Community herbal monograph on
Trigonella foenum-graecum
L., semen
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Trigonella foenum-graecum
L., semen (fenugreek)
i) Herbal substance
As defined in the Ph. Eur. monograph.
ii) Herbal preparations
a) Dry extract (DER 4:1), extraction solvent:
ethanol 20% v/v
b) Soft extract (DER 5-6:1), extraction solvent:
ethanol 60% v/v
1
The material complies with the Ph. Eur. monograph (ref.: 01/2008:1323 corrected 6.6).
2
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
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Well-established use
Traditional use
Herbal substance as herbal tea for oral use.
Herbal preparation in solid dosage form for oral
use.
Herbal substance for infusion preparation for
cutaneous use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Indication 1)
Traditional herbal medicinal product used for
temporary loss of appetite.
Indication 2)
Traditional herbal medicinal product for the
symptomatic treatment of minor inflammations of
the skin.
The product is a traditional herbal medicinal
product for use in specified indications exclusively
based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults and elderly
Indication 1)
i) Herbal substance
Herbal substance as a tea preparation:
1 to 6 g daily in divided doses.
ii) Herbal preparations
a) Dry extract: 295 mg, 2 times daily.
b) Soft extract: 500 mg, 2 times daily.
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Well-established use
Traditional use
Indication 2)
Herbal substance as an infusion preparation for
cutaneous use:
50 g/250 ml of water. The still warm infusion is
used in cataplasm.
The use in children and adolescents under 18
years of age is not recommended (see section 4.4
‘Special warnings and precautions for use’).
Duration of use
Indication 1)
If the symptoms persist more than two weeks
during the use of the medicinal product, a doctor or
a qualified health care practitioner should be
consulted.
Indication 2)
If the symptoms persist more than one week during
the use of the medicinal product, a doctor or a
qualified health care practitioner should be
consulted.
Method of administration
Indication 1)
Oral use.
Indication 2)
Cutaneous use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance(s).
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4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under 18
years of age has not been established due to
lack of adequate data.
Oral use
Due to a possible hypoglycaemic effect of
fenugreek, close monitoring of glycaemic control
should be considered in patients treated for
diabetes mellitus.
For extracts containing ethanol, the appropriate
labelling for ethanol, taken from the ‘Guideline
on excipients in the label and package leaflet of
medicinal products for human use’, must be
included.
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
None reported.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
There are no or limited data from use during
pregnancy and lactation.
Studies in animals have shown reproductive
toxicity (see section 5.3 ‘Preclinical safety data’).
The use is not recommended during pregnancy
and lactation.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
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4.8.
Undesirable effects
Well-established use
Traditional use
Oral use
Gastrointestinal disorders: flatulence, diarrhoea
may occur.
Nervous system disorders: dizziness may occur.
The frequency is not known.
Cutaneous use
Allergic reactions have been reported after local
application (facial angioedema, wheezing) or
ingestion (asthma, allergic rhinitis). The frequency
is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Well-established use
Traditional use
High doses (between 25 g and 100 g daily of
debitterised powder of fenugreek seeds divided
into two equal doses) have been reported to
cause minor gastrointestinal symptoms such as
diarrhoea and flatulence in 4 out of 10 cases.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
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5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on genotoxicity have not been performed.
Decreased thyroid hormone levels (T3,
triiodothyronine) were reported in rodents treated
with hydro-ethanolic extracts at 110 mg/kg/day
and above; a NOAEL was not determined.
Testicular toxicity (altered sperm parameters,
decreased testis weight, lowered / arrest of
spermatogenesis, and degenerating seminiferous
tubules) was reported in rats treated for 2 to 3
months with either fenugreek seed powder or the
steroidal fraction of seeds. These effects are
attributed to the treatment-related decrease in
testosterone; a NOAEL was not determined.
Conventional embryo-foetal and peri- and
postnatal toxicity studies were not performed.
Limited studies showed conflicting results
regarding the occurrence of malformations in rats.
Well-established use
Traditional use
Not applicable.
27 January 2011
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Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 4
1.3. Search and assessment methodology....................................................................
6
2. Historical data on medicinal use ........................................................................................ 6
2.1. Information on period of medicinal use in the Community ........................................
6
preparations and indications.......................................................................................
7
3. Non-Clinical Data ............................................................................................................... 8
preparation(s) and relevant constituents thereof ...........................................................
8
3.1.1. Primary pharmacodynamics ..............................................................................
8
3.1.2. Secondary pharmacodynamics ..........................................................................
8
Hypoglycaemic effect ............................................................................................................. 8
Hypolipidaemic effect .......................................................................................................... 10
Other effects ........................................................................................................................ 10
3.1.3. Safety pharmacology ..................................................................................... 1
1
preparation(s) and relevant constituents thereof ......................................................... 1
7
preparation(s) and constituents thereof ..................................................................... 1
7
3.3.1. Single-dose toxicity ....................................................................................... 1
7
3.3.2. Repeat-dose toxicity ...................................................................................... 1
7
3.3.3. Genotoxicity ................................................................................................. 1
8
3.3.4. Carcinogenicity ............................................................................................. 1
8
3.3.5. Reproduction toxicity ..................................................................................... 1
9
3.3.6. Other studies ................................................................................................ 2
1
3.4. Overall conclusions on non-clinical data............................................................... 3
0
Pharmacology ...................................................................................................................... 30
Toxicology............................................................................................................................ 30
Monograph........................................................................................................................... 31
4. Clinical Data ..................................................................................................................... 32
4.1. Clinical Pharmacology ....................................................................................... 3
2
including data on relevant constituents ...................................................................... 3
2
including data on relevant constituents ...................................................................... 3
2
4.2. Clinical Efficacy ................................................................................................ 3
2
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Appetite stimulant effect ..................................................................................................... 32
Hypoglycaemic and antihyperlipidemic properties ............................................................... 34
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 3
8
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 3
8
5. Clinical Safety/Pharmacovigilance................................................................................... 39
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 3
9
5.2. Patient exposure .............................................................................................. 3
9
5.3. Adverse events and serious adverse events and deaths ......................................... 3
9
5.4. Laboratory findings .......................................................................................... 4
0
5.5. Safety in special populations and situations ......................................................... 4
0
5.6. Overall conclusions on clinical safety ................................................................... 4
1
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1.
Introduction
The aim of this report is to assess the non-clinical and clinical available data on Trigonellae foenugraeci
semen for preparing a Community herbal monograph. This report is based on the documentation
published in the literature.
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
•
Herbal substance(s)
Fenugreek seed
•
Herbal preparation(s)
Powder, dry extract, soft extract
Fenugreek seed is rich in mucilage polysaccharide (consisting mainly in galactomannans 25–45%) and
contains a small amount of essential oil (0.015%) 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 flavonoids,
among which are orientin, isoorientin and isovitexin (WHO, 2007). Furthermore, the nutrition
composition of fenugreek seeds is : moisture 2.4 %, protein 30 %, lipids 7 %, saponins 4.8 %, total
dietetary fibre 48.% (insoluble 28.%, soluble 20.%), and ash 3.9 % (WHO, 2003; ESCOP 2003;
MURALIDHARA et al, 1999; BRUNETON 1998; RAO et al, 1996; PARIS AND MOYSE, 1967.
The European Pharmacopoeia does not prescribe any assay (monograph ref. 01/2008:1323 corrected
6.6).
•
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
Not applicable.
1.2.
Information about products on the market in the Member States
Fenugreek as single active substance is authorised in France, Poland and Spain.
The active substance is present on the market as herbal substance for herbal tea and for infusion for
external use (Poland, over 30 years; Spain), powder (France 1990, Spain 1990, 1992), dry extract
(solvent ethanol 20 % V/V, DER: 4:1) (France 1970, 2003), soft extract (solvent ethanol 60 % V/V,
DER: 5-6:1) (France 1970, 2003).
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Belgium
MA
TRAD
Other TRAD
Other Specify: Only as food supplement
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Member State Regulatory Status
Comments (not
mandatory field)
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Denmark
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify: Only one standard
marketing authorisation
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Italy
MA
TRAD
Other TRAD
Other Specify: Only as food supplement
Latvia
MA
TRAD
Other TRAD
Other Specify: Only in combinations
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Slovenia
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
MA: Marketing Authorisation
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TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3.
Search and assessment methodology
Non-clinical and clinical strategies
Online databases were used to research available non-clinical and clinical data on fenugreek
preparations. No data was provided by the interested parties.
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
Based on the feedback obtained from Member States, a use is reported for a long period in the EU.
Moreover, publications also report a use in non EU countries, in line with the fact that this plant is
cultivated in the Indian continent, in the Mediterranean region and in North Africa.
2.2.
Information on traditional/current indications and specified
substances/preparations
Fenugreek (
Trigonella foenum-graecum
L.
