Rabu, 03 Februari 2010

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
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press,
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of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any
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Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
The mention of specifi c companies or of certain manufacturers’ products does not imply that they are endorsed
or recommended by the World Health Organization in preference to others of a similar nature that are not
mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial
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reader. In no event shall the World Health Organization be liable for damages arising from its use.
Printed in Spain
iii
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
iv
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
Contents
v
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.

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
2
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-
Introduction
3
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

5
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
6
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
General technical notices
7
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.
General technical notices

9
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).
10
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).
11
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
Not less than 16% (2).
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).
Fructus Ammi Majoris
12
WHO monographs on selected medicinal plants
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.
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).
O O O
R2
R1
O-CH2-CH=C(CH3)2
OCH3 H
R1
H
R2
OCH3
H
furanocoumarins
bergapten
imperatorin
xanthotoxin
13
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).
Fructus Ammi Majoris
14
WHO monographs on selected medicinal plants
The median lethal doses (LD50) 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
LD50 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 (ID50) 0.0072 mg after 5 days of
treatment), while imperatorin was the least irritant (ID50 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
15
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
Fructus Ammi Majoris
16
WHO monographs on selected medicinal plants
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).
17
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
Fructus Ammi Majoris
18
WHO monographs on selected medicinal plants
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
See Contraindications.
Paediatric use
See Contraindications.
19
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
Fructus Ammi Majoris
20
WHO monographs on selected medicinal plants
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.
21
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.
Fructus Ammi Majoris
22
WHO monographs on selected medicinal plants
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.
23
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.
Selected vernacular names
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).
Geographical distribution
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).
Plant material of interest: dried ripe fruits
General appearance
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
24
commissural side, a large oily orthospermous endosperm and a small apical
embryo. Carpophore single, passing into the raphe of each mericarp (1, 2).
Organoleptic properties
Odour: slightly aromatic; taste: aromatic, bitter, slightly pungent (1, 2).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations, microchemical tests (1–3), and
thin-layer chromatography for the presence of khellin and visnagin (3, 6, 9).
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 (10).
WHO monographs on selected medicinal plants
25
Foreign organic matter
Not more than 2% (3).
Total ash
Not more than 8% (2).
Acid-insoluble ash
Not more than 3.5% (1).
Loss on drying
Not more than 10% (3).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (11). For other pesticides, see the European pharmacopoeia
(11), and the WHO guidelines on quality control methods for medicinal
plants (10) and pesticide residues (12).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (10).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (10) for the analysis of radioactive isotopes.
Other purity tests
Chemical, sulfated ash, water-soluble extractive and alcohol-soluble extractive
tests to be established in accordance with national requirements.
Chemical assays
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).
Major chemical constituents
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
Fructus Ammi Visnagae
26
WHO monographs on selected medicinal plants
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.
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
As an antispasmodic, muscle relaxant and vasodilator (1).
Uses described in traditional medicine
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
Experimental 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
O O
R1 O
R3
R2
H
OCH3 OH OCH3
OCH3 H OCH3
OCH3
OCH3
OH
OCH3 O-Glc H
OH H
OCH3 H H
R1 R2 R3
ammiol
khellin
khellinin
khellinol
khellol
visnagin
visnadin
O O O
O
H3C
H3C
H
H3C O
H CH3
H
O CH3
O
O
OH
HO
HO
OH
β-D-glucopyranosyl
Glc =
27
(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 (LD50) of the fruits
were 2.24 g/kg bw and > 370.0 mg/kg bw, respectively (25). In rats, the
oral LD50 was > 4.0 g/kg bw, and in rabbits, the intravenous LD50 was
Fructus Ammi Visnagae
28
WHO monographs on selected medicinal plants
50.0 mg/kg bw. In dogs, the oral and intravenous LD50 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 LD50 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).
Clinical pharmacology
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).
Adverse reactions
Pseudoallergic reactions and reversible cholestatic jaundice have been reported
(35). High oral doses of khellin (100.0 mg/day) reversibly elevated
29
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).
Contraindications
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).
Drug interactions
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).
Carcinogenesis, mutagenesis, impairment of fertility
A 95% ethanol extract of Fructus Ammi Visnagae, 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 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).
Pregnancy: non-teratogenic effects
See Contraindications.
Fructus Ammi Visnagae
30
WHO monographs on selected medicinal plants
Nursing mothers
Owing to the lack of safety data, Fructus Ammi Visnagae should be taken
internally only under the supervision of a health-care provider.
Paediatric use
Owing to the lack of safety data, Fructus Ammi Visnagae should be taken
internally only under the supervision of a health-care provider.
Other precautions
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
(Unless otherwise indicated)
Average daily dose: Fructus Ammi Visnaga 0.05–0.15 g (1).
References
1. Egyptian pharmacopoeia. Vol. 2, 3rd ed. Cairo, General Organization for
Government Printing, 1972.
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].
6. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
7. Physician’s desk reference for herbal medicine. Montvale, NJ, Medical
Economics Co., 1998.
8. 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).
9. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas,
2nd ed. Berlin, Springer, 1996.
31
10. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
11. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
12. 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).
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 Ca2+ channel
blocking mode of action in the pharmacology of Ammi visnaga fruits. Planta
Medica, 1994, 60:101–105.
Fructus Ammi Visnagae
32
WHO monographs on selected medicinal plants
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.
37. 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.
33
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.
Selected vernacular names
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).
Geographical distribution
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).
Plant material of interest: dried ripe fruits
General appearance
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
34
WHO monographs on selected medicinal plants
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).
Organoleptic properties
Odour: characteristic, aromatic; taste: characteristic, pleasant (1, 4, 5).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (1, 2), and thin-layer chromatography
(2).
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 (16).
Chemical
Not less than 3.0% essential oil (2).
Foreign organic matter
Not more than 2.0% (1).
35
Total ash
Not more than 11.0% (1).
Acid-insoluble ash
Not more than 1.5% (2).
Water-soluble extractive
Not less than 15.0% (2).
Alcohol-soluble extractive
Not less than 4.0% (2).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (17). For other pesticides, see the European pharmacopoeia
(17), and the WHO guidelines on quality control methods for medicinal
plants (16) and pesticide residues (18).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (16).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (16) for the analysis of radioactive isotopes.
Other purity tests
Loss on drying test to be established in accordance with national requirements.
Chemical assays
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.
Major chemical constituents
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).
Fructus Anethi
36
WHO monographs on selected medicinal plants
Dillapiol is found in the essential oil obtained from plants cultivated in
Egypt, India and Japan (24). Representative structures are presented below.
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
Treatment of dyspepsia (25), gastritis and fl atulence (1, 26), and stomach
ache (27).
Uses described in traditional medicine
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
Experimental 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
c a r v o n e
an d e n an tio m er O
C H 3
C H 3
C H 3
1 , 8 - c i n e o l e
O
C H 3
H 3C H
H 2 C
d i h y d r o c a r v o n e
a nd e n a n tio m er
O
H 3 C H
H 2 C C H 3
H
C H 3
H 3 C
C H 3
C H 3 C H 3
H 3 C H
H 3 C
H 3C H
H 2 C
an d e na n t io m e r
C H 3
H 3 C
C H 3
C H 3
H 3 C
H 3 C
H
H
p-cymene (+)-limonene (-)-α-phellandrene α-pinene α-terpinene
37
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).
Clinical pharmacology
No information available.
Adverse reactions
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).
Contraindications
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
No information available.
Fructus Anethi
38
WHO monographs on selected medicinal plants
Precautions
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
Other precautions
No information available on general precautions or precautions concerning
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
(Unless otherwise indicated)
Average daily dose: Fructus Anethi 3 g; essential oil 0.1–0.3 g; or equivalent
for other preparations (25).
References
1. African pharmacopoeia. Vol. 1. Lagos, Organization of African Unity, Scientifi
c, Technical and Research Commission, 1985.
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.
39
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.
9. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
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.
13. Physician’s desk reference for herbal medicine. Montvale, NJ, Medical
Economics Co., 1998.
14. Saber AH. Practical pharmacognosy, 2nd ed. Cairo, Al-Etemad Press, 1946.
15. Wallis TE. Textbook of pharmacognosy, 4th ed. London, J & A Churchill,
1960.
16. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
17. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
18. 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).
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.
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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.
25. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
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 3H-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.
41
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.
Fructus Anethi
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.
Selected vernacular names
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).
Geographical distribution
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.
43
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
General appearance
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).
Organoleptic properties
Odour: characteristic, aromatic; taste: sweet, strongly aromatic (1).
Microscopic characteristics
Not applicable.
Powdered plant material
Not applicable.
General identity tests
Thin-layer chromatography for the presence of anethole, anisaldehyde
and linalool. A gas chromatography method is also available (5).
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 (12).
Chemical
Soluble in three parts ethanol (90%) at 20 oC (4). Relative density 0.978–
0.994 (5). Refractive index 1.552–1.561 (5). Freezing-point 15–19 oC (5).
Acid value not more than 1.0 (5).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
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
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (12).
Aetheroleum Anisi
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WHO monographs on selected medicinal plants
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (12) for the analysis of radioactive isotopes.
Other purity tests
Tests for foreign organic matter, total ash, acid-insoluble ash, water-soluble
extractive, alcohol-soluble extractive and loss on drying not applicable.
Chemical assays
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).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
Treatment of dyspepsia and mild infl ammation of the respiratory tract
(14, 15).
Uses described in traditional medicine
As an aphrodisiac, carminative, emmenagogue, galactagogue and insecticide.
Treatment of chronic bronchitis (8, 10).
Pharmacology
Experimental pharmacology
Antimicrobial activity
Aetheroleum Anisi, 500 mg/l, inhibited the growth of Alternaria alternata,
Alternaria tenuissima, Aspergillus spp., Botryodiplodia spp., Cladotrans-
anethole
H3CO
CH3
H3CO
CH2
methylchavicol
H3C
CH2
CH3 H OH
and enantiomer
β-linalool p-anisaldehyde
CHO
H3CO
45
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 [3H]-glutamate
binding and as a non-competitive antagonist of [3H]-dizocilpine binding
in mouse cortical membranes. The effects of linalool were investigated on
[3H]-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).
Aetheroleum Anisi
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WHO monographs on selected medicinal plants
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 -
47
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 (LD50) 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 LD50 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 LD50 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).
Clinical pharmacology
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).
Aetheroleum Anisi
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WHO monographs on selected medicinal plants
Adverse reactions
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.
Contraindications
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
Carcinogenesis, mutagenesis, impairment of fertility
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;
49
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
Paediatric use
See Contraindications.
Other precautions
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
(Unless otherwise indicated)
Average daily dose for internal use: essential oil 0.3 g; equivalent for other
preparations (15).
References
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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.
5. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
6. African pharmacopoeia. Vol. 1. Lagos, Organization of African Unity, Scientifi
c, Technical and Research Commission, 1985.
Aetheroleum Anisi
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WHO monographs on selected medicinal plants
7. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 6,
Drogen P–Z, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 6,
Drugs P–Z, 5th ed.] Berlin, Springer, 1994.
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12. Quality control methods for medicinal plant materials. Geneva, World Health
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Austin, TX, American Botanical Council, 1998.
16. Shukla HS, Tripathi SC. Antifungal substance in the essential oil of
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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,
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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.
51
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 [3H] MK801
and [3H] 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
of Ethnopharmacology, 2001, 74:83–88.
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,
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34. Boyd EM, Pearson GL. On the expectorant action of volatile oils. American
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35. Van Dongen K, Leusink H. The action of opium-alkaloids and expectorants
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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.
Aetheroleum Anisi
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WHO monographs on selected medicinal plants
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
[methoxy14C]-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,
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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.
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1995, 326:199–209.
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Journal, 1984, 117:28–29.
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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
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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
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Toxicology, 1996, 34:337–345.
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rats. Indian Journal of Physiology and Pharmacology, 1995, 39:63–67.
53
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.
Selected vernacular names
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).
Geographical distribution
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).
54
WHO monographs on selected medicinal plants
Plant material of interest: dried ripe fruits
General appearance
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).
Organoleptic properties
Odour: characteristic, aromatic; taste: sweet, strongly aromatic (1, 2).
Microscopic characteristics
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).
55
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (2, 3), and thin-layer chromatography
for the presence of anethole (3).
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 (10).
Foreign organic matter
Not more than 2.0% (3).
Total ash
Not more than 12.0% (3).
Acid-insoluble ash
Not more than 2.5% (1, 3).
Loss on drying
Not more than 7.0% (3).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (3). For other pesticides, see the European pharmacopoeia (3),
and the WHO guidelines on quality control methods for medicinal plants
(10) and pesticide residues (11).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (10).
Fructus Anisi
56
WHO monographs on selected medicinal plants
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (10) for the analysis of radioactive isotopes.
Other purity tests
Chemical, water-soluble extractive and alcohol-soluble extractive tests to
be established in accordance with national requirements.
Chemical assays
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).
Major chemical constituents
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%), α-
terpineol (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.
Medicinal uses
Uses supported by clinical data
No information available.
Uses described in pharmacopoeias and well established documents
Treatment of dyspepsia and mild infl ammation of the respiratory tract
(13, 14).
Uses described in traditional medicine
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
Experimental 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 barbituratetrans-
anethole
H3CO
CH3
H3CO
CH2
methylchavicol
H3C
CH2
CH3 H OH
and enantiomer
β-linalool p-anisaldehyde
CHO
H3CO
57
induced sleeping time when administered to mice in doses of up to
200.0 mg/kg body weight (bw) (16).
Antimicrobial activity
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 [3H]-glutamate binding and as a non-competitive antagonist
of [3H]-dizocilpine binding in mouse cortical membranes. The effects
of linalool on [3H]-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.
Anti-infl ammatory activity
External application of 2.0 mg of a methanol extract of the fruits inhibited
ear infl ammation induced by 12-O-tetradecanoylphorbol-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
Fructus Anisi
58
WHO monographs on selected medicinal plants
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 (LD50) 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
59
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 LD50 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).
Clinical pharmacology
No information available.
Adverse reactions
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).
Contraindications
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
No information available.
Precautions
Carcinogenesis, mutagenesis, impairment of fertility
A 95% ethanol extract of Fructus Anisi, 10.0 mg/plate, was inactive in the
Salmonella/microsome assay in S. typhimurium TA102 (41). Inconsistent
Fructus Anisi
60
WHO monographs on selected medicinal plants
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
Paediatric use
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
drug interactions; drug and laboratory test interactions; or teratogenic
effects in pregnancy.
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
(Unless otherwise indicated)
Average oral daily dose for internal use: Fructus Anisi 3.0 g; equivalent
for other preparations (14).
61
References
1. Egyptian pharmacopoeia, 3rd ed. Cairo, General Organization for Government
Printing, 1972.
2. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African
Unity, Scientifi c, Technical and Research Commission, 1985.
3. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
4. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 6,
Drogen P–Z, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 6,
Drugs P–Z, 5th ed.] Berlin, Springer, 1992.
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.
7. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
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).
8. Wichtl M, ed. Teedrogen, 2nd ed. [Drugs used for infusion, 2nd ed.] Stuttgart,
Wissenschaftliche Verlagsgesellschaft, 1989.
9. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
10. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
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. 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.
13. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,
1996.
14. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
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.
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WHO monographs on selected medicinal plants
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.
22. Elisabetsky E et al. Sedative properties of linalool. Fitoterapia, 1995, 66:407–
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 [3H] MK801
and [3H] muscimol binding in mouse cortical membranes. Phytotherapy
Research, 2001, 15:422–425.
25. Silva Brum LF et al. Effects of linalool on glutamate release and uptake in
mouse cortical synaptosomes. Neurochemical Research, 2001, 26:191–194.
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 3H-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
of Ethnopharmacology, 2001, 74:83–88.
30. Dhar ML et al. Screening of Indian plants for biological activity: part I.
Indian Journal of Experimental Biology, 1968, 6:232–247.
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
of Ethnopharmacology, 1995, 49:41–49.
35. 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.
63
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.
37. Truhaut R et al. Chronic toxicity/carcinogenicity study of trans-anethole in
rats. Food and Chemical Toxicology, 1989, 27:11–20.
38. Albert-Puleo M. Fennel and anise as estrogenic agents. Journal of Ethnopharmacology,
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.
41. 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.
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.
45. Dhar SK. Anti-fertility activity and hormonal profi le of trans-anethole in
rats. Indian Journal of Physiology and Pharmacology, 1995, 39:63–67.
Fructus Anisi
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).
Selected vernacular names
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).
Geographical distribution
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).
65
Plant material of interest: dried ripe seeds
General appearance
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).
Organoleptic properties
Odourless; taste: bitter (1, 3, 4).
Microscopic characteristics
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).
Powdered plant material
See characteristic features under Microscopic characteristics (1, 2).
