing levels of administered amygdalin (23, 

24). 

Diets containing 10% ground seeds were fed to young and breeding 

male and female rats. The seeds were obtained from 35 specifi c apricot 

cultivars and divided into groups containing low amygdalin (cyanide 

< 50.0 mg/100 g), moderate amygdalin (cyanide 100–200.0 mg/100 g), or 

high amygdalin (cyanide > 200.0 mg/100 g). Growth of young male rats 

was greatest in the low and moderate amygdalin groups, indicating that 

the animals were more sensitive to the bitter taste of the kernels with high 

amygdalin content. In female rats, but not males, liver rhodanase activity 

and blood thiocyanate levels were increased with the high-amygdalin diet, 

but both males and females effi ciently excreted thiocyanate, indicating effi 

cient detoxifi cation and clearance of cyanide hydrolysed from the dietary 

amygdalin. No other changes in blood chemistry were observed (26). 

Toxic amounts of cyanide were released into the blood of rats following 

intragastric administration of amygdalin (proprietary laetrile) (dose not 

specifi ed); cyanide blood concentrations and toxicity were lower when 

amygdalin was given intravenously (dose not specifi ed). Analysis of the 

time course of cyanogenesis suggests that cyanide could accumulate in 

blood after repeated oral doses of amygdalin (27). Following intraperitoneal 

administration of 250.0 mg/kg bw, 500.0 mg/kg bw or 750.0 mg/kg 

bw of amygdalin per day to rats for 5 days, mortalities were 30.8%, 44.1% 

and 56.8%, respectively. The mode of death and the elevated serum cyanide 

levels in the dying animals strongly suggested cyanide poisoning as 

the cause of death (28). 

The systemic effects of an oil prepared from the seeds containing 94% 

unsaturated fatty acids, and oleic and linoleic acids were assessed in a 13week 

feeding study in rats. The animals were fed a diet containing 10% oil. 

No toxic effects were observed and no macroscopic or microscopic lesions 

in any of the organs were found (29). External applications of 0.5 ml of the 

seed oil to rabbits did not produce any observable toxic effects (25). 

68




The term “laetrile” is an acronym used to describe a purifi ed form of 

amygdalin, a cyanogenic glucoside found in the pits of many fruits and 

raw nuts and in other plants, such as lima beans, clover and sorghum (30). 

However, the chemical composition of a proprietary laetrile preparation 

patented in the United States of America (Laetrile ® ), which comprises 

mandelonitrile-β-glucuronide, a semisynthetic derivative of amygdalin, is 

different from that of natural laetrile/amygdalin, which consists of mandelonitrile 

β-d-gentiobioside and is made from crushed apricot pits. Mandelonitrile, 

which contains cyanide, is a structural component of both 

products. It has been proposed that the cyanide is an active anticancer 

ingredient in laetrile, but two other breakdown products of amygdalin, 

prunasin (which is similar in structure to the proprietary product) and 

benzaldehyde, have also been suggested. The studies discussed in this 

summary used either Mexican laetrile/amygdalin or the proprietary formulation. 

Laetrile can be administered orally as a pill, or it can be given 

by injection (intravenous or intramuscular). It is commonly given intravenously 

over a period of time followed by oral maintenance therapy. The 

incidence of cyanide poisoning is much higher when laetrile is taken orally 

because intestinal bacteria and some commonly eaten plants contain 

enzymes (β-glucosidases) that activate the release of cyanide following 

laetrile ingestion (31). Relatively little breakdown to yield cyanide occurs 

when laetrile is injected (32). 

Laetrile has been used as an anticancer treatment in humans worldwide. 

While many anecdotal reports and case reports are available, results 

from only two clinical trials have been published (33, 34). No controlled 

clinical trial (a trial including a comparison group that receives no additional 

treatment, a placebo, or another treatment) of laetrile has ever been 

conducted. Case reports and reports of case series have provided little 

evidence to support laetrile as an anticancer treatment (35). The absence 

of a uniform documentation of cancer diagnosis, the use of conventional 

therapies in combination with laetrile, and variations in the dose and duration 

of laetrile therapy complicate evaluation of the data. In a published 

case series, fi ndings from ten patients with various types of metastatic 

cancer were reported (36). These patients had been treated with a wide 

range of doses of intravenous proprietary laetrile (total dose range 9– 

133 g). Pain relief (reduction or elimination) was the primary benefi t reported. 

Some responses, such as decreased adenopathy (swollen lymph 

nodes) and decreased tumour size, were noted. Information on prior or 

concurrent therapy was provided; however, patients were not followed 

69


long-term to determine whether the benefi ts continued after treatment 

ceased. Another case series, published in 1953, included 44 cancer patients 

and found no evidence of objective response that could be attributed to 

laetrile (37). Most patients with reported cancer regression in this series 

had recently received or were receiving concurrent radiation therapy or 

chemotherapy. Thus, it is impossible to determine which treatment produced 

the positive results. 

In 1978, the United States National Cancer Institute (NCI), at the 

National Institutes of Health, requested case reports from practitioners 

who believed their patients had benefi ted from laetrile treatment (38). Of 

the 93 cases submitted, 67 were considered suitable for evaluation. An 

expert panel concluded that only two of the 67 patients had complete responses, 

and that four others had partial responses while using laetrile. 

On the basis of these six responses, NCI agreed to sponsor phase I and 

phase II clinical trials. The phase I study was designed to test the doses, 

routes of administration and schedule of administration. Six patients with 

advanced cancer were treated with amygdalin given intravenously at 

4.5 g/m 2 per day. The drug was largely excreted unchanged in the urine 

and produced no clinical or laboratory evidence of a toxic reaction. 

Amygdalin given orally, 0.5 g three times daily, produced blood cyanide 

levels of up to 2.1 μg/ml. No clinical or laboratory evidence of toxic reaction 

was seen in the six patients taking the drug at this dosage. However, 

two patients who ate raw almonds while undergoing oral treatment developed 

symptoms of cyanide poisoning (33). 

In the phase II clinical trial, 175 patients with various types of cancer 

(breast, colon, lung) were treated with amygdalin plus a “metabolic therapy” 

programme consisting of a special diet, with enzymes and vitamins. 

The great majority of these patients were in good general condition before 

treatment. None was totally disabled or in a preterminal condition. 

One-third had not received any previous chemotherapy. The amygdalin 

preparations were administered by intravenous injection for 21 days, followed 

by oral maintenance therapy, dosages and schedules being similar 

to those evaluated in the phase I study. Vitamins and pancreatic enzymes 

were also administered as part of a metabolic therapy programme that 

included dietary changes to restrict the use of caffeine, sugar, meats, dairy 

products, eggs and alcohol. A small subset of patients received higherdose 

amygdalin therapy and higher doses of some vitamins as part of the 

trial. Patients were followed until there was defi nite evidence of cancer 

progression, elevated blood cyanide levels or severe clinical deterioration. 

Among 175 patients suitable for assessment, only one met the criteria for 

response. This patient, who had gastric carcinoma with cervical lymph 

70


node metastasis, experienced a partial response that was maintained for 

10 weeks while on amygdalin therapy. In 54% of patients there was measurable 

disease progression at the end of the intravenous course of treatment, 

and all patients had progression 7 months after completing intravenous 

therapy; 7% reported an improvement in performance status 

(ability to work or to perform routine daily activities) at some time during 

therapy, and 20% claimed symptomatic relief. In most patients, these 

benefi ts did not persist. Blood cyanide levels were not elevated after intravenous 

amygdalin treatment; however, they were elevated after oral therapy 

(34). On the basis of this phase II study, NCI concluded that no further 

investigation of laetrile was warranted. 


The side-effects associated with amygdalin treatment are the same as the 

symptoms of cyanide poisoning. Cyanide is a neurotoxin that initially 

causes nausea and vomiting, headache and dizziness, rapidly progressing 

to cyanosis (bluish discoloration of the skin due to oxygen-deprived haemoglobin 

in the blood), liver damage, marked hypotension, ptosis (droopy 

upper eyelid), ataxic neuropathies (diffi culty in walking due to damaged 

nerves), fever, mental confusion, convulsions, coma and death. These 

side-effects can be potentiated by the concurrent administration of raw 

almonds or crushed fruit pits, eating fruits and vegetables that contain βglucosidase, 

such as celery, peaches, bean sprouts and carrots, or high 

doses of vitamin C (35). 

Numerous cases of cyanide poisoning from amygdalin have been reported 

(39–42). After ingestion, amygdalin is metabolized in the gastrointestinal 

tract to produce prunasin and mandelonitrile, which are further 

broken down to benzaldehyde and hydrocyanic acid, the latter of which 

is highly toxic. Overdose causes dizziness, nausea, vomiting and headache, 

which may progress to dyspnoea, spasms, dilated pupils, arrhythmias 

and coma. A 65-year-old woman with cirrhosis and hepatoma lapsed 

into deep coma, and developed hypotension and acidosis after ingestion 

of 3 g of amygdalin. After initial treatment, the patient regained consciousness, 

but massive hepatic damage led to her death (42). A 67-yearold 

woman with lymphoma suffered severe neuromyopathy following 

amygdalin treatment, with elevated blood and urinary thiocyanate and 

cyanide levels. Sural nerve biopsy revealed a mixed pattern of demyelination 

and axonal degeneration, the latter being prominent. Gastrocnemius 

muscle biopsy showed a mixed pattern of denervation and myopathy 

with type II atrophy (41). 

71



Semen Armeniacae should not be administered during pregnancy or 

nursing, or to children (43, 44). 

Warnings 

Overdose may cause fatal intoxication (4, 43, 44). The lethal dose is 

reported to be 7–10 kernels in children and 50–60 kernels (approximately 

30 g) in adults (45). 

Precautions 


No effects on fertility were observed in rats fed a diet containing 10% 

Semen Armeniacae for 5 weeks (26). An aqueous extract of the seeds was not 

mutagenic in the Salmonella/microsome assay using S. typhimurium strains 

TA98 and TA100, or in the Bacillus subtilis H-17 recombinant assay at concentrations 

of up to 100.0 mg/ml (46). However, a hot aqueous extract of the 

seeds was mutagenic in the Salmonella/microsome assay in S. typhimurium 

strains TA98 and TA100 at a concentration of 12.5 mg/plate (47). 


Intragastric administration of amygdalin (dose not specifi ed) to pregnant 

hamsters induced skeletal malformations in the offspring, and intravenous 

administration resulted in embryopathic effects. Oral laetrile increased in 

situ cyanide concentrations, while intravenous laetrile did not. Thiosulfate 

administration protected embryos from the teratogenic effects of oral 

laetrile. The embryopathic effects of oral laetrile appear to be due to cyanide 

released by bacterial β-glucosidase activity (48). A pregnant woman 

who took laetrile as daily intramuscular injections (dose not specifi ed) during 

the last trimester gave birth to a live infant at term. There was no laboratory 

or clinical evidence of elevated cyanide or thiocyanate levels (49). 


Offspring of breeding rats fed a high-amygdalin diet (cyanide > 200.0 mg/ 

100 g) for 18 weeks had lower 3-day survival indices, lactation indices and 

weaning weights than those in a low-amygdalin group (cyanide < 50.0 mg/ 

100 g). This may indicate that the cyanide present in the milk may not be 

effi ciently detoxifi ed to thiocyanate and excreted by neonates (26). 



72






drug interactions; or drug and laboratory test interactions. 

Dosage forms 

Processed (see Posology) dried ripe seeds (4); seed oil. Store in a cool, dry 

place, protected from moths (4). 

Posology 


Average daily dose: 3.0–9.0 g of dried ripe seeds processed by breaking 

into pieces, rinsing in boiling water and stir-frying until yellow, then adding 

to a decoction when nearly fi nished (4). 

References 

1. Asian crude drugs, their preparations and specifi cations. Asian pharmacopoeia. 

Manila, Federation of Asian Pharmaceutical Associations, 1978. 

2. The Japanese pharmacopoeia, 13th ed. (English version). Tokyo, Ministry of 

Health and Welfare, 1996. 

3. Pharmacopoeia of the Republic of Korea, 7th ed. Seoul, Taechan yakjon, 

1998. 

4. Pharmacopoeia of the People’s Republic of China. Vol. I (English ed.). 

Beijing, Chemical Industry Press, 2000. 




6. Petelot A. Les plantes médicinales du Camboge, du Laos et du Viêtnam, Tome 

I. [Medicinal plants in Cambodia, Laos and Viet Nam, Vol. I.] Saigon, Centre 

de Recherches Scientifi ques et Techniques, 1952. 





Illinois at Chicago, 9 February, 2000 production (an online database available 



9. Medicinal plants in China. Manila, World Health Organization Regional 

Offi ce for the Western Pacifi c, 1989 (WHO Regional Publications, Western 

Pacifi c Series, No. 2). 

73


10. Medicinal plants in the Republic of Korea. Manila, World Health Organization 

Regional Offi ce for the Western Pacifi c, 1998 (WHO Regional Publications 

Western Pacifi c Series, No. 21). 

11. Chevalier A. The encyclopedia of medicinal plants. London, Dorling Kindersley, 

1996. 







15. He LY, Li BM. Micro HPLC determination of amygdalin in Semen pruni 

armeniacae and Semen pruni persicae. Biomedical Chromatography, 1988, 

2:271–273. 

16. Gao JJ, Jin CQ. [Comparison of glucoside content of bitter apricot seeds 

processed in different ways and stored routinely for one year.] Zhongguo 

Zhongyao Zazhi, 1992, 17:658–659 [in Chinese]. 

17. Ahmed MS, Honda G, Miki W. Herb drugs and herbalists in the Middle East. 

Tokyo, Institute for the Study of Languages and Cultures of Asia and Africa, 

Tokyo University for Foreign Studies, 1979. 

18. Yuan D et al. Pharmacological properties of traditional medicines. XXV. Effects 

of ephedrine, amygdalin, glycyrrhizin, gypsum and their combinations 

on body temperature and body fl uid. Biological and Pharmaceutical Bulletin, 

1999, 22:165–171. 

19. Zhu YP, Su ZW, Li CH. [Analgesic effect and no physical dependence of 

amygdalin.] Chung Kuo Chung Yao Tsa Chih, 1994, 19:105–107, 128 [in 

Chinese]. 

20. Chitnis MP, Adwankar MK, Amonkar AJ. Studies on high-dose chemotherapy 

of amygdalin in murine P388 lymphocytic leukaemia and P815 mast cell 

leukaemia. Journal of Cancer Research and Clinical Oncology, 1985, 109:208– 

209. 

21. Miyagoshi M, Amagaya S, Ogihara Y. Antitussive effects of L-ephedrine, 

amygdalin, and makyokansekito (Chinese traditional medicine) using a 

cough model induced by sulfur dioxide gas in mice. Planta Medica, 1986, 

52:275–278. 

22. Huang KC. The pharmacology of Chinese herbs. Boca Raton, FL, CRC 

Press, 1993. 

23. Adewusi SR, Oke OL. On the metabolism of amygdalin. 1. The LD 50 and 

biochemical changes in rats. Canadian Journal of Physiology and Pharmacology, 

1985, 63:1080–1083. 

24. Adewusi SR, Oke OL. On the metabolism of amygdalin. 2. The distribution 

of beta-glucosidase activity and orally administered amygdalin in rats. Canadian 

Journal of Physiology and Pharmacology, 1985, 63:1084–1087. 

25. Stosic D, Gorunovic M, Popovic B. Étude toxicologique préliminaire du noyau 

et de l’huile de quelques espèces du genre Prunus. [Preliminary 

74


toxicological study of the nuts and oils from various Prunus species.] Plantes 

médicinales et phytothérapie, 1987, 21:8–13. 

26. Miller KW, Anderson JL, Stoewsand GS. Amygdalin metabolism and effect 

on reproduction of rats fed apricot kernels. Journal of Toxicology and Environmental 

Health, 1981, 7:457–467. 

27. McAnalley BH, Gardiner TH, Garriott JC. Cyanide concentrations in blood 

after amygdalin (laetrile) administration in rats. Veterinary and Human Toxicology, 

1980, 22:400–402. 

28. Khandekar JD, Edelman H. Studies of amygdalin (laetrile) toxicity in 

rodents. Journal of the American Medical Association, 1979, 242:169–171. 

29. Gandhi VM et al. Safety evaluation of wild apricot oil. Food and Chemical 

Toxicology, 1997, 35:583–587. 

30. Lewis JP. Laetrile. Western Journal of Medicine, 1977, 127:55–62. 

31. Herbert V. Laetrile: the cult of cyanide. Promoting poison for profi t. American 

Journal of Clinical Nutrition, 1979, 32:1121–1158. 

32. Unproven methods of cancer management. Laetrile. CA: A Cancer Journal 

for Clinicians, 1991, 41:187–192. 

33. Moertel CG et al. A pharmacologic and toxicological study of amygdalin. 

Journal of the American Medical Association, 1981, 245:591–594. 

34. Moertel CG et al. A clinical trial of amygdalin (Laetrile) in the treatment of 

human cancer. New England Journal of Medicine, 1982, 306:201–216. 

35. Howard-Ruben J, Miller NJ. Unproven methods of cancer management. 

Part II: current trends and implications for patient care. Oncology Nursing 

Forum, 1984, 11:67–73. 

36. Navarro MD. Five years experience with laetrile therapy in advanced cancer. 

Acta Unio Internationalis contra Cancrum, 1959, 15(Suppl. 1):209–221. 

37. Cancer Commission of the California Medical Association: The treatment of 

cancer with “laetriles”. California Medicine, 1953, 78:320–326. 

38. Newell GR, Ellison NM. Ethics and designs: laetrile trials as an example. 

Cancer Treatment Reports, 1980, 64:363–365. 

39. Smith FP et al. Laetrile toxicity: a report of two patients. Cancer Treatment 

Reports, 1978, 62:169–171. 

40. Rubino MJ, Davidoff F. Cyanide poisoning from apricot seeds. Journal of 

the American Medical Association, 1979, 241:350. 

41. Kalyanaraman UP et al. Neuromyopathy of cyanide intoxication due to 

“laetrile” (amygdalin). A clinicopathologic study. Cancer, 1983, 51:2126– 

2133. 

42. Leor R et al. Laetrile intoxication and hepatic necrosis: a possible association. 

Southern Medical Journal, 1986, 79:259–260. 

43. Chandler RF, Anderson LA, Phillipson JD. Laetrile in perspective. Canadian 

Pharmaceutical Journal, 1984, 117:517–520. 

44. Chandler RF et al. Controversial laetrile. Pharmaceutical Journal, 1984, 

232:330–332. 

45. McGuffi n M et al., eds. Botanical safety handbook, Boca Raton, FL, CRC 

Press, 1997. 

75


46. Morimoto I et al. Mutagenicity screening of crude drugs with Bacillus subtilis 

rec-assay and Salmonella/microsome reversion assay. Mutation Research, 

1982, 97:81–102. 

47. Yamamoto H, Mizutani T, Nomura H. [Studies on the mutagenicity of crude 

drug extracts. I.] Yakugaku Zasshi, 1982, 102:596-601 [in Japanese]. 

48. Willhite CC. Congenital malformations induced by laetrile. Science, 1982, 

215:1513–1515. 

49. Peterson RG, Rumack BH. Laetrile and pregnancy. Clinical Toxicology, 

1979, 15:181–184. 

76

Flos Arnicae 

Defi nition 

Flos Arnicae consists of the dried fl ower heads (capitula) of Arnica montana 

L. (Asteraceae) (1–3). 

Synonyms 

Doronicum arnica Desf., D. montanum Lam. (4). Asteraceae are also 

known as Compositae. 


Arnica, arnika, arnique, bétoine des montagnes, betouana, Bergwohlverleih, 

celtic bane, dokhanolfouh, Echtes Wolferlei, estourniga, estrunica, 

Fallkraut, Kraftwurz, leopard’s bane, mountain arnica, mountain tobacco, 

St Luzianskraut, Stichwurzel, strunica, Verfangkraut, Wohlverleih, 

wolf’s bane, Wundkraut (4–9). 


Indigenous to central Europe. Widely cultivated around the world (1, 4, 7). 

Description 

A perennial herb, 20–50 cm high. Aerial portion consists of a basal 

rosette of entire oblanceolate leaves up to 17 cm long, five to seven 

veins, from the centre of which projects an erect, simple, glandular 

hairy stem up to 0.6 m high. Stem bears two to four pairs of cauline 

leaves, ovate, elliptic-oblong, lanceolate or oblanceolate, with rounded 

or rounded-toothed apex and clothed with numerous nonglandular 

and glandular hairs, up to 16 cm long and 5 cm wide. Peduncles, one 

to three, bearing alternate bracteoles, extending from the uppermost 

pair of cauline leaves; glandular–puberulent, each terminating in a 

hemispherical or turbinate capitulum bearing orange-yellow flowers, 

which are tubular. Fruits, black to brown, five-ribbed, with a bristle 

tuft of hairs (5, 8). 

77


Plant material of interest: dried fl ower heads 


Capitulum about 20 mm in diameter and 15 mm deep, with a peduncle 

2–3 cm long. Involucre with 18–24 elongated lanceolate bracts, 8–10 mm 

long with acute apices, arranged in one or two rows, green with yellowishgreen 

external hairs visible under a lens. Receptacle, about 6 mm in diameter, 

convex, alveolate and covered with hairs; periphery bears about 20 

ligulate fl orets 20–30 mm long; disc bears a greater number of tubular 

fl orets about 15 mm long. Ovary, 4–8 mm long, crowned by a pappus of 

whitish bristles 4–8 mm long. Some brown achenes, crowned or not by a 

pappus, may be present (3). 


Odour: characteristic aromatic (1, 3, 5); taste: bitter and acrid (1, 5). 


Epidermis of corolla papillose, containing yellow-orange globular masses, 

some cells also containing dark brown–black patches of phytomelan; 

base of corolla tube of ligulate fl orets with uniseriate covering trichomes 

of four to six cells, up to 1 mm in length; bristles of pappus four to six 

cells in diameter and barbed by exertion of the pointed cell apices. Cells 

of ovary or fruit walls contain abundant black patches of phytomelan. 

Corolla and ovary wall with numerous composite glandular trichomes; 

ovary wall with numerous appressed twin hairs each composed of two 

narrow parallel cells diverging at the tips. Pollen grains spiky, spherical 

35–52 μm in diameter, with fi nely granular exine, spines up to 8 μm long, 

three pores and furrows (1). 


Light yellowish-brown to light olive-brown. Epidermis of the involucre 

bracts with stomata and trichomes, which are more abundant on the outer 

surface. Trichomes include: uniseriate multicellular covering trichomes, 

50–500 μm long, particularly abundant on the margins; secretory trichomes 

about 300.0 μm long with uni- or biseriate multicellular stalks 

and with multicellullar, globular heads, abundant on the outer surface; 

similar trichomes, 80.0 μm long, abundant on the inner surface of the 

bract. Epidermis of the ligulate corolla consists of lobed or elongated 

cells, a few stomata and trichomes of different types: covering trichomes, 

with very sharp ends, whose length may exceed 500 μm; secondary trichomes 

with multicellular stalks and multicellular globular heads. Ligule 

ends in rounded papillose cells. Epidermis of the ovary covered with trichomes: 

secondary trichomes with short stalks and multicellular globular 

78

heads; twinned covering trichomes usually consisting of two longitudinally 

united cells, with common punctuated walls, their ends sharp and 

sometimes bifi d. Epidermis of the calyx consists of elongated cells bearing 

short, unicellular, covering trichomes pointing towards the upper end of 

the bristle. Pollen grains, about 30 μm in diameter, rounded, with spiny 

exine, and three germinal pores (3). 


Macroscopic and microscopic examinations (1, 3–5), and thin-layer chromatography 

for phenolic compounds (3). 

Purity tests 







Total ash 




Sulfated ash 





Not less than 15% using 45% ethanol (1). 



Flos Arnicae 



0.05 mg/kg (12). For other pesticides, see the European Pharmacopoeia 

79


(12) and the WHO guidelines on quality control methods for medicinal 


Heavy metals 




Where applicable, consult the WHO guidelines on quality control 

methods for medicinal plants (10) for the analysis of radioactive isotopes. 


Chemical tests to be established in accordance with national requirements. 


Contains not less than 0.40% of total sesquiterpene lactones calculated as helenalin 

tiglate, determined by high-performance liquid chromatography (3). 


The major constituents include the essential oil (0.5%), fatty acids (content 

not specifi ed), thymol (content not specifi ed), pseudoguaianolide 

sesquiterpene lactones (0.2–0.8%) and fl avonoid glycosides (0.2–0.6%) 

(4, 9, 14). The primary sesquiterpene lactones are helenalin, 11α,13-dihydrohelenalin 

and their fatty acid esters. Flavonoids include glycosides 

and/or glucuronides of spinacetin, hispidulin, patuletin and isorhamnetin, 

among others (4, 7, 9, 14–16). The structures of helenalin and 11α,13dihydrohelenalin 

are presented below. 

helenalin 



None. 


As a topical counterirritant for treatment of pain and infl ammation resulting 

from minor injuries and accidents, including bruises, ecchymoses, 

80 

H 3 C 

H 

H 

H 

CH 

O 

3 

H 

H OH 

O CH 2 

O 

11α,13-dihydrohelenalin 

H 3 C 

H 

O 

H 

H 

CH 

O 

3 

H 

H OH 

H 

CH3 O

Flos Arnicae 

haematomas and petechiae (1, 17). Treatment of infl ammation of the oral 

mucous membranes, insect bites and superfi cial phlebitis (17). 


Treatment of indigestion, cardiovascular disease, and rheumatism. As an 

emmenagogue (9). 

Pharmacology 


Analgesic and anti-infl ammatory activity 

In vitro, helenalin, 5.0 μmol/l, signifi cantly (P < 0.01) suppressed the activity 

of prostaglandin synthetase in mouse and rat homogenates, and human 

polymorphonuclear neutrophils, indicating an anti-infl ammatory 

effect (18). Human polymorphonuclear neutrophil chemotaxis was 

inhibited by helenalin, 5.0 μmol/l, in vitro. It was concluded that the 

α-methylene-γ-lactone moiety played a role in the anti-infl ammatory 

activity of this compound (18). Helenalin, 4.0 μmol/l, selectively inhibited 

the transcription factor nuclear factor (NF)-κβ (19). 

Intragastric administration of 100.0 mg/kg body weight (bw) of an 

80% ethanol extract of Flos Arnicae reduced carrageenan-induced hind 

paw oedema by up to 29% in rats (20). Intraperitoneal administration of 

2.5–5.0 mg/kg bw of helenalin signifi cantly (P < 0.001) inhibited carrageenan-induced 

hind paw oedema in rats by 77% after 72 hours (21). Intraperitoneal 

administration of 20.0 mg/kg bw of helenalin strongly inhibited 

acetic acid-induced writhing by 93% in mice but did not have 

analgesic effects in mice in the hot-plate test. Intraperitoneal administration 

of 2.5 mg/kg bw of helenalin to rats inhibited arthritis induced by 

Mycobacterium butyricum by 87% (21). 

Antioxidant activity 

The effect of a tincture of Flos Arnicae on lipid peroxidation and glutathione 

metabolism in rat liver was assessed following induction of hepatitis 

by the administration of carbon tetrachloride. Intragastric administration 

of 0.2 ml/g bw of the tincture to rats decreased the rate of lipid oxidation 

and increased the activities of the enzymes involved in glutathione metabolism 

(22). Intragastric administration of 0.2 ml/g bw of the tincture 

per day for 14 days to rats with hepatitis induced by carbon tetrachloride 

led to a normalization of the hydrolytic enzymes (23). 


Helenalin is cytotoxic to a wide variety of cancer cell lines in vitro, with a 

median effective dose (ED 50 ) range of 0.03–1.0 μg/ml (24–27). Intraperi- 

81


toneal administration of 1.5–33.3 mg/kg bw of helenalin to mice and rats 

had antitumour activity against a variety of chemically induced tumours 

(28–30). 


Flos Arnicae and extracts of the fl ower heads have cardiotonic and hypotensive 

effects in various animal models. Intravenous administration of a 

single dose of 1.0 ml of a tincture of the fl ower heads to rabbits had negative 

chronotropic effects and reduced blood pressure (31). Intravenous administration 

of 1.0 ml of an aqueous or 95% ethanol extract of the fl ower 

heads had cardiotonic effects in frogs, and a tincture demonstrated hypotensive 

activity in rabbits after intravenous administration of 1.0 ml (32, 

33). A 30% ethanol extract of the fl ower heads, 0.1–0.3% in the bath medium, 

had positive inotropic effects in isolated guinea-pig hearts (33). 

Intravenous administration of 5.0 g/kg bw of a fl uid extract or tincture of 

the fl ower heads increased the blood pressure of cats and guinea-pigs (34). 

Helenalin, 50.0 μg/ml, decreased intracellular calcium levels in cultured 

fi broblasts, and potentiated the responses induced by vasopressin 

and bradykinin (35). Intravenous administration of helenalin had cardiotoxic 

effects in mice (25.0 mg/kg bw) and dogs (90.0 mg/kg bw) (36). 

Choleretic activity 

Intravenous administration of 1.0 ml of a 95% ethanol extract of the fl ower 

heads to dogs increased bile secretion by 25–120% (37). Intragastric administration 

of a hot aqueous extract of the fl ower heads had choleretic effects 

in rats (dose not specifi ed) (38) and dogs (50.0 ml/animal) (39). 

Toxicology 

The oral median lethal dose (LD 50 ) of a 30% ethanol extract of the fl ower 

heads was 37.0 ml/kg in mice (33). The intragastric LD 50 for helenalin has 

been established for numerous species: mice 150.0 mg/kg bw, rats 

125.0 mg/kg bw, rabbits 90.0 mg/kg bw, hamsters 85.0 mg/kg bw and 

ewes 125.0 mg/kg bw (40). 

Uterine stimulant effects 

Intragastric administration of a tincture of the fl ower heads (dose not 

specifi ed) had uterine stimulant effects in guinea-pigs (41). Intragastric 

administration of a hot aqueous extract of the fl ower heads (dose not 

specifi ed) stimulated uterine contractions in rats (38). 


No information available. Clinical trials of homeopathic preparations 

were not assessed. 

82

Flos Arnicae 


Numerous cases of dermatitis of toxic or allergic origin have been reported 

(42), usually following prolonged, external application of a tincture 

of Flos Arnicae. The compounds responsible for the hypersensitivity 

reaction are the sesquiterpene lactones helenalin and helenalin acetate 

(43). Cross-reactivity to other Asteraceae fl owers has been reported (44–47). 

The fl ower heads are irritant to the mucous membranes and ingestion 

may result in gastroenteritis, muscle paralysis (voluntary and cardiac), an 

increase or decrease in pulse rate, heart palpitations, shortness of breath 

and death. A fatal case of poisoning following the ingestion of 70.0 g of a 

tincture of the fl ower heads has been reported (48). 

A case of severe mucosal injuries following the misuse of an undiluted 

mouth rinse with a 70% alcohol content, which also contained oil of peppermint 

and Flos Arnicae, has been reported (49). 


Flos Arnicae is used in traditional systems of medicine as an emmenagogue 

(9), and its safety during pregnancy and nursing has not been established. 

Therefore, in accordance with standard medical practice, the fl ower 

heads should not be administered to pregnant or nursing women. Flos 

Arnicae is also contraindicated in cases of known allergy to Arnica or 

other members of the Asteraceae (Compositae) (37, 42, 50, 51). 

Warnings 

A fatal case of poisoning following the ingestion of 70.0 g of a tincture of 

Flos Arnicae has been reported (48). Internal use of Flos Arnicae or extracts 

of the fl ower heads is not recommended. For external use only. Do 

not apply to open or broken skin. Keep out of the reach of children (17). 

Precautions 

General 

Avoid excessive use. Chronic, frequent external applications may induce 

allergy-related skin rashes with itching, blister formation, ulcers and superfi 

cial necrosis. Prolonged treatment of damaged or injured skin or indolent 

leg ulcers may induce the formation of oedematous dermatitis with 

the formation of pustules (17). 


Helenalin has cytotoxic effects in vitro (see Experimental pharmacology). 

However, in the Salmonella/microsome assay, helenalin was not muta- 

83


genic in S. typhimurium strains TA102, TA98 or TA100 at concentrations 

of up to 30 μg/ml (52, 53). 


Intraperitoneal administration of 6.0–20.0 mg/kg bw of helenalin was not 

teratogenic in mice (21). 






See Warnings. For external use only. Do not apply to abraded or broken 

skin. 


No information available on precautions concerning drug interactions; or 

drug and laboratory test interactions. 

Dosage forms 

Dried fl ower heads and other galenical preparations. Store protected from 

light and moisture (7). 

Posology 


For external applications only, apply undiluted externally on the affected 

area two or three times daily: infusion for compresses, 2 g of Flos Arnicae 

per 100 ml water; tincture for compresses, one part Flos Arnicae to 10 

parts 70% ethanol; mouth rinse, 10-fold dilution of tincture, do not swallow; 

ointment, 20–25% tincture of Flos Arnicae or not more than 15% 

essential oil (vehicle not specifi ed) (17). 

References 


1996. 

2. Pharmacopoeia helvetica, 8th ed. Berne, Federal Department of the Interior, 

1997. 

3. European pharmacopoeia, 3rd ed. Suppl. 2001. Strasbourg, Council of Europe, 

2000. 

84

Flos Arnicae 








1959. 


Press, 1994. 



9. Farnsworth NR, ed. NAPRALERT database. Chicago, University of 

Illinois at Chicago, IL, 9 February, 2001 production (an online database 

available directly through the University of Illinois at Chicago 

or through the Scientific and Technical Network (STN) of Chemical 

Abstracts Services). 



11. Karnick CR, ed. Pharmacopoeial standards of herbal plants. Delhi, Sri 

Satguru Publications, 1994 (Indian Medical Science Series, No. 36). 




from Food Safety, World Health Organization, 1211 Geneva 27, 

Switzerland). 

14. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier 

Publishing, 1995. 

15. Merfort I. Flavonol glycosides of Arnicae Flos DAB 9. 36th Annual 

Congress on Medicinal Plant Research, Hamburg, 22–27 September 1986. 

Planta Medica, 1986, Abstr. K24. 

16. Merfort I, Wendisch D. Flavonolglucuronide aus den Blüten von Arnica 

montana. [Flavonoid glucuronides from the fl owers of Arnica montana.] 

Planta Medica, 1988, 54:247–250. 



18. Hall IH et al. Mode of action of sesquiterpene lactones as anti-infl ammatory 

agents. Journal of Pharmaceutical Sciences, 1980, 69:537–543. 

19. Lyss G et al. Helenalin, an anti-infl ammatory sesquiterpene lactone from 

Arnica, selectively inhibits transcription factor NF-κβ. Biological Chemistry, 

1997, 378:951–961. 

20. Mascolo N et al. Biological screening of Italian medicinal plants for antiinfl 

ammatory activity. Phytotherapy Research, 1987, 1:28–31. 

21. Hall IH et al. Anti-infl ammatory activity of sesquiterpene lactones and 

related compounds. Journal of Pharmaceutical Sciences, 1979, 68:537–542. 

85


22. Yaremy IM, Grygorieva NP, Meshchishen IF. [Effect of Arnica montana on 

the state of lipid peroxidation and protective glutathione system of rat liver 

in experimental toxic hepatitis.] Ukrainskii Biokhimicheskii Zhurnal, 1998, 

70:78–82 [in Russian]. 

23. Yaremy IM, Grygorieva NP, Meshchishen IF. [Effect of Arnica montana 

tincture on some hydrolytic enzyme activities of rat liver in experimental 

toxic hepatitis.] Ukrainskii Biokhimicheskii Zhurnal, 1998, 70:88–91 [in 

Russian]. 

24. Lee KH et al. Cytotoxicity of sesquiterpene lactones. Cancer Research, 1971, 

31:1649–1654. 

25. Lee KH et al. Antitumor agents. 11. Synthesis and cytotoxic activity of 

epoxides of helenalin related derivatives. Journal of Medicinal Chemistry, 

1975, 18:59–63. 

26. Woerdenbag HJ et al. Cytotoxicity of fl avonoids and sesquiterpene lactones 

from Arnica species. Planta Medica, 1993, 59(Suppl.):A681. 

27. Beekman AC et al. Structure–cytotoxicity relationships of some helenanolide-type 

sesquiterpene lactones. Journal of Natural Products, 1997, 60:252– 

257. 

28. Pettit GR, Cragg GM. Antineoplastic agents 32. The pseudoguaianolide 

helenalin. Experientia, 1973, 29:781. 

29. Hall IH et al. Antitumor agents XXX. Evaluation of α-methylene-γ-lactonecontaining 

agents for inhibition of tumor growth, respiration, and nucleic 

acid synthesis. Journal of Pharmaceutical Sciences, 1978, 67:1235–1239. 

30. Hall IH et al. Antitumor agents XLII. Comparison of antileukemic activity 

of helenalin, brusatol and bruceantin, and their esters on different strains of 

P-388 lymphocytic leukemic cells. Journal of Pharmaceutical Sciences, 1981, 

70:1147–1150. 

31. Stimpson HS. Arnica montana. Journal of the American Institute of 

Homeopathy, 1926, 19:213–215. 

32. Barz E. Action of different constituents of Arnica montana on the 

isolated frog heart. Zeitschrift für die Gesamte experimentelle Medizin, 1943, 

111:690–700. 

33. Leslie GB. A pharmacometric evaluation of nine Bio-Strath herbal remedies. 

Medita, 1978, 8:3–19. 

34. Forst AW. Zur Wirkung der Arnica montana aus den Kreislauf. [The effect of 

Arnica montana on the circulation.] Archives of Experimental Pathology and 

Pharmacology, 1943, 201:243–260. 

35. Narasimhan TR, Kim HL, Safe SH. Effects of sesquiterpene lactones on mitochondrial 

oxidative phosphorylation. General Pharmacology, 1989, 

20:681–687. 

36. Szabuniewicz M, Kim HL. Pharmacodynamic and toxic action of Helenium 

microcephalum extract and helenalin. Southwest Veterinarian, 1972, 25:305– 

311. 

86

Flos Arnicae 

37. Hausen BM. The sensitizing capacity of Compositae plants. III. Test results 

and cross-reactions in Compositae-sensitive patients. Dermatologica, 1979, 

159:1–11. 

38. Kreitmair H. Pharmakologische Versuche mit einigen einheimischen Pfl anzen. 

[Pharmacological trials with some domestic plants.] E Merck’s Jahresbericht 

über Neuerungen auf den Gebieten der Pharmakotherapie und 

Pharmazie, 1936, 50:102–110. 

39. Pasechnik IK. [The possibility of using preparations of Arnica montana and 

Matricaria chamomilla for some affections of the liver, bile ducts, and gall 

bladder.] In: [Information on the Fifth Scientifi c and Practical Conference of 

Ternopol’ Medical Institute], 1963, 61 [in Russian]. 

40. Witzel DA, Ivie W, Dollahite JW. Mammalian toxicity of helenalin the toxic 

principle of Helenium microcephalum (smallhead sneezeweed). American 

Journal of Veterinary Research, 1976, 37:859–861. 

41. Brunzell A, Wester S. Arnica chamissonis and Arnica montana compared. 

Svensk Farmacevtisk Tidskrift, 1947, 51:645–651. 

42. Hörmann HP, Korting HC. Allergic acute contact dermatitis due to Arnica 

tincture self-medication. Phytomedicine, 1995, 4:315–317. 

43. Hermann HD, Willuhn G, Hausen B. Helenalin methacrylate, a new pseudoguaianolide 

from the fl owers of Arnica montana L. and the sensitizing 

capacity of their sesquiterpene lactones. Planta Medica, 1978, 34:229–304. 

44. Paschould JM. Kontaktekzem durch Chrysanthemen-Gekreuzte Überempfi 

ndlichkeitsreaktion mit Arnicatinktur. [Contact eczema due to chrysanthemum-Arnica 

tincture cross-reactive hypersensitivity.] Hautarzt, 1965, 

16:229–231. 

45. Hausen BM, Oestmann G. Untersuchungen über die Häufi gkeit berufsbedingter 

allergischer Hauterkrankungen auf einem Blumengrossmarkt. 

[Studies on the incidence of occupationally induced allergic skin disease in 

fl ower market vendors.] Dermatosen, 1988, 36:117–124. 

46. Pirker C et al. Cross-reactivity with Tagetes in Arnica contact eczema. 

Contact Dermatitis, 1992, 26:217–219. 

47. Machet L et al. Allergic contact dermatitis from sunfl ower (Helianthus annuus) 

with cross-sensitivity to Arnica. Contact Dermatitis, 1993, 28:184–185. 

48. Schulz V, Hänsel R, Tyler VE, eds. Rational phytotherapy. A physicians’ guide 

to herbal medicine. Berlin, Springer, 1998. 

49. Moghadam BK, Gier R, Thurlow T. Extensive oral mucosal ulcerations 

caused by misuse of a commercial mouthwash. Cutis, 1999, 64:131–134. 

50. Rudzki E, Grzywa Z. Dermatitis from Arnica montana. Contact Dermatitis, 

1977, 3:281–282. 

51. Ippen H. Grundfragen zur “Arnika-Allergie”. [Rationale for “Arnica allergy”.] 

Dermatosen, 1994, 42:250–252. 

52. MacGregor JT. Mutagenic activity of hymenovin, a sesquiterpene lactone 

from western bitterweed. Food and Cosmetics Toxicology, 1977, 15:225. 

53. Stuppner H, Stuppner H, Rodriguez E. A novel enol-pseudoguaianolide 

from Psilostrophe cooperi. Phytochemistry, 1988, 27:2681–2684. 

87

88 

Folium Azadirachti 

Defi nition 

Folium Azadirachti consists of the dried leaves of Azadirachta indica A. 

Juss. (Meliaceae) (1–4). 

Synonyms 

Melia azadirachta L., M. indica (A. Juss.) Brand., M. indica Brand. (1–3). 


Abodua, aforo-oyinbo, anwe egyane, arista, azad dirakht, azadarakht, 

azedarach, bead tree, bevinama, bevu, bewina mara, bodetso, bo-nim, 

cape lilac, chajara hourra, chichaâne arbi, China berry, China tree, cót 

anh, darbejiya, dogo yaro, dogo’n yaro, dogonyaro, dogoyaro, dongo 

yaro, dua gyane, gori, gringging, holy tree, igi-oba, imba, Indian lilac, 

Indian lilac tree, Indian neem tree, Indian sadao, Intaran, isa-bevu, jaroud, 

kahibevu, kingtsho, kiswahhili, kohhomba, kohumba, koummar, kuman 

masar, kuman nasara, kwinin, labkh, lilac de perse, lilas des indes, liliti, 

limb, limba, limbado, limado, linigbe, mahanim, mahanimba, mahnimu, 

mak tong, margosa, margosa tree, margose, marrar, mimba, mindi, miro 

tahiti, mwarobaini, neeb, neem, neem sikha, nim, nim tree, nimba, nimbatikta, 

nimgach, nivaquine, ogwu akom, oilevevu, ouchi, Persian lilac, phãk 

kã dão, picumarda, sa-dao, sa-dao baan, sadao India, sdau, salien, sandan, 

sandannoki, sãu dâu, senjed talhk, shajarat el horrah, shereesh, tâak, 

tâakhak, touchenboku, vembu, vemmu, vepa, veppam, veppu, white cedar, 

xoan dào, zanzalakht, zaytoon (1–9). 


Indigenous to India, and widely distributed in South and South-East Asia. 

Cultivated in Africa, the South Pacifi c Islands, South and Central America 

and Australia, and in southern Florida and California, United States of 

America (1–3, 8–11).

Description 

A straight-boled deciduous tree 6–25 m high. Bark dark-brown, externally 

fi ssured, with a buff inner surface, fi brous fracture. Leaves alternately 

arranged, pinnately compound, up to 40 cm long, composed of 8– 

18 short-petiolate narrow-ovate, pointed, curved toothed leafl ets, 3–10 cm 

long and 1–4 cm wide arranged in alternate pairs. Infl orescences axillary 

panicles; fl owers numerous, white, pedicillate, about 1.0 cm wide. Fruits 

yellowish drupes, oblong, about 1.5 cm long, containing thin pulp surrounding 

a single seed. When bruised, leaves and twigs emit an onion-like 

odour (1–3, 8, 11). 

Plant material of interest: dried leaves 

Other plant parts used, but not included in this monograph: fl owers, 

seeds, stem bark, oil (1–3, 8, 10, 12). 


Compound leaves up to 40 cm long composed of 8–18 short-petiolate 

narrow-ovate, pointed, curved toothed leafl ets, 3–10 cm long and 1–4 cm 

wide arranged in alternate pairs. Glabrous dark green upper surface, paler 

underside (1–3). 


Odour: characteristic, alliaceous; taste: bitter (1–3). 



Lower epidermis with anomocytic stomata and occasional unicellular trichomes. 

Two layers of palisade cells are found below the upper epidermis. 

Spongy parenchyma exhibits intercellular spaces and secretory cells, 

which are abundant on the borderline with the palisade cells. Anticlinal 

cell walls are almost straight. Mesophyll contains rosette crystals. Collenchyma 

interrupts mesophyll on both upper and lower surfaces in the 

midrib region. Vascular bundles strongly curved, lignifi ed, collateral 

(1–3). 


Green and characterized by the presence of cortical cells of the rachis, 

fragments of palisade cells, hairs, fi bres, wood fi bres, spiral lignifi ed vascular 

elements, epidermal tissues of the leaf with characteristic anomocytic 

stomata and large pit cells with intercellular spaces. Epidermal cell 

walls straight (2, 3). 

89



Macroscopic and microscopic examinations (1–3), microchemical tests (2) 

and thin-layer chromatography (2). 

Purity tests 







Total ash 















Heavy metals 





methods for medicinal plants (13) for the analysis of radioactive isotopes. 

90



Chemical and sulfated ash tests to be established in accordance with 

national requirements. 


High-performance liquid chromatography methods are available for the 

quantitative determination of oxidized tetranortriterpenes (16, 17). 


The major characteristic constituents are oxidized tetranortriterpenes 

including azadirachtin (azadirachtin A), 3-tigloylazadirachtol (azadirachtin 

B), 1-tigloyl-3-acetyl-11-hydroxy-meliacarpin (azadirachtin 

D), 11-demethoxycarbonyl azadirachtin (azadirachtin H), 1-tigloyl-3acetyl-11-hydroxy-11-demethoxycarbonyl 

meliacarpin (azadirachtin 

I), azadiriadione, azadirachtanin, epoxyazadiradione, nimbin, deacetylnimbin, 

salannin, azadirachtolide, isoazadirolide, margosinolide, nimbandiol, 

nimbinene, nimbolin A, nimbocinone, nimbocinolide, nimbolide, 

nimocin, nimocinol and related derivatives (9, 11, 18–20). The 

structures of azadirachtin, nimbin and deacetylnimbin are presented 

below. 

O 

O CH3 H3C H3C O 

H 

CH3 H 

O 

O 

O 

O 

H 

H 

O 

O 

H 

OH 

CH3 H O 

OH 

H 

H 

O 

O 

OH 

H 

CH3 O CH3 azadirachtin 



External applications for treatment of ringworm (21). However, data from 

controlled clinical trials are lacking. 


Treatment of worm and lice infections, jaundice, external ulcers, cardiovascular 

disease, diabetes, gingivitis, malaria, rheumatism and skin 

disorders. External applications for treatment of septic wounds and boils 

(6, 8). 

H 3C 

O 

O 

H 3C 

CH 3 

H CH3 O 

O H 

H3C O 

H 

CH3 O 

H 

R 

O 

nimbin 

deacetylnimbin 

H 

R = CO-CH 3 

R = H 

H 

O 

91



Treatment of allergic skin reactions, asthma, bruises, colic, conjunctivitis, 

dysentery, dysmenorrhoea, delirium in fever, gout, headache, itching due 

to varicella, jaundice, kidney stones, leprosy, leukorrhoea, psoriasis, scabies, 

smallpox, sprains and muscular pain, syphilis, yellow fever, warts 

and wounds (10, 22). Also used as an antivenin, contraceptive, emmenagogue, 

tonic, stomatic and vermicide (9). 

Pharmacology 


Anxiolytic and analgesic activities 

Intragastric administration of 10.0–200.0 mg/kg body weight (bw) of an 

aqueous extract of Folium Azadirachti produced anxiolytic effects similar 

to those of 1.0 mg/kg bw of diazepam in rats in the elevated-plus-maze 

and open-fi eld behaviour tests (23). 

The analgesic effect of an extract of the leaves was assessed in mice 

using the acetic acid writhing test and the tail fl ick test. Intragastric 

administration of 10.0–100.0 mg/kg bw of the extract reduced the incidence 

of writhing and enhanced tail-withdrawal latencies (24). 

Antiandrogenic activity 

Intragastric administration of 20.0 mg, 40.0 mg or 60.0 mg of powdered 

leaves per day to rats for 24 days resulted in a decrease in the weight of the 

seminal vesicles and ventral prostate, and a reduction in epithelial height, 

nuclear diameter and secretory material in the lumen of these organs. Decreases 

in total protein and acid phosphatase activities were also observed. 

These regressive histological and biochemical changes suggest that the 

leaves have an antiandrogenic property (25). Histological and biochemical 

changes were also observed in the caput and cauda epididymis of rats 

treated orally with similar doses of the powdered leaves given daily for 

24 days. The height of the epithelium and the diameter of the nucleus in 

both regions were reduced. Serum testosterone concentrations were also 

reduced in animals receiving the highest dose (26). Intragastric administration 

of an aqueous extract of the leaves (dose not specifi ed) to male 

mice daily for 10 weeks resulted in a signifi cant (P < 0.01) reduction in 

total serum testosterone and bilirubin (27). 

Antihepatotoxic activity 

The effect of an aqueous extract of the leaves was evaluated in paracetamolinduced 

hepatotoxicity in rats. Intragastric administration of 500.0 mg/kg 

bw of the extract signifi cantly (P < 0.01) reduced elevated levels of serum 

92


aspartate aminotransferase, alanine aminotransferase and γ-glutamyl 

transpeptidase (28). 


Intragastric administration of 200.0 mg/kg bw of an aqueous extract of 

the leaves to rats decreased infl ammation and swelling in the cotton pellet 

granuloma assay (29). Intraperitoneal injection of 200.0–400.0 mg/kg bw 

of an aqueous extract of the leaves to rats reduced carrageenan-induced 

footpad oedema (30). 

Antihyperglycaemic activity 

A hypoglycaemic effect was observed in normal and alloxan-induced diabetic 

rabbits after administration of 50.0 mg/kg bw of an ethanol extract 

of the leaves. The effect was more pronounced in diabetic animals, and 

reduced blood glucose levels. The hypoglycaemic effect was comparable 

to that of glibenclamide. Pretreatment with the extract 2 weeks prior to 

alloxan treatment partially prevented the rise in blood glucose levels as 

compared with control diabetic animals (31). Intragastric administration 

of 50.0–400.0 mg/kg bw of a 70% ethanol extract of the leaves signifi - 

cantly (P < 0.001) reduced elevated blood glucose levels in normal and 

streptozocin-induced diabetic rats (32–34). A 70% ethanol extract of the 

leaves signifi cantly (P < 0.05) blocked the inhibitory effect of serotonin 

on insulin secretion mediated by glucose in isolated rat pancreas (35). 

Antimalarial activity 

An aqueous or ethanol extract of the leaves inhibited the growth of Plasmodium 

falciparum in vitro, with median inhibitory concentrations of 

115.0 μg/ml and 5.0 μg/ml, respectively. Nimbolide, a constituent of the 

extract, inhibited the growth of P. falciparum in vitro with a median effective 

concentration of 2.0 μg/ml (36). However, intragastric administration 

of 746.0 mg/kg bw of the aqueous extract, 62.5 mg/kg bw of the ethanol 

extract or 12.5 mg/kg bw of nimbolide had no such effect in Plasmodiuminfected 

mice (36). P. berghei-infected mice showed parasite suppression 

after intragastric administration of 125.0–500.0 mg/kg bw of a dried 

methanol extract of the leaves per day for 4 days, but all the animals died 

after 5 days (37). A 95% ethanol extract of the leaves at concentrations of 

up to 500.0 mg/ml did not inhibit the growth of P. falciparum in vitro 

(38). 

Antimicrobial and antiviral activity 

A methanol extract of the leaves, 1.0 mg/ml, inhibited plaque formation 

in six antigenic types of coxsackievirus B at 96 hours in vitro. The minimal 

inhibitory concentrations were not toxic to Vero African green mon- 

93


key kidney cells. The subtoxic concentration was 8.0 mg/ml and the cytotoxic 

concentration was 10.0 mg/ml (39). 

An aqueous extract of the leaves, at various concentrations depending 

on the organism, inhibited the growth of Bacteroides gingivalis, B. intermedius, 

Streptococcus salivarius and S. viridans in vitro (40). A petroleum 

ether extract of the leaves, at various concentrations depending on the 

organism, inhibited the growth of Epidermophyton fl occosum, Microsporum 

canis, M. gypseum, Trichophyton concentricum, T. violaceum and 

T. rubrum (41). 


The effect of the leaves on hepatic lipid peroxidation and antioxidant status 

during gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine 

was assessed in rats. Intragastric administration of 

100.0 mg/kg bw of an aqueous extract of the leaves decreased lipid peroxidation 

in the liver of tumour-bearing animals, which was accompanied 

by a decrease in the activities of glutathione peroxidase, glutathione-Stransferase 

and γ-glutamyl transpeptidase, and a reduction in glutathione 

level. Administration of 100.0 mg/kg bw of an extract of the leaves suppressed 

lipid peroxidation and increased hepatic levels of glutathione and 

glutathione-dependent enzymes (42). Intragastric administration of 

100.0 mg/kg bw of an aqueous extract of the leaves three times per week 

to hamsters with buccal pouch carcinogenesis induced by 7,12-dimethylbenz[α]anthracene 

reduced lipid peroxidation and increased the glutathione 

concentration in the oral mucosa of tumour-bearing animals (43). 

Antiulcer activity 

The antiulcer effects of an aqueous extract of the leaves were investigated 

in rats exposed to 2-hour cold-restraint stress or given ethanol for 1 hour. 

The extract, administered orally in doses of 10.0 mg/kg bw, 40.0 mg/kg 

bw or 160.0 mg/kg bw as single- or fi ve-dose pretreatments produced a 

dose-dependent reduction in the severity of gastric ulcers induced by 

stress and a decrease in gastric mucosal damage provoked by ethanol. The 

extract prevented mast cell degranulation and increased the amount of 

adherent gastric mucus in stressed animals (44). Intragastric administration 

of 40.0 mg/kg bw of an aqueous extract of the leaves per day for 

5 days to rats inhibited stress-induced depletion of gastric wall adherent 

cells and mucus production (44). 


Intragastric administration of 200.0 mg/kg bw of an alcohol extract of the 

leaves to anaesthetized rabbits decreased the heart rate from 280 to 

94


150 beats per minute, and had a weak antiarrhythmic effect against ouabain-induced 

dysrhythmia (45). Intravenous administration of 100.0 mg/ 

kg bw, 300.0 mg/kg bw or 1000.0 mg/kg bw of an ethanol extract of the 

leaves to rats resulted in initial bradycardia followed by cardiac arrhythmias. 

The treatment produced a dose-related fall in blood pressure that 

was immediate, sharp and persistent. Pretreatment with atropine or mepyramine 

failed to prevent the hypotensive effect of the extract (46). 

Immune effects 

The effect of an aqueous extract of the leaves on humoral and cell-mediated 

immune responses was assessed in mice treated with ovalbumin. At 

doses of 10.0 mg/kg bw, 30.0 mg/kg bw or 100.0 mg/kg bw, the extract 

produced no appreciable effects on organ/body weight indices for liver, 

spleen and thymus compared with controls. In tests for humoral immune 

responses, IgM and IgG levels, and antiovalbumin antibody titres were 

higher in mice receiving the highest dose of extract than in animals in the 

control group. In tests for cell-mediated immune responses, mice receiving 

the highest dose of extract showed enhancement of macrophage migration 

inhibition and footpad thickness (47). Intragastric administration 

of 100.0 mg/kg bw of an aqueous extract of the leaves to normal and 

stressed rats lowered blood glucose and triglyceride levels, attenuated 

stress-induced elevations of cholesterol and urea, and suppressed humoral 

responses (48). 

The effect of powdered leaves on humoral and cell-mediated immune 

responses was assessed in chickens infected with infectious bursal disease. 

A dose of 2.0 g/kg bw per day given in the diet increased antibody titres 

against Newcastle disease virus antigen and enhanced infl ammatory reactions 

to chloro-2,4-dinitrobenzene in the skin contact test (49). 

Toxicology 

Chickens fed diets containing the powdered leaves, 2% or 5%, from the 

7th to the 35th day of age, and then a control diet for 2 weeks, showed a 

reduction in body weight gain and effi ciency of feed use compared with 

controls. The main pathological changes observed included an increase in 

lactic dehydrogenase, glutamic-oxaloacetic transaminase and alkaline 

phosphatase activities, an increase in uric acid and bilirubin concentrations, 

and a decrease in total serum protein levels. There were marked 

reductions in the values of erythrocyte count, haemoglobin concentration, 

packed cell volume, mean corpuscular volume and mean corpuscular 

haemoglobin, which were associated with yellow discoloration on the 

legs and hepatonephropathy (50). 

95


Intragastric administration of 50.0 mg/kg bw or 200.0 mg/kg bw of 

aqueous suspensions of the leaves per day to goats and guinea-pigs over a 

period of up to 8 weeks produced a progressive decrease in body weight, 

weakness, inappetence, loss of condition and decreases in the pulse and 

respiratory rates. In goats, the higher dose produced tremors and ataxia 

during the last few days of treatment. No statistically signifi cant haematological 

changes were observed, although there was a tendency towards 

lowered erythrocyte counts, packed cell volume and haemoglobin levels. 

The treatment increased aspartate transferase and sorbitol dehydrogenase 

activities, and concentrations of cholesterol, urea, creatinine and potassium 

in the plasma. No signifi cant changes in the plasma concentrations of 

sodium, chloride or bilirubin were detected. Autopsy of treated goats revealed 

areas of haemorrhagic erosion. The hearts appeared fl appy and in 

some animals there was hydropericardium. Histopathologically, there 

was evidence of various degrees of haemorrhage, congestion, and degeneration 

in the liver, kidney, lung, duodenum, brain and seminiferous tubules 

(51). 

The effect of intragastric administration of 40.0 mg/kg bw and 

100.0 mg/kg bw of an aqueous extract of the leaves per day for 20 days on 

thyroid function was assessed in male mice. The higher dose decreased 

serum tri-iodothyronine and increased serum thyroxine concentrations. 

There was a concomitant increase in hepatic lipid peroxidation and a decrease 

in glucose-6-phosphatase activity. The lower dose produced no 

signifi cant changes (52). 

The median lethal dose of a 50% ethanol extract of the leaves in mice 

was 681.0 mg/kg bw when administered by intraperitoneal injection (53). 


A 70% ethanol extract of the leaves was used for the treatment of ringworm 

in seven patients. External applications of a 40% solution of the 

extract twice per day to the affected areas for 5–10 days were reported to 

be effective (no further details available) (21). 


A case of ventricular fi brillation and cardiac arrest due to neem leaf poisoning 

has been reported (54–56). Contact dermatitis has also been reported (57). 


Owing to potential genotoxic effects (58), the leaves should not be 

administered during pregnancy or nursing, or to children under the age of 

12 years. 

96

Warnings 


Precautions 


Administration of Folium Azadirachti may reduce blood glucose levels 

and should therefore be used with caution in insulin-dependent diabetic 

patients or patients taking oral antihyperglycaemic drugs. 


A petroleum ether extract of the leaves was not mutagenic in the 

Salmonella/microsome assay at concentrations of 0.1 ml/plate using 

S. typhimurium strains TA98, TA100, TA1535 and TA1537 (59). 

Intragastric administration of 5.0 mg/10 g bw, 10.0 mg/10 g bw or 

20.0 mg/10 g bw of an ethanol extract of the leaves per day for 7 days to 

mice signifi cantly (P < 0.05) increased the incidence of structural and mitotic 

disruptive changes in metaphase chromosomes of bone marrow cells 

on days 8, 15 and 35 (58). Intragastric administration of 100.0 mg/kg bw 

of an ethanol extract of the leaves per day for 21 days had no effect on 

spermatogenesis in male rats, and no effect on implantation in female animals 

mated with treated males (60). 


Intragastric administration of 200.0 mg/kg bw of an acetone or 50% ethanol 

extract of the leaves to pregnant rats on days 1–7 of pregnancy did not 

produce any teratogenic or embryotoxic effects (61). 








drug and laboratory test reactions; or non-teratogenic effects in 

pregnancy. 

Dosage forms 

Dried leaves for infusions and decoctions, and extracts and tinctures (8). 

Store leaves in a cool, dry place (3). 

97


Posology 


Infusion (1:20): 15–30 ml. Tincture (1:5): 4–8 ml (8). External applications: 

70% ethanol extract of the leaves diluted to 40%, apply twice daily (21). 

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101

102 

Oleum Azadirachti 

Defi nition 

Oleum Azadirachti consists of the fi xed oil obtained from dried seeds of 

Azadirachta indica A. Juss. (Meliaceae). 

Synonyms 

Melia azadirachta L., M. indica (A. Juss.) Brand., M. indica Brand. (1–3). 


Abodua, aforo-oyinbo, anwe egyane, arista, azad dirakht, azadarakht, azedarach, 

bead tree, bevinama, bevu, bewina mara, bodetso, bo-nim, cape lilac, 

chajara hourra, chichaâne arbi, China berry, China tree, cót anh, darbejiya, 

dogo yaro, dogo’n yaro, dogonyaro, dogoyaro, dongo yaro, dua gyane, gori, 

gringging, holy tree, igi-oba, imba, Indian lilac, Indian lilac tree, Indian neem 

tree, Indian sadao, Intaran, isa-bevu, jaroud, kahibevu, kingtsho, kiswahhili, 

kohhomba, kohumba, koummar, kuman masar, kuman nasara, kwinin, labkh, 

lilac de perse, lilas des indes, liliti, limb, limba, limbado, limado, linigbe, mahanim, 

mahanimba, mahnimu, mak tong, margosa, margosa tree, margose, 

marrar, mimba, mindi, miro tahiti, mwarobaini, neeb, neem, neem sikha, nim, 

nim tree, nimba, nimbatikta, nimgach, nivaquine, ogwu akom, oilevevu, ouchi, 

Persian lilac, phãk kã dão, picumarda, sa-dao, sa-dao baan, sadao India, 

sdau, salien, sandan, sandannoki, sãu dâu, senjed talhk, shajarat el horrah, 

shereesh, tâak, tâakhak, touchenboku, vembu, vemmu, vepa, veppam, veppu, 

white cedar, xoan dào, zanzalakht, zaytoon (1–9). 


Indigenous to India, and widely distributed in South and South-East Asia. 

Cultivated in Africa, the South Pacifi c Islands, South and Central America 

and Australia, and in southern Florida and California, United States of 

America (1–3, 7, 10, 11). 

Description 

A straight-boled deciduous tree 6–25 m high. Bark dark-brown, externally 

fi ssured, with a buff inner surface, fi brous fracture. Leaves alter-

nately arranged, pinnately compound, up to 40 cm long, composed of 8– 

18 short-petiolate narrow-ovate, pointed, curved toothed leafl ets, 3–10 cm 

long and 1–4 cm wide arranged in alternate pairs. Infl orescences axillary 

panicles; fl owers numerous, white, pedicillate, about 1.0 cm wide. Fruits 

yellowish drupes, oblong, about 1.5 cm long, containing thin pulp surrounding 

a single seed. When bruised, leaves and twigs emit an onion-like 

odour (1–3, 7, 11). 

Plant material of interest: fi xed oil 




Odour: characteristic alliaceous (10); taste: no information available. 


Macroscopic examination and thin-layer chromatography (2). 


Purity tests 





Chemical 

Relative density 0.913–0.919 (13); refractive index 1.462–1.466 (13); saponifi 

cation value 196.0 (13). 






Heavy metals 






103



A high-performance liquid chromatography procedure is available for 

the quantitative determination of oxidized tetranortriterpenes (16). 


The major constituents are oxidized tetranortriterpenes including azadirachtin 

(azadirachtin A), azadiriadione, epoxyazadiradione, azadirone, 

nimbidin, nimbin, deacetylnimbin, salannin, gedunin, mahmoodin, 17hydroxydiradione 

and related derivatives (9, 11, 17–19). The structures of 

azadirachtin, nimbin and deacetylnimbin are presented below: 

O 

O CH3 H3C H3C O 

H 

CH3 H 

O 

O 

O 

O 

H 

H 

O 

O 

H 

OH 

CH3 H O 

OH 

H 

H 

O 

O 

OH 

H 

CH3 O CH3 nimbin 

R = CO-CH3 azadirachtin 



deacetylnimbin R = H 

As a contraceptive for intravaginal use (20), as a mosquito repellent (21), and 

for treatment of vaginal infections (22). However, further controlled clinical 

trials are needed before the oil can be recommended for general use. 


Treatment of gastric ulcers, cardiovascular disease, malaria, rheumatism 

and skin disorders. External applications for treatment of septic wounds, 

ulcers and boils (7). 


Treatment of allergic skin reactions, asthma, bruises, colic, conjunctivitis, 

dysmenorrhoea, fever, gout, headache, itching due to varicella, kidney 

stones, leukorrhoea, psoriasis, scabies, sprains and muscular pain, and 

wounds (10, 11). As an emmenagogue, tonic, stomatic and vermicide (9). 

Pharmacology 


Antifertility activity 

Oleum Azadirachti, 0.6 ml, was given to female rats by intragastric administration 

on days 8–10 of pregnancy, after confi rming the presence 

104 

H 3C 

O 

O 

H 3C 

CH 3 

H CH3 O 

O H 

H3C O 

H 

CH3 O 

H 

R 

O 

H 

H 

O


and number of embryo implants surgically on day 7. The animals were 

examined again under anaesthesia on day 15 of pregnancy to check the 

number of developing embryos. Controls received an equivalent regime 

of peanut oil. Complete resorption of embryos was observed on day 15 of 

pregnancy in every animal treated with Oleum Azadirachti while embryos 

were developing normally in controls (23). Intragastric administration 

of 6.0 ml of the oil per day for 60 days to female baboons induced 

abortion in pregnant animals (24). 

A single intrauterine application of 100.0 μl of the oil produced a reversible 

block in fertility lasting for 107–180 days in female rats (25) and 

7–11 months in monkeys (26). In an attempt to fi nd an alternative to vasectomy 

for long-term male contraception, the effect of a single intra-vas 

application of the oil was assessed in male rats. Animals with proven fertility 

were given a single dose of 50.0 μl of the oil in the lumen of the vas 

deferens on each side. Control animals received the same volume of peanut 

oil. Animals were allowed free access to mating for 4 weeks after the 

treatment, with females of proven fertility. While the control animals impregnated 

their female partners, all males treated with Oleum Azadirachti 

remained infertile throughout the 8-month observation period. Epididymal 

and vas histologies were normal, with no infl ammatory changes or 

obstruction. Intra-vas administration of the oil resulted in a block of spermatogenesis 

without affecting testosterone production. The seminiferous 

tubules, although reduced in diameter, appeared normal and contained 

mostly early spermatogenic cells. No anti-sperm antibodies were detected 

in the serum (27). 

Subcutaneous administration of up to 0.3 ml of the oil to rats had no 

estrogenic, anti-estrogenic or progestational activity, and appeared not to 

interfere with the action of progesterone (28). Intravaginal application of 

2.50 μl–0.25 ml of the oil to pregnant rats induced abortion (29). 