Fabaceae
) is one of the oldest medicinal plants, originating
in India and Northern Africa.
An annual plant, fenugreek grows to an average height of two feet. The leaves and seeds, which
mature in long pods, are used to prepare extracts or powders for medicinal use. Applications of
fenugreek were documented in ancient Egypt, where it was used in incense and to embalm mummies.
In modern Egypt, fenugreek is still used as a supplement in wheat and maize flour for bread-making.
In ancient Rome, fenugreek was purportedly used to aid labour and delivery. In traditional Chinese
medicine, fenugreek seeds are used as a tonic, as well as a treatment for weakness and oedema of the
legs. In India, fenugreek is commonly consumed as a condiment and used medicinally as a lactation
stimulant. There are numerous other folkloric uses of fenugreek, including the treatment of indigestion
and baldness. The possible hypoglycaemic and antihyperlipidemic properties of oral fenugreek seed
powder have been suggested by the results of preliminary animal and human trials.
The medicinal part of fenugreek is the seed. It was already mentioned in the French Pharmacopoeia
published in 1908. Herbal preparations like powder or liquid extract have been used in the past to
stimulate the appetite (PARIS and MOYSE, 1967).
An internal use as adjuvant therapy in diabetes mellitus, anorexia, as an adjunct to a low fat diet in the
treatment of mild to moderate hypercholesterolemia and an external use in case of furonculosis, ulcers
and eczema are mentioned in the ESCOP Monograph.
Fenugreek is also a part of the ayurvedic pharmacopoeia and used in arthritis and spondylosis, adjunct
in diabetes mellitus and hyperlipidaemia (Selected medicinal Plants of India, 1992).
Fenugreek has been used as herbal substance since 1970 in France and over 30 years in Poland.
In France, Poland and Spain, fenugreek is a traditional herbal medicinal product. The current
therapeutic indications in these European Countries are:
For
oral use
:
In
France
: traditionally used to help weight gain
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In
Poland
:
- as appetite stimulant
- in lack of appetite
- orally as gastrointestinal emollient
In
Spain
: loss of appetite
For
external use
:
In
Poland
:
- topically in a form of cataplasms in skin inflammations, as emollient, coating and for skin healing,
- topically in skin inflammations, topically in wounds, rashes, furunculosis,
- traditionally used externally in a form of cataplasms in skin inflammations (eruptions, furunculosis)
as healing promotion,
- externally in skin inflammation conditions
In
Spain
: in minor local skin inflammations
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
In
France
: 2 herbal medicinal products (extracts) have been on the market since 1970 and 1 (powder)
since 1990 for oral use:
1.
Dry extract (solvent ethanol 20 % V/V, DER 4: 1): 295 mg 2 times daily.
2.
Soft extract (solvent ethanol 60 % V/V, DER: 5-6: 1): 500mg 2 times daily.
3.
495 mg 3 to 5 times daily traditionally used to help weight gain.
In
Poland
: 5 herbal medicinal products for oral use (herbal tea) and external use (cataplasm) have
been on the market for over 30years:
1.
Externally in a form of cataplasms in skin inflammations, as emollient, coating and for skin healing:
50 g of seeds, bring to the boil 5 min in 250 ml of water, use the obtained warm pulp as cataplasm
2 – 3 times daily.
Orally as appetite stimulant: 1 teaspoon (2 g) of grained seeds, use before meals.
2.
Orally in lack of appetite: 1-2 teaspoons (3 – 6 g) take before meals. Topically in skin
inflammations, mix grinded seeds with water (25 g of seeds to 100 ml of water), bring to the boil 5
min. Use the obtained warm paste such a warm cataplasm 2 – 3 times daily.
3.
Orally in lack of appetite: 1 – 6 g of grinded seeds before meals.
Topically in wounds, rashes, furunculosis: mix 20 g of seeds with 100 ml of water (1/2 of glass),
heat 5 min. Use as warm cataplasms 2 – 3 times daily.
4.
Orally: use a decoction, 8 g seeds in a glass of water, bring to the boil 15 min. Drink 2 – 3 times
daily, before meals. Externally in a form of cataplasms in skin inflammations (eruptions,
furunculosis) 50 g of seeds in 250 ml of water, bring to the boil. Use the warm pulp as a cataplasm
2 – 3 times daily.
5.
Orally in lack of appetite. 1.6 g of grinded seeds (1/4 of teaspoon), 3 times daily.
Externally in skin inflammation conditions, mix 50 g of grinded seeds with 250 ml (1 glass) of
water, heat and use such a warm cataplasm several times a day.
In
Spain
: 1 herbal medicinal product on the market for external use and 3 herbal medicinal products
on the market for oral use (1 herbal tea and 2 powders (1990 and 1992)).
1.
Up to 50 g/day for external use, minor local skin inflammations.
2.
Up to 3 times a day (6 g of herbal substance a day).
3.
1100 mg 3 times a day.
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4.
380 to 760 mg 3 times a day.
Used in loss of appetite.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
The WHO described the medicinal uses of fenugreek seeds, either supported by clinical data, described
in pharmacopoeias and well-established documents, or described in traditional medicine (WHO, 2003).
3.1.1.
Primary pharmacodynamics
Only one study dealing with the effect of fenugreek seeds on appetite was located in the literature.
Petit et al (1993) showed in rats that oral administration of a hydro-ethanolic seed extract increased
food intake and motivation to eat. However, treatment had no preventing effect on drug-induced
anorexia / decreased motivation to eat (see
Table 2
).
Assessor’s comment
Only sparse non-clinical pharmacology study is available to support the use of fenugreek seeds for loss
of appetite.
3.1.2.
Secondary pharmacodynamics
Hypoglycaemic effect
Most of the data found in the literature were performed to support the use of fenugreek seeds in
diabetes mellitus. They are summarized in
Table 3
.
Fenugreek seeds as well as some water and ethanol extracts were shown to have a hypoglycaemic
effect in normal as well as in diabetic models of rats. The seed powder was not tested in normal and
diabetic mice, however aqueous and ethanol extracts induced the same effect. The hypoglycaemic
effect of fenugreek seeds was also tested in a non-rodent species, namely the dog. The lipid extract
was shown to have no effect on blood glucose levels. The remaining part termed defatted fraction, and
more precisely the testa and endosperm, was the active fraction of the seed on glycaemia.
The mechanism underlying this effect is not clearly established. A widely found hypothesis is that
fenugreek interferes with intestinal glucose absorption as a result of local effects at the gastro-
intestinal level mainly due to dietary fibers contained in fenugreek seeds and/or viscosity of the
preparation. However, Abajnoor and Tilmisany (1988) excluded the involvement of gastrointestinal
action of fibre to explain the hypoglycaemic effect they reported in mice because i) they used fasting
mice and ii) they administered extract instead of the whole seed. Instead, they suggested that the
mechanism of antidiabetic action of fenugreek seeds may be similar to that of tolbutamide,
i.e.
stimulation of pancreatic insulin secretion, but did not exclude other pathways. Yadav et al (2008) also
suggested that fenugreek seeds, more precisely the water extract, act as an insulin secretor but
unfortunately, they did not monitor insulin levels in their experiments. Interestingly, increased insulin
secretion was observed in the experiments conducted by Petit et al (1993), Devi et al (2003), Eidi et al
(2007). Further, Vijayakumar and Bhat (2008) also report that hypoglycaemic effect of fenugreek
seeds, at least in part, is contributed by its action on the modulation of insulin secretion.
Others author suggested that fenugreek inhibits intestinal glycosidase or digestive enzymes (Riyad et
al, 1988 cited by Eidi et al, 2007, Wong et al 1985 and Edwards et al 1985 both cited by Zia et al,
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2001). However, Vijayakumar and Bhat (2008) mention that this mechanism could not explain the
hypoglycaemic effect they observed in mice because they used the intraperitoneal route of
administration. The ability of fenugreek seeds to modulate key glucose metabolising enzymes such as
hexokinase (glycolysis), glucose-6-phosphatase or fructose-1,6-bisphosphatase (gluconeogenesis) was
also considered as a possible mechanism (Devi et al, 2003; Raju et al, 2001; Vijayakumar and Bhat,
2008).
In vitro
investigations conducted by Vijayakumar et al (2005) showed that fenugreek seed extract
stimulates insulin signalling pathway resulting in enhanced glucose transporter GLUT4 translocation to
the cell surface in CHO cells and so enhanced mediated glucose uptake. It was notably shown in
HepG2 cells that tyrosine phosphorylation of IR-
β
(insulin-receptor
β
) is activated, thus subsequently
enhancing tyrosine phosphorylation of IRS-1 and p85 subunit of PI3-kinase.
In addition, the compound(s) responsible for the hypoglycaemic effect is(are) not clearly identified.