General identity tests
Macroscopic and microscopic examinations, and microchemical tests
(1, 2, 4).
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 (12).
Pesticide residues
The recommended maximum limit 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
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (12).
Semen Armeniacae
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WHO monographs on selected medicinal plants
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (12) for the analysis of radioactive isotopes.
Other purity tests
Chemical, foreign organic matter, total ash, acid-insoluble ash, sulfated
ash, alcohol-soluble extractive, water-soluble extractive and loss on drying
tests to be established in accordance with national requirements.
Chemical assays
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).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
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).
Uses described in traditional medicine
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).
amygdalin
O
OH
HO
HO
HO
O
O
OH
HO
OH
O
H CN
67
Pharmacology
Experimental 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 (ED50)
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).
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WHO monographs on selected medicinal plants
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 (LD50) 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 13-
week 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).
69
Clinical pharmacology
Antitumour activity
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
Semen Armeniacae
70
WHO monographs on selected medicinal plants
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/m2 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
71
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.
Adverse reactions
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 β-
glucosidase, 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).
Semen Armeniacae
72
WHO monographs on selected medicinal plants
Contraindications
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
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: teratogenic effects
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).
Pregnancy: non-teratogenic effects
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).
Nursing mothers
See Contraindications.
73
Paediatric use
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
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
(Unless otherwise indicated)
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.
5. 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.
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.
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. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
Illinois at Chicago, 9 February, 2000 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).
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).
Semen Armeniacae
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WHO monographs on selected medicinal plants
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.
12. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
13. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
14. 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).
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 LD50 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
75
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.
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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.
77
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.
Selected vernacular names
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).
Geographical distribution
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).
78
WHO monographs on selected medicinal plants
Plant material of interest: dried fl ower heads
General appearance
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).
Organoleptic properties
Odour: characteristic aromatic (1, 3, 5); taste: bitter and acrid (1, 5).
Microscopic characteristics
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).
Powdered plant material
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
79
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).
General identity tests
Macroscopic and microscopic examinations (1, 3–5), and thin-layer chromatography
for phenolic compounds (3).
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 (10).
Foreign organic matter
Not more than 5.0% (3).
Total ash
Not more than 10% (3).
Acid-insoluble ash
Not more than 1.2% (11).
Sulfated ash
Not more than 13% (2).
Water-soluble extractive
Not less than 17% (2).
Alcohol-soluble extractive
Not less than 15% using 45% ethanol (1).
Loss on drying
Not more than 10% (3).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (12). For other pesticides, see the European Pharmacopoeia
Flos Arnicae
80
WHO monographs on selected medicinal plants
(12) and the WHO guidelines on quality control methods for medicinal
plants (10) and pesticide residues (13).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (10).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control
methods for medicinal plants (10) for the analysis of radioactive isotopes.
Other purity tests
Chemical tests to be established in accordance with national requirements.
Chemical assays
Contains not less than 0.40% of total sesquiterpene lactones calculated as helenalin
tiglate, determined by high-performance liquid chromatography (3).
Major chemical constituents
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,13-
dihydrohelenalin are presented below.
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
As a topical counterirritant for treatment of pain and infl ammation resulting
from minor injuries and accidents, including bruises, ecchymoses,
helenalin
O
O
H
H3C
O H OH CH2
CH3 H H
H
O
O
H
H3C
O H OH
CH3 H H
H
CH3
H
11α,13-dihydrohelenalin
81
haematomas and petechiae (1, 17). Treatment of infl ammation of the oral
mucous membranes, insect bites and superfi cial phlebitis (17).
Uses described in traditional medicine
Treatment of indigestion, cardiovascular disease, and rheumatism. As an
emmenagogue (9).
Pharmacology
Experimental 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).
Antitumour activity
Helenalin is cytotoxic to a wide variety of cancer cell lines in vitro, with a
median effective dose (ED50) range of 0.03–1.0 μg/ml (24–27). Intraperi-
Flos Arnicae
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WHO monographs on selected medicinal plants
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).
Cardiovascular effects
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 (LD50) of a 30% ethanol extract of the fl ower
heads was 37.0 ml/kg in mice (33). The intragastric LD50 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).
Clinical pharmacology
No information available. Clinical trials of homeopathic preparations
were not assessed.
83
Adverse reactions
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).
Contraindications
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).
Carcinogenesis, mutagenesis, impairment of fertility
Helenalin has cytotoxic effects in vitro (see Experimental pharmacology).
However, in the Salmonella/microsome assay, helenalin was not muta-
Flos Arnicae
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WHO monographs on selected medicinal plants
genic in S. typhimurium strains TA102, TA98 or TA100 at concentrations
of up to 30 μg/ml (52, 53).
Pregnancy: teratogenic effects
Intraperitoneal administration of 6.0–20.0 mg/kg bw of helenalin was not
teratogenic in mice (21).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
Paediatric use
See Warnings. For external use only. Do not apply to abraded or broken
skin.
Other precautions
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
(Unless otherwise indicated)
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
1. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,
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.
85
4. 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.
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. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
8. Physician’s desk reference for herbal medicine. Montvale, NJ, Medical
Economics Co., 1998.
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).
10. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
11. Karnick CR, ed. Pharmacopoeial standards of herbal plants. Delhi, Sri
Satguru Publications, 1994 (Indian Medical Science Series, No. 36).
12. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
13. 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).
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.
17. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
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.
Flos Arnicae
86
WHO monographs on selected medicinal plants
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.
87
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.
Flos Arnicae
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).
Selected vernacular names
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).
Geographical distribution
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).
89
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).
General appearance
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).
Organoleptic properties
Odour: characteristic, alliaceous; taste: bitter (1–3).
Microscopic characteristics
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).
Powdered plant material
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).
Folium Azadirachti
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WHO monographs on selected medicinal plants
General identity tests
Macroscopic and microscopic examinations (1–3), microchemical tests (2)
and thin-layer chromatography (2).
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 (13).
Foreign organic matter
Not more than 2% (4).
Total ash
Not more than 10% (4).
Acid-insoluble ash
Not more than 1% (4).
Water-soluble extractive
Not less than 19% (4).
Alcohol-soluble extractive
Not less than 13% (4).
Loss on drying
Not more than 3% (2).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (14). For other pesticides, see the European pharmacopoeia
(14) and the WHO guidelines on quality control methods for medicinal
plants (13) and pesticide residues (15).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (13).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control
methods for medicinal plants (13) for the analysis of radioactive isotopes.
91
Other purity tests
Chemical and sulfated ash tests to be established in accordance with
national requirements.
Chemical assays
High-performance liquid chromatography methods are available for the
quantitative determination of oxidized tetranortriterpenes (16, 17).
Major chemical constituents
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-3-
acetyl-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.
Medicinal uses
Uses supported by clinical data
External applications for treatment of ringworm (21). However, data from
controlled clinical trials are lacking.
Uses described in pharmacopoeias and well established documents
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).
Folium Azadirachti
O H
H
O
OH
H
H
O CH3
H3C
O
O
O
H3C
CH3
H
O
O
O
OH
CH3
CH3
H
O
OH
O
O
CH3
O
H
H
H
azadirachtin
O
H3C O
H
CH3
H
O
CH3
O
O
H3C
O
H3C
O
H CH3
H
O
R
H
H
nimbin
deacetylnimbin
R = CO-CH3
R = H
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WHO monographs on selected medicinal plants
Uses described in traditional medicine
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
Experimental 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
93
aspartate aminotransferase, alanine aminotransferase and γ-glutamyl
transpeptidase (28).
Anti-infl ammatory activity
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-
Folium Azadirachti
94
WHO monographs on selected medicinal plants
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).
Antioxidant activity
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).
Cardiovascular effects
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
95
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).
Folium Azadirachti
96
WHO monographs on selected medicinal plants
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).
Clinical pharmacology
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).
Adverse reactions
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).
Contraindications
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.
97
Warnings
No information available.
Precautions
Drug interactions
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.
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: teratogenic effects
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).
Nursing mothers
See Contraindications.
Paediatric use
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
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).
Folium Azadirachti
98
WHO monographs on selected medicinal plants
Posology
(Unless otherwise indicated)
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).
References
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performance liquid chromatography procedure for the isolation of major tri-
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terpenoids and their quantitative determination in neem oil. Journal of
Liquid Chromatography, 1995, 18:3465–3471.
17. Schaaf O et al. Rapid and sensitive analysis of azadirachtin and related
triterpenoids from neem (Azadiracta indica) by high-performance liquid
chromatography-atmospheric pressure chemical ionization mass spectrometry.
Journal of Chromatography A, 2000, 886: 89–97.
18. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier
Publishing, 1995.
19. 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.
20. Akhila A, Rani K. Chemistry of the neem tree (Azadirachta indica A. Juss.).
In: Herz W, et al. eds. Fortschritte der Chemie Organischer Naturstoffe, 1999,
78:47–149.
21. Singh N et al. Melia azadirachta in some common skin disorders. Antiseptic,
1979, 76:677–680.
22. Perry LM, Metzger J. Medicinal plants of East and Southeast Asia: attributed
properties and uses. Cambridge, MA, MIT Press, 1980.
23. Jaiswal AK, Bhattacharya SK, Acharya SB. Anxiolytic activity of Azadirachta
indica leaf extract in rats. Indian Journal of Experimental Biology, 1994,
32:489–491.
24. Khanna N. Antinociceptive action of Azadirachta indica (neem) in mice:
possible mechanisms involved. Indian Journal of Experimental Biology,
1995, 33:848–850.
25. Kasturi M et al. Effects of Azadirachta indica leaves on the seminal vesicles
and ventral prostate in albino rats. Indian Journal of Physiology and Pharmacology,
1997, 41:234–240.
26. Kasturi M et al. Changes in the epididymal structure and function of albino
rat treated with Azadirachta indica leaves. Indian Journal of Experimental
Biology, 1995, 33:725–729.
27. Parshad O et al. Effect of aqueous neem (Azadirachta indica) extract on testosterone
and other blood constituents in male rats. A pilot study. West
Indian Medical Journal, 1994, 43:71–74.
28. Bhanwra S, Singh J, Khosla P. Effect of Azadirachta indica (Neem) leaf
aqueous extract on paracetamol-induced liver damage in rats. Indian Journal
of Physiology and Pharmacology, 2000, 44:64–68.
29. Chattopadhyay RR. Possible biochemical mode of anti-infl ammatory action
of Azadirachta indica A. Juss. in rats. Indian Journal of Experimental
Biology, 1998, 36:418–420.
30. Chattopadhyay RR et al. A comparative evaluation of some anti-infl ammatory
agents of plant origin. Fitoterapia, 1994, 65:146–148.
31. Khosla P et al. A study of hypoglycaemic effects of Azadirachta indica (neem)
in normal and alloxan diabetic rabbits. Indian Journal of Physiology and
Pharmacology, 2000, 44:69–74.
Folium Azadirachti
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WHO monographs on selected medicinal plants
32. Chattopadhyay RR et al. Preliminary report on antihyperglycemic effect of
a fraction of leaves of Azadirachta indica (beng. Neem). Bulletin of the
Calcutta School of Tropical Medicine, 1987, 35:29–33.
33. Chattopadhyay RR et al. The effect of a fraction of fresh leaves of Azadirachta
indica (beng. Neem) on glucose uptake and glycogen content in the
rat isolated hemidiaphragm. Bulletin of the Calcutta School of Tropical Medicine,
1987, 35:29–33.
34. Chattopadhyay RR. A comparative evaluation of some blood sugar lowering
agents of plant origin. Journal of Ethnopharmacology, 1999, 67:367–372.
35. Chattopadhyay RR. Possible mechanism of antihyperglycemic effect of Azadirachta
indica leaf extract: Part V. Journal of Ethnopharmacology, 1999,
67:373–376.
36. Rochanakij S et al. Nimbolide, a constituent of Azadirachta indica, inhibits
Plasmodium falciparum in culture. Southeast Asian Journal of Tropical Medicine
and Public Health, 1985, 16:66–72.
37. Abatan MO, Makinde MJ. Screening Azadirachta indica and Pisum sativum
for possible antimalarial activities. Journal of Ethnopharmacology, 1986,
17:85–93.
38. Bray DH et al. Plants as sources of antimalarial drugs. Part 7. Activity of
some species of Meliaceae plants and their constituents limonoids. Phytotherapy
Research, 1990, 4:29–35.
39. Badam L, Joshi SP, Bedekar SS. ‘In vitro’ antiviral activity of neem (Azadirachta
indica. A. Juss) leaf extract against group B coxsackieviruses. Journal
of Communicable Diseases, 1999, 31:79–90.
40. Patel VK, Venkatakrishna-Bhatt H. Folklore therapeutic indigenous plants
in periodontal disorders in India (review, experimental and clinical approach).
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1988, 26:176–184.
41. Khan M et al. Experimentelle Untersuchungen über die Wirkung von Bestandteilen
des Niembaumes und daraus hergestellten Extrakten auf Dermatophyten,
Hefen und Schimmelpilzen. [The effect of raw materials of the
neem tree, neem oils and neem extracts on dermatophytes, yeasts and
moulds.] Zeitschrift für Hautkrankheiten, 1988, 63:499–502.
42. Arivazhagan S, Balasenthil S, Nagini S. Garlic and neem leaf extracts enhance
hepatic glutathione and glutathione dependent enzymes during N-methyl-
N’-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in
rats. Phytotherapy Research, 2000, 14:291–293.
43. Balasenthil S et al. Chemopreventive potential of neem (Azadirachta indica)
on 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch
carcinogenesis. Journal of Ethnopharmacology, 1999, 67:189–195.
44. Garg GP, Nigam SK, Ogle CW. The gastric antiulcer effects of the leaves of
the neem tree. Planta Medica, 1993, 59:215–217.
45. Thompson EB, Anderson CC. Cardiovascular effects of Azadirachta indica
extract. Journal of Pharmaceutical Sciences, 1978, 67:1476–1478.
101
46. Koley KM, Lal J. Pharmacological effects of Azadirachta indica (neem) leaf
extract on the ECG and blood pressure of rat. Indian Journal of Physiology
and Pharmacology, 1994, 38:223–225.
47. Ray A, Banerjee BD, Sen P. Modulation of humoral and cell-mediated immune
responses by Azadirachta indica (Neem) in mice. Indian Journal of
Experimental Biology, 1996, 34:698–701.
48. Sen P, Mediratta PK, Ray A. Effects of Azadirachta indica A Juss on some
biochemical, immunological and visceral parameters in normal and stressed
rats. Indian Journal of Experimental Biology, 1992, 30:1170–1175.
49. Sadekar RD et al. Immunopotentiating effects of Azadirachta indica (neem)
dry leaves powder in broilers, naturally infected with IBD virus. Indian
Journal of Experimental Biology, 1998, 36:1151–1153.
50. Ibrahim IA et al. On the toxicology of Azadirachta indica leaves. Journal of
Ethnopharmacology, 1992, 35:267–273.
51. Ali BH. The toxicity of Azadirachta indica leaves in goats and guinea pigs.
Veterinary and Human Toxicology, 1987, 29:16–19.
52. Panda S, Kar A. How safe is neem extract with respect to thyroid function in
male mice? Pharmacological Research, 2000, 41:419–422.
53. Abraham Z et al. Screening of Indian plants for biological activity: Part XII.
Indian Journal of Experimental Biology, 1986, 24:48–68.
54. Sivashanmugham R, Bhaskar N, Banumathi N. Ventricular fi brillation and
cardiac arrest due to neem leaf poisoning. Journal of the Association of Physicians
of India, 1984, 32:610–611.
55. Tiwary RS. Neem leaf poisoning. Journal of the Association of Physicians of
India, 1985, 33:817.
56. Balakrishnan V, Pillai NR, Santhakumari G. Ventricular fi brillation and cardiac
arrest due to neem leaf poisoning. Journal of the Association of Physicians
of India, 1986, 34:536.
57. Pasricha JS, Bhaumik P, Agarwal A. Contact dermatitis due to Xanthium
strumarium. Indian Journal of Dermatology, Venereology and Leprology,
1990, 56:319–321.
58. Awasthy KS, Chaurasia OP, Sinha SP. Prolonged murine genotoxic effects of
crude extract from neem. Phytotherapy Research, 1999, 13:81–83.
59. Riazuddin S, Malik MM, Nasim A. Mutagenicity testing of some medicinal
herbs. Environmental and Molecular Mutagenesis, 1987, 10:141–148.
60. Choudhary DN et al. Antifertility effects of leaf extracts of some plants in
male rats. Indian Journal of Experimental Biology, 1990, 28:714–716.
61. Prakash AO. Potentialities of some indigenous plants for antifertility activity.
International Journal of Crude Drug Research, 1986, 24:19–24.
Folium Azadirachti
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).
Selected vernacular names
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).
Geographical distribution
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-
103
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
General appearance
No information available.