The oil, 10–25%, inhibited fertilization in isolated mouse ova as assessed 

by sperm–egg interaction, and impaired the development of fertilized 

ova in vitro (30). In other investigations, the active constituents of 

the oil were identifi ed to be a mixture of six compounds comprising saturated, 

mono and di-unsaturated free fatty acids and their methyl esters 

(31). The oil, 0.25–25.00 mg/ml, had spermicidal effects on human and rat 

sperm in vitro (32, 33). 


Intragastric administration of 21.0 mg/kg body weight (bw) of the oil reduced 

blood glucose levels in rats (34). A signifi cant (P < 0.01) reduction 

in blood glucose levels was observed in normal and alloxan-induced dia- 

105


betic rabbits after administration of 200.0 mg of the oil; the effect was 

more pronounced in diabetic animals (35). 


The anti-infl ammatory effects of nimbidin were assessed and compared 

with phenylbutazone. Intramuscular administration of 40.0 mg/kg bw 

of nimbidin reduced acute paw oedema in rats induced by carrageenan 

and kaolin. Formalin-induced arthritis in ankle joints and fl uid exudation 

due to granuloma induced by croton oil in rats were also suppressed 

by similar treatment with the compound. In the acute phase of infl ammation, 

nimbidin at 40.0 mg/kg bw was more active than phenylbutazone 

at 100.0 mg/kg bw (36). Intramuscular administration of 

50.0 mg/kg bw of the oil reduced granuloma induced by cotton pellet in 

rats (37). 

Antimicrobial and antiviral activity 

The effi cacy of a petroleum ether extract of the oil was investigated for 

its antimicrobial activity against certain bacteria and fungi and poliovirus, 

as compared with the oil. The extract had stronger antimicrobial 

activity than the oil and, in vitro at 2.0 mg/ml, inhibited the growth of 

Escherichia coli and Klebsiella pneumoniae, which were not inhibited by 

the oil. The extract was active against Candida albicans (minimum inhibitory 

concentration 0.25 mg/ml) and had antiviral activity against poliovirus 

replication in Vero African green monkey kidney cell lines at 

50.0 μg/ml (38). 

Intravenous administration of 60.0 mg/kg bw of the oil twice per day 

for 7 days protected mice from systemic candidiasis, as shown by enhanced 

survival and a reduction in colony-forming units of C. albicans in 

various tissues (38). 

The oil inhibited the growth of Escherichia coli, Klebsiella pneumoniae, 

Pseudomonas aeruginosa, Staphylococcus aureus and S. pyogenes in 

vitro at a concentration of 1.5–6.0% (39). A petroleum ether extract of the 

oil inhibited the growth of Epidermophyton fl occosum, Microsporum canis, 

M. gypseum, Trichophyton concentricum, T. rubrum and T. violaceum 

(40). 


Intragastric administration of 40.0 mg/kg bw of nimbidin showed antiulcer 

activity in various experimental models (gastric lesions induced by 

acetylsalicylate, stress, serotonin and indometacin) in rats. The compound 

also protected against cysteamine- and histamine-induced duodenal lesions 

in rodents (41). 

106



Subcutaneous administration of 0.2–6.0 ml/kg bw of the oil to normal or 

ovariectomized rats had no estrogenic effects: there was no increase in 

uterine wet weight or disruption of the estrous cycle (28, 29). 

Immune effects 

Mice received Oleum Azadirachti, 150.0 μl/animal, or an emulsifying 

agent, with or without peanut oil, by intraperitoneal injection. Peritoneal 

lavage on subsequent days showed an increase in the number of leukocytic 

cells on day 3 following treatment with Oleum Azadirachti, and 

peritoneal macrophages exhibited enhanced phagocytic activity and expression 

of major histocompatability complex class II antigens. Treatment 

also induced the production of γ-interferon. The spleen cells of oil-treated 

animals showed a signifi cantly higher lymphocyte proliferative response 

to in vitro challenge with concanavalin A or tetanus toxin than those of 

controls. Pretreatment with the oil did not augment the anti-tetanus-toxin 

antibody response. The results of this study indicate that the oil acts as 

a nonspecifi c immunostimulant and that it selectively activates cell-mediated 

immune mechanisms to elicit an enhanced response to subsequent 

mitogenic or antigenic challenge (42). Intraperitoneal administration of 

the oil to mice (150.0 μl/animal) and rats (120.0 μl/animal) enhanced 

phagocytosis of macrophages (42, 43). 

Toxicology 

Studies of the oral acute toxicity of the oil in rats and rabbits showed 

dose-related pharmacotoxic symptoms along with a number of biochemical 

and histopathological indices of toxicity. The 24-hour oral median lethal 

dose was 14.0 ml/kg bw in rats and 24.0 ml/kg bw in rabbits. Prior to 

death, all animals exhibited pharmacotoxic symptoms of a similar type 

and severity; the lungs and central nervous system were the target organs (44). 

Intragastric administration of the oil to mice was not toxic at a dose of 

2.0 ml. The oil (dose not specifi ed) was nonirritant when applied to the 

skin of rabbits in a primary dermal irritation test. In a subacute dermal 

toxicity study, rabbits exposed to the oil (dose not specifi ed) daily for 21 

days showed no signifi cant changes in body weight or organ:body weight 

ratio, serum oxaloacetic transaminase and pyruvic transaminase levels, 

and blood glucose and urea nitrogen values. No treatment-related histopathological 

changes were observed (45). 

In a three-generation study carried out according to a World Health 

Organization/United States Food and Drug Administration protocol, 

groups of 15 male and 15 female rats were fed a diet containing 10% Oleum 

Azadirachti or peanut oil. Reproductive toxicology was monitored 

107


for three generations. There were no adverse effects on the reproductive 

parameters in either group (46). 

A group of 10 pregnant rats received 2.0 ml/kg bw of the oil by gastric 

administration daily and the animals were allowed to deliver at term. Six 

of the treated animals died between days 6 and 13 of pregnancy. Among 

the four remaining animals that delivered, one delivered a seemingly normal 

pup on day 27, but the pup died after 4 days. Autopsy performed on 

day 16 of pregnancy suggested that fetal resorption had occurred; however, 

no indication was given as to whether fetuses were normal (47). 


Contraceptive activity 

In an uncontrolled clinical trial involving 225 healthy fertile women aged 

18–35 years performed to assess the effi cacy of the oil as an antifertility 

agent, subjects were instructed to insert 1 ml of the oil into the vagina 

with a plastic applicator 5 minutes prior to coitus. No other contraception 

was used. After 16 months of use only three pregnancies due to drug 

failure were reported; there were 30 pregnancies due to noncompliance 

(i.e. in women who did not use the oil as instructed) (20). 

Antibacterial activity 

In a 2-week double-blind, placebo-controlled clinical trial involving 

55 women with abnormal vaginal discharge due to bacterial vaginosis, 

subjects were instructed to insert 5.0 ml of the oil or placebo oil into the 

vagina daily. Treatment with the test oil was reported to cure the symptoms 

of the infection (22). 

Insect repellent activity 

In a fi eld study carried out to evaluate the mosquito repellent action of 

the oil in villages in a forested area in Mandla District, Madhya Pradesh, 

India, various concentrations of the oil were mixed with coconut oil 

(1–4%) and applied to the exposed body parts of human volunteers. The 

mixture provided 81–91% protection from the bites of anopheline mosquitoes 

during a 12-hour period of observation (21). 

Treatment of skin disorders 

In one case report, administration of 100.0 mg of oil twice daily for 

34 days completely healed chronic skin ulcers up to 1 cm deep (48). 


A 60-year-old male was admitted to hospital with neurological and psychotic 

symptoms following ingestion of 60.0 ml of Oleum Azadirachti. 

108

However, correlation of the adverse effects with ingestion of the oil was 

not defi nitely proven (49). 


Oral administration of Oleum Azadirachti is contraindicated during 

pregnancy, nursing and in children under the age of 12 years. 

Warnings 

A number of cases of toxicity, including toxic encephalopathy, poisoning 

and Reye-like syndrome, following ingestion of excessive doses of Oleum 

Azadirachti have been reported (50–52). 

Precautions 


Administration of the oil may reduce blood glucose levels. It should 

therefore be used with caution in insulin-dependent diabetic patients or 

patients taking oral antihyperglycaemic drugs. 


An acetone extract of the oil was inactive at concentrations of up to 

200.0 mg/plate in the Salmonella/microsome assay using Salmonella 

typhimurium strains TA98 and TA100 (53). In the same test, the oil 

(concentration not specifi ed) was not mutagenic using Salmonella typhimurium 

strains TA98 and TA100, with or without metabolic activation (54). 

The oil has demonstrated antifertility effects in numerous animal and 

human studies (see Pharmacology). 


The oil had embryotoxic effects after vaginal administration to pregnant 

rats at a dose of 0.25 ml/animal (32, 33). Embryotoxic effects were also 

reported following intragastric administration of 4.0 ml/kg bw of the oil 

to pregnant rats on days 6–8 of pregnancy (47). 








109





Dosage forms 

Oil. Store in a tightly sealed container away from heat and light. 

Posology 


Dose: 1.0–5.0 ml of oil for intravaginal applications (20, 22). 

References 

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Scientifi c, Technical and Research Commission, 1985. 


drugs of Unani medicine – part II. New Delhi, Ministry of Health and Family 


3. Ghana herbal pharmacopoeia. Accra, Ghana, The Advent Press, 1992. 



1959. 

5. Indian medicinal plants. Vol. I. New Delhi, Orient Longman, 1971. 





Press, 1993. 








10. Vijayalakshmi K, Radha KS, Shiva V. Neem: a user’s manual. Madras, Centre 

for Indian Knowledge Systems; New Delhi, Research Foundation for 

Science, Technology and Natural Resource Policy, 1995. 

11. Medicinal plants in the South Pacifi c. Manila, World Health Organization 





110


13. Ali MH et al. Studies on the fatty acids and glyceride compositions of nim 

(Melia azadirachta indica) seed oil. Bangladesh Journal of Scientifi c and 

Industrial Research, 1996, 31:99–106. 



Geneva, World Health Organization, 1997 (WHO/FSF/FOS/97.7; 

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performance liquid chromatography procedure for the isolation of major triterpenoids 

and their quantitative determination in neem oil. Journal of 

Liquid Chromatography, 1995, 18:3465–3471. 



18. Kraus W. Biologically active ingredients: Azadirachtin and other triterpenoids. 

In: Schmutterre H, ed. The neem tree Azadirachta indica A. Juss. and 

other meliaceous plants. Weinheim, VCH, 1995. 

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78:47–149. 

20. Schawat D, Tyagi RK, Kishore P. The clinical studies on contraceptive effect 

of Nimba taila. Journal of the Royal Ayurveda Society, 1998, 19:1–8. 

21. Mishra AK, Singh N, Sharma VP. Use of neem oil as a mosquito repellent in 

tribal villages of Mandla District, Madhya Pradesh. Indian Journal of 

Malariology, 1995, 32:99–103. 

22. Mittal A et al. Clinical trial with Praneem polyherbal cream in patients with 

abnormal vaginal discharge due to microbial infections. Australian and New 

Zealand Journal of Obstetrics and Gynecology, 1995, 35:190–191. 

23. Mukherjee S, Talwar GP. Termination of pregnancy in rodents by oral administration 

of praneem, a purifi ed neem seed extract. American Journal of 

Reproductive Immunology, 1996, 35:51–56. 

24. Mukherjee S et al. Purifi ed neem (Azadirachta indica) seed extracts (Praneem) 

abrogate pregnancy in primates. Contraception, 1996, 53:375–378. 

25. Upadhyay SN, Kaushic C, Talwar GP. Antifertility effects of neem (Azadirachta 

indica) oil by single intrauterine administration: a novel method of 

contraception. Proceedings of the Royal Society of London B, 1990, 242:175– 

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26. Upadhyay SN et al. Long-term contraceptive effects of intrauterine neem 

treatment (IUNT) in bonnet monkeys: an alternate to intrauterine contraceptive 

devices (IUCD). Contraception, 1994, 49:161–169. 

27. Upadhyay SN, Dhawan S, Talwar GP. Antifertility effects of neem (Azadirachta 

indica) oil in male rats by single intra-vas administration: an alternate 

approach to vasectomy. Journal of Andrology, 1993, 14:275–281. 

111


28. Prakash AO, Tewari RK, Mathur R. Non-hormonal post-coital contraceptive 

action of neem oil in rats. Journal of Ethnopharmacology, 1988, 

23:53–59. 

29. Riar SS et al. Mechanism of antifertility action of neem oil. Indian Journal of 

Medical Research, 1988, 88:339–342. 

30. Juneja SC, Williams RS. Mouse sperm–egg interaction in vitro in the presence 

of neem oil. Life Sciences, 1993, 279–284. 

31. Garg S, Talwar GP, Upadhyay SN. Immunocontraceptive activity guided 

fractionation and characterization of active constituents of neem (Azadirachta 

indica) seed extracts. Journal of Ethnopharmacology, 1998, 60:235–246. 

32. Sinha KC et al. Anti-implantation effect of neem oil. Indian Journal of Medical 

Research, 1984, 80:708–710. 

33. Riar SS et al. Volatile fraction of neem oil as a spermicide. Contraception, 

1990, 42:479–487. 

34. Sharma MK, Khare AK, Feroz H. Effect of neem oil on blood sugar levels of 

normal, hyperglycaemic and diabetic animals. Nagarjun, 1983, 26:247–250. 

35. Dixit VP, Sinha R, Tank R. Effect of neem seed oil on the blood glucose concentration 

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1986, 17:95–98. 

36. Pillai NR, Santhakumari G. Anti-arthritic and anti-infl ammatory actions of 

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37. Shankaranarayan D. Effect of neem oil and its constituents on cotton pellet 

infl ammation. Mediscope, 1978, 20:273–274. 

38. SaiRam M et al. Anti-microbial activity of a new vaginal contraceptive NIM- 

76 from neem oil (Azadirachta indica). Journal of Ethnopharmacology, 2000, 

71:377–382. 

39. Rao DVK et al. In vitro antibacterial activity of neem oil. Indian Journal of 

Medical Research, 1986, 84:314–316. 

40. Khan M et al. Experimentelle Untersuchungen über die Wirkung von Bestandteilen 

des Niembaumes und daraus hergestellten Extrakten auf Dermatophyten, 

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tree, neem oils and neem extracts on dermatophytes, yeasts and moulds.] 

Zeitschrift für Hautkrankheiten, 1988, 63:499–502. 

41. Pillai NR, Santhakumari G. Effects of nimbidin on acute and chronic gastroduodenal 

ulcer models in experimental animals. Planta Medica, 1984, 50:143– 

146. 

42. Upadhyay SN et al. Immunomodulatory effects of neem (Azadirachta indica) 

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43. SaiRam M et al. Immunomodulatory effects of NIM-76, a volatile fraction 

from neem oil. Journal of Ethnopharmacology, 1997, 55:133–139. 

44. Gandhi M et al. Acute toxicity study of the oil from Azadirachta indica seed 

(neem oil). Journal of Ethnopharmacology, 1988, 23:39–51. 

45. Gupta S et al. Safety evaluation of Azadirachta indica seed oil, a herbal wound 

dressing agent. Fitoterapia, 1995, 66: 6972. 

112


46. Chinnasamy N et al. Toxicological studies on debitterized neem oil (Azadirachta 

indica). Food and Chemical Toxicology, 1993, 31:297–301. 

47. Lal R et al. Antifertility effects of Azadirachta indica oil administered per os 

to female albino rats on selected days of pregnancy. Fitoterapia, 1987, 58:239– 

242. 

48. Pillai NGK et al. Ropana guna of Nimbatikta in Dushta Vrana – a case 

report. Vagbhata, 1983, 1:37–38. 

49. Sivashanmugam R. Neem leaf poisoning. Reply from the authors. Journal of 

the Association of Physicians of India, 1985, 33:817. 

50. Sinniah D et al. Reye-like syndrome due to margosa oil poisoning: report of 

a case with postmortem fi ndings. American Journal of Gastroenterology, 

1982, 77:158–161. 

51. Sundaravalli N, Raju BB, Krishnamoorty KA. Neem oil poisoning. Indian 

Journal of Pediatrics, 1982, 49:357–359. 

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53. Jongen WMF, Koeman JH. Mutagenicity testing of two tropical plant materials 

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Mutagenesis, 1983, 5:687–694. 

54. Polasa K, Rukmini C. Mutagenicity tests of cashewnut shell liquid, rice-bran 

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system. Food and Chemical Toxicology, 1987, 25:763–766. 

113

114 

Flos Carthami 

Defi nition 

Flos Carthami consists of the dried fl owers of Carthamus tinctorius L. 

(Asteraceae) (1–3). 

Synonyms 

Asteraceae are also known as Compositae. 


American saffron, baharman, barre, bastard saffron, benibana, biri, centurakam, 

chôm pu, dok kham, dyer’s saffron, esfer, fake saffron, false saffron, 

hong hoa, hong hua, hong-hua, honghua, huang hua, hung hua, 

hung-hua, Hungarian saffron, ik-kot, Indian saffl ower, kafi shah, kajirah, 

karizeh, kazirah, kanar, kasube, kasubha, kasumba, kembang pulu, kham, 

kham foi, kham yong, khoinbo, kouranka, kusum, kusuma, kusumba, 

kusumphul, lago, qurtum, rum, saff-fl ower, saffl ower, safl or, safran bâtard, 

sáfrányos szeklice, saffron, saffron thistle, Safl or, senturakam, shawrina, 

sufi r, usfur, wild saffron, za’afran (3–8). 


Indigenous to the Arabian peninsula, north-west India and Islamic Republic 

of Iran; also found in the Mediterranean region of North Africa 

and in Cambodia, China, India, Indonesia, Lao People’s Democratic Republic 

and Viet Nam. Widely cultivated around the world (4, 6, 9–11). 

Description 

An annual herb, 0.4–1.3 m high, much branched, glabrous, spiny. Branches 

stiff, cylindrical, whitish in colour. Leaves simple, spirally arranged, 

without petiole; oblong, ovate, lanceolate or elliptic; dark green, glossy, 

3–15 cm long, 1.5 cm wide, spinous along the margin and at the tip. Flowers 

solitary, terminal, 2.5–4.0 cm in diameter with spreading outer leafy 

spiny bracts and inner triangular bracts, spine tipped, forming a conical 

involucre, with small opening at the tip. Florets, 30–90, tubular,

hermaphrodite, usually orange-yellow in colour; corolla tubes 4 cm long, 

with fi ve pointed segments. Fruits white or grey, tetragonal achenes, about 

8 mm long, without pappus (6). 

Plant material of interest: dried fl owers 


Red to red-brown corollas, yellow styles and stamens, rarely mixed with 

immature ovaries; corollas tubular, 1–2 cm long, with fi ve segments; long 

pistils surrounded by fi ve stamens; pollen grains yellow and spherical, 

approximately 50.0 μm in diameter, with fi ne protrusions on the surface 

(1–3). 


Odour: characteristic aromatic; taste: slightly bitter (1–3). 


Information to be developed according to national requirements. 


Orange-yellow with fragments of corolla, fi lament and stigma. Long tubular 

secretory cells, up to 66 μm in diameter, usually accompanied by 

vessels containing yellowish-brown to reddish-brown secretion. Outer 

walls of terminal epidermal cells of corolla lobes projecting to be tomentellate. 

Upper epidermal cells of stigma and style differentiated into conical 

unicellular hairs, acuminate or slightly obtuse at the apex. Pollen grains 

subrounded, elliptical or olivary, with three germinal pores, exine dentate 

spinose. Parenchymatous cells containing crystals of calcium oxalate, 

2–6 μm in diameter (3). 


Macroscopic and microscopic examinations (1–3), microchemical tests, 

spectrometry (1–3), and thin-layer chromatography (3). 

Purity tests 






Not more than 2% (1–3). 

Flos Carthami 

115


Total ash 





The recommended maximum limit for the sum of aldrin and dieldrin is 

not more than 0.05 mg/kg (13). For other pesticides, see the European 

pharmacopoeia (13) and the WHO guidelines on quality control methods 

for medicinal plants (12) and pesticide residues (14). 

Heavy metals 







Chemical, acid-insoluble ash, sulfated ash, water-soluble extractive and 

alcohol-soluble extractive tests to be established in accordance with national 

requirements. 


To be established in accordance with national requirements. A highperformance 

liquid chromatography method for analysis of carthamin, 

saffl or yellow A and other related pigments is available (15). 


The major constituent is the chalcone C-glucoside carthamin (up to 8.5%) 

(16). Other signifi cant constituents include fatty acids, the chalcone 

hydroxysaffl or yellow A; the nitrogenous chalcone tinctormine; the quinoid 

C-glycosides saffl or yellow A and saffl or yellow B; the fl avonoids 

neocarthamin, quercetin, rutin, kaempferol and related hydroxy derivatives 

and glycosides; dotriacontane-6,8-diol, erythrohentriacontane-6,8-diol, 

heptacosane-8,10-diol, triacontane-6,8-diol and related alkanes (8, 17, 18). 

Representative structures of chalcones, quinoid C-glycosides and a fl avanone 


116

carthamin 

HO 

Glc 

HO 

HO 

* 

O 

Glc 

HO 

OH 

OH 

OH 

Glc 

O 

O 

OH 

O and epimer at C* 

HO 

H 

HO 

H 

hydroxysafflor yellow A safflor yellow A 

safflor yellow B 

HO 

Glc OH HO 

HO 

OH HO 

O O HO 

H 

H 

HO 

HO 

OH 

H 

OH 

H 

OH 



None. 

O 

H 

H 

O 

Glc 

O 

HO 

H 

OH 

O 

* 

O 

neocarthamin 

Glc 

OH 

Flos Carthami 


Treatment of amenorrhoea, dysmenorrhoea and wounds or sores with 

pain and swelling, and prevention of atherosclerosis (3, 19). 


As an antipyretic, antidiarrhoeal, contraceptive, diaphoretic, emmenagogue, 

expectorant, laxative, sedative and stimulant (8, 20, 21). Treatment 

of bronchitis, boils, haemorrhoids, respiratory tract infections, ringworm 

and scabies (8, 20). 

Pharmacology 


Analgesic and antipyretic activities 

Intragastric administration of 500.0 mg/kg body weight (bw) of a 95% 

ethanol extract of Flos Carthami reduced the responsiveness of mice as 

measured in the hot-plate test, indicating an analgesic effect, and also 

HO 

HO 

Glc 

OH 

O 

and epimer at C* 

OH 

O 

HO 

H 

O 

* 

H 

OH 

O 

and epimer at C* 

H 

HO 

H 

N 

HO HO 

H 

OH 

β-D-glucopyranosyl 

* 

O 

Glc 

tinctormine 

Glc = 

OH 

OH 

O and epimer at C* 

HO 

HO 

OH 

O 

OH 

117


decreased yeast-induced fevers (22). Subcutaneous administration of 

10.0 g/kg bw of an aqueous extract of the fl owers to mice did not reduce 

pain perception as measured in the hot-plate test (23). However, subcutaneous 

administration of 1.0–3.0 g/kg bw of a 50% methanol extract of the 

fl owers to mice reduced writhing induced by acetic acid (23). Intragastric 

administration of 30.0 g/kg bw of a 50% methanol extract of the fl owers 

to mice also reduced writhing induced by acetic acid (24). 


Intraperitoneal injection of a methanol extract of 100.0 mg/kg bw of the 

fl owers to rats reduced the increased activities of alkaline phosphatase, 

glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase 

and lactate dehydrogenase, and reduced the plasma concentration of bilirubin 

in hepatotoxicity induced by the administration of α-naphthylisothiocyanate 

(25). However, intraperitoneal administration of 300.0 mg/kg 

bw of a methanol extract of the fl owers to rats had no effect on hepatotoxicity 

induced by carbon tetrachloride (26). Conversely, administration 

of the fl owers to rats prevented the development of liver cirrhosis induced 

by carbon tetrachloride in eight out of nine animals. In the control group, 

seven out of nine rats developed cirrhosis when treated with carbon tetrachloride 

(27). 


Intragastric administration of 30.0 mg/kg bw of a 50% methanol extract 

of the fl owers inhibited infl ammation as measured by footpad oedema in 

mice, induced by carrageenan, serotonin, bradykinin, histamine or prostaglandin 

(24). Subcutaneous administration of 10.0 g/kg bw of an aqueous 

or 50% methanol extract of the fl owers inhibited carrageenan-induced 

footpad oedema in mice (23). 

In vitro, 1-butanol and petroleum ether extracts of the fl owers had 

albumin-stabilizing effects, indicating anti-infl ammatory activity; however, 

the aqueous extract was not active in this assay (28). 


An ethanol extract of the fl owers inhibited the growth of Staphylococcus 

aureus in vitro at a concentration of 0.5 mg/plate, but was not effective 

against Escherichia coli (29). A 95% ethanol extract of the fl owers inhibited 

the growth of Bacillus subtilis, Candida albicans, Salmonella typhosa 

and Staphylococcus aureus in vitro at a concentration of 100.0 μg/plate, 

but was not effective against E. coli and Shigella dysenteriae (30). A hot 

aqueous extract of the fl owers (concentration not specifi ed) inhibited replication 

of poliomyelitis virus type 1 in vitro (31). 

118

Flos Carthami 


Intragastric administration of 4.0 g/kg bw of a 50% methanol extract of 

the fl owers to male rats did not reduce congestive oedema induced by 

bilateral ligation of the jugular vein (32). Intravenous administration of 

2.0 g/kg bw of a decoction of the fl owers to dogs reduced ST-segment 

elevation and the increased heart rate induced by occlusion of the apical 

branch of the coronary artery (33). Intraperitoneal administration of a hot 

aqueous extract of 10.0 g/kg bw of the fl owers to gerbils reduced ischaemia 

and neurological damage induced by unilateral carotid artery ligation 

when compared with untreated animals (34). In vitro, an aqueous 

extract of the fl owers (concentration not specifi ed) displayed calciumchannel 

blocking activity by displacing nitrendipine or diltiazem from 

receptor sites (35). Tinctormine (concentration not specifi ed) isolated 

from the fl owers, also showed in vitro calcium antagonist activity (17). 

A 95% ethanol extract of the fl owers (dose not specifi ed) induced vasodilation 

in guinea-pigs and rabbits (36). Saffl ower yellow (containing 

chalconoid compounds of which 75% is saffl omin A) extracted from the 

fl owers (dose not specifi ed) lowered blood pressure in spontaneously hypertensive 

rats; 5 weeks later, the plasma renin activity and angiotensin II 

levels were reduced in these animals, suggesting that the reduction in 

blood pressure was mediated by the renin-angiotensin system (37). An 

aqueous extract of the fl owers, 10.0 μg/ml, inhibited the activity of stressactivated 

protein kinases from isolated ischaemic rat hearts by 50%; when 

the isolated hearts were treated prior to the induction of ischaemia, the 

inhibition was 95% (38). 

Central nervous system depressant activity 

Subcutaneous administration of 1.0–10.0 g/kg bw of an aqueous or 50% 

methanol extract of the fl owers had central nervous system depressant 

effects in mice and relaxed skeletal muscles (23). Intraperitoneal administration 

of 500.0 mg/kg bw of a methanol extract of the fl owers per day for 

3 days did not potentiate barbiturate-induced sleeping time in mice (39). 

Subcutaneous administration of 10.0 g/kg bw of a 50% methanol extract 

of the fl owers inhibited pentylenetetrazole-induced convulsions in mice 

(23). 

Immune system effects 

Intraperitoneal administration of 50.0–450.0 mg/kg bw of saffl ower yellow 

extracted from the fl owers per day for 6 days suppressed antibody 

formation in mice (40). Intraperitoneal administration of 50.0 mg of an 

aqueous extract of the fl owers per day for 6 days to mice delayed cutaneous 

hypersensitivity reactions, demonstrating immune suppressant activ- 

119


ity. Administration of the extract resulted in decreased lysozyme concentrations, 

decreased phagocytosis of macrophages and leukocytes, and 

diminished production of plaque-forming cells, rosette-forming cells, and 

antibodies. The extract also delayed the responsiveness and activation of 

T-suppressor lymphocytes (40). 


Intraperitoneal administration of 30.0 mg of an aqueous extract of the 

fl owers to mice reduced platelet aggregation induced by adenosine 

diphosphate (ADP) by 65% in γ-irradiated animals (41). Intraperitoneal 

administration of 0.1 g/kg bw of an ethyl acetate or aqueous extract of the 

fl owers to mice had no effects on platelet aggregation (42). 

An aqueous extract of the fl owers, 2.27 mg/ml, inhibited ADPinduced 

platelet aggregation by 24.7% in platelets isolated from irradiated 

rabbits (41). Aqueous, hexane and 90% ethanol extracts of the fl owers, 

5.0 mg/ml, inhibited platelet aggregation induced by ADP, arachidonic 

acid and collagen in rat platelets (43). 


Intraperitoneal administration of a hot aqueous extract of the fl owers 

(dose not specifi ed) increased uterine contractions in pregnant female rats 

(31). 

Toxicology 

Intragastric or subcutaneous administration of 10.0 g/kg bw of a 50% 

ethanol extract of the fl owers to mice had no toxic effects (44). The intraperitoneal 

median lethal dose (LD 50 ) of a decoction of the fl owers in mice 

was 1.2 g/kg bw (19). The intravenous LD 50 of a 50% ethanol extract of 

the fl owers in mice was 5.3 g/kg bw. The intravenous and oral LD 50 values 

of carthamin in mice were 2.35 g/kg bw and > 8.0 g/kg, respectively. No 

toxic effects or death of animals was reported after intraperitoneal administration 

of 12.5 g/kg of a decoction of the fl owers per day for 2 days to 

mice. Chronic administration of 0.015–1.5 g/kg bw of carthamin in the 

diet per day for 3 months had no toxic effects on the heart, liver, kidneys 

or gastrointestinal tract of young rats (19). 




Increased menstrual fl ow may occur (19). Dizziness, skin eruptions and 

transient urticaria have been reported (19). 

120


Owing to its traditional use as an emmenagogue and its stimulatory 

effects on the uterus, Flos Carthami should not be administered during 

pregnancy. Flos Carthami is also contraindicated in haemorrhagic diseases, 

peptic ulcers and excessive menstruation (19). 

Warnings 


Flos Carthami 

Precautions 


Although no drug interactions have been reported, extracts of Flos Carthami 

inhibit platelet aggregation (41, 43). The fl owers should therefore 

be used with caution in patients taking anticoagulants or antiplatelet 

drugs. 


An aqueous or methanol extract of the fl owers was not mutagenic in concentrations 

up to 100.0 mg/ml in the Salmonella/microsome assay using 

S. typhimurium strains TA98 and TA100 with or without metabolic activation 

with liver microsomes (45, 46). An aqueous or methanol extract of 

the fl owers, 100.0 mg/ml, was not mutagenic in the Bacillus subtilis recombination 

assay (45). However, other investigators have reported that 

aqueous extracts of the fl owers were mutagenic at concentrations of 

50.0 μg/ml and 5.0 mg/plate in S. typhimurium strains TA98 and TA100 

(29, 47). Intraperitoneal administration of 4.0 g/kg bw of an aqueous 

extract of the fl owers to mice was mutagenic (46). 

Intragastric administration of 240 mg of an aqueous extract of the 

fl owers to female rats had no effects on fetal implantation and no embryotoxic 

effects (8). Intragastric administration of 2.0 g/kg bw of an 

aqueous extract of the fl owers twice per day to female rats throughout 

pregnancy had no effect on implantation, gestation or duration of fetal 

expulsion, but did cause fetal loss by resorption (48). 


Pregnant mice were treated with varying doses of an aqueous extract of 

the fl owers during days 0–8 of gestation, and the embryos were isolated 

and evaluated on day 13 of the gestational period. The results showed 

that, at doses of 1.6 mg/kg bw and 2.0 mg/kg bw per day, the extract induced 

embryo absorption, while at 1.2 mg/kg bw per day, changes in the 

121


external, internal and longitudinal diameters, open neuropore, cellular 

orientation and cellular degeneration were observed (49). 




No information available. However, owing to possible mutagenic effects, 

use of Flos Carthami during nursing should be only on the advice of a 

health-care professional. 


No information available. However, owing to possible mutagenic effects, 

use of Flos Carthami in children should be only on the advice of a healthcare 

professional. 




Dosage forms 

Dried fl owers for infusions and decoctions; extracts. Store in a cool dry 

place protected from moisture (3). 

Posology 


Average daily dose: 3.0–9.0 g of Flos Carthami as an infusion or decoction; 

equivalent for other preparations (2, 3). 

References 





3. Pharmacopoeia of the People’s Republic of China. Vol. I. (English ed.). 






1959. 

122

Flos Carthami 

6. Farnsworth NR, Bunyapraphatsara N, eds. Thai medicinal plants. Bangkok, 

Medicinal Plant Information Center, Faculty of Pharmacy, Mahidol University, 

1992. 

7. Bensky D, Gamble A, Kaptchuk T, eds. Chinese herbal medicine, materia 

medica, rev. ed. Seattle, WA, Eastland Press, 1993. 





9. Paris PR, Moyse H. Précis de matière médicale. Tome III. Paris, Libraires de 

l’Académie de Médicine, 1971. 

10. Medicinal plants in China. Manila, Philippines, World Health Organization 



11. Medicinal plants in the Republic of Korea. Manila, Philippines, World Health 

Organization Regional Offi ce for the Western Pacifi c, 1998 (WHO Regional 

Publications, Western Pacifi c Series, No. 21). 







Switzerland). 

15. Nakano K et al. High-performance liquid chromatography of carthamin, 

saffl or yellow A and a precursor of carthamin. Application to the investigation 

of an unknown red pigment produced in cultured cells of saffl ower. 

Journal of Chromatography, 1988, 438:61–72. 

16. Kasumov MA, Amirov VA. [Natural yellow color from saffl ower fl owers.] 

Pishchevaya Promushlennost (Moscow), 1991, 3:50–51 [in Russian]. 

17. Meselhy MR et al. Two new quinochalcone yellow pigments from Carthamus 

tinctorius and Ca 2+ antagonistic activity of tinctormine. Chemical and 

Pharmaceutical Bulletin, 1993, 41:1796–1802. 

18. Akihisa T et al. Erythro-hentriacontane-6,8-diol and 11 other alkane 6,8diols 

from Carthamus tinctorius. Phytochemistry, 1994, 36:105–108. 

19. Chang HM, But PPH, eds. Pharmacology and applications of Chinese materia 

medica. Vol. 1. Singapore, World Scientifi c, 1986. 

20. Indian medicinal plants. Vol. 1. New Delhi, Orient Longman, 1971. 

21. Chatterjee A, Pakrashi SJ, eds. The treatise on Indian medicinal plants. 

Vol. 5. NISCOM, New Delhi, 1997. 

22. Mohsin A et al. Analgesic, antipyretic activity and phytochemical screening 

of some plants used in traditional Arab system of medicine. Fitoterapia, 1989, 

60:174–177. 

123


23. Kasahara Y et al. [Pharmacological studies on fl ower petals of Carthamus 

tinctorius central actions and antiinfl ammation.] Shoyakugaku Zasshi, 1989, 

43:331–338 [in Japanese]. 

24. Kasahara Y et al. [Pharmacological studies on fl ower petals of Carthamus 

tinctorius (II) anti-infl ammatory effect.] Shoyakugaku Zasshi, 1991, 45:306– 

315 [in Japanese]. 

25. Kumazawa N et al. [Protective effects of various methanol extracts of crude 

drugs on experimental hepatic injury induced by alpha-naphthylisothiocyanate 

in rats.] Yakugaku Zasshi, 1991, 111:199–204 [in Japanese]. 


drugs on experimental hepatic injury induced by carbon tetrachloride in 

rats.] Yakugaku Zasshi, 1990, 110:950–957 [in Japanese]. 

27. Wang ZL. [Experimental study of preventing liver cirrhosis by using four 

kinds of Chinese herbs.] Chung Kuo Chung His I Chieh Ho Ysa Chih, 1992, 

12:357–358 [in Chinese]. 

28. Han BH et al. [Screening on the anti-infl ammatory activity of crude drugs.] 

Korean Journal of Pharmacognosy, 1972, 4:205–209 [in Korean]. 

29. Takeda N, Yasui Y. Identifi cation of mutagenic substances in roselle color, 

elderberry color and saffl ower yellow. Agricultural and Biological Chemistry, 

1985, 49:1851–1852. 

30. Avirutnant W, Pongpan A. The antimicrobial activity of some Thai fl owers 

and plants. Mahidol University Journal of Pharmaceutical Sciences, 1983, 

10:81–86. 

31. Li CP. Chinese herbal medicine. Washington, DC, United States Department 

of Health, Education, and Welfare, 1974 (Publication No. (NIH) 75-732). 

32. Yamahara J et al. Effect of crude drugs on congestive edema. Chemical and 


33. Wang BZ et al. [Effect of hong-hua (Flos Carthami) on the extent of myocardial 

ischemia in the different infarct zones following coronary occlusion 

in the dog.] Yao Hsueh Hsueh Pao, 1979, 14:474–479 [in Chinese]. 

34. Kuang PG et al. Cerebral infarction improved by saffl ower treatment. 

American Journal of Chinese Medicine, 1983, 11:62–68. 

35. Han GQ et al. The screening of Chinese traditional drugs by biological assay 

and the isolation of some active components. International Journal of 

Chinese Medicine, 1991, 16:1–17. 

36. Li SY et al. [Preliminary study on the effect of Carthamus tinctorius L. upon 

peripheral blood vessels.] National Medical Journal of China, 1979, 59:550– 

553 [in Chinese]. 

37. Liu F et al. [Hypotensive effects of saffl ower yellow in spontaneously hypertensive 

rats and infl uence on plasma rennin activity and angiotensin II levels.] 

Yao Xue Xue Bao, 1992, 27:785–787 [in Chinese]. 

38. Siow YL et al. Effect of Flos carthami on stress-activated protein kinase activity 

in the isolated reperfused rat heart. Molecular and Cellular Biochemistry, 

2000, 207:41–47. 

124

Flos Carthami 

39. Shin KH, Woo WS. A survey of the response of medicinal plants on drug 

metabolism. Korean Journal of Pharmacognosy, 1980, 11:109–122. 

40. Lu ZW et al. [Suppressive effects of saffl ower yellow on immune functions.] 

Chung-kuo Yao Li Hsueh Pao, 1991, 12:537–542 [in Chinese]. 

41. Wang HF et al. Radiation-protective and platelet aggregation inhibitory effects 

of fi ve traditional Chinese drugs and acetylsalicylic acid following highdose 

γ-irradiation. Journal of Ethnopharmacology, 1991, 34:215–219. 

42. Kosuge T et al. [Studies on active substances in the herbs used for oketsu, 

blood coagulation, in Chinese medicine. I. On anticoagulative activities of 

the herbs used for oketsu.] Yakugaku Zasshi, 1984,104:1050–1053 [in Japanese]. 

43. Yun-Choi HS et al. Modifi ed smear method for screening potential inhibitors 

of platelet aggregation from plant sources. Journal of Natural Products, 

1985, 48:363–370. 

44. Mokkhasmit M et al. Study on toxicity of Thai medicinal plants. Bulletin of 

the Department of Medicinal Sciences, 1971, 12:36–65. 



1982, 97:81–102. 

46. Yin XJ et al. A study on the mutagenicity of 102 raw pharmaceuticals used in 

Chinese traditional medicine. Mutation Research, 1991, 260:73–82. 

47. Watanabe F et al. [Mutagenicity screening of hot water extracts from crude 

drugs.] Shoyakugaku Zasshi, 1983, 37:237–240 [in Japanese]. 

48. Smitisiri Y. Effects of Carthamus tinctorius L. (fl owers), Cyperus rotundus 

L. (tubers) and Eupatorium odoratum L. (leaves) on the implantation, length 

of gestation, duration of fetal expulsion and fetal loss in rats. Journal of the 

National Research Council of Thailand, 1978, 21:22–23. 

49. Nobakht M et al. A study on the teratogenic and cytotoxic effects of saffl 

ower extract. Journal of Ethnopharmacology, 2000, 73:453–459. 

125

126 

Stigma Croci 

Defi nition 

Stigma Croci consists of the dried stigmas of Crocus sativus L. (Iridaceae) 

(1, 2). 

Synonyms 

Crocus offi cinalis Martyn (3). 


Açcfrão, azaferan, azafran, crocus, crocus hispanicus, crocus orientalis, 

dye saffron, Echter Safran, fan-hung-hua, Gewürzsafran, hay saffron, 

kamkana, kesar, keshara, koema-koema, kumkum, Safran, saffraon, saffron, 

saffron crocus, sáfrány, sapran, Spanish saffron, true saffron, szafran, 

szafrana, z’afaran, za afran l-hor, zaafaran, zafaran, zafarfon, zafferano, 

zang hong hua, zafrane hor (1–6). 


Indigenous to southern Europe and south-western Asia. Cultivated in 

the Eastern Mediterranean and in China, France, India, Italy and Spain (4, 

5). 

Description 

A perennial, low growing (8–30 cm high), bulbous herb with an underground 

globular corm, producing six to nine sessile leaves, surrounded in 

its lower part by four or fi ve broad membranous scales. Flowers borne on 

the terminal region of a scape, each fl ower consisting of a pale reddishpurple 

perianth showing a cylindrical tube about 10 cm long and six 

oblong oval segments, an androecium of three stamens and a gynoecium 

of three syncarpous carpels. Ovary inferior, three-locular. Style slender, 

elongated and pale yellow in the perianth tube, divided in its upper part 

into three drooping, deep-red stigmas (4, 7).

Plant material of interest: dried stigmas 


Thin cord-like stigmas, dark yellow-red to red-brown, 1.5–3.5 cm long, 

tripartite or separate, the upper part broader and slightly fl attened, the 

distal end split longitudinally and rolled into a slender funnel with a crenate 

edge. Margin of the apex irregularly dentate, with a short slit at the 

inner side, sometimes with a small piece of style remaining at the lower 

end. Texture light, lax and soft, without oily lustre (1, 2, 8). 


Odour: characteristic, aromatic, slightly irritant; taste: pungent, slightly 

bitter (1, 2, 8). 


When softened by immersion in water, upper ends of the stigmas show 

numerous tubular protrusions about 150 μm long, with a small number of 

pollen grains, which are spherical, smooth and without spines (1, 9, 10). 


Orange-red. Epidermal cells long, thin-walled, slightly sinuous, stripeshaped 

in the surface view; outer walls sometimes protrude, showing papillae, 

with indistinct fi ne striations. Terminal epidermal cells of stigma 

are papillose, 26–56 μm in diameter, with sparse striations on the surface. 

Parenchymatous cells are crowded with round-fascicle, fusiform or subsquare 

granular crystals of calcium oxalate, 2–14 μm in diameter (2). 


Macroscopic and microscopic examinations, microchemical and spectrophotometric 

tests (1, 2), and thin-layer chromatography (11). 

Purity tests 





Total ash 



Not more than 12.0% (1, 2). 

Stigma Croci 

127







Heavy metals 







Chemical, foreign organic matter, acid-insoluble ash, water-soluble 

extractive and alcohol-soluble extractive tests to be established in 

accordance with national requirements. 


Colorimetric (1) and spectrophotometric (2) assays are used. Qualitative 

and quantitative high-performance liquid chromatography methods are 

available for picrocrocin, safranal and crocins (15–17). 


The major constituents include essential oils (0.4–1.3%) with α- and 

β-pinene, 1,8-cineole (eucalyptol), a monoterpene glucoside, picrocrocin 

(4%), safranal, which can be obtained by hydrolysis of picrocrocin, and a 

series of carotenoid glucosides known as crocins (2%), dimethylcrocetin 

and their aglycone crocetin (3, 8). Representative structures are presented 

below. 



None. Although Stigma Croci showed antioxidant effects in human studies 

(18), data from controlled clinical trials are lacking. 


As a tonic and antiarteriosclerotic (19, 20), and as a sedative and emmenagogue 

(2, 5, 21). 

128

R2O 

H 3 C 

O 

CH 3 

O OR2 

CH 3 

CH 3 

H 3 C OR1 

picrocrocin 

O 

H 

Glc 

gentiobiosyl : 

+ 

CH 3 

H3C CH3 CHO 

CH 3 

6−Ο−β-D-glucopyranosylβ-D-glucopyranosyl 

Gen 

O 

CH 3 

HO 

safranal 

O 

CH 3 

OR1 

H3C CH3 CHO 

Stigma Croci 

R1 R2 

α-crocetin (crocetin) H H 

β-crocetin H CH3 and CH3 H 

γ-crocetin (dimethylcrocetin) CH3 CH3 A-crocin (crocin) Gen Gen 

B-crocin (crocin 2) Gen Glc 

and Glc Gen 

C-crocin (crocin 3) Gen H 

and H Gen 

D-crocin (crocin 4) Glc Glc 

E-crocin Glc H 

and H Glc 


As an emmenagogue and for treatment of ammenorrhoea, abdominal 

pain, coughs, depression, digestive ailments, fever and pain due to wounds 

(22, 23). Also as an aphrodisiac, appetite stimulant, diaphoretic, contraceptive, 

antispasmodic and nerve sedative (6, 22). 

Pharmacology 


Antiarteriosclerotic effects 

Administration of a monthly intramuscular injection of crocetin (dose 

not specifi ed) to rabbits fed an atherosclerosis-inducing diet reduced 

serum cholesterol concentrations by 50%, and reduced the severity of 

atherosclerosis by ~30% (24). 

Anticoagulant activity 

A hot aqueous extract of Stigma Croci, 10–100.0 mg/ml, prolonged partial 

thromboplastin and prothrombin times, and inhibited platelet aggregation in 

human platelets induced by adenosine diphosphate and collagen in vitro (25). 

Cell proliferation inhibition 

Treatment of cervical epitheloid carcinoma (HeLa) cells with a concentrated 

extract (undefi ned) of the stigmas, 50.0–150.0 μg/ml, for 3 hours 

CH 3 

O O 

OH 

O 

HO 

= 

OH 

HO 

HO 

OH 

β-D-glucopyranosyl Glc = 

HO 

HO 

OH 

O 

OH 

129


inhibited colony formation by 25% and decreased the synthesis of 

deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) by 50% in 

vitro (26, 27). 

Crocin and crocetin, 0.8–2.0 μmol/l, isolated from an extract of the 

stigmas, inhibited the growth of human acute promyelocytic leukaemia 

cells in vitro (28). Crocetin, 35–55.0 μg/ml, inhibited the synthesis of nucleic 

acids and protein in cervical epitheloid carcinoma, lung carcinoma 

and transformed fetal fi broblast malignant human cell lines (29). Incubation 

of cervical epitheloid carcinoma cells (HeLa), lung adenocarcinoma 

cells (A549) and SV-40 transformed fetal lung fi broblast cells with varying 

concentrations of crocetin for 3 hours resulted in a dose-dependent 

reduction in DNA and RNA synthesis, and suppression of RNA polymerase 

II activity (26). 

Central nervous system effects 

Intragastric administration of 125–250.0 mg/kg body weight (bw) of a 

50% ethanol extract of the stigmas had a tranquillizing effect in mice, and 

potentiated the sedative effects of barbiturates (30). 

Chemical carcinogenesis inhibition 

Topical application of 100 mg/kg bw of a 95% ethanol extract of the stigmas 

inhibited two-stage initiation and promotion of skin carcinogenesis 

in mice, delaying the onset of papilloma formation and reducing the mean 

number of papillomas per mouse (31). Intragastric administration of 

100.0 mg/kg bw of the same extract per day for 30 days reduced the incidence 

of soft tissue sarcomas induced by 20-methylcholanthrene by 10% 

in mice (31). Intragastric administration of 100.0 mg/kg bw of an ethanol 

extract of the stigmas to mice inhibited the growth of solid Dalton lymphoma 

ascites and sarcoma 180 tumours by 87% and 41%, respectively 

(23, 32). Subcutaneous administration of 400.0 mg/kg bw of crocin weekly 

for 13 weeks, slowed the growth of colon adenocarcinoma and increased 

the lifespan of female but not male mice (33). 

Intraperitoneal administration of 50 mg/kg bw of a 95% ethanol extract 

of the stigmas to mice partially prevented the decreases in body 

weight, haemoglobin levels and leukocyte counts caused by cisplatin 

treatments (32). 

Circulation effects 

External application of a 1% aqueous solution containing crocin analogues 

isolated from Crocus sativus signifi cantly (P < 0.05) increased blood fl ow 

to the retina and choroid in rabbits with ocular hypertension. Intraperitoneal 

administration of 10.0 mg/kg bw of crocin analogues to rats facili- 

130

Stigma Croci 

tated the recovery of retinal function after induction of retinal ischaemia 

by occlusion of the central retinal and posterior ciliary arteries (34). 

Cytotoxicity 

In vitro, crocin had potent cytotoxic effects on human and animal adenocarcinoma 

cells, with median lethal doses (LD 50 ) of 0.4 mmol/l and 

1.0 mmol/l, respectively (33). An aqueous extract of the stigmas (LD 50 

2.3 mg/ml), crocin (LD 50 3 mmol/l), picrocrocin (LD 50 3 mmol/l) and safranal 

(LD 50 0.8 mmol/l) inhibited the growth of HeLa cells in vitro. The 

cells treated with crocin exhibited wide cytoplasmic vacuole-like areas, 

reduced cytoplasm and cell shrinkage, indicating the induction of apoptosis 

(35). 

Nootropic effects 

An unspecifi ed alcohol extract of the stigmas enhanced learning and 

memory in learning-impaired mice (36). Intragastric administration of 

125.0–500.0 mg/kg bw of the extract did not affect learning behaviours in 

normal mice, but prevented ethanol-induced learning impairment, and 

prevented ethanol-induced inhibition of hippocampal long-term potentiation 

(a form of activity-dependent synaptic plasticity that may support 

learning and memory) in anaesthetized rats (30, 36). Intragastric administration 

of a single dose of 250.0 mg/kg bw of the same extract prevented 

acetaldehyde-induced inhibition of long-term potentiation in the dentate 

gyrus of anaesthetized rats (37). In a follow-up study, treatment of mice 

with an ethanol extract of 250.0 mg/kg bw of the stigmas improved 

ethanol-induced impairments of learning behaviours in mice and prevented 

ethanol-induced inhibition of hippocampal long-term potentiation (38). 

The effect was attributed to crocin, but not crocetin. 

Toxicity 

The LD 50 for Stigma Croci was reported to be 20.7 g/kg bw in rodents 

(23). The LD 50 of a 95% ethanol extract of the stigmas was > 600 mg/kg 

bw in mice (39). Mice treated with dimethylcrocetin isolated from the 

stigmas did not exhibit haematological or biochemical toxic effects after 

intragastric administration of up to 50.0 mg/kg bw (23). 


The antioxidant effects of the stigmas were assessed in a clinical trial involving 

30 subjects in three groups: 10 healthy volunteers, 10 patients 

with coronary artery disease and 10 healthy controls. The two test groups 

received 50 mg of Stigma Croci in 100.0 ml of milk twice daily for 6 weeks, 

the controls received milk only. Lipoprotein oxidation in blood samples 

131


decreased by 42.3% in healthy volunteers (P < 0.001) and 37.9% (P < 0.01) 

in patients with coronary artery disease compared with controls (18). 


The lethal dose of Stigma Croci is reported to be 20.0 g; however, smaller 

doses may cause vomiting, uterine bleeding, bloody diarrhoea, haematuria, 

bleeding from the nose, lips and eyelids, vertigo, numbness and yellowing 

of the skin and mucous membranes (5). Oral administration of 

5.0 g resulted in localized skin haemorrhages, marked thrombocytopenia, 

and abnormalities of blood clotting in one patient (40). 


Stigma Croci may induce uterine contractions and is therefore contraindicated 

during pregnancy (5). Owing to a lack of safety data, use of the 

stigmas in children and nursing mothers should be restricted to normal 

food use. Stigma Croci is contraindicated in bleeding disorders. 

Warnings 

At doses of 5.0 g or more, Stigma Croci may cause serious adverse reactions 

(see Adverse reactions). Overdose of Stigma Croci (12.0–20.0 g/day) 

may be fatal (7, 22). 

Precautions 


Stigma Croci inhibits platelet aggregation and should therefore be used 

with caution in patients taking anticoagulant or antiplatelet drugs. 


Ethyl acetate, methanol and aqueous extracts of Stigma Croci (concentrations 

not specifi ed) were not mutagenic in the Salmonella/microsome 

assay using S. typhimurium strains TA98 and TA100 with or without 

metabolic activation (41). Crocin and dimethylcrocetin,1.0 mg/plate, 

2.0 mg/plate and 4.0 mg/plate, were not mutagenic in the Salmonella/ 

microsome assay using S. typhimurium strain TA 1535 (23). A chloroform-methanol 

extract (2:1) of the stigmas, 100.0 mg/plate, was not mutagenic 

in pig kidney cells or in trophoblastic placenta cells (42). 





132



Stigma Croci 



drug and laboratory test interactions; or teratogenic effects in 

pregnancy. 

Dosage forms 

Dried stigmas; extracts of dried stigmas. Store the dried stigmas in a tightly 

sealed metal or glass container, protected from light and moisture (5). 

Posology 

There is insuffi cient information available to give an accurate assessment 

of dose range. No risk is associated with consumption in standard food 

use quantities (22, 43). The recommended therapeutic daily dose is 3.0– 

9.0 g (2). However, owing to a report of toxicity at 5.0 g (40), doses below 

5.0 g/day are recommended. 

References 




Beijing, China, Chemical Industry Press, 2000. 







Press, 1994. 





7. Physician’s desk reference for herbal medicines. Montvale, NJ, Medical Economics 

Co, 1998. 

8. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, 

Lavoisier Publishing, 1995. 


10. Wallis TE. Textbook of pharmacognosy, 4th ed. London, J & A Churchill, 

1960. 

133


11. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas. 








Switzerland). 

15. Sujata V, Ravishankar GA, Venkataraman LV. Methods for the analysis of the 

saffron metabolites crocin, crocetins, picrocrocin and safranal for the determination 

of the quality of the spice using thin-layer chromatography, highperformance 

liquid chromatography and gas chromatography. Journal of 

Chromatography, 1992, 624:497–502. 

16. Tarantilis PA, Polissiou M, Manfait M. Separation of picrocrocin, cistrans-crocins 

and safranal of saffron using high-performance liquid chromatography 

with photodiode-array detection. Journal of Chromatography A, 

1994, 664:55–61. 

17. Tarantilis PA, Tsoupras G, Polissiou M. Determination of saffron (Crocus 

sativus L.) components in crude plant extract using high-performance liquid 

chromatography–UV–visible photodiode-array detection–mass spectrometry. 

Journal of Chromatography A, 1995, 699:107–118. 

18. Verma SK, Bordia A. Antioxidant property of saffron in man. Indian Journal 

of Medical Sciences, 1998, 52:205–220. 

19. Grisolia S. Hypoxia, saffron, and cardiovascular disease. Lancet, 1974, 2:41– 

42. 

20. Indian pharmacopoeia. Vol. I. New Delhi, The Controller of Publications, 

Government of India Ministry of Health and Family Welfare, 1996. 


Könyuhiadó, 1963. 

22. Central Council for Research in Ayurveda and Siddha. Experimental cultivation 

of saffron (kumkum). New Delhi, Ministry of Health and Welfare, 

1995. 

23. Nair SC, Kurumboor SK, Hasegawa JH. Saffron chemoprevention in biology 

and medicine: A review. Cancer Biotherapy, 1995, 10:257–264. 

24. Gainer JW, Chisolm GM. Oxygen diffusion and atherosclerosis. Atherosclerosis, 

1974, 19:135–138. 

25. Nishio T et al. [Effect of crocus (Crocus sativus L, Iridaceae) on blood 

coagulation and fi brinolysis.] Shoyakugaku Zasshi, 1987, 41:271–276 [in 

Japanese]. 

26. Abdullaev FI, Frenkel GD. The effect of saffron on intracellular DNA, RNA 

and protein synthesis in malignant and nonmalignant human cells. Bio- 

Factors, 1992, 41:43–45. 

27. Abdullaev FI, de Mejia EG. Inhibition of colony formation of Hela cells by 

naturally occurring and synthetic agents. BioFactors, 1996, 5:133–138. 

134

Stigma Croci 

28. Tarantilis PA et al. Inhibition of growth and induction of differentiation of 

promyelocytic leukemia (HL-60) by carotenoids from Crocus sativus L. 

Anticancer Research, 1994, 14:1913–1918. 

29. Abdullaev FI. Inhibitory effect of crocetin on intracellular nucleic acid and 

protein synthesis in malignant cells. Toxicology Letters, 1994, 70:243–251. 

30. Zhang YX et al. Effects of Crocus sativus L. on the ethanol-induced impairment 

of passive avoidance performances in mice. Biological and Pharmaceutical 

Bulletin, 1994, 17:217–221. 

31. Salomi MJ, Nair SC, Panikkar KR. Inhibitory effects of Nigella sativa and 

saffron (Crocus sativus) on chemical carcinogenesis in mice. Nutrition and 

Cancer, 1991, 16:67–72. 

32. Nair SC et al. Modulatory effects of Crocus sativus and Nigella sativa extracts 

on cisplatin-induced toxicity in mice. Journal of Ethnopharmacology, 

1991, 31:75–83. 

33. Garcia-Olmo DC et al. Effects of long-term treatment of colon adenocarcinoma 

with crocin, a carotenoid from saffron (Crocus sativus L.): an 

experimental study in the rat. Nutrition and Cancer, 1999, 35:120–126. 

34. Xuan B et al. Effects of crocin analogs on ocular blood fl ow and retinal function. 

Journal of Ocular Pharmacology and Therapeutics, 1999, 15:143–152. 

35. Escribano J et al. Crocin, safranal and picrocrocin from saffron (Crocus sativus 

L.) inhibit the growth of human cancer cells in vitro. Cancer Letters, 

1996, 100:23–30. 

36. Sugiura M et al. Ethanol extract of Crocus sativus L. antagonizes the inhibitory 

action of ethanol on hippocampal long-term potentiation in vivo. 


37. Abe K et al. Saffron extract prevents acetaldehyde-induced inhibition of 

long-term potentiation in the rat dentate gyrus in vivo. Brain Research, 1999, 

851:287–289. 

38. Abe K et al. Effects of saffron extract and its constituents on learning behaviour 

and long-term potentiation. Phytotherapy Research, 2000, 14:149–152. 

39. Nair SC, Panikkar SB, Panikkar KR. Antitumour activity of saffron (Crocus 

sativus). Cancer Letters, 1991, 57:109–114. 

40. Frank A. Auffallende Purpurea bei artifi ziellem Abort. [Purpurea resulting 

from artifi cial abortion.] Deutsche Medizinische Wochenschrift, 1961, 

86:1618. 


drug extracts. I.] Yakugaku Zasshi, 1982, 102:596–601 [in Japanese]. 



43. McGuffi n M et al., eds. Botanical safety handbook. Boca Raton, FL, CRC 

Press, 1997. 

135

136 

Fructus Foeniculi 

Defi nition 

Fructus Foeniculi consists of the dried ripe fruits of Foeniculum vulgare 

Mill. (Apiaceae) (1–8). 1 

Synonyms 

Anethum foeniculum Clairv., A. foeniculum L., A. rupestre Salisb., Feniculum 

commune Bubani, Foeniculum azoricum Mill., F. capillaceum Gilib., 

F. dulce DC., F. foeniculum (L.) H. Karst., F. offi cinale All., F. panmorium 

DC., F. piperitum DC., F. sativum Bertol, Ligusticum divaricatum Hoffmannsegg 

et Link, L. foeniculum Crantz, Meum foeniculum (L.) Spreng., 

Ozodia foeniculacea Wight et Arn., Selinum foeniculum (L.) E.H.L. 

Krause (2, 3, 9, 10). Apiaceae are also known as Umbelliferae. 


Aneth doux, arap saçi, besbes, bitter fennel, Bitterfenchel, brotanis, common 

fennel, dill, édeskömény, erva doce, fãnksal, fannel, Fencel, Fenchel, 

fenchul, Fennekel, fennel, Fennichl, fennikel, Fennkol, fenouil, fenucchiello, 

fenucchio, fenykl, fi nkel, Finkel, fi nichio, fi nocchio, fi nucco, 

fi olho, fl orence fennel, foenoli doux, funcho, gemeiner Fenchel, Gemüsefenchel, 

giant fennel, guvamuri, hierba de anis, hinojo, hui-hsiang, 

imboziso, insilal, koper wloski, lady’s chewing tobacco, large fennel, 

madesi souf, madhurika, marathoron, maratrum, marui, misi, nafa, 

panmauri, razianeh, razianaj, sanuf, shamar, shomar, sladkij ukrop, 

sohoehyang, sopu, spingel, sup, thian khaao phlueak, thian klaep, venkel, 

sweet fennel, uikyo, uikyou, vegetable fennel, vinkel, wild fennel, xiao 

hui, xiaohuixiang, yi-ra (2, 3, 6, 8, 9, 11–14). 

1 The European pharmacopoeia (7) recognizes Foeniculum vulgare Mill. ssp. vulgare var. vulgare 

(Foeniculi amari fructus, Bitter Fennel) and F. vulgare Mill. ssp. vulgare var. dulce (Foeniculum 

dulcis fructus, Sweet Fennel) as distinct entities for which separate monographs are provided. However, 

in the biological literature, a clear delineation at the variety level is generally not made. Therefore, 

this monograph has not made the distinction between the “bitter” and “sweet” varieties.


Indigenous to the Mediterranean region. Cultivated in Europe, Asia and 

temperate regions of Africa and South America (2, 12, 15). 

Description 

Perennial aromatic herb, 1–3 m high with green, glaucous, furrowed, 

branched stems bearing alternate leaves, 2–5 times pinnate with extremely 

narrow leafl ets. Superior leaves with sheaths longer than the blade. Umbels 

compound, large, nearly regular, on long peduncles. Flowers yellow, 

no involucre; calyx with fi ve very slight teeth; petals fi ve, entire, tips involute; 

stamens fi ve; ovary two-celled; stylopodium large, conical. Fruit an 

oblong cremocarp, 6–10 mm long, 1–4 mm in diameter, greenish; glabrous 

mericarp compressed dorsally, semicylindrical, with fi ve prominent, 

nearly regular ribs. Seeds somewhat concave, with longitudinal furrows 

(3, 15, 16). 



Cremocarp, oblong 3.5–10.0 mm long, 1–3 mm wide, externally greyish 

yellow-green to greyish yellow often with pedicel 2–10 mm long. Mericarps 

usually free, glabrous, each bearing fi ve prominent slightly crenated 

ridges (1–4, 7, 8). 


Odour: characteristic, aromatic; taste: sweet to bitter (1–4, 8). 



Outer epidermis of the pericarp consists of thick-walled, rectangular, polygonal, 

colourless cells, with smooth cuticle, few stomata and no hairs. Mesocarp 

consists of brownish parenchyma; traversed longitudinally by six 

large schizogenous vittae, appearing elliptical in section and possessing 

brown epithelial cells; traversed in the ridges by vascular bundles, each 

having one inner xylem strand and two lateral phloem strands, and accompanied 

by strongly lignifi ed fi bres; some of the mesocarp cells, especially 

those about the vascular bundles, possess lignifi ed, reticulate cells. 

Endocarp composed of one layer of fl attened thin-walled cells varying in 

length, but mostly 4–6 μm thick, arranged parallel to one another in groups 

of fi ve to seven. Endosperm, formed of somewhat thick-walled polygonal 

cellulosic parenchyma containing fi xed oil, several aleurone grains (up to 

6 μm in diameter) enclosing a globoid, and one or more microrosette crys- 

137


tals of calcium oxalate, about 3 μm in diameter. Carpophore often not 

split, with thick-walled sclerenchyma in two strands (2, 8). 


Greyish-brown to greyish-yellow. Yellowish-brown-walled polygonal 

secretory cells, frequently associated with a layer of thin-walled transversely 

elongated cells 2–9 μm wide, in a parquet arrangement; reticulate 

parenchyma of the mesocarp; numerous fi bre bundles from the ridges, 

often accompanied by narrow spiral vessels; very numerous endosperm 

fragments containing aleurone grains, very small microrosette crystals of 

calcium oxalate, and fi bre bundles from the carpophore (7). 


Macroscopic and microscopic examinations (1–4, 7, 8), thin-layer chromatography 

for the presence of anethole and fenchone (7), and gas chromatography 

for the presence of anethole, fenchone and estragole (7). 

Purity tests 






Not more than 1.5% peduncles and not more than 1.5% other foreign 

matter (4, 7). 

Total ash 

Not more than 10% (1, 4, 7, 8, 18). 


Not more than 1.5% (1, 2, 4). 





Moisture 


138






Heavy metals 







Chemical and sulfated ash tests to be established in accordance with national 

requirements. 


Contains not less than 1.4% v/w essential oil (1, 2, 4, 6). 


The major constituent is the essential oil (2–6%), which contains transanethole 

(50–82%), (+)-fenchone (6–27%), estragole (methylchavicol) 

(3–20%), limonene (2–13%), p-anisaldehyde (6–27%), α-pinene (1–5%) 

and α-phellandrene (0.1–19.8%) (9, 12, 14, 21, 22). Representative structures 


CH3 

H3CO H3CO trans-anethole estragole 

H 2C 

H 3C 

H 

CH 3 

H 3C 

H 3 C 

CH 3 

(+)-limonene (-)-α-phellandrene 



None. 

H 

H 

CH2 

H3C H3C H 

CH 3 

H 3 CO 

anisaldehyde 

α-pinene 

CHO 


CH 3 

H 


O 

CH 3 

CH 3 


fenchone 

139



Symptomatic treatment of dyspepsia, bloating and fl atulence (9, 23–25). 

As an expectorant for mild infl ammation of the upper respiratory tract 

(24, 26). Treatment of pain in scrotal hernia, and dysmenorrhoea (8). 


Treatment of blepharitis, bronchitis, constipation, conjunctivitis, diabetes, 

diarrhoea, dyspnoea, fever, gastritis, headache, pain, poor appetite and 

respiratory and urinary tract infections (14). As an aphrodisiac, anthelminthic, 

emmenagogue, galactagogue and vermicide (14, 27, 28). 

Pharmacology 



Intragastric administration of 500 mg/kg body weight (bw) of a 95% ethanol 

extract of Fructus Foeniculi to mice reduced the perception of pain 

as measured in the hot-plate test, and decreased yeast-induced pyrexia 

(29). Intragastric administration of 500.0 mg/kg bw of a 95% ethanol extract 

of the fruits to rats had signifi cant (P < 0.05) analgesic activity in the 

hot-plate reaction test (30). In mice with yeast-induced pyrexia, treatment 

with 500.0 mg/kg bw of the same extract reduced rectal temperature from 

36.5 ºC to 34.7 ºC 90 minutes after administration (30). 


An essential oil from the fruits inhibited the growth of Alternaria species, 

Aspergillus fl avus, A. nidulans, A. niger, Cladosporium herbarum, Cunninghamella 

echinulata, Helminthosporium saccharii, Microsporum gypseum, 

Mucor mucedo, Penicillium digitatum, Rhizopus nigricans, Trichophyton 

roseum and T. rubrum in vitro (31, 32). In another study, an 

essential oil was not active against Aspergillus species in vitro but a methanol 

extract of the fruits inhibited the growth of Helicobacter pylori (the 

bacterium associated with gastritis and peptic ulcer disease) in vitro, minimum 

inhibitory concentration 50.0 μg/ml (33). An essential oil from the 

fruits inhibited the growth of Candida albicans, Escherichia coli, Lentinus 

lepideus, Lenzites trabea, Polyporus versicolor, Pseudomonas aeruginosa 

and Staphylococcus aureus (34), and Kloeckera apiculata, Rhodotorula 

rubra and Torulopsis glabrata (35) in vitro. An ethyl acetate extract of the 

seeds inhibited the growth of Shigella fl exneri (36), and an 80% ethanol 

extract of the seeds inhibited the growth of Bacillus subtilis and 

Salmonella typhi at concentrations of 250.0 μg/ml in vitro (37). 