The main hypotheses found in the literature are summarized in
Table 1
. Zia et al (2001) concluded
that the substance responsible for hypoglycaemic activity is probably polar in nature. Ribes et al
(1984, 1986, 1987) showed in diabetic dogs that hypoglycaemic effect of fenugreek seeds is due to the
defatted fraction, and more precisely the defatted fraction containing testa and endosperm. The lipid
extract had no such effect (Ribes et al, 1984, Valette et al, 1984).
Table 1 : compounds claimed to be involved in the hypoglycaemic activity of fenugreek
seeds
Compound
Ref.
Claimed mechanism of action or effect
4-
hydroxyisoleucine
Eidi et al,
2007
Insulinotropic property
in vitro
Stimulation of intestinal secretion
in vivo
Improvement of glucose tolerance in diabetic rats and dogs
Alkaloids
Eidi et al,
2007
Inhibition of glucose uptake
in vitro
Arginine
Eidi et al,
2007
Antidiabetic and hypoglycaemic effect
Coumarin
Shani et al,
1974
a,b
Main hypoglycaemic constituent of fenugreek seeds (from Shani et
al, 1974)
Nicotinic acid
Shani et al,
1974
a
Main hypoglycaemic constituent of fenugreek seeds (from Shani et
al, 1974)
Steroid saponins
Eidi et al,
2007
Inhibition of glucose uptake
in vitro
Yadav et
al, 2008
The highest hypoglycaemic activity observed with the water extract
may be related to higher content of saponins which are water
soluble and previously reported for hypoglycaemic potential
Tanins
Yadav et
al, 2008
The highest hypoglycaemic activity observed with the water extract
may be related to higher content of tanins which are water soluble
and previously reported for hypoglycaemic potential
Trigonelline
Eidi et al,
2007
Inhibition of glucose uptake
in vitro
Shani et al, Hypoglycaemic betain
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Compound
Ref.
Claimed mechanism of action or effect
1974
a,b
Tryptophan
Eidi et al,
2007
Antidiabetic and hypoglycaemic effect
a
cited by Abajnoor and Tilmisany, 1988;
b
cited by Ali et al, 1995
Hypolipidaemic effect
The data are summarized in
Table 3
.
Investigations were conducted on the ability of fenugreek seed to lower blood lipids levels. In normal
rats, Petit et al (1993) observed decreased levels of total cholesterol and VLDL-LDL total cholesterol in
normal rats given an hydro-ethanolic extract. No significant change was reported for levels of HDL-
cholesterol. In diabetic rats, hypolipidaemic effect with favourable impact on HDL-cholesterol was
shown by Xue et al (2007). Similar results were obtained by Eidi et al (2007).
In normal and diabetic dogs, hypocholesterolaemic effect was reported for the defatted fraction of
fenugreek seeds. Further work in diabetic dogs showed hypolipidaemic effect (decreased cholesterol
and/or triglycerides) for the defatted fraction containing testa and endosperm shown to induce also
hypoglycaemic effects. However, the defatted fraction containing cotyledon and axes also showed
hypolipidaemic effect in this experimental model, whereas it did not induce hypoglycaemic effect. The
authors conclude that saponins may play a role, but exclude any effect of amino acids on lipidaemia
(Ribes et al 1984, 1986, 1987; Valette et al, 1984).
Other effects
Ahmadiani et al (2001) reported an anti-inflammatory effect in the formalin induced rat paw oedema
model for a water extract of fenugreek leaves administered orally once of for 7 days. The effective
dose amounted to 1000 mg/kg/day. Further work performed by Parvizpur et al (2006) showed a lack
of inhibitory effect on COX enzyme. Ahmadiani et al (2001) also reported anti-pyretic effect in
hyperthermic rats (injected brewer’s yeast) for the same extract administered at 1000 mg/kg by both
oral and ip routes.
Assessor’s comments
Fenugreek seeds were shown to induce hypoglycaemic effects in various animal models of diabetes.
The mechanism underlying the hypoglycaemic effect remains unestablished but a number of
hypotheses were found in the literature: local action at the gastro-intestinal level to lower the
absorption of glucose, enhancement of insulin secretion, modulation of glucose metabolism,
stimulation of insulin signalling pathway at the cellular level. Similarly, the compound(s) responsible
for this effect are currently not identified. However, it was established in diabetic dogs that the active
part of fenugreek seeds is the defatted fraction.
A lower number of studies also showed that fenugreek seeds have an hypolipidaemic effect in diabetic
rats, and in both normal and diabetic dogs. It was also shown in dogs that the active part is the
defatted fraction.
According to the results that may be available in humans for effects on glycaemia, warnings could be
included in the monograph regarding potential interactions with treatments for diabetes mellitus.
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3.1.3.
Safety pharmacology
Two publications describing the results of experimental studies dealing with potential undesirable effect
of fenugreek preparations on some of the main physiological functions were found in the scientific
literature. A summary is provided in
Table 4
.
Abdo and Al-Kafawi (1969) investigated the effects of water and ethanol seed extracts on various
systems:
•
Either a slight effect or an effect similar to that reported for the control vehicle was reported on the
motility of isolated guinea pig intestine pieces;
•
A positive chronotropic effect was observed in isolated perfused guinea pig hearts with the water
extract; a negative chronotropic effect was reported for the ethanol extract and ethanol control
vehicle. However, no effect on blood pressure or respiratory movements was reported in
anaesthetized dogs treated with each extract;
•
Both extracts showed stimulating effect on uterine contractility, particularly in tissues obtained
from pregnant guinea pigs.
Parvizpur et al (2006) showed that a water extract of fenugreek leaves inhibits the aggregation of
rabbit platelet in a concentration-dependent way, that is related to some antagonistic effect on ADP.
Assessor’s comment
From the studies detailed above, two results may deserve a particular attention:
–
A water extract of fenugreek leaves was shown to inhibit the aggregation of rabbit platelet in a
concentration-dependent way, that is related to some antagonistic effect on ADP.
–
The uterine stimulant properties reported on pieces of guinea pig uterus should be viewed in the
context of its historical use as an abortifacient or for labour induction that is mentioned by Ulbricht
et al (2007).
Table 2: summary of primary pharmacodynamic studies
Ref.
Test-article
Test system (species, route,
dose, duration, parameters…)
Noteworthy findings
Plant
part
Formulation
Petit et
al, 1993
Seed
Hydro-
ethanolic
extract*
Rat
Oral route (diet)
10 and 100 mg/day/300 g bw
Up to 14 days
Parameters monitored
•
↑
food intake; the intensity of
the effect was similar between
treated groups. Reversible 3-5
days after treatment cessation.
•
↑
body weight gain; the
intensity of the effect was
similar between treated groups
•
Food intake, weight gain
•
Motivation to eat (food-rewarded
runway behaviour)
•
↑
motivation to eat
•
Preventing effect on d-
fenfluramine-induced anorexia
•
↑
plasma insulin
•
↓
plasma total cholesterol,
↓
HDL free cholesterol,
↓
VLDL-
LDL total cholesterol
•
Metabolic studies (blood glucose,
plasma insulin, plasma glucagon,
triglycerides and total+free
cholesterol levels)
•
No preventing effect on
d
-
fenfluramine-induced anorexia
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* 12.5% steroid saponins, 4.8% free amino acids, 0.002% 3-hydroxy-4,5-dimethyl-2(5H)-furanone
(HDMF) – no protein and lipids. Obtained from Monal Laboratories, Palaiseau, France
Table 3: summary of secondary pharmacodynamic studies dealing with potential
activity in diabetes and/or hyperlipidaemia
Ref.
Part Formulation Model
Route
Duration Minimal
effective
dose
Conclusion
Studies performed in mice
Vijayakumar
et al, 2005
Seed Aqueous
extract
Diabetic
(AXN)
Intraperitroneal Single
dose
1-5 mg/kg Hypoglycaemic
effect in diabetic
mice comparable to
that of 1.5 U/kg
insulin (at 15
mg/kg)
Vijayakumar
and Bhat,
2008
Seed Aqueous
extract
Diabetic
(AXN)
Intraperitroneal 5 days
15
mg/kg/day
Hypoglycaemic
effect in diabetic
mice
Vijayakumar
et al, 2005
Seed Aqueous
extract
Normal Intraperitroneal Single
dose
15 mg/kg Hypoglycaemic
effect in normal
mice
Vijayakumar
and Bhat,
2008
Seed Aqueous
extract
Normal Intraperitroneal Single
dose
15 mg/kg Hypoglycaemic
effect in normal
mice
Vijayakumar
and Bhat,
2008
Seed Aqueous
extract
Diabetic
(STZ)
Intraperitroneal Single
dose
15 mg/kg Hypoglycaemic
effect in diabetic
mice comparable to
that of 1.5 U/kg
insulin; enhanced
hepatic metabolism
of glucose
Ajabnoor
and
Tilmisany,
1988
Seed Decoction
Ethanol
extract
Normal
and
diabetic
(AXN)
Oral
Single
dose
Decoction:
0.5 mL
Hypoglycaemic
effect in normal and
diabetic mice.