Organoleptic properties
Odour: characteristic alliaceous (10); taste: no information available.
General identity tests
Macroscopic examination and thin-layer chromatography (2).
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 (12).
Chemical
Relative density 0.913–0.919 (13); refractive index 1.462–1.466 (13); saponifi
cation value 196.0 (13).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (14). For other pesticides, see the European pharmacopoeia
(14) and the WHO guidelines on quality control methods for medicinal
plants (12) and pesticide residues (15).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (12).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (12) for the analysis of radioactive isotopes.
Oleum Azadirachti
104
WHO monographs on selected medicinal plants
Chemical assays
A high-performance liquid chromatography procedure is available for
the quantitative determination of oxidized tetranortriterpenes (16).
Major chemical constituents
The major constituents are oxidized tetranortriterpenes including azadirachtin
(azadirachtin A), azadiriadione, epoxyazadiradione, azadirone,
nimbidin, nimbin, deacetylnimbin, salannin, gedunin, mahmoodin, 17-
hydroxydiradione and related derivatives (9, 11, 17–19). The structures of
azadirachtin, nimbin and deacetylnimbin are presented below:
Medicinal uses
Uses supported by clinical data
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.
Uses described in pharmacopoeias and well established documents
Treatment of gastric ulcers, cardiovascular disease, malaria, rheumatism
and skin disorders. External applications for treatment of septic wounds,
ulcers and boils (7).
Uses described in traditional medicine
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
Experimental 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
O H
H
O
OH
H
H
O CH3
H3C
O
O
O
H3C
CH3
H
O
O
O
OH
CH3
CH3
H
O
OH
O
O
CH3
O
H
H
H
azadirachtin
O
H3C O
H
CH3
H
O
CH3
O
O
H3C
O
H3C
O
H CH3
H
O
R
H
H
nimbin
deacetylnimbin
R = CO-CH3
R = H
105
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).
Antihyperglycaemic activity
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-
Oleum Azadirachti
106
WHO monographs on selected medicinal plants
betic rabbits after administration of 200.0 mg of the oil; the effect was
more pronounced in diabetic animals (35).
Anti-infl ammatory activity
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).
Antiulcer activity
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).
107
Estrogenic activity
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
Oleum Azadirachti
108
WHO monographs on selected medicinal plants
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).
Clinical pharmacology
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).
Adverse reactions
A 60-year-old male was admitted to hospital with neurological and psychotic
symptoms following ingestion of 60.0 ml of Oleum Azadirachti.
109
However, correlation of the adverse effects with ingestion of the oil was
not defi nitely proven (49).
Contraindications
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
Drug interactions
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.
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: teratogenic effects
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
Paediatric use
See Contraindications.
Oleum Azadirachti
110
WHO monographs on selected medicinal plants
Other precautions
No information available on general precautions or on precautions concerning
drug and laboratory test interactions.
Dosage forms
Oil. Store in a tightly sealed container away from heat and light.
Posology
(Unless otherwise indicated)
Dose: 1.0–5.0 ml of oil for intravaginal applications (20, 22).
References
1. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African Unity,
Scientifi c, Technical and Research Commission, 1985.
2. Central Council for Research in Unani Medicine. Standardization of single
drugs of Unani medicine – part II. New Delhi, Ministry of Health and Family
Welfare, 1992.
3. Ghana herbal pharmacopoeia. Accra, Ghana, The Advent Press, 1992.
4. Zahedi E. Botanical dictionary. Scientifi c names of plants in English, French,
German, Arabic and Persian languages. Tehran, Tehran University Publications,
1959.
5. Indian medicinal plants. Vol. I. New Delhi, Orient Longman, 1971.
6. 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.
7. Iwu MM. Handbook of African medicinal plants. Boca Raton, FL, CRC
Press, 1993.
8. 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.
9. 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).
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
Regional Offi ce for the Western Pacifi c, 1998 (WHO Regional Publications,
Western Pacifi c Series, No. 19).
12. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
111
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.
14. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
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).
16. Govindachari TR, Suresh G, Gopalakrishnan G. A direct preparative high
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.
17. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier
Publishing, 1995.
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.
19. Akhila A, Rani K. Chemistry of the neem tree (Azadirachta indica A. Juss.).
In: Herz W, et al. eds. Fortschritte der Chemie Organischer Naturstoffe, 1999,
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–
180.
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.
Oleum Azadirachti
112
WHO monographs on selected medicinal plants
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
of normal and alloxan diabetic rats. Journal of Ethnopharmacology,
1986, 17:95–98.
36. Pillai NR, Santhakumari G. Anti-arthritic and anti-infl ammatory actions of
nimbidin. Planta Medica, 1981, 43:59–63.
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,
Hefen und Schimmelpilzen. [The effect of raw materials of the neem
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)
oil. International Journal of Immunopharmacology, 1992, 14:1187–1193.
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.
113
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.
52. Lai SM, Lim KW, Cheng HK. Margosa oil poisoning as a cause of toxic encephalopathy.
Singapore Medical Journal, 1990, 31:463–465.
53. Jongen WMF, Koeman JH. Mutagenicity testing of two tropical plant materials
with pesticidal potential in Salmonella typhimurium: Phytolacca dodecandra
berries and oil from seeds of Azadirachta indica. Environmental
Mutagenesis, 1983, 5:687–694.
54. Polasa K, Rukmini C. Mutagenicity tests of cashewnut shell liquid, rice-bran
oil and other vegetable oils using the Salmonella typhimurium/microsome
system. Food and Chemical Toxicology, 1987, 25:763–766.
Oleum Azadirachti
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.
Selected vernacular names
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).
Geographical distribution
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,
115
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
General appearance
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).
Organoleptic properties
Odour: characteristic aromatic; taste: slightly bitter (1–3).
Microscopic characteristics
Information to be developed according to national requirements.
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (1–3), microchemical tests,
spectrometry (1–3), and thin-layer chromatography (3).
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 (12).
Foreign organic matter
Not more than 2% (1–3).
Flos Carthami
116
WHO monographs on selected medicinal plants
Total ash
Not more than 18% (1, 2).
Loss on drying
Not more than 13% (3).
Pesticide residues
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
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (12).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (12) for the analysis of radioactive isotopes.
Other purity tests
Chemical, acid-insoluble ash, sulfated ash, water-soluble extractive and
alcohol-soluble extractive tests to be established in accordance with national
requirements.
Chemical assays
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).
Major chemical constituents
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
are presented below.
117
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
Treatment of amenorrhoea, dysmenorrhoea and wounds or sores with
pain and swelling, and prevention of atherosclerosis (3, 19).
Uses described in traditional medicine
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
Experimental 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
Flos Carthami
O
OH
OH O
HO
OH
Glc
O
OH
HO
HO
O
H
O
Glc and epimer at C*
*
OH
O O
OH
HO HO Glc
HN
HO
HO
OH
H
H
H
*
and epimer at C*
OH
O O
HO
OH
HO Glc
Glc
*
and epimer at C*
OH
O O
OH
O
O
HO Glc
HO
HO
HO
H
H
H
H
H
*
and epimer at C*
OH
O O
HO
OH
HO Glc
HO
O O
OH
HO
Glc OH
H
OH
HO
H
H
OH
H
HO
HO
O
OH
HO
HO
OH
Glc =
carthamin
hydroxysafflor yellow A safflor yellow A
safflor yellow B
β-D-glucopyranosyl
tinctormine
neocarthamin
118
WHO monographs on selected medicinal plants
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).
Antihepatotoxic activity
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).
Anti-infl ammatory activity
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).
Antimicrobial activity
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).
119
Cardiovascular effects
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-
Flos Carthami
120
WHO monographs on selected medicinal plants
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).
Platelet aggregation inhibition
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).
Uterine stimulant effects
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 (LD50) of a decoction of the fl owers in mice
was 1.2 g/kg bw (19). The intravenous LD50 of a 50% ethanol extract of
the fl owers in mice was 5.3 g/kg bw. The intravenous and oral LD50 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).
Clinical pharmacology
No information available.
Adverse reactions
Increased menstrual fl ow may occur (19). Dizziness, skin eruptions and
transient urticaria have been reported (19).
121
Contraindications
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
No information available.
Precautions
Drug interactions
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.
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: teratogenic effects
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
Flos Carthami
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WHO monographs on selected medicinal plants
external, internal and longitudinal diameters, open neuropore, cellular
orientation and cellular degeneration were observed (49).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
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.
Paediatric use
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.
Other precautions
No information available on general precautions or on precautions concerning
drug and laboratory test interactions.
Dosage forms
Dried fl owers for infusions and decoctions; extracts. Store in a cool dry
place protected from moisture (3).
Posology
(Unless otherwise indicated)
Average daily dose: 3.0–9.0 g of Flos Carthami as an infusion or decoction;
equivalent for other preparations (2, 3).
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 People’s Republic of China. Vol. I. (English ed.).
Beijing, Chemical Industry Press, 2000.
4. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
5. Zahedi E. Botanical dictionary. Scientifi c names of plants in English, French,
German, Arabic and Persian languages. Tehran, Tehran University Publications,
1959.
123
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.
8. 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).
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
Regional Offi ce for the Western Pacifi c, 1989 (WHO Regional Publications,
Western Pacifi c Series, No. 2).
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).
12. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
13. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
14. 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).
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 Ca2+ 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 6,8-
diols 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.
Flos Carthami
124
WHO monographs on selected medicinal plants
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].
26. Kumazawa N et al. [Protective effects of various methanol extracts of crude
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
Pharmaceutical Bulletin, 1979, 27:1464–1468.
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.
125
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.
45. 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.
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.
Flos Carthami
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).
Selected vernacular names
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).
Geographical distribution
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).
127
Plant material of interest: dried stigmas
General appearance
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).
Organoleptic properties
Odour: characteristic, aromatic, slightly irritant; taste: pungent, slightly
bitter (1, 2, 8).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations, microchemical and spectrophotometric
tests (1, 2), and thin-layer chromatography (11).
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 (12).
Total ash
Not more than 7.5% (1, 2).
Loss on drying
Not more than 12.0% (1, 2).
Stigma Croci
128
WHO monographs on selected medicinal plants
Pesticide residues
The recommended maximum limit 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
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (12).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (12) for the analysis of radioactive isotopes.
Other purity tests
Chemical, foreign organic matter, acid-insoluble ash, water-soluble
extractive and alcohol-soluble extractive tests to be established in
accordance with national requirements.
Chemical assays
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).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
None. Although Stigma Croci showed antioxidant effects in human studies
(18), data from controlled clinical trials are lacking.
Uses described in pharmacopoeias and well established documents
As a tonic and antiarteriosclerotic (19, 20), and as a sedative and emmenagogue
(2, 5, 21).
129
Uses described in traditional medicine
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
Experimental 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
Stigma Croci
A-crocin (crocin)
B-crocin (crocin 2)
C-crocin (crocin 3)
D-crocin (crocin 4)
E-crocin
R2O
OR1
O
O
CH3 CH3
CH3 CH3
H3C OR1
O
CH3 CH3
H3C
O OR2
α-crocetin (crocetin)
+ γ-crocetin (dimethylcrocetin)
R1 R2
Glc
Gen
H
Glc Glc
H
and H Glc
and H Gen
and Glc Gen
Gen Glc
Gen Gen
β-crocetin
CH3
H CH3
and CH3 H
H H
CH3
safranal H3C CH3
CHO
CH3
picrocrocin H3C CH3
CHO
O CH3
H
Glc
O
OH
HO
HO
HO
O
6−Ο−β-D-glucopyranosyl-
β-D-glucopyranosyl Gen
O
OH
HO
OH
=
gentiobiosyl :
O
OH
HO
HO
OH
β-D-glucopyranosyl Glc =
130
WHO monographs on selected medicinal plants
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-
131
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 (LD50) of 0.4 mmol/l and
1.0 mmol/l, respectively (33). An aqueous extract of the stigmas (LD50
2.3 mg/ml), crocin (LD50 3 mmol/l), picrocrocin (LD50 3 mmol/l) and safranal
(LD50 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 LD50 for Stigma Croci was reported to be 20.7 g/kg bw in rodents
(23). The LD50 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).
Clinical pharmacology
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
Stigma Croci
132
WHO monographs on selected medicinal plants
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).
Adverse reactions
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).
Contraindications
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
Drug interactions
Stigma Croci inhibits platelet aggregation and should therefore be used
with caution in patients taking anticoagulant or antiplatelet drugs.
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
133
Paediatric use
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
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
1. The Japanese pharmacopoeia, 13th ed. (English version). Tokyo, Ministry of
Health and Welfare, 1996.
2. Pharmacopoeia of the People’s Republic of China. Vol. I (English ed.).
Beijing, China, Chemical Industry Press, 2000.
3. 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.
4. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
5. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
6. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
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).
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.
9. Saber AH. Practical pharmacognosy, 2nd ed. Cairo, Al-Etemad Press, 1946.
10. Wallis TE. Textbook of pharmacognosy, 4th ed. London, J & A Churchill,
1960.
Stigma Croci
134
WHO monographs on selected medicinal plants
11. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas.
2nd ed. Berlin, Springer, 1996.
12. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
13. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
14. 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).
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.
21. Halmai J, Novak I. Farmakognózia. [Pharmacognosy.] Budapest, Medicina
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.
135
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.
Phytotherapy Research, 1995, 9:100–104.
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.
41. Yamamoto H, Mizutani T, Nomura H. [Studies on the mutagenicity of crude
drug extracts. I.] Yakugaku Zasshi, 1982, 102:596–601 [in Japanese].
42. Rockwell P, Raw I. A mutagenic screening of various herbs, spices, and food
additives. Nutrition and Cancer, 1979, 1:10–15.
43. McGuffi n M et al., eds. Botanical safety handbook. Boca Raton, FL, CRC
Press, 1997.
Stigma Croci
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.
Selected vernacular names
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.
137
Geographical distribution
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).
Plant material of interest: dried ripe fruits
General appearance
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).
Organoleptic properties
Odour: characteristic, aromatic; taste: sweet to bitter (1–4, 8).
Microscopic characteristics
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-
Fructus Foeniculi
138
WHO monographs on selected medicinal plants
tals of calcium oxalate, about 3 μm in diameter. Carpophore often not
split, with thick-walled sclerenchyma in two strands (2, 8).
Powdered plant material
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).
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (17).
Foreign organic matter
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).
Acid-insoluble ash
Not more than 1.5% (1, 2, 4).
Water-soluble extractive
Not less than 20% (3).
Alcohol-soluble extractive
Not less than 11% (3).
Moisture
Not more than 8% (7).
139
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (19). For other pesticides, see the European pharmacopoeia
(19) and the WHO guidelines on quality control methods for medicinal
plants (17) and pesticide residues (20).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (17).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (17) for the analysis of radioactive isotopes.
Other purity tests
Chemical and sulfated ash tests to be established in accordance with national
requirements.
Chemical assays
Contains not less than 1.4% v/w essential oil (1, 2, 4, 6).
Major chemical constituents
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
are presented below.
Medicinal uses
Uses supported by clinical data
None.
Fructus Foeniculi
trans-anethole estragole
H3CO
CH3
H3CO
CH2
fenchone
CHO
anisaldehyde
CH3
CH3
O
CH3
H3CO
and enantiomer
H
H3C
H3C
CH3
α-pinene
CH3 CH3
(+)-limonene (-)-α-phellandrene
H3C H
H3C
H3C H
H2C and enantiomer
H
H
140
WHO monographs on selected medicinal plants
Uses described in pharmacopoeias and well established documents
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).
Uses described in traditional medicine
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
Experimental pharmacology
Analgesic and antipyretic activities
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).
Antimicrobial activity
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).
141
Antispasmodic activity
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 E2-induced contractions
of isolated rat uterus and reduced the frequency of the latter but not the
former (40).
Cardiovascular effects
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).
Fructus Foeniculi
142
WHO monographs on selected medicinal plants
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).
143
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 (LD50) 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 LD50 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).
Clinical pharmacology
No information available.
Fructus Foeniculi
144
WHO monographs on selected medicinal plants
Adverse reactions
In rare cases, allergic reactions such as asthma, contact dermatitis and
rhinoconjunctivitis have been reported in sensitive patients (67, 68).
Contraindications
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
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: teratogenic effects
An essential oil from the fruits, up to 500.0 μg/ml, had no teratogenic effects
in cultured rat limb bud cells (61).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
No restrictions on the use of infusions prepared from Fructus Foeniculi
or the seeds.
145
Paediatric use
No restrictions on the use of infusions prepared from Fructus Foeniculi
or the seeds. See also Contraindications.
Other precautions
No information available on general precautions or precautions concerning
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
(Unless otherwise indicated)
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
1. Asian crude drugs, their preparations and specifi cations. Asian pharmacopoeia.
Manila, Federation of Asian Pharmaceutical Associations, 1978.
2. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African Unity,
Scientifi c, Technical and Research Commission, 1985.
3. Standard of ASEAN herbal medicine. Vol. 1. Jakarta, ASEAN Countries,
1993.
4. The Japanese pharmacopoeia, 13th ed. (English version). Tokyo, Ministry of
Health and Welfare, Japan, 1996.
5. Pharmacopoeia of the Republic of Korea, 7th ed. Seoul, Taechan yakjon,
1998.
6. The Ayurvedic pharmacopoeia of India. Part I. Vol. I. New Delhi, Ministry
of Health and Family Welfare, Department of Indian System of Medicine
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8. Pharmacopoeia of the People’s Republic of China. Vol. I (English ed.).
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146
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11. Bensky D, Gamble A, Kaptchuk T, eds. Chinese herbal medicine, materia
medica, rev. ed. Seattle, WA, Eastland Press, 1993.
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13. Holmes P. The energetics of western herbs. Vol. 1, rev. 3rd ed. Boulder, CO,
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Publishing, 1995.
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Shoten, 1996 [in Japanese].
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plants. Planta Medica, 1980, 40:309–319.
24. Weiss RF. Lehrbuch der Phytotherapie, 7th ed. [Textbook of phytotherapy,
7th ed.] Stuttgart, Hippokrates, 1991.
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Austin, TX, American Botanical Council, 1998.
26. Reynolds JEF, ed. Fennel, fennel oil. In: Martindale – the extra pharmacopoeia,
30th ed. London, The Pharmaceutical Press, 1993.
27. Hare HA, Caspari C, Rusby HH. The national standard dispensatory. Philadelphia,
PA, Lea and Febiger, 1916.
28. Albert-Puleo M. Fennel and anise as estrogenic agents. Journal of Ethnopharmacology,
1980, 2:337–344.
29. Mascolo N et al. Biological screening of Italian medicinal plants for antiinfl
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vulgare dried fruit extract in experimental animals. Phytotherapy
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147
31. Sharma SK, Singh VP. The antifungal activity of some essential oils. Indian
Drugs and Pharmaceuticals Industry, 1979, 14:3–6.
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by the agar overlay technique. Pharmazeutisch Weekblad (Scientifi c Edition),
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food spoilage yeast. Journal of Food Science, 1984, 49:429–434.
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Arzneidrogen, galenischer Zubereitungen und Arzneifertigwaren, geprüft
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[Intensity and loss of the in situ effect of spasmolytically active drugs,
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spices. Phytotherapy Research, 1987, 1:91–92.
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45. Annusuya S et al. Effect of Foeniculum vulgare seed extracts on cervix and
vagina of ovariectomised rats. Indian Journal of Medical Research, 1988,
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Diseases and Human Immunodefi ciency Virus Research, 1996, 10:189–
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47. Mills S, Bone K. Principles and practice of phytotherapy. Edinburgh, Churchill
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48. Shukla HS, Upadhyay PD, Tripathi SC. Insect repellent properties of essential
oils of Foeniculum vulgare, Pimpinella anisum and anethole. Pesticides,
1989, 23:33–35.
49. Zondek B, Bergmann E. Phenol methyl esters as oestrogenic agents. Biochemical
Journal, 1938, 32:641–643.
50. Farook T et al. Effect of anethole on accessory sex tissue of albino rats. Journal
of Research in Ayurvedic Science, 1989, 15:167–170.
51. 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. Müller-Limmroth W, Fröhlich HH. Wirkungsnachweis einiger phytotherapeutischer
Expektorantien auf den mukoziliaren Transport. [Effect of various
phytotherapeutic expectorants on mucociliary transport.] Fortschrift für
Medizin, 1980, 98:95–101.
53. Boyd EM, Sheppard EP. An autumn-enhanced mucotropic action of inhaled
terpenes and related volatile agents. Pharmacology, 1971, 6:65–80.
54. Niiho Y, Takayanagi I, Takagi K. Effects of a combined stomachic and its
ingredients on rabbit stomach motility in situ. Japanese Journal of Pharmacology,
1977, 27:177–179.
55. Shipochliev T. [Pharmacological research into a group of essential oils. II.
Effect on the motor activity and general state of white mice in separate applications
or after iproniazid phosphate.] Veterinarno-Meditsinski Nauki.
1968, 5:87–92 [in Bulgarian].
56. Han YB, Shin KH, Woo WS. Effect of spices on hepatic microsomal enzyme
function in mice. Archives of Pharmacal Research, 1984, 7:53–56.
57. Shah AH, Qureshi S, Ageel AM. Toxicity studies in mice of ethanol extracts
of Foeniculum vulgare fruit and Ruta chalepensis aerial parts. Journal of
Ethno-pharmacology, 1991, 34:167–172.
58. Opdyke DLJ. Monographs on fragrance raw materials: fennel oil. Food and
Cosmetics Toxicology, 1974, 12:879–880.
59. Opdyke DLJ. Monographs on fragrance raw materials: fennel oil, bitter.
Food and Cosmetics Toxicology, 1976, 14:309.
60. Mokkhasmit M et al. Study on the toxicity of Thai medicinal plants. Bulletin
of the Department of Medical Science, 1971, 12:36–65.
61. Ostad SN, Khakinegad B, Sabzevari O. The study of teratogenic effect of
fennel essential oil in vitro. Toxicology Letters, 2000, 116:89 [abstract].
62. 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.
63. Truhaut R et al. Chronic toxicity/carcinogenicity study of trans-anethole in
rats. Food and Chemical Toxicology, 1989, 27:11–20.
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64. Howes AJ, Chan VS, Caldwell J. Structure-specifi city of the genotoxicity of
some naturally occurring alkenylbenzenes determined by the unscheduled
DNA synthesis assay in rat hepatocytes. Food and Chemical Toxicology,
1990, 28:537–542.
65. Fennel TR et al. Major role of hepatic sulfotransferase activity in the metabolic
activation, DNA adduct formation, and carcinogenicity of 1’-hydroxy-
2’,3’-dehydroestragole in infant male C57BL/J66 × C3H/HeJ F1 mice.
Cancer Research, 1985, 45:5310–5320.
66. Anthony A et al. Metabolism of estragole in rat and mouse and infl uence of
dose size on excretion of the proximate carcinogen 1’-hydroxyestragole.
Food and Chemical Toxicology, 1987, 25:799–806.
67. Jensen-Jarolim E et al. Characterization of allergens in Apiaceae spices: anise,
fennel, coriander and cumin. Clinical and Experimental Allergy, 1997,
27:1299–1306.
68. Schwartz HJ et al. Occupational allergic rhinoconjunctivitis and asthma due
to fennel seed. Annals of Allergy, Asthma and Immunology, 1997, 78:37–40.
69. Wüthrich B, Hoffer T. Nahrungsmittelallergie: das Sellerie-Beifuss-
Gerwürz-Syndrom. Assoziation mit einer Mangofrucht-Allergie? [Food
allergy: the celery-mugwort-spice syndrome. Association with mango
allergy?] Deutsche medizinische Wochenschrift, 1984, 109:981–986.
70. Stäger J, Wuthrich B, Johansson SG. Spice allergy in celery-sensitive patients.
Allergy, 1991, 46:475–478.
71. 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.
72. Yamamoto H, Mizutani T, Nomura H. [Studies on the mutagenicity of crude
drug extracts. I.] Yakugaku Zasshi, 1982, 102:596–601 [in Japanese].
73. Mahmoud I et al. Mutagenic and toxic activities of several spices and some
Jordanian medicinal plants. International Journal of Pharmacognosy, 1991,
30:81–85.
74. Marcus C, Lichtenstein EP. Interactions of naturally occurring food plant
components with insecticides and pentobarbital in rats and mice. Journal of
Agricultural and Food Chemistry, 1982, 30:563–568.
75. Sekizawa J, Shibamoto T. Genotoxicity of safrole-related chemicals in microbial
test systems. Mutation Research, 1982, 101:127–140.
76. Ishidate M et al. Primary mutagenicity screening of food additives currently
used in Japan. Food and Chemical Toxicology, 1984, 22:623–636.
Fructus Foeniculi
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).
Selected vernacular names
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).
Geographical distribution
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
General appearance
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-
151
kled, and more or less twisted; fractured surface yellow-brown and not
fi brous; cambium and its surroundings tinged dark brown (1, 2, 5).
Organoleptic properties
Odour: characteristic; taste: initially sweet, becoming persistently bitter
(1, 2, 4, 5). Bitterness value not less than 10 000 (4).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (13).
Radix Gentianae Luteae
152
WHO monographs on selected medicinal plants
Foreign organic matter
Not more than 2% (1, 2).
Total ash
Not more than 6% (2, 4, 5).
Acid-insoluble ash
Not more than 3% (1, 5).
Water-soluble extractive
Not less than 33% (4).
Loss on drying
Not more than 10% (1, 2).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (4). For other pesticides, see the European pharmacopoeia (4)
and the WHO guidelines on quality control methods for medicinal plants
(13) and pesticide residues (14).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (13).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (13) for the analysis of radioactive isotopes.
Other purity tests
Chemical, sulfated ash and alcohol-extractive tests to be established in
accordance with national requirements.
Chemical assays
High-performance liquid chromatography for the presence of gentiopicroside
and amarogentin (15–17).
Major chemical constituents
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-
153
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:
Medicinal uses
Uses supported by clinical data
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.
Uses described in pharmacopoeias and well established documents
Treatment of digestive complaints, such as loss of appetite, feeling of distension
and fl atulence (23). As an appetite stimulant during convalescence (24).
Uses described in traditional medicine
As a carminative, depurative, emmenagogue, febrifuge, tranquillizer and
tonic, and to facilitate labour (8, 10). Treatment of diabetes and dysmenorrhoea
(10).
Pharmacology
Experimental pharmacology
Antimicrobial activity
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).
Radix Gentianae Luteae
amarogentin gentiopicroside sweroside
O O
O
H
O
H
H2C
O
OH
HO
HO
H
O
OH
OH
HO
O
O O
O
H
O
H
H2C
O
OH
HO
HO
OH
O O
O
H
O
H
H2C
O
OH
HO
HO
OH
H
154
WHO monographs on selected medicinal plants
Antispasmodic activity
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).
Choleretic activity
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).
Clinical pharmacology
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
155
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
observed (21).
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).
Adverse reactions
On rare occasions, headaches may occur (23).
Contraindications
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
No information available.
Precautions
General
If symptoms persist, consult a physician. Overdose may lead to nausea or
vomiting (7, 24).
Carcinogenesis, mutagenesis, impairment of fertility
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).
Radix Gentianae Luteae
156
WHO monographs on selected medicinal plants
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).
Pregnancy: teratogenic effects
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
Paediatric use
See Contraindications.
Other precautions
No information available on precautions concerning drug interactions; or
drug and laboratory test interactions.
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
(Unless otherwise indicated)
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).
157
References
1. Egyptian pharmacopoeia. Vol. 1, 3rd ed. Cairo, General Organization for
Government Printing, 1972.
2. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African Unity,
Scientifi c, Technical and Research Commission, 1985.
3. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,
1996.
4. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
5. The Japanese pharmacopoeia, 13th ed. (English version). Tokyo, Ministry of
Health and Welfare, 1996.
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.
7. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 5,
Drogen E–O, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 5,
Drugs E–O, 5th ed.] Berlin, Springer, 1993.
8. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
9. 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.
10. 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).
11. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
12. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris,
Lavoisier Publishing, 1995.
13. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
14. 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).
15. Sticher O, Meier B. Quantitative Bestimmung der Bitterstoffe in Wurzeln
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.
Radix Gentianae Luteae
158
WHO monographs on selected medicinal plants
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.
23. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
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.
28. Leslie GB. A pharmacometric evaluation of nine Bio-Strath herbal remedies.
Medita, 1978, 8:31–47.
29. Reiter M, Brandt W. Relaxant effects on tracheal and ileal smooth muscles of
the guinea pig. Arzneimittelforschung, 1985, 35:408–414.
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.
159
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.
Radix Gentianae Luteae
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).
Selected vernacular names
Chinese gentian, dancao, Japanese gentian, kudancao, longdan, longdancao,
tourindou (1, 2, 4, 6, 7).
Geographical distribution
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).
Plant material of interest: dried roots and rhizomes
General appearance
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).
161
Organoleptic properties
Odour: characteristic; taste: bitter (1–4).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (1–4), microchemical tests (1,
3) and thin-layer chromatography (2, 4).
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 (12).
Total ash
Not more than 7% (1–4).
Acid-insoluble ash
Not more than 3% (1–3).
Alcohol-soluble extractive
Not less than 30% (3).
Radix Gentianae Scabrae
162
Loss on drying
Not more than 8% (3).
Pesticide residues
The recommended maximum limit 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
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (12).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (12) for the analysis of radioactive isotopes.
Other purity tests
Chemical, foreign organic matter and water-soluble extractive tests to be
established in accordance with national requirements.
Chemical assays
Contains not less than 1.0% gentiopicroside determined by highperformance
liquid chromatography (4).
Major chemical constituents
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.
WHO monographs on selected medicinal plants
amarogentin gentiopicroside sweroside
O O
O
H
O
H
H2C
O
OH
HO
HO
H
O
OH
OH
HO
O
O O
O
H
O
H
H2C
O
OH
HO
HO
OH
O O
O
H
O
H
H2C
O
OH
HO
HO
OH
H
163
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
Symptomatic treatment of liver disorders, cholecystitis and lack of appetite
(3, 6).
Uses described in traditional medicine
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
Experimental pharmacology
Antimicrobial activity
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).
Antihepatotoxic activity
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
Radix Gentianae Scabrae
164
WHO monographs on selected medicinal plants
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).
Anti-infl ammatory activity
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).
Antispasmodic activity
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).
Central nervous system effects
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).
Choleretic activity
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).
165
Toxicology
The oral median lethal doses (LD50) of gentianine and gentianadine in
mice were 400.0 mg/kg bw and 1250.0 mg/kg bw, respectively (6, 35). The
subcutaneous LD50 of gentianine in mice was > 500.0 mg/kg bw, and the
intravenous LD50 was 250.0–300.0 mg/kg bw (6). The intraperitoneal
LD50 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).
Clinical pharmacology
No information available.
Adverse reactions
Radix Gentiana Scabrae may cause impairment of digestion and, occasionally,
headaches, fl ushing of the face and vertigo when taken after a
meal (37).
Contraindications
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
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Radix Gentianae Scabrae
166
WHO monographs on selected medicinal plants
Nursing mothers
See Contraindications.
Paediatric use
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
drug interactions; drug and laboratory test interactions; or teratogenic
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
(Unless otherwise indicated)
Average daily dose: roots and rhizomes 3–6 g per day as an infusion or
decoction (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, Japan, 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, China, Chemical Industry Press, 2000.
5. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 6,
Drogen P–Z, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 6,
Drugs P–Z, 5th ed.] Berlin, Springer, 1994.
6. Chang HM, But PPH. Pharmacology and applications of Chinese materia
medica. Vol. 1. Singapore, World Scientifi c, 1986.
7. 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).
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.
167
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.
12. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
13. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
14. 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).
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.
20. 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].
21. Yun HS, Yu JC, Chang IM. [Plants with liver protective activities. (V) Liver
protective activities of Atractylodes japonica (alba) and Gentiana scabra.]
Korean Journal of Pharmacognosy, 1981, 12:23–25 [in Korean].
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.
Radix Gentianae Scabrae
168
WHO monographs on selected medicinal plants
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].
29. Reiter M, Brandt W. Relaxant effects on tracheal and ileal smooth muscles of
the guinea pig. Arzneimittelforschung, 1985, 35:408–414.
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.]
Korean Journal of Pharmacognosy, 1995, 26:349–354 [in Korean].
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.
38. 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.
39. Yamamoto H, Mizutani T, Nomura H. [Studies on the mutagenicity of crude
drug extracts. I.] Yakugaku Zasshi, 1982, 102:596–601 [in Japanese].
40. Yin XJ et al. A study on the mutagenicity of 102 raw pharmaceuticals used in
traditional Chinese medicine. Mutation Research, 1991, 260:73–82.
169
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).
Selected vernacular names
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).
Geographical distribution
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
General appearance
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).
170
WHO monographs on selected medicinal plants
Organoleptic properties
Odour: characteristic aromatic, balsamic; taste: aromatic, bitter, acrid
(2, 3, 6, 16).
Microscopic characteristics
Not applicable.
Powdered plant material
Not applicable.
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (21).
Foreign organic matter
Not more than 4% (3, 4).
Total ash
Not more than 5% (3, 4).
Acid-insoluble ash
Not more than 1% (3, 4).
Sulfated ash
Not more than 10% (2).
Water-soluble extractive
Not less than 53% (3, 4).