140



An ethanol extract of the fruits, 2.5–10.0 ml/l, 1 part fruits:3.5 parts 31% 

ethanol, inhibited acetylcholine- and histamine-induced guinea-pig ileal 

contractions in vitro (23). An essential oil from the fruits reduced intestinal 

spasms in mouse intestine, and was 26% as active as papaverine (38). 

Intragastric administration of 2.0–3.0 g/kg bw of an infusion of the fruits 

to cats inhibited acetylcholine- and histamine-induced ileum spasms by 

50% (39). An essential oil from the fruits, 25.0 μg/ml and 10.0 μg/ml, respectively, 

inhibited oxytocin- and prostaglandin E 2 -induced contractions 

of isolated rat uterus and reduced the frequency of the latter but not the 

former (40). 


Intravenous administration of a 50% ethanol extract of the fruits (dose 

not specifi ed) reduced blood pressure in dogs (41). An aqueous extract of 

the fruits, 10% in the diet, reduced blood pressure in rats. The effect was 

abolished by pretreatment of the animals with atropine (42). An unspecifi 

ed extract of the seeds had diuretic effects in rabbits after intragastric 

administration. The effect was blocked by pretreatment of the animals 

with morphine (43). 

Intragastric administration of 500.0 mg/kg bw of a 95% ethanol extract 

of the fruits to rats induced diuresis. The effect was comparable to 

that observed in animals treated with 960.0 mg/kg bw of urea, and was 

almost double that in controls (30). 

Estrogenic and antiandrogenic activities 

Intragastric administration of 2.5 mg/kg bw of an acetone extract of the 

seeds daily for 15 days to male rats decreased the protein concentration in 

the testes and vas deferens, and increased it in the seminal vesicles and 

prostate gland (44). The same dose of the same extract administered to 

female rats daily for 10 days increased the weight of the mammary glands, 

while higher doses induced vaginal cornifi cation, increased the weight of 

the oviduct, endometrium, myometrium, cervix and vagina, and induced 

estrus (44). A follow-up study demonstrated that the acetone extract induced 

cellular growth and proliferation of the endometrium, and stimulated 

metabolic changes in the myometrium of rats. These changes appeared 

to favour the survival of spermatocytes and the implantation of the 

zygote in the uterus (45). Conversely, intragastric administration of 2.0 g/ 

kg bw of an aqueous extract of the seeds per day for 25 days signifi cantly 

(P < 0.025) reduced female fertility in mice compared with controls. No 

effect was observed in male mice (46). 

141


Intragastric administration of 0.5 mg/kg bw or 2.5 mg/kg bw of an 

acetone extract of the fruits per day for 10 days to ovariectomized female 

rats had estrogenic effects (45). Intragastric administration (dose not 

specifi ed) of an essential oil from the fruits to goats increased the amount 

of milk produced and the fat content of the milk (47). Lactating mice fed 

the fruits in the diet (concentration not specifi ed) produced pups that ate 

a larger quantity of fennel-containing foods, suggesting that the constituents 

of the fruits may be passed in breast milk (48). Intragastric administration 

of 250.0 mg/kg bw of unspecifi ed extracts of the fruits induced 

estrus and increased the size of the mammary glands and oviducts in adult 

ovariectomized rats, and exerted an antiandrogenic effect in adult male 

mice. It also increased the weight of the cervix and vagina of ovariectomized 

rats, and increased the concentration of nucleic acids and protein in 

cervical and vaginal tissues. The hyperplasia and hypertrophy of the cervix 

and vagina were similar to changes seen during estrus in normal female 

rats (45). 

Subcutaneous administration of anethole (dose not specifi ed) to sexually 

immature female rats increased uterine weight and induced estrus. 

However, in ovariectomized mice the same treatment was not estrogenic 

(49). Intramuscular injection of 100.0 mg/kg bw or 500.0 mg/kg bw of 

anethole per day for 7 days to rats induced a signifi cant decrease in dorsolateral 

prostate weight (P < 0.05) (50). Intragastric administration of 

50.0 mg/kg bw, 70.0 mg/kg bw or 80.0 mg/kg bw of trans-anethole to rats 

had anti-implantation effects, with the maximum effect (100%) at the 

highest dose (51). The compound showed estrogenic effects, and did not 

demonstrate anti-estrogenic, progestational or androgenic effects (51). 

Expectorant and secretolytic effects 

Application of an infusion of Fructus Foeniculi, 9.14 mg/ml, to isolated 

ciliated frog oesophagus epithelium increased the transport velocity of 

fl uid by 12%, suggesting an expectorant effect (52). Administration of 

1.0–9.0 mg/kg bw anethole and 1.0–27.0 mg/kg bw fenchone by inhalation 

to urethanized rabbits produced a decrease in the specifi c gravity of 

the respiratory fl uid and enhanced the volume output of respiratory tract 

fl uid (53). 

Gastrointestinal effects 

Intragastric administration of 24.0 mg/kg bw of the fruits increased spontaneous 

gastric motility in unanaesthetized rabbits; at a dose of 25.0 mg/ 

kg bw the fruits reversed the reduction of gastric motility induced by 

pentobarbital (54). 

142

Sedative effects 

Intragastric administration of an essential oil from the fruits (dose not 

specifi ed) to mice reduced locomotor activity and induced sedation (55). 

A single intraperitoneal administration of 200.0 mg/kg bw of an ether extract 

of the seeds enhanced barbiturate induced sleeping time in mice. 

However, intragastric administration of 200.0 mg/kg bw of the extract 

per day for 7 days decreased barbiturate-induced sleeping time (56). 

Toxicology 

Intragastric administration of 3.0 g/kg bw of a 95% ethanol extract of the 

fruits induced piloerection and reduced locomotor activity in mice (30). 

Acute (24-hour) and chronic (90-day) oral toxicity studies with an ethanol 

extract of the fruits were performed in rodents. Acute doses were 

0.5 g/kg, 1.0 g/kg and 3.0 g/kg per day; the chronic dose was 100.0 mg/kg 

per day. No acute or chronic toxic effects were observed (57). The acute 

median lethal dose (LD 50 ) of anethole in rats was 3.8 mg/kg bw after intragastric 

administration (58, 59). Intragastric or subcutaneous administration 

of 10.0–16.0 g/kg bw of a 50% ethanol extract of the fruits to mice 

had no toxic effects (60). The oral LD 50 of an essential oil from the fruits 

in mice was 1326.0 mg/kg bw (61). 

Chronic use of high doses of trans-anethole in rodent dietary studies 

has been shown to induce cytotoxicity, cell necrosis and cell proliferation. 

In rats, hepatotoxicity was observed when dietary intake exceeded 30.0 mg/ 

kg bw per day (62). In female rats, chronic hepatotoxicity and a low incidence 

of liver tumours were reported with a dietary intake of trans-anethole 

of 550.0 mg/kg bw per day, a dose about 100 times higher than the 

normal human intake (62). In chronic feeding studies, administration of 

trans-anethole, 0.25%, 0.5% or 1% in the diet, for 117–121 weeks had no 

effect on mortality or haematology, but produced a slight increase in hepatic 

lesions in the treated groups compared with controls (63). 

Unscheduled DNA synthesis was not induced in vitro by anethole, 

but was induced by estragole, an effect that was positively correlated with 

rodent hepatocarcinogenicity (64). However, the dose of estragole used 

(dose not specifi ed) in the rodent studies was much higher than the dose 

normally administered to humans. Low doses of estragole are primarily 

metabolized by O-demethylation, whereas higher doses are metabolized 

primarily by 1'-hydroxylation, and the synthesis of 1'-hydroxyestragole, 

a carcinogenic metabolite of estragole (65, 66). 




143



In rare cases, allergic reactions such as asthma, contact dermatitis and 

rhinoconjunctivitis have been reported in sensitive patients (67, 68). 


The fruits are contraindicated in cases of known sensitivity to plants in 

the Apiacaeae (69, 70). Owing to the potential estrogenic effects of the 

essential oil from the seeds and anethole (44, 45, 50), its traditional use as 

an emmenagogue, and the lack of human studies demonstrating effi cacy, 

Fructus Foeniculi should not be used in pregnancy. Pure essential oils 

should not be given to infants and young children owing to the danger of 

laryngeal spasm, dyspnoea and central nervous system excitation (12). 

Warnings 

The pure essential oil from the fruits may cause infl ammation, and has an 

irritant action on the gastrointestinal tract. 

Precautions 


An aqueous extract of the fruits, up to 100.0 mg/ml, was not mutagenic in 

the Salmonella/microsome assay using S. typhimurium strains TA98 and 

TA100 with or without metabolic activation with homogenized rat liver 

microsomes (71, 72). Aqueous and methanol extracts of the fruits, up to 

100.0 mg/ml, were not mutagenic in the Bacillus subtilis recombination assay 

(71). However, a 95% ethanol extract, 10.0 mg/plate, was mutagenic in 

the Salmonella/microsome assay using S. typhimurium strains TA98 and 

TA102 (73). An essential oil from the fruits, 2.5 mg/plate, had mutagenic 

effects in the Salmonella/microsome assay in Salmonella typhimurium 

strain TA100 with metabolic activation (74), and in the Bacillus subtilis 

recombination assay (75). A similar essential oil had no effects in the chromosomal 

aberration test using Chinese hamster fi broblast cell lines (76). 


An essential oil from the fruits, up to 500.0 μg/ml, had no teratogenic effects 

in cultured rat limb bud cells (61). 




No restrictions on the use of infusions prepared from Fructus Foeniculi 

or the seeds. 

144



No restrictions on the use of infusions prepared from Fructus Foeniculi 

or the seeds. See also Contraindications. 



drug interactions; or drug and laboratory test reactions. 

Dosage forms 

Dried fruits, syrup and tinctures. Store the dried fruits in a well-closed 

container, protected from light and moisture (7). 

Posology 


Daily dose: fruits 5–7 g as an infusion or similar preparations, higher daily 

doses (> 7 g fruits) should not be taken for more than several weeks 

without medical advice (25); fennel syrup or honey 10–20 g; compound 

fennel tincture 5–7.5 g (5–7.5 ml). 

References 





3. Standard of ASEAN herbal medicine. Vol. 1. Jakarta, ASEAN Countries, 

1993. 


Health and Welfare, Japan, 1996. 


1998. 

6. The Ayurvedic pharmacopoeia of India. Part I. Vol. I. New Delhi, Ministry 



7. European pharmacopoeia, 3rd ed. Suppl. 2001. Strasbourg, Council of 

Europe, 2000. 




Drogen E–O, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 5, 

Drugs E–O, 5th ed.] Berlin, Springer, 1993. 

10. Tanaka T. ed. Nippon Yakuso Zensho. [Encyclopedia of Japanese Medicinal 

Plants.] Tokyo, Shin-Nihon Shuppan, 1995 [in Japanese]. 

145





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149

150 

Radix Gentianae Luteae 

Defi nition 

Radix Gentianae Luteae consists of the dried roots and rhizomes of Gentiana 

lutea L. (Gentianaceae) (1–6). 

Synonyms 

Asterias lutea Borckh., Swertia lutea Vest (2, 7). 


Bachaka, bachalchaka, balmoney, common gentian, daoua el hoya, esperou, 

European gentian, felwort, gall weed, gansona, ganssana, Gelber Enzian, 

genchiana, genciana, genciana amarilla, gentian, gentiana, genziana 

gialla, genziana maggiore, gentiane, gentiane jaune, grande gentiane, great 

yellow gentian, jintiana, juntiyana, kaf edheeb, kaf el arnab, kouchâd, 

kouched, pale gentian, tárnics, wild gentian (2, 6–10). 


Indigenous to mountainous regions of central and southern Europe (6, 8, 

11, 12). 

Description 

A perennial herb up to 1.5 m high, with erect rhizomes. Stem thick, hollow, 

bearing large, opposite, ovate leaves with fi ve to seven nerves and 

axillary cymes of orange-yellow, open-stellate fl owers. Roots beet-like, 

thickened and branched, starting from a short rhizome. Fruits ovate, capsules 

containing winged seeds (2, 8). 

Plant material of interest: dried roots and rhizomes 


Nearly cylindrical pieces, 3–20 cm long, 2–4 cm in diameter. Rhizome 

short, with fi ne, transverse wrinkles, and sometimes with buds and remains 

of leaves at the upper edge. Root longitudinally and deeply wrin-


kled, and more or less twisted; fractured surface yellow-brown and not 

fi brous; cambium and its surroundings tinged dark brown (1, 2, 5). 


Odour: characteristic; taste: initially sweet, becoming persistently bitter 

(1, 2, 4, 5). Bitterness value not less than 10 000 (4). 


Transverse section of the root shows a narrow zone of four to six layers 

of thin-walled cork cells; a cork cambium, a broad zone of secondary 

cortex with brown, thin-walled parenchyma cells, practically devoid of 

starch, but containing oil globules and minute acicular crystals; a narrow 

zone of phloem composed of many layers of collapsed phloem parenchyma 

and numerous strands of sieve tubes; a distinct cambium; and a 

broad xylem composed largely of yellowish-brown to yellow, thin-walled 

wood parenchyma, scattered through which are a few large vessels and 

some tracheids, isolated or in small groups. Medullary rays indistinct. 

Transverse section of the rhizome exhibits a similar structure except for 

islets of sieve tissue in the xylem, a central pith and a collenchymatous 

phelloderm. Longitudinal sections of rhizome and root exhibit reticulate 

and scalariform tracheae and tracheids with non-lignifi ed walls (8). 


Moderate yellowish-brown to yellowish-orange. Fragments of reticulate, 

scalariform and pitted vessels and tracheids; fragments of brownish cork 

tissue, frequently adhering to which are thick-walled cells, numerous 

somewhat collapsed, large parenchyma cells; occasional clumps of minute 

slender prismatic crystals of calcium oxalate (3–6 μm long) in angles of 

parenchyma cells; starch grains few or absent. Stone cells and fi bres absent 

(3, 8). 


Macroscopic and microscopic examinations (1, 2, 4–6) and microchemical 

tests (1, 2, 5), and thin-layer chromatography (4, 5) for detection of adulteration 

with other Gentiana species (4). 

Purity tests 





151




Total ash 

Not more than 6% (2, 4, 5). 









0.05 mg/kg (4). For other pesticides, see the European pharmacopoeia (4) 



Heavy metals 







Chemical, sulfated ash and alcohol-extractive tests to be established in 

accordance with national requirements. 


High-performance liquid chromatography for the presence of gentiopicroside 

and amarogentin (15–17). 


The major constituents are bitter secoiridoid monoterpenes including 

gentiopicroside (gentiopicrin; 2–8%, sometimes up to almost 10%), swertiamarin, 

sweroside (0.05–0.08%) and its acylglucoside derivative, amarogentin 

(0.03–0.08%), which is the bitterest of all compounds in this mat- 

152


erial. Other constituents include xanthones (up to 0.1%), such as gentisin 

and isogentisin, gentianose (2.5–8.0%) and gentioside, the alkaloid gentianine, 

and traces of essential oil (7, 10–12, 18, 19). Representative structures 

of the secoiridoid monoterpenes are presented below: 

amarogentin 

O gentiopicroside sweroside 

HO 

O O 

O 

O 

O O 

HO 

O O 

HO 

O O 

OH H 

H 

H 

O O 

O O 

HO 

HO 

O O 

H2C OH 

OH 

HO 

OH 

H 

H 

H2C OH 

HO 

OH 

H 

H 

H2C H 

OH 



None. For the results of three uncontrolled human studies, see Clinical 

pharmacology (20–22). Although the fi ndings suggest that Radix Gentianae 

Luteae may be of benefi t for the treatment of dyspepsia, data from 

controlled clinical trials are currently lacking. 


Treatment of digestive complaints, such as loss of appetite, feeling of distension 

and fl atulence (23). As an appetite stimulant during convalescence (24). 


As a carminative, depurative, emmenagogue, febrifuge, tranquillizer and 

tonic, and to facilitate labour (8, 10). Treatment of diabetes and dysmenorrhoea 

(10). 

Pharmacology 



A 95% ethanol extract of Radix Gentianae Luteae (concentration not 

specifi ed) inhibited the growth of Staphylococcus aureus, but was not active 

against Escherichia coli (25). A chloroform extract of the roots and 

rhizomes, 1.0 g/l, was not active against S. aureus (26). An aqueous extract 

of the roots and rhizomes, 500.0 mg/ml, inhibited the growth of the fungi 

Aspergillus fumigatus, A. niger, Botrytis cinerea, Fusarium oxysporum and 

Penicillium digitatum in vitro (27). 

153



A 30% ethanol extract of the roots and rhizomes, 300 mg/l, inhibited acetylcholine- 

and histamine-induced contractions in guinea-pig ileum in 

vitro (28). The essential oil of Radix Gentianae Luteae induced relaxation 

of smooth muscles in isolated guinea-pig trachea and ileum with median 

effective doses of 108.0 mg/l and 76.0 mg/l, respectively (29). 


Intragastric administration of a 95% ethanol extract of the roots and rhizomes 

(dose not specifi ed) to rats was reported to exert a choleretic effect, 

while an aqueous or methanol extract was not active (30, 31). Intraduodenal 

administration of 500 mg/kg body weight (bw) of a 95% 

ethanol extract of roots and rhizomes had choleretic effects in rats (32). 

Secretory activity 

Perfusion of a 30% ethanol extract of the roots and rhizomes, 4%, into 

the stomach of anaesthetized rats increased gastric secretions by 37.0% 

(28). Oral administration of a single dose of 5.0 g of an infusion of the 

roots and rhizomes to ewes stimulated the secretion of digestive enzymes 

in the small intestine (33). 

Intragastric administration of the equivalent of 12.6 mg/kg bw of an 

alcohol extract of the roots and rhizomes per day for 3 days increased 

bronchial secretions in treated rabbits as compared with control animals 

(34). 

Toxicology 

The acute median lethal dose of a 30% ethanol extract of the roots and 

rhizomes in mice was 25.0 ml/kg (28). Intragastric administration of 

1.6 ml/kg bw of a combination product containing alcohol extracts of 

Radix Gentianae, chamomile and liquorice per day for 13 weeks to rats 

produced no adverse effects and no changes in haemoglobin, red blood 

cells, packed cell volume, mean corpuscle haemoglobin concentration, 

total and differential white blood cell count or blood glucose. Histological 

examination showed no pathological changes in any organ system (35). 

Intragastric administration of 12.6 mg of an alcohol extract of the roots 

and rhizomes per day (treatment period not specifi ed) to rabbits did not 

induce any symptoms of toxicity, with the exception of slightly lower 

erythrocyte concentrations in the treatment group compared with 

controls (34). 


In one study without controls, oral administration of a single dose 

of 0.2 g of an ethanol extract of the roots 5 minutes prior to a meal 

154

stimulated the secretion of gastric juice (20). In the same study, oral 

administration of 0.2 g of the extract stimulated and prolonged gall bladder 

secretions as observed by X-ray contrast (20). In another uncontrolled 

clinical trial, 19 patients with colitis ulcerosa, Crohn disease, or other 

non-specifi c infl ammatory disorders and elevated secretory immune 

globulin (IgA) concentrations were treated with 20 drops of a tincture of 

the roots and rhizomes three times per day for 8 days. A control group of 

healthy volunteers received the same treatment. The IgA levels in both 

groups dropped and no statistical difference between the two groups was 


A multicentre trial, without controls, assessed the effect of the roots 

and rhizomes on the symptoms of dyspepsia in 205 patients. Each patient 

received fi ve capsules containing 120.0 mg of a 5:1 dry ethanol extract of 

the roots and rhizomes per day. Patients reported relief of symptoms such 

as constipation, fl atulence, appetite loss, vomiting, heartburn, abdominal 

pain and nausea (22). 


On rare occasions, headaches may occur (23). 


Owing to potential mutagenic activity (36–38), and its traditional use as 

an emmenagogue (10), Radix Gentianae Luteae should not be administered 

during pregnancy or nursing, or to small children. Radix Gentianae 

Luteae is contraindicated in gastric or duodenal ulcer, high blood pressure 

(11) and hyperacidity (7, 24). 

Warnings 



Precautions 

General 

If symptoms persist, consult a physician. Overdose may lead to nausea or 

vomiting (7, 24). 


Intragastric administration of 1.6 ml/kg bw of a combination product 

containing a 40% ethanol extract of Radix Gentianae Luteae, chamomile 

and liquorice per day for 13 weeks produced no effects on reproduction, 

fertility or mating in female rats and rabbits (35). 

155


The mutagenicity of a methanol extract of Radix Gentianae Luteae, 

and two isolated minor hydroxyxanthone constituents, gentisin and isogentisin, 

was assessed in vitro. The methanol extract was mutagenic in the 

Salmonella/microsome assay using S. typhimurium strain TA100 with 

metabolic activation with rat liver homogenate S9 enzyme mix. Gentisin 

and isogentisin, up to 50 μg/plate, were mutagenic after similar metabolic 

activation in S. typhimurium strains TA97, TA98, TA100 and TA2637 

(36–38). 


Intragastric administration of 1.6 ml/kg bw of a combination product 

containing alcohol extracts of Radix Gentianae, chamomile and liquorice 

per day for 13 weeks had no teratogenic effects in rabbits (35). 








No information available on precautions concerning drug interactions; or 


Dosage forms 

Dried roots and rhizomes; dried extracts of the roots and rhizomes for 

infusions, elixir, extracts, fl uidextracts, glycerinated elixir and tinctures (8, 

23). Store in a tightly sealed container away from heat and light. 

Posology 


Average adult daily dose: 0.1–2 g of the roots and rhizomes in 150 ml of 

water as an infusion, decoction or maceration, up to three times per day; 

fl uidextract, 2–4 g; tincture (1 part roots and rhizomes:5 parts ethanol 

45–70 % v/v) 1 ml three times per day; hydroethanolic extracts with an 

equivalent bitterness value (7, 8, 11, 24). 

To stimulate the appetite, administer a single dose of a Radix Gentianae 

Luteae preparation one hour prior to meals (11); for dyspepsia, a 

single dose after a meal (7, 24). 

156


References 






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6. Farmacopea homeopatica de los estados unidos Mexicanos. [Homeopathic 

pharmacopoeia of the United States of Mexico.] Mexico City, Secretaría de 

Salud, Comisión Permanente de la Farmacopea de Los Estados Unidos 

Mexicanos, 1998. 














Press, 1994. 








Switzerland). 

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von Gentiana lutea und Gentiana purpurea mit HPLC [Quantitative determination 

of the bitter principles in the root of Gentiana lutea and Gentiana 

purpurea with HPLC.] Planta medica, 1980, 40:55–67. 

16. Takino Y et al. Quantitative determination of bitter components in gentianaceous 

plants. Studies on the evaluation of crude drugs VIII. Planta medica, 

1980, 38:344–350. 

157


17. Menkovic N et al. Quantitative determination of secoirodoid and γ-pyrone 

compounds in Gentiana lutea cultured in vitro. Planta Medica, 2000, 66:96– 

98. 

18. Namba T. Genshoku Wakan-Yaku Zukan (Colored illustrations of Wakan- 

Yaku). Vol. 1. Osaka, Hoikusha Publishing, 1980. 

19. Sancin P et al. Evaluation of fl uid extracts of Gentiana lutea L., Acta Pharmaceutica 

Jugoslavica, 1981, 31:39–45. 

20. Glatzel H, Hackenberg K. Röntgenologische Untersuchungen der Wirkungen 

von Bittermitteln auf die Verdauungsorgane. [Radiological investigations 

on the effects of bitter drugs on the digestive organs.] Planta medica, 1967, 

15:223–232. 

21. Zimmermann W, Gaisbauer G, Gaisbauer M. Wirkung von Bitterstoff- 

Drogen auf das darmassoziierte Immunsystem. [The effect of the bitter 

principles of drugs on the gastrointestinal immune system.] Zeitschrift für 

Phytotherapie, 1986, 7:59–64. 

22. Wegener T. Anwendung eines Trockenextraktes Augentianae luteae radix 

bei dyspeptischem Symptomkomplex. [Use of a dry extract of Augentianae 

luteae radix in dyspepetic symptom complex.] Zeitschrift für phytotherapie, 

1998, 19:163–164. 



24. Weiss RF. Lehrbuch der Phytotherapie. 7th ed. [Textbook of phytotherapy, 

7th ed.] Stuttgart, Hippokrates, 1991. 

25. Gottshall RY et al. The occurrence of antibacterial substances active against 

Mycobacterium tuberculosis in seed plants. Journal of Clinical Investigation, 

1949, 28:920–923. 

26. Recio MC, Riós JL, Villar A. Antimicrobial activity of selected plants employed 

in the Spanish Mediterranean Area. Part II. Phytotherapy Research, 

1971, 3:77–80. 

27. Guérin JC, Réveillère HP. Activité antifongique d’extraits végétaux à usage 

thérapeutique. II. Étude de 40 extraits sur 9 souches fongiques. [Antifungal 

activity of plant extracts used in therapy. II. Study of 40 plant extracts against 

9 fungi species.] Annales Pharmaceutiques Françaises, 1985, 43:77–81. 


Medita, 1978, 8:31–47. 



30. Böhm K. Untersuchungen über choleretische Wirkungen einiger Arzneipfl 

anzen [Studies on the choleretic action of some medicinal plants.] Arzneimittelforschung, 

1959, 9:376–378. 

31. Miura M et al. [Basic study of assay method of choleretic effect and the 

screening of crude drugs.] Yakugaku Zasshi, 1987, 107:992–1000 [in Japanese]. 

32. Oztürk N et al. Choleretic activity of Gentiana lutea ssp. symphyandara in 

rats. Phytomedicine, 1998, 5:283–288. 

158


33. Kazakov BN. [The effect of plant bitters on the secretion of enzymes in the 

small intestine of sheep.] Materialy Vos’moi Nauchnoy Konferencii po 

Farmakologii. Moscow SB, 1963:63–65 [in Russian]. 

34. Chibanguza G, Marz R, Sterner W. Zur Wirksamkeit und Toxizität eines 

pfl anzlichen Sekretolytikums und seiner Einzeldrogen. [On the secretolytic 

and toxic effects of a phytomedical secretolytic drug combination and its 

components.] Arzneimittelforschung, 1984, 34:32–36. 

35. Leslie GB, Salmon G. Repeated dose toxicity studies and reproductive studies 

on nine Bio-Strath herbal remedies. Medita, 1979, 1:43–45. 

36. Morimoto I et al. Mutagenic activities of gentisin and isogenisitin from 

Gentianae radix (Gentianaceae). Mutation Research, 1983, 116: 103–117. 

37. Matsushima T et al. Mutagenicities of xanthone derivatives in Salmonella typhimurium 

TA100, TA98, TA97, and TA2637. Mutation Research, 1985, 

150:141–146. 

38. Göggelmann W, Schimmer O. Mutagenic activity of phytotherapeutical 

drugs. In: Knudsen I, ed. Genetic toxicology of the diet. New York, Alan R. 

Liss, 1986: 63–72. 

159

160 

Radix Gentianae Scabrae 

Defi nition 

Radix Gentianae Scabrae consists of the dried roots and rhizomes of Gentiana 

scabra Bunge (Gentianaceae) (1–4). 

Synonyms 

Gentiana buergeri Miq., G. fortunei Hook. (5). 


Chinese gentian, dancao, Japanese gentian, kudancao, longdan, longdancao, 

tourindou (1, 2, 4, 6, 7). 


Indigenous to the Korean peninsula and to China and Japan (8, 9). 

Description 

A perennial herb. Roots white, 10–15 cm long, with numerous short branches. 

Rhizomes rather short. Stems 20–100 cm long, with 10–20 pairs of leaves. 

Leaves lanceolate to narrowly deltoid-ovate, 4–8 cm long, 1–3 cm wide, gradually 

acuminate, three-nerved, green above, paler beneath, usually sessile, margin 

of upper leaves papillose. Flowers few to rather numerous, sessile, 4.5–6 cm 

long, purplish-blue; calyx tube 12–18 mm long, the lobes rather unequal, 

linear-lanceolate; corolla plaits deltoid, often toothed. Capsules stipitate, not 

exerted; seeds broadly lanceolate, short-caudate at both ends (10, 11). 



Irregular, cylindrical, short yellowish-brown to greyish-brown rhizome 

with numerous slender roots. Roots 10–15 cm long, about 0.3 cm in 

diameter, with longitudinal, coarse wrinkles on the outer surface; fl exible, 

fractured surface, smooth, yellow-brown. Rhizome about 2 cm long, 

0.7 cm in diameter, with buds or short remains of stems at the top (2).


Odour: characteristic; taste: bitter (1–4). 


Root section shows epidermis, endodermis and a few layers of primary 

cortex; usually the outermost layers of the endodermis consisting of characteristic 

cells divided into a few daughter cells, often with collenchyma 

of one to two layers in contact with the inner side; secondary cortex having 

rents here and there, and irregularly scattered sieve tubes; vessels ranging 

rather radially in the xylem, and sieve tubes existing in the phloem. 

Root and rhizomes have distinct pith, rarely with sieve tubes, and parenchymatous 

cells containing needle, plate or rhombic crystals of calcium 

oxalate, and oil droplets. Starch grains mostly absent (1, 2, 4). 


Fragments of parenchymatous cells containing oil droplets and minute 

needle crystals of calcium oxalate. Cells of exodermis spindle-shaped in 

surface view, each cell divided by transverse walls into several small rectangular 

cells. Cells of endodermis subrectangular in surface view, fairly 

large, periclinal walls showing minute transverse striations, each cell divided 

by longitudinal septa walls into several small palisade-like cells, 

longitudinal septa mostly beaded. Vessels mainly reticulate and scalariform, 

20–30 μm but can be up to 45 μm in diameter (2, 4). 


Macroscopic and microscopic examinations (1–4), microchemical tests (1, 

3) and thin-layer chromatography (2, 4). 

Purity tests 





Total ash 







161









Heavy metals 







Chemical, foreign organic matter and water-soluble extractive tests to be 

established in accordance with national requirements. 


Contains not less than 1.0% gentiopicroside determined by highperformance 

liquid chromatography (4). 


The major constituents are bitter secoiridoid monoterpenes including 

gentiopicroside (gentiopicrin; 0.5–10%), swertiamarin and sweroside. 

Xanthones, the alkaloid gentianine (0.05%) and gentianadine are other 

signifi cant constituents. The bitter principle amarogentin found in Gentiana 

lutea is absent (5, 7, 15–17). Representative structures of the secoiridoid 

monoterpenes are presented below. 

amarogentin 

O gentiopicroside sweroside 

HO 

O O 

O 

O 

O O 

HO 

O O 

HO 

O O 

OH H 

H 

H 

O O 

O O 

HO 

HO 

O O 

H2C OH 

OH 

HO 

OH 

H 

H 

H2C OH 

HO 

OH 

H 

H 

H2C H 

162 

OH



None. 



Symptomatic treatment of liver disorders, cholecystitis and lack of appetite 

(3, 6). 


Treatment of convulsions, eczema, fungal infections, hearing impairment, 

infl ammation, leukorrhoea, otitis media, urinary tract infections, herpes 

zoster and pruritus vulvae (3, 6, 7). 

Pharmacology 



A 90% ethanol extract of the roots did not inhibit the growth of Bacillus 

subtilis, Candida albicans, Escherichia coli, Staphylococcus aureus or 

Streptococcus faecalis in vitro (18). An infusion of Radix Gentianae Scabrae 

had no antiviral activity in vitro when tested against herpes simplex 

virus 1, measles virus or poliovirus 1 (19). 


Intraperitoneal administration of 1.0 g/kg body weight (bw) of a dried 

methanol extract of the roots and rhizomes, dissolved in normal saline, 

inhibited hepatotoxicity induced by carbon tetrachloride in rats but did 

not decrease the activity of alkaline phosphatase (20). Intraperitoneal administration 

of 1.0 g/kg bw of a dried methanol extract of the roots and 

rhizomes, dissolved in normal saline, to rats decreased increased glutamate-oxaloacetate 

transaminase activity induced by treatment with 

α-naphthylisothiocyanate and decreased plasma bilirubin concentrations, 

but did not decrease the activities of glutamate-pyruvate transaminase or 

lactate dehydrogenase (20). Intragastric administration of 670.0 mg/kg 

bw of a 1-butanol, chloroform or methanol extract of the roots and rhizomes 

prevented hepatotoxicity induced by carbon tetrachloride in mice 

(21, 22). The 1-butanol and chloroform extracts also inhibited the increased 

glutamate-pyruvate transaminase activity induced by carbon tetrachloride 

(20). Intraperitoneal administration of an aqueous or dried 

50% methanol extract of the roots and rhizomes (dose not specifi ed) prevented 

hepatotoxicity induced by carbon tetrachloride in mice (23). Intraperitoneal 

administration of 25.0–50.0 mg/kg bw of gentiopicroside 

163


inhibited liver injury induced by D-galactosamine/lipopolysaccharide in 

mice (24). Intraperitoneal pretreatment of mice with 30.0–60.0 mg/kg bw 

of gentiopicroside per day for 5 days, suppressed the increased concentrations 

of serum hepatic aminotransferases induced by carbon tetrachloride 

(25). 


Intraperitoneal administration of 90.0 mg/kg bw of gentianine to rats 

reduced swelling and infl ammation of the ankle joint of the hind leg 

induced by formalin or egg white (26, 27). 


A 95% ethanol extract of the roots and rhizomes, 200.0 μg/ml, did not 

inhibit barium- or histamine-induced smooth muscle contractions in 

guinea-pig ileum in vitro; however, an aqueous extract, 200.0 μg/ml, 

inhibited barium-induced contractions (28). The essential oil of Radix 

Gentianae Scabrae induced relaxation of smooth muscles in guinea-pig 

trachea and ileum in vitro, with median effective doses of 108.0 mg/l and 

76.0 mg/l, respectively (29). 


Intraperitoneal administration of 250.0 mg/kg bw of a methanol or 75% 

methanol extract of the roots and rhizomes per day for 3 days to mice did 

not enhance the effects of barbiturates or increase hexobarbital-induced 

sleeping times (30–32). Intragastric administration of 670.0 mg/kg bw of 

a 1-butanol or chloroform extract of the roots did not potentiate the effects 

of barbiturates in mice (20). An ethanol extract of the roots and rhizomes 

(concentration not specifi ed) inhibited the reuptake of serotonin in 

rat brainstem neurons in vitro (33). Intraperitoneal administration of 

25.0–100.0 mg/kg bw of gentianine or gentianadine potentiated the anaesthetic 

effects of pentobarbital and chloral hydrate in mice (6). Intragastric 

administration of 200.0–400.0 mg/kg bw of gentianine or 700.0–1000.0 mg/kg 

bw of gentianidine resulted in sedation and reduced spontaneous activity 

in mice (6). 


Intraduodenal administration of 50.0 g/kg bw of an aqueous extract of 

the roots and rhizomes to healthy rats or rats with hepatic injuries increased 

bile fl ow. A similar effect was observed in healthy dogs after intravenous 

administration of 4.5 g/kg bw of the extract (6). Intragastric 

administration of 1.8 g/kg bw of a dried methanol extract of the roots and 

rhizomes had choleretic effects in rats (34). 

164

Toxicology 

The oral median lethal doses (LD 50 ) of gentianine and gentianadine in 

mice were 400.0 mg/kg bw and 1250.0 mg/kg bw, respectively (6, 35). The 

subcutaneous LD 50 of gentianine in mice was > 500.0 mg/kg bw, and the 

intravenous LD 50 was 250.0–300.0 mg/kg bw (6). The intraperitoneal 

LD 50 of a 90% ethanol extract of the roots and rhizomes in mice was 

1.0 g/kg bw (18). 2-Hydroxy-3-methoxy benzoic acid glucose ester isolated 

from the roots and rhizomes was found to be a potent antagonist of 

platelet-activating factor in vitro (36). 




Radix Gentiana Scabrae may cause impairment of digestion and, occasionally, 

headaches, fl ushing of the face and vertigo when taken after a 

meal (37). 


Owing to potential mutagenic effects (38), Radix Gentianae Scabrae 

should not be used during pregnancy or nursing or in children under the 

age of 12 years. Radix Gentianae Scabrae is contraindicated in stomach 

disorders and liver failure (3). 

Warnings 

Overdose may lead to nausea or vomiting (3). 

Precautions 


An aqueous extract of the roots and rhizomes, 40.0 mg/plate or 50.0 mg/ 

disc, was not mutagenic in the Salmonella/microsome assay using S. typhimurium 

strains TA98 and TA100 (39, 40). In another investigation, an 

aqueous or methanol extract of the roots and rhizomes, 100.0 mg/ml, was 

active in the Salmonella/microsome assay and the Bacillus subtilis recombination 

assay (38). However, intraperitoneal injection of an aqueous extract 

of the roots and rhizomes at doses 10–40 times those used in traditional 

medicine had no mutagenic effects in mice (40). 




165









effects during pregnancy. 

Dosage forms 

Dried roots and rhizomes and dried extracts for infusions and decoction 

(3, 4). Store in a tightly sealed container away from heat and light. 

Posology 


Average daily dose: roots and rhizomes 3–6 g per day as an infusion or 

decoction (4). 

References 






1998. 

4. Pharmacopoeia of the People’s Republic of China. Vol I. (English ed.). 





6. Chang HM, But PPH. Pharmacology and applications of Chinese materia 

medica. Vol. 1. Singapore, World Scientifi c, 1986. 





8. Kariyone T, Koiso R. Atlas of medicinal plants. Osaka, Nihon Rinshosha, 

1973. 

9. Perry LM, Metzger J. Medicinal plants of East and Southeast Asia: attributed 

properties and uses. Cambridge, MA, MIT Press, 1980. 

166


10. Ohwi, J. Flora of Japan. Washington, DC, Smithsonian Institution, 1984. 

11. Toyokuni H, Yamazaki T. Gentianaceae. In: Iwatsuki K, ed. Flora of Japan. 

Tokyo, Kodansha, 1996. 







Switzerland). 

15. Hayashi T. [Studies on crude drugs originated from gentianaceous plants. I. 

Determination of gentiopicroside, the bitter principle of Gentianae radix and 

Gentianae scabrae radix.] Yakugaku Zasshi, 1976, 96:356–361 [in Japanese]. 

16. Hayashi T, Matsuda T, Yoneda K. [Studies on crude drugs originated from 

gentianaceous plants. VI. Contents of gentiopicroside in various parts of 

Gentiana scabra and accumulation of gentiopicroside in Gentiana trifl ora.] 

Yakugaku Zasshi, 1976, 96: 679–682 [in Japanese]. 

17. Namba, T. Genshoku Wakan-Yaku Zukan [Colored illustrations of Wakan- 

Yaku]. Vol. 1. Osaka, Hoikusha Publishing, 1980. 

18. Woo WS, Lee EB, Han BH. Biological evaluation of Korean medicinal plants 

(III). Archives of Pharmacal Research, 1979, 2:127–131. 

19. Kurokawa M et al. Antiviral traditional medicines against herpes simplex virus 

(HSV-1), poliovirus and measles virus in vitro and their therapeutic effi - 

cacies for HSV-1 infection in mice. Antiviral Research, 1993, 22:175–188. 




21. Yun HS, Yu JC, Chang IM. [Plants with liver protective activities. (V) Liver 

protective activities of Atractylodes japonica (alba) and Gentiana scabra.] 


22. Chang IM, Yun HS. Plants with liver-protective activities, pharmacology and 

toxicology of aucubin. In: Chang HM et al., eds. Advances in Chinese medicinal 

materials research. Singapore, World Scientifi c, 1984:269–285. 

23. Chang IM, Yun HS. Evaluation of medicinal plants with potential hepatonic 

activities and study on hepatonic activities of Plantago semen. Abstract. In: 

Proceedings of the Fourth Asian Symposium on Medicinal Plants and Spices, 

Bangkok, 15–19 September 1980. 1980:69. 

24. Hase K et al. Hepatoprotective principles of Swertia japonica Makino on 

D-galactosamine/lipopolysaccharide-induced liver injury in mice. Chemical 

and Pharmaceutical Bulletin, 1997, 45:1823–1827. 

25. Kondo Y, Takano F, Hojo H. Suppression of chemically and immunologically 

induced hepatic injuries by gentiopicroside in mice. Planta Medica, 

1994, 60:414–416. 

167


26. Sung CY, Chi HC, Liu KT. [Pharmacology of gentianine. I. Anti-infl ammatory 

effect and action of pituitary-adrenal function of the rat.] Acta Physiologica 

Sinica, 1958, 22:201–205 [in Chinese]. 

27. Chi HC, Liu KT, Sung CY. [The pharmacology of gentianine. II. The antiphlogistic 

effect of gentianine and its comparison with some clinically effective 

drugs.] Acta Physiologica Sinica, 1959, 23:151–157 [in Chinese]. 

28. Itokawa H et al. [Studies on the constituents of crude drugs having inhibitory 

activity against contraction of the ileum caused by histamine or barium 

chloride. (1) Screening test for the activity of commercially available crude 

drugs and the related plant materials.] Shoyakugaku Zasshi, 1983, 37:223–228 

[in Japanese]. 



30. Woo WS et al. A survey of the response of Korean medicinal plants on drug 

metabolism. Archives of Pharmacal Research, 1978, 1:13–19. 

31. Choi HSY, Chang IM. Plants with liver protective activities. Annual Reports 

of the Natural Products Research Institute, 1982, 21:49–53. 

32. Shin KH, Woo WS. A survey of the response of medicinal plants on drug 

metabolism. Korean Journal of Pharmacognosy, 1980, 11:109–122. 

33. Cho HM et al. [Inhibitory effects of extracts from traditional herbal drugs on 

5-hydroxytryptamine uptake in primary cultured rat brainstem neurons.] 


34. Miura M et al. [Basic study of assay method of choleretic effect and the 

screening of crude drugs.] Yakugaku Zasshi, 1987, 107:992–1000 [in Japanese]. 

35. Natarajan PN, Wan ASC, Zaman V. Antimalarial, antiamoebic and toxicity 

tests on gentianine. Planta Medica, 1974, 25:258–260. 

36. Huh H et al. PAF antagonistic activity of 2-hydroxy-3-methoxybenzoic acid 

glucose ester from Gentiana scabra. Archives of Pharmacal Research, 1998, 

21:436–439. 

37. Wang YS. Pharmacology and applications of Chinese materia medica. 

Beijing, People’s Health Publisher, 1983. 



1982, 97:81–102. 




traditional Chinese medicine. Mutation Research, 1991, 260:73–82. 

168

Gummi Gugguli 

Defi nition 

Gummi Gugguli consists of the air-dried oleo-gum resin exudate from 

the stems and branches of Commiphora mukul (Hook. ex Stocks) Engl. 

(Burseraceae) (1–4). 

Synonyms 

Balsamodendron mukul Hook. ex Stocks, B. roxburghii Stocks non Arn., 

Commiphora roxburghii (Stocks) Engl., C. wightii (Arn.) Bhandari (2, 5). 


Afl atan, baijahundana, bdellium, boe-jahudan, devadhüpa, gogil, gugaru, 

guggal, guggul, guggula, guggulu, gukkal, gukkulu, hill mango, Indian 

bdellium, Indian myrrh tree, itinnil, kiluvai, kondamamidi, koushikaka, 

kungiliyam, maisatchi, moghl, moghl-arabi, moghl-azragh, moghl-makki, 

moql, moqle-azraqi, mugul, mukul myrrh tree, pura, ranghan (5–12). 


Indigenous to Bangladesh, India and Pakistan (6, 7, 11, 13). 

Description 

Woody, bushy shrub 1–4 m high. Stems and branches thorny, covered 

with wax and ash-coloured bark that peels into thin rolls. Leaves small, 

alternate, simple or trifoliate. Flowers unisexual or bisexual with a fuzzy 

calyx and a brownish-red corolla. Fruits are ovoid drupes that turn red 

when ripe (6, 7, 13–15). 

Plant material of interest: dried oleo-gum resin 


Vermicular or stalactitic pale yellow or brown pieces; slightly sticky to 

touch; viscid and golden when fresh. Makes a milky emulsion in hot water; 

burns readily (2, 3, 6, 16–18). 

169



Odour: characteristic aromatic, balsamic; taste: aromatic, bitter, acrid 

(2, 3, 6, 16). 






Macroscopic appearance (2, 3, 6, 16–18), ultraviolet spectrophotometry 

of an ethanolic solution (2), and thin-layer chromatography (2, 19), and 

high-performance liquid chromatography for the presence of guggulsterones 

(2, 20). 

Purity tests 







Total ash 




Sulfated ash 



Not less than 53% (3, 4). 



Ethyl acetate-soluble extractive 


170

Moisture 


Gummi Gugguli 






Heavy metals 









Contains not less than 4.0% and not more than 6.0% of guggulsterones Z 

and E determined by high-performance liquid chromatography (2). 


A mixture of resins, essential oil (1.4–1.45%) (13, 16) and a water-soluble 

gum (made up of galactose, arabinose and 4-O-methylglucuronic acid (5, 

15). The major constituents of the essential oil fraction of the oleo-gum 

resin are the monoterpene myrcene and the diterpene camphorene. The 

resinous fraction contains the diterpenes cembrene A and mukulol; the 

lignans sesamin and guggullignan-I and -II; and the sterols guggulsterol-I, 

-II, -III, -IV and -V, and E- and Z-guggulsterone (up to 15%) (24). E- and 

Z-guggulsterone are characteristic constituents that distinguish Commiphora 

mukul from other Commiphora species (5, 11, 15, 17, 20, 25). 

The structures of E- and Z-guggulsterones, guggulsterols-I, -II and -III, 

cembrene and mukulol are presented below. 



Treatment of hyperlipidaemia and hypercholesterolaemia (1, 26–33). 

Clinical investigations to assess the use of extracts of the oleo-gum 

171


(E)-guggulsterone 

(Z)-guggulsterone 

guggulsterol II H 3 C 

HO 

H 

resin for the treatment of obesity were negative (34, 35) (see Clinical 

pharmacology). 


Treatment of atherosclerosis, rheumatic conditions, cough, sore throat 

and menopausal symptoms. As an emmenagogue (3, 4, 8, 9, 16). 


Internally as an expectorant and for treatment of diarrhoea, fatigue, headache, 

jaundice and indigestion; topically for treatment of burns (12, 16, 

36–38). Also as an insecticide and insect repellent (9). 

Pharmacology 



Intraperitoneal administration of 100.0 mg/kg body weight (bw) of an 

ethyl acetate extract of Gummi Gugguli to mice inhibited platelet aggregation 

(39). However, intraperitoneal administration of an aqueous extract 

of the oleo-gum resin to mice at the same dose was not active (39). 

Antihypercholesterolaemic activity 

Gummi Gugguli showed antihyperlipidaemic and antihypercholesterolaemic 

activities in animal models (24, 40). In chicks fed an atherosclerotic 

172 

CH 3 

H 

H H 

R = CH 3 , R' = H 

R = H, R' = CH3 

CH 3 

O 

OH 

CH 3 

OH 

H3C H 

H 

H H 

CH 3 

R 

CH 3 

R' 

OH 

H 

cembrene CH3 mukulol 

CH 3 

CH 3 

H 

H CH3 

CH 3 

O 

guggulsterol I 

O 

guggulsterol III 

H 3 C 

H 3 C 

CH 3 

CH 3 

H 

H 3C 

H H 

H 

H H 

H 3C 

CH 3 

H 3C CH 3 

H 3C 

H 

OH 

H 

CH 3 

OH 

OH OH 

H 

H 

OH 

H3C H 

H 

OH 

H3C CH 3 

CH 3

Gummi Gugguli 

diet, intragastric administration of a petroleum ether extract of the oleogum 

resin, 3.0 g/kg bw per day for 10 days or 2.0 g/kg bw per day for 

30 days, signifi cantly (P < 0.001) reduced serum cholesterol concentrations 

(1). In male chicks with estrogen-induced hyperlipidaemia, hypercholesterolaemia 

and weight gain, intragastric administration of 3 g/kg 

bw of a petroleum ether extract of the oleo-gum resin per day for 10 days 

reduced serum cholesterol concentrations and estradiol-induced weight 

gain (1). Histological examination showed an enhancement of the thyroid 

function in the treated animals, while suppression of thyroid function was 

observed in animals treated only with estradiol. In another study, intragastric 

administration of 5.0 mg/kg bw of a ketosteroid extract of the 

oleo-gum resin per day for one month to chicks fed an atherosclerotic 

diet and treated with carbimazole reduced serum cholesterol and triglyceride 

concentrations as compared with controls (1). In rats with dietaryinduced 

hyperlipidaemia, administration of 10 mg/kg bw, 30 mg/kg bw 

or 100 mg/kg bw of an ethyl acetate fraction of the oleo-gum resin per 

day in the diet for 4 weeks signifi cantly (P < 0.001) reduced total serum 

lipids and serum cholesterol, triglycerides and phospholipids (9). Similar 

hypolipidaemic effects of the oleo-gum resin have been observed in other 

animal species, such as dogs and monkeys (41). 

The cholesterol-reducing activities of the oleo-gum resin are attributed 

to two closely related steroidal ketones, trans- and cis-guggulsterone (E- 

and Z-guggulsterone) (20). While the other chemical constituents do not 

have cholesterol-reducing activity individually, they act synergistically to 

enhance the overall antihypercholesterolaemic effects of the oleo-gum 

resin (24). 


Intragastric administration of 500.0 mg/kg bw of an ethyl acetate fraction 

of the oleo-gum resin per day for a period of 5 months to rabbits decreased 

joint swelling induced by intra-articular injection of mycobacterial 

adjuvant (42). Intragastric administration of 400.0 mg/kg bw of an 

aqueous extract of the oleo-gum resin signifi cantly (P < 0.05) reduced 

carrageenan-induced hind-paw oedema in rats by 59% (43). Administration 

of 400.0 mg/kg bw of a petroleum ether extract of the oleo-gum resin 

per day for 18 days to rats with arthritis induced by Freund’s adjuvant 

signifi cantly (P < 0.05) reduced the development of infl ammation (43). 

Intraperitoneal administration of 200–400.0 mg/kg bw of a 100% ethanol 

extract of the oleo-gum resin reduced xylene-induced ear infl ammation in 

mice by 50% (44). Intraperitoneal administration of 5.0 mg/kg bw of a 

steroid-containing fraction of a petroleum ether extract of the oleo-gum 

173


resin to rats inhibited primary and secondary infl ammation induced by 

Freund’s adjuvant (45). 

Antiobesity activity 

Intragastric administration of 3.0 g/kg bw of the oleo-gum resin per day 

to rats and rabbits fed a high-fat and high-carbohydrate diet over a 

4-month period reduced weight gain and the percentage of body fat (1). 

However, in rats fed a high-fat diet, treatment with 10.0 mg/kg bw, 

30.0 mg/kg bw or 100.0 mg/kg bw of an ethyl acetate extract of the oleogum 

resin per day administered in the diet for 4 weeks did not reduce 

body weight as compared with controls (9). 

Effects on thyroid function 

Intragastric administration of a steroidal extract of 200.0 mg/kg bw of the 

oleo-gum resin per day for 15 days to mice induced triiodothyronine production 

and increased the triiodo thyronine:thyroxine ratio (46). Intragastric 

administration of a ketosteroid isolated from a petroleum ether 

extract of 10.0 mg/kg bw of the oleo-gum resin per day for 6 days to rats 

signifi cantly increased iodine uptake in the thyroid (P < 0.05) and enhanced 

the activities of thyroid peroxidase and protease (P < 0.001) (40). 

Toxicology 

Acute and chronic oral toxicity studies of an ethyl acetate extract of the 

oleo-gum resin were conducted in rats, mice and dogs (47). No mortality 

was observed in the 72 hours following administration of 5.0 mg/kg bw 

in all species. In dogs, no mortality was observed following oral administration 

of 1.0 g/kg bw per day over a period of 3 months. However, in 

rats, the mortality rate following administration of 250.0 mg/kg bw per 

day over the same period was 50%, compared with 20% in controls (47). 


The effect of the oleo-gum resin was assessed in a parallel, placebocontrolled 

clinical trial in 40 patients with hyperlipidaemia: 20 patients 

received 4.5 g of the oleo-gum resin per day in two divided oral doses for 

16 weeks; 20 controls received placebo administered at the same dose and 

in accordance with the same schedule. At the end of the 16-week treatment 

period, serum concentrations of cholesterol decreased by 21.75%; 

those of high-density lipids increased by 35.8% (P < 0.01) in the treated 

group as compared with controls. Serum triglyceride concentrations decreased 

by 27.1% in the treated group as compared with placebo control 

(P < 0.01) (32). 

The hypolipidaemic effects of a standardized ethyl acetate extract of 

the oleo-gum resin containing approximately 4.0 g of Z- and E-gug- 

174

Gummi Gugguli 

gulsterones per 100.0 g of extract were compared with those of ethyl-pchlorophenoxyisobutyrate 

(EPC) and a test substance (Ciba-13437-Su) 

in a randomized comparison trial in 44 patients with hyperlipidemia. Patients 

received 500.0 mg of oleo-gum resin extract twice per day, 500.0 mg 

of EPC three times per day, or 100.0 mg of the test substance three times 

per day for 6–36 weeks. Serum total lipids, cholesterol and triglycerides 

were measured before and after treatment. The oleo-gum resin extract 

signifi cantly reduced total serum lipids by 34%, cholesterol by 27% and 

triglycerides by 29% (P < 0.001), and was as effective as or superior to the 

two other compounds tested (26). 

A standardized ethyl acetate extract of the oleo-gum resin was compared 

with clofi brate in a long-term clinical trial. Of the 51 patients with 

hyperlipidaemia, 41 were treated with 1.5 g of the extract and 10 were 

treated with 2.0 g of clofi brate daily for a mean treatment period of 

75 weeks. The extract signifi cantly (P < 0.001) reduced serum cholesterol 

(26.2%) and triglycerides (36.5%). Clofi brate also signifi cantly (P < 0.001) 

reduced total serum cholesterol (31.3%) and triglyceride concentrations 

(33.3%) (28). 

In a phase I clinical trial to assess the safety of a standardized ethyl 

acetate extract of the oleo-gum resin, oral administration of 400.0 mg of 

the extract three times per day for 4 weeks to 21 hyperlipidaemic patients 

was safe and did not have any adverse effects on liver function, blood 

sugar, blood urea or haematological parameters (30). In a subsequent 

phase II clinical trial involving 19 patients with primary hyperlipidaemia 

(serum cholesterol > 250.0 mg/dl and serum triglycerides > 200.0 mg/dl), 

the same extract was administered orally, 500.0 mg three times per day for 

12 weeks following 6 weeks of dietary control. Follow-up at 4-week intervals 

indicated that serum cholesterol and triglyceride concentrations 

were lowered in 15 patients (76.9%) after 4 weeks of treatment. The average 

decreases were 17.5% and 30.3%, respectively (30). 

In a placebo-controlled trial, 120 obese patients with hyperlipidaemia 

received 2.0 g of the oleo-gum resin twice per day, 0.5 g of a petroleum 

ether fraction of the oleo-gum resin three times per day, a placebo daily or 

clofi brate daily for 21 days. The oleo-gum resin and clofi brate signifi - 

cantly decreased the mean serum cholesterol level after 10 days (P < 0.01 

and P < 0.1, respectively). The petroleum ether fraction also signifi cantly 

(P < 0.05) reduced serum cholesterol concentrations after 10 days of treatment 

as compared with placebo (27, 29). 

Oral administration of 50.0 mg of an ethyl acetate extract of the oleogum 

resin or placebo capsules twice per day for 24 weeks as adjuncts to a 

fruit- and vegetable-enriched diet were compared for the management of 

175


61 patients with hypercholesterolaemia in a randomized, double-blind 

study (33). The oleo-gum resin decreased the serum levels of total cholesterol 

(11.7%), low-density lipoprotein cholesterol (12.5%) and triglycerides 

(12.0%) in the treated group as compared with placebo; blood lipid 

peroxides, indicating oxidative stress also declined (33.3%) (33). 

The effects of an ethyl acetate extract of the oleo-gum resin on serum 

cholesterol, fi brinolytic activity and platelet adhesive index were assessed 

in 20 healthy subjects and 20 subjects with cardiovascular disease. Both 

groups received 500.0 mg of the extract twice per day for 30 days. Serum 

fi brinolytic activity in the two groups increased by 22% and 19% in 

healthy volunteers and patients with cardiovascular disease, respectively, 

after 24 hours, and by 40% and 30% after 30 days; platelet adhesive index 

decreased by 19% and 16%. There was no decrease in serum cholesterol 

concentrations (48). 

In a controlled clinical trial, 75 subjects were divided into three groups 

of 25 subjects, which received placebo, encapsulated oleo-gum resin 

(16.0 g) or a petroleum ether extract of the oleo-gum resin (dose equivalent 

to that of the oleo-gum resin) daily for 3 months. Serum cholesterol 

levels were signifi cantly reduced in both treatment groups as compared 

with controls: by 24.2% (P > 0.001) in the oleo-gum resin group; and by 

30.0% (P > 0.001) in the extract group (1). 

In a double-blind, placebo-controlled clinical trial, 62 subjects, at least 

10% overweight, received 1.5 g of an ethyl extract of the oleo-gum resin 

or matching placebo daily for 4 weeks. The extract signifi cantly (P < 0.01) 

decreased (~10%) total serum cholesterol compared with placebo. However, 

there was no effect on body weight in either group (34). 

In a randomized double-blind, placebo-controlled clinical trial, 

84 obese subjects, at least 10% overweight, received 1.5 g of an ethyl acetate 

extract of the oleo-gum resin or matching placebo daily for 12 weeks. 

The extract signifi cantly decreased (~20%) serum levels of total cholesterol 

(P < 0.01), total lipids (P < 0.05) and triglycerides (P < 0.05) compared 

with placebo. A slight, but signifi cant reduction in body weight 

was observed at 4 weeks (P < 0.05) in the extract group, but at 12 weeks 

no signifi cant effects on this parameter were observed (35). 


In clinical trials, minor adverse effects such as mild diarrhoea and restlessness 

have been reported (26, 28). In one clinical trial of the oleo-gum 

resin, gastrointestinal upset was noted in 17.5% of patients (27). Topical 

application of a diluted (8%) aqueous solution of an essential oil obtained 

from the oleo-gum resin was non-irritating, non-sensitizing and non- 

176

phototoxic (1). However, application of an extract (not further specifi ed) 

to human skin caused contact dermatitis (49–51). In clinical trials, the 

oleo-gum resin and petroleum ether extracts of the oleo-gum resin were 

reported to shorten the menstrual cycle and increase menstrual fl ow (1). 


Gummi Gugguli is used traditionally as an emmenagogue (12), and its 

safety during pregnancy has not been established. Therefore, in accordance 

with standard medical practice, the oleo-gum resin should not be 

used during pregnancy. 

Warnings 


Precautions 


An aqueous extract of the oleo-gum resin, 40.0 mg/plate, was not mutagenic 

in the Salmonella/microsome assay using S. typhimurium strains 

TA98 and TA100 (52). Intraperitoneal administration of an aqueous extract 

of the oleo-gum resin at a dose 10–40 times the normal therapeutic 

dose did not have mutagenic activity (52). A hot aqueous extract of the 

oleo-gum resin, 40.0 mg/plate, inhibited mutagenesis induced by afl atoxin 

B1 in S. typhimurium strains TA98 and TA100 (53). 

Intragastric administration of the oleo-gum resin (dose not specifi ed) 

reduced the weight of rat uterus, ovaries and cervix, with a concomitant 

increase in their glycogen and sialic acid concentrations, suggesting an 

antifertility effect (54). 



Gummi Gugguli 




effects in pregnancy; nursing mothers; or paediatric use. 

Dosage forms 

Powdered oleo-gum resin; petroleum ether or ethyl acetate extracts of the 

oleo-gum resin; other galenical preparations (1, 26, 30, 32). Store in a 

tightly sealed container away from heat and light. 

177


Posology 


Average daily dose: oleo-gum resin 3–4.5 g in two or three divided doses 

(30, 32); petroleum ether extracts of the oleo-gum resin 500 mg two or 

three times (26). 

References 

1. Studies on gugglu. New Delhi, Central Council for Research in Ayurveda 

and Siddha, Ministry of Health and Family Welfare, 1989. 

2. Indian pharmacopoeia. Vol. 1. New Delhi, The Controller of Publications, 

Ministry of Health and Family Welfare, 1996. 

3. The Ayurvedic pharmacopoeia of India. Part I. Vol. I. New Delhi, Ministry 



4. Unani pharmacopoeia of India. Part 1. Vol. 1. New Delhi, Ministry of Health 

and Family Welfare, Department of India Systems of Medicine and Homeopathy, 

1999. 




6. Atal CK, Gupta OP, Afaq SH. Commiphora mukul: source of guggal in Indian 

systems of medicine. Economic Botany, 1975, 29:208–218. 

7. Dastur JF. Medicinal plants of India and Pakistan. Bombay, Taraporevala and 

Sons, 1977. 

8. Medicinal plants of India. Vol. 1. New Delhi, Indian Council of Medical Research, 

1987. 

9. Pandy VN, Malhotra SC, eds. Pharmacological and clinical studies on gugulu 

(Commiphora wightii) in hyperlipidaemia and lipid metabolism. New Delhi, 

Central Council for Research in Ayurveda and Siddha, Ministry of Health 

and Family Welfare, 1992. 

10. Dekhoda A. Loghatnâme. Vol. 14, 2nd ed. [Encyclopedic dictionary, Vol. 14, 

2nd ed.] Tehran, Tehran University Publications, 1998 [in Farsi]. 

11. Schauss AG, Muunson SE. Guggul (Commiphora mukul): Chemistry, toxicology, 

and effi cacy of a hypolipidemic and hypocholesterolemic agent. Natural 

Medicine Journal, 1999, 2:7–11. 





13. Kakrani HK. Guggul – a review. Indian Drugs, 1981, 18:417–421. 

14. Baquar SR, Tasnif M. Medicinal plants of southern West Pakistan. Karachi, 

Pakistan Council of Scientifi c and Industrial Research, 1967 (Bulletin/Monograph, 

No. 3). 

178

Gummi Gugguli 



16. Mitra AP et al., eds. The wealth of India: A dictionary of Indian raw materials 

and industrial products: Raw materials, Vol. 2:B. New Delhi, Council of 

Scientifi c and Industrial Research, 1948. 

17. Dev S. Chemistry of resinous exudates of some Indian trees. Proceedings of 

the Indian National Science Academy, 1983, 49A:359–385. 

18. Ahmad F, Hashmi S. Pharmacognostical studies on mur-mukki – an unorganized 

crude drug. New Botanist, 1996, 23:21–29. 

19. Roy SK, Pal R, Sarin JPS. TLC separation and quantitative determination of 

guggulsterones. Indian Journal of Pharmaceutical Sciences, 1989, 51:251– 

253. 

20. Mesrob B et al. High-performance liquid chromatographic method for fi ngerprinting 

and quantitative determination of E- and Z-guggulsterones in 

Commiphora mukul resin and its products. Journal of Chromatography B, 

1998, 720:189–196. 







Switzerland). 

24. Bajaj AG, Dev S. Guggulu (resin from Commiphora mukul) some new steroidal 

components and stereochemistry of guggulsterol-1 at C-20 and C-22. 

Tetrahedron, 1982, 38:2949–2954. 

25. Patil VD, Nayak UR, Dev S. Chemistry of ayurvedic crude drugs – I. Guggulu 

(resin from Commiphora mukul) – I: Steroidal constituents. Tetrahedron, 

1972, 28:2341–2352. 

26. Malhotra SC, Ahuja MMS. Comparative hypolipidaemic effectiveness of 

gum guggulu (Commiphora mukul) fraction ‘A’, ethyl-p-chlorophenoxyisobutyrate 

and Ciba-13437-Su. Indian Journal of Medical Research, 1971, 

59:1621–1632. 

27. Kuppurajan K et al. Effect of guggulu (Commiphora mukul-Engl.) on serum 

lipids in obese subjects. Journal of Research in Indian Medicine, 1973, 8:1–8. 

28. Malhotra SC, Ahuja MMS, Sundaram KR. Long term clinical studies on the 

hypolipidaemic effect of Commiphora mukul (guggulu) and clofi brate. Indian 

Journal of Medical Research, 1977, 65:390–395. 

29. Kuppurajan K et al. Effect of guggulu (Commiphora mukul-Engl.) on serum 

lipids in obese, hypercholesterolemic and hyperlipemic cases. Journal of the 

Association of Physicians of India, 1978, 26:367–373. 

30. Agarwal RC et al. Clinical trial of gugulipid, a new hypolipidemic agent of 

plant origin in primary hyperlipidemia. Indian Journal of Medical Research, 

1986, 84:626–634. 

179


31. Satyavati GV. Gum guggul (Commiphora mukul) – the success story of an 

ancient insight leading to a modern discovery. Indian Journal of Medical Research, 

1988, 87:327–335. 

32. Verma SK, Bordia A. Effect of Commiphora mukul (gum guggulu) in patients 

of hyperlipidemia with special reference to HDL-cholesterol. Indian 

Journal of Medical Research, 1988, 87:356–360. 

33. Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of 

Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. 

Cardiovascular Drugs and Therapy, 1994, 8:659–664. 

34. Kotiyal JP, Singh DS, Bisht DB. Study of hypolipidaemic effect of Commiphora 

mukul (gum guggulu) fraction “A” in obesity. Journal of Research 

in Ayurveda and Siddha, 1980, 1:335–344. 

35. Kotiyal JP, Singh DS, Bisht DD. Gum guggulu (Commiphora mukul) fraction 

“A” in obesity – a double-blind clinical trial. Journal of Research in 

Ayurveda and Siddha, 1984, 6:20–35. 

36. Nadkarni KM. Indian materia medica. Bombay, Popular Prakashan, 1976. 

37. Frawley D, Lad V. The yoga of herbs: an Ayurvedic guide to herbal medicine. 

Twin Lakes, WI, Lotus Press, 1986. 


Press, 1993. 



the herbs used for oketsu.] Yakugaku Zasshi, 1984, 104:1050–1053 [in Japanese]. 

40. Tripathi YB, Malhotra OP, Tripathi SN. Thyroid stimulating action of Zguggulsterone 

obtained from Commiphora mukul. Planta Medica 1984, 

50:78–80. 

41. Dixit VP et al. Hypolipidemic activity of guggal resin (Commiphora mukul) 

and garlic (Allium sativum Linn.) in dogs (Canis familiaris) and monkeys 

(Presbytis entellus entellus Dufresne). Biochemistry and Experimental Biology, 

1980, 16:421–424. 

42. Sharma JN, Sharma JN. Comparison of the anti-infl ammatory activity of 

Commiphora mukul (an indigenous drug) with those of phenylbutazone and 

ibuprofen in experimental arthritis induced by mycobacterial adjuvant. Arzneimittelforschung, 

1977, 27:1455–1457. 

43. Duwiejua M et al. Anti-infl ammatory activity of resins from some species of 

the plant family Burseraceae. Planta Medica, 1993, 59:12–16. 

44. Atta AH, Alkofahi A. Anti-nociceptive and anti-infl ammatory effects of 

some Jordanian medicinal plant extracts. Journal of Ethnopharmacology, 

1998, 60:117–124. 

45. Arora RB et al. Anti-infl ammatory studies on a crystalline steroid isolated 

from Commiphora mukul. Indian Journal of Medical Research, 1972, 

60:929–931. 

180

Gummi Gugguli 

46. Panda S, Kar A. Gugulu (Commiphora mukul) induces triiodothyronine 

production: possible involvement of lipid peroxidation. Life Sciences, 1999, 

65:137–141. 

47. Malhotra SC et al. The effect of various fractions of gum guggulu on experimentally 

produced hypercholesterolaemia in chicks. Indian Journal of Medical 

Research, 1970, 58:394–395. 

48. Bordia A, Chuttani SK. Effect of gum guggulu on fi brinolysis and platelet 

adhesiveness in coronary heart disease. Indian Journal of Medical Research, 

1979, 70:992–996. 