Extract:
200 mg/kg
Zia et al,
2001
Seed Aqueous
extract
Normal Oral
Single
dose
500
Hypoglycaemic
effect in normal
mice
Zia et al,
2001
Seed Methanol
extract
Normal Oral
Single
dose
1000
Hypoglycaemic
effect in normal
mice
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Studies performed in rats
Jelodar et
al, 2005
Leaf Powder
Diabetic
(AXN)
Oral (diet)
15 days
>12.5%
BW in food
No effect of treatment
on the parameters
monitored; the
authors explain that
this may be due to
the plant part used
(leaf instead of seed)
Devi et al,
2003
Leaf Powder
Diabetic
(STZ)
Oral (diet)
45 days
500
mg/kg/day
Hypoglycaemic effect
in diabetic rats +
stimulation of insulin
secretion
Yadav et
al, 2008
Seed Aqueous
extract
Normal Oral
Single
dose
50 mg/kg Hypoglycaemic effect
in normal rats
Xue et al,
2007
Seed Aqueous
extract
Diabetic
(STZ)
Oral (gavage) 6 weeks 440
mg/kg/day
Hypoglycaemic effect
in diabetic rats
Hypolipidaemic
effects in diabetic rats
with favourable
impact on HDL-
cholesterol
Yadav et
al, 2008
Seed Aqueous,
ethanol,
methanol,
hexane and
chloroform
extracts
Normal Oral
Single
dose
200 mg/kg Hypoglycaemic effect
reported for aqueous
ethanol and methanol
extracts in normal
rats
Vats et al,
2002
Seed Ethanol
extract
Diabetic
(AXN)
Oral (gavage) 21 days
2000
mg/kg/day
Hypoglycaemic effect
in diabetic rats
Vats et al,
2002
Seed Ethanol
extract
Normal Oral (gavage) Single
dose
1000
mg/kg
Hypoglycaemic effect
in normal rats
Lack of effect after an
oral glucose load in
normal rats (suggests
that the extract failed
in affecting glucose
absorption from the
GI tract)
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Eidi et al,
2007
Seed Hydro-
ethanolic
extract (80%)
Normal
and
diabetic
(STZ)
Oral (gavage) 14 days
250
mg/kg/day
Hypoglycaemic effect
+ stimulation of
insulin secretion in
diabetic rats,
but not
in normal rats
Favourable effect on
cholesterol and
triacylglycerol, and on
hepatic transaminases
in diabetic rats
Raju et al,
2001
Seed Powder
Diabetic
(AXN)
Oral (diet)
21 days
12.5
g/kg/day
(5% in
diet)
Hypoglycaemic effect
in diabetic rats;
modulation of key
glucose metabolising
enzymes
Khosla et
al, 1995
Seed Powder
Normal
and
diabetic
(AXN)
Oral (diet)
1 and 2
weeks
2000
mg/kg/day
Hypoglycaemic effect
in normal and diabetic
rats
Mondal et
al, 2004
Seed Powder
(defatted)
Normal
and
diabetic
(STZ)
Oral
(assessor’s
hypothesis)
9 days
1250
mg/kg/day
Hypoglycaemic effect
in diabetic rats
Studies performed in dogs
Ribes et al,
1984
Valette et
al, 1984
Seed Defatted
fraction
a
Normal
and
diabetic
(AXN)
Oral (diet)
8 days
1860
mg/kg/day
Hypoglycaemic effect
in normal and diabetic
dogs – attributed in
part to the high
percentage of
dietetary fibers of the
preparation
Hypocholesterolaemic
effect in normal and
AXN-induced
hypercholesterolaemic
dogs
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Ribes et al,
1986
Ribes et al,
1987
Seed Defatted
fractions
C+A
c
Diabetic
(AXN)
Oral (diet)
21 days
>1126
mg/kg/day
(glycaemia)
1126
mg/kg/day
(lipids)
No effect on blood
glucose level
Hypolipidaemic effect
(decreased
cholesterol and/or
triglycerides);
saponins may play a
role, but not amino
acids.
Ribes et al,
1986
Ribes et al,
1987
Seed Defatted
fractions T+E
b
Diabetic
(AXN)
Oral (diet)
21 days
1145
mg/kg
Hypoglycaemic effect
in diabetic dogs -
dietetary fibers may
play a role
Hypolipidaemic effect
(decreased
cholesterol and/or
triglycerides);
saponins may play a
role, but not amino
acids.
Ribes et al,
1984
Valette et
al, 1984
Seed Lipid extract Normal Oral (diet)
8 days
>105
mg/kg/day
None
a
preparation containing 3.9% ash, 30.3% crude proteins, 53.9% dietary fibers (19.0% gum, 23.6%
hemicelluloses, 8.9% cellulose, 2.4% lignin), 4.8% steroid saponins
b
testa + endosperm: preparation containing 10.0% moisture, 3.0% ash, 6.8% crude proteins, 79.4%
dietary fibers (32.4% gum, 28.6% hemicelluloses, 14.6% cellulose, 3.8% lignin), 0.6% steroid
saponins
c
cotyledons + axes: preparation containing 9.6% moisture, 4.9% ash, 52.8% crude proteins, 6.7%
dietary fibers (traces of gum, 4.0% hemicelluloses, 2.1% cellulose, 0.6% lignin), 7.2% steroid
saponins
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Table 4: summary of safety pharmacology studies
Ref.
Part Formulation System
Test system (species,
route, dose, duration,
parameters,…)
Noteworthy findings
Abdo and
Al-
Kafawi,
1969
Seed Water and
ethanol
(liquid)
extracts
Gastro-
intestinal
tract
•
Isolated guinea pig
intestine pieces (5 cm)
•
Test solution (2 mL
from water or ethanol
extract) or control
(either water or
ethanol) added to a
bath containing
duodenum pieces in
oxygenated Tyrode’s
solution
•
Intestinal motility was
recorded by means of
a light lever on a
smoked drum paper
moving at slow speed
Water extract
Slight stimulating
effect on intestinal
motility
Ethanol extract
Inhibition of intestinal
motility, similar to that
observed with ethanol
control
Female
reproductive
tract
•
Isolated uterus pieces (4
cm) from pregnant and
non-pregnant guinea pig
•
Test solution (2 mL from
water or ethanol extract)
or control (either water
or ethanol) added to a
bath containing
duodenum pieces in
oxygenated Dale’s
solution
•
Uterine motility was
recorded by means of a
light lever on a smoked
drum paper moving at
slow speed
Water extract
Stimulating effect on
uterine contractility; the
effect is markedly
increased on tissues
obtained from pregnant
animals
Ethanol extract
Same results as those
obtained with water
extract
Cardiovascular
•
Isolated and perfused
guinea pig heart
•
Test solution (2 mL from
water or ethanol extract)
Water extract
Acceleration of heart
beats
Ethanol extract
Decrease in heart beats,
similar to that observed
with ethanol control
Cardiovascular
and respiratory
•
Anaesthetized dogs
•
Blood pressure recorded
from carotid artery
(manometer)
No effect reported for
both extracts
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Ref.
Part Formulation System
Test system (species,
route, dose, duration,
parameters,…)
Noteworthy findings
•
Respiratory movements
recorded by using a
sphymograph fitted
around the chest of
animals and connected
with a tambour
Parvizpur
et al, 2006
Leaf
Water extract Blood
•
Rabbit platelet-rich
plasma
•
Effect of extract (0.5, 1,
1.5 and 3 mg/mL) on
ADP-induced platelet
aggregation
Dose-dependent inhibition
of aggregation response
to ADP
⇒
some
antagonistic effect on ADP
(in rabbit platelet, COX
and arachidonic pathways
are not involved in
aggregation)
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data were found in the literature.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
3.3.1.
Single-dose toxicity
The available data are summarized in
Table 5
.
Assessor’s comment
Studies performed by Abdel-Barry and Al-Hakiem (2000) suggest a low acute toxic potential by oral
route (LD
50
= 7 g/kg). However, the preparation administered to mice is a glycosidic extract obtained
from fenugreek leaves and is not used traditionally.
Muralidhara et al (1999) also showed a low acute toxic potential in rodents with a debitterized powder
obtained from an unknown part of fenugreek.
3.3.2.
Repeat-dose toxicity
The available data are summarized in
Table 6
.
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Assessor’s comment
Two 90-day rat studies were found in the literature. The experimental protocols were similar.
Muralidhara et al (1999) administered the debitterized powder prepared from an unknown part of
fenugreek, at up to 10% in the diet. Udayasekhara Rao P et al (1996) administered a fenugreek seed
powder at up to 20% in the diet.