Alcohol-soluble extractive
Not less than 35% (2).
Ethyl acetate-soluble extractive
Not less than 25% (2).
171
Moisture
Not more than 14% (18).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (22). For other pesticides, see the European pharmacopoeia
(22), and the WHO guidelines on quality control methods for medicinal
plants (21) and pesticide residues (23).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (21).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (21) for the analysis of radioactive isotopes.
Other purity tests
Chemical tests to be established in accordance with national requirements.
Chemical assays
Contains not less than 4.0% and not more than 6.0% of guggulsterones Z
and E determined by high-performance liquid chromatography (2).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
Treatment of hyperlipidaemia and hypercholesterolaemia (1, 26–33).
Clinical investigations to assess the use of extracts of the oleo-gum
Gummi Gugguli
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WHO monographs on selected medicinal plants
resin for the treatment of obesity were negative (34, 35) (see Clinical
pharmacology).
Uses described in pharmacopoeias and well established documents
Treatment of atherosclerosis, rheumatic conditions, cough, sore throat
and menopausal symptoms. As an emmenagogue (3, 4, 8, 9, 16).
Uses described in traditional medicine
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
Experimental pharmacology
Anticoagulant activity
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
(E)-guggulsterone R
R'
CH3
CH3
O
H
H H
H3C
CH3 OH
CH3
O
H
H H
CH3
H3C
guggulsterol I OH OH
H
H
OH
H
H (Z)-guggulsterone
R = CH3, R' = H
R = H, R' = CH3
H3C
CH3 OH
CH3
O
H
H H
CH3
H3C
OH
H
guggulsterol II H3C
CH3 OH
CH3
H
H H
CH3
H3C
OH
H
H
guggulsterol III
HO
H
cembrene mukulol
CH3
CH3
CH3
H
CH3
CH3
H
H3C
H
OH
H3C
H3C
H3C CH3
173
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 (Eand
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).
Anti-infl ammatory activity
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
Gummi Gugguli
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WHO monographs on selected medicinal plants
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).
Clinical pharmacology
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-
175
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
Gummi Gugguli
176
WHO monographs on selected medicinal plants
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).
Adverse reactions
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-
177
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).
Contraindications
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
No information available.
Precautions
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Other precautions
No information available on general precautions or precautions concerning
drug interactions; drug and laboratory test interactions; teratogenic
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.
Gummi Gugguli
178
WHO monographs on selected medicinal plants
Posology
(Unless otherwise indicated)
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).
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181
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48. Bordia A, Chuttani SK. Effect of gum guggulu on fi brinolysis and platelet
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Gummi Gugguli
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).
Selected vernacular names
Afrikanische Teufelskralle, beesdubbeltjie, devil’s claw, duiwelsklou, grapple
plant, grapple vine, harpagophytum, kanako, khams, khuripe, legatapitse,
sengaparele, Teufelskralle, Trampelklette, wood spider xwate (3–8).
Geographical distribution
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
General appearance
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,
183
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).
Organoleptic properties
Odour: none; taste: bitter (1, 2).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations, and thin-layer chromatography
for the presence of harpagoside (1, 2).
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 (14).
Foreign organic matter
Not more than 2% (1, 2).
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184
WHO monographs on selected medicinal plants
Total ash
Not more than 8% (2).
Acid-insoluble ash
Not more than 5% (1).
Water-soluble extractive
Not less than 50% (1).
Loss on drying
Not more than 12% (2).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (15). For other pesticides, see the European pharmacopoeia
(15), and the WHO guidelines on quality control methods for medicinal
plants (14) and pesticide residues (16).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (14).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (14) for the analysis of radioactive isotopes.
Other purity tests
Chemical, sulfated ash and alcohol-soluble extractive tests to be established
in accordance with national requirements.
Chemical assays
Contains not less than 1.2% harpagoside as determined by high-performance
liquid chromatography (2).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
Treatment of pain associated with rheumatic conditions (17–24).
185
Uses described in pharmacopoeias and well established documents
Treatment of loss of appetite and dyspeptic complaints; supportive treatment
of degenerative rheumatism, painful arthrosis and tendonitis (25).
Uses described in traditional medicine
Treatment of allergies, boils, diabetes, liver disorders and sores (8).
Pharmacology
Experimental 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 B2 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
Radix Harpagophyti
O
OH
HO
HO
OH
β-D-glucopyranosyl
Glc =
harpagide
O
H
HO
H
HO
O
H
CH3
OH
Glc
O
H
HO
H
HO
O
H
O
CH3
O
Glc
harpagoside procumbide
O
H
HO
HO
H
O
H
CH3
H O
Glc
186
WHO monographs on selected medicinal plants
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
187
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).
Clinical pharmacology
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).
Anti-infl ammatory and analgesic activity
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).
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WHO monographs on selected medicinal plants
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
189
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).
Adverse reactions
Mild and infrequent gastrointestinal symptoms were reported in clinical
trials (18, 20, 45).
Contraindications
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
No information available.
Precautions
General
Patients with gallstones should consult a physician prior to using the
roots (25).
Drug interactions
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).
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WHO monographs on selected medicinal plants
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
See Contraindications.
Other precautions
No information available on precautions concerning drug and laboratory
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,
protected from light (2).
Posology
(Unless otherwise indicated)
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
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191
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unspezifi scher Rückenschemerzen. Effekte auf die sensible, motorische
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Radix Harpagophyti
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.
Selected vernacular names
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).
Geographical distribution
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
General appearance
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
195
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).
Organoleptic properties
Odour: faint, unpleasant; taste: bitter, persistent (1, 4, 6).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (1, 3, 4), and thin-layer chromatography
(1, 3).
Rhizoma Hydrastis
196
WHO monographs on selected medicinal plants
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 (7).
Chemical
Not less than 2.0% hydrastine and not less than 2.5% berberine (3).
Foreign organic matter
Not more than 2% (3).
Total ash
Not more than 9% (3).
Acid-insoluble ash
Not more than 5% (3).
Water-soluble extractive
Not less than 14% (1).
Loss on drying
Not more than 12% (3).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (8). For other pesticides, see the European pharmacopoeia (8),
and the WHO guidelines on quality control methods for medicinal plants
(7) and pesticide residues (9).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (7).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants for the analysis of radioactive isotopes (7).
Other purity tests
Sulfated ash and alcohol-soluble extractive tests to be established in accordance
with national requirements.
197
Chemical assays
Contains not less than 2.0% hydrastine and not less than 2.5% berberine
determined by high-performance liquid chromatography (3).
Major chemical constituents
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:
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
Treatment of digestive complaints, such as dyspepsia, gastritis, feeling of
distension and fl atulence (1).
Uses described in traditional medicine
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
Experimental pharmacology
Antimicrobial activity
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
berberine canadine
N+
O
O
H3CO
H3CO
N
O
O
H3CO
H3CO
H
and enantiomer
hydrastine
H3C
N
O
O
H
O
OCH3 O
H3CO
H
Rhizoma Hydrastis
198
WHO monographs on selected medicinal plants
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
ED50 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-
199
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).
Uterine stimulant effects
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).
Clinical pharmacology
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.
Adverse reactions
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).
Contraindications
Radix Hydrastis is contraindicated in cases of known allergy to the plant
material.
Warnings
No information available.
Rhizoma Hydrastis
200
WHO monographs on selected medicinal plants
Precautions
General
Use with caution in patients with high blood pressure, diabetes, glaucoma
and a history of cardiovascular disease.
Drug interactions
An ethanol extract of the rhizomes inhibited the activity of cytochrome
P450 (CYP3A4) in vitro, median inhibitory concentration <1 p="">Concomitant administration of Radix Hydrastis with drugs metabolized
via cytochrome P450 may therefore affect the metabolism of such
drugs (46).
Carcinogenesis, mutagenesis, impairment of fertility
The genotoxic effects of berberine in prokaryotic cells were assessed in
the SOS-ChromoTest in Saccharomyces cerevisiae (47). No genotoxic activity
with or without metabolic activation was observed, and no cytotoxic
or mutagenic effects were seen under nongrowth conditions. However,
in dividing cells, the alkaloid induced cytotoxic and cytostatic effects
in profi cient and repair-defi cient Saccharomyces cerevisiae. In dividing
cells, the induction of frameshift and mitochondrial mutations and crossing
over showed that the compound is not a potent mutagen (47).
Pregnancy: non-teratogenic effects
The safety of Rhizoma Hydrastis has not been established (31) and its use
is therefore not recommended during pregnancy.
Nursing mothers
The safety of Rhizoma Hydrastis has not been established (31) and its use
is therefore not recommended in nursing mothers.
Paediatric use
The safety of Rhizoma Hydrastis has not been established (31) and its use
is therefore not recommended in children.
Other precautions
No information available on precautions concerning drug and laboratory
test interactions; or teratogenic effects during pregnancy.
Dosage forms
Dried rhizomes and roots, dried extracts, fl uidextracts, and tinctures (1,
11). Store dried rhizomes and roots in a tightly sealed container away
from heat and light.
201
Posology
(Unless otherwise indicated)
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.
2. 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.
3. USP-NF 2000, Goldenseal. Pharmacopeial Previews: Monographs (NF),
The United States Pharmacopeial Convention, Inc. Pharmacopeial forum,
2000, 26:944–948.
4. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
5. 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).
6. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris,
Lavoisier Publishing, 1995.
7. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
8. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
9. 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).
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.
12. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas,
2nd ed. Berlin, Springer, 1996.
13. Newall CA, Anderson LA, Phillipson JD. Herbal medicines. A guide for
health-care professionals. London, The Pharmaceutical Press, 1996.
14. Bae EA et al. Anti-Helicobacter pylori activity of herbal medicines. Biological
and Pharmaceutical Bulletin, 1998, 21:990–992.
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.
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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.
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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.
46. Budzinski JW et al. An in vitro evaluation of human cytochrome P450 3A4
inhibition by selected commercial herbal extracts and tinctures. Phytomedicine,
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.
Rhizoma Hydrastis
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).
Selected vernacular names
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).
Geographical distribution
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
205
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).
Plant material of interest: dried roots and rhizomes
General appearance
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).
Organoleptic properties
Odour: slight, irritating, sternutatory; taste: bitter, nauseous, unpleasant
(1–4, 6, 9).
Microscopic characteristics
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
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WHO monographs on selected medicinal plants
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (1–6, 8, 9), microchemical
tests (1–3, 6, 8, 9), and thin-layer chromatography (4, 5).
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 (16).
Foreign organic matter
Not more than 2% (5, 9).
Total ash
Not more than 5% (2, 5, 6).
Acid-insoluble ash
Not more than 3% (2, 4, 5, 6).
207
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (5). For other pesticides, see the European pharmacopoeia (5),
and the WHO guidelines on quality control methods for medicinal plants
(16) and pesticide residues (17).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (16).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (16) for the analysis of radioactive isotopes.
Other purity tests
Chemical, sulfated ash, water-soluble extractive, alcohol-soluble extractive
and loss on drying tests to be established in accordance with national
requirements.
Chemical assays
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.
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
A syrup made from the roots is used as an emetic, to empty the stomach
in cases of poison ingestion (20).
Uses described in pharmacopoeias and well established documents
See Uses supported by clinical data (20).
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WHO monographs on selected medicinal plants
Uses described in traditional medicine
Treatment of parasites, the common cold and diarrhoea (13). Also to
stimulate uterine contractions and induce abortion (21).
Pharmacology
Experimental 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
N
H
OCH3
H3CO N
O
OCH3
CH3
H
H
R
psychotrine
O-methylpsychotrine
R = H
R = CH3
N
H
OCH3
H3CO HN
O
OCH3
CH3
H
H
R
H
cephaeline
emetine
R = H
R = CH3
N
HO
HO
O
CH3
O
O
O
CH3
H2C
O
Glc
H
H
H
H
ipecoside
O
OH
HO
HO
OH
Glc
=
β-D-glucopyranosyl
209
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).
Clinical pharmacology
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-
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WHO monographs on selected medicinal plants
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-
211
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
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WHO monographs on selected medicinal plants
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.
Adverse reactions
Large doses of Radix Ipecacuanhae have an irritant effect on the gastrointestinal
tract, and may induce persistent bloody vomiting or diarrhoea
213
(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).
Contraindications
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.
Radix Ipecacuanhae
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WHO monographs on selected medicinal plants
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).
Drug interactions
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).
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Paediatric use
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).
215
Other precautions
No information available on precautions concerning drug and laboratory
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,
protected from light (20).
Posology
(Unless otherwise indicated)
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
1. Egyptian pharmacopoeia, 3rd ed. Cairo, General Organization for Government
Printing, 1972.
2. Asian crude drugs, their preparations and specifi cations. Asian Pharmacopeia.
Manila, Federation of Asian Pharmaceutical Associations, 1978.
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
Organization, 1988.
5. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
6. The Japanese pharmacopoeia, 13th ed. (English version). Tokyo, Ministry of
Health and Welfare, Japan, 1996.
7. Pharmacopoeia of the Republic of Korea, 7th ed. Seoul, Taechan yakjon,
1998.
8. 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.
9. The United States pharmacopeia-national formulary, 19th ed. Rockville,
MD, United States Pharmacopeial Convention, 2000.
10. 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.
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11. 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.
12. Robbers JE, Speedie MK, Tyler VE. Pharmacognosy and pharmacobiotechnology.
Baltimore, MD, Williams and Wilkins, 1996.
13. 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
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14. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
15. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
16. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
17. 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).
18. American Academy of Clinical Toxicology. Position statement: ipecac syrup.
Clinical Toxicology, 1997, 35:699–709.
19. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier
Publishing, 1995.
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.
217
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.
40. Scharman EJ et al. Single dose pharmacokinetics of syrup of ipecac. Therapeutic
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.
44. Adler AG et al. Death resulting from ipecac syrup poisoning. Journal of the
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.
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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
Toxicology, 1997, 35:609–615.
52. Yamamoto H, Mizutani T, Nomura H. [Studies on the mutagenicity of crude
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Chiryo, 1999, 27:1055–1062 [in Japanese].
219
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).
Selected vernacular names
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).
Geographical distribution
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
220
WHO monographs on selected medicinal plants
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
General appearance
A clear colourless or pale yellow liquid, miscible with 90% alcohol, ether
and fatty oils (1–4).
Organoleptic properties
Odour: characteristic, fragrant, aromatic; taste: aromatic, slightly bitter
(1, 3).
Microscopic characteristics
Not applicable.
Powdered plant material
Not applicable.
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (16).
Chemical
Relative density 0.878–0.892 (4). Refractive index 1.455–1.466 (4). Optical
rotation -12.5–7o (4). Acid value not more than 1.0 (4).
221
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (17). For other pesticides, see the European pharmacopoeia
(17), and the WHO guidelines on quality control methods for medicinal
plants (16) and pesticide residues (18).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (16).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (16) for the analysis of radioactive isotopes.
Other purity tests
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.
Chemical assays
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).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
Inhalation therapy for symptomatic treatment of anxiety, restlessness and
to induce relaxation (19–22). Externally in balneotherapy for the treatment
of circulation disorders (23).
Aetheroleum Lavandulae
H3C
CH2
CH3 O CH3
R
and enantiomer
linalyl acetate
linalool R = H
R = CO-CH3
222
WHO monographs on selected medicinal plants
Uses described in pharmacopoeias and well established documents
Symptomatic treatment of insomnia, and as a carminative for the treatment
of gastrointestinal disorders of nervous origin (15, 24).
Uses described in traditional medicine
Orally as a cholagogue, diuretic and emmenagogue; externally for the
treatment of burns, diarrhoea, headaches, sore throats and wounds (15).
Pharmacology
Experimental 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 [3H]-glutamate binding and as a noncompetitive
antagonist of [3H]-dizocilpine binding in mouse cortical
membranes, suggesting interference of glutamatergic transmission. The
effects of linalool on [3H]-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.
Anti-infl ammatory activity
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
223
thromboxane B2 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).
Antispasmodic activity
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).
Clinical pharmacology
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
Aetheroleum Lavandulae
224
WHO monographs on selected medicinal plants
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).
Cardiovascular effects
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).
Adverse reactions
Allergic contact dermatitis has been reported in patients previously exposed
to the essential oil (45–49).
225
Contraindications
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
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
Owing to a lack of safety data, the essential oil should be administered
internally only under the supervision of a health-care provider.
Paediatric use
Owing to a lack of safety data, the essential oil should be administered
internally only under the supervision of a health-care provider.
Other precautions
No information available on general precautions or on precautions concerning
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,
protected from light (4).
Posology
(Unless otherwise indicated)
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).
Aetheroleum Lavandulae
226
WHO monographs on selected medicinal plants
References
1. Egyptian pharmacopoeia, 3rd ed. Cairo, General Organization for Government
Printing, 1972.