49. Lee TY, Lam TH. Allergic contact dermatitis due to a Chinese orthopaedic 

solution Tieh Ta Yao Gin. Contact Dermatitis, 1993, 28:89–90. 

50. Lee TY, Lam TH. Myrrh is the putative allergen in bonesetter’s herbs dermatitis. 

Contact Dermatitis, 1993, 29:279. 

51. Al-Suwaidan SN et al. Allergic contact dermatitis from myrrh, a topical 

herbal medicine used to promote healing. Contact Dermatitis, 1998, 39:137. 



53. Liu DX et al. [Antimutagenicity screening of water extracts from 102 kinds 

of Chinese medicinal herbs.] Chung-kuo Chung Yao Tsa Chi Li, 1990, 

10:617–622 [in Chinese]. 

54. Amma MK et al. Effect of oleoresin of gum guggul (Commiphora mukul) on 

the reproductive organs of female rats. Indian Journal of Experimental Biology, 

1978, 16:1021–1023. 

181

182 

Radix Harpagophyti 

Defi nition 

Radix Harpagophyti consists of the dried, tuberous, secondary roots of 

Harpagophytum procumbens DC. ex Meiss. (Pedaliaceae) (1, 2). 

Synonyms 

Harpagophytum burcherllii Decne (3). 


Afrikanische Teufelskralle, beesdubbeltjie, devil’s claw, duiwelsklou, grapple 

plant, grapple vine, harpagophytum, kanako, khams, khuripe, legatapitse, 

sengaparele, Teufelskralle, Trampelklette, wood spider xwate (3–8). 


Indigenous to the Kalahari desert and savannas of Angola, Botswana, 

Namibia and South Africa, being found southwards from central 

Botswana (6, 7, 9–11). 

Description 

Prostrate perennial mat-forming herb, up to 1.5 m across. Tuber up to 

6 cm in diameter, bark yellowish-brown, longitudinally striated. Leaves 

pinnately lobed and clothed with glandular hairs, the underside densely 

pubescent. Flowers bright red, solitary, rising abruptly from the leaf axils; 

corolla pentamerous, tubular, pink-purple, up to 7 cm long; androecium 

of four stamens with one staminodium. Fruits characteristically large, 

hooked, claw-like, tardily dehiscent two-locular capsules, fl attened at 

right angles to the septum, the edges bearing two rows of woody arms up 

to 8 cm long with recurved spines (6, 12, 13). 

Plant material of interest: dried, tuberous, secondary roots 


Irregular thick, fan-shaped or rounded slices or roughly crushed discs of 

tuber, 2–4 cm and sometimes up to 6 cm in diameter, 2–5 mm thick,

greyish-brown to dark brown. Darker outer surface traversed by tortuous 

longitudinal wrinkles. Paler cut surface shows a dark cambial zone 

and xylem bundles distinctly aligned in radial rows. Central cylinder 

shows fi ne concentric striations. Seen under a lens, the cut surface presents 

yellow to brownish-red granules, longitudinally wrinkled; transverse 

surface yellowish-brown to brown, central region raised, fracture short (1, 2). 


Odour: none; taste: bitter (1, 2). 


Several rows of large, thin-walled cork cells frequently with yellowishbrown 

contents; parenchymatous cortex with very occasional sclereids 

with reddish-brown contents, xylem arranged in concentric rings; reticulately 

thickened vessels, some with rounded perforations in the end walls 

(tracheidal vessels); abundant lignifi ed parenchymatous cells associated 

with the vessels and in the small central pith (1). 


Brownish-yellow with fragments of cork layer consisting of yellowishbrown, 

thin-walled cells; fragments of cortical parenchyma consisting of 

large, thin-walled cells, sometimes containing reddish-brown granular inclusions 

and isolated yellow droplets; fragments of reticulately thickened 

vessels and tracheidal vessels with associated lignifi ed parenchyma from 

the central cylinder; small needles and crystals of calcium oxalate present 

in the parenchyma. May show rectangular or polygonal pitted sclereids 

with dark reddish-brown contents. Parenchyma turns green when treated 

with a solution of phloroglucinol in hydrochloric acid (2). 


Macroscopic and microscopic examinations, and thin-layer chromatography 

for the presence of harpagoside (1, 2). 

Purity tests 








183


Total ash 













Heavy metals 







Chemical, sulfated ash and alcohol-soluble extractive tests to be established 



Contains not less than 1.2% harpagoside as determined by high-performance 

liquid chromatography (2). 


The major active constituents are harpagoside and the related iridoid glycosides, 

harpagide and procumbide, which occur in lesser amounts. Total 

iridoid glycoside content 0.5–3.3% (3, 7, 10, 11). The structures of the 

major iridoid glycosides are presented below. 



Treatment of pain associated with rheumatic conditions (17–24). 

184

H 

HO 

HO 

OH 

CH3 H 

O 

harpagide 

H 

O 

Glc 

H 

HO 

HO 

O 

O CH3 

H 

O 

H 

O 

Glc 

H 

HO 

H 

HO 

harpagoside procumbide 

O 

O 

Glc 



Treatment of loss of appetite and dyspeptic complaints; supportive treatment 

of degenerative rheumatism, painful arthrosis and tendonitis (25). 


Treatment of allergies, boils, diabetes, liver disorders and sores (8). 

Pharmacology 


Anti-infl ammatory and analgesic activity 

A 60% ethanol extract of Radix Harpagophyti, 100.0 μg/ml, standardized 

to contain 2.9% harpagoside, inhibited the release of tumour necrosis factor-α 

(TNF-α) induced by the treatment of human monocytes with lipopolysaccharide 

(LPS) in vitro. However, treatment of the monocytes with 

harpagoside and harpagide, 10.0 μg/ml, isolated from the roots, had no 

effect on LPS-induced TNF-α release (26). Harpagoside, 10.0–100.0 μmol/ 

l, reduced the synthesis of thromboxane B 2 in cells treated with calcium 

ionophore A23187 (27). 

The results of studies assessing the anti-infl ammatory activity of Radix 

Harpagophyti in animal models are confl icting. Intragastric administration 

of 20.0 mg/kg body weight (bw) of an aqueous or methanol extract 

of the root to rats inhibited oedema and infl ammation in the granuloma 

pouch and carrageenan-induced footpad oedema tests (28). Intragastric 

administration of 20 mg/kg bw of a methanol extract of the root inhibited 

erythema induced by ultraviolet light in rats (28). Intragastric administration 

of 20.0 mg/kg bw of the same methanol extract to mice exhibited 

analgesic activity in the hot-plate test, but did not inhibit benzoquinoneinduced 

writhing (28). Intraperitoneal pretreatment of rats with an aqueous 

extract of the roots reduced carrageenan-induced footpad oedema in 

a dose-dependent manner. Doses of 400 mg/kg bw and 1200 mg/kg bw 

reduced oedema by 43% and 64%, respectively, 3 hours after administration. 

The effi cacy of the higher dose was similar to that of indometacin, 

10 mg/kg bw (29). Intraperitoneal administration of 400.0 mg/kg bw of a 

O 

CH 3 

H 

H 

HO 

O 

Glc = OH 

HO 

OH 


185


chloroform extract of the roots to mice with carrageenan-induced footpad 

oedema and infl ammation reduced infl ammation by 60.3% 5 hours 

after treatment (30). 

Intraperitoneal administration of 200–400 mg/kg bw of an aqueous 

extract of the roots reduced carrageenan-induced footpad oedema in rats, 

but did not increase the reaction time of mice in the tail-fl ick hot-plate 

test. The anti-infl ammatory activity of the highest dose was more effi cient 

in rats than indometacin, 10.0 mg/kg bw. Treatment of the aqueous extract 

with 0.1 mol/l hydrochloric acid dramatically decreased the activity, 

suggesting that oral dosage forms should be enteric coated to protect the 

active principles from stomach acid. In the same study, harpagoside did 

not appear to be involved in the anti-infl ammatory activity (31). 

Intraperitoneal administration of 20.0 mg/kg bw of an aqueous extract 

of the roots to rats reduced formalin-induced arthritis. The effectiveness 

was comparable to that of phenylbutazone, 50.0 mg/kg bw. This study 

also demonstrated that intraperitoneal administration of 10–50 mg/kg bw 

of harpagoside to rats inhibits both formalin- and albumin-induced footpad 

oedema and formalin-induced arthritis (32). 

Intragastric administration of 200.0 mg of an aqueous extract of the 

roots to rats inhibited formalin-induced footpad oedema (33). However, 

another study showed that intragastric administration of 1.0 g/kg bw of 

the powdered roots to rats did not inhibit carrageenan-induced footpad 

oedema or adjuvant-induced arthritis, as compared with other antiinfl 

ammatory agents such as indometacin or acetylsalicyclic acid (34). Investigations 

of the antiphlogistic activity of harpagoside, harpagide and 

an aqueous extract of Radix Harpagophyti (doses not specifi ed) indicated 

that all three substances had anti-infl ammatory activity similar to that of 

phenylbutazone (35). In mice, intragastric administration of 100.0 mg/kg 

bw of harpagoside inhibited carrageenan-induced footpad oedema, and 

external application of 1.0 mg/ear reduced ear oedema induced by phorbol 

ester (36). 

Intragastric administration of up to 100 times the recommended daily 

dose of powdered roots (6.0 g/kg bw) to rats did not reduce footpad 

oedema induced by carrageenan or Mycobacterium butyricum. Furthermore, 

the root preparation, 100.0 mg/ml, failed to inhibit prostaglandin 

synthase activity in vitro (37). 

Antiarrhythmic activity 

Intragastric administration of 100 mg/kg bw of an aqueous or methanol 

extract of the roots protected rats against ventricular arrhythmias induced 

by epinephrine-chloroform or calcium chloride (38). Intraperitoneal administration 

of 25 mg/kg bw of a methanol extract of the roots inhibited 

186


cardiac arrhythmias induced by aconitine, epinephrine-chloroform or 

calcium chloride in fasted rats (38). Intragastric administration of 300– 

400 mg/kg bw of a methanol extract of the roots to normotensive rats 

reduced heart rate and arterial blood pressure (38). Other studies have 

demonstrated that lower doses of the extract have slight negative chronotropic 

and positive inotropic effects (39), whereas larger doses have a 

marked inotropic effect, with reductions in coronary blood fl ow. The 

inotropic effect is attributed to harpagide (40). 


Antidyspeptic activity 

A decoction of Radix Harpagophyti is one of the strongest bitter tonics 

known (41). Ingestion of a tea prepared from the root (dose not specifi ed) 

over a period of several days led to an improvement in the symptoms of 

disorders of the upper part of the small intestine, which were accompanied 

by disturbances of choleresis and bile kinesis (41). It has been proposed 

that, because the root is very bitter, is a good stomachic and stimulates 

the appetite, it may also be useful for the treatment of dyspeptic 

complaints (17, 42, 43). 


A randomized double-blind comparison study, involving 46 patients with 

active osteoarthritis of the hip, assessed the effects of oral administration 

of 480 ng of an ethanol extract of the roots twice daily in the successive 

reduction of ibuprofen use for pain and the Western Ontario and McMaster 

Universities (WOMAC) arthrosis index. Patients received, in conjunction 

with the extract or placebo, 800.0 mg of ibuprofen daily for 8 

weeks, then 400.0 mg daily for 8 weeks, then no ibuprofen. After 20 weeks 

of treatment, the WOMAC index decreased in the treatment group, with 

improvements in pain, stiffness and loss of function (23). In a randomized, 

double-blind clinical trial in 122 patients suffering from osteoarthritis 

of the knee and hip, the effi cacy and tolerance of the roots and diacerein 

were compared. Patients received the roots as 6 capsules per day, 

each containing 435.0 mg of powdered roots or 100.0 mg of diacerein 

daily for 4 months. Assessments of pain and functional disability were 

made on a 10-cm horizontal visual analogue scale, and the severity of osteoarthritis 

was evaluated using the Lequesne functional index. There was 

a reduction in spontaneous pain and a progressive reduction in the 

Lequesne index in both groups. Fewer side-effects were observed in the 

group treated with the powdered roots (8.1%) than in the group receiving 

diacerein (26.7%) (22). 

187


In a double-blind, placebo-controlled clinical trial, 50 patients with 

various arthroses were treated with 1200.0 mg of a hydroalcoholic extract 

of the roots, containing 1.5% iridoid glycosides, daily for 3-week courses. 

The severity of pain was assessed 10 days after completion of treatment. 

Each patient was given one to three courses of treatment. Compared with 

placebo, the extract produced a decrease in the severity of pain in individuals 

with a moderate pain level (44). 

In an uncontrolled study involving 630 patients with arthrosis, 42– 

85% of the patients showed improvements after 6 months of daily oral 

treatment with 3.0–9.0 g of an aqueous extract of the roots containing 

2.5% of iridoid glycosides (45). In an uncontrolled trial, the effi cacy of an 

orally administered aqueous extract of the roots (as tablets) was assessed 

in 13 patients, 11 with arthritis and two with psoriatic arthropathy. Treatment 

of the patients for 6 weeks with 1.23 g daily did not reduce pain or 

infl ammation in 12 patients, and one patient withdrew owing to sideeffects 

(46). In an uncontrolled study, benefi cial results were reported in 

80% of 60 patients with chronic polyarthritis after treatment with subcutaneous 

lateral and medial injections of aqueous root extracts on both 

sides of the knee joint (17). 

The effi cacy of a standardized hydroalcoholic extract of the roots for 

the treatment of chronic back pain was assessed in a double-blind, randomized, 

placebo-controlled trial. The 197 patients were treated orally 

with 600.0 mg or 1200.0 mg of the extract (standardized to contain a total 

of 50–100 mg of harpagoside) or placebo daily for 4 weeks. A total of 

183 patients completed the trial. Three, six and ten patients in the placebo, 

low-dose extract and high-dose extract groups, respectively, (P = 0.027) 

remained pain-free without the permitted pain medication (tramadol) for 

5 days in the last week (20). A 4-week randomized double-blind, placebocontrolled 

clinical trial assessed the safety and effi cacy of an ethanol extract 

of the roots in the treatment of acute attacks of pain in 118 patients 

with chronic back problems. Patients received two 400.0-mg tablets three 

times per day (equivalent to 6 g of roots containing 50.0 mg of harpagoside). 

Intake of a supplementary analgesic (tramadol) did not differ signifi 

cantly between the placebo and the treatment group. However, further 

analysis revealed that nine out of 51 patients who received the extract 

were pain free at the end of the treatment period, compared to only one 

out of 54 in the placebo group (18). The effi cacy of a dried ethanol extract 

of the roots was investigated in a 4-week, double-blind, placebo-controlled 

study in 118 patients with a history of chronic lower back pain. 

Patients were randomly assigned to receive two tablets of the extract or 

placebo three times per day. After 4 weeks of treatment, a reduction in the 

188

Arhus low back pain index was observed in the treated patients compared 

with those receiving placebo (19). A randomized, placebo-controlled, 

double-blind study investigated the effects of an ethanol extract of the 

roots on sensory, motor and vascular mechanism of muscle pain in 

65 patients with mild to moderate muscle tension or mild back, shoulder 

or neck pain. Patients received two doses of 480.0 mg of the extract or 

placebo daily for 4 weeks. At the end of the treatment period, a signifi cant 

reduction in muscle pain as measured by a visual analogue scale (P < 0.001) 

was observed in the extract group. Muscle stiffness and ischaemia were 

also improved in this group, but no changes were found in antinociceptive 

muscle refl exes or surface electromyography (24). 

Oral administration of powdered roots, four 500.0-mg capsules, standardized 

to contain 3% total iridoids, daily for 21 days to healthy volunteers 

did not statistically alter eicosanoid biosynthesis by the cyclooxygenase 

or 5-lipoxygenase pathways. The results indicated that in healthy 

humans Radix Hapagophyti did not inhibit arachidonic acid metabolism 

(47). 


Mild and infrequent gastrointestinal symptoms were reported in clinical 

trials (18, 20, 45). 


Radix Harpagophyti is contraindicated in gastric and duodenal ulcers, 

and cases of known hypersensitivity to the roots (25). Owing to a lack of 

safety data, Radix Harpagophyti should not be used during pregnancy 

and nursing. 

Warnings 



Precautions 

General 

Patients with gallstones should consult a physician prior to using the 

roots (25). 


An extract of the roots did not inhibit the activity of cytochrome P450 isoform 

3A4 in vitro, suggesting that Radix Harpagophyti would not interact 

with prescription drugs metabolized by this enzyme (48). 

189








test interactions; carcinogenesis, mutagenesis, impairment of fertility; 

teratogenic effects during pregnancy; or paediatric use. 

Dosage forms 

Dried roots for decoctions and teas; powdered roots or extract in capsules, 

tablets, tinctures and ointments (6, 7). Store in a well closed container, 


Posology 


Daily dose: for loss of appetite 1.5 g of the roots in a decoction, 3 ml of 

tincture (1:10, 25% ethanol) (25); for painful arthrosis or tendonitis 1.5– 

3 g of the roots in a decoction, three times, 1–3 g of the roots or equivalent 

aqueous or hydroalcoholic extracts (41). 

References 

1. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association. 

1996. 

2. European pharmacopoeia, 3rd ed., Suppl. 2001. Strasbourg, Council of 

Europe, 2000. 

3. Hänsel R et al., eds. Hagers handbuch der Pharmazeutischen Praxis. Bd 5, 



4. Hedberg I, Staugard F. Traditional medicine in Botswana, traditional medicinal 

plants. Gaborone, Ipeleng Publishers, 1989. 

5. Van den Eynden V, Vernemmen P, Van Damme P. The ethnobotany of the 

Topnaar. University of Ghent/EEC, 1992. 


Press, 1993. 


Press, 1994. 



190




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claw.] Zeitschrift für Phytotherapie, 1987, 8:17–20. 



11. Eich J, Schmidt M, Betti G. HPLC analysis of iridoid compounds of 

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12. Dyer RA. The genera of southern African fl owering plants. Vol. I. Pretoria, 

Botanical Research Institute, 1975. 

13. Betti GJR. Harpagophytum procumbens DC. Complexe d’éspèces. Description 

comparative du développement végétatif. Origine, prévention et conséquences 

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Italiana, 1994, Special issue, February. 







Switzerland). 

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with Harpagophytum.] Therapiewoche, 1972, 13:1072–1075. 

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of acute low back pain. Phytomedicine, 1996, 3:1–10. 

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(Burch.) De Candolle (“devil’s claw”). Erfahrungsheilkunde, 1997, 

6:330–335. 

20. Chrubasik S et al. Effectiveness of Harpagophytum extract WS 1531 in the 

treatment of exacerbation of low back pain: a randomized, placebocontrolled, 

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16:118–129. 

21. Wegener T. Therapie degenerativer Erkrankungen des Bewegungsapparates 

mit sudafrikanischer Teufelskralle (Harpagophytum procumbens D.C.). 

[Treatment of degenerative diseases of the locomotor system with south 

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Wochenschrift, 1999, 149:254–257. 

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diacerhein in the treatment of osteoarthritis. Phytomedicine, 2000, 7:177– 

183. 

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to the treatment of coxarthrosis.] Der Kassenarzt, 2001, 5:34–41. 

191


24. Göbel H et al. Harpagophytum-Extrakt LI174 (Teufelskralle) bei der Behandlung 

unspezifi scher Rückenschemerzen. Effekte auf die sensible, motorische 

und vaskuläre Muskelreagibilität. [Harpagophytum-extract LI174 (devil’s 

claw) for the treatment of non-specifi c back pain. Effects on sensory, motor 

and vascular muscle responsiveness.] Schmerz, 2001, 15:10–18. 



26. Fiebich et al. Inhibition of TNF-alpha synthesis in LPS-stimulated primary 

human monocytes by Hargophytum extract SteiHap 69. Phytomedicine, 

2001, 8:28–30. 

27. Tippler B et al. Harpagophytum procumbens: Wirkung von Extrakten auf die 

Eicosanoidbiosynthese in Ionophor A23187-stimuliertem menschlichem 

Vollblut. [Harpagophytum procumbens: Effect of extracts on eicosanoid biosynthesis 

in ionophore A23187-stimulated whole blood.] In: Loew D, 

Rietbrock N, eds. Phytopharmaka II: Forschung und klinische Anwendung. 

[Phytopharmacological drugs II. Research and clinical use.] Darmstadt, 

Steinkopff, 1996:95–100. 

28. Erdös A et al. Beitrag zur Pharmakologie und Toxicologie verschiedener Extracte, 

sowie des Harpagosids aus Harpagophytum procumbens DC. [Contribution 

to the pharmacology and toxicology of different extracts as well as 

the harpagosid from Harpagophytum procumbens DC.] Planta Medica, 1978, 

34:97–101. 

29. Baghdikian B et al. An analytical study, anti-infl ammatory and analgesic effects 

of Harpagophytum procumbens and Harpagophytum zeyheri. Planta 

Medica, 1997, 63:171–176. 

30. Mañez S et al. Selected extracts from medicinal plants as antiinfl ammatory 

agents. Planta Medica, 1990, 56:656. 

31. Lanhers MC et al. Anti-infl ammatory and analgesic effects of an aqueous 

extract of Harpagophytum procumbens. Planta Medica, 1992, 58:117–123. 

32. Eichler VO, Koch C. Über die antiphlogistische, analgetische und spasmolytische 

Wirksamkeit von Harpagosid, einem Glykosid aus der Wurzel von 

Harpagophytum procumbens. [On the antiphlogistic, analgesic and spasmolytic 

action of harpagoside, a glycoside from the roots of Harpagophytum 

procumbens DC.] Arzneimittelforschung, 1970, 20:107–109. 

33. Zorn B. Über die antiarthritische Wirkung der Harpagophytum-Wurzel. [On 

the anti-arthritic effect of Harpagophytum roots.] Zeitschrift für Rheumaforschung, 

1958, 17:134–138. 

34. McLeod DW, Revell P, Robinson BV. Investigations of Harpagophytum procumbens 

(devil’s claw) in the treatment of experimental infl ammation and 

arthritis in the rat. British Journal of Pharmacology, 1979, 66:140P–141P. 

35. Sticher O. Plant mono-, di- and sesquiterpenoids with pharmacological and 

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36. Recio M et al. Structural considerations on the iridoids as anti-infl ammatory 

agents. Planta Medica, 1994, 60:232–234. 

37. Whitehouse LW, Znamirowska M, Paul CJ. Devil's claw (Harpagophytum 

procumbens): no evidence for anti-infl ammatory activity in the treatment of 

arthritic disease. Canadian Medical Association Journal, 1983, 129:249–251. 

38. Circosta C et al. A drug used in traditional medicine: Harpagophytum procumbens 

DC. II. Cardiovascular activity. Journal of Ethnopharmacology, 

1984, 11:259–274. 

39. Occhiuto F et al. A drug used in traditional medicine: Harpagophytum procumbens 

DC. IV. Effects on some isolated muscle preparations. Journal of 


40. Costa de Pasquale R et al. A drug used in traditional medicine: Harpagophytum 

procumbens DC. III. Effects on hyperkinetic ventricular arrhythmias 

by reperfusion. Journal of Ethnopharmacology, 1985, 13:193–199. 

41. Weiss RF, Fintelmann V, eds. Herbal medicine, 2nd ed. Stuttgart, Thieme, 

2000. 

42. Czygan FC et al. Pharmazeutische-biologische Untersuchungen der Gattung 

Harpagophytum (Bruch.) DC ex Meissn. 1. Mitteilung: phytochemische 

Standardisierung von Tubern Harpagophyti. [Pharmaceutical-biological 

studies of the genus Harpagophytum. Part 1. Phytochemical standardization 

of tubera harpagophyti.] Deutsche Apotheker Zeitung, 1977, 117:1431. 

43. Jaspersen-Schib R. Harpagophyti radix: est-ce vraiment une drogue miracle? 

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1989, 11:265–270. 

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arthrosis.] Le Magazine, 1992, 15:27–30. 

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d’Harpagophytum procumbens. [Clinical study of 630 cases of arthrosis 

treated with an aqueous spray of Harpagophytum procumbens.] Phytotherapie, 

1982, 1:22–28. 

46. Grahame R, Robinson BV. Devil’s claw (Harpagophytum procumbens): 

pharmacological and clinical studies. Annals of Rheumatic Diseases, 1981, 

40:632. 

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no evidence for NSAID-like effect on whole blood eicosanoid production 

in humans. Prostaglandins, leukotrienes and essential fatty acids, 

1992, 46:283–286. 

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to the treatment of coxarthrosis.] Der Kassenarzt, 2001, 5:34–41. 

193

194 

Rhizoma Hydrastis 

Defi nition 

Rhizoma Hydrastis consists of the dried rhizomes and roots of Hydrastis 

canadensis L. (Ranunculaceae) (1–3). 

Synonyms 

Hydrastis canadensis was formerly classifi ed as a member of the family 

Berberidaceae. 


Eyebalm, golden seal, goldenseal, gorzknik kanadyjski, ground raspberry, 

hydraste, hydrastis, idraste, Indian dye, Indian paint, Indian turmeric, 

sceau d’or, warnera, wild curcuma, yellow puccoon (4, 5). 


Indigenous to North America (4, 6). 

Description 

A perennial herb. Underground portion consists of a horizontal, branching 

rhizome bearing numerous long slender roots. Aerial part consists of 

a single radical leaf and a short stem 10–18 cm high, which bears near its 

summit two petiolate, palmate (fi ve to seven lobes), serrate leaves and 

ends with a solitary greenish-white fl ower. Fruits are compound crimson 

berries somewhat similar to raspberries (4). 

Plant material of interest: dried rhizomes and roots 


Rhizomes horizontal or oblique, subcylindrical, 1–6 cm long, 2–10 mm in 

diameter, occasionally with stem bases; numerous short upright branches 

terminating in cup-shaped scars and bearing encircling cataphyllary 

leaves. Externally, brown-greyish or yellowish-brown, deep longitudinal 

wrinkles, marked by numerous stem and bud-scale scars. From the lower

and lateral surfaces, arise many long, slender, brittle, curved, and wiry 

roots, frequently broken off to leave short protuberances or circular, yellow 

scars. Fracture short and resinous; fractured surface yellowishorange 

at centre and greenish-yellow at margin with thick, dark yellow to 

yellowish-brown bark. Bright yellow, narrow xylem bundles separated 

by wide medullary rays; large pith. Roots numerous, fi liform up to 35 mm 

long and 1 mm in diameter, curved or twisted. Fracture short and brittle, 

fractured surface yellowish-orange to greenish-yellow (1, 3, 4). 


Odour: faint, unpleasant; taste: bitter, persistent (1, 4, 6). 



Rhizome cork yellowish-brown, polygonal cells with thin lignifi ed walls; 

secondary cortex contains abundant thin-walled, polygonal to round or 

elongated, parenchymatous cells and some collenchyma, with abundant 

starch grains, simple or rarely compound with two to six components, 

spherical or ovoid with small, round or slit-like hilum. Parenchyma contains 

numerous masses of granular, orange-brown matter. Lignifi ed tracheids 

present, usually small with slit-like pits, but occasionally large vessels 

with reticulate thickening. Root cork consists of a single layer of cells, 

irregularly elongated. Very occasional fragments of piliferous layer from 

young roots with root hairs; and a few thin-walled, lignifi ed fi bres associated 

with vessels present. Occasional fragments of epidermis of stem bases 

composed of cells with thick, lignifi ed, beaded walls, slightly elongated 

in surface view (1, 3, 4). 


Dark yellow to moderate greenish-yellow. Numerous spherical, simple 

starch grains, 2–15 μm in diameter, the larger grains exhibiting a central 

hilum; a few compound forms with two to six components. Fragments of 

starch-bearing parenchyma and fi brovascular tissue. Tracheal elements 

with simple and bordered pores, some with spiral thickenings and wood 

fi bres, 200–300 μm long, thin-walled and with simple pores. A few fragments 

of cork tissue, the cells of which have reddish-brown walls. Calcium 

oxalate crystals absent (3, 4). 


Macroscopic and microscopic examinations (1, 3, 4), and thin-layer chromatography 

(1, 3). 

195


Purity tests 





Chemical 

Not less than 2.0% hydrastine and not less than 2.5% berberine (3). 



Total ash 













Heavy metals 





for medicinal plants for the analysis of radioactive isotopes (7). 


Sulfated ash and alcohol-soluble extractive tests to be established in accordance 

with national requirements. 

196


Contains not less than 2.0% hydrastine and not less than 2.5% berberine 

determined by high-performance liquid chromatography (3). 


The major constituents are isoquinoline alkaloids (2.5–6.0%), principally 

hydrastine (1.5–5.0%), followed by berberine (0.5–4.5%), canadine (tetrahydroberberine, 

0.5–1.0%), and lesser quantities of related alkaloids including 

canadaline, corypalmine, hydrastidine and jatrorrhizine (5, 10– 

13). The structures of hydrastine, berberine and canadine (a mixture of 

α-canadine (R-isomer) and β-canadine (S-isomer)) are presented below: 

H 3 CO 

H 3 CO 

N + 

O 


berberine canadine 



None. 

O 

H 3 CO 

H 3 CO 

N 


Treatment of digestive complaints, such as dyspepsia, gastritis, feeling of 

distension and fl atulence (1). 


Treatment of cystitis, dysmenorrhoea, eczema, haemorrhoids, uterine 

haemorrhage, infl ammation, kidney diseases, menorrhagia, nasal congestion, 

tinnitus and vaginitis. As a cholagogue, diuretic, emmenagogue, 

haemostat, laxative and tonic (5). 

Pharmacology 



A methanol extract of Rhizoma Hydrastis and berberine inhibited the 

growth of Helicobacter pylori (the bacterium associated with dyspepsia, 

gastritis and peptic ulcer disease) in vitro, median inhibitory concentration 

H 

O 

O 

H 3 CO 


OCH 3 

H 

H3C N 

O 

O 

H 

hydrastine 

O 

O 

197


range 0.625–40.00 μg/ml (14, 15). A 95% ethanol extract of the rhizomes, 

1.0 mg/ml, inhibited the growth of Staphylococcus aureus, Klebsiella pneumoniae, 

Mycobacterium smegmatis and Candida albicans in vitro (16). Berberine 

was the active constituent of the extract, minimum inhibitory concentration 

25.0–50.0 μg/ml against Staphylococcus aureus and Mycobacterium 

smegmatis (16, 17). Berberine inhibited the growth of Bacillus 

subtilis and Salmonella enteritidis in vitro at concentrations of 1.0 mg/ml 

and 0.5 mg/ml, respectively (18). Berberine, 150.0 μg/ml, also inhibited the 

growth of Clostridium perfringens in vitro and, at 1.0 mg/ml, signifi cantly 

(P < 0.001) inhibited the growth of and induced morphological changes in 

Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis (19). 

Effects on smooth muscle 

A 70% ethanol extract of the rhizomes inhibited carbachol-induced contractions 

of isolated guinea-pig trachea in vitro, median inhibitory dose 

1.6 μg/ml (20). In rabbit bladder detrusor muscle strips, an ethanol extract 

of the rhizomes inhibited contractions induced by isoprenaline, 

median effective concentration 40 nmol/l (21). An alcohol extract of the 

rhizomes reduced contractions induced by serotonin, histamine and epinephrine 

in isolated rabbit aortas (22). Investigations using the major 

alkaloids from the rhizomes assessed the antispasmodic mechanism of 

action in isolated guinea-pig tracheas (23). The median effective concentrations 

of berberine, β-hydrastine, canadine and canadaline were 

34.2 μg/ml, 72.8 μg/ml, 11.9 μg/ml and 2.4 μg/ml, respectively. Timolol 

pretreatments antagonized the effects of canadine and canadaline, but 

not berberine or β-hydrastine (23). 

Berberine, 1 μmol/l, induced relaxation of norepinephrine-precontracted 

isolated rat aortas (24). Berberine, 10 -5 mol/l, induced relaxation in 

isolated precontracted rat mesenteric arteries (25, 26). Berberine, 0.1– 

100.0 μmol/l, suppressed basal tone and induced a concentration-dependent 

relaxation of phenylephrine-precontracted rabbit corpus cavernosum (27). 

Intracavernosal injection of 5.0 mg/kg of berberine to anaesthetized rabbits 

increased intracavernosal pressure from 12.7 mmHg to 63.4 mmHg, 

duration of tumescence ranging from 11.5 to 43.7 minutes (27). A hydroalcoholic 

extract of the rhizomes or berberine inhibited norepinephrine- and 

phenylephrine-induced contractions in isolated rabbit prostate strips with 

ED 50 values of 3.92 μmol/l and 2.45 μmol/l, respectively (28). 

Immunological effects 

Intragastric administration of an extract (type not specifi ed) of the rhizomes, 

6.6 g/l in drinking-water, to rats for 6 weeks increased production 

of antigen-specifi c immunoglobulin M (29). Intraperitoneal administra- 

198

tion of 10.0 mg/kg body weight (bw) of berberine per day for 3 days to 

mice before the induction of tubulointerstitial nephritis signifi cantly 

(P = 0.001) reduced pathological injury, improved renal function, and decreased 

the numbers of CD3+, CD4+ and CD8+ T-lymphocytes (30). 

Toxicology 

The oral median lethal dose of berberine in mice was 329.0 mg/kg bw (31). 

Oral administration of 2.75 g of berberine to dogs produced severe gastrointestinal 

irritation, profuse watery diarrhoea, salivation, muscular tremors 

and paralysis; respiration was not affected. Postmortem examination showed 

the intestines to be contracted, infl amed and empty or containing mucous 

and watery fl uid. Oral administration of berberine sulfate, 25.0 mg/kg bw, 

induced central nervous system depression in dogs lasting 6–8 hours; 

50.0 mg/kg bw caused salivation and sporadic emesis; 100.0 mg/kg bw induced 

persistent emesis and death of all animals 8–10 days later (31). 


Hot aqueous extracts of the rhizomes, 1:200 in the bath medium, stimulated 

contractions in isolated guinea-pig uteri (32). However, an alkaloidenriched 

extract of the rhizomes did not stimulate contractions in isolated 

mouse uteri (33). A 70% ethanol extract of the rhizomes inhibited spontaneous 

and oxytocin- and serotonin-induced contractions in isolated rat 

uteri, median inhibitory concentrations 10.0–19.9 μg/ml (20). 


No controlled clinical studies available for Radix Hydrastis. While berberine 

has been shown to be effective for the treatment of bacteriallyinduced 

diarrhoea (34–40), ocular trachoma (41) and cutaneous leishmaniasis 

(42–44), the data cannot generally be extrapolated to include 

extracts of the rhizomes. 


No information available on adverse reactions to Radix Hydrastis. However, 

high doses of hydrastine are reported to cause exaggerated refl exes, 

convulsions, paralysis and death from respiratory failure (45). 


Radix Hydrastis is contraindicated in cases of known allergy to the plant 

material. 

Warnings 



199


Precautions 

General 

Use with caution in patients with high blood pressure, diabetes, glaucoma 

and a history of cardiovascular disease. 


An ethanol extract of the rhizomes inhibited the activity of cytochrome 

P450 (CYP3A4) in vitro, median inhibitory concentration


Posology 


Daily dose: dried rhizomes and roots 0.5–1.0 g three times, or by decoction; 

liquid extract 1:1 in 60% ethanol, 0.3–1.0 ml three times; tincture 

1:10 in 60% ethanol, 2–4 ml three times (1). 

References 

1. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association. 

1996. 





3. USP-NF 2000, Goldenseal. Pharmacopeial Previews: Monographs (NF), 

The United States Pharmacopeial Convention, Inc. Pharmacopeial forum, 

2000, 26:944–948. 















Switzerland). 

10. Messana I, La Bua R, Galeffi C. The alkaloids of Hydrastis canadensis L. 

(Ranunculaceae). Two new alkaloids: hydrastidine and isohydrastidine. 

Gazzetta Chimica Italiano, 1980, 110:539–543. 

11. Bradley PR, ed. British herbal compendium. Vol. 1. Bournemouth, British 

Herbal Medicine Association, 1992. 



13. Newall CA, Anderson LA, Phillipson JD. Herbal medicines. A guide for 


14. Bae EA et al. Anti-Helicobacter pylori activity of herbal medicines. Biological 


15. Mahady GB, Pendland SL, Matsuura H. Screening of medicinal plants for in 

vitro activity against Helicobacter pylori. Abstract. In: Luijendijk T et al., eds. 

201


2000 years of natural products research – past, present and future. 

Amsterdam, American Society of Pharmacognosy, July 26–30, 1999:709. 

16. Gentry EJ et al. Antitubercular natural products: berberine from the roots of 

commercial Hydrastis canadensis powder. Isolation of inactive 8-oxotetrahydrothalifendine, 

canadine, β-hydrastine, and two new quinic acid esters, 

hycandinic acid esters-1 and -2. Journal of Natural Products, 1998, 61:1187– 

1193. 

17. Chi HJ, Woo YS, Lee YJ. [Effect of berberine and some antibiotics on the 

growth of microorganisms.] Korean Journal of Pharmacognosy, 1991, 22:45– 

50 [in Korean]. 

18. Iwasa K et al. Structure–activity relationships of protoberberines having 

antimicrobial activity. Planta Medica, 1998, 64:748–751. 

19. Kaneda Y et al. In vitro effects of berberine sulphate on the growth and structure 

of Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis. 

Annals of Tropical Medicine and Parasitology, 1991, 85:417–425. 

20. Cometa MF, Abdel-Haq H, Palmery M. Spasmolytic activities of Hydrastis 

canadensis L. on rat uterus and guinea-pig trachea. Phytotherapy Research, 

1998, 12(Suppl. 1):S83–S85. 

21. Bolle P et al. Response of rabbit detrusor muscle to total extract and major 

alkaloids of Hydrastis canadensis. Phytotherapy Research, 1998, 12(Suppl. 1): 

S86–S88. 

22. Palmery M et al. Effects of Hydrastis canadensis L. and the two major alkaloids 

berberine and hydrastine on rabbit aorta. Pharmacological Research, 

1993, 27(Suppl. 1):73–74. 

23. Abdel-Haq H et al. Relaxant effects of Hydrastis canadensis L. and its major 

alkaloids on guinea pig isolated trachea. Pharmacology and Toxicology, 2000, 

87:218–222. 

24. Wong KK. Mechanism of the aorta relaxation induced by low concentrations 

of berberine. Planta Medica, 1998, 64:756–757. 

25. Chiou WF, Yen MH, Chen CF. Mechanism of vasodilatory effect of berberine 

in rat mesenteric artery. European Journal of Pharmacology, 1991, 204:35– 

40. 

26. Ko WH et al. Vasorelaxant and antiproliferative effects of berberine. European 

Journal of Pharmacology, 2000, 399:187–196. 

27. Chiou WF, Chen J, Chen CF. Relaxation of corpus cavernosum and raised 

intracavernous pressure by berberine in rabbit. British Journal of Pharmacology, 

1998, 125:1677–1684. 

28. Baldazzi C et al. Effects of the major alkaloid of Hydrastis canadensis L., 

berberine, on rabbit prostate strips. Phytotherapy Research, 1998, 12:589– 

591. 

29. Rehman J et al. Increased production of antigen-specifi c immunoglobulins G 

and M following in vivo treatment with the medicinal plants Echinacea angustifolia 

and Hydrastis canadensis. Immunology Letters, 1999, 68:391–395. 

202


30. Marinova EK et al. Suppression of experimental autoimmune tubulointerstitial 

nephritis in BALB/c mice by berberine. Immunopharmacology, 2000, 

48:9–16. 

31. Lampe KF. Berberine. In: De Smet PA et al., eds. Adverse effects of herbal 

drugs. Vol. I. Berlin, Springer, 1992:97–104. 

32. Supek Z, Tomíc D. Pharmacological and chemical investigations of barberry 

(Berberis vulgaris). Lijecnicki Vjesnik, 1946, 68:16–18. 

33. Haginiwa J, Harada M. [Pharmacological studies on crude drugs. V. Comparison 

of the pharmacological actions of berberine type alkaloid containing 

plants and their components.] Yakugaku Zasshi, 1962, 82:726 [in Japanese]. 

34. Lahiri SC, Dutta NK. Berberine and chloramphenicol in the treatment of 

cholera and severe diarrhea. Journal of the Indian Medical Association, 1967, 

48:1–11. 

35. Chauhan RK, Jain AM, Bhandari B. Berberine in the treatment of childhood 

diarrhoea. Indian Journal of Pediatrics, 1970, 37:577–579. 

36. Sharda DC. Berberine in the treatment of diarrhoea in infancy and childhood. 

Journal of the Indian Medical Association, 1970, 54:22–24. 

37. Sharma R, Joshi CK, Goyal RK. Berberine tannate in acute diarrhoea. Indian 

Journal of Pediatrics, 1970, 7:496–501. 

38. Khin-Maung U et al. Clinical trial of berberine in acute watery diarrhoea. 

British Medical Journal, 1986, 291:1601–1605. 

39. Rabbani GH et al. Randomized controlled trial of berberine sulfate therapy 

for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. Journal 

of Infectious Diseases, 1987, 155:979–984. 

40. Tang W, Eisenbrand G. Chinese drugs of plant origin. London, Springer, 

1992. 

41. Mohan M et al. Berberine in trachoma. Indian Journal of Ophthalmology, 

1982, 30:69–75. 

42. Das Gupta BM, Dikshit BB. Berberine in the treatment of oriental boil. Indian 

Medical Gazette, 1929, 64:67–70. 

43. Devi AL. Berberine sulfate in oriental sore. Indian Medical Gazette, 1929, 

64:139–140. 

44. Das Gupta BM. The treatment of oriental sore with berberine acid sulfate. 

Indian Medical Gazette, 1930, 65:683–685. 

45. Genest K, Hughes DW. Natural products in Canadian pharmaceuticals. IV. 

Hydrastis Canadensis. Canadian Journal of Pharmaceutical Sciences, 1969, 

4:41–45. 



2000, 7:273–282. 

47. Pasqual MS et al. Genotoxicity of the isoquinoline alkaloid berberine in prokaryotic 

and eukaryotic organisms. Mutation Research, 1993, 286:243–252. 

203

204 

Radix Ipecacuanhae 

Defi nition 

Radix Ipecacuanhae consists of the dried roots and rhizomes of Cephaelis 

ipecacuanha (Brot.) A. Rich., of C. acuminata (Benth.) Karst. (Rubiaceae), 

or of a mixture of both species (1–9). 

Synonyms 

Cephaelis ipecacuanha: Callicocca ipecacuanha Brot., Cephaelis emetica 

Pers., Evea ipecacuanha (Brot.) Standl., Ipecacuanha offi cinalis (Brot.) 

Farw., Psychotria emetica Vell., P. ipecacuanha (Brot.) Muell. Arg. (also 

Stokes), Uragoga emetica Baill., U. ipecacuanha (Willd.) Baill. (3, 8, 

10). 

Cephaelis acuminata: Psychotria acuminata Benth., Uragoga acuminata 

(Benth.) O. Kuntze, U. granatensis Baill. (3, 10). 


Ark ad dhahab, Brazilian ipecac (= Cephaelis ipecacuanha (Brot.) 

A. Rich.), Cartagena ipecac (= Cephaelis acuminata (Benth.) Karst.), 

Cartagena ipecacuanha, ipeca, ipecac, ipecacuanha, ipecacuana, jalab, 

Kopfbeere, matto grosso, mayasilotu, Nicaragua ipecac (= Cephaelis acuminata 

(Benth.) Karst.), poaia, raicilla, raizcilla, Rio ipecac (= Cephaelis 

ipecacuanha (Brot.) A. Rich.), togeun (1, 3, 5, 10–13). 


Indigenous to Brazil and Central America (3, 8, 14). 

Description 

Cephaelis ipecacuanha: A low straggling shrub. Underground portion 

consists of a slender rhizome bearing annulated wiry roots and slender 

smooth roots. Rhizome arches upwards and becomes continuous with a 

short, green, aerial stem bearing a few opposite, petiolate, stipulate, entire, 

obovate leaves. Flowers small, white and capitate, occurring in the leaf

axils; corolla infundibuliform. Fruits are clusters of dark purple berries, 

each containing two plano-convex seeds (15). 

Cephaelis acuminata: Resembles Cephaelis ipecacuanha, but has a root 

with less pronounced annulations (15). 




Cephaelis ipecacuanha: Roots somewhat tortuous pieces, from dark 

reddish-brown to very dark brown, seldom more than 15 cm long or 

6 mm thick, closely annulated externally, completely encircled by rounded 

ridges; fracture short in the bark and splintery in the wood. Transversely 

cut surface shows a wide greyish bark and a small uniformly dense 

wood. Rhizome in short lengths usually attached to roots, cylindrical, up 

to 2 mm in diameter, fi nely wrinkled longitudinally, with pith occupying 

approximately one-sixth of the diameter (4, 5). 

Cephaelis acuminata: Roots generally resemble those of Cephaelis ipecacuanha 

but differ in the following particulars: often up to 9 mm thick; 

external surface greyish-brown or reddish-brown with transverse ridges, 

0.5–1.0 mm wide, at intervals of usually 1–3 mm, extending about halfway 

round the circumference and fading at the extremities into the general 

surface level (4, 5). 


Odour: slight, irritating, sternutatory; taste: bitter, nauseous, unpleasant 

(1–4, 6, 9). 


Cephaelis ipecacuanha: Root cork narrow, dark brown, formed of several 

layers of thin-walled cells, usually with brown granular contents; phelloderm 

cortex parenchymatous, containing numerous starch granules, and 

scattered idioblasts with bundles of calcium oxalate raphides; phloem 

very narrow with short wedges of sieve tissues, but no fi bres or sclereids; 

xylem wholly lignifi ed consisting of tracheids, with rounded ends and 

linear pits, narrow vessels with rounded lateral perforations near the ends, 

substitute fi bres with oblique, slit-like pits containing starch grains, a few 

lignifi ed fi bres, and traversed by medullary rays, one or two cells wide, 

lignifi ed, containing starch; primary xylem, three-arched at the centre. 

Rhizome cork has a narrow parenchymatous cortex; endodermis, pericycle 

with thick-walled, pitted and elongated rectangular sclereids; phloem 

with fi bres; xylem radiating with fi bres having linear pits and spiral 

205


vessels in the protoxylem and pith with isodiametric, lignifi ed, thin-walled 

cells. Starch granules, rarely simple, mostly compound with two to eight 

components; individual granules oval, rounded or muller-shaped, 4–10 μm 

but can be up to 15 μm in diameter (1, 3, 4). 

Cephaelis acuminata: Similar to C. ipecacuanha, but starch granules are 

larger, up to 22 μm in diameter (4). 


Cephaelis ipecacuanha: Greyish-brown to light brown; numerous fragments 

of thin-walled parenchymatous cells fi lled with starch granules, 

scattered cells with bundles of raphides of calcium oxalate; a few brown 

fragments of cork; a few fragments of wood showing tracheids, tracheidalvessels 

of fi brous cells with starch granules; calcium oxalate raphides, 

20–80 μm long scattered throughout the powder, sometimes in fragments; 

numerous starch granules, simple or mostly compound with two to eight 

components; individual granules oval, rounded or muller-shaped, up to 

15 μm in diameter. A few vessels and sclereids, and occasional phloem fi - 

bres from the rhizome (1, 3). 

Cephaelis acuminata: Similar to Cephaelis ipecacuanha, but starch grain 

up to 22 μm in diameter (1, 3). 


Macroscopic and microscopic examinations (1–6, 8, 9), microchemical 

tests (1–3, 6, 8, 9), and thin-layer chromatography (4, 5). 

Purity tests 







Total ash 

Not more than 5% (2, 5, 6). 


Not more than 3% (2, 4, 5, 6). 

206







Heavy metals 







Chemical, sulfated ash, water-soluble extractive, alcohol-soluble extractive 

and loss on drying tests to be established in accordance with national 

requirements. 


Contains not less than 2% of total alkaloids calculated as emetine, determined 

by titration (1–5, 9). Assay for emetine and cephaeline by column 

chromatography plus spectrophotometry (9). A high-performance liquid 

chromatography method is also available. 


The major active constituents are isoquinoline alkaloids (1.8–4.0%), with 

emetine and cephaeline accounting for up to 98% of the alkaloids present. 

Content in Cephaelis ipecacuanha: emetine 60–70%, cephaeline 30–40%; 

in Cephaelis acuminata: emetine 30–50%, cephaeline 50–70%. A 30-ml 

dose of ipecac syrup contains approximately 24 mg of emetine and 31 mg 

of cephaeline (18). Other alkaloids of note are psychotrine, O-methylpsychotrine 

and ipecoside (10, 13, 14, 19). Representative structures of 

the alkaloids are presented below. 



A syrup made from the roots is used as an emetic, to empty the stomach 

in cases of poison ingestion (20). 


See Uses supported by clinical data (20). 

207



Treatment of parasites, the common cold and diarrhoea (13). Also to 

stimulate uterine contractions and induce abortion (21). 

Pharmacology 


In vivo studies 

Experimental studies in animals are primarily limited to various investigations 

in dogs. In these studies most of the animals were not anaesthetized; 

however, some were premedicated to prevent spontaneous vomiting. The 

effi cacy of a syrup made from Radix Ipecacuanhae to induce emesis was 

investigated in fasting dogs, pretreated by intramuscular or intravenous 

administration of 25.0 mg of chlorpromazine, 25.0 mg of promethazine 

or 37.5–50.0 mg of promethazine to prevent spontaneous vomiting. The 

pretreatments were administered 30 minutes prior to the oral administration 

of 500.0 mg/kg body weight (bw) of sodium salicylate in tablet form. 

The animals were then given 25.0 ml of a syrup made from the roots. 

When the syrup was administered orally within 30 minutes of the sodium 

salicylate dose, almost 50% of the salicylate was recovered. Administration 

after 30 minutes reduced recovery to 35.9% (22). In dogs, oral administration 

of 5 g of barium sulfate in suspension as a marker was followed 

by intragastric administration of 1.5 ml/kg bw of a syrup made 

from the roots at 0, 30 or 60 minutes. Mean time to emesis was 46 minutes, 

and recovery of the barium was 62%, 44% and 31%, respectively in 

the three groups (23). Fasting puppies were given two gelatin capsules of 

208 

OCH 3 

H 3 CO N 

HO 

H 

N 

CH3 H 

psychotrine R = H 

O-methylpsychotrine 

Glc 

R = CH3 HO 

H2C O 

H 

H 

O 

ipecoside 

N 

H 

H 

H 

O 

O O 

CH3 CH3 O 

R 

OCH 3 

OCH 3 

H 3 CO HN 

H 

N 

cephaeline 

emetine 

H 

H 

H 

CH 3 

R = H 

R = CH3 Glc = 

HO 

HO 

OH 

O 

R 

OCH 3 

O 

OH 

β-D-glucopyranosyl


barium sulfate (1.0 g) as a marker, followed after 20 minutes by intragastric 

administration of 15–30.0 ml of the syrup. Mean time to emesis was 

29 minutes. Only three of the six dogs vomited and emesis resulted in a 

mean recovery of 19% (24). Paracetamol poisoning was induced in fasting 

dogs; drug emesis was 42.2% following intragastric administration of 20.0 

ml of a syrup made from the roots given 10 minutes after the paracetamol 

dose (25). 


In a randomized controlled crossover study, 10 fasting healthy volunteers 

received oral doses of paracetamol (3.0 g total dose), followed after 

60 minutes by oral administration of 30.0 ml of a syrup prepared from the 

roots and 240.0 ml of water. Mean time to fi rst emesis was 25.5 minutes. 

The 8-hour area under the curve for the paracetamol blood level in the 

syrup group was 21% lower than that for the control group (26). 

Oral administration of 30.0 ml of a syrup prepared from the roots and 

250.0 ml of water to 10 volunteers 60 minutes after the oral ingestion of 

5.0 g of ampicillin prevented approximately 38% of the drug from being 

absorbed (P < 0.01). Mean time to emesis was 16 minutes (27). 

In a randomized controlled crossover study, 10 of 12 volunteers were 

each given 24 acetylsalicylic acid tablets (81.0 mg/tablet) with 240.0 ml of 

water following a 12-hour fast. The two control subjects received no treatment. 

After 60 minutes, the volunteers were given 30.0 ml of a syrup prepared 

from the roots and 240.0 ml water; the dose was repeated in three 

subjects who did not vomit within 30 minutes of the initial dose. Time to 

emesis was approximately 30 minutes. Urine was collected for 48 hours. 

The proportion of ingested salicylate recovered in the urine was 96.3% for 

the control group and 70.2% for the treatment group (P < 0.01) (28). 

In a randomized controlled crossover study 12 fasting adults were 

given 20 acetylsalicylic acid tablets (75.0 mg/tablet) with 200.0 ml of water 

followed by 30.0 ml of a syrup prepared from the roots 60 minutes 

later or no further treatment (control group). The mean percentage of 

ingested salicylate recovered in the urine was 60.3% for the control group 

and 55.6% for the treatment group (P < 0.025) (29). 

In a controlled crossover study, oral administration of 1.0 g of 

paracetamol, 500.0 mg of tetracycline and 350.0 mg of a long-acting aminophylline 

preparation to six fasting adults was followed by oral administration 

of 20.0 ml of a syrup prepared from the roots and 300.0 ml of 

water administered either 5 minutes or 30 minutes later. Timed blood 

samples were collected over a 24-hour period. Mean time to onset of emesis 

was 14.3 minutes. For paracetamol, the mean peak serum concentra- 

209


tion was reduced signifi cantly (P < 0.01) to 4.4 mg/l after the administration 

of the syrup after 5 minutes compared with 14.9 mg/l in controls. 

Under these conditions the mean area under the curve was 35% of that in 

controls (P < 0.01). No statistically signifi cant reduction in the mean peak 

serum concentration or mean area under the curve was observed when the 

syrup was given after 30 minutes. For tetracycline, the mean peak serum 

concentration and area under the curve were reduced signifi cantly 

(P < 0.01) in both the 5- and 30-minute treatment groups. For aminophylline, 

the mean peak serum concentration was only reduced signifi - 

cantly (P < 0.05) in the 5-minute group (30). 

In a randomized, controlled crossover trial, oral administration of 20.0 mg 

of metoclopramide to seven fasted adults was followed 60 minutes later by 

oral administration of 400.0 mg of cimetidine and 10.0 mg of pindolol, and 

after a further 5 minutes by 400.0 ml of water or 20.0 ml of a syrup prepared 

from Radix Ipecacuanhae and 400.0 ml of water. Six of the seven subjects 

vomited, with a mean time delay of 17 minutes. The syrup reduced the absorption 

of both cimetidine (25% of that in controls) and pindolol (40% of 

that in controls) as measured by mean peak serum concentrations (31). 

In three investigations, markers were administered to emergency department 

patients presenting with potentially toxic ingestions, and recovery 

of the marker after syrup-induced emesis was measured. In one study, 

14 children received an oral dose of 1.0 g of magnesium hydroxide prior 

to oral administration of 20.0 ml of a syrup prepared from the roots. Mean 

time to emesis was 15 minutes (range 5–41 minutes) and mean recovery of 

magnesium hydroxide was 28% (32). In a similar study, 100 mg of liquid 

thiamine mixed with 30 ml of a syrup prepared from the roots was administered 

to 51 subjects (33). Mean time to emesis was 21 minutes and 

mean recovery of thiamine was 50%. In a randomized, controlled, singleblind 

study, barium-impregnated 3-mm polythene pellets were administered 

with water and 30.0 ml of a syrup prepared from the roots to 

20 patients. Time to emesis was 5–20 minutes. Abdominal X-rays were 

performed 15–80 minutes after ingestion of the pellets. In the syrup group, 

39.3% of the ingested pellets had moved into the small bowel compared 

with 16.3% in the control group (34). 

In a controlled, randomized prospective study, 592 acute oral drug 

overdose patients were evaluated to determine whether a syrup prepared 

from Radix Ipecacuanhae and activated charcoal or lavage and activated 

charcoal were superior to activated charcoal alone. The induction of emesis 

by the syrup before administration of activated charcoal and a cathartic 

(n = 214) did not signifi cantly alter the clinical outcome of patients 

who were awake and alert on presentation compared with those who re- 

210


ceived activated charcoal and a cathartic without the syrup (n = 262). The 

investigators concluded that induction of emesis in acutely poisoned patients 

who were alert and awake was of no benefi t, even when performed 

less than 60 minutes after a toxic ingestion (35). 

A prospective study was conducted to assess the effect of gastric emptying 

and activated charcoal upon clinical outcome in acutely self-poisoned 

patients. Presumed overdose patients (n = 808) were treated using 

an alternate-day protocol based on a 10-question cognitive function examination 

and presenting vital-sign parameters. Asymptomatic patients 

(n = 451) did not undergo gastric emptying. Activated charcoal was administered 

to asymptomatic patients only on even days. Gastric emptying 

in the remaining symptomatic patients (n = 357) was performed only on 

even days. On emptying days, alert patients had ipecac-induced emesis 

while obtunded patients underwent gastric lavage. Activated charcoal 

therapy followed gastric emptying. On non-emptying days, symptomatic 

patients were treated only with activated charcoal. No clinical deterioration 

occurred in the asymptomatic patients treated without gastric emptying. 

Use of activated charcoal did not alter outcome measures in asymptomatic 

patients. Gastric emptying procedures in symptomatic patients 

did not signifi cantly alter the duration of stay in the emergency department, 

mean duration of intubation, or mean duration of stay in the intensive 

care unit. Gastric lavage was associated with a higher prevalence of 

medical intensive care unit admissions (P = 0.0001) and aspiration pneumonia 

(P = 0.0001). The data support the management of selected acute 

overdose patients without gastric emptying and fail to show a benefi t from 

treatment with activated charcoal in asymptomatic overdose patients (36). 

A prospective, randomized, unblinded, controlled trial was conducted 

to determine the effect of a syrup of the roots on the time to administration 

and duration of retention of activated charcoal, and on total duration of 

emergency department stay. The study involved 70 children less than 6 years 

old, who presented with mild–moderate acute oral poison ingestions. The 

children were divided into two groups, group 1 received the syrup before 

activated charcoal and group 2 received only activated charcoal. Duration 

from arrival to administration of activated charcoal was signifi cantly longer 

in group 1 (2.6 h compared with 0.9 h, P < 0.0001) and group 1 children 

were signifi cantly more likely to vomit activated charcoal (18 of 32 compared 

with 6 of 38, P < 0.001). Patients receiving the syrup who were subsequently 

discharged spent signifi cantly more time in the emergency department 

than those receiving only activated charcoal (4.1 ± 0.2 h compared 

with 3.4 ± 0.2 h, P < 0.05). It was concluded that administration of the syrup 

delays the administration of activated charcoal, hinders its retention, and 

211


prolongs the emergency department stay in paediatric ingestion patients 

(37). In a prospective randomized controlled trial, 876 patients were assessed 

on presentation to an emergency room after ingestion of a toxic substance. 

On odd-numbered days, the patients received 30–50 ml of syrup 

prepared from the roots followed by 200 ml of water, or gastric lavage followed 

by activated charcoal. On even-numbered days, no gastric emptying 

was performed and patients received 50 g of activated charcoal alone. No 

signifi cant differences between the treatments were observed; syrup plus 

activated charcoal was not superior to activated charcoal alone (38). 

A comparison study assessed the difference between early and late administration 

of ipecac syrup on paracetamol plasma concentrations. A 

total of 50 children under the age of 5 years with accidental ingestion of 

150.0 mg/kg bw of paracetamol received ipecac syrup within 4 hours of 

ingestion: 23 received ipecac at home (mean time to administration 

26 minutes after paracetamol ingestion) and had measured plasma 

paracetamol concentrations of 23.0 mg/l; 27 children received ipecac syrup 

elsewhere (i.e. not at home; mean time to administration, 83 min) and 

had measured plasma paracetamol concentrations of 44.0 mg/l. The investigators 

concluded that the shorter the time between ingestion of 

paracetamol and the administration of ipecac, the more effective ipecac 

was in reducing plasma paracetamol concentrations (39). 

The rates of absorption and elimination of emetine and cephaeline 

from a syrup prepared from the roots were investigated in 10 healthy 

adults. Volunteers received an oral dose of 30 ml of the syrup and urine 

and blood samples were collected up to 180 minutes following ingestion. 

In all subjects emetine and cephaeline were detected in the blood 

5–10 minutes after dosing, with maximum concentrations observed after 

20 minutes. The mean areas under the curve were similar for both 

compounds. Less than 0.15% of the administered emetine and cephaeline 

doses was recovered in the urine at 3 hours. There was no relation 

between peak vomiting episodes and blood levels of emetine and cephaeline. 

At 3 hours neither alkaloid was detectable in the blood (40). 

The roots act as an emetic because of their local irritant effect on the 

digestive tract and its effect on the chemoreceptor trigger zone in the area 

postrema of the medulla (41). Charcoal should not be administered with 

syrup prepared from the roots, because charcoal can absorb the syrup and 

reduce the emetic effect. 


Large doses of Radix Ipecacuanhae have an irritant effect on the gastrointestinal 

tract, and may induce persistent bloody vomiting or diarrhoea 

212


(20). Mucosal erosions of the entire gastrointestinal tract have been reported. 

The absorption of emetine, which may occur if vomiting is not 

induced, may give rise to adverse effects on the heart, such as conduction 

abnormalities or myocardial infarction. These, in combination with dehydration, 

may cause vasomotor collapse followed by death. Chronic 

abuse of the roots to induce vomiting in eating disorders has been implicated 

in the diagnosis of cardiotoxicity and myopathy due to the accumulation 

of emetine (20). Adverse effects of repeated vomiting, such as metabolic 

complications, aspiration pneumonitis, parotid enlargement, dental 

abnormalities, and oesophagitis or haematemesis due to mucosal lacerations 

may be observed (20). Cardiovascular toxicity, manifesting as muscle 

weakness, hypotension, palpitations and arrhythmias, may occur (42, 

43). Death was reported for one subject who had ingested 90–120 ml of a 

syrup prepared from the roots per day for 3 months (44). 

Prolonged vomiting has been reported in 17% of patients given the 

roots for the treatment of poisoning, which may lead to gastric rupture, 

Mallory-Weiss lesions of the oesophagogastric junction, cerebrovascular 

events, pneumomediastinum and pneumoperitoneum (45). 

Allergy to the roots was reported after inhalation of powdered roots, 

characterized by rhinitis, conjunctivitis and chest tightness (46). 

There have been a number of deaths reported in small children due to 

an overdose owing to the substitution of 10.0–60.0 ml of a fl uidextract of 

the roots for a syrup prepared from the roots (18, 47, 48). It is believed 

that the fl uidextract was mistaken for the syrup. The fl uidextract is 

14 times more potent than the syrup (20). 

Other adverse reactions to the roots include severe diarrhoea, nausea 

and abdominal cramps (49). 


While emesis is usually indicated after poisoning resulting from oral ingestion 

of most chemicals, emesis induced by Radix Ipecacuanhae is contraindicated 

in the following specifi c situations: following ingestion of a corrosive 

poison, such as strong acid or alkali; when airway-protective 

refl exes are compromised, for example in patients who are comatose or in 

a state of stupor or delirium; following ingestion of a central nervous system 

stimulant, when vomiting may induce convulsions; in cases of strychnine 

poisoning; or following ingestion of a petroleum distillate (18, 41). 

Radix Ipecacuanhae has been used as an abortifacient in traditional medicine 

and its use is therefore contraindicated during pregnancy. See also 

Warnings, and Precautions. 

213


Warnings 

Numerous deaths have occurred owing to the administration of a fl uidextract 

of Radix Ipecacuanhae instead of a syrup prepared from the roots. 

The fl uidextract is 14 times stronger than the syrup and should never be 

administered as a substitute for the syrup. 

Precautions 

General 

Radix Ipecacuanhae should not be used as an emetic in patients whose 

condition increases the risk of aspiration or in patients who have taken 

substances that are corrosive or petroleum products that may be dangerous 

if aspirated (20). The roots should not be given to patients in shock, 

at risk of seizure, or with cardiovascular disorders (20). 


The emetic action of the roots may be delayed or diminished if given with 

or after charcoal. Concomitant administration of milk was believed to 

reduce the effi ciency of emesis induced by the roots. However, no signifi 

cant differences in the time to onset of vomiting, the duration of vomiting, 

or the number of episodes were observed in 250 children who were 

given a syrup prepared from the roots with milk compared with 250 children 

given the syrup with clear fl uids (50). 

Decreases in the absorption of paracetamol, tetracycline and aminophylline 

were observed after concomitant administration of 20.0 ml of an 

aqueous extract of the roots (30, 51). 


An aqueous extract of the roots, 50.0 μg/ml, was not mutagenic in the 

Salmonella/microsome assay in S. typhimurium strains TA98 and TA100 

(52). The mutagenicity of a fl uidextract of the roots was evaluated in the 

Salmonella/microsome assay, the chromosomal aberration test in cultured 

Chinese hamster lung cells and the mouse bone marrow micronucleus 

test (oral administration). No mutagenic effects were observed (53). 




Do not exceed recommended doses. Do not give the fl uidextract to children. 

For children up to 6 months of age, the syrup should only be administered 

under the supervision of a physician (18). 

214




test interactions; teratogenic effects during pregnancy; or nursing mothers. 

Dosage forms 

Dried roots and rhizomes, liquid extracts, fl uidextract, syrup and tincture 

(20). Dried roots and rhizomes should be stored in a tightly sealed container, 


Posology 


As an emetic in cases of poisoning other than corrosive or petroleumbased 

products. Doses should be followed by ingestion of copious volumes 

of water. Doses may be repeated once, 20–30 minutes after the initial 

administration, if emesis has not occurred (20). Adults: Ipecac Syrup, 

15–30 ml (21–42 mg total alkaloids). Children: 6 months–1 year, 7–14 mg 

of total alkaloids (5–10 ml) of Ipecac Syrup; older children, 21 mg of total 

alkaloids represented in 15 ml Ipecac Syrup (9). 

References 



2. Asian crude drugs, their preparations and specifi cations. Asian Pharmacopeia. 


3. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African 

Unity, Scientifi c, Technical and Research Commission, 1985. 

4. The international pharmacopoeia. Vol. 3, 3rd ed., Geneva, World Health 






1998. 





9. The United States pharmacopeia-national formulary, 19th ed. Rockville, 

MD, United States Pharmacopeial Convention, 2000. 




215





12. Robbers JE, Speedie MK, Tyler VE. Pharmacognosy and pharmacobiotechnology. 

Baltimore, MD, Williams and Wilkins, 1996. 






Press, 1994. 








Switzerland). 

18. American Academy of Clinical Toxicology. Position statement: ipecac syrup. 

Clinical Toxicology, 1997, 35:699–709. 



20. Parfi tt K, ed. Martindale. The complete drug reference, 32nd ed. London, 

The Pharmaceutical Press, 1999. 

21. Gonzalez F, Silva M. A survey of plants with antifertility properties described 

in the South American folk medicine. In: Proceedings of the Princess Congress 

on Natural Products, Bangkok, Thailand, December 10–13, 1987. 

22. Arnold FJ et al. Evaluation of the effi cacy of lavage and induced emesis in 

treatment of salicylate poisoning. Pediatrics, 1959, 23:286–301. 

23. Abdallah AH, Tye A. A comparison of the effi cacy of emetic drugs and 

stomach lavage. American Journal of Diseases of Childhood, 1967,113:571– 

575. 

24. Corby DO et al. The effi ciency of methods used to evacuate the stomach 

after acute ingestions. Pediatrics, 1967, 40:871–874. 

25. Teshima D et al. Effi cacy of emetic and United States Pharmacopoeia ipecac 

syrup in prevention of drug absorption. Chemical and Pharmaceutical 

Bulletin, 1990, 38:2242–2245. 

26. McNamara RM et al. Effi cacy of charcoal cathartic versus ipecac in reducing 

serum acetaminophen in a simulated overdose. Annals of Emergency Medicine, 

1989, 18:934–938. 