No toxic effect was observed in the first study. Udayasekhara Rao P et al (1996) reported increased
liver weight in females receiving 10 and 20% of seed powder with increased ALP levels. However, this
did not correlated with any hepatic finding at histopathological examination. Chronic interstitial
pneumonitis was observed at similar incidence in all groups including controls (
≈
70-85%). This is
described to be due to murine respiratory mycoplasmosis, whose main causative agent is
Mycoplasma
pulmonis
. An inbred colony of rats was used in this study, and the results suggest that it was infected
by
Mycoplasma pulmonis
. Therefore, some doubts remain regarding the sanitary conditions of the
animals.
In both studies, the list of organs selected for histopathological examination was quite limited.
Contrary to results obtained in rats and rabbits which are further detailed in the reproduction toxicity
section, no testicular finding was reported. In addition, no decrease in blood glucose levels (or
corroborating finding) was noted in both studies, although this was expected due to the hypoglycaemic
effect of fenugreek seeds (see pharmacology).
3.3.3.
Genotoxicity
The available data are summarized in
Table 7
.
In addition, the WHO monograph on Semen Trigonellae Foenugraeci reports that 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 (Rockwell and Raw, 1979 and Mahmoud et al, 1992 /
cited by WHO 2007).
Assessor’s comment
Flammang et al (2004) performed an ICH-compliant battery of 3 genotoxicity tests which yielded
negative results. However, the tests were performed with an extract of fenugreek seeds called “THL”.
Neither the mode of extraction, nor the composition (qualitative and quantitative) is described, it is
just mentioned that THL contains a minimum of 40% of 4-hydroxyisoleucine.
The data reported in the WHO monograph were obtained with irrelevant extracts, and the number of
strains used is not sufficient.
Overall, it is considered that conventional genotoxicity data obtained with a clinically relevant herbal
preparation is lacking, thus precluding the inclusion of
Trigonella foenum-graecum
in the list of herbal
substances, preparations and combinations thereof for use in traditional herbal medicinal products.
3.3.4.
Carcinogenicity
No conventional carcinogenicity study is available.
Assessor’s comment
From a non-clinical perspective, the duration of treatments with fenugreek seeds preparations should
not exceed 6 months due to the lack of conventional carcinogenicity study.
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3.3.5.
Reproduction toxicity
The available data are summarized in
Table 8
.
Kamal et al (1993) treated male rats with the steroidal fraction of fenugreek seed extract for 2
months. The sperm count and motility of treated animals were decreased. In addition, the weight of
reproductive tissues and androgen-dependent parameters (protein, sialic acid and fructose) were
lower, thus indicating reduced levels of circulating androgens. These findings were shown to have
histological correlates (arrest of spermatogenesis, degeneration of seminiferous tubules and
epididymis). Cholesterol levels were higher in treated vs control animals in serum and testis so that the
authors concluded that it may be co-related with its non-utilisation thus leading to decreased
circulating androgen and altered testicular histoarchitecture. The functional consequence was a loss of
fertility for 20/20 treated males. They conclude that the test-article exerts both antifertility and
antiandrogenic activities.
Kassem et al (2006) showed that administration of fenugreek seed powder in feed (30%) for 3 months
induced testicular toxicity in rabbits, as shown by marked decreases in testosterone levels, testes
weight and sperm count. This correlated histologically with decreased number of seminiferous tubules
and disruption of spermatogenesis (mild hypoplasia). According to the authors, these results are
coherent with those of Kamal et al (1993). However, they indicate that fenugreek may induce
testicular toxicity rather than antifertility effects based on the lack of difference in the number of litter
size when treated males were mated with untreated females.
In female rabbits treated the same way as their male counterparts, prebreeding estrogen and
progesterone levels were decreased, whereas gestational progesterone levels were markedly
increased. Histopathological examination reported increased ovulation (increased number of corpus
luteum), and proliferative changes of endometrial glands. The development of foetuses obtained after
mating of treated males and females is reported as abnormal, due to marked decreases in “fetal +
placental” weight (-80% on GD20) and litter size (-75%).
Sethi et al (1990) administered fenugreek seed powder to rats during the first ten days of gestation at
175 mg/kg/day. The number of resorptions was increased. This is coherent with the results published
by Elbetieha et al (1996) and Adhikary (1990) with fenugreek seed extracts administered from the
beginning up to the 6
th
or 10
th
day of pregnancy, respectively. In addition, some gross and visceral
anomalies were reported in the study published by Sethi et al (1990).
The only negative study was conducted by Mital and Gopaldas (1986) by administration of up to 20%
fenugreek seed powder in the diet of rats for the whole gestation period.
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Assessor’s comment
Studies published by Kamal et al (1993) and Kassem et al (2006) were designed to evaluate the effect
of fenugreek seeds preparation on fertility. Both studies report testicular toxicity shown by decreased
testosterone levels, altered sperm parameters, decreased testis weight, lowered / arrest of
spermatogenesis, degenerating seminiferous tubules. This toxicity is attributed to the treatment-
related decrease in testosterone, which seems consistent. A NOAEL was not determined. A potential
impact on fertility cannot be excluded.
In female rabbits, changes in estrogen and progesterone levels were reported by Kassem et al (2006).
Three studies showed that fenugreek seeds preparations (extract or powder) could increase the
number of resorptions when given to rats from the first day up to the 10
th
day of gestation. In two
studies, the number of implantations was not reported to be affected, in the third the authors did not
indicate whether this parameter has been monitored. In the study performed by Kassem et al (2006)
in rabbits, the number of implantations was also not affected by administration of seed powder, but
the litter size was decreased by 75% compared to controls. In the study performed by Kamal et al
(1993), successful mating occurred, but there is no data provided regarding the number of
implantations. Therefore, it seems reasonable to conclude that fenugreek seed induces embryolethality
in rats. This conclusion is also supported by the reported historical / theoretical use of fenugreek as an
abortifacient and labour inducer (Ulbricht et al, 2007). Other supportive data were summarized by
Farnsworth et al (1975) who performed an extensive review of published articles dealing with the
effects of various plants on fertility, and the underlying mechanism. Fenugreek was classified among
plants having abortifacient and emmenagogue (which induces or hastens menstrual flow) applications
based on the following data:
Type of activity Plant part
Other details
Casey RC, 298 alleged anti-fertility
plants of India. Indian J Med Sci,
1960.
Abortifacient
Saha JC et al, 1961
Emmenagogue
Whole plant,
seed
Emmenagogue
Seed
Goto M. Takeda Kenkyusho Nempo,
1957.
Uterine stimulant Seed
Abdo MS and Al-Kafawi AA,
Experimental studies on the effect of
Trigonella foenum-graecum. Planta
Medica, 1969
Uterine stimulant Seed
Formulation: water and alcoholic
extract
Species: guinea pig (
in vitro
study)
Regarding the impact of fenugreek seed on embryo-fetal development, contradictory results were
obtained in rats. Sethi et al (1990) reported gross and visceral malformations in rats at non
maternotoxic doses, whereas Mital and Gopaldas (1986) did not observe any effect on reproduction in
the same species.
The design of both studies is not in line with current recommendations for evaluation of embryo-fetal
toxicity. Indeed, the number of animals and that of dose levels were insufficient, and the duration of
treatment was not optimal – the test-article should have been administered for the whole period of
organogenesis, i.e. from GD 6-7 to GD 15-18.
Therefore, the information on embryo-fetal toxicity is considered limited, and the malformations
reported in rats by Sethi et al (1990) have to be considered as a safety signal. In the future,
conventional embryo-fetal toxicity studies in 2 species should be performed to clarify this point. No
information is available regarding potential effects on pre-post-natal development.
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No information is available regarding potential effects on pre-post-natal development.
3.3.6.
Other studies
Some studies focused on the impact of fenugreek seeds on thyroid function because thyroid hormones
are involved in carbohydrate metabolism. The data are summarized in
Table 9.
Assessor’s comment
Results from 3 experiments in rodents showed that an hydro-ethanolic extract of fenugreek seeds
induced a decrease in T3 levels. In 2 experiments, there were concomitant increase in T4 levels and
decrease in T3/T4 ratio. These results suggest decreased conversion of T4 to T3. Unfortunately, TSH
levels were not monitored. The decrease in T3/T4 ratio reveals decreased 5’-deiodinase activity since
the majority of circulating serum T3 is produced by peripheral conversion of T4 to T3. A NOAEL was
not determined.
Table 5: summary of single-dose toxicity studies
Ref.