2. Ekstra Farmakope Indonesia. Jakarta, Departemen Kesehatan, Republik
Indonesia, 1974.
3. Asian crude drugs, their preparations and specifi cations. Asian pharmacopoeia.
Manila, Federation of Asian Pharmaceutical Associations, 1978.
4. European pharmacopoeia, 3rd ed. Suppl. 2001. Strasbourg, Council of
Europe, 2000.
5. Chiej R. Encyclopedia of medicinal plants, 2nd ed. Rome, MacDonald, 1984.
6. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African Unity,
Scientifi c Technical and Research Commission, 1985.
7. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,
1996.
8. Oyen LPA, Nguyen XD, eds. Plant resources of South-east Asia, No. 19.
Essential-oil plants. Bogor, PROSEA, 1999.
9. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 5,
Drogen E–O, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 5,
Drugs E–O, 5th ed.] Berlin, Springer, 1993.
10. Zahedi E. Botanical dictionary. Scientifi c names of plants in English, French,
German, Arabic and Persian languages. Tehran, Tehran University Publications,
1959.
11. Schlimmer JL. Terminologie médico-pharmaceutique et française-persane,
2nd ed. [French-Persian medico-pharmaceutical terminology, 2nd ed.]
Tehran, University of Tehran Publications, 1979.
12. Bellakhdar J et al. Repertory of standard herbal drugs in the Moroccan pharmacopoeia.
Journal of Ethnopharmacology, 1991, 35:123–143.
13. Central Council for Research in Unani Medicine. Standardization of single
drugs of Unani medicine – part III. New Delhi, Ministry of Health and Family
Welfare, 1992.
14. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
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).
15. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
16. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
17. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
18. 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).
227
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.
24. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
25. Ghelardini C et al. Local anaesthetic activity of the essential oil of Lavandula
angustifolia. Planta Medica, 1999, 65:700–703.
26. Elisabetsky E et al. Sedative properties of linalool. Fitoterapia, 1995, 15:407–
414.
27. Elisabetsky E, Silva Brum LF, Souza DO. Anticonvulsant properties of linalool
on glutamate-related seizure models. Phytomedicine, 1999, 6:107–113.
28. Silva Brum LF, Elisabetsky E, Souza D. Effects of linalool on [3H] MK801
and [3H] muscimol binding in mice cortical membranes. Phytotherapy Research,
2001, 15:422–425.
29. Silva Brum LF et al. Effects of linalool on glutamate release and uptake in
mouse cortical synaptosomes. Neurochemical Research, 2001, 26:191–194.
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.
33. 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.
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.
Aetheroleum Lavandulae
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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.
Contact Dermatitis, 1999, 41:111.
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.
229
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).
Selected vernacular names
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).
Geographical distribution
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
230
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
General appearance
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).
Organoleptic properties
Odour: fragrant, aromatic; taste: aromatic, bitter, somewhat camphoraceous
(1, 2).
Microscopic characteristics
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).
Powdered plant material
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
WHO monographs on selected medicinal plants
231
radiating 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).
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (13).
Foreign organic matter
Not more than 2.0% (3).
Total ash
Not more than 9.0% (3).
Acid-insoluble ash
Not more than 1.0% (2).
Water-soluble extractive
Not less than 18.0% (2).
Alcohol-soluble extractive
Not less than 12.0% (2).
Moisture
Not more than 10.0% (3).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (14). For other pesticides, see the European pharmacopoeia
(14), and the WHO guidelines on quality control methods for medicinal
plants (13) and pesticide residues (15).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (13).
Flos Lavandulae
232
WHO monographs on selected medicinal plants
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants for the analysis of radioactive isotopes (13).
Other purity tests
Chemical tests to be established in accordance with national requirements.
Chemical assays
Contains not less than 1.3% (v/w) essential oil determined by steam distillation
(3).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
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).
Uses described in traditional medicine
As a diuretic and an emmenagogue, and for the treatment of burns, diarrhoea,
headaches, sore throats and wounds (10).
Pharmacology
Experimental pharmacology
Antimicrobial activity
Aqueous, chloroform, hexane and methanol extracts of Flos Lavandulae,
60.0 μg/ml, inhibited the growth of Streptococcus pneumoniae in vitro
H3C
CH2
CH3 O CH3
R
and enantiomer
linalyl acetate
linalool R = H
R = CO-CH3
233
(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).
Antioxidant activity
A 50% ethanol extract of the fl owers had antioxidant activity in vitro,
median effective dose 45.0 mg/ml (19).
Antiulcer activity
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 [3H]-glutamate binding and as a non-competitive antagonist
of [3H]-dizocilpine binding in mouse cortical membranes, suggesting interference
of glutamatergic transmission. The effects of linalool on [3H]-
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.
Adverse reactions
No information available.
Contraindications
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
No information available.
Flos Lavandulae
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WHO monographs on selected medicinal plants
Precautions
Pregnancy: non-teratogenic effects
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
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
(Unless otherwise indicated)
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
1. African pharmacopoeia. Vol. 1. Lagos, Nigeria, Organization of African Unity,
Scientifi c, Technical and Research Commission, 1985.
2. Central Council for Research in Unani Medicine. Standardization of single
drugs of Unani medicine – part III. New Delhi, Ministry of Health and Family
Welfare, 1992.
3. European pharmacopoeia, 3rd ed. Suppl. 2001. Strasbourg, Council of
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.
6. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 5,
Drogen E–O, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 5,
Drugs E–O, 5th ed.] Berlin, Springer, 1993.
7. Zahedi E. Botanical dictionary. Scientifi c names of plants in English, French,
German, Arabic and Persian languages. Tehran, Tehran University Publications,
1959.
8. Schlimmer JL. Terminologie médico-pharmaceutique et française-persane,
2nd ed. [French-Persian medico-pharmaceutical terminology.] Tehran, University
of Tehran Publications, 1979.
9. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
Illinois at Chicago, 10 January 2001 production (an online database available
235
directly through the University of Illinois at Chicago or through the Scientifi
c and Technical Network (STN) of Chemical Abstracts Services).
10. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
11. British herbal pharmacopoeia, 2nd ed. Part 2. Cowling, British Herbal Medicine
Association, 1979.
12. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas,
2nd ed. Berlin, Springer, 1996.
13. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
14. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
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).
16. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
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.
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.
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.
23. Elisabetsky E, Silva Brum LF, Souza DO. Anticonvulsant properties of linalool
on glutamate-related seizure models. Phytomedicine, 1999, 6:107–113.
24. Silva Brum LF, Elisabetsky E, Souza D. Effects of linalool on [3H] MK801
and [3H] muscimol binding in mouse cortical membranes. Phytotherapy Research,
2001, 15:422–425.
25. Silva Brum LF et al. Effects of linalool on glutamate release and uptake in
mouse cortical synaptosomes. Neurochemical Research, 2001, 26:191–194.
26. San Martin AJ. Medicinal plants in central Chile. Economic Botany, 1983,
37:216–227.
Flos Lavandulae
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).
Selected vernacular names
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).
Geographical distribution
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
237
yellowish-green to pale brown, ovate, membranous, scaly bracts, each enclosing
a brown glandular achene (7).
Plant material of interest: dried strobiles
General appearance
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).
Organoleptic properties
Odour: strong, characteristically aromatic, becoming valerian-like on
ageing; taste: aromatic, bitter (7).
Microscopic characteristics
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).
Powdered plant material
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).
Strobilus Lupuli
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WHO monographs on selected medicinal plants
General identity tests
Macroscopic and microscopic examinations (1, 7), and thin-layer chromatography
(1, 2).
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 (8).
Foreign organic matter
Not more than 2% (1, 2).
Total ash
Not more than 12% (2).
Acid-insoluble ash
Not more than 5% (1).
Water-soluble extractive
Not less than 10% (2).
Alcohol-soluble extractive
Not less than 25% in 70% (v/v) ethanol (2).
Loss on drying
Not more than 10% (2).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (9). For other pesticides, see the European pharmacopoeia (9),
and the WHO guidelines on quality control methods for medicinal plants
(8) and pesticide residues (10).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (8).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (8) for the analysis of radioactive isotopes.
239
Other purity tests
Chemical and sulfated ash tests to be established in accordance with national
requirements.
Chemical assays
High-performance liquid chromatography for bitter substances and
xanthohumol (3).
Major chemical constituents
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 β-
myrcene (3, 5, 6, 11, 12). The essential oil also contains traces of 2-
methylbut-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.
Medicinal uses
Uses supported by clinical data
None.
Strobilus Lupuli
humulone
H3C CH3
O OH
CH3 OH CH3
HO
CH3
H3C
O
lupulone
H3C CH3
HO O
CH3 OH CH3
CH3
H3C
H3C
CH3
O
xanthohumol
CH3
H3CO OH
O OH CH3
HO
humulene
CH3
H3C
CH3
CH3
H2C
CH3
H3C OH
2-methylbut-3-en-2-ol
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WHO monographs on selected medicinal plants
Uses described in pharmacopoeias and well established documents
As a sedative for the treatment of nervous tension and insomnia. Treatment
of dyspepsia and lack of appetite (5, 15–17).
Uses described in traditional medicine
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
Experimental pharmacology
Antimicrobial activity
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).
241
Antioxidant activity
A methanol extract of the strobiles had antioxidant and radical scavenging
activities in vitro (24, 25).
Central nervous system depressant activity
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).
Estrogenic activity
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
Strobilus Lupuli
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WHO monographs on selected medicinal plants
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 (LD50) 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 LD50 in rats was 2700.0 mg/kg bw (29). The oral LD50
for lupulone was 525.0 mg/kg bw in mice and 1800.0 mg/kg bw in rats
(3). The intraperitoneal LD50 of an ethanol extract of the strobiles in mice
was 175.0 mg/kg bw (17).
Clinical pharmacology
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).
Adverse reactions
Strobilus Lupuli may cause drowsiness (31).
243
Contraindications
Strobilus Lupuli is contraindicated in cases of known allergy to the plant
material.
Warnings
No information available.
Precautions
Drug interactions
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.
Carcinogenesis, mutagenesis, impairment of fertility
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).
Other precautions
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
(Unless otherwise indicated)
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).
Strobilus Lupuli
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WHO monographs on selected medicinal plants
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of hops. American Perfumer and Aromatics, 1960, 75:61–62.
36. Strenicovskaya AG. [Use of the hormonal properties of the carbon dioxide
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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
Chemical Toxicology, 1999, 37:271–285.
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.
247
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).
Selected vernacular names
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).
Geographical distribution
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
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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
General appearance
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).
Organoleptic properties
Odour: characteristic, aromatic, balsamic; taste: aromatic, bitter, acrid
(1–3, 7, 10).
Microscopic characteristics
Not applicable.
Powdered plant material
Not applicable.
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (14).
Total ash
Not more than 10.0% (1). Not more than 7.0 % (4).
Acid-insoluble ash
Not more than 5.0% (1).
Water-soluble extractive
Not less than 48% (2).
Alcohol-insoluble residue
Not more than 70.0% (1, 4).
249
Moisture
Not more than 15.0% (4).
Pesticide residues
The recommended maximum limit for aldrin and dieldrin is not more
than 0.05 mg/kg (15). For other pesticides, see the European pharmacopoeia
(15), and the WHO guidelines on quality control methods for medicinal
plants (14) and pesticide residues (16).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (14).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants for the analysis of radioactive isotopes (14).
Other purity tests
Chemical and foreign organic matter tests to be established in accordance
with national requirements.
Chemical assays
Not less than 6% essential oil (3). Qualitative and quantitative highperformance
liquid chromatography for furanosesquiterpenes (17).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
None.
Uses described in pharmacopoeias and well established documents
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).
Gummi Myrrha
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Uses described in traditional medicine
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
Experimental pharmacology
Analgesic and antipyretic activities
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).
Anticoagulant activity
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).
H2C
H2C
O
X CH3
CH3
H
CH3
and enantiomer
curzerenone
curzerene
X = O
X = H2
furanoeudesma-1,3-diene
O
CH CH3 3
CH3
H
O
CH3
CH CH3 3
H3CO
H
2-methoxyfuranodiene
O
CH3
CH3 H CH3
O
4,5-dihydrofuranodien-6-one
and enantiomer
O
CH3
H3C
CH3
furanodiene
251
Antihyperglycaemic activity
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).
Anti-infl ammatory activity
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).
Gummi Myrrha
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WHO monographs on selected medicinal plants
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).
Clinical pharmacology
No information available.
Adverse reactions
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).
Contraindications
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
Drug interactions
Although no drug interactions have been reported, internal ingestion of
Gummi Myrrha may interfere with existing antidiabetic therapy owing to
253
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.
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
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.
Paediatric use
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
health-care practitioner.
Other precautions
No information available on general precautions or on precautions concerning
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.
Gummi Myrrha
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WHO monographs on selected medicinal plants
Posology
(Unless otherwise indicated)
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
1. African pharmacopoeia. Vol. 1. Lagos, Organization of African Unity, Scientifi
c, Technical and Research Commission, 1985.
2. Central Council for Research in Unani Medicine. Standardization of single
drugs of Unani medicine – part II. New Delhi, Ministry of Health and Family
Welfare, 1992.
3. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,
1996.
4. European pharmacopoeia, Suppl. 2001, 3rd ed. Strasbourg, Council of
Europe, 2000.
5. Halmai J, Novak I. Farmakognózia. [Pharmacognosy.] Budapest, Medicina
Könyvkiadó, 1963.
6. 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.
7. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
8. 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.
9. Iwu MM. Handbook of African medicinal plants. Boca Raton, FL, CRC
Press, 1993.
10. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
11. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
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).
12. Namba T. The encyclopedia of Wakan-Yaku (traditional Sino-Japanese medicine).
Tokyo, Hoikusha Publishing, 1980.
13. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas,
2nd ed. Berlin, Springer, 1996.
255
14. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
15. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
16. 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. 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
health-care professionals. London, The Pharmaceutical Press, 1996.
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.
20. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
21. Bradley PR, ed. British herbal compendium. Vol. 1. Bournemouth, British
Herbal Medicine Association, 1992.
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.
28. 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 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-
Gummi Myrrha
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WHO monographs on selected medicinal plants
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.
Contact Dermatitis, 1993, 29:279.
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.
44. Yin XJ et al. A study on the mutagenicity of 102 raw pharmaceuticals used in
Chinese traditional medicine. Mutation Research, 1991, 260:73–82.
45. 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].
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.
257
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).
Selected vernacular names
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).
Geographical distribution
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
General appearance
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
258
WHO monographs on selected medicinal plants
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).
Organoleptic properties
No distinctive odour; taste: bitter (2).
Microscopic characteristics
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).
259
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (2, 3), and thin-layer chromatography
for the presence of fl avonoids (2, 3, 9).
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 (10).
Chemical
Contains not more than 0.01% harman alkaloids (11).
Foreign organic matter
Not more than 2% (3).
Total ash
Not more than 13% (3).
Acid-insoluble ash
Not more than 3.0% (2).
Water-soluble extractive
Not less than 15% (2).
Loss on drying
Not more than 10% (3).
Pesticide residues
The recommended maximum limit for aldrin and dieldrin is not more than
0.05 mg/kg (12). For other pesticides, see the European pharmacopoeia
Herba Passifl orae
260
WHO monographs on selected medicinal plants
(12), and the WHO guidelines on quality control methods for medicinal
plants (10) and pesticide residues (13).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (10).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (10) for the analysis of radioactive isotopes.
Other purity tests
Sulfated ash and alcohol-soluble extractive tests to be established in accordance
with national requirements.
Chemical assays
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).
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
None.
261
Uses described in pharmacopoeias and well established documents
Internally as a mild sedative for nervous restlessness, insomnia and anxiety.
Treatment of gastrointestinal disorders of nervous origin (1, 5, 11).
Uses described in traditional medicine
As an anodyne, antispasmodic and mild stimulant (1, 6). Treatment of
dysmenorrhoea, neuralgia and nervous tachycardia (1).
Pharmacology
Experimental pharmacology
Analgesic and antipyretic activities
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).
Anti-infl ammatory activity
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).
Herba Passifl orae
O
O H O
O
R 8
R 6
O H
R2 O
O H
HO
HO
O H
β-D-glucopyranosyl
O
OH
O H
α-L-arabinopyranosyl
HO
G lc
Ara =
=
harman maltol
HN
N
CH3
O
O
CH3
O H
lucenin-2
orientin
iso-orientin
isovitexin
vitexin
isoschaftoside
schaftoside
vicenin-2
G lc
Ara
O H
O H
O H
H
H
H
H
H
G lc
H
H
G lc Glc
Ara
G lc
G lc
G lc Glc
G lc
G lc
H
H
R 2 R6 R 8
262
WHO monographs on selected medicinal plants
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).
Antimicrobial activity
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).
Cardiovascular effects
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).
Central nervous system depressant activity
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
263
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).