27. Tenenbein M, Cohen S, Sitar DS. Effi cacy of ipecac-induced emesis, orogastric 

lavage, and activated charcoal for acute drug overdose. Annals of Emergency 

Medicine, 1987, 16:838–841. 

216


28. Curtis RA, Barone J, Giacona N. Effi cacy of ipecac and activated charcoal/ 

cathartic. Prevention of salicylate absorption in a simulated overdose. 

Archives of Internal Medicine, 1984, 144:48–52. 

29. Danel V, Henry JA, Glucksman E. Activated charcoal, emesis, and gastric 

lavage in aspirin overdose. British Medical Journal, 1988, 296:1507. 

30. Neuvonen PJ, Vartiainen M, Tokola O. Comparison of activated charcoal 

and ipecac syrup in prevention of drug absorption. European Journal of 

Clinical Pharmacology, 1983, 24:557–562. 

31. Neuvonen PJ, Olkkola KT. Activated charcoal and syrup of ipecac in prevention 

of cimetidine and pindolol absorption in man after administration of 

metoclopramide as an antiemetic agent. Journal of Toxicology. Clinical Toxicology, 

1984, 22:103–114. 

32. Corby DO et al. Clinical comparison of pharmacologic emetics in children. 

Pediatrics, 1968, 42:361–364. 

33. Auerbach PS et al. Effi cacy of gastric emptying: gastric lavage versus emesis 

induced with ipecac. Annals of Emergency Medicine, 1986, 15:692–698. 

34. Saetta JP et al. Gastric emptying procedures in the self-poisoned patient: are 

we forcing gastric content beyond the pylorus? Journal of the Royal Society 

of Medicine, 1991, 84:274–276. 

35. Kulig K et al. Management of acutely poisoned patients without gastric emptying. 

Annals of Emergency Medicine, 1985, 14:562–567. 

36. Merigian KS et al. Prospective evaluation of gastric emptying in the selfpoisoned 

patient. American Journal of Emergency Medicine, 1990, 8:479– 

483. 

37. Kornberg AE, Dolgin J. Pediatric ingestions: charcoal alone versus ipecac 

and charcoal. Annals of Emergency Medicine, 1991, 20:648–651. 

38. Pond SM et al. Gastric emptying in acute overdose: a prospective randomized 

controlled trial. Medical Journal of Australia, 1995, 163:345–349. 

39. Amitai Y et al. Ipecac-induced emesis and reduction of plasma concentrations 

of drugs following accidental overdose in children. Pediatrics, 

1987:80:364–367. 

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Drug Monitoring, 2000, 22:566–573. 

41. Hardman JG et al., eds. Goodman & Gilman’s: the pharmacological basis of 

therapeutics. 9th ed. New York, NY, McGraw-Hill, 1996. 

42. Murphy DH. Anatomy of ipecac misuse: three case studies. American Pharmacy, 

1985, 25:24–28. 

43. Ho PC, Dweik R, Cohen MC. Rapidly reversible cardiomyopathy associated 

with chronic ipecac ingestion. Clinical Cardiology, 1998, 21:780–783. 

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American Medical Association, 1980, 243:1927–1928. 

45. Bateman DN. Adverse reactions to antidotes. Adverse Drug Reaction Bulletin, 

1988, 133:496–499. 

46. Luczynska CM et al. Occupational allergy due to inhalation of ipecacuanha 

dust. Clinical Allergy, 1984, 14:169–175. 

217


47. Decker WJ. In quest of emesis: fact, fable, and fancy. Clinical Toxicology, 

1971, 4:383–387. 

48. Rose NJ. Report of accidental poisoning death from a fl uidextract of ipecac. 

Illinois Medical Journal, 1970, 137:338. 

49. Manno BR, Manno JE. Toxicology of ipecac: a review. Clinical Toxicology, 

1977, 10:221–242. 

50. Klein-Schwartz W et al. The effect of milk on ipecac-induced emesis. Journal 

of Toxicology. Clinical Toxicology, 1991, 29:505–511. 

51. Saincher A, Sitar DS, Tenenbein M. Effi cacy of ipecac during the fi rst hour 

after drug ingestion in human volunteers. Journal of Toxicology. Clinical 

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218

Aetheroleum Lavandulae 

Defi nition 

Aetheroleum Lavandulae consists of the essential oil obtained by steam 

distillation from the fresh fl owering tops of Lavandula angustifolia Mill. 

or of L. intermedia Loisel (Lamiaceae) (1–4). 

Synonyms 

Lavandula offi cinalis Chaix, L. spica Loisel., L. vera DC., L. vulgaris 

Lam. (5–8). Lamiaceae are also known as Labiatae. In most formularies 

and older reference books, Lavandula offi cinalis Chaix is regarded as the 

correct species name. However, according to the International Rules of 

Botanical Nomenclature, Lavendula angustifolia Mill. is the legitimate 

name for the species (8, 9). 


Al birri, alhucema, arva neh, aspic, broad-leaved lavenda, common lavender, 

Echter Lavendel, English lavender, espi, espic, espliego commún, fi rigla, 

frigous, garden lavendar, grando, hanan, hanene, hzama, khazama, 

khirii, khouzamaa, khouzami, khuzama, khuzama fassiya, khuzama zerqua, 

Kleiner Speik, Lavanda, lavande, lavande femelle, lavande véritable, 

lavando, lavandula vraie, Lavendel, lavender, lawanda, lófi nda, ostoghodous, 

postokhodous, spigandos, true lavender (6, 8–14). 


Indigenous to the northern Mediterranean region. Cultivated in southern 

Europe, and in Bulgaria, Russian Federation, United States of America, 

and the former Yugoslavia (8, 15). 

Description 

An aromatic shrub, 1–2 m high. Branches grey-brown to dark brown 

with long fl owering and short leafy shoots, bark longitudinally peeling. 

Leaves clustered on leafy shoots, widely spaced on fl owering shoots; petiole 

very short; blade linear-lanceolate to linear, 17 mm long, 2 mm wide 

219


on leafy shoots, 2–6 cm long, 3–6 mm wide on fl owering shoots; grey 

stellate tomentose, base attenuate, margin entire, revolute, apex obtuse. 

Infl orescence a crowded, interrupted or nearly continuous spike, 2–8 cm 

long; verticillasters numerous, with 6–10 fl owers, upper ones densely 

crowded; peduncle about three times longer than the spike; bracts papery, 

rhombic-ovate, 3–8 mm long, rust coloured when dry; bracteoles absent 

or up to 2.5 mm long, pedicel 1.0–1.5 mm long; calyx 4–7 mm long, 

densely grey stellate tomentose outside, with 13 longitudinal ribs, upper 

lip entire, appendage obcordate, lower lip four-toothed; corolla 10–12 mm 

long, blue, base subglabrous, throat and limb glandular hairy, upper lips 

straight, lower lips spreading. Nutlets narrowly cylindrical (8). 

Plant material of interest: essential oil 


A clear colourless or pale yellow liquid, miscible with 90% alcohol, ether 

and fatty oils (1–4). 


Odour: characteristic, fragrant, aromatic; taste: aromatic, slightly bitter 

(1, 3). 






Macroscopic examinations (1, 3, 4); refractive index, specifi c gravity and 

optical rotation measurements (2); thin-layer chromatography for the 

presence of linalyl acetate and linalool (4), and gas chromatography (4). 

Purity tests 





Chemical 

Relative density 0.878–0.892 (4). Refractive index 1.455–1.466 (4). Optical 

rotation -12.5–7 o (4). Acid value not more than 1.0 (4). 

220






Heavy metals 







Tests for foreign organic matter, total ash and acid-insoluble ash not applicable. 

Tests for water-soluble extractive and acid-soluble extractive to 

be established in accordance with national requirements. 


Offi cial analysis by gas chromatography shows the following composition: 

limonene, cineole, 3-octanone, camphor, linalool, linalyl acetate, terpinen-4-ol, 

lavandulyl acetate, lavandulol, α-terpineol (4). 


Contains: linalyl acetate (25–46%), linalool (20–45%), terpinen-4-ol (1.2– 

6.0%), lavendulyl acetate (> 1.0%), 1,8-cineole (1,8-cineol, cineol, cineole, 

eucalyptol) (< 2.5%), 3-octanone (< 2.5%), camphor (< 1.2%), limonene 

(< 1.0%), and α-terpineol (< 2.0%) (4). The structures of linalyl acetate 

and linalool are presented below. 

H 3C 

CH 3 

O 

R 


CH3 CH2 Aetheroleum Lavandulae 

linalool R = H 

linalyl acetate R = CO-CH3 Medicinal uses 


Inhalation therapy for symptomatic treatment of anxiety, restlessness and 

to induce relaxation (19–22). Externally in balneotherapy for the treatment 

of circulation disorders (23). 

221



Symptomatic treatment of insomnia, and as a carminative for the treatment 

of gastrointestinal disorders of nervous origin (15, 24). 


Orally as a cholagogue, diuretic and emmenagogue; externally for the 

treatment of burns, diarrhoea, headaches, sore throats and wounds (15). 

Pharmacology 


Anaesthetic activity 

In vitro, the essential oil, linalyl acetate and linalool, 0.01–10.0 μg/ml in 

the bath medium, reduced electrically-evoked contractions of a rat phrenichemidiaphragm 

(25). In the rabbit conjunctiva test in vivo, administration 

of an aqueous solution of the essential oil, linalyl acetate or linalool, 30.0– 

2500.0 μg/ml, into the conjunctival sac increased the number of stimuli 

needed to provoke the refl ex (25). 

Anticonvulsant and sedative activities 

Intraperitoneal administration of 2.5 g/kg body weight (bw) of linalool to 

rodents protected against convulsions induced by pentylenetetrazole, 

picrotoxin and electroshock (26, 27). In mice, intraperitoneal administration 

of 2.5 g/kg bw of linalool interfered with glutamate function and 

delayed N-methyl-d-aspartate-induced convulsions (28). Linalool acts as 

a competitive antagonist of [ 3 H]-glutamate binding and as a noncompetitive 

antagonist of [ 3 H]-dizocilpine binding in mouse cortical 

membranes, suggesting interference of glutamatergic transmission. The 

effects of linalool on [ 3 H]-glutamate uptake and release in mouse cortical 

synaptosomes were investigated. Linalool reduced potassium-stimulated 

glutamate release (29). These data suggest that linalool interferes with 

elements of the excitatory glutamatergic transmission system. 


The effect of Aetheroleum Lavandulae on immediate-type allergic reactions 

was investigated in vitro and in vivo. External and intradermal administration 

of aqueous dilutions of the essential oil, 1:500, 1:100, 1:10, 

1:1 and 1:0, to mice inhibited mast cell-dependent ear oedema induced by 

compound 48/80 (30). Administration of the essential oil (same dose 

range) to rats inhibited passive cutaneous anaphylaxis induced by antidinitrophenyl 

(DNP) IgE, compound 48/80-induced histamine release 

and anti-DNP IgE-induced tumour necrosis factor-α secretion from peritoneal 

mast cells (30). Inhalation of 0.3 ml of the essential oil inhibited 

222


thromboxane B 2 release induced by arachidonic acid in mice, suggesting 

an anti-infl ammatory effect (31). 

Antimicrobial and acaricidal activities 

The undiluted essential oil inhibited the growth of Bacillus subtilis, Escherichia 

coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus 

pneumoniae in vitro (32, 33). The undiluted essential oil, 10.0 μl/ 

disc, inhibited the growth of Mycobacterium chelonae, M. fortuitum, 

M. kansasii, M. marinum and M. scrofulaceum (34). The undiluted essential 

oil inhibited the growth of fi lamentous fungi in vitro (35). The essential 

oil, linalool, linalyl acetate and camphor had miticidal activity against 

Psoroptes cuniculi in rabbits (36). 


Addition of the essential oil to the bath medium, 0.02 mg/ml and 0.2 mg/ 

ml, reduced the twitching response and relaxed the muscle tone of rat 

phrenic nerve diaphragm preparations in vitro (37). The antispasmodic 

activity of the essential oil and linalool was mediated through the cyclic 

adenosine monophosphate signal transduction system, determined using 

a guinea-pig ileum smooth muscle preparation (38). 

Central nervous system depressant effects 

Inhalation of the essential oil (dose not specifi ed) by mice reduced 

caffeine-induced hyperactivity, which was correlated with linalool serum 

levels (39). Intragastric administration of the essential oil (dose not specifi 

ed) to rats produced anxiolytic effects and prolonged pentobarbital 

sleeping time (40). 

Intragastric administration of 1.6 g/kg bw of the essential oil increased 

the lever-pressing response rate during the alarm phase of the Geller-type 

confl ict test in animals, suggesting that the oil had an anticonfl ict effect 

similar to that of diazepam (41). Intragastric administration of 25.0 ml/kg 

bw of the essential oil, diluted 60 times in olive oil, prolonged pentobarbital 

sleeping times in mice (42). Inhalation of 0.3 ml of the essential oil 

inhibited strychnine-induced convulsions in mice (31). 


Anxiolytic activity 

In a comparison clinical trial without placebo, 40 healthy volunteers received 

aromatherapy (inhalation) with Aetheroleum Lavandulae or essential 

oil of rosemary (Rosmarinus offi cinalis) and were then asked to perform 

some simple mathematical computations. In the group treated with 

Aetheroleum Lavandulae, the electroencephalogram showed an increase in 

beta power, suggesting increased drowsiness. The subjects treated with this 

223


oil also reported feeling less depressed and more relaxed, and performed 

the mathematical computation more accurately after the therapy (20). 

In an uncontrolled trial in 13 healthy volunteers, inhalation of Aetheroleum 

Lavandulae signifi cantly (P < 0.001) decreased alpha-1 frequencies 

(8–10 Hertz) shortly after inhalation, and the subjects reported feeling 

“comfortable” in a subjective evaluation of the treatment (22). 

In a randomized study involving 122 patients admitted to a general 

intensive care unit, patients received either massage, aromatherapy with 

the oil (1% essential oil in grapeseed oil; 1–3 treatments over a 5-day period) 

or a period of rest to assess the effi cacy of these factors on the stress 

response and anxiety. No difference between the three therapies was observed 

for the stress response. However, patients treated with the oil aromatherapy 

reported improvements in mood and a reduction of anxiety 

(19). 

In 14 patients on chronic haemodialysis, inhalation of the essential oil 

over a one-week period decreased the mean score in the Hamilton anxiety 

rating scale compared with controls undergoing inhalation of odourless 

substances (21). 

Analgesic activity 

In a preliminary clinical trial without controls, addition of six drops of 

the essential oil to bath water daily for 10 days following childbirth did 

not reduce the incidence of perineal discomfort except for the period between 

days 3 and 5 postpartum (43). In a single-blind randomized clinical 

trial in 635 postpartum women, subjects were given pure Aetheroleum 

Lavandulae, synthetic lavender oil or an inert oil to use as a bath additive 

for 10 days postpartum. No difference between the therapies in the reduction 

of perineal discomfort was observed (44). 


In a randomized crossover controlled study, healthy volunteers (number 

not specifi ed) sat with their feet soaking in hot water for 10 minutes with 

or without the addition of the oil. Electrocardiogram, fi ngertip blood 

fl ow and respiration rate measurements indicated that treatment with the 

oil increased parasympathetic nerve activity and increased blood fl ow but 

had no effects on heart or respiratory rates (23). 


Allergic contact dermatitis has been reported in patients previously exposed 

to the essential oil (45–49). 

224


Aetheroleum Lavandulae is contraindicated in cases of known allergy to 

the plant material. Owing to its traditional use as an emmenagogue and 

abortifacient, the essential oil should not be used internally during pregnancy 

(50–52). 

Warnings 

Essential oils should be used with caution in children. Keep out of the 

reach of children. 

Precautions 





Owing to a lack of safety data, the essential oil should be administered 



Owing to a lack of safety data, the essential oil should be administered 




drug interactions; drug and laboratory test interactions; carcinogenesis, 

mutagenesis, impairment of fertility; or teratogenic effects during 

pregnancy. 

Dosage forms 

Essential oil (15). Store in a well-closed container, in a cool, dry place, 


Posology 


Essential oil by inhalation, 0.06–0.2 ml three times per day (7); internally, 

1–4 drops (approximately 20–80.0 mg) on a sugar cube per day (24). 

225


References 



2. Ekstra Farmakope Indonesia. Jakarta, Departemen Kesehatan, Republik 

Indonesia, 1974. 




Europe, 2000. 

5. Chiej R. Encyclopedia of medicinal plants, 2nd ed. Rome, MacDonald, 1984. 


Scientifi c Technical and Research Commission, 1985. 


1996. 

8. Oyen LPA, Nguyen XD, eds. Plant resources of South-east Asia, No. 19. 

Essential-oil plants. Bogor, PROSEA, 1999. 






1959. 




12. Bellakhdar J et al. Repertory of standard herbal drugs in the Moroccan pharmacopoeia. 

Journal of Ethnopharmacology, 1991, 35:123–143. 


drugs of Unani medicine – part III. New Delhi, Ministry of Health and Family 







Press, 1994. 







Switzerland). 

226


19. Dunn C, Sleep J, Collett D. Sensing an improvement: an experimental study 

to evaluate the use of aromatherapy, massage and periods of rest in an intensive 

care unit. Journal of Advanced Nursing, 1995, 21:34–40. 

20. Diego MA et al. Aromatherapy positively affects mood, EEG patterns of 

alertness and math computations. International Journal of Neuroscience, 

1998, 96:217–224. 

21. Itai T et al. Psychological effects of aromatherapy on chronic hemodialysis 

patients. Psychiatry and Clinical Neurosciences, 2000, 54:393–397. 

22. Masago R et al. Effect of inhalation of essential oils on EEG activity and 

sensory evaluation. Journal of Physiological Anthropology and Applied Human 

Science, 2000, 19:35–42. 

23. Saeki Y. The effect of foot-bath with or without the essential oil of lavender 

on the autonomic nervous system: a randomized trial. Complementary Therapies 

in Medicine, 2000, 8:2–7. 



25. Ghelardini C et al. Local anaesthetic activity of the essential oil of Lavandula 

angustifolia. Planta Medica, 1999, 65:700–703. 


414. 


on glutamate-related seizure models. Phytomedicine, 1999, 6:107–113. 

28. Silva Brum LF, Elisabetsky E, Souza D. Effects of linalool on [ 3 H] MK801 

and [ 3 H] muscimol binding in mice cortical membranes. Phytotherapy Research, 

2001, 15:422–425. 



30. Kim HM, Cho SH. Lavender oil inhibits immediate-type allergic reaction in 

mice and rats. Journal of Pharmacy and Pharmacology, 1999, 51:221–226. 

31. Yamada K, Mimaki Y, Sashida Y. Anticonvulsive effects of inhaling lavender 

oil vapour. Biological and Pharmaceutical Bulletin, 1994,17:359–360. 

32. Ross SA, El-Keltawi NE, Megalla SE. Antimicrobial activity of some Egyptian 

aromatic plants. Fitoterapia, 1980, 51:201–205. 



1986, 8:289–292. 

34. Gabbrielli G et al. Activity of lavandino essential oil against non-tubercular 

opportunistic rapid growth mycobacteria. Pharmacological research communications, 

1988, 20(Suppl):37–40. 

35. Larrondo JV, Agut M, Calvo-Torras MA. Antimicrobial activity of essences 

from labiates. Microbios, 1995, 82:171–172. 

36. Perrucci S et al. Acaricidal agents of natural origin against Psoroptes cuniculi. 

Parassitologia, 1994, 36:269–271. 

227


37. Lis-Balchin M, Hart S. A preliminary study of the effect of essential oils on 

skeletal and smooth muscle in vitro. Journal of Ethnopharmacology, 1997, 

58:183–187. 

38. Lis-Balchin M, Hart S. Studies on the mode of action of the essential oil of 

lavender (Lavandula angustifolia P. Miller). Phytotherapy Research, 1999, 

13:540–542. 

39. Buchbauer G et al. Aromatherapy: evidence for sedative effects of the essential 

oil after inhalation. Zeitschrift für Naturforschung, 1991, 46:1067–1072. 

40. Delaveau P et al. Sur les propriétés neuro-depressives de l’huile essentielle de 

lavande. [On the neurodepressant properties of essential oil of lavender.] 

Comptes Rendus des Séances de la Societé de Biologie et de ses Filiales, 1989, 

183:342–348. 

41. Umezu T. Behavioral effects of plant-derived essential oils in the Geller type 

confl ict test in mice. Japanese Journal of Pharmacology, 2000, 83:150–153. 

42. Guillemain J, Rousseau A, Deleveau P. Effets neurodepresseurs de l’huile essentielle 

de Lavandula angustifolia Mill. [Neurodepressive effects of essential 

oil of Lavandula angustifolia Mill.] Annales Pharmaceutiques Françaises, 

1989, 47:337–343. 

43. Cornwell S, Dale A. Lavender oil and perineal repair. Modern Midwife, 1995, 

5:31–33. 

44. Dale A, Cornwell S. The role of lavender oil in relieving perineal discomfort 

following childbirth: a blind randomized clinical trial. Journal of Advances in 

Nursing, 1994, 19:89–96. 

45. Rademaker M. Allergic contact dermatitis from lavender fragrance in Diffl 

am gel. Contact Dermatitis, 1994, 31:58–59. 

46. Schaller M, Korting HC. Allergic airborne contact dermatitis from essential 

oils used in aromatherapy. Clinical and Experimental Dermatology, 1995, 

20:143–145. 

47. Coulson IH, Khan AS. Facial ‘pillow’ dermatitis due to lavender oil allergy. 


48. Sugiura M et al. Results of patch testing with lavender oil in Japan. Contact 

Dermatitis, 2000, 43:157–160. 

49. Varma S et al. Combined contact allergy to tea tree oil and lavender oil complicating 

chronic vulvovaginitis. Contact Dermatitis, 2000, 42:309–310. 

50. Superbi C, Crispolti E. Ricerche intorno all’azione esercitata sulla muscolatura 

uterina da infusi ed estratti di alcune erbe in uso fra gli indigeni della 

Tripolitania. [Effect on the uterine muscle of infusions and extracts of certain 

herbs used by the natives of Tripoli.] Annali di ostetricia e ginecologia, 1935, 

57:253–267. 

51. Hafez ESE. Abortifacients in primitive societies and in experimental animal 

models. In: Hafez ESE, ed. Contraceptive delivery systems. Lancaster, MTP 

Press, 1982. 

52. San Martin AJ. Medicinal plants in central Chile. Economic Botany, 1983, 

37:216–227. 

228

Flos Lavandulae 

Defi nition 

Flos Lavandulae consists of the dried fl owers of Lavandula angustifolia 

Mill. (Lamiaceae) (1–3). 

Synonyms 

Lavandula offi cinalis Chaix, L. spica Loisel., L. vera DC, L. vulgaris Lam. 

(1, 4, 5). Lamiaceae are also known as Labiatae. In most formularies and 

older reference books, Lavandula offi cinalis Chaix is regarded as the correct 

species name. However, according to the International Rules of Botanical 

Nomenclature, Lavandula angustifolia Mill. is the legitimate name 

for the species (5, 6). 


Al birri, alhucema, arva neh, aspic, broad-leaved lavenda, common lavender, 

Echter Lavendel, English lavender, espi, espic, espliego commún, fi rigla, 

frigous, garden lavendar, grando, hanan, hanene, hzama, khazama, 

khirii, khouzamaa, khouzami, khuzama, khuzama fassiya, khuzama zerqua, 

Kleiner Speik, Lavanda, lavande, lavande femelle, lavande véritable, 

lavando, lavandula vraie, Lavendel, lavender, lawanda, lófi nda, ostoghodous, 

postokhodous, spigandos, true lavender (1, 2, 5–9). 


Indigenous to the northern Mediterranean region. Cultivated in southern 

Europe and in Bulgaria, Russian Federation, United States of America 

and the former Yugoslavia (5, 10). 

Description 

An aromatic shrub, 1–2 m high. Branches grey-brown to dark brown 

with long fl owering and short leafy shoots, bark longitudinally peeling. 

Leaves clustered on leafy shoots, widely spaced on fl owering shoots; petiole 

very short; blade linear-lanceolate to linear, 17 mm long, 2 mm wide 

on leafy shoots, 2–6 cm long, 3–6 mm wide on fl owering shoots; grey 

229


stellate tomentose, base attenuate, margin entire, revolute, apex obtuse. 

Infl orescence a crowded, interrupted or nearly continuous spike, 2–8 cm 

long; verticillasters numerous, with 6–10 fl owers, upper ones densely 

crowded; peduncle about three times longer than the spike; bracts papery, 

rhombic-ovate, 3–8 mm long, rust coloured when dry; bracteoles absent 

or up to 2.5 mm long, pedicel 1.0–1.5 mm long; calyx 4–7 mm long, 

densely grey stellate tomentose outside, with 13 longitudinal ribs, upper 

lip entire, appendage obcordate, lower lip four-toothed; corolla 10–12 mm 

long, blue, base subglabrous, throat and limb glandular hairy, upper lips 

straight, lower lips spreading. Nutlets narrowly cylindrical (5). 

Plant material of interest: dried fl owers 


Consists mainly of tubular-ovoid, ribbed, bluish-grey calices with fi ve 

teeth, four of which are short, while the fi fth forms an oval or cordate 

projecting lip. Petals, much crumpled, are fused into a tube with a lower 

lip consisting of three small lobes and an upper lip comprising two larger 

erect lobes; the colour varies from deep bluish grey to a discoloured 

brown. Corolla contains four stamens and a superior ovary (10). 


Odour: fragrant, aromatic; taste: aromatic, bitter, somewhat camphoraceous 

(1, 2). 


Calyx and corolla bear glandular hairs with a very short unicellular stalk 

and a head of four to eight cells, of a labiaceous type, and characteristic 

branching unicellular and multicellular non-glandular hairs with pointed 

ends and a somewhat streaked or warty cuticle. Corolla bears also, on the 

inner surface at the throat, characteristic glandular hairs with a unicellular, 

glandular head and a bicellular stalk, its basal cell being long and knotted 

and the other cell short and cylindrical. Anthers covered with whipshaped, 

unicellular, non-glandular trichomes; pollen grains, almost 

rounded, with six germ pores (1). 


Grey-blue with fragments of calyx, elongated epidermal cells with wavy 

anticlinal walls, and multicellular non-glandular covering trichomes. Encapsulated 

labiate oil glands. Corolla fragments, almost oval and slightly 

wavy-walled epidermal cells, labiate oil glands and branched covering 

hairs; unicellular glandular hairs. Pollen grains spherical to ellipsoidal, 

24–30 μm in diameter, with six furrows, six germ pores and lines of pits 

230

adiating from the poles. Leaf fragments, almost straight-walled epidermal 

cells, covering branched trichomes and labiate oil glands, glandular 

hairs with a unicellular stalk and a bicellular head (11). 


Macroscopic and microscopic examinations (1–3), microchemical tests 

(2), and thin-layer chromatography for the presence of linalyl acetate and 

linalool (3, 12). 

Purity tests 







Total ash 








Moisture 








Heavy metals 



231








Contains not less than 1.3% (v/w) essential oil determined by steam distillation 

(3). 


Contains 1.0–3.0% essential oil, of which the major constituents are linalyl 

acetate (30–55%) and linalool (20–50%). Other constituents include 

β-ocimene, 1,8-cineole (1,8-cineol, cineol, cineole, eucalyptol), camphor 

and caryophyllene oxide (6, 9, 10). The structures of linalyl acetate and 

linalool are presented below. 



None. 


Symptomatic treatment of restlessness, insomnia, and as a carminative 

and antispasmodic for gastrointestinal disorders of nervous origin (10, 

16). Externally in balneotherapy for the treatment of cardiovascular disorders 

(10, 16). 


As a diuretic and an emmenagogue, and for the treatment of burns, diarrhoea, 

headaches, sore throats and wounds (10). 

Pharmacology 



Aqueous, chloroform, hexane and methanol extracts of Flos Lavandulae, 

60.0 μg/ml, inhibited the growth of Streptococcus pneumoniae in vitro 

232 

H 3C 

CH 3 

O 

R 


CH3 CH2 linalool R = H 

linalyl acetate R = CO-CH3

(17). A methanol extract of the fl owers inhibited the growth of Helicobacter 

pylori (the bacterium associated with peptic ulcer disease) in vitro, 

minimum inhibitory concentration 100.0 μg/ml (18). 


A 50% ethanol extract of the fl owers had antioxidant activity in vitro, 

median effective dose 45.0 mg/ml (19). 


Intragastric administration of 400.0 mg/kg body weight (bw) of an 80% 

ethanol extract of the fl owers to mice signifi cantly (P < 0.05) reduced 

ethanol-induced gastric ulcerations by 62.9% (20). 

Uterine stimulating activity 

A hot aqueous extract of the fl owers (dose not specifi ed) stimulated uterine 

contractions in isolated pregnant guinea-pig uterus (21). 

Anticonvulsant and sedative activities 

Intraperitoneal administration of 2.5 g/kg bw of linalool to rodents protected 

against convulsions induced by pentylenetetrazole, picrotoxin and 

electroshock (22, 23). In mice, intraperitoneal administration of 2.5 g/kg 

bw of linalool interfered with glutamate function and delayed N-methyld-aspartate-induced 

convulsions (24). Linalool acts as a competitive antagonist 

of [ 3 H]-glutamate binding and as a non-competitive antagonist 

of [ 3 H]-dizocilpine binding in mouse cortical membranes, suggesting interference 

of glutamatergic transmission. The effects of linalool on [ 3 H]glutamate 

uptake and release in mouse cortical synaptosomes were investigated. 

Linalool reduced potassium-stimulated glutamate release (25). 

These data suggest that linalool interferes with elements of the excitatory 

glutamatergic transmission. 




Flos Lavandulae is contraindicated in cases of known allergy to the plant 

material. Owing to their traditional use as an emmenagogue and abortifacient, 

the fl owers should not be used during pregnancy (21, 26). 

Warnings 



233


Precautions 





drug interactions; drug and laboratory test interactions; carcinogenesis, 

mutagenesis, impairment of fertility; teratogenic effects during 

pregnancy; nursing mothers; or paediatric use. 

Dosage forms 

Dried fl owers, tablets, capsules, fl uidextract, syrup, tincture and tonics (10). 

Store in a well closed container, in a cool, dry place, protected from light (1). 

Posology 


Internally as a tea, dried fl owers, 1–2 teaspoonfuls per cup, three times 

per day; tincture (1:5) in 60% ethanol, 2–4 ml three times per day (11). 

Externally as bath therapy, dried fl owers, 20–100 g per 20 l of water (16). 

References 




drugs of Unani medicine – part III. New Delhi, Ministry of Health and Family 



Europe, 2000. 

4. Chiej R. Encyclopedia of medicinal plants, 2nd ed. Rome, MacDonald, 1984. 

5. Oyen LPA, Nguyen XD, eds. Plant resources of South-east Asia, No. 19. 

Essential-oil plants. Bogor, PROSEA, 1999. 






1959. 


2nd ed. [French-Persian medico-pharmaceutical terminology.] Tehran, University 

of Tehran Publications, 1979. 



234





Press, 1994. 

11. British herbal pharmacopoeia, 2nd ed. Part 2. Cowling, British Herbal Medicine 

Association, 1979. 






15. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, 

World Health Organization, 1997 (WHO/FSF/FOS/97.7; available from Food 

Safety, World Health Organization, 1211 Geneva 27, Switzerland). 



17. Alkofahi A, Masaadeh H, Al-Khalil S. Antimicrobial evaluation of some 

plant extracts of traditional medicine of Jordan. Alexandria Journal of Pharmacy, 

1996, 10:123–126. 



2000, 7:(Suppl. II):79. 

19. Lamaison JL, Petitjean-Freytet C, Carnat A. Teneures en acide rosmarinique 

en derivés hydroxycinnamiques totaux et activité antioxydante chez les Apiacées, 

les Boraginacées et les Lamiacées médicinales. [Rosmarinic acid, total 

hydroxycinnamic derivative contents and antioxidant activity of medicinal 

Apiaceae, Boraginaceae and Lamiaceae.] Annales Pharmaceutiques Françaises, 

1990, 48:103–108. 

20. Alkofahi A, Atta AH. Pharmacological screening of the anti-ulcerogenic effects 

of some Jordanian medicinal plants in rats. Journal of Ethnopharmacology, 

1999, 67:341–345. 

21. Superbi C, Crispolti E. Ricerche intorno all’azione esercitata sulla muscolatura 

uterina da infusi ed estratti di alcune erbe in uso fra gli indigeni della Tripolitania. 

[Effect on the uterine muscle of infusions and extracts of certain herbs used 

by the natives of Tripoli.] Annali ostetricia e ginecologie, 1935, 57:253–267. 

22. Elisabetsky E et al. Sedative properties of linalool. Fitoterapia, 1995, 15:407–414. 


on glutamate-related seizure models. Phytomedicine, 1999, 6:107–113. 

24. Silva Brum LF, Elisabetsky E, Souza D. Effects of linalool on [ 3 H] MK801 

and [ 3 H] muscimol binding in mouse cortical membranes. Phytotherapy Research, 

2001, 15:422–425. 



26. San Martin AJ. Medicinal plants in central Chile. Economic Botany, 1983, 

37:216–227. 

235

236 

Strobilus Lupuli 

Defi nition 

Strobilus Lupuli consists of the dried strobiles or infl orescences of the 

female plants of Humulus lupulus L. (Cannabaceae) (1, 2). 

Synonyms 

Humulus lupulus L. var. cordifolius (Miq.) Maxim. in Franch. et Sav. = 

H. cordifolius Miq., H. lupulus L. var. lupuloides E. Small = H. americanus 

Nutt., H. lupulus L. var. lupuloides = Cannabis lupulus (L.) Scop., H. 

lupulus L. var. brachystachyus Zapalowicz, H. lupulus L. var. neomexicanus 

Nelson et Cockerell = H. neomexicanus (Nelson et Cockerell) Rydberg, 

H. volubilis Salisb., H. vulgaris Gilib., Lupulus communis Gaertn., 

L. humulus Mill., L. scandens Lam. (3). 


Betiguera, bine, common hops, Echter Hopfen, European hops, hachichet 

addinar, hoblon, hombrecillo, hop, hop vine, Hopfen, hops, houblon, 

houblon grimpant, houblon vulgaire, humulus, lupio, luppulo, lupol, lupulin, 

lupulo, pijiuha, razak, vidarria, vigne du nord, xianshema (3–6). 


Distributed in Europe, Asia and North America. Cultivated widely in the 

temperate zones of the world (5, 7). 

Description 

A perennial, dioecious, twining herb, up to 6 m high. Aerial parts consist 

of several long, angular, rough-hairy, entwining stems bearing cordate, 

palmate, three-lobed, occasionally fi ve- to seven-lobed, scabrous, dark 

green, stipulate leaves. Staminate fl owers, with fi ve bracts and fi ve stamens, 

borne in axillary panicles. Pistillate fl owers pale green, each consisting 

of an entire cup-like perianth and a unilocular ovary with a single 

ovule, and two long stigmas, borne on a leafy conical catkin. Fruits are 

ovate to ovate-cylindrical strobiles consisting of a fl exuous rachis bearing


yellowish-green to pale brown, ovate, membranous, scaly bracts, each enclosing 

a brown glandular achene (7). 

Plant material of interest: dried strobiles 


Strobiles ovoid-cylindrical or cone-like, leafy, 3–4 cm long and up to 3 cm 

wide, consisting of a narrow, hairy, fl exuous rachis and numerous imbricated, 

yellowish-green to dusky yellow, obliquely ovate, membranous 

bracts, the base of each with numerous orange to yellowish-orange, glandular 

trichomes, and frequently infolded on one side, enclosing a light 

brown subglobular glandular achene (7). 


Odour: strong, characteristically aromatic, becoming valerian-like on 

ageing; taste: aromatic, bitter (7). 


Epidermal cells of stipules and bracteoles irregularly polygonal with sinuous 

anticlinal walls, usually thin, occasionally slightly beaded and thickened; 

rare anomocytic stomata and cicatrices. Mesophyll seen in section 

shows small cluster crystals of calcium oxalate; glandular trichomes with 

a two-celled stalk and a spherical glandular head of eight cells; numerous 

large yellow glands, 100–250 μm in diameter, each consisting of thinwalled 

cells with a dome-shaped cuticle, circular in surface view and cupshaped 

in side view, attached to the stipule or bracteole by a short twocelled 

stalk. Epicarp of fruit consists of sclerenchymatous cells, 

irregularly elongated, pale brown with thick walls showing numerous 

small pits and striations (1). 


Greenish-yellow; fragments of bracts and bracteoles covered by polygonal, 

irregular epidermal cells with wavy walls; unicellular, conical, straight 

or curved covering trichomes with thin, smooth walls; rare anomocytic 

stomata; fragments of mesophyll containing small calcium oxalate cluster 

crystals; many characteristic orange-yellow glandular trichomes with 

short, bicellular, biseriate stalks, bearing a partial widening into a cup, 

150–250 μm in diameter, made up of a hemispherical layer of secretory 

cells with a cuticle that has been detached and distended by the accumulation 

of oleoresinous secretions; fragments of elongated sclerenchymatous 

cells of the testa with thick walls showing striations and numerous 

pits (2). 

237




(1, 2). 

Purity tests 







Total ash 







Not less than 25% in 70% (v/v) ethanol (2). 








Heavy metals 






238



requirements. 


High-performance liquid chromatography for bitter substances and 

xanthohumol (3). 


The major constituents are bitter substances (15–25%) in the resins. The 

resins are differentiated into hard (petroleum-ether insoluble) and soft 

resins. The lipophilic soft resins contain mainly α-acids (e.g. α-humulene 

(2,6,9-humulatriene) and related humulones) and β-acids (lupulones). 

The major chemical constituents of the soft resins are humulone and lupulone 

and their related derivatives, 2–10% and 2–6%, respectively. The 

hard resin contains a hydrophilic fraction, δ-resin, and a lipophilic fraction, 

γ-resin. The essential oil (0.3–1.0%) contains mainly monoterpenes 

and sesquiterpenes such as β-caryophyllene, farnesene, humulene and βmyrcene 

(3, 5, 6, 11, 12). The essential oil also contains traces of 2methylbut-3-ene-2-ol, 

which increases in amount to a maximum of 

0.15% after storage of the strobiles for 2 years, owing to degradation of 

the humulones and lupulones. Other constituents include the chalcone 

xanthohumol, prenylfl avonoids and other fl avonoids (e.g. kaempferol, 

rutin) and tannins (3, 6, 13, 14). Representative structures are presented 

below. 

H 3 C 

CH 3 

O 

OH CH 3 

O OH 

HO 

H3C humulone 

H3C OH 

H2C CH3 2-methylbut-3-en-2-ol 

CH 3 

CH 3 

H 3 C 

H 3 C 

CH 3 

H 3C 



None. 

O 

HO O 

CH 3 

CH 3 

humulene 

CH 3 

OH CH 3 

H 3 C 

lupulone 

CH 3 

CH 3 

CH 3 

HO 

O 


OH CH 3 

H3CO OH 

xanthohumol 

CH 3 

239



As a sedative for the treatment of nervous tension and insomnia. Treatment 

of dyspepsia and lack of appetite (5, 15–17). 


Treatment of abdominal cramps, anaemia, bacterial infections, dermatitis, 

diarrhoea, dysmenorrhoea, leukorrhoea, migraine and oedema (6). As an 

analgesic, anthelminthic, antipyretic, aphrodisiac, carminative, depurative, 

digestant, diuretic, diaphoretic and tonic (6). 

Pharmacology 



The essential oil of the strobiles, 2.5 μl/disc, inhibited the growth of 

Staphylococcus aureus, Bacillus subtilis, Trichophyton interdigitale, 

Candida albicans and Escherichia coli (18). Other researchers reported 

antimicrobial effects against Gram-positive bacteria (Staphylococcus 

aureus and Bacillus subtilis) and the fungus Trichophyton mentagrophytes 

var. interdigitale at a concentration of 20 mg/ml, but no activity 

against a Gram-negative bacterium (Escherichia coli) or the yeast Candida 

albicans (19). A methanol extract of the strobiles inhibited the 

growth of Helicobacter pylori, minimum inhibitory concentration 

(MIC) range 63.0–130.0 μg/ml (20). Lupulone and humulone were isolated 

from the methanol extract as the active constituents. The MIC 

range for lupulone was estimated at 0.63–13.0 μg/ml (20). A decoction 

of the strobiles and lupulone inhibited the growth of Mycobacterium 

tuberculosis, MIC 1.0–10 μg/ml for lupulone and 7.5 μg/ml for the decoction 

(17). 

The antibacterial activity of the weak acids derived from Strobilus Lupuli 

increases with decreasing pH of the medium. The MICs of these 

compounds against Lactobacillus brevis IFO 3960 at a pH range of 4– 

7 suggest that undissociated molecules are mainly responsible for the inhibition 

of bacterial growth (21). 

Anti-oedema activity 

External application of a methanol extract of Strobilus Lupuli to mouse 

ears, 2.0 mg/ear, inhibited 12-O-tetradecanoylphorbol-13-acetate-induced 

infl ammation by 90% (22). Humulone, 1 mg/animal, inhibited 

ear infl ammation induced by 12-O-tetradecanoylphorbol-13-acetate 

and ear oedema induced by arachidonic acid in mice (23). 

240



A methanol extract of the strobiles had antioxidant and radical scavenging 

activities in vitro (24, 25). 


Intraperitoneal administration of 100.0 mg/kg body weight (bw) of a 

methanol extract of the strobiles had analgesic effects, as shown by the 

increased latency of licking the forepaws in the hot-plate test in mice (26, 

27). Intraperitoneal administration of the extract also reduced spontaneous 

motor activity and decreased performance on an animal coordination 

meter (Rota-Rod) by 59% at doses above 250.0 mg/kg bw. At a dose of 

250.0 mg/kg bw the extract also produced a dose-dependent increase in 

pentobarbital-induced sleeping time in mice (26, 27). However, oral doses 

of up to 500.0 mg/kg of an ethanol extract of the strobiles did not have 

any sedative effects in mice (28). Oral administration of a methanol extract 

of the strobiles, 500.0 mg/kg bw, inhibited pentylenetetrazoleinduced 

convulsions and reduced body temperature in mice (26, 27). Intraperitoneal 

administration of 0.8 g/kg bw of the 2-methylbut-3-ene-2-ol, 

extracted from the essential oil of the strobiles to mice induced narcosis 

lasting 8 hours (29). Intraperitoneal administration of 206.5 mg/kg bw of 

2-methylbut-3-ene-2-ol to rats caused a 50% decrease in motility (30). 

Administration of an essential oil of the strobiles via nasogastric tube 

(dose not specifi ed) induced central nervous system depression in pigeons 

(31). Intramuscular administration of an essential oil (dose not specifi ed) 

to mice had unspecifi ed sedative activity (29). A commercial extract (no 

further information available) of the strobiles, ≤2 μg/ml, bound to the 

γ-aminobutyric acid, the glutamate and the N-methyl-d-asparate receptors, 

as well as the chloride ion channel and glycine receptors in vitro (32). 


Subcutaneous administration of an aqueous or a 95% ethanol extract of the 

strobiles at various concentrations had estrogenic effects in mice and rats as 

assessed by the Allen-Doisy assay (which measures vaginal cornifi cation in 

ovariectomized animals) (33–37). The activity was reported to be equivalent 

to that of 20–300 μmol/g bw of 17-β-estradiol (33). Using the Allen- 

Doisy assay, the estrogenic hormonal activity of a lipophilic extract of the 

strobiles was greater than that of an aqueous extract of 17-β-estradiol 

equivalents (1250 μg/g bw compared with 30–300 μg/g bw) (35). However, 

other investigators reported no estrogenic effects in mice following subcutaneous 

administration of doses of up to 51.0 mg/kg bw (38, 39). 

Subcutaneous administration of 5.0 mg of an alcohol extract of the 

strobiles to rats had a luteal suppressant effect (40). An extract of the 

241


strobiles (unspecifi ed) administered to ovariectomized rats in the diet 

(dose not specifi ed) bound to estrogen receptors in vitro, and increased 

the concentration of hepatic ceruloplasmin messenger RNA, indicating 

an hepatic estrogenic response (41). 

A polyphenolic fraction isolated from an alcohol extract of the strobiles 

stimulated the activity of alkaline phosphatase in human endometrial 

cells, Ishikawa variety I in vitro (42). A phytoestrogen, 8-prenylnaringenin, 

isolated from the polyphenolic fraction, 1 nmol/l, bound to 

estrogen receptors isolated from rat uteri (42). Methanol extracts of the 

strobiles competitively bound to estrogen receptors-alpha and -beta 

from rat uteri (43). The extracts also induced the expression of alkaline 

phosphatase activity and upregulated progesterone receptor messenger 

RNA (43). 

Miscellaneous activity 

Intragastric administration of three doses of an essential oil of the strobiles, 

30 mg/animal, given over 2 days, stimulated the activity of glutathione-S-transferase 

in the liver and intestine of mice (44). Six fl avonoid 

compounds isolated from the strobiles, 0.1–100.0 μmol/l, inhibited the 

growth of human breast cancer (MCF-7), colon cancer (HT-29) and 

ovarian cancer (A-2780) cells in vitro (45). Flavonoid compounds isolated 

from the strobiles, namely xanthohumol, isoxanthohumol and 

8-prenylnaringenin, 10.0 μmol/l, inhibited the 7-ethoxyresorufi n- 

O-deethylase activity of the CYP1A1 and CYP1A2 isozymes of cytochrome 

P450 (46). 

Toxicology 

The median lethal dose (LD 50 ) of orally administered ethanol extracts of 

the strobiles or lupulones in mice was found to be 500.0–3500.0 mg/kg 

bw (29). The oral LD 50 in rats was 2700.0 mg/kg bw (29). The oral LD 50 

for lupulone was 525.0 mg/kg bw in mice and 1800.0 mg/kg bw in rats 

(3). The intraperitoneal LD 50 of an ethanol extract of the strobiles in mice 

was 175.0 mg/kg bw (17). 


In a small study without controls, oral administration of 250.0 mg of a 

lipophilic concentrate of the strobiles daily for 5 days to 15 healthy volunteers 

had no sleep-inducing effects (47). 


Strobilus Lupuli may cause drowsiness (31). 

242


Strobilus Lupuli is contraindicated in cases of known allergy to the plant 

material. 

Warnings 



Precautions 


While no drug interactions have been reported, fl avonoid constituents of 

Strobilus Lupuli have been shown to inhibit the activity of cytochrome 

P450, and concurrent administration of the strobiles with prescription 

drugs metabolized by these enzymes may adversely infl uence the pharmacokinetics 

of these drugs. 


Subcutaneous administration of 20.0–50.0 mg/kg bw of purifi ed fractions 

of the strobiles twice daily for 3 days to female rats pretreated by subcutaneous 

injection with 25 IU of pregnant mare’s serum gonadotrophin 

did not induce any changes in uterine weight, but ovarian weight decreased 

signifi cantly (P < 0.05) (48). 


No information available on general precautions or on precautions 

concerning drug and laboratory test interactions; teratogenic or nonteratogenic 

effects in pregnancy; nursing mothers; or paediatric use. 

Dosage forms 

Dried strobiles and dried extracts for infusions and decoctions, dry extracts, 

fl uidextracts, and tinctures (7, 16). Store in a tightly sealed container 

away from heat and light. 

Posology 


Cut or powdered strobiles or dry powder for infusion, decoctions and 

other preparations, single dose of 0.5 g; liquid and solid preparations for 

internal use, infusion or decoction, 0.5 g in 150 ml of water; fl uidextract 

1:1 (g/ml) 0.5 ml; tincture 1:5 (g/ml) 2.5 ml; native dry extract 6–8:1 (w/w) 

0.06–0.08 g (16). 

243


References 


1996. 


Europe, 2001. 




4. Hoppe HA. Drogenkunde. Bd 1, Angiospermum, 8th ed. [Science of drugs. 

Vol. 1, Angiosperms, 8th ed.] New York, NY, W.G. de Gruyler, 1975. 


Press, 1994. 













Switzerland). 



12. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier, 

1995. 

13. Hölzl J. Inhaltsstoffe des Hopfens (Humulus lupulus L.). [Constituents of 

hops (Humulus lupulus L.).] Zeitschrift für Phytotherapie, 1992, 13:155–161. 

14. Stevens JF et al. Prenylfl avonoids from Humulus lupulus. Phytochemistry, 

1997, 44:1575–1585. 

15. Chang HM, But PPH. Pharmacology and applications of Chinese materia 

medica. Vol. II. Singapore, World Scientifi c, 1987. 



17. Kee CH. The pharmacology of Chinese herbs, 2nd ed. Boca Raton, FL, CRC 

Press, 1999. 

18. Gottshall RY et al. The occurrence of antibacterial substances active against 

Mycobacterium tuberculosis in seed plants. Journal of Clinical Investigation, 

1949, 28:920–923. 

244


19. Langezaal CR, Chandra A, Scheffer JJC. Antimicrobial screening of essential 

oils and extracts of some Humulus lupulus L. cultivars. Pharmazeutisch 

Weekblad (Scientifi c Edition), 1992, 14:353–356. 

20. Ohsugi M et al. Antibacterial activity of traditional medicines and an active 

constituent lupulone from Humulus lupulus against Helicobacter pylori. 

Journal of Traditional Medicines, 1997, 14:186–191. 

21. Simpson WJ et al. Factors affecting antibacterial activity of hop compounds 

and their derivatives. Journal of Applied Bacteriology, 1992, 72:327–334. 


ear oedema in mice. Phytotherapy 

Research, 1993, 7:185–189. 

23. Yasukawa K, Takeuchi M, Takido M. Humulone, a bitter in the hop, inhibits 

tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage 

carcinogenesis in mouse skin. Oncology, 1995, 52:156–158. 

24. Oyaizu M et al. [Antioxidative activity of extracts from hop (Humulus lupulus 

L.).] Yukagaku Zasshi, 1993, 42:1003–1006 [in Japanese]. 

25. Tagashira M, Watanabe M, Uemitsu N. Antioxidative activity of hop bitter 

acids and their analogues. Bioscience, Biotechnology and Biochemistry, 1995, 

59:740–742. 

26. Lee KM et al. Neuropharmacological activity of Humulus lupulus extracts. 

Korean Journal of Pharmacognosy, 1993, 24:231–234. 

27. Lee KM et al. Effects of Humulus lupulus extract on the central nervous system 

in mice. Planta Medica, 1993, 59(Suppl.):A691. 

28. Hänsel R, Wagener HH. Versuche, sedativ-hypnotische Wirkstoffe im Hopfen 

nachzuweisen. [Does hop contain sedative and hypnotic agents?] Arzneimittelforschung, 

1967, 17:79–81. 

29. Hänsel R et al. Versuche, sedativ-hypnotische Wirkstoffe im Hopfen nachzuweisen 

II. [Investigations to detect sedative-hypnotic agents in hops II.] 

Zeitschrift für Naturforschung, 1980, 35c:1096–1097. 

30. Wohlfart R, Hansel R, Schmidt H. Nachweis sedativ-hypnotischer Wirkstoffe 

im Hopfen. 4. Mitteilung: Die Pharmakologie des Hopferinhaltstoffes 

2-methyl-3-buten-2-ol. [The sedative-hypnotic principle of hops. 4. Communication: 

Pharmacology of 2-methyl-3-buten-2-ol.] Planta Medica, 1983, 

48:120–123. 

31. Sikorski H, Rusiecki W. The sedative action of various constituents of hops. 

Bulletin of the International Academy of Polish Science and Clinical Medicine, 

1936, 73–83. 

32. Cott J. Medicinal plants and dietary supplements: sources for innovative 

treatments or adjuncts? Psychopharmacology Bulletin, 1995, 31:131–137. 

33. Koch W, Heim G. Östrogene Hormone in Hopfen und Bier. [Estrogenic 

hormones in hops and beer.] Münchener Medizinische Wochenschrift, 1953, 

95:845. 

34. Chury J. Über den phytoöstrogen gehalt einiger Pfl anzen. [The phytoestrogen 

content of some plants.] Experientia, 1960, 16:194. 

245


35. Zenisek A, Bednar IJ. Contribution to the identifi cation of the estrogen activity 

of hops. American Perfumer and Aromatics, 1960, 75:61–62. 

36. Strenicovskaya AG. [Use of the hormonal properties of the carbon dioxide 

extract of hops in cosmetics.] Maslozhirovaya Promyshlennost, 1971, 37:23– 

24 [in Russian]. 

37. Hoelscher M. Exposure to phytoestrogens may surpass DES exposure. Feedstuffs, 

1979, 51:54–68. 

38. Bravo L et al. Pharmacodynamic study of hops (Humulus lupulus). Ars Pharmaceutica, 

1971, 12:421–425. 

39. Fenselau C, Talalay P. Is oestrogenic activity present in hops? Food, Cosmetics 

and Toxicology, 1973, 11:597–603. 

40. Kumai A et al. [Extraction of biologically active substances from hop.] 

Nippon Naibunpi Gakkai Zasshi, 1984, 60:1202–1213 [in Japanese]. 

41. Eagon CL et al. Medicinal botanicals: estrogenicity in rat uterus and liver. 

Proceedings of the American Association of Cancer Research, 1997, 38:193. 

42. Milligan SR et al. Identifi cation of a potent phytoestrogen in hops (Humulus 

lupulus L.) and beer. Journal of Clinical Endocrinology and Metabolism, 

1999, 83:2249–2252. 

43. Liu J et al. Evaluation of estrogenic activity of plant extracts for the potential 

treatment of menopausal symptoms. Journal of Agricultural and Food Chemistry, 

2001, 49:2472–2479. 

44. Lam LKT, Zheng BL. Effects of essential oils on glutathione s-transferase 

activity in mice. Journal of Agricultural and Food Chemistry, 1991, 39:660– 

662. 

45. Miranda CL et al. Antiproliferative and cytotoxic effects of prenylated fl avonoids 

from hops (Humulus lupulus) in human cancer cell lines. Food and 


46. Henderson MC et al. In vitro inhibition of P450 enzymes by prenylated fl avonoids 

from hops, Humulus lupulus. Xenobiotica, 2000, 30:235–251. 

47. Stocker HR. Sedative und hypnogene Wirkung des Hopfens. [Sedative and 

hypnotic effects of hops.] Schweizer Brauerei-Rundschau, 1967, 78:80–89. 

48. Kumai A, Okamoto R. Extraction of the hormonal substance from hop. 

Toxicology Letters, 1984, 21:203–207. 

246

Gummi Myrrha 

Defi nition 

Gummi Myrrha consists of the air-dried oleo-gum resin exudates from 

the stems and branches of Commiphora molmol Engler (Burseraceae) and 

other related Commiphora species (1–4), including C. abyssinica Engl., 

C. erythraea and C. schimperi Engl. (5), but excluding C. mukul. 

Synonyms 

For Commiphora molmol Engl.: Balsamodendron myrrha Nees, Commiphora 

myrrha Holm, C. myrrha (Nees) Engl. var. molmol Engl. (2, 6). 


Abyssinian myrrh, arbre à myrrhe, bal, barakande, bisabol myrrh, bol, 

bola, dashi ‘biskiti, gandharsh, guban myrrh, habaq-hagar-ad, heerbol, 

heerabol myrrh, hirabol myrrh, Männliche myrrhe, mbebe, mbele, mo 

yao, morr, morrh, mur, murr, myrr, myrrh, Myrrhenbaum, myrrha, molmol, 

myrrhe des somalis, ogo myrrh, turari, Somali myrrh (1, 2, 6–11). 


Various Commiphora species are indigenous to arid and tropical regions 

of Africa. Commiphora molmol is indigenous to Somalia and is cultivated 

in the Arabian Peninsula and North Africa and in Ethiopia, India, Kenya 

and United Republic of Tanzania (1, 2, 9). 

Description 

Commiphora species are shrubs or small trees, about 3 m high, with 

rounded tops, thick trunks, dark brown bark and large, sharply pointed 

thorns on the stem. Branches numerous, irregular or rough, stunted and 

spiny. Leaves unequal, ternate, alternate. Flowers small, dioecious, 

yellow-red fascicled, polygamous, arranged in terminal panicles. Calyx 

tubular, teeth usually four, valvate petals usually found inserted on the 

edge of the disk; stamens 8–10 on disk alternately long and short fi laments, 

dialated below. Fruits are oval-lanceolate drupes, about 0.3 cm 

247


long. When stems are damaged or incised, oleo-gum resins exude from 

the schizogenous resin ducts (1, 2, 7, 10). 

Plant material of interest: dried oleo-gum resin 


Rounded or irregular tears or lumps of agglutinated tears of variable sizes; 

brownish-yellow to reddish-brown or almost black. The surface is mostly 

covered with a greyish or yellowish powder; the internal surface is yellowish 

or reddish-brown, sometimes marked with white spots or lines; 

brittle; fracture, waxy, granular, conchoidal and yields thin translucent 

fragments (1, 3, 7, 10). 


Odour: characteristic, aromatic, balsamic; taste: aromatic, bitter, acrid 

(1–3, 7, 10). 






Macroscopic (1, 7, 10) and microscopic (10) examinations; microchemical and 

spectroscopic tests (1, 3, 7, 12), and thin-layer chromatography (2–4, 13). 

Purity tests 





Total ash 

Not more than 10.0% (1). Not more than 7.0 % (4). 





Alcohol-insoluble residue 

Not more than 70.0% (1, 4). 

248

Moisture 



The recommended maximum limit for aldrin and dieldrin is not more 

than 0.05 mg/kg (15). For other pesticides, see the European pharmacopoeia 



Heavy metals 







Chemical and foreign organic matter tests to be established in accordance 



Not less than 6% essential oil (3). Qualitative and quantitative highperformance 

liquid chromatography for furanosesquiterpenes (17). 


The oleo-gum resin obtained from C. molmol contains: resins (25–40%), 

essential oil (3–8%) and a water-soluble gum (30–60%) (1, 18). The gum 

is composed of 20% proteins and 65% carbohydrates made up of galactose, 

4-O-methylglucuronic acid and arabinose. The major constituents 

of the essential oil are furanosesquiterpenes (10), and the monoterpenes 

α-, β- and γ−bisabolene. Representative structures are presented below. 



None. 

Gummi Myrrha 


Topical treatment of mild infl ammations of the oral and pharyngeal mucosa 

(3, 19, 20). As a gargle or mouth rinse for the treatment of aphthous 

ulcers, pharyngitis, tonsillitis, common cold and gingivitis (3, 21). 

249



As an emmenagogue, expectorant and antidote for poisons, and to inhibit 

blood coagulation. Treatment of menopausal symptoms, arthritic 

pain, diarrhoea, fatigue, headache, jaundice and indigestion, and applied 

topically for treatment of burns and haemorrhoids (9, 11, 22, 23). 

Pharmacology 



Intragastric administration of an aqueous suspension of Gummi Myrrha, 

10% in saline solution, 10.0 ml/kg body weight (bw) had analgesic 

effects in mice, as assessed by the hot-plate test (24). Intragastric administration 

of 50.0 mg/kg bw of a sesquiterpene, furanoeudesma-1,3-diene, 

isolated from the resin also had analgesic effects in mice as measured by 

the acetic acid writhing test (24). Intragastric administration of 400.0 mg/ 

kg bw of a 100% ethanol extract of the resin reduced writhing induced 

by acetic acid in mice by 25% (25). Intragastric administration of 

500.0 mg/kg bw of a petroleum ether extract or a 95% ethanol extract of 

the resin signifi cantly (P < 0.05) suppressed yeast-induced pyrexia in 

mice (26, 27). 


Intraperitoneal administration of 100.0 mg/kg bw of an ethyl acetate extract 

of the resin inhibited platelet aggregation in mice. However, an aqueous 

extract of the resin given by the same route was not active (28). Intraperitoneal 

administration of 100.0 mg/kg bw of an ethyl acetate extract of 

the resin, had antithrombotic activity in mice (29). 

250 

H2C H2C H 3C 

H 

CH 3 

CH 3 

X 


CH 3 

O 

furanodiene 

O 

CH 3 

curzerene 

curzerenone 

CH 3 

X = H 2 

X = O 

H CH3O CH3 CH3 and enantiomer 

4,5-dihydrofuranodien-6-one 

O 

CH 3 

H 

CH3 O 

CH 3 

furanoeudesma-1,3-diene 

H3CO H 

CH 3 

CH 3 

O 

CH 3 

2-methoxyfuranodiene

Gummi Myrrha 


Intragastric administration of 10.0 ml/kg bw of a hot aqueous extract of 

the resin per day for 7 days, reduced blood glucose levels in diabetic rats 

(30). Intragastric administration of 150–175.0 mg/kg bw of two furanosesquiterpenes 

isolated from the resin signifi cantly (P < 0.0036–0.0009) 

reduced blood glucose levels in genetically altered obese diabetic mice, 

measured 27 hours after administration (31). 


Intragastric administration of 400.0 mg/kg bw of an aqueous extract of 

the resin to rats signifi cantly (P < 0.05) reduced carrageenan-induced 

footpad oedema by up to 59% (32). Intragastric administration of 

400.0 mg/kg bw of a petroleum ether extract of the resin per day for 18 

days to rats with Freund’s adjuvant-induced arthritis signifi cantly 

(P < 0.05) reduced the development of infl ammation (32). Intragastric administration 

of 80.0 mg/kg bw of a petroleum ether extract of the resin 

inhibited carrageenan-induced footpad oedema in rats (33). Intraperitoneal 

administration of 200–400.0 mg/kg bw of a 100% ethanol extract of 

the resin reduced xylene-induced ear infl ammation in mice by 50% (25). 

Intragastric administration of 500.0 mg/kg bw of a petroleum ether extract 

of the resin reduced carrageenan-induced footpad oedema and cotton 

pellet-induced granuloma in rats (26). 

Cytoprotectant activity 

Intragastric administration of 250.0 mg/kg bw of an aqueous suspension 

of the resin reduced the formation of ulcers induced by ethanol, sodium 

chloride and indometacin in rats by increasing the production of gastric 

mucus (34). 

Toxicology 

An ethanol extract of the resin was administered to rats by gastric lavage 

(1000.0 mg/kg bw), intramuscular injection (500.0 mg/kg bw) or intraperitoneal 

injection (250.0 mg/kg bw) daily for 2 weeks. Depression, 

huddling, jaundice, ruffl ed hair, hepatonephropathy, haemorrhagic myositis 

and patchy peritonitis at the injection site, and death were observed. 

Increases in serum alanine phosphatase, alanine transferase activities, bilirubin, 

cholesterol and creatinine concentrations, and decreases in total 

protein and albumin levels, macrocytic anaemia and leukopenia were also 

seen. When the doses were halved, the adverse effects were reduced (35). 

The oral lethal dose of the essential oil is 1.65 g/kg bw in rats (36). 

However, no deaths were reported in mice after intragastric administration 

of 3.0 g/kg bw of a 95% ethanol extract of the resin (27). 

251


Intragastric administration of 1.0–5.0 g/kg bw of the resin per day to 

Nubian goat kids caused grinding of teeth, salivation, soft faeces, inappetence, 

jaundice, dyspnoea, ataxia and recumbency. Death occurred between 

days 5 and 16. Enterohepatonephrotoxicity was accompanied by 

anaemia, leukopenia, increases in serum alanine phosphatase activity and 

concentrations of bilirubin, cholesterol, triglycerides and creatinine, and 

decreases in total protein and albumin. An oral dose of 0.25 g/kg bw per 

day was not toxic (37). 

In acute (24-h) and chronic (90-day) oral toxicity studies in mice, the 

resin was administered at doses of 0.5 g/kg bw, 1.0 g/kg bw or 3.0 g/kg 

bw, and 100.0 mg/kg bw per day, respectively. No signifi cant increase in 

mortality was observed in either study. In the chronic study, however, 

there was an increase in body weight and increases in the weight of the 

testes, caudae epididymides and seminal vesicles in treated animals as 

compared with untreated controls. Treated animals also showed an increase 

in red blood cells and haemoglobin levels. No spermatotoxic effects 

were observed in treated animals (38). 




Topical application of a diluted (8%) solution of an essential oil obtained 

from the resin was non-irritating, non-sensitizing and non-phototoxic 

when applied to human skin (36). Application of an unspecifi ed extract of 

the resin to human skin caused contact dermatitis (39–41). 


Gummi Myrrha is used in traditional systems of medicine as an emmenagogue, 

and its safety during pregnancy has not been established. Therefore, 

in accordance with standard medical practice, Gummi Myrrha 

should not be used during pregnancy (42, 43). 

Warnings 

Use of the undiluted tincture may give rise to a transient burning sensation 

and irritation of the palate (3). 

Precautions 


Although no drug interactions have been reported, internal ingestion of 

Gummi Myrrha may interfere with existing antidiabetic therapy owing to 

252

the ability of the resin to reduce blood glucose levels. Patients taking anticoagulant 

drugs or with a history of bleeding disorders should consult 

their health-care provider prior to using the resin. 


An aqueous extract of the resin, 40.0 mg/plate, was not mutagenic in the 

Salmonella/microsome assay using Salmonella typhimurium strains TA98 

and TA100 (44). Intraperitoneal administration of an aqueous extract of 

the resin at doses 10–40 times the normal therapeutic dose did not have 

mutagenic effects (44). A hot aqueous extract of the resin, 40.0 mg/plate, 

inhibited afl atoxin B1-induced mutagenesis in S. typhimurium strains 

TA98 and TA100 (45). The genotoxic, cytotoxic and antitumour properties 

of the resin were investigated in normal mice and mice bearing Ehrlich 

ascites carcinoma cells. The genotoxic and cytotoxic activity was 

evaluated on the basis of the frequency of micronuclei and the ratio of 

polychromatic to normochromatic cells in the bone marrow of normal 

mice. Intragastric administration of 125.0–500.0 mg/kg bw of the resin 

did not have clastogenic effects, but was cytotoxic in normal mice. In the 

mice bearing tumours, the resin had antitumour activity, and was reported 

to be as effective as the antitumour agent cyclophosphamide (46). 



Gummi Myrrha 


Owing to the lack of data concerning the safety and effi cacy of Gummi 

Myrrha, it should not be used by nursing mothers without consulting a 

health-care practitioner. 


Owing to the lack of data concerning the safety and effi cacy of Gummi 

Myrrha, it should not be administered to children without consulting a 




drug and laboratory test interactions; or teratogenic effects in pregnancy. 

Dosage forms 

Powdered resin, capsules, myrrh tincture, and other galenical preparations 

for topical use (20). Store in a tightly sealed container away from 

heat and light. 

253


Posology 


Myrrh tincture (1:5 g/ml, 90% ethanol), undiluted tincture applied to the 

affected area two or three times per day; mouth rinse or gargle, 5–10 drops 

of the tincture in a glass of water (20); mouthwash or gargle solution, 

30–60 drops of the tincture in a glass of warm water (19); paint, undiluted 

tincture applied to the affected areas on the gums or the mucous membranes 

of the mouth with a brush or cotton swab, two or three times per 

day (19); dental powder, 10% powdered oleo-gum resin (20). 

References 




drugs of Unani medicine – part II. New Delhi, Ministry of Health and Family 



1996. 

4. European pharmacopoeia, Suppl. 2001, 3rd ed. Strasbourg, Council of 

Europe, 2000. 


Könyvkiadó, 1963. 










Press, 1993. 


Press, 1994. 





12. Namba T. The encyclopedia of Wakan-Yaku (traditional Sino-Japanese medicine). 

Tokyo, Hoikusha Publishing, 1980. 



254

Gummi Myrrha 







Switzerland). 

17. Maradufu A, Warthen JD Jr. Furanosesquiterpenoids from Commiphora 

myrrh oil. Plant Science, 1988, 57:181–184. 

18. Newall CA, Anderson LA, Phillipson JD. Herbal medicines, a guide for 


19. Braun R et al. Standardzulassungen für Fertigarzneimittel – Text und Kommentar. 

[Standard licensing of fi nished drugs – text and commentary.] Stuttgart, 

Deutscher Apotheker Verlag, 1997. 