Part Formulation Species Route, dose
Parameters
Noteworthy
findings
Muralidhara
et al, 1999
–
Debitterized
powder
a
Mouse
(CFT
Swiss)
•
Oral gavage
•
0, 250, 500,
1000, 2000
mg/kg
•
Mortality and
clinical signs for
up to 14 days
postdose
•
Body weight,
food intake
•
Weight and
microscopic
examination of
liver, lungs,
kidneys and
spleen
None
Muralidhara
et al, 1999
–
Debitterized
powder
a
Rat (CFT
Wistar)
•
Oral gavage
•
0, 1000, 2000,
4000
b
, 5000
b
mg/kg
•
Mortality and
clinical signs for
up to 14 days
postdose
•
Body weight,
food intake
•
Weight and
microscopic
examination of
liver, lungs,
kidneys and
spleen
None
Abdel-
Barry and
Al-Hakiem,
2000
Leaf Glycosidic
extract
Mouse
(Wistar)
•
Intraperitoneal
•
0, 200, 400,
500, 800,
1000 mg/kg
•
Mortality and
clinical signs for
up to 7 days
postdose
•
Body weight,
food intake
•
Histopathological
examination of
liver, kidney,
stomach and
•
LD50=650
mg/kg
•
CNS effects
Mild CNS
stimulation at
low and
intermediate
doses
10/group
Tachypnea,
twitches,
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Ref.
Part Formulation Species Route, dose
Parameters
Noteworthy
findings
large intestine
strabtail,
tremors,
generalized
convulsions at
higher doses
•
Early liver
degeneration
and mild
hepatitis
observed only
in animals
which died
before the end
of the study
Abdel-
Barry and
Al-Hakiem,
2000
Leaf Glycosidic
extract
Mouse
(Wistar)
•
Oral gavage
•
0, 1000, 2000,
4000, 6000,
8000, 10000
mg/kg (oral)
•
Mortality and
clinical signs for
up to 7 days
postdose
•
Body weight,
food intake
•
Histopathological
examination of
liver, kidney,
stomach and
large intestine
•
LD50=7000
mg/kg
10/group
•
CNS effects
Mild CNS
stimulation at
low and
intermediate
doses
Tachypnea,
twitches,
strabtail,
tremors,
generalized
convulsions at
higher doses
a
supplied by M/s Sterling Home Products (Chennai, India)
b
divided into two equal doses and dosed at 2-hourly intervals
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Table 6: su
mmary of repeat-dose toxicity studies
Ref.
Part Formulation Species
Duration,
route,
dose
Parameters
Noteworthy
findings
Muralidhara
et al, 1999
–
Debitterized
powder
a
Rat (CFT
Wistar) aged
28 days
90 -95 days
•
Mortality and
clinical signs
•
Body weight,
food intake
•
Haematological
examination
•
Biochemistry:
serum ALP, AST,
ALT, cholesterol,
creatinine and
urea
•
Weight and
microscopic
examination of
adrenals, brain,
heart, kidneys,
liver, lungs,
ovaries, spleen
and testes
None
Oral route
0, 1, 5, 10
% in diet
Udayasekhara
Rao P et al,
1996
Seed Powder
Rat
(Wistar/NIN)
90 days
Oral route
0, 5, 10, 20
% in diet
•
Mortality and
clinical signs
•
Body weight,
food intake
•
Haematological
examination
•
Biochemistry:
serum ALP, AST,
ALT, cholesterol,
and fatty acid
profile
•
Weight and
microscopic
examination of
liver, kidney,
lung, spleen,
gastrointestinal
tract, pancreas,
testis, ovary
Body weights,
Food intake
Transient
decrease in food
intake during the
first few days (
≥
5%)
12/sex/group
Biochemistry
↑
(dose-related)
serum ALP (M,
significant at 20%
only)
↓
cholesterol level
(M, 10 and 20%)
Organ weights
↑
relative liver
weight (F, +15%
at 10% and +28%
at 20% compared
to controls)
Histopathological
examination
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Lungs: mild to
moderate chronic
interstitial
pneumonitis:
17/24, 18/24,
16/24, 18/24 (at
0, 5, 10, 20%,
higher frequency
in males)
Lungs: severe
chronic interstitial
pneumonitis:
3/24, 0/24, 1/24,
0/24 (at 0, 5, 10,
20%)
a
supplied by M/s Sterling Home Products (Chennai, India)
Table 7: summary of genotoxicity studies
Ref.
Part
Formulation
Type of
test
Test
system
Concentration
metabolising
system
Results
Wu et al,
1997
Trigonelline,
heated for 20
min at 250°C
then let cool
down at room’s
temperature
Gene
mutation in
bacteria
Salmonella
typhimurium
strains TA98,
YG1024 and
YG1029
Concentration range
not detailed, but 4
different
concentrations were
used to establish a
dose-response curve
Potent mutagenic
activity with and without
detected in this model
mimicking coffee
roasting
The authors report that
pure trigonelline is not
mutagenic when not
heated (Fung et al,
Mutat Res, 1988)
+/- S9
(chlorophene-
induced rat liver)
Flammang
et al,
2004
Seed Extract
(THL)*
Gene
mutations in
bacteria
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA98, TA100
33.3 to 5000
µg/plate
Negative
+/- S9 (aroclor-
induced rat liver)
Escherichia
coli
strain
WP2
uvr
A
Flammang
et al,
2004
Seed Extract
(THL)*
Gene
mutations in
mammalian
cells
L5178Y
mouse
lymphoma
cells (TK
locus)
+S9: 500 to 5000
µg/mL
Negative
The authors indicate
that THL caused dose-
related increase in
cytotoxicity as
measured by the
-S9: 150 to 4000
µg/mL
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Ref.
Part
Formulation
Type of
test
Test
system
Concentration
metabolising
system
Results
reduction in relative
total growth
Comment:
According to OECD
guideline no.476**, RTG
should range from 10 to
20% if the maximum
concentration is based
on cytotoxicity.
In this experiment, RTG
reached 19.4% at 4000
µg/mL without S9, and
29.1% at 5000 µg/mL
with S9. Therefore, the
level of cytotoxicity is
acceptable. It is also
noted that the maximal
concentrations used are
in line with the OECD
guideline no.476 (5
mg/mL for relatively
non-cytotxic
compounds)
Flammang
et al,
2004
Seed Extract
(THL)*
Chromosomal
aberrations in
vivo
Mouse,
micronuclei in
bone marrow
500, 1000, 2000
mg/kg/day for 3
days by oral gavage
Negative
*containing
≥
40% 4-hydroxyisoleucine, mode of extraction not detailed; **OECD guidelines for the
testing of chemicals, Test n°476:
in vitro
mammalian cell gene mutation test, 1997.
Table 8: summary of reproduction toxicity studies
Ref. Part Formulation
Species
Duration,
route,
dose
Parameters
Noteworthy
findings
Kamal et
al, 1993
Seed Steroidal
fraction of
extract obtained
via extraction
with toluene and
n-hexane
a
Rat
(Holtzman)
60 days
Body weight
Organ weight
↓
weight of
epididymis, ventral
prostate, seminal
vesicles
Oral route
Fertility test
(mating with
untreated
females on Day
61 and check for
implantation sites
7 days
thereafter)
20M/group
0, 100
mg/day/rat,
i.e. approx.