Uterine stimulant effects
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).
Clinical pharmacology
No clinical data available for mono-preparations of Herba Passifl orae.
Adverse reactions
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-
Herba Passifl orae
264
WHO monographs on selected medicinal plants
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.
Contraindications
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
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
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
health-care practitioner.
Paediatric use
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.
Other precautions
265
No information available on general precautions or on precautions concerning
drug interactions; drug and laboratory test interactions; or teratogenic
effects in pregnancy.
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
(Unless otherwise indicated)
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
1. Bradley PR, ed. British herbal compendium. Vol. 1. Bournemouth, British
Herbal Medicine Association, 1992.
2. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,
1996.
3. European pharmacopoeia, 3rd ed. Suppl. 2001. Strasbourg, Council of Europe,
2000.
4. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 6,
Drogen P–Z, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 6,
Drugs P–Z, 5th ed.] Berlin, Springer, 1994.
5. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
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. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA, Blakiston,
1950.
8. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris,
Lavoisier Publishing, 1995.
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.
10. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
Herba Passifl orae
266
WHO monographs on selected medicinal plants
11. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
12. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
13. 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).
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.
18. Leslie GB. A pharmacometric evaluation of nine Bio-Strath herbal remedies.
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.
21. 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.
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.
267
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.
Herba Passifl orae
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).
Selected vernacular names
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).
Geographical distribution
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).
269
Plant material of interest: dried seed coats (epidermis)
General appearance
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).
Organoleptic properties
Odour: weak, characteristic; taste: mucilaginous (9).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
Macroscopic and microscopic examinations (2) and thin-layer chromatography
for the presence of arabinose, xylose and galactose (2).
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 (10).
Foreign organic matter
Complies with the test for foreign matter determined on 5.0 g of material
(2).
Testa Plantaginis
270
WHO monographs on selected medicinal plants
Total ash
Not more than 4% (2).
Loss on drying
Not more than 12% (2).
Swelling index
Not less than 40 (2).
Pesticide residues
The recommended maximum limit for aldrin and dieldrin is not more
than 0.05 mg/kg (11). For other pesticides, see the European pharmacopoeia
(11), and the WHO guidelines on quality control methods for medicinal
plants (10) and pesticide residues (12).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (10).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (10) for the analysis of radioactive isotopes.
Other purity tests
Chemical, sulfated ash, acid-insoluble ash, water-soluble extractive and
alcohol-soluble extractive tests to be established in accordance with national
requirements.
Chemical assays
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).
Major chemical constituents
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).
271
Medicinal uses
Uses supported by clinical data
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).
Uses described in pharmacopoeias and well established documents
Short-term use for the symptomatic treatment of diarrhoea of various
etiologies (29–31).
Uses described in traditional medicine
As an expectorant, antitussive and diuretic. Treatment of rheumatism,
gout, glandular swelling and bronchitis (5, 8).
Pharmacology
Experimental 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).
Antihypercholesterolaemic activity
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-
Testa Plantaginis
272
WHO monographs on selected medicinal plants
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).
Antihyperglycaemic activity
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).
Gastrointestinal effects
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,
273
a 70% methanol extract of the seed coats, 6.0 mg/ml, stimulated contractions
of isolated guinea-pig ileum (48).
Clinical pharmacology
Antidiarrhoeal activity
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).
Antihypercholesterolaemic activity
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-
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WHO monographs on selected medicinal plants
cebo. No effects on serum HDL or triacylglycerol concentrations were
observed (26).
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).
275
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
Testa Plantaginis
276
WHO monographs on selected medicinal plants
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).
Adverse reactions
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).
277
Contraindications
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.
Testa Plantaginis
278
WHO monographs on selected medicinal plants
Drug interactions
Bulking agents may diminish the absorption of some minerals (calcium,
magnesium, copper and zinc), vitamins (B12), 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).
Other precautions
No information available on precautions concerning drug and laboratory
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
No information available.
References
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15. Marteau P et al. Digestibility and bulking effect of ispaghula husks in healthy
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23. Olson BH et al. Psyllium-enriched cereals lower blood total cholesterol and
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24. Anderson JW et al. Effects of psyllium on glucose and serum lipid responses
in men with type 2 diabetes and hypercholesterolemia. American Journal of
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25. Anderson JW et al. Long-term cholesterol-lowering effects of psyllium as an
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26. Anderson JW et al. Cholesterol-lowering effects of psyllium intake adjunctive
to diet therapy in men and women with hypercholesterolemia: metaanalysis
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283
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).
Selected vernacular names
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).
Geographical distribution
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.
284
WHO monographs on selected medicinal plants
base of corolla, anthers not coherent, disc ring-like, poorly developed;
ovary superior, stigma two-lobed. Fruits are capsules (6, 8).
Plant material of interest: dried roots and rhizomes
General appearance
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).
Organoleptic properties
Odour: characteristic; taste: slightly sweet, followed by a slight bitterness
(1, 2, 4).
Microscopic characteristics
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).
Powdered plant material
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).
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (10).
285
Total ash
Not more than 6% (1, 2, 4).
Acid-insoluble ash
Not more than 2.5% (1, 2).
Water-soluble extractive
Not less than 65% (3, 4).
Pesticide residues
The recommended maximum limit for aldrin and dieldrin is not more
than 0.05 mg/kg (11). For other pesticides, see the European pharmacopoeia
(11), and the WHO guidelines on quality control methods for medicinal
plants (10) and pesticide residues (12).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (10).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (10) for the analysis of radioactive isotopes.
Other purity tests
Chemical, foreign organic matter, sulfated ash, alcohol-soluble extractive
and loss on drying tests to be established in accordance with national requirements.
Chemical assays
To be established in accordance with national requirements.
Major chemical constituents
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.
Radix Rehmanniae
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Medicinal uses
Uses supported by clinical data
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.
Uses described in pharmacopoeias and well established documents
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).
Uses described in traditional medicine
As an antispasmodic, diuretic and emmenagogue. Treatment of burns,
diarrhoea, dysentery, metrorrhagia and impotence (7, 20, 22, 23).
aucubin
monomelittoside
O
H
O
Glc
R
H
HO
HO
H
rehmannioside C
O
H
O
Glc
HO H
H
CH3
O R ajugol
H
R = H
R = Gal
R = H
R = OH
O
H
O
Glc
H
HO
HO
H
melittoside
rehmannioside D
O
OH
HO
HO
O
O
R
R = H
R = Glc
catalpol
rehmannioside A
rehmannioside B
O
H
H
O
H
HO
O
H
R2
H
O
OH
O
HO
OH
O
R1
R1 R2
H H
Gal
Gal
H
H
β-D-galactopyranosyl β-D-glucopyranosyl
O
OH
HO
OH
HO O
OH
HO
HO
OH
Gal = Glc =
287
Pharmacology
Experimental 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).
Antidiarrhoeal activity
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).
Antihepatotoxic activity
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).
Antihyperglycaemic activity
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).
Anti-infl ammatory activity
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).
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WHO monographs on selected medicinal plants
Antitumour activity
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).
Antiulcer activity
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
Intragastric administration of 2.5 g/kg bw of an aqueous extract of the
roots prolonged pentobarbital-induced sleeping time in mice with stressor
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-
289
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).
Immunological effects
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).
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Platelet aggregation inhibition
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).
Clinical pharmacology
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).
Adverse reactions
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).
Contraindications
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
No information available.
291
Precautions
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: teratogenic effects
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).
Pregnancy: non-teratogenic effects
See Contraindications.
Nursing mothers
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.
Paediatric use
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.
Other precautions
No information available on general precautions or on precautions concerning
drug interactions; or drug and laboratory test interactions.
Dosage forms
Dried roots and rhizomes for infusions and decoctions. Store in a wellclosed
container in a cool, dry place, protected from light (4).
Radix Rehmanniae
292
WHO monographs on selected medicinal plants
Posology
(Unless otherwise indicated)
Daily dose: 9–15 g of dried roots and rhizomes as an infusion or decoction
(4).
References
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11. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
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14. Shoyama Y, Matsumoto M, Nishioka I. Phenolic glycosides from diseased
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15. Sasaki H et al. Hydroxycinnamic acid esters of phenethylalcohol glycosides
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16. Chen LZ et al. [Immuno-tumoricidal effect of Rehmannia glutinosa polysaccharide
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17. Tomoda M et al. Characterization of two polysaccharides having activity on
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19. Chang HM, But PPH, eds. Pharmacology and applications of Chinese materia
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Ethno pharmacology, 1987, 19:103–110.
21. Kim HM et al. Effect of Rehmannia glutinosa on immediate type allergic
reaction. International Journal of Immunopharmacology, 1998, 20:231–240.
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pharmacopée. Agence de coopération culturelle et technique, 1990.
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roots. Phytochemistry, 1993, 33:233–234.
24. Gaw HZ, Wang HP. Survey of Chinese drugs for presence of antibacterial
substances. Science, 1949, 110:11–12.
25. Yoo JS et al. [Inhibitory effects of extracts from traditional herbal drugs on
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34. Kiho T et al. [Hypoglycemic activity of polysaccharide fraction from rhizome
of Rehmannia glutinosa Libosch. F. hueichingensis Hsiao and the effect
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112:393–400 [in Japanese].
35. Kubo M et al. Studies on Rehmanniae Radix. I. Effect of 50% ethanolic extract
from steamed and dried Rehmanniae Radix on hemorheology in arthritic
and thrombotic rats. Biological and Pharmaceutical Bulletin, 1994,
17:1282–1286.
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47. Matsuda H et al. [Studies on Rehmanniae radix II. Effects of a 50% ethanol
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Wakan Iyakugaku Zasshi, 1995, 12:250–256 [in Japanese].
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49. Chen LZ, Feng XW, Zhou JH. [Effects of Rehmannia glutinosa polysaccharide
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Radix Rehmanniae
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).
Selected vernacular names
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).
Geographical distribution
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.
297
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).
Plant material of interest: dried ripe fruits
General appearance
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).
Organoleptic properties
Odour of pulp: slight; odour of seed: aromatic on crushing; taste of pulp:
sour; taste of seed: pungent and slightly bitter (1, 3).
Microscopic characteristics
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).
Powdered plant material
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).
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WHO monographs on selected medicinal plants
General identity tests
Macroscopic and microscopic examinations (1–3), and thin-layer chromatography
for the presence of deoxyschizandrin (schisandrin A) (2, 3, 7).
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 (11).
Foreign organic matter
Not more than 1.0% (1, 3).
Total ash
Not more than 5.0% (1, 2).
Acid-insoluble ash
Not more than 1.0% (2).
Water-soluble extractive
Not less than 35% (2).
Alcohol-soluble extractive
Not less than 40% (2).
Moisture
Not more than 8.0% (2).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (12). For other pesticides, see the European pharmacopoeia
(12) and the WHO guidelines on quality control methods for medicinal
plants (11) and pesticide residues (13).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (11).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (11) for the analysis of radioactive isotopes.
Other purity tests
Chemical tests to be determined in accordance with national requirements.
299
Chemical assays
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).
Major chemical constituents
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:
Medicinal uses
Uses supported by clinical data
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.
Uses described in pharmacopoeias and well established documents
Treatment of chronic cough and asthma, diabetes, urinary tract disorders.
As a general tonic for treating fatigue associated with illness (3, 7, 9, 16).
Uses described in traditional medicine
As an astringent, antitussive, antidiarrhoeal, expectorant and sedative (8).
Fructus Schisandrae
H3CO
H3CO
H3CO
H3CO
O
O
H
CH3
H
CH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R
CH3
H
CH3
H3CO
H3CO
H3CO
H3CO
R
CH3
H
CH3
O
O
gomisin N
schisandrin A
schisandrol A
schisandrin B
schisandrol B
R = H
R = OH
R = H
R = OH
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WHO monographs on selected medicinal plants
Pharmacology
Experimental pharmacology
Anti-infl ammatory activity
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
(ED50) 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-
301
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-
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WHO monographs on selected medicinal plants
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).
Antioxidant activity
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).
303
Antitumour activity
The effect of gomisin A on hepatocarcinogenesis induced by 3'-methyl-4-
dimethylaminoazobenzene (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).
Central nervous system effects
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,
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WHO monographs on selected medicinal plants
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).
305
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
(LD50) 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 LD50 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 LD50
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).
Clinical pharmacology
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).
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WHO monographs on selected medicinal plants
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
307
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).
Adverse reactions
Minor adverse effects such as heartburn, acid indigestion, stomach pain,
anorexia, allergic skin reactions and urticaria have been reported (66).
Contraindications
No information available.
Warnings
Symptoms of overdose include restlessness, insomnia or dyspnoea (67).
Precautions
Drug interactions
The fruits may have depressant effects on the central nervous system and
should not therefore be used in conjunction with other CNS depressants,
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WHO monographs on selected medicinal plants
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).
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: non-teratogenic effects
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).
309
Nursing mothers
Owing to a lack of safety data, the use of Fructus Schisandrae during
nursing is not recommended.
Other precautions
No information available on general precautions or on precautions concerning
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
(Unless otherwise indicated)
Average daily dose: 1.5–6.0 g of the dried fruits (3).
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24. Chen YY, Shu ZB, Lin LN. Studies on Fructus Schisandrae. IV. Isolation and
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29. Hirotani Y et al. Effects of gomisin A on rat liver regeneration after partial
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30. Hikino H et al. Antihepatotoxic action of lignoids from Schizandra chinensis
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31. Ohkura Y et al. Effect of gomisin A (TJN-101) on the arachidonic acid cascade
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32. Lu H, Liu GT. Effect of dibenzo[a,c]cyclooctene lignans isolated from Fructus
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34. Ip SP et al. Schisandrin B protects against carbon tetrachloride toxicity by
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4-dimethylaminobenzene in rats. Japanese Journal of Pharmacology, 1991,
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Fructus Schisandrae
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.
Selected vernacular names
Baical skullcap, huang chin, huang lien, huang qin, huangqin, hwanggum,
hwang-keum, Koganebana, skull cap, senohgon, whang-geum, whangegum,
wogon (3, 6, 7).
Geographical distribution
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
General appearance
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,
315
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).
Organoleptic properties
Odour, slight; taste, slightly bitter (1–4).
Microscopic characteristics
To be established according to national requirements. For guideline to
microscopic characteristics, see Powdered plant material.
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).
General identity tests
Macroscopic and microscopic examinations (1–4), microchemical tests (1,
4) and high-performance liquid chromatography for the presence of baicalin
(2, 4).
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 (10).
Total ash
Not more than 6% (1–4).
Acid-insoluble ash
Not more than 1% (3).
Water-soluble extractive
Not less than 40% (3).
Alcohol-soluble extractive
Not less than 15% (3).
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Loss on drying
Not more than 12% (2).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (11). For other pesticides, see the European pharmacopoeia
(11) and the WHO guidelines on quality control methods for medicinal
plants (10) and pesticide residues (12).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (10).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (10) 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 9.0% of baicalin determined by high-performance
liquid chromatography (4). Other high-performance liquid chromatography
methods are available (2, 13).
Major chemical constituents
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.
baicalin
baicalein
wogonin
O
OH O
O
R6
R8
R7
R6 R7 R8
OH H H
OH GlcA H
H H OCH3
O
OH
CO2H
HO
OH
β-D-glucopyranuronosyl GlcA =
317
Medicinal uses
Uses supported by clinical data
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.
Uses described in pharmacopoeias and well established documents
Treatment of fever, nausea and vomiting, acute dysentery, jaundice,
coughs, carbuncles and sores, and threatened abortion (3, 4).
Uses described in traditional medicine
Treatment of allergies, arteriosclerosis, diarrhoea, dermatitis and hypertension
(7).
Pharmacology
Experimental pharmacology
Antihepatotoxic activity
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).
Anti-infl ammatory activity
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 (ED50) 120.6 mg/kg bw, intragastric route) was superior to
that in carrageenan-induced footpad oedema (ED50 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 (IC50) 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
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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).
Antioxidant activity
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).
Antimicrobial activity
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-
319
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).
Antitumour activity
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, IC50 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 (IC50 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
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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).
Immunological effects
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,
IC50 20.0 μg/ml (50).
Platelet aggregation inhibition
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
321
inhibited production of plasminogen activator inhibitor-1 in cultured human
umbilical vein endothelial cells induced by treatment with thrombin
and thrombin receptor agonist peptide, IC50 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 (LD50) 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 LD50 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 LD50 of
baicalin in mice was 3.1 g/kg bw (17).
Clinical pharmacology
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
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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).
Adverse reactions
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.
Contraindications
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
No information available.
Precautions
Carcinogenesis, mutagenesis, impairment of fertility
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/
323
kg bw of the aqueous extract to mice, equal to 10–40 times the amount
used in humans, was mutagenic (59).
Pregnancy: teratogenic effects
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).