22. Nadkarni KM. Indian materia medica. Bombay, Popular Prakashan, 1976. 

23. Frawley D, Lad V. The yoga of herbs: an Ayurvedic guide to herbal medicine. 

Twin Lakes, WI, Lotus Press, 1986. 

24. Dolara P et al. Characterization of the action of central opioid receptors of 

furaneudesma-1,3-diene, a sesquiterpene extracted from myrrh. Phytotherapy 

Research, 1996, 10:S81–S83. 

25. Atta AH, Alkofahi A. Anti-nociceptive and anti-infl ammatory effects of 

some Jordanian medicinal plant extracts. Journal of Ethnopharmacology, 

1998, 60:117–124. 

26. Tariq M et al. Anti-infl ammatory activity of Commiphora molmol. Agents 

and Actions, 1985, 17:381–382. 

27. Mohsin A et al. Analgesic, antipyretic activity and phytochemical screening 

of some plants used in traditional Arab system of medicine. Fitoterapia, 1989, 

60:174–177. 



the herbs for oketsu.] Yakugaku Zasshi, 1984, 104:1050–1053 [in Japanese]. 

29. Olajide OA. Investigation of the effects of selected medicinal plants on experimental 

thrombosis. Phytotherapy Research, 1999, 13:231–232. 

30. Al-Awadi FM, Gumaa KA. Studies on the activity of individual plants of an 

antidiabetic plant mixture. Acta Diabetologica Latina, 1987, 24:37–41. 

31. Ubillas RP et al. Antihyperglycemic furanosesquiterpenes from Commiphora 

myrrha. Planta Medica, 1999, 65:778–779. 

32. Duwiejua M et al. Anti-infl ammatory activity of resins from some species of 

the plant family Burseraceae. Planta Medica, 1993, 59:12–16. 

33. Mossa JS et al. Studies on anti-infl ammatory activity of Balsamodendron 

myrrhanees. In: Chang HM, ed. Advances in Chinese medicinal material re- 

255


search: an international symposium held in Meridien Hotel, Hong Kong, 12– 

14 June, 1984. 

34. Al-Harbi MM et al. Gastric antiulcer and cytoprotective effect of Commiphora 

molmol in rats. Journal of Ethnopharmacology, 1997, 55:141–150. 

35. Omer SA, Adam SE, Khalid HE. Effects on rats of Commiphora myrrha 

extract given by different routes of administration. Veterinary and Human 

Toxicology, 1999, 41:193–196. 

36. Monographs on the fragrance of raw materials. Myrrh oil. Food and Chemical 

Toxicology, 1976, 14:621. 

37. Omer SA, Adam SE. Toxicity of Commiphora myrrha to goats. Veterinary 

and Human Toxicology, 1999, 41:299–301. 

38. Rao RM, Khan ZA, Shah AH. Toxicity studies in mice of Commiphora molmol 

oleo-gum-resin. Journal of Ethnopharmacology, 2001, 76:151–154. 

39. Lee TY, Lam TH. Myrrh is the putative allergen in bonesetter’s herbs dermatitis. 


40. Lee TY, Lam TH. Allergic contact dermatitis due to a Chinese orthopaedic 

solution Tieh Ta Yao Gin. Contact Dermatitis, 1993, 28:89–90. 

41. Al-Suwaidan SN et al. Allergic contact dermatitis from myrrh, a topical 

herbal medicine used to promote healing. Contact Dermatitis, 1997, 39:137. 

42. Saha JC, Savini EC, Kasinathan S. Ecbolic properties of Indian medicinal 

plants. Part I. Indian Journal of Medical Research, 1961, 49:130–151. 

43. Pernet R. Phytochimie des Burseraceae. [Phytochemistry of the Burseraceae.] 

Lloydia, 1972, 35:280–287. 




of Chinese medicinal herbs.] Chung-kuo Chung Yao Tsa Chi Li, 1990, 

10:617–622 [in Chinese]. 

46. Qureshi S et al. Evaluation of the genotoxic, cytotoxic, and antitumor properties 

of Commiphora molmol using normal and Ehrlich ascites carcinoma 

cell-bearing Swiss albino mice. Cancer Chemotherapy and Pharmacology, 

1993, 33:130–138. 

256

Herba Passifl orae 

Defi nition 

Herba Passifl orae consists of the dried aerial parts of Passifl ora incarnata 

L. (Passifl oraceae) (1–3). 

Synonyms 

Granadilla incarnata Medik., Passifl ora kerii Spreng. (4). 


Apricot vine, fl or de la pasión, Fleischfarbene Passionsblume, fi ore della 

passione, fl eur de la passion, grenadille, maracujá, may apple, may fl ower, 

may-pop, pasionaria, passifl ora, passifl ora roja, passifl ore, passion vine, 

rose-coloured passion fl ower, water lemon, white passion fl ower, wild 

passion fl ower (2, 4–6). 


Indigenous to North America (5, 7, 8). 

Description 

A perennial, creeping herb, climbing by means of axillary tendrils. Leaves 

alternate, palmately three to fi ve serrate lobes. Flowers large, solitary, 

with long peduncles, whitish, with a triple purple and pink crown. Fruits 

are ovate berries containing numerous ovoid, fl attened seeds covered with 

a yellowish or brownish aril (7). 

Plant material of interest: dried aerial parts 


Stems lignifi ed, green, greyish-green or brownish, usually less than 5 mm 

in diameter; rounded, longitudinally striated and often hollow. Leaves alternate 

with furrowed, often twisted petioles, possessing two extra-fl oral 

nectaries at the apex; lamina 6–15 cm long, broad, green to brownish 

green, palmate with three to fi ve lanceolate lobes covered with fi ne hairs 

257


on the lower surface; margin serrate. Tendrils borne in leaf axils, smooth, 

round and terminating in cylindrical spirals. Flowers 5–9 cm in diameter 

with peduncles up to 8 cm long, arising in leaf axils; fi ve, white, elongated 

petals; calyx of fi ve thick sepals, upper surface green and with a horn-like 

extension; involucre of three pointed bracts with papillose margins; fi ve 

large stamens, joined at the base and fused to the androgynophor; ovary 

greyish-green, superior; style hairy with three elongated stigmatic branches. 

Fruits 4–5 cm long, oval, fl attened and greenish-brown containing numerous 

seeds 4–6 mm long, 3–4 mm wide and 2 mm thick, with a brownish-yellow, 

pitted surface (2). 


No distinctive odour; taste: bitter (2). 


Transverse section of older stem shows epidermis of isodiametric cells 

with strongly thickened, convex external walls; some cells containing 

crystals of calcium oxalate, others developing uniseriate trichomes two to 

four cells long, terminating in a rounded point and frequently hooked; 

hypodermis consisting of a layer of tangentially elongated cells, outer 

cortex with groups of collenchyma, containing cells with brown, tanniferous 

contents; pericycle with isolated yellow fi bres and partially lignifi 

ed walls; inner cortex of parenchymatous cells containing cluster crystals 

of calcium oxalate; xylem consisting of groups of vessels up to 300 μm 

in diameter with pitted, lignifi ed tracheids; pith of lignifi ed parenchyma 

containing numerous starch grains 3–8 μm in diameter, simple or as aggregates. 

Leaf upper and lower epidermis shows sinuous anticlinal cell 

walls; numerous anomocytic stomata in the lower epidermis, which also 

has numerous uniseriate covering trichomes of one to three cells, terminal 

cells comparatively long, pointed and curved; groups of brown tannin 

cells occur in the marginal teeth and in the mesophyll; cluster crystals of 

calcium oxalate 10–20 μm in diameter isolated in the mesophyll or arranged 

in fi les associated with the veins. Sepal upper epidermis has large, 

irregular, polygonal cells with some thickened walls, striated cuticle, rare 

stomata and numerous small crystals of calcium oxalate; lower epidermis 

comprises two layers, the outer layer consisting of polygonal cells with 

numerous stomata and small crystals of calcium oxalate, the inner layer of 

smaller polygonal cells. Epidermal cells of the petals papillose, especially 

in the fi liform appendices. Pollen grains 65–75 μm in diameter, with a 

cross-ridged surface and three acuminate germinal pores. Pericarp composed 

of large cells with few stomata and groups of calcium oxalate crystals; 

endocarp of thickened, sclerous cells (2). 

258


Light green and characterized by fragments of leaf epidermis with sinuous 

cell walls and anomocytic stomata; numerous cluster crystals of calcium 

oxalate isolated or aligned along the veins; many isolated or grouped 

fi bres from the stems associated with pitted vessels and tracheids; uniseriate 

trichomes with one to three thin-walled cells, straight or slightly 

curved, ending in a point or sometimes a hook. If fl owers are present, 

papillose epidermis of the petals and appendages and pollen grains with a 

reticulate exine. If mature fruits are present, scattered brown tannin cells 

and brownish-yellow, pitted fragments of the testa (3). 



for the presence of fl avonoids (2, 3, 9). 

Purity tests 





Chemical 

Contains not more than 0.01% harman alkaloids (11). 



Total ash 










The recommended maximum limit for aldrin and dieldrin is not more than 


259




Heavy metals 







Sulfated ash and alcohol-soluble extractive tests to be established in accordance 



Contains not less than 1.5% of total fl avonoids, expressed as vitexin, determined 

by spectrophotometry (3). A high-performance liquid chromatography 

method for fl avonoids is also available (14). 


The major constituents are fl avonoids (up to 2.5%) with the principal compounds 

being the C-glycosyl of apigenin (R2 = H) and luteolin (R2 = OH), 

including mono-C-glucosyl derivatives isovitexin (up to 0.32%), iso-orientin 

and their 2''-β-d-glycosides, and di-C-glycosyl derivatives schaftoside 

(up to 0.25%), isoschaftoside (up to 0.15%) and swertisin (1, 15, 16). 

Also found are di-C-glucosyl derivatives vicenin-2 and lucenin-2 and small 

amounts of mono-C-glucosyl derivatives orientin and vitexin (1). Other 

chemical constituents include maltol (3-hydroxy-2-methyl-γ-pyrone) 

(0.05%), chrysin and a cyanogenic glycoside, gynocardin. Traces of the 

indole (β-carboline) alkaloids (e.g. harman, harmol, harmine) have been 

reported in the source plants; however, these alkaloids are undetectable in 

most commercial materials (4–6, 8, 16). The structures of the alkaloid harman 

and characteristic fl avonoids are presented below. 



None. 

260

O 

R 6 

R 8 

OH 


Internally as a mild sedative for nervous restlessness, insomnia and anxiety. 

Treatment of gastrointestinal disorders of nervous origin (1, 5, 11). 


As an anodyne, antispasmodic and mild stimulant (1, 6). Treatment of 

dysmenorrhoea, neuralgia and nervous tachycardia (1). 

Pharmacology 

O 

O 

R2 

OH 

orientin 

iso-orientin 

H 

N 

CH3 harman 

N 

maltol 

lucenin-2 

schaftoside 

isoschaftoside 

vicenin-2 

vitexin 

isovitexin 

O 

O 

R2 R6 R 8 

OH H Glc 

OH Glc H 




Intragastric administration of 5.0 g/kg body weight (bw) of a 60% ethanol 

extract of Herba Passifl orae per day for 3 weeks to rats did not reduce the 

pain response as measured in the tail-fl ick test using radiant heat, and no 

reductions in body temperature were observed (17). Intragastric administration 

of a 30% ethanol extract of the aerial parts reduced phenylbenzoquinone-induced 

writhing in mice, median effective dose 1.9 ml/kg bw (18). 


Intragastric administration of 75.0–500.0 mg/kg bw of an ethanol extract 

of the aerial parts to rats reduced carrageenan-induced infl ammation in 

the hind-paw model 60 minutes after administration (19). Intragastric administration 

of 500.0 mg/kg bw of the same extract to rats signifi cantly 

reduced (16–20%; P < 0.05–0.001) the weight of granulomas induced by 

the implantation of cotton pellets (19). 

OH 

H 

H 

H 

H 

H 

CH 3 

OH 

Glc Glc 

Glc 

Ara 

Ara 

Glc 

Glc Glc 

H Glc 

Glc H 

Glc 

HO 

OH 

HO 

OH 


Ara = 

= 

HO 

OH 

OH 

α-L-arabinopyranosyl 

O 

O 

261


Total leukocyte migration into the rat pleural cavity was reduced by 

approximately 40% in rats with induced pleurisy following intragastric 

administration of 500.0 mg/kg bw of an ethanol extract of the aerial parts. 

This effect was due to the suppression of polymorphonuclear and mononuclear 

leukocyte migration, and the effect was similar to that of 250.0 mg/ 

kg bw of acetylsalicylic acid (19). 


A 50% ethanol extract of up to 500.0 mg/ml of the aerial parts did not 

inhibit the growth of the following fungi: Aspergillus fumigatus, Botrytis 

cinerea, Fusarium oxysporum, Penicillium digitatum, Rhizopus nigricans 

and Candida albicans (20). A methanol extract of the aerial parts inhibited 

the growth of Helicobacter pylori, minimum inhibitory concentration 

50.0 μg/ml (21). 


In vitro perfusion of guinea-pig heart with a 30% ethanol extract of the 

aerial parts, 0.001%, increased the force of contraction of the heart muscle. 

Intravenous administration of 0.05 ml/kg bw of the extract had no 

effect on blood pressure in guinea-pigs or rats (18). 


Intraperitoneal injection of 25.0 mg/kg bw of an aqueous extract of the 

aerial parts to mice reduced spontaneous locomotor activity and coordination. 

However, intraperitoneal administration of the same dose of a fl uidextract 

to mice did not reduce motor activity (22). Intraperitoneal or intragastric 

administration of 60.0–250.0 mg/kg bw of a 30% ethanol or 

40% ethanol extract to mice reduced spontaneous locomotor activity. Intragastric 

administration of 60.0 mg/kg bw of the 40% ethanol extract 

also potentiated pentobarbital-induced sleeping time, and intraperitoneal 

administration of 50 mg/kg bw signifi cantly (P < 0.05) delayed the onset 

of pentylenetetrazole-induced seizures (23). 

The effects of an aqueous or 30% ethanol extract of the aerial parts 

were assessed in mice using the unconditioned confl ict test, the light/dark 

box choice procedure and the staircase test. The extracts were administered 

at doses of 100.0 mg/kg bw, 200.0 mg/kg bw, 400.0 mg/kg bw or 

800.0 mg/kg bw, while control animals received normal saline. The aqueous 

extract reduced motor activity in the staircase and free exploratory 

tests, as measured by the number of rears, steps climbed or locomotor 

crossings following administration of the 400.0 mg/kg and 800.0 mg/kg 

doses. The aqueous extract also potentiated pentobarbital-induction of 

sleep. The 30% ethanol extract was not active in these tests, but appeared 

262


to increase activity of the animals, having an anxiolytic effect at the 

400.0 mg/kg dose (24). 

Intraperitoneal administration of 160.0–250.0 mg/kg bw of an aqueous 

extract of the aerial parts to mice delayed pentylenetetrazole-induced 

convulsions, increased pentobarbital-induced sleeping time and reduced 

spontaneous motor activity (25). 

Intragastric administration of a 30% ethanol extract of the aerial parts, 

corresponding to 5.0 g/kg bw, per day for 3 weeks to rats had no effect on 

body weight, rectal temperature, tail-fl ick or motor coordination. However, 

in a one-armed radial maze, the treated animals demonstrated a reduction 

in motor activity. No changes were observed in electroencephalographic 

parameters in the treated animals (17). 

Intragastric administration of 800.0 mg/kg bw of a dried 30% ethanol 

extract of the aerial parts (containing 2.6% fl avonoids) to mice did not 

affect locomotor activity, but did prolong hexobarbital-induced sleeping 

time (26). 

Chrysin displayed high affi nity for the benzodiazepine receptors in 

vitro, and reduced locomotor activity in mice following intraperitoneal 

administration of 30.0 mg/kg bw (27, 28). At the same dose, chrysin also 

increased pentobarbital-induced hypnosis (28). 


A fl uidextract of the aerial parts, 1.0 mol/l, stimulated strong contractions 

in guinea-pig and rabbit uterus (not pregnant) in vitro (22). However, a 

fl uidextract, 1.0–2.0 mol/l, did not stimulate contractions in the isolated 

uterus from pregnant guinea-pigs (29). 

Toxicology 

The oral median lethal dose of a 30% ethanol extract of the aerial parts in 

mice was 37.0 ml/kg bw (18). Toxicity in mice of an aqueous extract was 

observed only after intraperitoneal administration of 900.0 mg/kg bw 

(25). No acute toxicity was observed in mice given extracts of the aerial 

parts at doses of 500.0 mg/kg bw or 900.0 mg/kg bw (25, 30). 


No clinical data available for mono-preparations of Herba Passifl orae. 


A single case of hypersensitivity with cutaneous vasculitis and urticaria 

following ingestion of tablets containing an extract of Herba Passifl orae 

was reported (31). In one case, use of the aerial parts was associated with 

IgE-mediated occupational asthma and rhinitis (32). A single case of se- 

263


vere nausea, vomiting, drowsiness, prolonged QT segment and episodes 

of non-sustained ventricular tachycardia was reported in a female subject 

after self-administration of a therapeutic dose of the aerial parts (33). 

However, the clinical signifi cance of this reaction has not been evaluated. 


Herba Passifl orae has been shown to stimulate uterine contractions in 

animal models (22). Its use is therefore contraindicated during pregnancy. 

Warnings 

May cause drowsiness. The ability to drive a car or operate machinery 

may be impaired. 

Precautions 


A fl uidextract of Herba Passifl orae was not genotoxic at concentrations 

up to 1.3 mg/ml in Aspergillus nidulans, as assessed in a plate incorporation 

assay that permitted the detection of somatic segregation as a result 

of mitotic crossing-over, chromosome mal-segregation or clastogenic effects. 

No signifi cant increase in the frequency of segregant sectors per 

colony were observed at any tested dose (34). 




Owing to the lack of data concerning its safety and effi cacy, Herba Passifl 

orae should not be used by nursing mothers without consulting a 



Owing to the lack of data concerning its safety and effi cacy, Herba Passifl 

ora should not be administered to children without consulting a healthcare 

practitioner. 


264





Dosage forms 

Powdered dried aerial parts, capsules, extracts, fl uidextract and tinctures 

(5). Store in a tightly sealed container away from heat and light. 

Posology 


Daily dose, adults: as a sedative: 0.5–2.0 g of aerial parts three to four 

times; 2.5 g of aerial parts as an infusion three to four times; 1.0–4.0 ml 

tincture (1:8) three to four times; other equivalent preparations accordingly 

(2, 11). 

References 




1996. 

3. European pharmacopoeia, 3rd ed. Suppl. 2001. Strasbourg, Council of Europe, 

2000. 





Press, 1994. 






1950. 



9. Lutomski J, Malek B. Pharmakochemische Untersuchungen der Drogen der 

Gattung Passifl ora. 4. Mttlg.: Der Vergleich des Alkaloidgehaltes in verschiedenen 

Harmandrogen. [Pharmacological investigation on raw materials of 

the genus Passifl ora. 4. The comparison of contents of alkaloids in some harman 

raw materials.] Planta medica, 1975, 27:381–384. 



265








Switzerland). 

14. Schmidt PC, Ortega GG. Passionsblumenkraut: Bestimmung des Gesamtfl 

avonoid gehaltes von Passifl orae herba. [Passion fl owers: Determination of 

total fl avonoids in pharmacognostic preparations.] Deutsche Apotheker Zeitung 

1993, 133:4457–4466. 

15. Li Q et al. Mass spectral characterization of C-glycosidic fl avonoids isolated 

from a medicinal plant (Passifl ora incarnata). Journal of Chromatography, 

1991, 562:435–446. 

16. Meier B. Passifl ora incarnata L. – Passionsblume. [Passifl ora incarnata L. – 

passion fl ower.] Zeitschrift für Phytotherapie, 1995, 16:115–126. 

17. Sopranzi N et al. Parametri biologici ed electroencefalografi ci nel ratto correlati 

a Passifl ora incarnata L. [Biological and electroencephalographic parameters 

in rats associated with Passifl ora incarnata L.] Clinica Terapia, 1990, 

132:329–333. 


Medita, 1978, 8:3–19. 

19. Borrelli F et al. Anti-infl ammatory activity of Passifl ora incarnata L. in rats. 

Phytotherapy Research, 1996, 10:S104–S106. 

20. Guérin JC, Réveillère HP. Activité antifungique d’extraits végétaux à usage 

thérapeutique. II. Étude de 40 extraits sur 9 souches fongiques. [Antifungal 

activity of plant extracts used in therapy. II. Study of 40 plant extracts against 

9 fungi species.] Annales Pharmaceutiques Françaises, 1985, 43:77–81. 



2000, 7(Suppl. II):79. 

22. Ruggy GH, Smith CS. A pharmacological study of the active principle of 

Passifl ora incarnata. Journal of the American Pharmaceutical Association. 

Scientifi c Edition, 1940, 29:245. 

23. Speroni E et al. Sedative effects of crude extract of Passifl ora incarnata after 

oral administration. Phytotherapy Research, 1996, 10:S92–S94. 

24. Soulimani R et al. Behavioural effects of Passifl ora incarnata L. and its indole 

alkaloid and fl avonoid derivative and maltol in the mouse. Journal of Ethnopharmacology, 

1997, 57:11–20. 

25. Speroni E, Minghetti A. Neuropharmacological activity of extracts from 

Passifl ora incarnata. Planta Medica, 1988, 54:488–491. 

26. Della Loggia R, Tubaro A, Redaelli C. Valutazione dell’attività sul S.N.C. del 

topo di alcuni estratti vegetali e di una loro associazione. [Evaluation of the 

activity on the mouse CNS of several plant extracts and a combination of 

them.] Rivista Neurologia, 1981, 51:297–310. 

266


27. Medina JH et al. Chrysin (5,7-dihydroxyfl avone) a naturally occurring ligand 

for the benzodiazepine receptors, with anticonvulsant properties. Biochemical 

Pharmacology, 1990, 40:2227–2231. 

28. Speroni E et al. Role of chrysin in the sedative effects of Passifl ora incarnata 

L. Phytotherapy Research, 1996, 10:S98–S100. 

29. Pilcher JD, Mauer RT. The action of “female remedies” on the intact uteri of 

animals. Surgery, Gynecology and Obstetrics, 1918, 27:97–99. 

30. Aoyagi N, Kimura R, Murata T. Studies on Passifl ora incarnata dry extract. 

I. Isolation of maltol and pharmacological action of maltol and ethyl maltol. 

Chemical and Pharmaceutical Bulletin, 1974, 22:1008–1113. 

31. Smith GW, Chalmers TM, Nuki G. Vasculitis associated with herbal preparation 

containing Passifl ora extract. British Journal of Rheumatology, 1993, 

32:87–88. 

32. Giavina-Bianchi PF et al. Occupational respiratory allergic disease induced 

by Passifl ora alata and Rhamnus purshiana. Annals of Allergy, Asthma, and 

Immunology, 1997, 79:449–454. 

33. Fisher AA, Purcell P, Le Couteur DG. Toxicity of Passifl ora incarnata L. 

Journal of Toxicology. Clinical Toxicology, 2000, 38:63–66. 

34. Ramos-Ruiz A et al. Screening of medicinal plants for induction of somatic 

segregation activity in Aspergillus nidulans. Journal of Ethnopharmacology, 

1996, 52:123–127. 

267

268 

Testa Plantaginis 

Defi nition 

Testa Plantaginis consists of the epidermis and collapsed adjacent layers 

removed from the seeds of Plantago ovata Forsk. (Plantaginaceae) (1, 

2). 

Synonyms 

Plantago brunnea Morris, P. decumbens Forsk., P. fastigiata Morris, 

P. gooddingii Nelson et Kennedy, P. insularis Eastw., P. ispaghula Roxb. 

ex Flem., P. lanata Willd. ex Spreng., P. leiocephala Wallr., P. microcephala 

Poir., P. minima Cunn., P. trichophylla Nab., P. villosa Moench. 

(3). 


Ashwagolam, aspaghol, aspagol, bazarqutuna, blond psyllium, Blondes 

Psyllium, Ch’-Ch’ientzu, esfarzeh, esopgol, esparzeh, fi syllium, ghoda, 

grappicol, Indian plantago, Indische Psyllium, isabakolu, isabgol, isabgul, 

isabgul gola, isapagala-vittulu, ishppukol-virai, ispaghula, isphagol, vithai, 

issufgul, jiru, kabbéche, lokmet an naâja, obako, psyllium, plantain, spogel 

seed plantain (3–5). 


Indigenous to Asia and the Mediterranean countries. Cultivated extensively 

in India and Pakistan; adapts to western Europe and subtropical 

regions (6–8). 

Description 

An annual, acaulescent herb. Stem highly ramifi ed bearing linear leaves, 

which are lanceolate, dentate and pubescent. Flowers white and grouped 

into cylindrical spikes; sepals characterized by a distinct midrib extending 

from the base to the summit; petal lobes oval with a mucronate summit. 

Seeds oval, clearly carinate, 2–3 mm long, light grey-pink, with a brown 

line running along their convex side (6).

Plant material of interest: dried seed coats (epidermis) 


Pinkish-beige fragments or fl akes up to 2 mm long and 1 mm wide, some 

showing a light brown spot corresponding to the location of the embryo 

before it was removed from the seed (2). 


Odour: weak, characteristic; taste: mucilaginous (9). 



Particles angular, edges straight or curved and sometimes rolled. Composed 

of polygonal prismatic cells with four to six straight or slightly 

curved walls; cells vary in size in different parts of the seed coat, from 

about 25–60 μm long at the summit of the seed to 25–100 μm for the remainder 

of the epidermis, except at the edges of the seed, where the cells 

are smaller, about 45–70 μm (3). 


Pale to medium buff-coloured, having a slight pinkish tinge and a weak 

characteristic odour. Entire or broken epidermal cells, which appear polygonal 

to slightly rounded in surface view and are fi lled with mucilage. 

Occasional single and compound (two to four components) starch granules, 

the individual grains being spheroidal plano- to angular-convex 2– 

25 μm in diameter, embedded in the mucilage. Mucilage stains red with 

ruthenium red and lead acetate TS. Also present, some elongated and rectangular 

cells from the lower part of epidermis, and radially swollen epidermal 

cells (2). 


Macroscopic and microscopic examinations (2) and thin-layer chromatography 

for the presence of arabinose, xylose and galactose (2). 

Purity tests 






Complies with the test for foreign matter determined on 5.0 g of material 

(2). 

269


Total ash 




Swelling index 

Not less than 40 (2). 






Heavy metals 







Chemical, sulfated ash, acid-insoluble ash, water-soluble extractive and 

alcohol-soluble extractive tests to be established in accordance with national 

requirements. 


To be established in accordance with national requirements. Plantago 

products can be assayed for their fi bre content by the Association of Offi 

cial Analytical Chemists method (13). 


The major constituent is a mucilaginous hydrocolloid (20–30%), which is 

a soluble polysaccharide fraction composed primarily of an arabinoxylan 

(up to 85%). The polymer backbone is a xylan with 1→ 3 and 1→ 4 linkages 

with no apparent regularity in their distribution. The monosaccharides 

in this main chain are substituted on C-2 or C-3 by l-arabinose, 

d-xylose, and α-d-galacturonyl-(1→2)-l-rhamnose. Fixed oil (5–10%) 

is another major constituent (5, 9, 14–16). 

270




A bulk-forming laxative used therapeutically for restoring and maintaining 

bowel regularity (15, 17–26). Treatment of chronic constipation, temporary 

constipation due to illness or pregnancy, irritable bowel syndrome 

and constipation related to duodenal ulcer or diverticulitis (18, 27). Also 

indicated for stool softening in the case of haemorrhoids, or after anorectal 

surgery (18, 20). As a dietary supplement in the management of hypercholesterolaemia, 

to reduce the risk of coronary heart disease (28), and 

reduce the increase in blood sugar levels after eating (24). 


Short-term use for the symptomatic treatment of diarrhoea of various 

etiologies (29–31). 


As an expectorant, antitussive and diuretic. Treatment of rheumatism, 

gout, glandular swelling and bronchitis (5, 8). 

Pharmacology 


Antidiarrhoeal activity 

Intragastric administration of 0.4 g of Testa Plantaginis per day inhibited 

Escherichia coli-induced diarrhoea in pigs (32). Intragastric administration 

of the seed coats to calves, 18.89 g/l of oral rehydration solution, did 

not reduce the number or frequency of stools (33). 


Administration of the seed coats in the diet, 10%, to African green monkeys 

fed a high-cholesterol diet for 3.5 years signifi cantly (P < 0.05) reduced 

plasma cholesterol levels by 39% and inhibited the activity of 

3-hydroxy-3-methylglutaryl-coenzyme A reductase in the liver and 

intestine (34). A further study in these animals also showed that this administration 

of the seed coats reduced plasma cholesterol concentrations 

by decreasing the synthesis of low-density lipoproteins (LDL) (35). Administration 

of the seed coats in the diet, 7.5%, to hamsters reduced cholesterol 

concentrations and increased sterol loss in the liver. The mechanism 

of action appears to involve a reduction of LDL cholesterol 

production and an increase in receptor-mediated LDL clearance (36). Administration 

of the seed coats, 7.5 g/100 g body weight (bw) daily to guinea-pigs 

fed a high-cholesterol diet signifi cantly (P < 0.0001) reduced plas- 

271


ma cholesterol levels by 39% as compared with controls (37). Alterations 

in hepatic cholesterol metabolism were observed in guinea-pigs after the 

administration of the seed coats (dose not specifi ed). Treated animals fed 

a high fat and sucrose diet showed reductions in plasma LDL cholesterol, 

triacylglycerol, apolipoprotein B and hepatic cholesteryl ester concentrations, 

and a 45% increase in the number of hepatic apolipoprotein A/E 

receptors (38). 

Administration of Testa Plantaginis in the diet, 5.0%, to rats reduced 

serum cholesterol concentrations (39). Administration of the seed coats in 

the diet, 10.0%, reduced total serum cholesterol concentrations and increased 

high-density lipoprotein (HDL) cholesterol in rats fed a highcholesterol 

diet (40). Administration of the seed coats in the diet, 5.0%, to 

rats signifi cantly (P < 0.0001) lowered an increase in serum cholesterol 

concentrations induced by feeding the animals trans-fatty acids (corn-oil 

margarine) (41). 


Administration of the seed coats in the diet, 2.5%, for 18 weeks to mice 

with genetically-induced diabetes reduced blood glucose levels and increased 

blood insulin concentrations (42). 

Effects on bile acids 

Administration of the seed coats in the diet, 5.0%, for 5 weeks to rats increased 

bile acid synthesis and lowered the hydrophobicity of the bile 

acid pool (43). Administration of the seed coat in the diet, 5.0%, to dogs 

fed a lithogenic diet for 6 weeks reduced the incidence of cholesterol gallstones 

by reducing the biliary cholesterol saturation index (44). Administration 

of the seed coats in the diet, 4.0–6.0%, for 5 weeks to hamsters fed 

a lithogenic diet increased faecal bile acid excretion by 400%, and reduced 

the concentration of taurine-conjugated bile acids in those receiving the 

highest dose. In addition, the treatment normalized the lithogenic index 

and prevented cholesterol gallstone formation as compared with controls 

(45). Administration of the seed coats in the diet, 8.0%, for 5 weeks to 

hamsters increased daily faecal neutral sterol excretion by 90% owing to 

higher faecal output. Daily faecal bile acid excretion and total faecal bile 

acid concentrations were also increased (46). 


Administration of the seed coats in the diet, 10.0–20.0%, for 4 weeks to 

rats resulted in increased levels of gastric, intestinal and colonic mucin, 

and increased faecal weight compared with control animals (47). In vitro, 

272


a 70% methanol extract of the seed coats, 6.0 mg/ml, stimulated contractions 

of isolated guinea-pig ileum (48). 



In patients with acute and chronic diarrhoea, 10 g of Testa Plantaginis per 

day for 7 days increased the viscosity of the intestinal contents, owing to 

the binding of fl uid by the seed coats, thereby decreasing the frequency of 

defecation (29, 30). 

In a placebo-controlled trial, 10 female patients with diarrhoeapredominant 

irritable bowel syndrome were treated with 3.4 g of the 

seed coats three times per day for 4 weeks after an initial 4-week baseline 

placebo period. The treatment signifi cantly improved patient global 

satisfaction with bowel function (P < 0.02), and urge to defecate (P < 0.01) 

compared with placebo. Treatment also reduced movement frequency 

and doubled stool viscosity (31). 

Eight subjects participated in a randomized, placebo-controlled crossover 

study on the moderation of lactulose-induced diarrhoea in irritable 

bowel syndrome. Gastric emptying and small bowel and colonic transit 

were measured following consumption of 20 ml of lactulose three times 

per day with or without 3.5 g of Testa Plantaginis three times per day. 

The seed coats signifi cantly delayed gastric emptying by 50% (P < 0.05); 

small bowel transit was unchanged, and progression through the colon 

was delayed. It was concluded that the seed coats probably delayed gastric 

emptying by increasing meal viscosity, and reduced the acceleration 

of colon transit by delaying the production of gaseous fermentation 

products (49). 


Numerous clinical investigations with the seed coats have demonstrated a 

reduction in serum cholesterol levels in patients with mild to moderate 

hypercholesterolaemia (23, 26). A meta-analysis assessed the hypolipidaemic 

effects and safety of the seed coats when used as an adjunct to a 

low-fat diet in men and women with hypercholesterolaemia. Eight clinical 

trials met the criteria for the meta-analysis and included a total of 384 

and 272 subjects receiving the seed coats or cellulose placebo, respectively. 

All of the trials evaluated the hypocholesterolaemic effects of 10.2 g of the 

seed coats daily together with a low-fat diet for ≥ 8 weeks. Consumption 

of seed coats signifi cantly lowered serum total cholesterol by 4% 

(P < 0.0001), LDL cholesterol by 7% (P < 0.0001), and the ratio of apolipoprotein 

B to apolipoprotein A-I by 6% (P < 0.05) compared with pla- 

273


cebo. No effects on serum HDL or triacylglycerol concentrations were 


Another meta-analysis assessed the effi cacy of the consumption of a 

cereal product enriched with the seed coats in reducing blood total, LDL 

and HDL cholesterol levels in 404 adults with mild to moderate hypercholesterolaemia, 

who were also consuming a low-fat diet. Studies were 

considered to be eligible for inclusion in the meta-analysis if they were 

randomized controlled trials, and included a control group that ate cereal 

containing at least 3.0 g of soluble fi bre daily. Eight published and four 

unpublished studies, conducted in four countries, met the criteria. The 

results of the meta-analysis demonstrated that subjects who consumed 

cereals containing the seed coats had lower total and LDL cholesterol 

concentrations, with differences of 5% and 9%, respectively, than subjects 

who ate a control cereal; HDL cholesterol concentrations were unaffected. 

The analysis indicates that consumption of cereals enriched with 

the seed coats as part of a low fat diet improves the blood lipid profi le in 

hypercholesterolaemic adults to a greater extent than the low-fat diet 

alone (23). 

A multicentre clinical investigation assessed the long-term effectiveness 

of Testa Plantaginis fi bre as an adjunct to diet in the treatment of 

primary hypercholesterolaemia. Subjects were required to follow an 

American Heart Association Step I diet for 8 weeks (dietary adaptation 

phase). Eligible subjects with serum LDL-cholesterol concentrations of 

3.36–4.91 mmol/l were then randomly assigned to receive 5.1 g of the seed 

coats or a cellulose placebo twice per day for 26 weeks in conjunction 

with diet therapy. The results demonstrated that serum total and LDL 

cholesterol concentrations were 4.7% and 6.7% lower, respectively, in the 

treatment group than in the placebo group after 24–26 weeks (P < 0.001) 

(25). A multicentre, double-blind, placebo-controlled, randomized trial 

assessed the cholesterol-level-lowering effect of the seed coats with dietary 

advice compared with placebo and dietary advice in 340 patients 

with mild-to-moderate hypercholesterolaemia. An initial 8-week dietonly 

period was followed by a 2-week treatment period. Treatment with 

7.0 g or 10.5 g of the seed coats per day was continued for a further 

12 weeks in some patients. Levels of total, LDL and HDL cholesterol, 

triglycerides and apolipoproteins A1 and B were measured. Treatment 

with the seed coats at both doses produced signifi cantly greater reductions 

in LDL cholesterol levels than did placebo (P = 0.009 and P < 0.001). 

The seed coats plus modifi cation of diet reduced LDL cholesterol levels 

by 10.6–13.2% and total cholesterol levels by 7.7–8.9% during the 

6-month period (50). 

274


A randomized controlled clinical trial assessed the effects of the seed 

coats as an adjunct to a traditional diet for diabetes in the treatment of 

34 subjects with type 2 diabetes and mild-to-moderate hypercholesterolaemia. 

After a 2-week dietary stabilization phase, subjects were randomly 

assigned to receive 5.1 g of the seed coats or cellulose placebo twice per 

day for 8 weeks. The group treated with the seed coats showed signifi cant 

improvements in glucose and lipid values as compared with the placebo 

group. Serum total and LDL-cholesterol concentrations were 8.9% 

(P < 0.05) and 13.0% (P = 0.07) lower, respectively, than in the placebo 

group. All-day and post-lunch postprandial glucose concentrations were 

11.0% (P < 0.05) and 19.2% (P < 0.01) lower in the treated group (24). 

In a clinical trial, the diet of six normal and fi ve ileostomy subjects was 

supplemented with 10.0 g of the seed coats per day for 3 weeks, while six 

normal and four ileostomy subjects received 10.0 g of Plantago ovata 

seeds per day. Faecal and ileostomy output, sterol excretion, serum cholesterol 

and triglycerides were measured before and after supplementation. 

The seed coats had no effect on cholesterol or triglyceride concentrations 

in either normal or ileostomy subjects. Total and HDL 

cholesterol concentrations were reduced on average by 6.4% and 9.3%, 

respectively, in the normal group after seed supplementation. No effect 

on faecal bile acid excretion in the normal subjects was found in either 

group. Ileostomy bile acids were increased (on average 25%) after seed 

supplementation, whereas no effect on cholesterol concentrations was 

found. These results suggest that the seeds might be more effective than 

the seed coats in reducing serum cholesterol, that this cholesterol-lowering 

effect is not mediated by increased faecal bile acid losses, and that increased 

ileal losses of bile acids might be compensated for by enhanced 

reabsorption in the colon (51). 

In a double-blind, placebo-controlled study involving 26 men, supplementation 

of the diet with 3.4 g of the seed coats three times per day for 8 

weeks produced a decrease in serum cholesterol (-14.8%) and LDL cholesterol 

(-20.2%) (52). In a similar study, in which the seed coats were 

added to a low-fat diet, improvements in cholesterol parameters were observed 

after 8 weeks of therapy (53). The reduction in serum cholesterol 

may be due to increased excretion of bile acids in the faeces, which in turn 

stimulates synthesis of new bile acids from cholesterol (22, 54). 

In a clinical study to assess the effect of the seed coats on faecal bile 

acid weights and concentrations, 16 healthy adults consumed 7.0 g of the 

seed coats per day for the middle 8 weeks of a 12-week period. Stool 

samples were collected and analysed for faecal bile acid content, and their 

form and dry weight were determined. Administration of the seed coats 

275


signifi cantly (P < 0.01) lowered faecal lithocholic and isolithocholic acids 

and the weighted ratio of lithocholic acids to deoxycholic acid. The change 

in the faecal bile acid profi le indicates a reduction in the hydrophobicity 

of the bile acids in the enterohepatic circulation (55). 

Laxative activity 

Administration of the seed coats, solubilized in water, increases the volume 

of the faeces by absorbing fl uids in the gastrointestinal tract, thereby stimulating 

peristalsis (56). The seed coats also reduce intraluminal pressure, 

increase colon transit time, and increase the frequency of defecation (18, 20, 

57). Soluble fi bres, such as those contained in the seed coats, are rapidly 

metabolized by colonic bacteria to volatile fatty acids, which are then absorbed 

by the colon, and increase the production of colonic mucin. 

The therapeutic effi cacy of the seed coats is due to the swelling of the 

mucilaginous fi bre when mixed with water, which gives bulk and lubrication 

(22). The seed coats increase stool weight and water content owing to 

the water-bound fi bre residue, and an increased faecal bacterial mass (18, 

20). Clinical studies have demonstrated that ingestion of 18.0 g of the seed 

coats increases faecal fresh and dry weights as compared with placebo 

(15). 

The digestibility of the seed coats and their faecal bulking effect were 

studied in seven healthy volunteers who ingested a low-fi bre diet plus 

either placebo or the seed coats, 18 g/day, during two 15-day periods. 

There were no differences between the groups in whole gut transit time 

and gas excretion in breath and fl atus. Faecal wet and dry weights rose 

signifi cantly (P = 0.009 and P = 0.037, respectively) in the treated subjects. 

Faecal short-chain fatty acid concentrations and the molar proportions 

of propionic and acetic acids also increased in the treated group 

(15). 


Sudden increases in dietary fi bre may cause temporary gas and bloating. 

These side-effects may be reduced by a gradual increase of fi bre intake, 

starting at one dose per day and gradually increasing to three doses per 

day (58). Occasional fl atulence and bloating can be reduced by decreasing 

the amount of the seed coats taken for a few days (58). 

Allergic reactions to ingestion or inhalation of Plantago products have 

been reported, especially after previous occupational exposure to these 

products (59–64). These reactions range from urticarial rashes to anaphylactic 

reactions (rare) (60, 65). One rare case of fatal bronchospasm has 

been reported in a Testa Plantaginis-sensitive patient with asthma (62). 

276



Testa Plantaginis should not be used by patients with faecal impaction, 

undiagnosed abdominal symptoms, abdominal pain, nausea or vomiting 

unless advised by their health-care provider. Testa Plantaginis is also contraindicated 

following any sudden change in bowel habits that persists for 

more than 2 weeks, in rectal bleeding or failure to defecate following use 

of a laxative, and in patients with constrictions of the gastrointestinal 

tract, potential or existing intestinal blockage, megacolon, diabetes mellitus 

that is diffi cult to regulate, or known hypersensitivity to the seed coats 

(14, 22). 

Warnings 

To minimize the potential for allergic reaction, health professionals who 

frequently dispense powdered products prepared from Testa Plantaginis 

should avoid inhaling airborne dust while handling these products. To 

prevent generating airborne dust, the product should be spooned from 

the packet directly into a container and then the liquid should be added 

(58). 

Testa Plantaginis products should always be taken with suffi cient 

amounts of liquid, e.g. 5.0 g of the seed coats with 150 ml of liquid. Failure 

to do so may result in swelling of the seed coats and blockage of the 

oesophagus, which may cause choking. Intestinal obstruction may occur 

if an adequate fl uid intake is not maintained. The seed coats should not be 

used by those with diffi culty in swallowing or throat problems. Anyone 

experiencing chest pain, vomiting or diffi culty in swallowing or breathing 

after taking Testa Plantaginis should seek immediate medical attention. 

Treatment of the elderly and the debilitated requires medical supervision. 

Testa Plantaginis should be taken at least 2 h before or after other medications 

to prevent delayed absorption of other drugs (66). If bleeding, or 

no response and abdominal pain occur 48 h after ingesting the seed coats, 

treatment should be discontinued and medical advice sought (58). 

Precautions 

General 

Testa Plantaginis should be taken with adequate volumes of fl uid. Products 

should never be taken orally in dried powder form owing to possibility 

of causing bowel or oesophageal obstruction. In patients confi ned to 

bed or undertaking little physical exercise, a medical examination may be 

necessary prior to treatment with the seed coats. 

277



Bulking agents may diminish the absorption of some minerals (calcium, 

magnesium, copper and zinc), vitamins (B 12 ), cardiac glycosides and coumarin 

derivatives (3, 52, 67–68). However, more recent studies suggest 

that since seed coats do not contain phytates, they will not bind to vitamins 

and minerals and are therefore no cause for concern (69–71). The 

co-administration of the seed coats with lithium salts may reduce plasma 

concentrations of the latter and inhibit their absorption from the gastrointestinal 

tract (72). The seed coats may also decrease the rate and extent 

of carbamazepine absorption, and induce subclinical levels of the drug. 

Ingestion of lithium salts or carbamazepine and the seed coats should 

therefore be separated by as long an interval as possible (73). Ingestion of 

the seed coats 2 hours before or after the administration of other drugs is 

suggested (66). Individual monitoring of the plasma levels of these drugs, 

especially in patients also taking products containing Testa Plantaginis is 

also recommended. Insulin-dependent diabetics may require less insulin 

(14). 



test interactions; carcinogenesis, mutagenesis, impairment of fertility; 

teratogenic and non-teratogenic effects in pregnancy; nursing mothers; or 

paediatric use. 

Dosage forms 

Dried seed coats available commercially as chewable tablets, granules, 

wafers and powder. Store in a well closed container, in a cool dry place, 

protected from light (2, 19). 

Posology 


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71. Davidson MH et al. Long-term effects of consuming foods containing 

psyllium seed husk on serum lipids in subjects with hypercholesterolemia. 

American Journal of Clinical Nutrition, 1998, 67:367–376. 

72. Pearlman BB. Interaction between lithium salts and ispaghula husks. Lancet, 

1990, 335:416. 

73. Etman MA. Effect of a bulk forming laxative on the bioavailability of carbamazepine 

in man. Drug development and industrial pharmacy, 1995, 21:1901–1906. 

282

Radix Rehmanniae 

Defi nition 

Radix Rehmanniae consists of the dried roots and rhizomes of Rehmannia 

glutinosa Libosch. or Rehmannia glutinosa Libosch. var. purpurea 

Makino (Scrophulariaceae) (1–4). 1 

Synonyms 

Digitalis glutinosa Gaertn., Gerardia glutinosa Bunge, Rehmannia chinensis 

Libosch., R. sinensis (Buc’hoz) Libosch. ex Fisch. et C.A. Mey. (5). 


Akayajio, di-huang, cû sinh dja, dihuang, dihuáng, dja hoâng, fi gwort, 

ji-whang, rehmannia, sheng dihuang, sheng-ti-pien, shu di, sin dja, ti 

huang (4–7). 


Indigenous to China. Cultivated in China, Japan and Republic of Korea 

(6, 8). 

Description 

A perennial herb 10–40 cm high, with a thick, orange tuberous root, about 

3–6 cm in diameter. Basal leaves fasciculate, obovate or long elliptic, 3– 

10 cm long, 1.5–2.0 cm wide; apex obtuse; tapering to a short petiole, 

coarsely dentate, pubescent, the underside often reddish. Flowers are solitary, 

borne in leaf axils; calyx fi ve-lobed, upper lobes longest; corolla 

obliquely funnel form, slightly swollen on lower side, about 4 cm long, 

dull purple-brown and creamy yellow, densely glandular-pubescent, twolipped; 

upper lobes shorter than the three lower lobes; tube with two 

ridges extending inside from sinuses of lower lip; four stamens borne near 

1 In the Pharmacopoeia of the People’s Republic of China (4), fresh plant material is also permitted. 

In The Japanese Pharmacopoeia (2), steam-treated root material is also permitted. 

283


base of corolla, anthers not coherent, disc ring-like, poorly developed; 

ovary superior, stigma two-lobed. Fruits are capsules (6, 8). 



Fusiform root, 5–12 cm long, 1–6 cm in diameter, often broken or markedly 

deformed in shape. Externally, yellow-brown to blackish brown, with 

deep, longitudinal wrinkles and constrictions. Texture soft and tenacious, 

not easily broken. In transverse section yellow-brown to blackish brown, 

and cortex darker than xylem in colour. Pith hardly observable (1, 2, 4). 


Odour: characteristic; taste: slightly sweet, followed by a slight bitterness 

(1, 2, 4). 


Transverse sections of the root show 7–15 layers of cork cells. Cortex 

parenchyma cells loosely arranged. Outer region of cortex composed of 

scattered secretory cells containing orange-yellow oil droplets. Stone cells 

occasionally found. Phloem relatively broad. Cambium is in a ring. 

Xylem rays broad, vessels sparse and arranged radially (1, 2, 4). 


Dark brown. Cork cells brownish, subrectangular in lateral view, regularly 

arranged. Parenchyma cells subrounded, containing subrounded nuclei. 

Secretory cells similar to ordinary parenchyma cells in shape, containing 

orange or orange-red oil droplets. Border pitted and reticulated 

vessels up to about 92 μm in diameter (3, 4). 


Macroscopic and microscopic examinations (1–4), and thin-layer chromatography 

(3, 4). A high-performance liquid chromatography method 

for catalpol, the major iridoid monoterpene, is available (9). 

Purity tests 





284

Total ash 

Not more than 6% (1, 2, 4). 




Not less than 65% (3, 4). 






Heavy metals 







Chemical, foreign organic matter, sulfated ash, alcohol-soluble extractive 

and loss on drying tests to be established in accordance with national requirements. 


To be established in accordance with national requirements. 



The major constituents are iridoid monoterpenes (2.6–4.8%) (13) including 

catalpol, ajugol, aucubin, rehmanniosides A–D, monomelittoside, 

melittoside, verbascoside, jionosides A1, A2, B1, B2, C, D and E (5, 7, 14, 

15). In addition, immunomodulating polysaccharides have also been reported 

(16–18). Representative structures of the iridoid monoterpenes are 

presented below. 

285


O 

H 

O 

rehmannioside C 

Glc 

R 

O 

CH3 H 

ajugol 

HO 

O 

R1 

H 

H 

O O 

OH 

HO HO 

OH O 

H 

R2 

H 

H 

O 

O 

H 

H 

catalpol 

rehmannioside A 

rehmannioside B 



None. Although published case reports indicate that Radix Rehmanniae 

is used for the treatment of rheumatoid arthritis and hypertension (19), 

data from controlled clinical trials are lacking. 


Internally for the symptomatic treatment of fevers, diabetes, hypertension, 

skin eruptions and maculation, sore throat, hypermenorrhoea 

and polymenorrhoea (4, 20). As a tonic to stimulate the immune system 

(21). 


As an antispasmodic, diuretic and emmenagogue. Treatment of burns, 

diarrhoea, dysentery, metrorrhagia and impotence (7, 20, 22, 23). 

286 

R1 R2 

H H 

Gal H 

H Gal 

HO 

R = H 

R = Gal 

HO 

HO 

HO H 

H 

HO HO 

OH 

H 

O 

O 

HO 

O 

R 

melittoside 

rehmannioside D 

O 

H 

O 

aucubin 

monomelittoside 

Glc 

H 

R = H 

R = OH 

R 

O 

H 

Glc 

O 

R = H 

R = Glc 

HO O 

O 

Gal = 

OH 

Glc = OH 

HO 

OH 

OH 

β-D-galactopyranosyl 


HO


Pharmacology 


Antibacterial activity 

A hot aqueous extract of Radix Rehmanniae (concentration not specifi ed) 

did not inhibit the growth of Staphylococcus aureus or Escherichia coli in 

vitro (24). 


Intragastric administration of 2.0 g/kg body weight (bw) of an aqueous extract 

of the roots had no effects on serotonin-induced diarrhoea in mice (25). 


A decoction of the roots, 25.0 μl/ml, inhibited hepatitis antigen expression 

in cultured hepatocytes infected with hepatitis B virus (26). An 80% 

methanol extract of the roots, 1.0 mg/ml, signifi cantly inhibited (P < 0.05) 

the release of lactate dehydrogenase, glutamate-oxaloacetate transaminase 

(GOT) and glutamate-pyruvate transaminase (GPT) induced by carbon 

tetrachloride treatments in rat hepatocytes (27). 

Intraperitoneal administration of 500.0 mg/kg bw of a methanol extract 

of roots to rats inhibited the increase in blood alkaline phosphatase, 

GOT and GPT activities caused by hepatotoxicity induced by α-naphthyl-isothiocyanate 

or carbon tetrachloride (28, 29). 


Intragastric administration of an aqueous or methanol extract of the roots, 

200.0 mg/kg bw or 111.5 mg/kg bw, to rats decreased streptozocin-induced 

hyperglycaemia (30). However, no such effects were observed in 

diabetic rats treated orally with 1.6–2.0 g/kg bw of a hot aqueous extract 

or a decoction of the roots daily for 8 days. These data suggest that the 

chemical constituents responsible for the activity may be heat sensitive 

(31–33). 

Intraperitoneal administration of 100.0 mg/kg bw of a polysaccharideenriched 

extract of the roots to mice decreased streptozocin-induced hyperglycaemia, 

reduced the activities of glucose-6-phosphatase and phosphofructokinase, 

stimulated the activities of glucose-6-phosphate 

dehydrogenase and hexokinase, and stimulated insulin release from the 

pancreas (34). 


Intragastric administration of 200.0 mg/kg bw of a 50% ethanol extract of 

the roots to rats did not inhibit carrageenan-induced footpad oedema or 

adjuvant-induced arthritis (35). 

287



After 24 h of treatment with polysaccharides isolated from the roots, 

0.1 mg/ml, p53 gene expression in Lewis lung cancer cells increased almost 

four-fold (36). Intraperitoneal administration of 20.0 mg/kg bw or 

40.0 mg/kg bw of polysaccharides isolated from the roots to mice increased 

the expression of the proto-oncogene c-fos by ~50% and decreased 

the expression of c-myc by ~ 30% compared with administration 

of saline (37). Intraperitoneal administration of 20.0–40.0 mg/kg bw of a 

polysaccharide isolated from the roots daily for 8 days after the second 

day of tumour transplantation inhibited the growth of solid tumours 

S180, Lewis B16, and H22 in mice. Oral treatment was only effective 

against S180. Treatment also enhanced the proliferation of splenic T lymphocytes 

and blocked the inhibition of natural killer cell activity caused 

by tumour cell growth (16). 


Intragastric administration of 6.0 g/kg bw of an aqueous extract of the 

roots to rats reduced absolute ethanol-induced gastric mucosal damage 

by 74.7%. The protective effects of the extract were reduced when the 

animals were pretreated with a decoction of chilli fruits (40–80%), suggesting 

that they were mediated by capsaicin-sensitive neurons in the gastric 

mucosa (38). 

Central nervous system depressant effects 


roots prolonged pentobarbital-induced sleeping time in mice with stress- 

or yohimbine-induced sleep deprivation (39). 

Enzyme-inhibiting effects 

A petroleum ether extract of the roots inhibited the activity of aldose reductase, 

median inhibitory concentration (MIC) 8.5 μg/ml (40). An aqueous 

extract of the roots (concentration not specifi ed) inhibited the activity 

of angiotensin II (41). A decoction of the roots inhibited the activity of a 

sodium/potassium adenosine triphosphatase isolated from horse kidney, 

MIC 5.76 mg/ml. A 95% ethanol extract of the roots was not active in 

this assay (42). 

Haematological effects 

Intragastric administration of 10.0–20.0 mg/kg bw of an oligosaccharide 

fraction isolated from the roots daily for 8 days to senescence-accelerated 

mice enhanced DNA synthesis in bone marrow cells, increased the 

number of granulocyte/macrophage progenitors, and increased early- 

288


and late-differentiated erythrocyte progenitors (43). Intragastric administration 

of (10.0–20.0 mg/kg bw of an oligosaccharide fraction isolated 

from the roots to senescence-accelerated mice enhanced the proliferation 

of hematopoietic stem cells, and increased the number of colonyforming-unit 

granulocytes/macrophages, colony-forming- and burstforming-unit 

erythroid cells, and the concentration of peripheral 

leukocytes (44). Intragastric administration of a decoction of the roots 

(dose not specifi ed) to mice inhibited blood clotting induced by acetylsalicylic 

acid (45). A 50% ethanol extract of the roots increased erythrocyte 

deformability and erythrocyte ATP concentrations, and inhibited 

polybrene-induced erythrocyte aggregation and the activity of the fi brinolytic 

system (46). Intragastric administration of 200.0 mg/kg bw of a 

50% extract of the roots to rats inhibited the reduction of fi brinolytic 

activity and erythrocyte deformability, decrease in erythrocyte counts, 

and increase in connective tissue in the thoracic artery in arthritis induced 

by chronic infl ammatory adjuvant (35). Intragastric administration 

of a 50% ethanol extract of the roots (dose not specifi ed) to rats 

increased blood fl ow in the dorsal skin, abdominal vein and spleen tissue 

(47). 


Intraperitoneal administration of 10.0 mg/kg bw or 20.0 mg/kg bw of 

a polysaccharide extract isolated from the roots to mice bearing sarcoma 

180 tumours increased cytotoxic T-lymphocyte activity on day 

9 after administration, but did not significantly change interleukin-2 

concentrations (48). In another study, administration of the same 

polysaccharide at the same dose to mice with the same tumour prevented 

the suppression of cytotoxic T lymphocyte activity and interleukin 

2 secretion caused by excessive tumour growth (49). Intraperitoneal 

administration of 0.1 mg/kg bw of an aqueous extract of the 

roots to mice 1 hour prior to treatment with compound 48/80 inhibited 

compound 48/80-induced fatal shock by 53.3% and reduced 

plasma histamine release (21). In rat peritoneal mast cells, the same 

extract, 1.0 mg/ml, significantly (P < 0.05) inhibited anti-dinitrophenol 

IgE-induced histamine release and tumour necrosis factor-α production 

(21). 

Intragastric administration of 100.0 mg/kg bw of jionoside B and verbascoside 

isolated from the roots to mice produced a 36% and 18% suppression 

of haemolytic plaque-forming cells in the spleen, respectively, 

compared with a 52.5% suppression following the administration of cyclophosphamide 

(50). 

289



Aqueous, hexane and methanol extracts of the roots, 1.0%, inhibited 

platelet aggregation induced by adenosine diphosphate, arachidonic acid 

and collagen in isolated rat platelets (51). 

Toxicology 

Intragastric administration of 60.0 g/kg bw of a decoction of the roots per 

day for 3 days to mice produced no adverse effects or death of the animals 

(19). Intragastric administration of 18.0 g/kg bw of a decoction of the roots 

per day for 45 days to rats produced no change in body weight or liver 

enzymes (19). Intragastric administration of 600.0 mg/kg bw of a 90% 

methanol extract of the roots per day for 4 days to mice had no toxic effects 

and did not induce weight loss (52). Intragastric administration of 400.0 mg/ 

kg bw of a 90% methanol extract of the roots per day for 4 days to mice 

inhibited DNA synthesis in the bone marrow (52). The median oral lethal 

dose of a 70% methanol extract of the roots in mice was >2.0 g/kg (53). 


Treatment of 23 cases of arthritis with a decoction of the roots (dose not 

specifi ed) improved symptoms in most patients. Patients reported a decrease 

in joint pain, a reduction in swelling and improvements in joint 

movement. In addition, a normalization of the erythrocyte sedimentation 

rate was observed (19). 

A decoction of the roots, corresponding to 30.0–50.0 g of roots, administered 

daily for 2 weeks to 62 patients with hypertension reduced blood 

pressure, serum cholesterol and triglycerides, and improved cerebral blood 

fl ow and the electrocardiogram (no further details available) (19). 


Diarrhoea, abdominal pain, oedema, fatigue, vertigo and heart palpitations 

have been reported. However, these adverse effects were transient 

and disappeared within several days (19, 54). 


Radix Rehmanniae is contraindicated in chronic liver or gastrointestinal 

diseases and in patients with diarrhoea (3). Owing to its potential antiimplantation 

effects (55), the use of Radix Rehmanniae during pregnancy 

is also contraindicated. 

Warnings 


290

Precautions 


An aqueous extract of Radix Rehmanniae, 40.0–50.0 mg/plate, was not 

mutagenic in the Salmonella/microsome assay using Salmonella typhimurium 

strains TA98, and TA100 (56, 57). However, intraperitoneal 

administration of 4.0 mg/kg bw of the aqueous extract to mice, equal to 

10–40 times the amount used in humans, was mutagenic (57). Intraperitoneal 

administration of a hot aqueous extract of the roots (dose not 

specifi ed) to mice did not enhance cyclophosphamide-induced chromosomal 

damage (58). Subcutaneous administration of a hot aqueous extract 

of the roots (dose not specifi ed) inhibited embryonic implantation 

in treated female mice (55). No effects were observed after in vitro treatment 

of human sperm with an aqueous extract of the roots, 100.0 mg/ 

ml (59). 


No teratogenic or abortifacient effects were observed in rats following 

intragastric administration of 500.0 mg/kg bw of a 70% methanol extract 

of the roots starting on the 13th day of pregnancy (53). 





Owing to a lack of data on the safety and effi cacy of Radix Rehmanniae, 

its use by nursing mothers is not recommended without supervision by a 

health-care provider. 


Owing to a lack of data on the safety and effi cacy of Radix Rehmanniae, 

its use in children is not recommended without supervision by a healthcare 

provider. 




Dosage forms 

Dried roots and rhizomes for infusions and decoctions. Store in a well- 

closed container in a cool, dry place, protected from light (4). 

291


Posology 


Daily dose: 9–15 g of dried roots and rhizomes as an infusion or decoction 

(4). 

References 



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293


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295

296 

Fructus Schisandrae 

Defi nition 

Fructus Schisandrae consists of the dried ripe fruits of Schisandra chinensis 

(Turcz.) Baill. (Schisandraceae) (1–3). 1 

Synonyms 

Idesia polycarpa Morr. et de Vos, Kadsura chinensis Turcz., Maximowiczia 

amurensis Rupr., M. chinensis Rupr., M. sinensis Rupr., Maximowitschia 

japonica A. Gray, Polycarpa maximowiczii Morr. et de Vos, Schisandra 

chinensis var. typica Nakai, Schizandra japonica Sieb. et Zucc., 

Sphaerostemma japonicum A. Gray (4). 


Bac ngu vi tu, bei wuweizi, Chinesischer Limonenbaum, Chinese magnolia 

vine, Chinese mock-barberry, chosen-gomishi, lemonwood, limonnik 

kitajskij, matsbouza, m mei gee, ngu mei gee, northern magnoliavine, 

o-mee-ja, o-mi-d’ja, o-mi-ja, omicha, ornija, pen ts’ao, schisandra, 

dheng-mai-yin, wu-wei-zi, wu-weitzu (4–8). 


Indigenous to Russia (Primorsk and Khabarovsk regions, the Kuril islands, 

southern Sakhalin) north-eastern China, Japan and the Korean 

peninsula. Cultivated in China and Republic of Korea (7, 9). 

Description 

A deciduous woody climbing vine, up to 8 m long. Leaves alternate, petiolate, 

ovate or oblong-obovoid, 5–11 cm long, 2–7 cm wide, apex acute or 

acuminate; base cuneate or broadly cuneate, membranous. Flowers uni- 

1 The Pharmacopoeia of the People’s Republic of China (3) also recognizes the fruits of Schisandra 

sphenanthera Rehd. et Wils.


sexual, dioecious, solitary or clustered axillary, yellowish-white to 

pinkish; male fl ower stalked, with fi ve stamens, fi laments united into a 

short column; female fl ower has numerous carpels. Fruits, 5–8 mm in diameter, 

arranged into a long spike with globular, deep-red berries. Seeds, 

one to two per berry, reniform, shiny, smooth, yellowish brown, 4.5 mm 

long, 3.5 mm in diameter (5, 7, 9, 10). 



Irregularly spheroidal or compressed-spheroidal, 5–8 mm in diameter. 

Externally dark red to blackish-red or covered with “white powder”, 

wrinkled, oily, with soft pulp. Seeds, one to two, reniform, externally 

brownish-yellow to dark red-brown, lustrous, with distinct raphe on the 

dorsal side; testa thin and fragile (1, 3). 


Odour of pulp: slight; odour of seed: aromatic on crushing; taste of pulp: 

sour; taste of seed: pungent and slightly bitter (1, 3). 


Pericarp with one layer of square or rectangular epidermal cells, walls 

relatively thickened, covered with cuticle, oil cells scattered. Mesocarp 

with 10 or more layers of parenchymatous cells containing starch grains, 

scattered with small collateral vascular bundles. Endocarp with one layer 

of parenchymatous cells. Outermost layer of testa consists of radially 

elongated stone cells, thick walled, with fi ne and close pits and pit canals; 

then several lower layers of stone cells, subrounded, triangular or polygonal 

with larger pits, and a few layers of parenchymatous cells and raphe, 

with vascular bundles. Endosperm cells contain yellowish-brown coloured 

oil droplets and aleurone grains (3). 


Dark purple in colour. Stone cells of epidermis of testa polygonal or elongated-polygonal 

in surface view, 18–50 μm in diameter, wall thickened 

with very fi ne and close pit canals, lumina containing dark brown contents. 

Stone cells of the inner layer of the testa polygonal, subrounded or 

irregular, up to 83 μm in diameter, walls slightly thickened, with relatively 

large pits. Epidermal cells of the pericarp polygonal in surface view, anticlinal 

walls slightly beaded, with cuticle striations, scattered with oil cells. 

Mesocarp cells shrivelled, with dark brown contents and starch granules 

(3). 

297



Macroscopic and microscopic examinations (1–3), and thin-layer chromatography 

for the presence of deoxyschizandrin (schisandrin A) (2, 3, 7). 

Purity tests 







Total ash 








Moisture 







Heavy metals 







Chemical tests to be determined in accordance with national requirements. 

298


Contains not less than 0.4% schizandrin (schisandrin, schisandrol A, 

wuweizichun A) determined by high-performance liquid chromatography 

(3). Additional high-performance liquid chromatography and highperformance 

liquid chromatography–mass spectrometry methods are 

available (14, 15). 


The major constituents are lignans of biological interest with the dibenzo[a,c]cyclooctadiene 

skeleton. Among the approximately 30 lignans 

are schizandrin (schisandrin, schisandrol A, wuweizichun A, 0.2–0.7%), 

gomisin A (schisandrol B, wuweizichun B, wuweizi alcohol B, 0.1–3.0%), 

deoxyschizandrin (deoxyschisandrin, schisandrin A, wuweizisu A, 0.1– 

9.0%), (±)-γ-schizandrin (schisandrin B, γ-schisandrin B, wuweizisu B, 

0.1–5.0%), and gomisin N (pseudo-γ-schisandrin B, 0.1–0.5%) (7, 8). The 

structures of schizandrin, deoxyschizandrin, gomisin N, gomisin A and 

(±)-γ-schizandrin are presented below: 

H3CO H3CO H 3CO 

H 3 CO 

O 

gomisin N 

O 

CH3 H 

H 

CH 3 

schisandrin A 

schisandrol A 

H 3 CO 

H 3 CO 

H 3 CO 

H 3 CO 

H 3 CO 

H 3CO 

R = H 

R = OH 




None. Although some clinical evidence supports the use of Fructus 

Schisandrae for the treatment of psychosis, gastritis, hepatitis and fatigue 

(16, 17), data from controlled clinical trials are lacking. 


Treatment of chronic cough and asthma, diabetes, urinary tract disorders. 

As a general tonic for treating fatigue associated with illness (3, 7, 9, 16). 


As an astringent, antitussive, antidiarrhoeal, expectorant and sedative (8). 

CH3 R 

H 

CH 3 

schisandrin B 

schisandrol B 

H 3 CO 

H 3 CO 

H 3 CO 

O 

H 3 CO 

O 

R = H 

R = OH 

CH3 R 

H 

CH 3 

299


Pharmacology 



External application of gomisin A (schisandrol B), 0.6 mg/ear, inhibited 

infl ammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) 

in mice. External application of gomisin J and schisandrin C also inhibited 

the infl ammation induced by TPA in mice. The median effective dose 

(ED 50 ) of these compounds ranged between 1.4 μmol and 4.4 μmol, with 

gomisin A having the strongest anti-infl ammatory effect (18). 

Antihepatotoxic activities 

In vivo studies have demonstrated that the fruits have liver-protectant effects. 