450
mg/kg/day
b
Sperm parameters
↓
motility
↓
density in cauda
epididymis and testis
Biochemistry
Fertility
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Ref. Part Formulation
Species
Duration,
route,
dose
Parameters
Noteworthy
findings
(serum and
reproductive
tissues)
100% negative
results in treated
animals in spite of
successful matings
(confirmed by vaginal
plug)
Sperm
parameters
(count, motility)
Organ weight:
liver, heart,
kidney, adrenal,
reproductive
tissues
Tissue biochemistry
Testis:
↓
protein,
↑
cholesterol,
↓
glycogen,
↓
fructose
Seminal vesicle:
↓
protein,
↓
sialic acid,
↓
fructose
Histopathology:
testis,
epididymides, vas
deferens, seminal
vesicles
Epididymides:
↓
protein,
↓
sialic acid
Ventral prostate:
↓
protein,
↓
sialic acid
Serum biochemistry
↑
cholesterol,
↓
protein,
↓
phospholipids,
↓
triglycerides
Histopathology
Testis: arrest of
spermatogenesis,
degenerating
seminiferous tubules
Cauda epididymis:
severe degenerative
changes
Vas deferens:
↓
lumen diameter,
↑
thickness of lamina
propria
Kassem
et al,
2006
Seed Powder
Rabbit(NZW)
3 months;
sacrifice on
GD10,
GD20, or
after
parturition
Body weight
Parental Animals
4M+12F/group
Hormonal
assessment:
determination of
plasma
progesterone,
estrogen and
Hormone assessment
↓
testosterone (-
66%)
↓
estrogen (-18%)
↓
progesterone
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Ref. Part Formulation
Species
Duration,
route,
dose
Parameters
Noteworthy
findings
Oral route
testosterone
(prebreeding, -14%)
0, 30 % in
diet
Mating
parameters
↑
progesterone
(GD10 and GD20,
+78% and +111%)
Implantations,
corporea lutea,
resorptions
Sperm parameters
↓
sperm count (-
47%)
Fetal weight,
litter size,
newborn weight
Organ weight
↓
testicular weight (-
25%)
Sperm count
Histopathology:
ovaries, uterus,
testes
Histopathology:
Testis:
↓
number of
seminiferous tubules
Testis: mild
spermatogenesis
hypoplasia
Ovary: higher
development of the
secondary and
tertiary follicles in the
cortex area
Ovary:
↑
number of
corpus luteum
→
↑
ovulation activity
Uterus: proliferative
changes of some
endometrial glands
Uterus:
↑
proliferation
of the endometrial
glands with
hyperplastic changes
Embryo-fetal
development
↓
fetal + placenta
weight on GD20 (-
80%)
Newborns
↓
litter size (-75%)
↑
newborn weight
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Ref. Part Formulation
Species
Duration,
route,
dose
Parameters
Noteworthy
findings
(+26%)
Elbetieha
et al,
1996
Seed Aqueousextract Rat(SD)
GD1-GD6
(C-section
on GD20)
Number of
implantations
↑
number of total
resorptions
9F/group
Number of
resorptions
↑
number of dams
with resorptions
Oral route
(gavage)
Number of live
fetuses
0, 800
mg/kg/day
Adhikary,
1990
–
Petroleum
extract (60-
80%)
Rat
GD1-GD10
Screening for
antifertility
activity
60-66% antifertility
activity
Oral route
500-1250
mg/kg/day
Sethi,
1990
Seed Powder
Rat(Charles
Foster)
GD1-GD10
(C-section
on GD20)
Dams
↑
number of
resorptions
Number of
implantations
5F/group
Treated: 54 corporea
lutea, 54
implantations, 44 live
births, 0 still births,
10 resorptions
⇒
10/54 = 18%
abortifacient activity
Oral route
Number of
resorptions
0, 175
mg/kg/day
Fetuses
Number of live
births
Controls: 47 corporea
lutea, 47
implantations, 46 live
births, 0 still births, 1
resorptions
⇒
1/47 =
2% abortifacient
activity
Number of still
births
Malformations
(gross, skeletal
and visceral)
↓
fetal body weight
and fetal crown-rump
length (-41% and -
22% compared to
controls)
Various gross
anomalies including
notably
inverted/everted claw
(18% and 21% vs
0% and 0% in
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Ref. Part Formulation
Species
Duration,
route,
dose
Parameters
Noteworthy
findings
controls), shoulder
joint defect (18% vs
0%), tail kinking
(18% vs 0%) and
clubbing of hind limb
(9% vs 0%)
Visceral anomalies:
neuralpore (18% vs
0%), enlarged neural
canal (6% vs 0%)
Skeletal effects:
nonossified skull
bones (18% vs 0%)
Mital and
Gopaldas,
1986
Seed Powder
Rat(Charles
Foster)
GD1-GD21
(C-section
on GD22)
Dams
None
Body weights,
food consumption
5-8F/group
Oral route
Number of
implantations
0, 5, 20 %
in diet
Number of
resorptions
Placenta weight
Fetuses
Body weight
a
containing 0.6% total steroidal sapogenin;
b
assuming a body weight value of 225 g as mentioned in
the article
Table 9: summary of studies focused on effects on thyroid
Ref. Part Formulation Species Duration,
route,
dose
Parameters
Noteworthy
findings
Tahiliani
and Kar,
2003
Seed Hydro-ethanolic
extract (20%)
Rat
15 days
Serum levels of: T3, T4,
glucose, cholesterol,
AST, ALT
↓
T3 levels (-
40%)
Oral route
(gavage)
No other effect
(notably on
glucose and T4
levels)
0, 220
mg/kg/day
Panda et
al, 1999
Seed Hydro-ethanolic
extract (20%
Mouse
(7M/group)
15 days
Body weight
↑
body weight
Oral route
(gavage)
Serum T3 and T4 levels
Thyroid
hormones:
↓
T3,
↑
T4,
↓
T3/T4 ratio
Hepatic biochemistry:
protein, hepatic lipid
0, 110
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Ref. Part Formulation Species Duration,
route,
dose
Parameters
Noteworthy
findings
mg/kg/day
peroxidation, superoxide
dismutase (SOD)and
catalase (CAT) activities
↓
SOD activity
Rat
15 days
Body weight
↑
body weight
(statistical
significance not
reached)
(7M/group)
Oral route
(gavage)
Serum T3 and T4 levels
Hepatic biochemistry:
protein, hepatic lipid
peroxidation, superoxide
dismutase (SOD)and
catalase (CAT) activities
0, 110
mg/kg/day
Thyroid
hormones:
↓
T3,
↑
T4,
↓
T3/T4 ratio
↓
SOD activity
3.4.
Overall conclusions on non-clinical data
Pharmacology
Fenugreek seeds were shown to induce hypoglycaemic effects in various animal models of diabetes.
The mechanism underlying the hypoglycaemic effect remains unestablished but a number of
hypotheses were found in the literature: local action at the gastro-intestinal level to lower the
absorption of glucose, enhancement of insulin secretion, modulation of glucose metabolism,
stimulation of insulin signalling pathway at the cellular level. Similarly, the compound(s) responsible
for this effect are currently not identified. However, it was established in diabetic dogs that the active
part of fenugreek seeds is the defatted fraction.
A lower number of studies also showed that fenugreek seeds have an hypolipidaemic effect in diabetic
rats, and in both normal and diabetic dogs. It was also shown in dogs that the active part is the
defatted fraction.
No specific safety pharmacology study is available which is acceptable according to current guidelines.
The inhibition of rabbit platelet aggregation with a water extract, and uterine stimulant properties
reported in guinea pigs with a water and ethanolic extracts could however be taken into consideration.
Toxicology
Two 90-day repeat-dose toxicity studies in rats did not identify any target organ, but some doubts
remain regarding the sanitary conditions of the animals in one study due to the occurrence of murine
respiratory mycoplasmosis. In addition, the lack of effects on testes is rather surprising in view of the
testicular toxicity consistently reported in reproduction toxicity studies.
Specific studies conducted in rats with an hydro-ethanolic extract of fenugreek seeds reported a
decrease in T3 levels with concomitant increase in T4 levels and decrease in T3/T4 ratio. These results
suggest decreased conversion of T4 to T3 – unfortunately, TSH levels were not monitored. The
decrease in T3/T4 ratio suggests a decrease in 5’-deiodinase activity.
An ICH-compliant battery of tests did not report any genotoxic effect for a proprietary extract of
fenugreek seeds. However, this extract is not characterized so that these results cannot be taken into
account. Overall, it is considered that relevant information on genotoxicity is lacking. In addition,
conventional carcinogenicity studies are lacking.
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Testicular toxicity was reported in rats treated for 2 or 3 months with either seed powder or the
steroidal fraction of seeds. It was characterized by altered sperm parameters, decreased testis weight,
lowered / arrest of spermatogenesis, and degenerating seminiferous tubules. These effects are
attributed to the treatment-related decrease in testosterone. Therefore, a potential impact on fertility
cannot be excluded.
Three studies showed that fenugreek seeds preparations (extract or powder) could increase the
number of resorptions when given to rats from the first day up to the 10
th
day of gestation. From the
available data, it seems reasonable to conclude that fenugreek seed induces embryolethality in rats.
This conclusion is coherent with the reported historical / theoretical use of fenugreek as an
abortifacient and for labour induction.
The information on embryo-fetal toxicity is rather limited. Available studies showed conflicting results
but were not designed adequately. In this context, the malformations reported in rats by Sethi et al
(1990) have to be considered as a safety signal. In the future, conventional embryo-fetal toxicity
studies in 2 species should be performed to clarify this point.
No information is available regarding potential effects on pre-post-natal development.
Overall, the administration of fenugreek seeds impacted on various components of the endocrine
system: pancreas (effect on insulin levels), thyroid (effect on T3 and T4 levels), and gonads (effects on
testosterone, estrogen and progesterone levels).
Monograph
•
Some warnings could be included for patients treated for diabetes mellitus and thyroid disorders
•
Treatment-related testicular toxicity due to decrease in testosterone levels as well as interference
with thyroid hormone levels were reported in animals. In addition, female hormone levels were
affected in one study in rabbits. In view of the paramount importance of gonads and thyroid during
development, these points should be considered for administration in patients under 18 years of
age.
•
Embryolethal effects could be reported in the monograph. Regarding embryo-fetal toxicity, it
should be indicated in section 5.3 that only limited data are available.
•
The wording proposed for section 5.3 is:
“Tests on genotoxicity have not been performed with preparations of fenugreek covered by this
monograph.
Decreased thyroid hormone levels (T3, triiodothyronine) were reported in rodents treated with hydro-
ethanolic extracts at 110 mg/kg/day and above; a NOAEL was not determined.