Pregnancy: non-teratogenic effects
Intragastric administration of 24.98 g/kg bw of an aqueous extract of the
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).
Nursing mothers
See Contraindications.
Paediatric use
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
drug interactions; or drug and laboratory test interactions.
Dosage forms
Dried roots, extracts, infusions and decoctions. Store in a well closed container
in a cool, dry place, protected from moisture (4).
Posology
(Unless otherwise indicated)
Daily dose: 3–9 g of dried roots as an infusion or decoction (4).
References
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3. Pharmacopoeia of the Republic of Korea, 7th ed. Seoul, Taechan yakjon,
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Radix Scutellariae
324
WHO monographs on selected medicinal plants
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baikal’skogo sukhoi v kachestve gemostimuliatora v usloviakh protivoopukholevoi
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plants used in dermatological disorders. Fitoterapia, 2001, 72:221–229.
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from Scutellaria baicalensis Georgy roots. Agents and Actions, 1993, 39:C49–
C51.
25. Chung CP, Park JB, Bae KH. Pharmacological effects of methanolic extract
from the root of Scutellaria baicalensis and its fl avonoids on human gingival
fi broblasts. Planta Medica, 1995, 61:150–153.
26. Kimura Y et al. Effects of fl avonoids isolated from scutellariae radix on the
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extracted from the radix of Scutellaria baicalensis Georgi. Biochimica et Biophysica
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29. Shao ZH et al. Extract from Scutellaria baicalensis Georgi attenuates oxidant
stress in cardiomyocytes. Journal of Molecular and Cell Cardiology, 1999,
31:1885–1895.
30. Lim BO et al. The antioxidant effect of ganhuangenin against lipid peroxidation.
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31. Wakabayashi I. Inhibitory effects of baicalein and wogonin on lipopolysaccharide-
induced nitric oxide production in macrophages. Pharmacology
and Toxicology, 1999, 84:288–291.
32. Lam TL et al. A comparison of human immunodefi ciency virus type-1 protease
inhibition activities by the aqueous and methanol extracts of Chinese
medicinal herbs. Life Sciences, 2000, 67:2889–2896.
33. Zhou LG et al. [Antifungal activities in vitro of fl avonoids and steroids from
medicinal plants.] Natural Product Research and Development, 1998, 9:24–
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Radix Scutellariae
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34. Franzblau SG, Cross C. Comparative in vitro antimicrobial activity of Chinese
medicinal herbs. Journal of Ethnopharmacology, 1986, 15:279–288.
35. Tsao TF et al. Effect of Chinese and Western antimicrobial agents on selected
oral bacteria. Journal of Dental Research, 1982, 61:1103–1106.
36. Chan FL et al. Induction of apoptosis in prostate cancer cell lines by a fl avonoid,
baicalin. Cancer Letters, 2000, 160:219–228.
37. So FV et al. Inhibition of proliferation of estrogen receptor-positive MCF-7
human breast cancer cells by fl avonoids in the presence and absence of excess
estrogen. Cancer Letters, 1997, 112:127–133.
38. Ng TB et al. Anti-human immunodefi ciency virus (anti-HIV) natural products
with special emphasis on HIV reverse transcriptase inhibitors. Life
Sciences, 1997, 61:933–949.
39. Nagai T et al. [Inhibition of infl uenza virus sialidase and anti-infl uenza virus
activity by plant fl avonoids.] Chemical and Pharmaceutical Bulletin (Tokyo),
1990, 38:1329–1332 [in Japanese].
40. Nagai T et al. In vivo anti-infl uenza virus activity of plant fl avonoids possessing
inhibitory activity for infl uenza virus sialidase. Antiviral Research,
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41. Nagai T et al. [Antiviral activity of plant fl avonoid, 5,7,4’-trihydroxy-8-methoxyfl
avone, from the roots of Scutellaria baicalensis against infl uenza A
(H3N2) and B viruses.] Biological and Pharmaceutical Bulletin (Tokyo),
1995, 18:295–299 [in Japanese].
42. Nagai T et al. Mode of action of the anti-infl uenza virus activity of plant
fl avonoid, 5,7,4’-trihydroxy-8-methoxyfl avone, from the roots of Scutellaria
baicalensis. Antiviral Research, 1995, 26:11–25.
43. Baylor NW et al. Inhibition of human T cell leukemia virus by the plant fl avonoid
baicalein (7-glucuronic acid, 5,6-dihydroxyfl avone). Journal of Infectious
Diseases, 1992, 165:433–437.
44. Li BQ et al. Flavonoid baicalin inhibits HIV-1 infection at the level of viral
entry. Biochemical and Biophysical Research Communications, 2000, 276:534–
538.
45. Hui KM, Wang XH, Xue H. Interaction of fl avones from the roots of Scutellaria
baicalensis with the benzodiazepine site. Planta Medica, 2000, 66:91–
93.
46. Liao JF et al. Benzodiazepine binding site-interactive fl avones from Scutellaria
baicalensis root. Planta Medica, 1998, 64:571–572.
47. Lin MT et al. Effects of Chinese herb huang chin (Scutellaria baicalensis) on
thermo regulation in rats. Japanese Journal of Pharmacology, 1980, 30:59–64.
48. Liu CS et al. [Inhibitory effect of four agents on bovine testis aldose reductase.]
Acta Academiae Medicinae Shanghai, 1997, 24:433–435 [in Chinese].
49. Kim HM et al. The nitric oxide-producing activities of Scutellaria baicalensis.
Toxicology, 1999, 135:109–115.
50. Fukuda K. Modulation of nitric oxide production by crude drugs and Kampo
medicines. Journal of Traditional Medicines. 1998, 15:22–32.
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51. Son KH et al. [Screening of platelet activating factor (PAF) antagonists from
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Korean].
52. 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.
53. Yun-Choi HS et al. Platelet anti-aggregating plant materials. Korean Journal
of Pharmacognosy, 1986, 17:161–167.
54. Kimura Y, Matsushita N, Okuda H. Effects of baicalein isolated from Scutellaria
baicalensis on interleukin 1β- and tumour necrosis factor α-induced
adhesion molecule expression in cultured human umbilical vein endothelial
cells. Journal of Ethnopharmacology, 1997, 57:63–67.
55. Chen ZY et al. Endothelium-dependent contraction and direct relaxation induced
by baicalein in rat mesenteric artery. European Journal of Pharmacology,
1999, 374:41–47.
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Pharmacognosy, 1982, 13:116–121 [in Korean].
57. Parker S. Herbal medicines, adverse reactions. The Regulatory Affairs Journal,
1994, 5:29.
58. Kim SH et al. Teratogenicity study of Scutellariae radix in rats. Reproductive
Toxicology, 1993, 7:73–79.
59. Yin XJ et al. A study on the mutagenicity of 102 raw pharmaceuticals used in
Chinese traditional medicine. Mutation Research, 1991, 260:73–82.
60. Morimoto I et al. Mutagenicity screening of crude drugs with Bacillus subtilis
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61. Woo WS, Lee EB. [The screening of biological active plants in Korea using
isolated organ preparations (I) Anticholinergic and oxytocic actions in the
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Seoul National University, 1976, 138–140 [in Korean].
Radix Scutellariae
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).
Selected vernacular names
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).
Geographical distribution
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).
329
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
General appearance
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).
Organoleptic properties
Odour, slight; taste, slightly bitter (1, 11).
Microscopic characteristics
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).
Powdered plant material
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).
Radix cum Herba Taraxaci
330
WHO monographs on selected medicinal plants
General identity tests
Macroscopic and microscopic examinations (1, 4, 5).
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 (13).
Foreign organic matter
Not more than 2% (3).
Total ash
Not more than 17% (3).
Water-soluble extractive
Not less than 30% (3).
Loss on drying
Not more than 11% (3).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (14). For other pesticides, see the European pharmacopoeia
(14) and the WHO guidelines on quality control methods for medicinal
plants (13) and pesticide residues (15).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (13).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (13) for the analysis of radioactive isotopes.
Other purity tests
Chemical, acid-insoluble ash, sulfated ash and alcohol-soluble extractive
tests to be established in accordance with national requirements.
Chemical assays
To be established in accordance with national requirements.
331
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
No information available.
Uses described in pharmacopoeias and well established documents
To stimulate diuresis (2, 5), increase bile fl ow and stimulate appetite, and
for treatment of dyspepsia (2).
Uses described in traditional medicine
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).
Radix cum Herba Taraxaci
H3C CH3
CH3 CH3 CH3
H
H CH3
HO
H
H
H3C
H
H
H3C CH3
CH3 CH3 CH3
H
H CH3
HO
H
H
H3C
H
H
taraxasterol CH2 ψ-taraxasterol CH3
O
H
OH
H
CH3
O
H
taraxacolide β-D-glucoside tetrahydroridentin B
O
O
H
H
CH3
O
H
taraxinic acid β-D-glucosyl ester
H
H
CH3
H CH3
HO
H
H
H CH3
H
CH3
O
Glc
O
H3C
O O
O
CH2
H
H
Glc
O
OH
HO
O
OH
O
HO
O
taraxacoside O
O
O
OH
HO
HO
OH
β-D-glucopyranosyl
Glc =
332
WHO monographs on selected medicinal plants
Pharmacology
Experimental pharmacology
Anti-infl ammatory and analgesic activity
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).
Antimicrobial activity
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).
Antiulcer activity
Intragastric administration of 2.0 g/kg bw of an aqueous extract of the
whole plant to rats protected the animals against ethanol-induced gastric
ulceration. A methanol extract, however, was not active (22).
Choleretic activity
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
333
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).
Immunological effects
Intragastric administration of 3.3 g/kg bw of an aqueous extract of the
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 (LD50) of a 95% ethanol extract
of the whole plant in rats was 28.8 mg/kg bw (24). In rats, the maximum
Radix cum Herba Taraxaci
334
WHO monographs on selected medicinal plants
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).
Clinical pharmacology
No information available.
Adverse reactions
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).
Contraindications
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
Drug interactions
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).
Carcinogenesis, mutagenesis, impairment of fertility
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).
Pregnancy: teratogenic effects
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).
335
Other precautions
No information available on general precautions or on precautions concerning
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
(Unless otherwise indicated)
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
1. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,
1996.
2. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
3. Deutscher Arzneimittel-Codex. [German drug codex.] Stuttgart, Deutsche
Apotheker, 1998.
4. Pharmacopoeia of the People’s Republic of China (English edition). Vol. I.
Beijing, China, Chemical Industry Press, 2000.
5. Pharmacopoeia of the Republic of Korea, 7th ed. Seoul, Taechan yakjon,
1998.
6. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 6,
Drogen P–Z, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 6,
Drugs P–Z, 5th ed.] Berlin, Springer, 1994.
7. Zahedi E. Botanical dictionary. Scientifi c names of plants in English, French,
German, Arabic and Persian languages. Tehran, Tehran University Publications,
1959.
8. 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.
9. 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).
10. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
Illinois at Chicago, 9 February 2001 production (an online database available
Radix cum Herba Taraxaci
336
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directly through the University of Illinois at Chicago or through the Scientifi
c and Technical Network (STN) of Chemical Abstracts Services).
11. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
12. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA,
Blakiston, 1950.
13. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
14. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
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).
16. 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.
17. Tita B et al. Taraxacum offi cinale W.: Pharmacological effect of an ethanol
extract. Pharmacology Research, 1993, 27(Suppl. 1):23–24.
18. Mascolo N et al. Biological screening of Italian medicinal plants for antiinfl
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.
Journal of Ethnopharmacology, 1990, 30:55–73.
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,
1994, 114:980–994 [in Japanese].
23. Böhm K. Untersuchungen über choleretische Wirkungen einiger Arzneipfl
anzen. [Studies on the choleretic action of some medicinal plants.]
Arzneimittelforschung, 1959, 9:376–378.
24. Racz-Kotilla E, Racz G, Solomon A. The action of Taraxacum offi cinale extracts
on the body weight and diuresis of laboratory animals. Planta Medica,
1974, 26:212–217.
25. Leslie GB. A pharmacometric evaluation of nine Bio-Strath herbal remedies.
Medita, 1978, 8:3–19.
26. Hook I, McGee A, Henman M. Evaluation of dandelion for diuretic activity
and variation in potassium content. International Journal of Pharmacognosy,
1993, 31:29–34.
27. Dhar ML et al. Screening of Indian plants for biological activity: part 1.
Indian Journal of Experimental Biology, 1968, 6:232–247.
337
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.
37. Lovell CR, Rowan M. Dandelion dermatitis. Contact Dermatitis, 1991,
25:185–188.
38. Chivato T et al. Anaphylaxis induced by ingestion of a pollen compound.
Journal of Investigational Allergology and Clinical Immunology, 1996,
6:208–209.
39. Dawe RS et al. Daisy, dandelion and thistle contact allergy in the photosensitivity
dermatitis and actinic reticuloid syndrome. Contact Dermatitis, 1996,
32:109–110.
40. Mark KA et al. Allergic contact and photoallergic contact dermatitis to plant
and pesticide allergens. Archives of Dermatology, 1999, 135:67–70.
41. Fernandez C et al. Analysis of cross-reactivity between sunfl ower pollen and
other pollens of the Compositae family. Journal of Allergy and Clinical Immunology,
1993, 92:660–667.
42. Zhu M, Wong PY, Li RC. Effects of Taraxacum mongolicum on the bioavailability
and disposition of ciprofl oxacin in rats. Journal of Pharmaceutical
Sciences, 1999, 88:632–634.
43. Leslie GB, Salmon G. Repeated dose toxicity studies and reproductive studies
on nine Bio-Strath herbal remedies. Schweizerische Zeitschrift für Medizin
und Medizinische Technik, 1979, 1:1–3.
Radix cum Herba Taraxaci
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.
Selected vernacular names
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).
Geographical distribution
Indigenous to the Mediterranean region, China, India and Indonesia.
Cultivated in these countries (5, 13).
339
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
General appearance
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).
Organoleptic properties
Odour: characteristic, aromatic; taste: slightly bitter (1, 2, 6, 7).
Microscopic characteristics
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).
Powdered plant material
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
Semen Trigonellae Foenugraeci
340
WHO monographs on selected medicinal plants
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).
General identity tests
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
Microbiological
Tests for specifi c microorganisms and microbial contamination limits are
as described in the WHO guidelines on quality control methods for medicinal
plants (14).
Foreign organic matter
Not more than 2% (1, 2, 4, 6).
Total ash
Not more than 5% (3, 6).
Acid-insoluble ash
Not more than 2% (1, 2, 5).
Water-soluble extractive
Not less than 35% (5).
Alcohol-soluble extractive
Not less than 5% (4).
Loss on drying
Not more than 12% (6).
Swelling index
Not less than 6 (3, 6).
Pesticide residues
The recommended maximum limit of aldrin and dieldrin is not more than
0.05 mg/kg (15). For other pesticides, see the European pharmacopoeia
341
(15) and the WHO guidelines on quality control methods for medicinal
plants (14) and pesticide residues (16).
Heavy metals
For maximum limits and analysis of heavy metals, consult the WHO
guidelines on quality control methods for medicinal plants (14).
Radioactive residues
Where applicable, consult the WHO guidelines on quality control methods
for medicinal plants (14) for the analysis of radioactive isotopes.
Other purity tests
Chemical and sulfated ash tests to be established in accordance with national
requirements.
Chemical assays
To be established in accordance with national requirements.
Major chemical constituents
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.
Medicinal uses
Uses supported by clinical data
As an adjunct for the management of hypercholesterolaemia, and hyperglycaemia
in cases of diabetes mellitus (18–21). Prevention and treatment
of mountain sickness (22).
Uses described in pharmacopoeias and well established documents
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).
Semen Trigonellae Foenugraeci
trigonelline
N+
CO2
-
CH3
342
WHO monographs on selected medicinal plants
Uses described in traditional medicine
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
Experimental pharmacology
Antihypercholesterolaemic activity
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).
Antihyperglycaemic activity
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).
343
Antioxidant activity
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).
Gastrointestinal effects
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).
Clinical pharmacology
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
Semen Trigonellae Foenugraeci
344
WHO monographs on selected medicinal plants
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).
345
Adverse reactions
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).
Contraindications
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
No information available.
Precautions
Drug interactions
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.
Carcinogenesis, mutagenesis, impairment of fertility
An aqueous and a chloroform/methanol extract of the seeds were not
mutagenic in the Salmonella/microsome assay using S. typhimurium
strains TA98 and TA100 (47, 48). The extracts were also not mutagenic in
pig kidney cells or in trophoblastic placental cells (47).
Pregnancy: non-teratogenic effects
See Contraindications.
Other precautions
No information available on general precautions or on precautions concerning
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.
Semen Trigonellae Foenugraeci
346
WHO monographs on selected medicinal plants
Posology
(Unless otherwise indicated)
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).

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