Intragastric administration of 80.0 mg/kg bw of a lignan-enriched 

extract of the fruits to rats prevented hepatotoxicity induced by carbon 

tetrachloride, prevented glutathione depletion and stimulated the activity 

of glutathione reductase (19, 20). In experimental models, the activity of 

serum glutamic pyruvic transaminase (SGPT) induced by the administration 

of carbon tetrachloride or paracetamol in mice, thioacetamide in rats, 

and ethinyl estradiol 3-cyclopentylether in rabbits was reduced by oral 

administration of 1.0–10.0 g/kg bw of a 95% ethanol extract of fruits (21, 

22). A 95% ethanol extract of the fruits lowered elevated SGPT levels in 

mice treated with carbon tetrachloride or thioacetamide (23). Lignans, 

isolated from the fruits, have also been shown to have liver-protectant 

activities in vivo (24, 25). Intragastric administration of the lignans to 

mice, specifi cally 50.0 mg/kg bw of gomisin A, 50.0 mg/kg bw of gomisin 

B, 50.0–100.0 mg/kg bw of schisandrin A, 50–100.0 mg/kg bw of schisandrin 

B and 50.0–100.0 mg/kg bw of γ-schisandrin, decreased elevated 

SGPT levels in mice treated with carbon tetrachloride (25). Treatment 

with the lignans also prevented the elevation of SGPT levels and the morphological 

changes in the liver, such as infl ammatory infi ltration and liver 

cell necrosis, induced by carbon tetrachloride. Intragastric administration 

of 100 mg/kg bw of gomisin A, B or schisandrin also protected against 

thioacetamide-induced liver damage in mice (23, 25). 

Oral pretreatment of rats with 50.0 mg/kg bw of gomisin A prevented 

the rise in SGPT and serum glutamic oxaloacetic transaminase (SGOT), 

as well as necrosis of hepatocytes induced by paracetamol (26). Intragastric 

administration of 30.0 mg/kg bw or 100.0 mg/kg bw of gomisin A 

per day for 4 days, increased liver weight in normal rats or animals with 

liver injury. Gomisin A suppressed the increase in serum transaminase 

activity and the appearance of histological changes, such as hepatocyte 

degeneration and necrosis, infl ammatory cell infi ltration and fatty depo- 

300


sition induced by carbon tetrachloride, galactosamine or ethionine. 

Gomisin A also increased the activities of microsomal cytochrome B5, 

P450, NADPH cytochrome C reductase, aminophenazone-N-demethylase 

and 7-ethoxycoumarin O-deethylase, and decreased the activity of 

3,4-benzopyrene hydroxylase (27). 

Intragastric administration of 10.0–100.0 mg/kg bw of gomisin A per 

day for 4 days increased liver regeneration in rats after partial hepatectomy, 

increased the regeneration rate of the liver cells, and improved the 

serum retention rate of the foreign dye sulfobromophthalein. In addition, 

gomisin A enhanced the incorporation of radiolabelled phenylalanine 

into liver protein and decreased hexobarbital-induced sleeping time. Ultrastructural 

studies of liver tissue by electron microscopy showed an increase 

in rough and smooth endoplasmic reticulum in the groups receiving 

gomisin A. Gomisin A enhanced the proliferation of hepatocytes and 

the recovery of liver function after partial hepatectomy and increased hepatic 

blood fl ow. Liver enlargement induced by repeated administration 

of gomisin A may be due to the proliferation of endoplasmic reticulum 

(27). Intragastric administration of 10.0 mg/kg bw or 30.0 mg/kg bw of 

gomisin A per day for 3 or 6 weeks decreased fi brosis and accelerated 

liver regeneration and the recovery of liver function after partial hepatectomy 

in rats with chronic liver damage induced by carbon tetrachloride 

(28). Intragastric administration of 100.0 mg/kg bw of gomisin A per day 

for 14 days promoted hepatocyte growth after mitosis during regeneration 

of partially resected rat liver, and induced proliferation of non-parenchymal 

cells by increasing the c-myc product, a gene that precedes DNA 

replication in proliferating cells (29). 

In vitro studies with cultured rat hepatocytes treated with an ethyl 

ether, ethyl acetate, methanol or water extract of the fruits, 0.1–1.0 mg/ 

ml, reduced cytotoxicity induced by galactosamine and carbon tetrachloride 

(30). Gomisin A, 0.1 mg/ml, suppressed the biosynthesis of leukotrienes 

induced by calcium ionophore A2318 in rat peritoneal macrophages. 

This effect was partially associated with its antihepatotoxic effects (31). 

Intragastric administration of 100.0–200.0 mg/kg bw of schisandrol A 

or schisandrin B reduced liver malondialdehyde formation induced by 

the administration of 50% ethanol to rats (32). Intragastric administration 

of 4.0–16.0 mg/kg bw of schisandrin B per day for 3 days increased the 

activities of hepatic glutathione S-transferase (GST) and glutathione reductase 

in mice treated with carbon tetrachloride (33). The mechanism by 

which schisandrin B exerts its hepatoprotectant effect appears to be 

through the enhancement of the hepatic glutathione antioxidant status in 

mice with carbon tetrachloride induced hepatotoxicity (34, 35). The ac- 

301


tivities of glucose-6-phosphate dehydrogenase, selenium-glutathione 

peroxidase and γ-glutamylcysteine synthetase were reduced in a dosedependent 

manner by schisandrin B (33). Pretreatment of mice with 

1.0 mg/kg bw of schisandrin B per day for 3 days protected the animals 

against menadione-induced hepatic oxidative damage, and reduced the 

plasma level of alanine aminotransferase and the hepatic level of malondialdehyde 

as compared with menadione-intoxicated controls (36). 

Intragastric administration of 12.0 mg/kg bw schisandrin B per day 

for 3 days to mice increased the hepatic mitochondrial glutathione concentration, 

whereas butylated hydroxytoluene decreased hepatic glutathione 

(34). Pretreatment with schisandrin B at the same dose sustained 

the hepatic mitochondrial glutathione level in carbon tetrachloride intoxicated 

mice and protected against carbon tetrachloride induced hepatotoxicity. 

Schisandrin B also increased the hepatic ascorbic acid (vitamin 

C) level in control animals, and sustained a high concentration of hepatic 

vitamins C and E in carbon tetrachloride intoxicated mice, which may 

partially explain its mechanism of action. Pretreatment of mice with intragastric 

administration of 1.2–12.0 mg/kg bw schisandrin B per day for 3 

days had a dose-dependent protective effect on carbon tetrachloride induced 

lipid peroxidation and hepatocellular damage (37). 

Administration of the powdered fruits in the diet, 5%, to mice induced 

a three-fold increase in activity of hepatic cytochrome P450. Total benzopyrene 

metabolism was increased 1.6-fold, and phenol II formation relative 

to total metabolites was signifi cantly increased as compared with the 

control group. In addition, 7-ethoxycoumarin O-deethylase and aryl hydrocarbon 

hydroxylase activities were increased and the binding of afl atoxin 

to DNA was decreased (38). 


Inhibition of lipid peroxidation in rat liver microsomes was observed after 

treatment with schisandrol, schisandrin C and schisandrin B, 1.0 mmol/ 

l, in vitro (39). Schisandrol and schisandrin B, 1.0 mmol/l, inhibited gossypol-induced 

superoxide anion generation in rat liver microsomes (40). 

Schisandrol, 1 mmol/l, scavenged oxygen radicals in human neutrophils 

induced by tetradecanoylphorbol acetate (41). Schisandrin B suppressed 

lipid peroxidation induced by carbon tetrachloride in hepatocytes in vitro 

(42). The release of GPT and lactate dehydrogenase was also reduced, 

thereby increasing hepatocyte viability and the integrity of the hepatocyte 

membrane (39). Schisandrin B, 10 mmol/l, inhibited NADPH oxidation 

in mouse liver microsomes incubated with carbon tetrachloride (43). 

Schisandrin B, 110.0 μmol/l, inhibited oxidation of erythrocyte membrane 

lipids induced by ferric chloride in vitro (37). 

302



The effect of gomisin A on hepatocarcinogenesis induced by 3'-methyl-4dimethylaminoazobenzene 

(3'-MeDAB) in rats was assessed. Oral administration 

of 30 mg/kg bw of gomisin A per day for 5 weeks inhibited 

the appearance in the liver of foci for GST (placental form, GST-P), a 

marker enzyme of preneoplasm. Gomisin A also decreased the number of 

altered hepatic foci, such as the clear cell and basophilic cell type, in the 

early stages (44, 45). Administration of gomisin A in the diet, 0.03%, for 

10 weeks decreased the concentration of GST-P, and the number and size 

of GST-P positive foci in the liver after treatment with 3'-MeDAB (46). 

This indicates that gomisin A may inhibit 3'-MeDAB-induced hepatocarcinogenesis 

by enhancing the excretion of the carcinogen from the 

liver and reversing the normal cytokinesis (47). 


Intraperitoneal administration of 10.0 mg/kg bw of a 50% ethanol extract 

of the fruits to mice potentiated the sedative effects of barbiturates (48). 

However, intraperitoneal administration of 5.0 mg/kg bw of an ethanol 

and petroleum ether extract of the fruits decreased barbiturate-induced 

sleeping times (49). Intraperitoneal administration of 50.0 mg/kg bw of an 

unspecifi ed extract of the fruits to mice 30 minutes prior to the injection of 

pentobarbital, ethanol, or exposure to ether signifi cantly reduced the 

sleeping time of the treated group by 41.4%, 51.5% and 27%, respectively 

(P < 0.001 for all differences) (50). However, other researchers have demonstrated 

that the effects of the fruits on pentobarbital sleeping time depended 

upon the time of administration, and the type of extract or individual 

schisandrin derivatives administered. Schisandrin B or schisandrol 

B, 12.5 mg/kg bw, administered 1 hour prior to the injection of pentobarbital 

potentiated sleeping time. However, if the compounds were administered 

24 hours prior to injection of pentobarbital, a decrease in sleeping 

time was observed. Administration of schisandrin C prolonged pentobarbital-induced 

sleeping time regardless of when it was administered (24). 

Effects on drug metabolism 

The activity of the fruits in restoring hepatic drug metabolism and phase 

I oxidative metabolism in livers damaged by carbon tetrachloride was investigated 

in vivo by assessing the pharmacokinetics of antipyrine (51). 

Intragastric administration of 160.0 mg/kg bw of a lignan-rich extract of 

the fruits to rats 30 minutes prior to administration of carbon tetrachloride 

and a single dose of antipyrine improved antipyrine elimination, decreased 

its clearance and reduced the half-life of the drug. In addition, 

303


normalization of the levels of SGPT and SGOT and cytochrome P450 

was observed (51). 

Intragastric administration of 200.0 mg/kg bw of schizandrin B and 

schisanhenol per day for 3 days increased liver GST and microsomal cytochrome 

P450 levels in mice and rats. Both compounds reduced an increase 

in uterus weight in animals treated with estradiol, and decreased 

serum estradiol levels in mice. An enhancement in metabolism by liver 

microsomes, specifi cally the induction of drug-metabolizing phase I and 

phase II enzymes was also noted (52). 

Ergogenic effects 

The effects of the fruits on fatigue in and the endurance of horses has been 

assessed in a number of small studies. In one study, a dried 50% ethanol 

extract of the fruits or saline solution (48 g) was administered orally to 

thoroughbred horses prior to an 800-m race at maximum speed and to 

polo horses before a 12-minute gallop at a speed of 400 m/min. Treatment 

of the animals with the extract reduced serum lactic acid levels and increased 

plasma glucose levels after the test. Horses treated with the extract 

were also able to run faster and completed the 800-m race in 50.4 seconds 

compared with 52.2 seconds for the control animals (P < 0.05), 

indicating an increase in physical performance (53). 

In a randomized double-blind, crossover study, 12.0 g of a dried 50% 

ethanol extract of the fruits, standardized to contain 1.2% schizandrins, 

was administered orally to 20 race horses 30 minutes prior to competition. 

Horses treated with the extract had signifi cantly reduced heart rates for 

up to 20 minutes following the race (P < 0.01). The rate of respiration was 

also reduced immediately after the race, and was maintained for 15 minutes 

(P < 0.05). In addition, plasma glucose concentrations increased signifi 

cantly (P < 0.05) and concentrations of lactic acid were signifi cantly 

lower (P < 0.01) in the treated group than in the control group. Treated 

horses also completed the circuit in a shorter time than controls (117.5 seconds 

compared with 120.3 seconds) (54). A placebo-controlled study involving 

24 sports horses with performance problems, as well as high levels 

of serum γ-glutamyltransferase (SGT), SGOT and creatinine phosphokinase, 

assessed the effects of the fruits on performance. Oral administration 

of 3.0 g of a dried 50% ethanol extract of the fruits per day to 12 horses 

signifi cantly reduced SGT, SGOT and creatinine phosphokinase levels 

(P < 0.05, P < 0.01 and P < 0.01, respectively), and improved performance 

after 7 and 14 days, as compared with 12 placebo controls (55). 

Intragastric administration of 1.6 g/kg bw of a petroleum ether extract 

of the fruits to rats signifi cantly (P < 0.01) reduced exercise-induced elevation 

of plasma creatine phosphokinase (56). 

304


Toxicology 

Intragastric administration of 0.6 g/kg bw or 1.3 g/kg bw of the fruits per 

day for 10 days to mice resulted in only mild toxic effects, such as decreased 

physical activity, piloerection, apathy and an increase in body 

weight (57). The intragastric and intraperitoneal median lethal doses 

(LD 50 ) of a petroleum ether extract of the fruits in mice were 10.5 g/kg bw 

and 4.4 g/kg bw, respectively. The symptoms of toxicity included depressed 

motor activity, short cataleptic periods and a lack of coordination 

of motor functions, which were followed by tonic seizures and marked 

mydriasis (58). In a 7-day study, no deaths occurred after oral administration 

of high doses of schisandrins A and C (2000.0 mg/kg bw), and 

schisandrol A (500.0 mg/kg bw); schisandrol B (250.0 mg/kg bw) and 

schisandrin B (250.0 mg/kg bw) showed relatively higher levels of toxicity 

(24). 

The toxicity of an ethanol extract containing schisandrin B, and of the 

schisandrins A and C, 2000.0 mg/kg bw) and schisandrol A, 1000.0 mg/ 

kg bw, was reported after intragastric administration to mice. Death of 

mice occurred within 7 days after administration of schisandrins A and C. 

Schisandrol B, 500 mg/kg bw, is reported to have a relatively higher toxicity 

after intragastric administration to mice. The LD 50 of schisandrol B in 

mice is reported to be 878.0 mg/kg bw by the intragastric route and 

855.0 mg/kg bw after subcutaneous administration. The intragastric LD 50 

values for petrol-ether extracts with schisandrin contents of 10%, 40% 

and 80% were 10.5 g/kg bw, 2.8 g/kg bw and 1.4 g/kg bw, respectively 

(4). 


Studies on healthy subjects 

Oral administration of 5–10.0 mg/kg bw of a 70% ethanol extract of the 

fruits, reduced fatigue and increased the accuracy of telegraphic transmission 

and reception by 22% (59). In another study, healthy male volunteers 

were given an oral preparation of the fruit (dose and form not specifi 

ed), and were required to thread a needle at the same time as taking a 

message delivered through headphones. The results demonstrated that 

when compared to other undefi ned stimulants, the extract increased the 

accuracy and quality of work (57). 

Other uncontrolled investigations have demonstrated that oral administration 

of the fruits increases physical performance in human subjects. A 

decrease in fatigue and acceleration of recovery after exercise were reported 

for athletes, such as long-distance runners, skiers and gymnasts, 

after consuming 1.5–6.0 g of the fruits daily over a 2-week period (60). 

305


The effect of the fruits on physical stress was investigated in a controlled 

study involving 59 airline stewardesses (aged 22–29 years) during seven 

nonstop 9-hour fl ights. The study measured several stress parameters before 

and after the fl ights, with and without treatment with 0.5 g of an 

undefi ned extract of the fruits. Control subjects displayed a signifi cant 

increase in heart rate (P < 0.001) and blood pressure (P < 0.01) during 

fl ights, while those taking the extract did not. The report further described 

the effect of oral administration of 2.0 g of an extract of the fruits to 58 

untrained soldiers (aged 19–23 years) and 62 highly trained sportsmen 

(aged 19–30 years). Physical work capacity as measured by a step-ergometer, 

signifi cantly increased 24 hours after treatment (P < 0.05), while 

that of the controls remained the same (61). 

A double-blind, placebo-controlled clinical trial assessed the effects of a 

standardized extract of the fruits on the concentration of nitric oxide in human 

saliva, blood neutrophils, lymphocytes and monocytes, and working 

capacity, as a measure of adaptogenic potential in heavy exercise. The level 

of nitric oxide in the saliva of beginner athletes was found to increase after 

exercise while that in the saliva of well-trained athletes was high and did not 

increase further after exercise. Tablets containing an extract of the fruits, 

91.1 mg standardized to 3.1 mg of schisandrin and γ-schisandrin, were administered 

twice daily for 8 days. There was a signifi cant increase in the 

pre-exercise levels of nitric oxide in both beginners (n = 17) and athletes 

(n = 46) (P < 0.05); there were no changes in the other parameters (62). 

A placebo-controlled clinical trial involving 134 healthy subjects assessed 

the effects of a single administration of the encapsulated fruits on 

night vision and acceleration of adaptation to darkness. Visual function 

was assessed 15–20 minutes prior to administration and 3 hours after. Administration 

of a single dose of 3.0 g of the fruits increased visual acuity 

under low illumination and extended the visual fi eld margins for white 

and red colours by 8–25° (16). In a second study of 150 subjects, a single 

administration of 3 g of the fruits increased visual acuity in 90% of subjects. 

Administration of the drug decreased the time recognition of an 

object in darkness (from 32.3 seconds to 18.4 seconds), 4.5 hours after 

administration (63). 

Clinical trials in patients 

In an uncontrolled study, a tincture of the fruits was used for the treatment 

of stomach and duodenal ulcers in 140 patients with acute and 

chronic ulcers, who had been ill for 1–10 years. Patients were treated with 

30–40 drops per day for 3–4 weeks. All subjects reported a reduction in 

symptoms within a few days, with ulcer healing reported in 96.5% of 

patients after 35 days of treatment. Recurrent episodes of peptic ulcer 

306

disease were reported in only 9 of 90 patients followed over a period of 

1–6 years (64). 

A review of the Chinese literature mentioned reports of more than 

5000 cases of hepatitis treated with preparations of the fruits, which had 

resulted in reductions of elevated liver enzymes. Elevated SGPT activities 

returned to normal in 75% of treated patients after 20 days of treatment. 

In subjects with elevated SGPT due to drug toxicity, SGPT levels reportedly 

returned to normal in 83 of 86 cases after 1–4 weeks of treatment. 

Enzyme levels reportedly decreased even without the discontinuation of 

the hepatotoxic drugs (17). It must be stressed that these are uncontrolled 

observational studies with questionable methodology. Further well designed, 

controlled clinical trials are needed to ascertain their validity. 

In a controlled trial involving 189 patients with chronic viral hepatitis 

B and elevated SGPT levels, an ethanol extract of the fruits, containing 

20 mg of lignans and corresponding to 1.5 g of the fruits, was administered 

orally to 107 of the patients daily, while the control group (n = 82) 

received liver extracts and vitamins (65). Normal SGPT levels were observed 

in 72 (68%) of patients receiving the extract after 4 weeks. In the 

control group, normal SGPT levels were observed in 36 (44%), with an 

average recovery time of 8 weeks. However, improvements in SGPT were 

only temporary, and levels rose again 6–12 weeks after treatment was discontinued. 

Relapse rates were highest (46–69%) in chronic persistent 

hepatitis, elderly patients, and in those receiving long courses of treatment 

with hepatotoxic drugs. Most patients responded to resumption of 

treatment with a return to their previously reduced SGPT levels (17, 65). 


Minor adverse effects such as heartburn, acid indigestion, stomach pain, 

anorexia, allergic skin reactions and urticaria have been reported (66). 




Warnings 

Symptoms of overdose include restlessness, insomnia or dyspnoea (67). 

Precautions 


The fruits may have depressant effects on the central nervous system and 

should not therefore be used in conjunction with other CNS depressants, 

307


such as sedatives or alcohol. They have been shown to stimulate the activity 

of hepatic cytochrome P450 (68). While no drug interactions have 

been reported, co-administration of prescription drugs metabolized 

through cytochrome P450, such as cyclosporin, warfarin, protease inhibitors, 

St John’s wort, estrogen and progesterone combinations, should 

only be undertaken under the supervision of a health-care provider, 

owing to the inductive effects of the fruits on phase I and II drugmetabolizing 

enzymes (51, 52). 


An aqueous or methanol extract of the fruits was not mutagenic in the 

Salmonella/microsome assay using S. typhimurium strains TA98 and 

TA100, or in the Bacillus subtilis H-17 recombination assay at concentrations 

of up to 100.0 mg/ml (69, 70). 


In one uncontrolled investigation, 20–25 drops of a tincture (70% ethanol) 

of the fruits were administered to pregnant women three times per 

day for 3 days. Induction of labour was observed after the second dose 

followed by an increase in active labour 2–3 hours after the initial induction. 

The activity was most pronounced in women who had previously 

given birth. Shortened labour times were reported and no negative effects 

regarding blood pressure, elimination of the placenta, or postnatal health 

of mother and infant were observed (7, 71). In another investigation, an 

increase in the amplitude of uterine contractions (28 mm compared with 

5 mm in controls) and uterine tension was observed after subcutaneous 

administration of 0.1 ml/kg bw of a tincture of the fruits to pregnant rabbits. 

The activity was observed 1.5 hours after administration and persisted 

for 4 hours (71). 

A study conducted on women living in the Bryansk region of Ukraine, 

near the site of the Chernobyl nuclear reactor accident, assessed the effects 

of adaptogen administration on the health status of developing fetuses 

in pregnant women exposed to constant low-level radiation. The 

symptoms of placental insuffi ciency improved, fetal protein status was 

stabilized, obstetric complications were reduced, and the health status of 

the newborn infants was improved. No substantiating data were provided 

in this report, and no information regarding the preparations or dosages 

administered or the effect of the preparation on uterine contractions was 

given (7, 72). 

Owing to a lack of further safety data regarding the effect of Fructus 

Schisandrae on neonatal development, its use during pregnancy is not recommended 

(7). 

308


Owing to a lack of safety data, the use of Fructus Schisandrae during 

nursing is not recommended. 



drug and laboratory test interactions; teratogenic effects in pregnancy; 

or paediatric use. 

Dosage forms 

Dried fruits and tinctures, extracts and powders prepared from the fruits. 

Store in a tightly sealed container away from heat and light. 

Posology 


Average daily dose: 1.5–6.0 g of the dried fruits (3). 


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313

314 

Radix Scutellariae 

Defi nition 

Radix Scutellariae consists of the dried roots of Scutellaria baicalensis 

Georgi (Lamiaceae) (1–4). 

Synonyms 

Scutellaria grandifl ora Adams, S. lanceolaria Miq., S. macrantha Fisch. 

(5). Lamiaceae are also known as Labiatae. 


Baical skullcap, huang chin, huang lien, huang qin, huangqin, hwanggum, 

hwang-keum, Koganebana, skull cap, senohgon, whang-geum, whangegum, 

wogon (3, 6, 7). 


Indigenous to the Korean peninsula and to China, Japan, Mongolia and 

Russian Federation (6, 8, 9). 

Description 

A spreading perennial herb up to 20–60 cm high. Stems erect, tetragonal, 

branching near base, glabrous or pubescent in the stem margins. Leaves 

opposite, simple, with short petioles 2 mm long; limb lanceolate, 1.5– 

4.0 cm long, 5 mm wide; tip obtuse, entire. Flowers blue to purple, in racemes. 

Calyx campanulate, bilabiate, the superior lip with a crest at the 

back; corolla tube long, much longer than the calyx, enlarged towards the 

top, swelling at the base; limb bilabiate; stamens four, didymous, fertile, 

ascending under the superior lip; anthers ciliate; ovary superior. Fruits are 

collections of small tuberculate nutlets, nearly globular, leathery (6, 8). 

Plant material of interest: dried roots 


Conical, twisted or fl attened root, 5–25 cm long, 0.5–3.0 cm in diameter. 

Externally yellow brown, with coarse and marked longitudinal wrinkles,

and with scattered scars of lateral root and remains of brown periderm; 

scars of stem or remains of stem at the crown; xylem rotted in old roots; 

hard in texture and easily broken; fractured surface fi brous and yellow in 

colour, reddish-brown in the centre (1–4). 


Odour, slight; taste, slightly bitter (1–4). 


To be established according to national requirements. For guideline to 

microscopic characteristics, see Powdered plant material. 


Yellow brown. Fragments of parenchyma cells containing small amounts 

of starch grains, spheroidal, 2–10 μm in diameter, hila distinct. Elongated, 

thick-walled stone cells. Reticulated vessels numerous, 24–72 μm in 

diameter. Phloem fi bres scattered singly or in bundles, fusiform, 60– 

250 μm long, 9–33 μm in diameter, thick-walled, with fi ne pit-canals. 

Cork cells brownish-yellow, polygonal. Fragmented wood fi bres, about 

12 μm in diameter, with oblique pits (1–4). 


Macroscopic and microscopic examinations (1–4), microchemical tests (1, 

4) and high-performance liquid chromatography for the presence of baicalin 

(2, 4). 

Purity tests 





Total ash 









315









Heavy metals 







Chemical, foreign organic matter and sulfated ash tests to be established 



Contains not less than 9.0% of baicalin determined by high-performance 

liquid chromatography (4). Other high-performance liquid chromatography 

methods are available (2, 13). 


The major constituents are fl avonoids, chiefl y baicalin (up to 14%) (14), 

baicalein (up to 5%) (15), wogonin (0.7%) (15) and wogonin-7-Oglucuronide 

(wogonoside, 4.0%) (14, 16). The structures of baicalin, 

baicalein and wogonin are presented below. 

316 

R7 

O 

R6 

R8 

OH 

O 

O 

β-D-glucopyranuronosyl 

GlcA = 

baicalein 

baicalin 

wogonin 

HO 

R6 R7 R8 

OH H H 

OH GlcA H 

H H OCH3 CO 2 H 

OH 

O 

OH




None. Although clinical case reports suggest that Radix Scutellariae may 

stimulate the immune system and induce haematopoiesis (17–19), data 

from controlled clinical trials are lacking. 


Treatment of fever, nausea and vomiting, acute dysentery, jaundice, 

coughs, carbuncles and sores, and threatened abortion (3, 4). 


Treatment of allergies, arteriosclerosis, diarrhoea, dermatitis and hypertension 

(7). 

Pharmacology 



Intragastric administration of 400.0 mg/kg body weight (bw) of an aqueous 

extract of Radix Scutellariae to rats prevented increases in the activities 

of liver enzymes, such as alkaline phosphatase, lactate dehydrogenase 

and alanine aminotransferase, induced by carbon tetrachloride or galactosamine 

(20). Baicalein, 185.0 μmol/l, inhibited the proliferation of cultured 

hepatic stellate cells (21). Baicalein, 10.0 μmol/l, also signifi cantly 

(P < 0.001) decreased the incorporation of tritiated thymidine in cultured 

rat hepatic stellate cells stimulated with platelet-derived growth factor-B 

subunit homodimer or fetal calf serum (22). 


External application of 0.5 mg/ear of a 50% ethanol extract of the roots to 

the ears of mice with ear oedema induced by 12-O-tetradecanoylphorbol-13-acetate 

or arachidonic acid signifi cantly reduced infl ammation 

(P < 0.01) (23). The anti-infl ammatory effect of baicalein in treating 

chronic infl ammation in rats with adjuvant-induced arthritis (median effective 

dose (ED 50 ) 120.6 mg/kg bw, intragastric route) was superior to 

that in carrageenan-induced footpad oedema (ED 50 200.0 mg/kg bw, intragastric 

route) (24). Baicalein also inhibited leukotriene C4 biosynthesis 

in vitro in rat resident peritoneal macrophages stimulated with calcium 

ionophore A23187, median inhibitory concentration (IC 50 ) 9.5 μm (24). 

Three fl avonoids isolated from the roots, wogonin, baicalein and baicalin, 

1.0 μg/ml, inhibited lipopolysaccharide-induced production of interleukin-1β 

in human gingival fi broblasts by 50% (25). The effects of nine 

317


fl avonoids, isolated from the roots, on adhesion molecule expression induced 

by interleukin-1β and tumour necrosis factor-α in cultured human 

umbilical vein endothelial cells were assessed. Baicalein only showed a 

dose-dependent inhibition of the induced expression of endothelial leukocyte 

adhesion molecule-1 and intracellular adhesion molecule-1, with 

50% inhibition observed at concentrations of 0.23 μmol/l and 0.4 μmol/l, 

respectively. These data suggest that Radix Scutellariae may exert its antiinfl 

ammatory effects through the inhibition of leukocyte adhesion to the 

endothelium (26). Baicalin has been shown to inhibit the binding of chemokines 

to human leukocytes and cells transfected with chemokine receptors. 

Coinjection of baicalin with CXC chemokine interleukin-8 into 

rat skin inhibited neutrophil infi ltration elicited by interleukin-8 (27). 


The free-radical scavenging and antioxidant activities of baicalein, baicalin, 

wogonin and wogonoside were tested in vitro. Electron spin resonance 

results showed that baicalein and baicalin scavenged hydroxyl radical 

and alkyl radical in a dose-dependent manner, while wogonin and 

wogonoside had no effect. Baicalein and baicalin, 10 μmol/l, inhibited 

lipid peroxidation of rat brain cortex mitochondria induced by Fe(2+)/ 

ascorbic acid or NADPH, while wogonin and wogonoside had effects 

only on NADPH-induced lipid peroxidation. In a study on cultured human 

neuroblastoma SH-SY5Y, baicalein and baicalin, 10 μmol/l, protected 

cells against hydrogen peroxide-induced injury (28). An aqueous extract 

of the roots or baicalein, 25–100 μmol/l, signifi cantly (P < 0.001) 

attenuated ischaemia/reperfusion oxidative stress in cultured chick embryonic 

ventricular cardiomyocytes. Cell death due to ischaemia/reperfusion 

injury decreased from 47% to 26% in treated cells. After treatment 

of the cells with antimycin A, an extract of the roots decreased cell death 

to 23% in treated cells compared with 47% in untreated cells (29). 

Pretreatment with ganhuangenin, isolated from the roots, suppressed 

the formation of phosphatidylcholine hydroperoxide initiated by the peroxyl-generating 

oxidant, 2,2'-azobis-2-aminopropane hydrochloride 

(30). Baicalein, 5.0–25.0 μmol/l, and wogonin, 5.0–50.0 μmol/l, inhibited 

lipopolysaccharide-induced nitric oxide generation in a macrophagederived 

cell line, RAW 264.7 in a concentration-dependent manner. The 

same two compounds, 25.0 μmol/l, also inhibited protein expression of 

inducible nitric oxide synthase (31). 


An aqueous or methanol extract of the roots, 200 μg/ml, elicited signifi - 

cant inhibition (> 90%) (P < 0.01) of the activity of human immuno- 

318


defi ciency virus type-1 protease (32). Baicalein inhibited the growth of 

Fusarium oxysporum and Candida albicans in vitro, minimum inhibitory 

concentrations 0.112 g/l and 0.264 g/l, respectively (33). 

A hot aqueous extract of the roots inhibited the growth of Alcaligenes 

calcoaceticus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus 

aureus at concentrations of 200.0–400.0 μg/ml but was not 

active against Escherichia coli in vitro at concentrations of up to 1600.0 μg/ 

ml (34). 

A hot aqueous extract of the roots, 0.25–1.0 μg/ml, inhibited the 

growth of Actinomyces naeslundii, A. odontolyticus, Actinobacillus actinomycetemcomitans, 

Fusobacterium nucleatum, Bacteroides gingivalis, 

B. melaninogenicus and Streptococcus sanguis (35). 


The in vitro effects of baicalin on growth, viability, and induction of apoptosis 

in several human prostate cancer cell lines, including DU145, PC3, 

LNCaP and CA-HPV-10 were investigated. Baicalin inhibited the proliferation 

of prostate cancer cells but the responses were different in the 

different cell lines. DU145 cells were the most sensitive and LNCaP cells 

the most resistant. Baicalin caused a 50% inhibition of DU145 cells at 

concentrations of 150 μg/ml or higher. Inhibition of prostate cancer cell 

proliferation by baicalin was associated with induction of apoptosis (36). 

Baicalein inhibited the proliferation of estrogen receptor-positive human 

breast cancer MCF-7 cells in vitro, median effective concentration 5.3 μg/ 

ml (37). 

Antiviral activity 

Baicalin inhibited retroviral reverse transcriptase activity in human immunodefi 

ciency virus type 1 (HIV-1) activity in infected H9 cells, as well 

as HIV-1 specifi c core antigen p24 expression and quantitative focal syncytium 

formation on CEM-SS monolayer cells. Baicalin was a noncompetitive 

inhibitor of HIV-1 reverse transcriptase, IC 50 22.0 μmol/l. It also 

inhibited reverse transcriptase from Maloney murine leukaemia virus, 

Rous-associated virus type 2 and cells infected with human T-cell leukaemia 

virus type I (HTLV-I) (38). A fl avone, 5,7,4'-trihydroxy-8-methoxyfl 

avone, isolated from the roots, inhibited the activity of infl uenza virus 

sialidase but not mouse liver sialidase in vitro (39). The compound also 

had anti-infl uenza virus activity in Madin-Darby canine kidney cells, in 

the allantoic sac of embryonated eggs (IC 50 55.0 μmol/l) and in vivo in 

mice (39–41). The compound, 50.0 μmol/l, was also shown to reduce the 

single-cycle replication of mouse-adapted infl uenza virus A/PR/8/34 in 

Madin-Darby canine kidney cells by inhibiting the fusion of the virus 

319


with endosome/lysosome membrane and the budding of the progeny virus 

from the cell surface in the virus infection cycle (42). Baicalein produced 

a concentration-dependent inhibition of HTLV-I replication in 

infected T and B cells, as well as inhibiting the activity of reverse transcriptase 

in cells infected with HTLV-I (43). The mechanism by which 

baicalin exerts its anti-HIV-1 activities appears to involve the binding of 

baicalin to form complexes with selected cytokines and attenuates their 

ability to bind and activate receptors on the cell surface. Baicalin also 

binds to the HIV-1 envelope proteins and the cellular CD4 and chemokine 

co-receptors, thereby blocking HIV-1 entry into the cell (44). 

Central nervous system activity 

Four chemical constituents isolated from the roots bound to the benzodiazepine-binding 

site of the γ-aminobutyric acid A receptor as follows; 

wogonin (2.03 μmol/l) > baicalein (5.69 μmol/l) > scutellarein (12.00 μmol/ 

l) > baicalin (77.00 μmol/l) (45). Results of a benzodiazepine-binding assay 

showed that three fl avones, baicalein, oroxylin A and skullcapfl avone 

II, from an aqueous extract of the roots bound to the benzodiazepinebinding 

site with Ki values of 13.1 μmol/l, 14.6 μmol/l and 0.36 μmol/l, 

respectively (46). 

Intragastric administration of an aqueous extract of the roots (dose not 

specifi ed) to rats produced an increase in cutaneous vasodilation resulting 

in a fall in rectal temperature. No changes in metabolic rate or respiratory 

evaporative heat loss were observed (47). 

Enzyme inhibition 

Baicalin inhibited the activity of aldose reductase isolated from bovine 

testes, inhibitory concentration 5.0 μg/ml (48). 


Treatment of mouse peritoneal macrophages with an aqueous extract of 

the roots, 0.1–100.0 μg/ml, following treatment with recombinant interferon-γ, 

resulted in a signifi cant (P < 0.05) increase in the production of 

nitric oxide (49). However, a decoction of the roots inhibited nitric oxide 

production induced by lipopolysaccharide treatments of murine macrophages, 

IC 50 20.0 μg/ml (50). 


A 1-butanol, chloroform or ethyl acetate extract of the roots, 400.0 μg/ 

ml, inhibited platelet-activating factor binding to rabbit platelets in vitro 

(51). An aqueous or hexane extract of the roots, 5.0 mg/ml, inhibited 

platelet aggregation induced by arachidonic acid, adenosine diphosphate 

and collagen in rat platelets in vitro (52, 53). Baicalein dose-dependently 

320


inhibited production of plasminogen activator inhibitor-1 in cultured human 

umbilical vein endothelial cells induced by treatment with thrombin 

and thrombin receptor agonist peptide, IC 50 values 6.8 μmol/l and 

3.5 μmol/l, respectively (54). 

Smooth muscle effects 

The vascular effect of purifi ed baicalein was assessed in isolated rat mesenteric 

arteries. Baicalein exerted both contractile and relaxant effects on 

the thromboxane receptor agonist U46619-, phenylephrine- or high potassium-contracted 

endothelium-intact arteries. In endothelium-denuded 

arteries, the contractile response to baicalein, 0.3–10 μmol/l, was absent 

while the relaxant response to baicalein, 30–300.0 μmol/l, remained. Pretreatment 

with 100.0 μmol/l of NG-nitro-l-arginine (L-NNA) abolished 

the effect. Pretreatment with baicalein, 3–10.0 μmol/l, attenuated relaxation 

induced by acetylcholine or calcium ionophore A23187. At low 

concentrations, baicalein caused a contractile response and inhibited the 

endothelium-dependent relaxation, probably through inhibition of endothelial 

nitric oxide formation/release. At higher concentrations, baicalein 

relaxed the arterial smooth muscle, partially through inhibition of protein 

kinase C (55). 

Toxicology 

Intragastric administration of 10.0 g/kg bw of a decoction of the roots or 

intravenous administration of 2.0 g/kg bw of an ethanol extract to rabbits 

induced sedation but no toxic effects were observed (17). Intravenous administration 

of 2.0 g/kg bw of an aqueous extract of the roots to rabbits 

initially produced sedation. However, 8–12 hours later all the animals 

died. When the dose was decreased to 1.0 g/kg bw no deaths occurred. 

The median oral lethal dose (LD 50 ) of a 70% methanol extract of the roots 

in mice was > 2.0 g/kg (56). 

Intragastric administration of 12.0–15.0 g/kg bw of an aqueous extract 

of the roots to dogs caused emesis but no other toxic effects. Oral administration 

of 4.0–5.0 g/kg bw of the same extract three times per day for 

8 weeks to dogs did not cause any toxic effects. The subcutaneous LD 50 in 

mice was 6.0 g/kg bw for an ethanol extract of the roots, 6.0 g/kg bw for 

baicalin and 4.0 g/kg bw for wogonin (17). The intraperitoneal LD 50 of 

baicalin in mice was 3.1 g/kg bw (17). 


Chemotherapy of patients with lung cancer is associated with a decrease 

in immune function owing to a decrease in the relative number of T-lymphocytes. 

Administration of a dry extract of the roots to cancer patients 

321


receiving chemotherapy produced a tendency towards an increase in lymphocytes. 

The immunoregulation index in this case was approximately 

twice the background values during the whole period of investigation. 

The inclusion of the roots in the therapeutic regimen promoted an increase 

in the level of immunoglobulin A and stabilized the concentration 

of immunoglobulin G (no further details available) (19). 

A decoction of the roots was used to treat upper respiratory infections 

in children up to 5 years old and younger. The dose administered was 

6.0 ml for children under the age of 1 year, and 8.0–10.0 ml for children up 

to 5 years of age. Of 63 cases (51 with respiratory tract infections, 11 with 

acute bronchitis, and one with acute tonsillitis), 51 showed benefi t, and 

body temperature normalized after 3 days of treatment (17). 

Haematopoiesis was studied in 88 patients with lung cancer during 

antitumour chemotherapy given in combination with a dry extract of the 

roots. Oral administration of the roots induced haematopoiesis, intensifi - 

cation of bone-marrow erythro- and granulocytopoiesis and an increase 

in the content of circulating precursors of erythroid and granulomonocytic 

colony-forming units (18). 


Rare gastrointestinal discomfort and diarrhoea are associated with oral 

administration of Radix Scutellariae (17). Although liver damage due to 

administration of the roots has been suggested (57), no direct correlations 

of ingestion of the roots to any published cases of liver damage have been 

published. 


Owing to possible teratogenic and mutagenic effects (58, 59), and a lack 

of safety data, use of Radix Scutellariae is contraindicated during pregnancy 

and nursing and in children under the age of 12 years. 

Warnings 


Precautions 


An aqueous extract of Radix Scutellariae, 40.0 mg/plate, was not mutagenic 

in the Salmonella/microsome assay in S. typhimurium strains TA98 

and TA100 (59, 60). However, intraperitoneal administration of 4.0 mg/ 

322

kg bw of the aqueous extract to mice, equal to 10–40 times the amount 

used in humans, was mutagenic (59). 


Intragastric administration of 500.0 mg/kg bw of a 70% methanol extract 

of the roots daily to rats starting on the 13th day of pregnancy had no 

teratogenic or abortifacient effects (56). An aqueous extract of the roots, 

24.98 g/kg bw, given by intragastric administration to pregnant rats on 

days 8–18 of pregnancy was teratogenic (58). 



roots to pregnant rabbits on days 8–18 of pregnancy had no abortifacient 

effects (58). A methanol extract of the roots, 1.0 mg/ml, inhibited oxytocininduced 

contractions in isolated rat uterus (61). 








Dosage forms 

Dried roots, extracts, infusions and decoctions. Store in a well closed container 

in a cool, dry place, protected from moisture (4). 

Posology 


Daily dose: 3–9 g of dried roots as an infusion or decoction (4). 


References 






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323




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in Scutellaria.] Yaowu Fenxi Zazhi, 1983, 3:18–21 [in Chinese]. 

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improved method for extracting baicalin and the preparation of new methylated 

compounds.] Yao Hsueh Hsueh Pao, 1957, 5:47–57 [in Chinese]. 

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medica, Vol. II. Singapore, World Scientifi c, 1987. 

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baikal’skogo sukhoi v kachestve gemostimuliatora v usloviakh protivoopukholevoi 

khimioterapii bol’nykh rakom legkogo. [Dry extract of Scutellaria 

baicalensis as a hemostimulant in antineoplastic chemotherapy in patients 

with lung cancer.] Eksperimentalnaya i Kliniceskaya Farmakologiya, 1997, 

60:28–30. 

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324


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327

328 

Radix cum Herba Taraxaci 

Defi nition 

Radix cum Herba Taraxaci consists of the entire plant of Taraxacum 

offi cinale Weber ex Wiggers (Asteraceae) (1–3). 1 

Synonyms 

For Taraxacum offi cinale: Leontodon offi cinale With., L. taraxacum L. 

Taraxacum offi cinale (With.) Wigg., T. dens leonis Desf., T. vulgare 

Schrank, (6). 


Ackerzichorie, amargon, blowball, Butterblume, cankerwort, capo di frate, 

chicoria amarga, cicoria sarvatica, cicouureya de la bonne, cicoureya deis 

prats, dandelion, dent-de-lion, dente di leone, dhudal, diente de leon, dhorsat 

al ajouz, dudhi, engraissa-porc, fl orion d’or, gol ghased, Gemeiner 

Löwenzahn, gobesag, Irish daisy, hindabaa beri, hokgei, kanphul, kanphuli, 

kasni sahraii, Kettenblume, khass berri, Kuhblume, lagagna, laiteron, lechuguilla, 

lion’s tooth, Löwenzahn, maaritpauncin, marrara, milk gowan, 

min-deul-rre, monk’s head, mourayr, mourre de por, mourre de pouerc, 

oduwantschiki, paardebloem, patalagagna, peirin, Pfaffendistel, Pfaffenröhrlein, 

Pferdeblume, pilli-pilli, piochoublit, piss-a-bed, pissa-chin, pissanliech, 

pissenlit, poirin, po-kong-young, porcin, pu gong ying, puffball, 

pugongying, Pusteblume, ringeblume, salatta merra, sanalotodo, saris berri, 

seiyo-tanpopo, sofi one, srissi, tarakh-chaqoune, tarkhshaquin, tarassaco, 

taraxaco, telma retaga, Wiesenlattich, witch gowan, yellow gowan (4–10). 


Taraxacum offi cinale is indigenous to the northern hemisphere (11). 

T. mongolicum, T. sinicum and related species are found in the Korean 

peninsula and China (4, 5). 

1 Taraxacum mongolicum Hand.-Mazz. and T. sinicum Kitag. are also recognized in the Pharmacopoeia 

of the People’s Republic of China (4) and the Pharmacopoeia of the Republic of Korea (5).

Description 

A perennial herb consisting of an underground, long, straight, tapering, 

fl eshy brown root, which is continued upward as a simple or branched 

rhizome. From the rhizome arises a rosette of bright-green runcinate 

leaves and later, from the centre of the rosette, a hollow scape, 6–30 cm 

high bearing on its summit a broad orange-yellow head of ligulate fl owers. 

Fruits are fusiform, greenish-brown achenes, terminating in a slender 

stalk crowned by a silky, spreading pappus, and borne on a globular fruiting 

head (12). 

Plant material of interest: dried whole plants 


A crumpled and rolled mass. Roots conical, frequently curved, tapering, 

often broken into irregular pieces, externally brown. Root stock with 

brown or yellowish-white hairs. Leaves basal, frequently crumpled and 

broken; when whole, oblanceolate, greenish-brown or dark green with a 

pronounced midrib; apex acute or obtuse; margins lobate or pinnatifi d. 

Pedicels one or more, each with a capitulum; involucre several rows, the 

inner row relatively long; corolla yellowish-brown or pale yellowishwhite 

(1, 4, 5). 


Odour, slight; taste, slightly bitter (1, 11). 



Epidermal cells on both leaf surfaces have sinuous anticlinal walls, cuticle 

striations distinct or sparsely visible. Both leaf surfaces bear non-glandular 

hairs with three to nine cells, 17–34 μm in diameter. Stomata, occurring 

more frequently on the lower surface, anomocytic or anisocytic, with 

three to six subsidiary cells. Mesophyll contains fi ne crystals of calcium 

oxalate. Transverse section of root shows cork with several layers of 

brown cells. Phloem broad, groups of laticiferous tubes arranged in several 

interrupted rings. Xylem relatively small, with indistinct rays, vessels 

large, scattered. Parenchymatous cells contain inulin (1). 


Greenish yellow. Large root parenchymatous cells, brown reticulate vessels 

and tracheids and non-lignifi ed fi bres. Leaf fragments with sinuous, 

anticlinal-walled epidermal cells and a few anomocytic stomata. Numerous 

narrow annular thickened vessels and fragments of brown laticiferous 

tissues (1). 

329



Macroscopic and microscopic examinations (1, 4, 5). 

Purity tests 







Total ash 











Heavy metals 







Chemical, acid-insoluble ash, sulfated ash and alcohol-soluble extractive 




330


The characteristic constituents are sesquiterpenes, including the bitter 

eudesmanolides tetrahydroridentin B and taraxacolide β-d-glucopyranoside; 

and the germacranolides, taraxinic acid β-d-glucopyranoside and 

11,13-dihydrotaraxic acid β-d-glucopyranoside. Also present are the phydroxyphenylacetic 

acid derivative, taraxacoside; the triterpenes, taraxasterol, 

ψ-taraxasterol and taraxerol; and inulin (2–40%) (4, 10, 11). Representative 

structures are presented below. 

taraxasterol 

H 

CH2 ψ-taraxasterol 

H3C H 

H 

HO 

H 

H3C CH3 CH3 CH3 H CH3 H CH 3 




H 

HO 

H 

H3C CH3 H 

H3C CH3 CH3 H CH3 H CH 3 


taraxacolide β-D-glucoside taraxinic acid β-D-glucosyl ester tetrahydroridentin B 

O 

H 

O 

O 

H CH O 3 

H H 

H CH3 

O 

Glc 

CH3 H 

H 

H3C O O 

H 

Glc 

O 

O 

CH2 H CH O 3 

HO 

H 

H H 

H CH3 

OH 

CH3 H 

H 

taraxacoside 

HO 

O 

HO 

O 

O O 

OH 

OH 

O 

O 


To stimulate diuresis (2, 5), increase bile fl ow and stimulate appetite, and 

for treatment of dyspepsia (2). 


As a galactagogue, laxative and tonic. Treatment of boils and sores, diabetes, 

fever, infl ammation of the eye, insomnia, sore throat, lung abscess, 

jaundice, rheumatism and urinary tract infections (10). 

CH 3 

H 

HO 

O 

Glc = 

OH 

HO 

OH 


331


Pharmacology 



External applications of 2.0 mg/ear of a methanol extract of the dried 

leaves to mice reduced ear infl ammation induced by 12-O-tetradecanoylphorbol-13-acetate 

(16). Intragastric administration of 1.0 g/kg 

body weight (bw) of a 95% ethanol extract of the whole plant to mice 

inhibited benzoquinone-induced writhing (17). Intraperitoneal administration 

of 100.0 mg/kg bw of a 95% ethanol extract of the whole plant to 

mice inhibited carrageenan-induced footpad oedema by 42%, and reduced 

pain as measured by the hot-plate test and benzoquinone-induced 

writhing (17). Intragastric administration of 100.0 mg/kg bw of an 80% 

ethanol extract of the dried roots to rats inhibited carrageenan-induced 

footpad oedema by 25%, compared with 45% inhibition resulting from 

administration of 5.0 mg/kg bw of indometacin (18). 


A 95% ethanol extract of the dried aerial parts, 1.0 mg/ml, did not inhibit 

the growth of Bacillus globifer, B. mycoides, B. subtilis, Escherichia 

coli, Fusarium solani, Klebsiella pneumoniae, Penicillium notatum, Proteus 

morganii, Pseudomonas aeruginosa, Salmonella gallinarum, Serratia 

marcescens, Staphylococcus aureus, Mycobacterium smegmatis or Candida 

albicans in vitro (19, 20). No antibacterial effects were observed using a 

50% ethanol extract of the whole plant, 50 μl/plate, against Escherichia 

coli, Salmonella enteritidis, Salmonella typhosa, Shigella dysenteriae or 

Shigella fl exneri (21). 



whole plant to rats protected the animals against ethanol-induced gastric 

ulceration. A methanol extract, however, was not active (22). 


Intragastric administration of an aqueous or 95% ethanol extract of the 

whole plant (dose not specifi ed) to rats increased bile secretion by 40% 

(23). 

Diuretic activity 

Intragastric administration of 8.0–50.0 ml/kg bw of a 95% ethanol extract 

of the whole plant to rats induced diuresis and reduced body weight (24). 

Intragastric administration of 0.1 ml/kg bw of a 30% ethanol extract of 

the whole plant to mice induced diuresis (25). However, intragastric 

332


administration of 50.0 mg/kg bw of a chloroform, methanol or petroleum 

ether extract of the roots to mice did not consistently increase urine output 

(26). 

Hypoglycaemic activity 

Intragastric administration of a 50% ethanol extract of the whole plant to 

rats, 250.0 mg/kg bw, or rabbits, 1.0 g/kg bw, reduced blood glucose concentrations 

(27). However, intragastric administration of 2.0 g/kg bw of 

the powdered whole plant to rabbits did not reduce blood sugar concentrations 

in alloxan-induced hyperglycaemia (28). Intragastric administration 

of 25.0 mg/kg bw of an aqueous extract of the dried root to mice reduced 

glucose-induced hyperglycaemia (29, 30). However, a decoction or 

80% ethanol extract of the dried roots had no effect (30). 



whole plant to mice daily for 20 days signifi cantly (P < 0.01) decreased 

cyclophosphamide-induced immune damage (31). Treatment of scalded 

mice with suppressed immune functions with an aqueous extract of the 

whole plant (dose and route not specifi ed) stimulated the immune response 

(32). Nitric oxide synthesis inhibition induced by cadmium in 

mouse peritoneal macrophages stimulated with recombinant interferon-γ 

and lipopolysaccharide was counteracted by treatment of the cells with an 

aqueous extract of the whole plant, 100 μg/ml. The results were mainly 

dependent on the induction of tumour necrosis factor-α (TNF-α) secretion 

stimulated by the aqueous extract (33). Treatment of primary cultures 

of rat astrocytes with an aqueous extract of the whole plant, 100.0 μg/ 

ml, inhibited TNF-α production induced by lipopolysaccharide and substance 

P. The treatment also decreased the production of interleukin-1 in 

astrocytes stimulated with lipopolysaccharide and substance P. The study 

indicated that Radix cum Herba Taraxaci may inhibit TNF-α production 

by inhibiting interleukin-1 production, thereby producing anti-infl ammatory 

effects (34). Treatment of mouse peritoneal macrophages with an 

aqueous extract of the whole plant, 100 μg/ml, after treatment of the cells 

with recombinant interferon-γ, resulted in increased nitric oxide synthesis 

owing to an increase in the concentration of inducible nitric oxide synthase. 

The results were dependent on the induction of TNF-α secretion 

by Radix cum Herba Taraxaci (35). 

Toxicology 

The intraperitoneal median lethal dose (LD 50 ) of a 95% ethanol extract 

of the whole plant in rats was 28.8 mg/kg bw (24). In rats, the maximum 

333


tolerated dose of a 50% ethanol extract of the whole plant administered 

by the intraperitoneal route was 500.0 mg/kg bw (27). No visible signs 

of toxicity were observed in rabbits after intragastric administration of 

the powdered whole plant at doses of 3–6 g/kg bw per day for up to 

7 days (36). 




Allergic reactions including anaphylaxis and pseudoallergic contact dermatitis 

have been reported (37–40). Cross-reactivity has been reported in 

individuals with an allergy to the pollen of other members of the Asteraceae 

(41). 


Radix cum Herba Taraxaci is contraindicated in obstruction of the biliary 

or intestinal tract, and acute gallbladder infl ammation. In case of gallbladder 

disease, Radix cum Herba Taraxacum should only be used under the 

supervision of a health-care professional (2). 

Warnings 

May cause stomach hyperacidity, as with all drugs containing amaroids 

(2). 

Precautions 


A decrease in the maximum plasma concentration of ciprofl oxacin was 

observed in rats treated with concomitant oral administration of 2.0 g/kg 

bw of an aqueous extract of the whole plant and 20.0 mg/kg bw of ciprofl 

oxacin (42). 


No effects on fertility were observed in female rabbits or rats after intragastric 

administration of 1.6 ml/kg bw of a 40% ethanol extract of the 

whole plant during pregnancy (43). 


No teratogenic or embryotoxic effects were observed in the offspring of 

rabbits or rats after intragastric administration of 1.6 ml/kg bw of a 40% 

ethanol extract of the whole plant during pregnancy (43). 

334




drug and laboratory test interactions; non-teratogenic effects in 

pregnancy; nursing mothers; or paediatric use. 

Dosage forms 

Dried whole plant, native dry extract, fl uidextract and tincture (1, 2). 

Store in a tightly sealed container away from heat and light. 

Posology 


Average daily dose: 3–4 g of cut or powdered whole plant three times; 

decoction, boil 3–4 g of whole plant in 150 ml of water; infusion, steep 1 

tablespoonful of whole plant in 150 ml of water; 0.75–1.0 g of native dry 

extract 4:1 (w/w); 3–4 ml fl uidextract 1:1 (g/ml) (2); 5–10 ml of tincture 

(1:5 in 45% alcohol) three times (1). 

References 


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extract. Pharmacology Research, 1993, 27(Suppl. 1):23–24. 


ammatory activity. Phytotherapy Research, 1987, 1:28–31. 

19. Mitscher LA et al. Antimicrobial agents from higher plants. I. Introduction, 

rationale, and methodology. Lloydia, 1972, 35:157–166. 

20. Recio MC, Ríos JL, Villar A. Antimicrobial activity of selected plants employed 

in the Spanish Mediterranean area. Part II. Phytotherapy Research, 

1989, 3:77–80. 

21. Caceres A, Cano O, Samayoa B et al. Plants used in Guatemala for the treatment 

of gastrointestinal disorders. 1. Screening of 84 plants against enterobacteria. 


22. Muto Y et al. [Studies on antiulcer agents. I. The effects of various methanol 

and aqueous extracts of crude drugs on antiulcer activity.] Yakugaku Zasshi, 

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anzen. [Studies on the choleretic action of some medicinal plants.] 

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on the body weight and diuresis of laboratory animals. Planta Medica, 

1974, 26:212–217. 


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26. Hook I, McGee A, Henman M. Evaluation of dandelion for diuretic activity 

and variation in potassium content. International Journal of Pharmacognosy, 

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28. Akhtar MS, Khan QM, Khaliq T. Effects of Portulaca oleracae (kulfa) and 

Taraxacum offi cinale (dhudhal) in normoglycaemic and alloxan-treated hyperglycaemic 

rabbits. Journal of the Pakistan Medical Association, 1985, 

35:207–210. 

29. Neef H, DeClercq P, Laekeman G. Hypoglycemic activity of selected European 

plants. Pharmacy World and Science, 1993, 15:H11. 

30. Neef H, DeClercq P, Laekeman G. Hypoglycemic activity of selected European 

plants. Phytotherapy Research, 1995, 9:45–48. 

31. Hong Y et al. [The effect of Taraxacum mongolicum on immune function in 

mouse.] Journal of Guiyang Medical College, 1997, 22:137–139 [in Chinese]. 

32. Luo ZH. [The use of Chinese traditional medicines to improve impaired immune 

functions in scald mice.] Chung Hua Cheng Hsing Shao Shang Wai Ko 

Tsa Chih, 1993, 9:56–58 [in Chinese]. 

33. Kim HM et al. Taraxacum offi cinale restores inhibition of nitric oxide production 

by cadmium in mouse peritoneal macrophages. Immunopharmacology 

and Immunotoxicology, 1998, 20:283–297. 

34. Kim HM et al. Taraxacum offi cinale inhibits tumor necrosis factor-alpha 

production from rat astrocytes. Immunopharmacology and Immunotoxicology, 

2000, 22:519–530. 

35. Kim HM, Oh CH, Chung CK. Activation of inducible nitric oxide synthase 

by Taraxacum offi cinale in mouse peritoneal macrophages. General Pharmacology, 

1999, 32:683–688. 

36. Akhtar MS. Hypoglycemic activities of some indigenous medicinal plants 

traditionally used as antidiabetic drugs. Journal of the Pakistan Medical Association, 

1992, 42:271–277. 

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25:185–188. 

38. Chivato T et al. Anaphylaxis induced by ingestion of a pollen compound. 

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39. Dawe RS et al. Daisy, dandelion and thistle contact allergy in the photosensitivity 

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337

338 

Semen Trigonellae Foenugraeci 

Defi nition 

Semen Trigonellae Foenugraeci consists of the dried ripe seeds of Trigonella 

foenum-graecum L. (Fabaceae) (1–7). 

Synonyms 

Buceras foenum-graecum (L.) All., Foenum-graecum offi cinale Moench, 

F. offi cinale Moench var. cultum Alef., F. sativum Med., Folliculigera graveolens 

Pasq., Tels foenum-graecum (L.) Kuntze, Trigonella foenum-graecum 

L. subsp. culta (Alef.) Gams, T. graeca St Lag. and T. jemenensis 

(Serp.) Sinsk. (8). Fabaceae are also known as Leguminosae. 


Alholvabockshorn, bahubeeja, bahupatrika, bhaji, Bockshornklee, bothinee, 

boukeros, bukkehorn, chamliz, chanbalid, chanbalila, chanbalit, 

chandrika, chilebe, deepanee, el halbah, fariqua, feenugreek, fenacho, fenigrek, 

fenogreco, fenogreco, fénugrec, fenugreek, fenugriego, fi eno-greco, 

foenugreek, fumugrec, gandhaphala, goat’s horn, Greek hay, halba, halbet, 

hay trigonella, helba, henogriego, hilba, hinojogriego, hoolbah, hula-pa, 

hulba, huluba, hulupa, jyoti, kelabat, kelabet, klabet, koroha, kozieradka 

pospolita, Kuhhornklee, kunchika, l-helba, maithi, maithy, mathi, 

menle, mentepale, menthiam, menthi, menti-kuroa, methi, methika, methiky, 

methini, methra, methuka, methisak, mentikoora, mentulu, methun, 

methy, mitha, monte soffu, munichhada, pe-nam-ta-zi, penan-ta, 

peetabeeja, samli, schöne Margret, schöne Marie, senegré, shamlit, shamlid, 

shamlitz, shanbalileh, shandalid, thenthya, tifi das, tilis, uluhaal, uluva, 

vendayam, venthiam, ventayam (1, 4, 8–12). 


Indigenous to the Mediterranean region, China, India and Indonesia. 

Cultivated in these countries (5, 13).


Description 

Annual aromatic herb, up to 60 cm high with a well developed taproot 

and much branched roots. Stem solitary or basally branched, terete, slightly 

pubescent, green to purple. Leaves petiolate, alternate, trifoliolate; stipules 

triangular, small, adnate to the petiole. Rachis short. Leafl ets obovate 

or oblong, 1.5–4.0 cm long, 0.5–2.0 cm wide, upper part of margin denticulate. 

Flowers whitish, solitary, axillary, subsessile, 12–15 mm long. Calyx 

campanulate, fi nely pubescent, tube 4.5 mm long, with fi ve lobes. Pistil 

with sessile ovary, glabrous style and capitate stigma. Fruits straight to 

occasionally sickle-shaped, linear pods, glabrous, with fi ne longitudinal 

veins, terminating in a beak 2–3 cm long. Seeds oblong-rhomboidal, 3– 

5 mm long and 2–3 mm wide, with a deep furrow dividing each into two 

unequal lobes, with rounded corners, rather smooth, brownish (11). 

Plant material of interest: dried ripe seeds 


Oblong-rhomboidal, 3.0–5.0 mm long, 2.0–3.0 mm wide, 1.5–2.0 mm 

thick, with rounded corners, rather smooth. Yellowish-brown to reddishbrown, 

with a deep furrow dividing each seed into two unequal lobes, and 

a deep hilum at the intersection of the two furrows. Texture hard, not easily 

broken. Testa thin, endosperm translucent and viscous; cotyledons 

two, pale yellow, radicle curved, plump and long (1, 6, 7, 11). 


Odour: characteristic, aromatic; taste: slightly bitter (1, 2, 6, 7). 


Transverse section shows an epidermis of palisade cells, one layer, with 

thick cuticle and thick lamellated walls, and a relatively large lumen at the 

lower part. Longitudinal pit-canals fi ne and close. Subepidermal layer of 

basket-like cells, with bar-like thickening on the radial walls, followed by 

a parenchymatous layer. Endosperm of several layers of polyhedral cells 

with stratifi ed mucilaginous contents and thickened walls. Cotyledons of 

parenchymatous cells containing fi xed oil and aleurone grains up to 15 μm 

in diameter (1, 2, 7). 


Yellowish-brown showing fragments of the testa in sectional view with thick 

cuticle covering epidermal cells, with an underlying hypodermis of large 

cells, narrower at the upper end and constricted in the middle, with bar-like 

thickenings of the radial walls. Yellowish-brown fragments of the epidermis 

339


in surface view, composed of small polygonal cells with thickened and pitted 

walls, frequently associated with the hypodermal cells, circular in outline 

with thickened walls. Fragments of the hypodermis viewed from below, 

composed of polygonal cells with bar-like thickenings extending to the upper 

and lower walls. Parenchyma of the testa with elongated, rectangular 

cells with slightly thickened walls. Fragments of endosperm with irregularly 

thickened, sometimes elongated cells, containing mucilage (1, 2, 6). 


Macroscopic and microscopic examinations (1, 2, 5–7, 11), microchemical tests 

(5), and thin-layer chromatography for the presence of trigonelline (5, 6). 

Purity tests 






Not more than 2% (1, 2, 4, 6). 

Total ash 



Not more than 2% (1, 2, 5). 







Swelling index 

Not less than 6 (3, 6). 




340



Heavy metals 








requirements. 




Semen Trigonellae Foenugraeci is rich in mucilage (25–45%) and contains 

a small amount of essential oil (0.01%) and a variety of secondary metabolites, 

including protoalkaloids, trigonelline (up to 0.37%), choline 

(0.05%); saponins (0.6–1.7%) derived from diosgenin, yamogenin, tigogenin 

and other compounds; sterols including β-sitosterol; and fl avonoids, 

among which are orientin, isoorientin and isovitexin (8, 12, 13, 17). 

The structure of trigonelline is presented below. 

trigonelline 




As an adjunct for the management of hypercholesterolaemia, and hyperglycaemia 

in cases of diabetes mellitus (18–21). Prevention and treatment 

of mountain sickness (22). 


Internally for loss of appetite, and externally as a poultice for local infl 

ammations (23). Treatment of pain, and weakness and oedema of the 

legs (7). 

CH 3 

N + 

CO 2 - 

341



As an aphrodisiac, carminative, diuretic, emmenagogue, emollient, galactagogue 

and tonic (12, 23). Treatment of abdominal colic, bronchitis, diarrhoea, 

eczema, gout, indigestion, dropsy, fever, impotence, chronic cough, 

liver disorders, wounds and the common cold (5, 12). 

Pharmacology 



Intragastric administration of 30.0 g/kg body weight (bw) or 50.0 g/kg 

bw of an ethanol extract of Semen Trigonella daily for 4 weeks to hypercholesterolaemic 

rats reduced plasma cholesterol levels by 18% and 25%, 

respectively. Treatment also lowered liver cholesterol concentrations in 

these animals (24). 


Oral administration of 250.0 mg of an aqueous or methanol extract of 

seeds daily to normal and diabetic rats signifi cantly reduced blood glucose 

levels after eating or the administration of glucose (P < 0.05) (25). 

Intragastric administration of 250.0 mg of an ethanol extract of the seeds 

daily for 28 days reduced blood glucose levels in rats with streptozotocininduced 

diabetes (26), and increased the number of beta cells and the diameter 

of pancreatic islet cells (27). 

Intragastric administration of 2.0 g/kg bw or 8.0 g/kg bw of the seeds 

to rats with or without alloxan-induced diabetes produced a signifi cant 

decrease (P < 0.05) in blood glucose (28). Intragastric administration of a 

single dose of 0.5 ml of a decoction or 200.0 mg/kg bw of an ethanol extract 

of the seeds to mice with or without alloxan-induced diabetes reduced 

serum glucose levels (29). Chronic administration of a high-fi bre 

defatted extract of the seeds in the diet (content not specifi ed) to dogs 

with alloxan-induced diabetes for 21 days decreased hyperglycaemia and 

glucosuria, and reduced the high levels of plasma glucagon and somatostatin 

(30). Intragastric administration of an acetone extract of the seeds 

(dose not specifi ed) to fasted rats antagonized hyperglycaemia induced by 

cadmium or alloxan but had no effect on normal animals (31). 

Anti-implantation activity 

Extracts of the seeds (undefi ned) exhibited anti-implantation effects (approximately 

30%) in rats when administered orally in a single dose of 

25.0 mg/kg bw from day 1 to day 10 of pregnancy. The average number 

of fetal implants was signifi cantly decreased (P < 0.05) (32). 

342



Administration of 2 g/kg bw of the seeds in the diet of rats with alloxaninduced 

diabetes lowered lipid peroxidation, increased the glutathione 

and β-carotene concentrations and reduced the α-tocopherol content in 

the blood (33). 


Administration of 10.0 mg/300 g bw, 12.5 mg/300 g bw or 100.0 mg/300 g 

bw of a steroid-enriched extract of the seeds per day in the diet to rats 

with or without streptozotocin-induced diabetes signifi cantly (P < 0.01) 

increased food intake and the motivation to eat. The treatment also decreased 

total plasma cholesterol without changing the level of triglycerides 

(34, 35). 

Toxicology 

Intragastric administration of a debitterized powder of the seeds to mice 

and rats, 2.0 g/kg bw and 5.0 g/kg bw respectively, did not produce any 

signs of acute toxicity or mortality. In a 90-day subchronic study, weanling 

rats were fed with the powder in the diet, 1.0%, 5.0% or 10.0%. 

Terminal autopsy showed no signs of organ damage, increase in liver enzymes, 

haematological changes or toxicity (36). 

Administration of a saponin fraction from the seeds by intramuscular 

injection, by intraperitoneal injection, 50.0 mg/kg bw per day, or in drinking-water, 

500.0 mg/kg bw, to chicks for 21 days decreased body weight 

and increased liver enzymes. Pathological changes observed included fatty 

cytoplasmic vacuolation in the liver, necrosis of hepatocytes with lymphocytic 

infi ltration, epithelial degeneration of the renal tubules, catarrhal 

enteritis, myositis and peritonitis (37). 

Intragastric administration of an aqueous or 95% ethanol extract of 

the seeds (dose not specifi ed) stimulated uterine contractions in healthy 

and pregnant rats, mice and guinea-pigs (38, 39). In vitro, a 50% ethanol 

extract of the seeds, 2%, had spermicidal effects and immediately immobilized 

human sperm on contact (40, 41). 


Numerous clinical studies have assessed the effects of the seeds on serum 

cholesterol and glucose levels in patients with mild to moderate hypercholesterolaemia 

or diabetes (18–21, 42). 

In a crossover trial, the effects of a powder of the seeds of Momordica 

charantia (MC) or Trigonella foenum-graecum (TF), or a combination of 

the two on total serum cholesterol, high-density-lipoprotein cholesterol, 

low-density-lipoprotein cholesterol, very-low-density-lipoprotein 

343


cholesterol and triglycerides were investigated in 20 hypercholesterolaemic 

non-insulin dependent diabetes mellitus patients. Each subject was 

given 4.0 mg of MC, 50.0 mg of TF or a 50% combination of the two per 

day for 14 days. Mean serum total cholesterol was 271.4 mg/dl at the start 

of the study, and was signifi cantly (P < 0.001) decreased to 234.1 mg/dl, 

230.6 mg/dl and 225.8 mg/dl after MC, TF or the combination treatment, 

respectively. All other lipid parameters were also signifi cantly decreased 

(P < 0.001) (21). 

In a placebo-controlled clinical trial, the effect of ginger and Semen 

Trigonella on blood lipids, blood sugar, platelet aggregation, and fi brinogen 

and fi brinolytic activity was investigated. The subjects included 

healthy volunteers and patients with coronary artery disease and/or insulin-dependent 

diabetes mellitus. Healthy subjects treated with 2.5 g of the 

seeds twice per day for 3 months showed no changes in blood lipids and 

blood sugar (either fasting or after eating). However, in diabetic patients 

with cardiovascular disease, the treatment signifi cantly (P < 0.001) decreased 

total cholesterol and triglycerides, without affecting high-density-lipoprotein 

concentrations. In diabetic patients without cardiovascular 

disease, the seeds reduced blood sugar levels in both fasting and non-fasting 

subjects, although the treatment was not effective in patients with severe 

diabetes (20). 

A prescribed diet with or without the seeds, 25.0 g/day, was given to 

60 patients with non-insulin dependent diabetes for a 7-day preliminary period 

and then for a 24-week trial. The diet containing the seeds lowered 

fasting blood glucose and improved glucose tolerance. The 24-hour urinary 

sugar excretion was signifi cantly reduced (P < 0.001), and glycosylated haemoglobin 

was signifi cantly reduced (P < 0.001) by week 8 of the trial (19). 

The effect of the seeds on blood glucose and the serum lipid profi le was 

assessed in 10 patients with insulin-dependent (type I) diabetes patients. Isocaloric 

diets with or without the seeds, 100.0 g/day, were administered in a 

randomized manner for 10 days. The diet containing the seeds signifi cantly 

reduced (P < 0.001) fasting blood sugar and improved glucose tolerance 

tests. There was a 54% reduction in 24-hour urinary glucose excretion. Serum 

total cholesterol, low-density-lipoprotein cholesterol, very-low-density-lipoprotein 

cholesterol and triglycerides were also reduced. The highdensity-lipoprotein 

cholesterol concentrations remained unchanged (18). 

In a long-term study, 60 patients with diabetes ingested 25.0 g of seeds 

per day for 24 weeks. No changes in body weight or levels of liver enzymes, 

bilirubin or creatinine were observed, but blood urea levels decreased 

after 12 weeks. No evidence of renal or hepatic toxicity was observed 

(43). 

344


Allergic reactions to the seeds following ingestion or inhalation have been 

reported (44, 45). These reactions range from rhinorrhoea, wheezing, 

fainting and facial angioedema (45). A 5-week-old infant had a 10-minute 

episode of unconsciousness after drinking a tea prepared from the seeds; 

however, upon medical examination, all tests were normal (46). 


Semen Trigonellae Foenugraeci is contraindicated in cases of allergy to 

the plant material. Owing to its stimulatory effects on the uterus, the 

seeds should not be used during pregnancy (39). 

Warnings 


Precautions 


Owing to its effect on blood glucose levels in diabetic patients, Semen 

Trigonellae Foenugraeci should only be used in conjunction with oral antihyperglycaemic 

agents or insulin under the supervision of a health-care 

professional. 


An aqueous and a chloroform/methanol extract of the seeds were not 


strains TA98 and TA100 (47, 48). The extracts were also not mutagenic in 

pig kidney cells or in trophoblastic placental cells (47). 






drug and laboratory test interactions; teratogenic effects in pregnancy; 

nursing mothers; or paediatric use. 

Dosage forms 

Dried seeds, extracts, fl uidextracts and tinctures (23). Store in a tightly 

sealed container away from heat and light. 

345


Posology 


Average daily dose. Internal use, cut or crushed seed, 6 g, or equivalent of 

preparations; infusion, 0.5 g of cut seed macerated in 150 ml cold water 

for 3 hours, several cups; fl uidextract 1:1 (g/ml), 6 ml; tincture 1:5 (g/ml), 

30 ml; native extract 3–4:1 (w/w), 1.5–2 g. External use: bath additive, 50 g 

of powdered seed mixed with 250 ml water, added to a hot bath; poultice, 

semi-solid paste prepared from 50 g of powdered seed per litre of hot 

water, apply locally (23). 

References 



2. Materia medika Indonesia. Jilid VI. Jakarta, Departmen Kesehatan Republik 

Indonesia, 1995. 


1996. 




5. Malaysian herbal monograph. Vol. 1. Kuala Lumpur, Malaysian Monograph 

Committee, 1999. 


Europe, 2000. 



8. Hänsel R et al., eds. Hagers Handbuch der Pharmazeutischen Praxis. Bd 6, 

Drogen P–Z, 5th ed. Band. 6. [Hager’s handbook of pharmaceutical practice. 

Vol. 6, Drugs P–Z, 5th ed.] Berlin, Springer, 1994. 



1959. 

10. Raghunathan K, Mitra R. Pharmacognosy of indigenous drugs. Vol. II. New 

Delhi, Central Council for Research in Ayurveda and Siddha, 1982. 

11. de Guzman CC, Siemonsma JS, eds. Plant resources of South-east Asia, No. 

13. Spices. Bogor, PROSEA, 1999. 

12. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of Illinois 

at Chicago, 9 February 2001 production (an online database available 




Press, 1994. 

346






World Health Organization, 1997 (WHO/FSF/FOS/97.7; available 


17. Newall CA, Anderson LA, Phillipson JD. Herbal medicines, a guide for 


18. Sharma RD, Raghuram TC, Rao NS. Effect of fenugreek seeds on blood 

glucose and serum lipids in type I diabetes. European Journal of Clinical 

Nutrition, 1990, 44:301–306. 

19. Sharma RD et al. Use of fenugreek seed powder in the management of noninsulin 

dependent diabetes mellitus. Nutrition Research, 1996, 16:1331–1339. 

20. Bordia A, Verma SK, Srivastava KC. Effect of ginger (Zingiber offi cinale 

Rosc.) and fenugreek (Trigonella foenum graecum L.) on blood lipids, blood, 

sugar and platelet aggregation in patients with coronary artery disease. Prostaglandins, 

Leukotrienes and Essential Fatty Acids, 1997, 56:379–384. 

21. Awal MA et al. Effects of karela and fenugreek on lipid profi le in hypercholesterolemic 

diabetic patients. Bangladesh Journal of Physiology and Pharmacology, 

1999, 15:6–8. 



23. Blumenthal M et al. eds. Herbal medicine, expanded Commission E monographs. 

Newton, Integrative Medicine Communications, 2000. 

24. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek 

(Trigonella foenum-graecum) on bile acid absorption and cholesterol levels 

in rats. British Journal of Nutrition, 1993, 69:277–287. 

25. Ali L et al. Characterization of the hypoglycemic effects of Trigonella foenum 

graecum seed. Planta Medica, 1995, 61:358–360. 

26. Awal MA et al. Effects of Trigonella foenumgraecum and spirulina on blood 

glucose level in streptozotocin-induced diabetic rats. Bangladesh Journal of 

Physiology and Pharmacology, 1994, 10:16–17. 

27. Awal MA et al. Histomorphological changes of the islets cells of pancreas 

due to fenugreek in normal and streptozotocin-induced diabetic rats. 

Bangladesh Journal of Physiology and Pharmacology, 1997, 13:6–8. 

28. Khosla P, Gupta DD, Nagpal RK. Effect of Trigonella foenum graecum (fenugreek) 

on blood glucose in normal and diabetic rats. Indian Journal of Physiology 

and Pharmacology, 1995, 39:173–174. 

29. Ajabnoor MA, Tilmisany AK. Effect of Trigonella foenum graecum on blood 

glucose levels in normal and alloxan-diabetic mice. Journal of Ethnopharmacology, 

1988, 22:45–49. 

30. Ribes G et al. Antidiabetic effects of subfractions from fenugreek seeds in 

diabetic dogs. Proceedings of the Society of Experimental Biology and Medicine, 

1986, 182:159–166. 

347


31. Ghafghazi T et al. Antagonism of cadmium and alloxan-induced hyperglycemia 

in rats by Trigonella foenum graecum. Pahlavi Medical Journal, 1977, 8:14–25. 

32. Rastogi RP, Mehrotra BN, eds. Compendium of Indian medicinal plants, Vol. 

III. Lucknow, Central Drug Research Institute and New Delhi, Publication 

and Information Directorate, 1993. 

33. Ravikumar P, Anuradha CV. Effect of fenugreek seed on blood lipid peroxidation 

and antioxidants in diabetic rats. Phytotherapy Research, 1999, 13:197–201. 

34. Petit P et al. Effects of a fenugreek seed extract on feeding behaviour in the 

rat: metabolic–endocrine correlates. Pharmacological and Biochemical Behaviour, 

1993, 45:369–374. 

35. Petit P et al. Steroid saponins from fenugreek seeds: extraction, purifi cation 

and pharmacological investigation on feeding behavior and plasma cholesterol. 

Steroids, 1995, 60:674–680. 

36. Muralidhara NK, Viswanatha S, Ramesh BS. Acute and subchronic toxicity 

assessment of debitterized fenugreek powder in the mouse and rat. Food and 


37. Nakhla HB et al. The effect of Trigonella foenum graecum (fenugreek) crude 

saponins on Hisex-type chicks. Veterinary and Human Toxicology, 1991, 

33:561–564. 

38. Abdo MS, Al-Kafawi AA. Experimental studies on the effect of Trigonella 

foenum-graecum. Planta Medica, 1969, 17:14–18. 

39. Sharaf A. Food plants as possible factor in fertility control. Qualitas Plantarum 

et Materiae Vegetabiles, 1969, 17:153–160. 

40. Setty BS et al. Spermicidal potential of saponins isolated from Indian medicinal 

plants. Contraception, 1976, 14:571–578. 

41. Dhawan BN et al. Screening of Indian plants for biological activity: Part VI. 


42. Al-Habbori M, Raman A. Antidiabetic and hypocholesterolaemic effects of 

fenugreek. Phytotherapy Research, 1998, 12:233–242. 

43. Sharma RD et al. Toxicological evaluation of fenugreek seeds: a long term 

feeding experiment in diabetic patients. Phytotherapy Research, 1996, 10:519– 

520. 

44. Dugue P, Bel J, Figueredo M. Le fenugrec responsable d’un nouvel asthme 

professionnel. [Fenugreek responsible for a new occupational asthma.] La 

Presse Médicale, 1993, 22:922. 

45. Patel SP, Niphadkar PV, Bapat MM. Allergy to fenugreek. Annals of Allergy, 

Asthma and Immunology, 1997, 78:297–300. 

46. Sewell AC, Mosandl A, Bohles H. False diagnosis of maple syrup urine disease 

owing to ingestion of herbal tea. New England Journal of Medicine, 

1999, 341:769. 






348

Cortex Uncariae 

Defi nition 

Cortex Uncariae consists of the dried stem bark of Uncaria tomentosa 

(Willd.) DC. (Rubiaceae). 

Synonyms 

Nauclea aculeata auct. Non Willd., N. cinchoneae DC, N. polycephala A. 

Rich., N. tomentosa Willd., Ourouparia polycephala Baill., Uncaria surinamensis 

Miq., U. tomentosa DC, Uruparia tomentosa (Willd.) O. Kuntze 

(1, 2). 


Bejuco de agua, cat’s claw, cat’s thorn, deixa, garabato, garabato amarillo, 

garabato colorado, garra gavilán, hank’s clay, jipotatsa, Katzenkralle, kug 

kukjaqui, micho-mentis, paotati-mosha, paraguyayo, rangaya, saventaro, 

toroñ, tsachik, tua juncara, uña de gato, uña de gato de altura, uncucha, 

unganangi, unganangi, unha de gato (1–5). 


Indigenous to Central America and northern South America including 

Belize, Bolivia, Brazil, Colombia, Costa Rica, Ecuador, Guatemala, Honduras, 

Nicaragua, Peru, Suriname, Trinidad and Tobago, and Venezuela, 

with Peru being the main source (1, 6, 7). 

Description 

A scrambling liana, up to 20–30 m long, main stem up to 25 cm in diameter. 

Branches obtusely quadrangular, generally puberulous. Stipules 

widely ovate-triangular, minutely and densely puberulous outside. Leaves 

opposite, petiolate; petioles 1.0–1.5 cm long, minutely puberulous or hirtellous; 

leaf blades ovate to ovate-oblong, 6.0–14.5 cm long, 2.5–8.5 cm 

wide; apex obtuse to acuminate; base rounded or subtruncate or subcordate; 

margin entire or occasionally crenulate in the upper half, glabrous or 

subglabrous above except strigillose on veins, area between veins densely 

349


puberulent to subglabrous beneath; lateral veins six to ten pairs, level 

above, prominent beneath, tertiary veins distinct. Spines strongly recurved, 

tomentose in younger branches, glabrous in older ones. Infl orescences 

thyrsic with three to nine nodes, lateral units with one to eight 

pseudo-heads, the bracts reduced; heads small, 12–20 mm in diameter; peduncles 

densely hirtellous, 1.5–4 cm long. Flowers sessile; calyx tubular, 

0.5–0.8 mm long with the obtuse lobes 0.2–0.3 mm long, densely villosulous 

outside, densely sericeous inside at the base; corolla densely retrorsely 

adpressed, puberulous outside, glabrous inside, tubes 3.5–5.0 mm long, 

0.7–0.8 mm wide at the base, 1.0 mm wide at the mouth, lobes suborbicular, 

rounded, 1–1.5 mm long, 1–1.5 mm wide. Stamens fi ve, some sterile; 

anthers 1.0–1.5 mm long, obtuse at the apex, prolonged and attenuated at 

the base; fi laments around 0.2 mm long. Ovary 1.4–1.6 long, 0.9–1.3 mm 

wide, densely villosulous, style 6.5–9 mm long, glabrous; stigma 1.0 mm 

long, clavate. Capsules 0.8–1.2 cm long, pubescent outside; seeds with 

two long narrow wings, one bifi d, 3.4 mm long (6, 8–10). 

Plant material of interest: dried stem bark 


Shavings or chopped stem bark contain numerous bast fi bres up to 7 cm 

long, fi bre bundles and fi ne-crumbling rind/bark breaking into pieces. The 

sawdust-like chopped stem bark consists of wood fi bres up to 1 cm long 

with a small fraction of short bast fi bres and traces of powdered bark (4). 


No characteristic odour or taste (4). 


Rings dark, partly elevated, but hardly structured. Under illumination, 

bast fi bres show net-like or reticulate structure; with illumination from 

above, they glimmer with a brownish shimmer. Powdered stem bark consists 

of fi nely broken pieces of wood, bast and bark, and clear, crystalline 

particles of dried sap (4). 




Macroscopic and microscopic examinations (1, 4), thin-layer chromatography 

(4, 11), and high-performance liquid chromatography for the 

presence of characteristic oxindole alkaloids (4, 12, 13). 

350


Purity tests 










Heavy metals 





methods for medicinal plants (14) for the analysis of radioactive 

isotopes. 


Chemical, foreign organic matter, total ash, acid-insoluble ash, 

sulfated ash, water-soluble extractive, alcohol-soluble extractive and 

loss on drying tests to be established in accordance with national 

requirements. 


Not more than 0.02% total tetracyclic oxindole alkaloids determined by 

high-performance liquid chromatography (4, 12, 13). 


The major constituents are indole alkaloids (0.15–4.60%), primarily 

pentacyclic oxindoles. The principal pentacyclic oxindole alkaloids 

are pteropodine, isopteropodine, speciophylline, uncarine F, mitraphylline 

and isomitraphylline. Tetracyclic oxindoles present include 

isorhynchophylline and rhynchophylline (1, 4, 5, 12, 17). The structures 

of the major pentacyclic oxindole alkaloids are presented 

below. 

351


HN 

H 3 C 

HN 

H 3C 



None. Although two clinical studies have suggested that Cortex Uncariae 

may be an immunostimulant and increase the number of white blood cells 

(18, 19), data from controlled clinical trials are lacking. 


Symptomatic treatment of arthritis, rheumatism and gastric ulcers (7, 10, 20). 


Treatment of abscesses, asthma, fevers, urinary tract infections, viral infections 

and wounds. As an emmenagogue (4, 5, 21). 

Pharmacology 



Addition of an undefi ned extract of the stem bark to the cell medium at a 

concentration of 100 μg/ml signifi cantly attenuated (P < 0.05) peroxynitrite-induced 

apoptosis in HT29 (epithelial cells) and RAW 264.7 cells 

(macrophages). The extract further inhibited lipopolysaccharide-induced 

nitric oxide synthase gene expression (iNOS), nitrite formation, cell death, 

and the activation of nuclear transcription factor-κβ in RAW 264.7 cells. 

Oral administration of the extract in drinking-water, 5 mg/ml, attenuated 

indometacin-enteritis in rodents as evidenced by reduced myeloperoxi- 

352 

mitraphylline 

O 

isomitraphylline 

O 

N 

H H 

O 

H 

O 

N 

H H 

O 

H 

O 

O 

O 

CH 3 

H 

CH 3 

H 

HN 

H 3 C 

HN 

H 3C 

O 

pteropodine 

N 

H H 

O 

H 

O 

O 

isopteropodine 

O 

N 

H H 

O 

H 

O 

O 

CH 3 

H 

CH 3 

H 

HN 

H 3 C 

HN 

H 3C 

O 

uncarine F 

N 

H H 

O 

H 

O 

O 

speciophylline 

O 

N 

H H 

O 

H 

O 

CH 3 

H 

CH 3 

H 

O


dase activity, morphometric damage and liver metallothionein expression 

(22). 

The anti-infl ammatory activities of two types of extracts from the stem 

bark: a hydroalcoholic extract containing 5.61% alkaloids (mainly of the 

pentacyclic type, extract A) and an aqueous freeze-dried extract containing 

0.26% alkaloids (extract B) were assessed in the carrageenan-induced 

rat paw oedema test. Extract A was signifi cantly more active than extract 

B, suggesting that the effect could be due to the presence of pentacyclic 

oxindole alkaloids. Both extracts showed little inhibitory activity on cyclooxygenase-1 

and -2. Only a slight inhibitory activity on DNA-binding 

of NF-κB was observed (23). 

The effects of a decoction of the stem bark, 10.0 μg/ml freeze-dried, on 

tumour necrosis factor-α (TNF-α) production and cytotoxicity in lipopolysaccharide-stimulated 

murine macrophages (RAW 264.7 cells) was assessed 

in vitro. The decoction prevented oxidative- and ultraviolet irradiation-induced 

cytotoxicity. It also suppressed TNF-α production by 

approximately 65–85% (P < 0.01) at concentrations of 1.2–28.0 ng/ml (24). 

Cinchonain Ib, a procyanidin from the stem bark, inhibited the activity 

of 5-lipoxygenase, ≥ 100% at 42.5 μmol/ml, indicating an anti-infl ammatory 

effect (25). 


Growth inhibitory activities of an aqueous extract of the stem bark were 

examined in vitro using two human leukaemic cell lines (K562 and HL60) 

and one human Epstein–Barr virus-transformed B lymphoma cell line 

(Raji). Cell proliferation of HL60 and Raji cells was strongly suppressed in 

the presence of the aqueous extract, while K562 was more resistant to the 

inhibition. The suppressive effect was mediated through induction of apoptosis, 

which was shown by characteristic morphological changes, internucleosomal 

DNA fragmentation after agarose gel electrophoresis and DNA 

fragmentation quantifi cation. The extract also induced a delayed type of 

apoptosis becoming most dose-dependently prominent after 48 hours of 

exposure. Both DNA single- and double-strand breaks were increased 24 

hours following treatment (26). Leukaemic HL60 and U-937 cells were 

incubated with pure alkaloids from U. tomentosa root. The pentacyclic oxindole 

alkaloids inhibited the growth, median inhibitory concentration 

(IC 50 ) 10 -5 –10 -4 mol/l; the most pronounced effect was found for uncarine 

F. Selectivity between leukaemic and normal cells was observed (13). 

Immune stimulating activity 

Addition of 1 μmol/l of pentacyclic oxindole alkaloids (POA) induced 

endothelial cells to release some as yet to be determined factor(s) into the 

353


supernatant, which enhanced the proliferation of normal human resting 

or weakly activated B and T lymphocytes. In contrast, proliferation of 

normal human lymphoblasts and of both the human lymphoblastoid B 

cell line Raji and the human lymphoblastoid T cell line Jurkat was inhibited, 

while cell viability was not affected. However, it was shown that the 

tetracyclic oxindole alkaloids had antagonistic effects to the POA, and 

dose-dependently reduced the proliferation of lymphocytes stimulated 

by POA (27). 

Two commercial extracts of the stem bark, containing approximately 

6 mg/g total oxindoles were assessed for the ability to stimulate the production 

of interleukin-1 (IL-1) and interleukin-6 (IL-6) in alveolar macrophages. 

A phosphate-buffered saline solution of the extracts stimulated 

IL-1 and IL-6 production by rat macrophages in a dose-dependent manner 

in the concentration range 0.025–0.1 mg/ml. In lipopolysaccharide 

(LPS)-stimulated macrophages, the extracts potentiated the stimulating 

effects of LPS on IL-1 and IL-6 production indicating an immune stimulating 

effect (20). 

The immune effects of an aqueous stem bark extract were assessed after 

intragastric administration of the extract, 5.0–80.0 mg/kg body weight 

(bw) per day for 8 consecutive weeks. Phytohaemagglutinin (PHA)-stimulated 

lymphocyte proliferation was signifi cantly (P < 0.05) increased in 

splenocytes of rats treated at doses of 40.0 mg/kg bw and 80.0 mg/kg bw. 

White blood cells from the groups treated with 40.0 mg/kg bw and 

80.0 mg/kg bw per day for 8 weeks or 160.0 mg/kg bw per day for 4 weeks 

were signifi cantly elevated (P < 0.05) as compared with controls. Repair 

of DNA single- and double-strand breaks 3 hours after 12 whole body 

irradiations were also signifi cantly improved (P < 0.05) in rats treated 

with the stem bark (19). 

Aqueous extracts of the stem bark, depleted of indole alkaloids 

(< 0.05%, w/w), were assessed for the treatment of chemically-induced 

leukopenia in rats. The animals were treated fi rst with doxorubicin (DXR), 

three intraperitoneal injections of 2 mg/kg bw given at 24-hour intervals, 

to induce leukopenia. Beginning 24 hours after the last DXR treatment, 

the rats received 80 mg/kg bw of the aqueous extract per day by intragastric 

administration for 16 days. Animals treated with the extract recovered 

signifi cantly sooner (P < 0.05) than those receiving DXR alone, and 

all fractions of white blood cells were proportionally increased. The 

mechanism of action on white blood cells is not known; however, data 

showing enhanced effects on DNA repair and immune cell proliferative 

response support a general immune enhancement (28). 

354

Intraperitoneal administration of 10.0 mg/kg bw of an oxindole alkaloid-enriched 

extract of the stem bark enhanced phagocytosis in mice as 

assessed by the clearance of colloidal carbon. However, the pure alkaloids 

were not active without the presence of catechins such as the catechin tannin 

fraction of the root (29). In vitro, alkaloids from the stem bark were 

tested in two chemoluminescence models (granulocyte activation, phagocytosis) 

for their ability to enhance phagocytotic activity. Isopteropodine 

showed the strongest activity (55%), followed by pteropodine, isomitraphylline 

and isorhynchophylline (29). 

Toxicity 

The median lethal and toxic dose of a single oral dose of an aqueous extract 

of the stem bark in rats was > 8.0 g/kg bw. Although the rats were 

treated daily with aqueous extracts at doses of 10–80 mg/kg bw for 

8 weeks or 160 mg/kg bw for 4 weeks, no symptoms of acute or chronic 

toxicity were observed. In addition, no changes in body weight, food 

consumption and organ weight, or kidney, liver, spleen and heart pathological 

changes were found to be associated with treatment (19). 

Aqueous extracts of the stem bark were analysed for the presence of 

toxic compounds in Chinese hamster ovary cells and bacterial cells (Photobacterium 

phosphoreum) in vitro. At concentrations of 10.0–20.0 mg/ 

ml, the extracts were not cytotoxic (30). 


Immune stimulating activity 

In a human volunteer study, an aqueous extract of the stem bark was administered 

to four healthy volunteers daily at a dose of 350.0 mg/day for 

6 consecutive weeks. No side-effects were reported as judged by haematology, 

body weight changes, diarrhoea, constipation, headache, nausea, 

vomiting, rash, oedema or pain. A signifi cant increase (P < 0.05) in the 

number of white blood cells was observed after 6 weeks of treatment (19). 

Oral administration of two doses of 350 mg of an extract of the stem 

bark containing 0.05% oxindol alkaloids and 8–10% carboxy alkyl esters 

per day to human volunteers stimulated the immune system, as evidenced 

by an elevation in the lymphocyte/neutrophil ratios of peripheral blood 

and a reduced decay in 12 serotype antibody titre responses to pneumococcal 

vaccination at 5 months (18). 




355



Owing to its traditional use as an emmenagogue, Cortex Uncariae is contraindicated 

during pregnancy. 

Warnings 


Precautions 


Commercial extracts of the stem bark inhibited the activity of human cytochrome 

P450, IC 50 < 1%. Cortex Uncariae should only be taken in conjunction 

with prescription drugs metabolized via cytochrome P450, such 

as protease inhibitors, warfarin, estrogens and theophylline under the supervision 

of a health-care provider (31). 






Owing to the lack of safety data, the use of Cortex Uncariae during nursing 

is not recommended, unless under the supervision of a health-care 

provider. 


Owing to the lack of safety data, the use of Cortex Uncariae in children 

under the age of 12 years is not recommended, unless under the supervision 

of a health-care provider. 



drug and laboratory test interactions; and teratogenic effects in pregnancy. 

Dosage forms 

Dried stem bark for infusions and decoctions, and extracts. Capsules and 

tablets. Store in a tightly sealed container away from heat and light. 

356


Posology 


Average daily dose: extracts, 20.0–350.0 mg (10, 19). Capsules and tablets: 

300.0–500.0 mg, one capsule or tablet two to three times. 

References 




2. Pollito PAZ, Indachchea IL, Bernal HY. Agrotechnología para el cultivo de 

uña de gato o bejuco de agua. [Agrotechnology for the cultivation of cat’s 

claw, a water bindweed.] In: Martínez JV, Bernal HY, Caceres A, eds. Fundamentos 

de agrotecnologia de cultivo de plantas medicinales iberoamericanas. 

[Fundamentals of agrotechnology for the cultivation of Latin American medicinal 

plants, Vol. IV.] Bogota, CYTED, 2000. 

3. Plantas medicinales amazonicas: realidad y perspectivas. [Amazonian medicinal 

plants: reality and perspectives.] Lima, Peru, Tratado de Cooperacion 

Amazonica Secretaria Pro-Tempore, 1995. 

4. Laus G, Keplinger K. Radix Uncariae tomentosae (Willd.) DC – eine monographische 

Beschreibung. [Radix Uncariae tomentosae (Willd.) DC – a monograph.] 

Zeitschrift für Phytotherapie, 1997, 18:122–126. 


at Chicago, 1 January 2002 production (an online database available 



6. Teppner H, Keplinger K, Wetsching W. Karyosytematics of Uncaria tomentosa 

and U. guianensis (Rubiaceae – Cinchonaceae). Phyton (Horn, Austria), 

1984, 24:125–134. 

7. Cabieses F. The saga of cat’s claw. Lima, Via Lactea Editores, 1994. 

8. Steyermark JA. Rubiaceae. Flora de Venezuela, 1974, 9:32–38. 

9. Andersson L, Taylor CM. Rubiaceae-Cinchoneae-Coptosapelteae. In: Harling 

G, Andersson L, eds. Flora of Ecuador 50. Copenhagen, Council for 

Nordic Publications in Botany, 1994. 

10. Keplinger K, Laus G, Wurm M. Uncaria tomentosa (Willd.) DC – ethnomedicinal 

use and new pharmacological, toxicological and botanical results. 


11. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas. 


12. Laus G, Keplinger K. Separation of stereoisomeric oxindole alkaloids from 

Uncaria tomentosa by high performance liquid chromatography. Journal of 

Chromatography A, 1994, 662:243–249. 

13. Stuppner H, Sturm S, Konwalinka G. HPLC analysis of the main oxindole 

alkaloids from Uncaria tomentosa. Chromatographia, 1992, 34:597–600. 

357






World Health Organization, 1997 (WHO/FSF/FOS/97.7; available from 

Food Safety, World Health Organization, 1211 Geneva 27, Switzerland). 

17. Reinhard K-H. Uncaria tomentosa (Willd.) DC– Cat’s claw, uña de gato oder 

Katzenkralle. [Uncaria tomentosa (Willd.) DC– cat’s claw, uña de gato or 

Katzenkralle.] Zeitschrift für Phytotherapie, 1997, 18:112–121. 

18. Lamm S, Sheng Y, Pero RW. Persistent response to pneumococcal vaccine in 

individuals supplemented with a novel water soluble extract of Uncaria tomentosa, 

C-Med-100 ® . Phytomedicine, 2001, 8:267–282. 

19. Sheng Y, Bryngelsson C, Pero RW. Enhanced DNA repair, immune function 

and reduced toxicity of C-MED-100, a novel aqueous extract from Uncaria 

tomentosa. Journal of Ethnopharmacology, 2000, 69:115–126. 

20. Lemaire I et al. Stimulation of interleukin-1 and -6 production in alveolar 

macrophages by the neotropical liana, Uncaria tomentosa. Journal of Ethnopharmacology, 

1999, 64:109–115. 

21. Laus G, Brössner D, Keplinger K. Alkaloids of Peruvian Uncaria tomentosa. 

Phytochemistry, 1997, 45:855–860. 

22. Sandoval-Chacon M et al. Antiinfl ammatory actions of cat’s claw: the role of 

NF-kappaB. Alimentary Pharmacology and Therapeutics, 1998,12:1279–1289. 

23. Aguilar JL et al. Anti-infl ammatory activity of two different extracts of Uncaria 

tomentosa (Rubiaceae). Journal of Ethnopharmacology, 2002, 81:271–276. 

24. Sandoval M et al. Cat’s claw inhibits TNFα production and scavenges free radicals: 

role in cytoprotection. Free Radical Biology and Medicine, 2000, 1:71–78. 

25. Wirth C, Wagner H. Pharmacologically active procyanidines from the bark 

of Uncaria tomentosa. Phytomedicine, 1997, 4:265–266. 

26. Sheng Y et al. Induction of apoptosis and inhibition of proliferation in human 

tumor cells treated with extracts of Uncaria tomentosa. Anticancer Research, 

1998, 18:3363–3368. 

27. Wurm M et al. Pentacyclic oxindole alkaloids from Uncaria tomentosa induce 

human endothelial cells to release a lymphocyte-proliferation-regulating 

factor. Planta Medica, 1998, 64:701–704. 

28. Sheng Y, Pero RW, Wagner H. Treatment of chemotherapy-induced leukopenia 

in a rat model with aqueous extract from Uncaria tomentosa. Phytomedicine, 

2000, 7:137–143. 

29. Wagner H, Kreutzkamp B, Jurcic K. Die Alkaloide von Uncaria tomentosa und 

ihre phagocytose-steigernde Wirkung. [The alkaloids of Uncaria tomentosa and 

their phagocytosis-stimulating action.] Planta Medica, 1985, 5:419–423. 

30. Santa Maria A et al. Evaluation of the toxicity of Uncaria tomentosa by bioassays 

in vitro. Journal of Ethnopharmacology, 1997, 57:183–187. 



2000, 7:273–282. 

358

Fructus Zizyphi 

Defi nition 

Fructus Zizyphi consists of the dried ripe fruits of Zizyphus jujuba Mill. 

(1) 1 or Z. jujuba var. inermis Rehd. (Rhamnaceae) (1–5). 

Synonyms 

Rhamnus ziziphus L., Zizyphus mauritiana Lam., Z. sativa Gaertn., Z. 

vulgaris Lam., Z. vulgaris Lam. var. inermis Bunge, Z. zizyphi Karst. (5– 

8). 


Annab, badari, bayear, ber, black date, bor, borakoli, borehannu, brustbeeren, 

Chinese date, Chinese jujube, common jujube, da t’sao, desi ber, hei 

zao, hong zao, ilandai, jujube, jujube date, jujube plum, kamkamber, koli, 

kul, kul vadar, lanta, lantakkura, narkolikul, natsume, onnab, phud sa chin, 

red date, regi, spine date, unnab, vadai, vadar, vagari, zao (1–3, 5–12). 


Indigenous over a wide area, from Southern Europe to South-East and East 

Asia. Cultivated in China, India, Japan and Republic of Korea (5, 9–11). 

Description 

A spiny, deciduous shrub or a small tree, up to 10 m high; spines in groups 

of two, one straight, up to 2.5 cm long and one curved. Leaves alternate, 

petiolate, oval-lanceolate, 2–7 cm long, 2.5–3.0 cm wide; apex slightly obtuse; 

base oblique; margin closely serrulate, with three veins. Infl orescence 

an axillary cyme. Flowers perfect, seven to eight in each cluster; 

calyx with cupuliform tube and fi ve segments; petals fi ve, yellow; disk 

lining the calyx tube; stamens fi ve; ovary depressed into the disk. Fruits 

1 Included in the Pharmacopoeia of the People’s Republic of China (1) as Fructus Jujubae. 

359


are fl eshy drupes, ovoid or oblong, 1.5–5.0 cm long, dark reddish brown 

when ripe (7, 9, 10). 



Ellipsoidal or broad ovoid, 2–3 cm long, 1–2 cm in diameter; externally 

reddish brown with coarse wrinkles, or dark greyish red with fi ne wrinkles, 

lustrous; both ends slightly dented, with a scar of style at one end 

and a scar of peduncle at the other; epicarp thin and leathery; mesocarp 

thick, dark greyish brown, spongy, soft and adhesive; endocarp extremely 

hard, fusiform and divided into two loculi; seeds fl at and ovoid (1, 3, 4). 


Odour: slightly aromatic; taste: sweet (1, 3, 4). 


To be established according to national requirements. 


To be established according to national requirements. 


Macroscopic examination (1, 3, 4) and thin-layer chromatography (1, 5). 

Purity tests 







Total ash 






360

Alcohol-insoluble extractive 










Heavy metals 





methods for medicinal plants (13) for the analysis of radioactive 

isotopes. 




Qualitative and quantitative high-performance liquid chromatography 

for the presence of 3-O-trans- and 3-O-cis-p-coumaroylalphitolic acid 

(16), and jujubosides A and B (17). 


Major characteristic constituents are triterpenes and triterpene saponins, 

including alphitolic, betulinic, maslinic, oleanolic, ursolic, 3-O-trans-alphitolic, 

3-O-cis-p-alphitolic alphitolic, 3-O-cis-p-coumaroylalphitolic, 

and 3-O-trans-p-coumaroylalphitolic acids; and zizyphus saponins I, II, 

III, jujuboside B, spinosin and swertisin (12, 18–22). Three triterpene oligoglycosides, 

jujubosides A1 and C, and acetyljujuboside B have been 

isolated from the seeds (23, 24). Also present in the fruit are the biologically 

active compounds cyclic AMP and cyclic GMP (25), with concentrations 

estimated at 100–500.0 nmol/g and 30–50.0 nmol/g, respectively 

(26). A polysaccharide named ziziphus-arabinan has also been isolated 

from the fruit (27). The structures of representative triterpene and saponins 


361


alphitolic acid 

HO H 

H 

HO 

3 

H CH3 H 

H3C CH3 HO 



None. Although one uncontrolled human study has suggested that Fructus 

Zizyphi may be of some benefi t for the treatment of insomnia (28), 

data from controlled clinical trials are lacking. 


To promote weight gain, improve muscular strength, and as an immunostimulant 

to increase physical stamina. Treatment of insomnia due to irritability 

and restlessness (1). 


As an antipyretic, diuretic, emmenagogue, expectorant, sedative and 

tonic. Treatment of asthma, bronchitis, diabetes, eye diseases, infl ammatory 

skin conditions, liver disorders, scabies, ulcers and wounds 

(12, 29). 

362 

H3C H 

CH 2H 

CH3 CH3 H CO2H CH 3 

HO 

HO 

O O 

H 

O O 

H3C H 

H 

CH3 OH 

O R2 

cis-p-coumaroyl 

HO 

O R1 

O 

betulinic acid 

H3C H 

CH 2H 

CH3 CH3 H CO2H H 

HO 

3 

H CH3 H 

H3C CH3 C 

CH 3 

H 3C 

H 

OH 

O 

O 

H 

H3C CH 3 

trans-p-coumaroyl 

HO 

maslinic acid 

HO H 

H 3 C 

H 

HO 

3 

H CH3 H 

H3C CH3 CH 3 

CH3 CH3 H CO2H jujuboside B 

zizyphus saponin I 

zizyphus saponin II 

zizyphus saponin III 

HO O 

O 

O 

Rha = CH3 dTal = CH3 Xyl = 

OH 

HO 

HO 

OH OH 

OH OH 

OH 

6-deoxy-α-L-mannopyranosyl 6-deoxy-α-L-talopyranosyl β-D-xylopyranosyl 

O 

C 

R1 R2 

Rha Xyl 

dTal H 

Rha 

H 

dTal Xyl


Pharmacology 


Antiallergenic activity 

Intraperitoneal injection of 100.0 mg/kg body weight (bw) of a 100% ethanol 

extract of the Fructus Zizyphi or the active constituent of the ethanol 

extract, ethyl α-d-fructofuranoside, daily for 5 days, inhibited haemagglutination-induced 

anaphylaxis in rats (30). A saline extract (0.85% sodium 

chloride) of the fruits (concentration not specifi ed) prevented hypotonic 

and heat stress-induced haemolysis of erythrocyte membranes in vitro (31). 

Three triterpene oligoglycosides, jujubosides A1 and C, and acetyljujuboside 

B, in varying concentrations inhibited histamine release from rat peritoneal 

exudate cells induced by antigen–antibody reaction (23). 


A methanol extract of the fruits, 0.1 mg/ml, did not suppress interleukin- 

8 induction in lipopolysaccharide-activated rat macrophages in vitro (32). 

A polysaccharide isolated from an aqueous extract of the fruits, Ziziphusarabinan, 

500.0 μg/ml, had anti-complementary activity in human serum 

in vitro (27). Both the n-butanol and diethyl ether extracts of the seeds 

exhibited anti-infl ammatory activity in vitro as assessed by the albuminstabilizing 

assay (33). 

Intragastric administration of 500.0 mg/kg bw of a 95% ethanol extract 

of the fruits to rats daily for 4 days, produced a signifi cant inhibition 

of carrageenan-induced footpad oedema (50.0% reduction, P < 0.05), and 

cotton pellet-induced granulomas (25.0% reduction, P < 0.05) (29). 

Analgesic activity 

A hot aqueous extract of the fruits did not inhibit conduction in the frog 

sciatic nerve when added to the bath medium at a concentration of 2.0% 

(34). Intragastric administration of 500.0 mg/kg bw of a 95% ethanol extract 

of the fruits to mice reduced the responsiveness of mice in the hotplate 

and tail-fl ick tests, thereby demonstrating analgesic effects (29). 


Intragastric administration of a single dose of 1.0 g/kg bw of a 95% ethanol 

extract of the dried seeds suspended in water lowered the mean blood 

glucose concentrations in rabbits with alloxan-induced diabetes (35). 

CNS depressant activity and toxicity 

Chronic administration of 100.0 mg/kg bw of a 95% ethanol extract of 

the fruits to mice in drinking-water daily for 3 months had no effects on 

mortality, haematology, organ weight or sperm production (29). Intragas- 

363


tric administration of an aqueous extract of the fruits, three doses of 

0.5 mg/kg bw, 1.0 mg/kg bw or 3.0 mg/kg bw over 24 hours, to mice had 

no acute toxic effects (29). Intragastric administration of a 95% ethanol 

extract of the fruits, three doses of 1.0 g/kg bw over 24 hours, had no 

acute toxic effects. However, sedation was noted in animals treated with 

three doses of 3.0 g/kg bw (29). 

Subcutaneous administration of 500.0 mg/kg bw of an aqueous extract 

of the seeds daily to mice depressed central nervous system activity, 

as measured by the potentiation of hexobarbital-induced sleeping 

time and antagonism of caffeine-induced hyperactivity (36). However, 

intraperitoneal administration of 500.0 mg/kg bw of a 75% methanol 

extract of the seeds to mice failed to have any effect on barbiturate-induced 

sleeping time (37). A saponin fraction of a defatted seed extract 

potentiated barbiturate-induced sleeping time when administered by 

intraperitoneal injection, 50.0 mg/kg bw (38, 39). Intraperitoneal and 

intragastric administration of up to 1.0 g/kg of a butanol, methanol or 

alkaloid-enriched fraction of a methanol extract of the fruits had tranquillizing 

effects in mice (37, 40). Intraperitoneal administration of 

500.0 mg/kg bw of the fl avonoids spinosin and swertisin, isolated from 

a petroleum ether extract of the dried seeds, had mild CNS-depressant 

effects in mice and potentiated hexobarbital-induced sleeping time by 

50% (39). 

An aqueous extract of the fruits, 100.0 mg/kg bw per day, administered 

to mice in the drinking-water for 3 months reduced average weight 

gain when compared with the controls (no extract). Two mice developed 

alopecia of the snout, one was anaemic and one was suffering from protrusion 

of the penis (29). The mortality rate compared to control animals 

was not signifi cantly different, and there were no signifi cant haematological 

changes (P > 0.05). Intragastric administration of 50.0 g/kg bw of 

a decoction of the fruits to mice had no toxic effects (41). No deaths occurred 

in mice given an aqueous extract of the fruits (15 g). The intraperitoneal 

median lethal dose (LD 50 ) of the decoction was 14.3 g/kg bw 

in rats. Subcutaneous administration of 10–15.0 g/kg bw of a 50% ethanol 

extract of the seeds to mice killed all animals within 30–60 minutes 

(41). 

Immune stimulation 

A purifi ed polysaccharide, 0.5 mg/ml, isolated from an aqueous extract of 

the fruits, had anti-complement activity in human serum in vitro (27). 

Intragastric administration of 1.0 g/kg bw of a polysaccharide-enriched 

fraction from an aqueous extract of the fruits to mice enhanced the activity 

of natural killer cells (42). 

364


A hexane and 90% methanol extract of the dried seeds, 5.0 mg/ml, inhibited 

collagen-induced platelet aggregation in vitro (43). 


Fructus Zizyphi is often a constituent in multicomponent prescriptions 

used in Kampo and traditional Chinese medicine. Numerous clinical trials 

have assessed the effects of the fruits in combination with other medicinal 

plants for anticonvulsant effects, memory-enhancing effects and 

anti-infl ammatory effects. However, a review of these trials is beyond the 

scope of this monograph, and is therefore not included. 

In one uncontrolled study, oral administration of the dried seeds to 

human subjects produced CNS depressant effects, and was reported to be 

effective for the treatment of insomnia at a dose of 0.8 g/day (28). No 

further details of this study are available. 





Warnings 



Precautions 


An aqueous and a methanol extract of the fruits were not mutagenic in the 

Salmonella/microsome assay using S. typhimurium strains TA98 and 

TA100 or the Bacillus subtilis recombination assay at concentrations up to 

100.0 mg/ml (44). A 70% ethanol extract of the fruits, up to 4.0 mg/ml, 

was not mutagenic in either the SOS-chromotest (Escherichia coli PQ37) 

or the SOS-umu test (Salmonella typhimurium TA1535) (41). 

Intragastric administration of 1.0 g of the fruits per day to rats for 

15 months inhibited the growth of adenocarcinomas of the stomach induced 

by N-methyl-N-nitro-N-nitrosoguanidine (45). Administration of 

a 95% ethanol extract of the fruits in drinking-water, average daily dose 

100 mg/kg bw, to mice for 3 months had no signifi cant spermatotoxic effects 

(29). 

365





or non-teratogenic effects in pregnancy; nursing mothers; or paediatric 

use. 

Dosage forms 

Dried fruits, aqueous and hydroalcoholic extracts. Store in a tightly sealed 

container away from heat and light. 

Posology 


Daily dose: fruits 6–15 g (1). 

References 



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3-O-cis-p-coumaroylalphitolic acid in Zizyphi Fructus by high performance 

liquid chromatography.] Shoyakugaku Zasshi, 1989, 43:348–352 [in Japanese]. 

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three new p-coumaroylates of alphitolic acid. Chemical and Pharmaceutical 

Bulletin, 1978, 26:1798–1802. 

19. Yagi A et al. Studies in the constituents of Zizyphi Fructus. II. Structure of 

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1978, 26:3075–3079. 

20. Okamura N et al. Studies on the constituents of Ziziphi Fructus. III. Structures 

of dammarane-type saponins. Chemical and Pharmaceutical Bulletin, 

1981, 29:676–683. 

21. Kozai K. [Isolation and mode of action of anti-plaque agents derived from 

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of Zizyphi Spinosi Semen, the seeds of Zizyphus jujuba Mill. var. spinosa 

Hu (1): structures and histamine release-inhibitory effect of jujubosides 

A1 and C and acetyljujuboside B. Chemical and Pharmaceutical Bulletin, 

1997, 45:1186–1192. 

24. Matsuda H et al. Bioactive saponins and glycosides XIV. Structure elucidation 

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triterpene bisdesmosides, protojujubosides A, B and B1 from the seeds of 

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25. Hikino H. Recent research on Oriental medicinal plants. In: Wagner H, 

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26. Cyong JC, Takahashi M. Identifi cation of guanosine 3’,5’-monophosphate in 

the fruit of Ziziphus jujuba. Phytochemistry, 1982, 21:1871–1874 

27. Yamada H et al. Relationship between chemical structure and anti-complementary 

activity of plant polysaccharides. Carbohydrate Research, 1985, 

144:101–111. 

28. Li CP. Chinese herbal medicine. Washington, DC, United States Department 

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29. Shah AH et al. Zizyphus sativa fruits: evaluation of some biological activity 

and toxicity. Phytotherapy Research, 1989, 3:232–236. 

30. Yagi A et al. [Studies on the constituents of Zizyphi fructus. IV. Isolation of 

an anti-allergic component. Ethyl α-d-fructofuranoside from ethanol extract 

of Zizyphi Fructus.] Yakugaku Zasshi, 1981, 101:700–707 [in Japanese]. 

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of RBC membrane systems. Fitoterapia, 1989, 60:525–532. 

32. Lee GI et al. Inhibitory effects of oriental herbal medicines on IL-8 induction 

in lipo poly saccharide-activated rat macrophages. Planta Medica, 1995, 

61:26–30. 

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Planta Medica, 1979, 37:274–276. 

35. Raju R, Murthy PS, Prabhu KM. Hypoglycemic activity of an indigenous 

plant material. Diabetes Research, 1994, 27:89–90. 

36. Shibata M, Fukushima M. [Acute toxicity and sedative action of Zizyphus 

seeds.] Yakugaku Zasshi, 1975, 95:465–469 [in Japanese]. 

37. Han BH, Park MH. Sedative activity and its active constituents of Zizyphi 

fructus. Archives of Pharmacal Research, 1987, 10:208–211. 

38. Woo WS. C-Gylcosylfl avonoids from Zizyphus seeds. Annual reports of the 

Natural Products Research Institute, Seoul National University, 1980, 

19:133–135. 

39. Woo WS, Shin KH, Kang SS. [Chemistry and pharmacology of fl avone-Cglycoside 

from Zizyphus seeds.] Saengyak Hakhoe Chi, 1980, 11:141–148 

[in Chinese]. 

40. Han BH, Park MH. Alkaloids are the sedative principles of the seeds of Zizyphus 

vulgaris var. spinosus. Archives of Pharmacal Research, 1987, 10:203– 

207. 

41. Chang IM et al. Assay of potential mutagenicity and antimutagenicity of 

Chinese herbal drugs by using SOS chromotest (E. coli PQ37) and SOS 

UMU test (S. typhimurium TA 1535/pSK 1002). In: Proceedings of the fi rst 

Korea-Japan toxicology symposium safety assessment of chemicals in vitro. 

Korean Society of Toxicology, 1989:133–145. 

42. Yamaoka Y et al. A polysaccharide fraction of Zizyphi fructus in augmenting 

natural killer activity by oral administration. Biological and Pharmaceutical 

Bulletin, 1996, 19:936–939. 

368


43. Yun-Choi HS. [Screening of potential inhibitors of platelet aggregation from 

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1982, 97:81–102. 

45. Lin BS, Dou GR, Cui ZH. [The effect of administration of Chinese date on 

adenocarcinomas of the glandular stomach in rats induced by N-methyl-Nnitro-N-nitroso-guanidine 

(MNNG).] Tienchin I Yao Zhongliuxue Fukan, 

1982, 9:62–64 [in Chinese]. 

369

370 

Annex 1 

Participants in the 

Third WHO Consultation on Selected Medicinal Plants, 

The Governmental Conference Centre, 

Ottawa, Canada, 16–19 July, 2001 

Professor Mansour S. Al-Said, Dean, College of Pharmacy, King Saud 

University, Riyadh, Saudi Arabia 

Dr Steven K. H. Aung, Associate Clinical Professor, Departments of 

Medicine and Family Medicine, University of Alberta, Edmonton, Alberta, 

Canada 

Dr Raymond Boudet-Dalbin, Laboratoire de Chimie Thérapeutique, 

Faculté des Sciences Pharmaceutiques et Biologiques de Paris-Luxembourg, 

University René Descartes, Paris, France 

Dr David Briggs, Chemicals and Non-Prescription Medicines Branch, 

Therapeutic Goods Administration, Woden, ACT, Australia 

Professor Perla M. de Buschiazzo, Cátedra de Farmacologia, Facultad de 

Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina 

Dr Margaret Chan, Director of Health, Department of Health, Wan Chai, 

China, Hong Kong Special Administrative Region 

Dr Peter Chan, Director, Product Regulation, Natural Health Products 

Directorate, Health Products and Food Branch, Health Canada, Ottawa, 

Ontario, Canada 

Dr Tharnkamol Chanprapaph, Senior Pharmacist, Drug Control Division, 

Food and Drug Administration, Ministry of Public Health, 

Nonthaburi, Thailand 

Professor Francesco De Simone, Dean, Faculty of Pharmacy, University 

of Salerno, Fisciano, Salerno, Italy 

Professor Elaine Elisabetsky, Department of Pharmacology, Federal University 

of Rio Grande do Sol, Porto Alegre RS, Brazil 

Professor Norman R. Farnsworth, Director, WHO Collaborating Centre 

for Traditional Medicine, College of Pharmacy, The University of Illinois 

at Chicago, Chicago, IL, USA

Annex 1 

Professor Hassan Farsam, Department of Medicinal Chemistry, Faculty 

of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic 

Republic of Iran 

Professor Bohdan A. Fitak,* Department Head, Department of Drug 

Analysis, Medical University, Warsaw, Poland 

Professor Harry H. S. Fong, WHO Collaborating Centre for Traditional 

Medicine, College of Pharmacy, The University of Illinois at Chicago, 

Chicago, IL, USA 

Dr Motasim Habibullah, Technical Director, Zayed Complex for Herbal 

Research and Traditional Medicine, Ministry of Health, Abu Dhabi, 

United Arab Emirates 

Dr Huang Luqi, Director, Institute of Chinese Materia Medica, China 

Academy of Traditional Chinese Medicine, WHO Collaborating Centre 

for Traditional Medicine, Beijing, China 

Professor Konstantin Keller, Director, Federal Institute for Drugs and 

Medical Devices, Bonn, Germany 

Dr Prem Kishore, Consultant, Department of Indian Systems of Medicine 

and Health, Government of India, New Delhi, India 

Dr Mawuli Kofi -Tsekpo, Chief Research Offi cer, Kenya Medical Research 

Institute, Mbagathi Road, Nairobi, Kenya 

Dr Ting Hung Leung, Assistant Director, Department of Health, Wan 

Chai, China, Hong Kong Special Administrative Region 

Professor Lin Rui Chao, Director, Division of Chinese Materia Medica 

and Natural Products, National Institute for the Control of Pharmaceutical 

& Biological Products, State Drug Administration, Beijing, 

China 

Dr Gail B. Mahady, WHO Collaborating Centre for Traditional Medicine, 

College of Pharmacy, The University of Illinois at Chicago, Chicago, 

IL, USA 

Mr Isaac B. Mayeng, International Health Attaché, Department of Health, 

Pretoria, South Africa 

Professor Tamás Paál, Director-General, National Institute of Pharmacy, 

Budapest, Hungary 

Dr Joana Rosario, Director, Offi ce of International Health Research, 

National Center for Complementary and Alternative Medicine, WHO 

Collaborating Centre for Traditional Medicine, Bethesda, MD, USA 

Dr Motoyoshi Satake, Japan Pharmacists Education Center, Tokyo, Japan 

* It was a great sorrow to learn of the death of Professor Fitak in February 2002. He had been 

working with Traditional Medicine, WHO, Geneva and supporting its projects for many years, 

especially the development of Volumes 1–3 of the WHO monographs on selected medicinal plants. 

His great contributions to WHO’s work will always be remembered. 

371


Dr Sri Harsodjo Wijono Suwandi, Vice Director, Traditional Drug, Food 

Supplement and Cosmetics Standardization, National Agency of Food 

and Drug Control, Jakarta, Indonesia 

Dr Philip Waddington, Director General, Natural Health Products Directorate, 

Health Products and Food Branch, Health Canada, Ottawa, 

Ontario, Canada 

Professor Charles O. N. Wambebe, Director-General, National Institute 

for Pharmaceutical Research and Development, Abuja, Nigeria 

Mr Xu Yimin, Evaluation Executive, National Pharmaceutical Administration, 

Ministry of Health, Singapore, Singapore 

WHO Secretariat 

Dr Chen Ken, Regional Adviser, Traditional Medicine, WHO Regional 

Offi ce for the Western Pacifi c, Manila, Philippines 

Mr Peter Graaff, Regional Adviser, Essential Drugs and Biologicals, 

WHO Regional Offi ce for the Eastern Mediterranean, Cairo, Egypt 

Dr Ossy Kasilo, Regional Adviser, Traditional Medicine, WHO Regional 

Offi ce for Africa, Harare, Zimbabwe 

Dr Sandra Land, Focal Point Health of the Indigenous People Initiative/ 

Health Service Organization, WHO Regional Offi ce for the Americas, 

Washington, DC, USA 

Ms Yukiko Maruyama, Technical Offi cer, Traditional Medicine, Department 

of Essential Drugs and Medicines Policy, World Health Organization, 


Ms Sheila M. Poole, Editor, World Health Organization, Geneva, Switzerland 

Dr Pascale Vanbel, Technical Offi cer, Quality Assurance & Safety: Medicines, 

Department of Essential Drugs and Medicines Policy, World 

Health Organization, Geneva, Switzerland 

Dr Xiaorui Zhang, Acting Coordinator, Traditional Medicine, Department 

of Essential Drugs and Medicines Policy, World Health Organization, 


372

Annex 2 


(in alphabetical order of plant name) 

For the convenience of users of Volume 3, the monographs described in Volumes 1 

and 2 are also listed in this index. The numbers printed in bold type, preceding the 

page numbers, indicate the volume in which the indexed item is to be found. Monographs 

are listed in alphabetical order of the plant name. 

A 

Bulbus Allii Cepae, 1, 5 

Bulbus Allii Sativi, 1, 16 

Aloe, 1, 33 

Aloe Vera Gel, 1, 43 

Radix Althaeae, 2, 5 

Fructus Ammi Majoris, 3, 9 

Fructus Ammi Visnagae, 3, 23 

Herba Andrographidis, 2, 12 

Fructus Anethi, 3, 33 

Radix Angelicae Sinensis, 2, 25 

Aetheroleum Anisi, 3, 42 

Fructus Anisi, 3, 53 

Semen Armeniacae, 3, 64 

Flos Arnicae, 3, 77 

Radix Astragali, 1, 50 

Folium Azadirachti, 3, 88 

Oleum Azadriachti, 3, 102 

B 

Fructus Bruceae, 1, 59 

Radix Bupleuri, 1, 67 

C 

Flos Calendulae, 2, 35 

Flos Carthami, 3, 114 

Flos Caryophylli, 2, 45 

Herba Centellae, 1, 77 

Flos Chamomillae, 1, 86 

Rhizoma Cimicifugae Racemosae, 2, 

55 

Cortex Cinnamomi, 1, 95 

Rhizoma Coptidis, 1, 105 

Folium cum Flore Crataegi, 2, 66 

Stigma Croci, 3, 126 

Rhizoma Curcumae Longae, 1, 115 

E 

Radix Echinaceae, 1, 125 

Herba Echinaceae Purpureae, 1, 136 

Radix Eleutherococci, 2, 83 

Herba Ephedrae, 1, 145 

Aetheroleum Eucalypti, 2, 97 

Folium Eucalypti, 2, 106 

F 

Fructus Foeniculi, 3, 136 

Cortex Frangulae, 2, 114 

G 

Radix Gentianae Luteae, 3, 150 

Radix Gentianae Scabrae, 3, 160 

Folium Ginkgo, 1, 154 

Radix Ginseng, 1, 168 

Radix Glycyrrhizae, 1, 183 

Gummi Gugguli, 3, 169 

373


H 

Folium et Cortex Hamamelidis, 2, 124 

Radix Harpagophyti, 3, 182 

Semen Hippocastani, 2, 137 

Rhizoma Hydrastis, 3, 194 

Herba Hyperici, 2, 149 

I 

Radix Ipecacuanhae, 3, 204 

L 

Aetheroleum Lavandulae, 3, 219 

Flos Lavandulae, 3, 229 

Strobilus Lupuli, 3, 236 

M 

Aetheroleum Melaleucae Alternifoliae, 

2, 172 

Folium Melissae, 2, 180 

Aetheroleum Menthae Piperitae, 2, 

188 

Folium Menthae Piperitae, 2, 199 

Gummi Myrrha, 3, 247 

O 

Folium Ocimi Sancti, 2, 206 

Oleum Oenotherae Biennis, 2, 217 

P 

Radix Paeoniae, 1, 195 

Herba Passifl orae, 3, 257 

Rhizoma Piperis Methystici, 2, 231 

Semen Plantaginis, 1, 202 

Testa Plantaginis, 3, 268 

Radix Platycodi, 1, 213 

Cortex Pruni Africanae, 2, 246 

R 

Radix Rauwolfi ae, 1, 221 

Radix Rehmanniae, 3, 283 

Cortex Rhamni Purshianae, 2, 259 

Rhizoma Rhei, 1, 231 

S 

Flos Sambuci, 2, 269 

Fructus Schisandrae, 3, 296 

Radix Scutellariae, 3, 314 

374 

Radix Senegae, 2, 276 

Folium Sennae, 1, 241 

Fructus Sennae, 1, 250 

Fructus Serenoae Repentis, 2, 285 

Fructus Silybi Mariae, 2, 300 

T 

Herba Tanaceti Parthenii, 2, 317 

Radix cum herba Taraxaci, 3, 328 

Herba Thymi, 1, 259 

Semen Trigonellae foenugraeci, 3, 338 

U 

Cortex Uncariae, 3, 349 

Radix Urticae, 2, 329 

Folium Uvae Ursi, 2, 342 

V 

Herba Valerianae, 1, 267 

Z 

Fructus Zizyphi, 3, 359 

Rhizoma Zingiberis, 1, 277

Annex 3 


(in alphabetical order of plant material of interest) 

For the convenience of users of Volume 3, the monographs described in Volumes 1 

and 2 are also listed in this index. The numbers printed in bold type, preceding the 

page numbers, indicate the volume number in which the indexed item is to be found. 

Monographs are listed in alphabetical order of the plant material of interest. 

Aetheroleum 

Anisi, 3, 42 

Eucalypti, 2, 97 

Lavandulae, 3, 219 

Melaleucae Alternifoliae, 2, 172 

Menthae Piperitae, 2, 188 

Bulbus 

Allii Cepae, 1, 5 

Allii Sativi, 1, 16 

Cortex 

Cinnamomi, 1, 95 

Frangulae, 2, 114 

Hamamelidis, 2, 124 (see also 

Folium) 

Pruni Africanae, 2, 246 

Rhamni Purshianae, 2, 259 

Uncariae, 3, 349 

Dried juice of the leaves 

Aloe, 1, 33 

Flore 

Crataegi, 2, 66 (see also Folium) 

Flos 

Arnicae, 3, 77 

Calendulae, 2, 35 

Carthami, 3, 114 

Caryophylli, 2, 45 

Chamomillae, 1, 86 

Lavandulae, 3, 229 

Sambuci, 2, 269 

Folium 

Azadirachti, 3, 88 

Crataegi, 2, 66 (see also Flore) 

Eucalypti, 2, 106 

Ginkgo, 1, 154 

Hamamelidis, 2, 124 (see also 

Cortex) 

Melissae, 2, 180 

Menthae Piperitae, 2, 199 

Ocimi Sancti, 2, 206 

Sennae, 1, 241 

Uvae Ursi, 2, 342 

375

Fructus 

Ammi Majoris, 3, 9 

Ammi Visnagae, 3, 23 

Anethi, 3, 33 

Anisi, 3, 53 

Bruceae, 1, 59 

Foeniculi, 3, 136 

Schisandrae, 3, 296 

Sennae, 1, 250 

Serenoae Repentis, 2, 285 

Silybi Mariae, 2, 300 

Zizyphi, 3, 359 

Gel 

Aloe Vera, 1, 43 

Gummi 

Gugguli, 3, 169 

Myrrha, 3, 247 

Herba 

Andrographidis, 2, 12 

Centellae, 1, 77 

Echinaceae Purpureae, 1, 136 

Ephedrae, 1, 145 

Hyperici, 2, 149 

Passifl orae, 3, 257 

Tanaceti Parthenii, 2, 317 

Taraxaci, 3, (see also Radix) 328 

Thymi, 1, 259 

Valerianae, 1, 267 

Oleum 

Azadriachti, 3, 102 

Oenotherae Biennis, 2, 217 

Radix 

Althaeae, 2, 5 

Angelicae Sinensis, 2, 25 

Astragali, 1, 50 

Bupleuri, 1, 67 

Echinaceae, 1, 125 

Eleutherococci, 2, 83 

376 

Gentianae Luteae, 3, 150 

Gentianae Scabrae, 3, 160 

Ginseng, 1, 168 

Glycyrrhizae, 1, 183 

Harpagophyti, 3, 182 

Ipecacuanhae, 3, 204 

Paeoniae, 1, 195 

Platycodi, 1, 213 

Rauwolfi ae, 1, 221 

Rehmanniae, 3, 283 

Scutellariae, 3, 314 

Senegae, 2, 276 

Taraxaci, 3, (see also Herba) 328 

Urticae, 2, 329 

Rhizoma 

Cimicifugae Racemosae, 2, 55 

Coptidis, 1, 105 

Curcumae Longae, 1, 115 

Hydrastis, 3, 194 

Piperis Methystici, 2, 231 

Rhei, 1, 231 

Zingiberis, 1, 277 

Semen 

Armeniacae, 3, 64 

Hippocastani, 2, 137 

Plantaginis, 1, 202 

Trigonellae Foenugraeci, 3, 338 

Stigma 

Croci, 3, 126 

Strobilus 

Lupuli, 3, 236 

Testa 

Plantaginis, 3, 268

Selected WHO publications of related interest 

Information on medicinal plants: 

WHO monographs on selected medicinal plants, Volume 2 

(ISBN 92 4 154537 2), 2002 

WHO monographs on selected medicinal plants, Volume 1 

(ISBN 92 4 154517 8), 1999 

Quality assurance and control of herbal medicines: 

WHO Guidelines on good agricultural and collection practices (GACP) for medicinal plants 

(ISBN 92 4 154627 1), 2003 

Quality control methods for medicinal plant materials 

(ISBN 92 4 154510 0), 1998 

Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms 

(ISBN 92 4 154513 5), 1998 

Good manufacturing practices: Updated supplementary guidelines for the 

manufacture of herbal medicines, Annex 3 of WHO Expert Committee on Specifications 

for Pharmaceutical Preparations, Thirty-fourth report 

(ISBN 92 4 120937 2), WHO Technical Report Series, No. 937, 2006 

Regulation, evaluation and safety monitoring of herbal medicines: 

Summary report of the global survey on national policy on traditional medicine and 

complementary/alternative medicine and regulation of herbal medicines 

(ISBN 92 4 159323 7), 2005 

WHO guidelines on safety monitoring and pharmacovigilance of herbal medicines 

(ISBN 92 4 159221 4) , 2004 

General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine 

WHO/EDM/TRM/2000.1, 2000 

Consumer information: 

WHO guidelines on development of consumer information on proper use of 

traditional medicine and complementary/alternative medicine 

(ISBN 92 4 159170 6), 2004 

Further information on WHO technical documents in the field of 

traditional medicine including those listed above, can be found at the address below: 

http://www.who.int/medicines/areas/traditional/

WHO published Volume 1 of the WHO monographs on selected 

medicinal plants, containing 28 monographs, in 1999, and Volume 

2 including 30 monographs in 2002. This third volume contains 

an additional collection of 32 monographs describing the quality 

control and use of selected medicinal plants. 

Each monograph contains two parts, the first of which provides 

pharmacopoeial summaries for quality assurance purposes, 

including botanical features, identity tests, purity requirements, 

chemical assays and major chemical constituents. The second part, 

drawing on an extensive review of scientific research, describes 

the clinical applications of the plant material, with detailed 

pharmacological information and sections on contraindications, 

warnings, precautions, adverse reactions and dosage. Also included 

are two cumulative indexes to the three volumes. 

The WHO monographs on selected medicinal plants aim to provide 

scientific information on the safety, efficacy, and quality control 

of widely used medicinal plants; provide models to assist Member 

States in developing their own monographs or formularies for 

these and other herbal medicines; and facilitate information 

exchange among Member States. WHO monographs, however, are 

not pharmacopoeial monographs, rather they are comprehensive 

scientific references for drug regulatory authorities, physicians, 

traditional health practitioners, pharmacists, manufacturers, 

research scientists and the general public. 

ISBN 978 92 4 154702 4

selected medicinal plants - World Health Organization

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