Testicular toxicity (altered sperm parameters, decreased testis weight, lowered / arrest of
spermatogenesis, and degenerating seminiferous tubules) was reported in rats treated for 2 to 3
months with either fenugreek seed powder or the steroidal fraction of seeds. These effects are
attributed to the treatment-related decrease in testosterone, and a NOAEL was not determined.
Conventional embryo-fetal and peri-post-natal toxicity studies were not performed. Limited studies
showed conflicting results regarding the occurrence of malformations in rats.”
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4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
Clinical pharmacology on fenugreek is not well documented in humans. The majority of
pharmacological effects have been studied in animals mainly in rats and dogs, and to a lesser extent in
rabbits, either through
in vitro
or
in vivo
experiments to search or reveal the hypocholesterolaemic and
hypoglycaemic effects of fenugreek (see data previously detailed in the non-clinical section).
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
Pharmacokinetic data are not available for all components of fenugreek or for the compound as a
whole. In humans, it has been shown that saponins present in fenugreek are believed to be primarily
absorbed in the terminal ileum as a potential mechanism assessed for its hypocholestaerolemic
activity.
In a rabbit study by Zhao et al aimed at studying the pharmacokinetics of trigonelline determined by
HPLC, after post-intragastric injection of fenugreek extract, the pharmacokinetic parameters of one
compartment model were half-life, t1/2 = 0.9 hour, t1/2 = 2.2 hours, volume of distribution =
0.64 l/kg and AUC = 1.93 mg.min/l.
4.2.
Clinical Efficacy
4.2.1.
Dose response studies
According to the provided literature, no dose-finding studies have been conducted with fenugreek.
According to the WHO monograph, available dosage recommendations are the following:
- for internal use, average daily dose, cut or crushed seed, 6 g or equivalent of preparations; infusions,
0.5 g of cut seed macerated in 150 ml cold water for 3 hours, several cups.
According to the ESCOP monograph, available dosage recommendations are the following:
- for internal use, in adults, as adjuvant therapy in diabetes or for hypercholesterolaemia, 25 g of
powdered seeds or equivalent preparations daily; for lack of appetite, 1-6 g of powdered drug up to
three times daily with water before meals.
- for external use, in adults, as an emollient 50 g of powdered seeds boiled in 250 ml of water for 5
minutes then applied as a warm moist poultice.
4.2.2.
Clinical studies (case studies and clinical trials)
Appetite stimulant effect
The French approved indication stated as follows: “traditionally used to gain weight in adults” is
granted for more than 30 years in France. The traditional use of fenugreek is based on the experience
and historical use of this herbal product in the European Community.
When searching reference to substantiate the efficacy/safety of fenugreek in the literature in this
indication only one reference has been found:
M. Rguibi and R. Belahsen. Fattening practices
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among Moroccan Saharawi Women. Eastern Mediterranean Health Journal, Vol.12, No.5,
2006.
This reference reports a survey of Moroccan Saharawi women as regards their fattening practices for
gaining weight as a socio-cultural willingness of increasing their physical attractiveness.
Use of fenugreek is reported as an appetite enhancer in this survey.
Methodology of the survey
All participants were interviewed face-to-face by an interviewer who belonged to this Saharawi ethnic
group. A discussion guide was developed including questions on sociodemographic characteristics,
satisfaction with their body size, dietary history and practical behaviours used to lose or to gain weight.
To determine the perceptions of body weight, participants were invited to answer the following
questions: Have you wanted to gain weight in the past? Do you want to gain weight now? Do you want
to lose weight now? Participants were asked to describe any actions that they have taken to lose or
gain weight. All fattening practices used by the women were recorded, as well as other details such as
portions size, frequency of eating, food composition and food preparation techniques.
This survey is conducted between October 2001 and April 2002 on a sample of 249 urban non
pregnant women aged 15 to 70 years old, without any previous systemic disease.
Demographic characteristics
•
Women belonging to the Saharawi ethnic group: communication skills in Hassaniyya dialects,
traditional clothing, history of their family’s residence. Informed consent obtained verbally before
they took part to the survey.
•
Body Mass Index (BMI) was calculated as weight (kg) and height (m
2
) The World Health
Organization (WHO) definitions were used for underweight (BMI < 18.5 kg/m
2
), normal weight
(18.5 ≤ BMI < 25 kg/m
2
), overweight (25 ≤ BMI < 30 kg/m
2
) and obesity (BMI ≥ 30 kg/m
2
).
•
Sociodemographic characteristics were recorded: marital status, educational level.
•
Investigations regarding their perceptions of body weight have been recorded as well as their
potential actions that they have taken to lose or gain weight.
Clinical Results
Sociodemographic characteristics of the study sample ( n = 249 women)
Variable
Value
Mean (SD)
Range
Age
(years)
36.8 (11.8)
15.0-70.0
BMI
(kg/m
2
)
29.6 (5.3)
17.3-41.4
Number
Percentage
Marital status
Single
50
20.1
Married
166
66.7
Divorced
19
7.6
Widow
14
5.6
Education
Never attended school
155
62.2
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Sociodemographic characteristics of the study sample ( n = 249 women)
Primary school
47
18.9
Secondary school
47
18.9
The mean BMI was 29.6 kg/m
2
and 30% of women were overweight and 49% were obese.
A
large majority of women (79.9%) described their weight as appropriate and only 50 described it as
inappropriate (8 desired to lose weight and 42 desired to gain it). The desire to gain weight was in
most cases accompanied by practising certain behaviours, for example using drugs, overfeeding and
restriction of physical activity. The fattening practices changed between the past and currently as
shown in the following table.
Fattening practices used by Saharawi women desiring to gain weight
Practice
In the past (n=175)
Currently (n=42)
Appetite stimulant
71 (40.6)
3 (7.1)
Overeating
56 (32.0)
30 (71.4)
Corticosteroids (drugs
intentionally used for their
promotion of weight gain as a
side effect)
41 (23.4)
4 (9.5)
Other
7 (4.0)
5 (11.9)
In addition to the therapeutic medication, the women reported that some seeds such as
fenugreek (halba) consumed directly or added to dishes have been used to stimulate
hunger.
Assessor’s comment:
This study is the main “clinical support” of the use of fenugreek as appetite stimulant besides the
animal data. It is an observational survey where fenugreek is “mentioned” as being used by women
desiring to gain weight. However, the study description does not enable to quantify the use of
fenugreek among the appetite enhancers and ultimately to appreciate the potential contribution of
fenugreek in the weight gain.
Therefore per nature, this observational study is of no relevance to substantiate the efficacy and safety
of fenugreek as appetite enhancer.
To complete the data above, there are some information in the WHO monographs on selected
medicinal plants which are also substantiated to some extent by the literature data, in particular
hypoglycemic/hypolipemiant effects which are described hereafter.
Hypoglycaemic and antihyperlipidemic properties
The possible hypoglycaemic and antihyperlipidemic properties of oral fenugreek seed powder are
suggested in the literature. However, the references suffer from critical methodological limitations
(most available studies are case series lacking proper controls, randomization or blinding
)
precluding
any formal conclusion on these properties.
They could only be regarded as exploratory.
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As an illustration, the Rapporteur will particularly describe one
recent
study (2009) from Chevassus et
al and a
long-term
study from Sharma et al, 1996.
•
A fenugreek seed extract selectively reduces spontaneous fat consumption in healthy volunteers.
Chevassus H
,
Molinier N
,
Costa F,
Galtier F
,
Renard E
,
Petit P.
Eur J Clin Pharmacol.
2009
Dec;65(12):1175-8. Epub 2009 Oct 7.
Aim
The aim of the study was to investigate the effects of a repeated administration of a fenugreek seed
extract on the eating behaviour of overweight subjects.
Study design
The study was designed as a 6-week double-blind randomized placebo-controlled parallel trial.
Data analysis and statistics
The sample size (40 subjects to be enrolled in two groups of 20) was determined using data obtained
in a previous study, with an expected mean difference for energy consumption (main outcome)
between the fenugreek seed extract and placebo of 216 kcal per day, a common standard deviation
(SD) of 238 kcal per day, a two-sided alpha of 0.05 and statistical power of 80%.
Test compound
The test compound was a marketed dry hydro-alcoholic fenugreek seed extract administered three
times daily as oral coated tablets. The total daily dose of 1176 mg (approximately 14 mg kg
-1
) is
double the daily dose of extract commonly prescribed for human consumption.
Investigations
The diet and physical activity of the patients were assessed under free-living conditions before and at
the end of the ambulatory treatment period, using a 7-day record that was reviewed by a trained
dietician and a physician for its accuracy. The main
endpoints
were
energy intake
, assessed in
volunteers under normal ambulatory and free-living conditions by a 3-day detailed dietary record and
during a meal test,
weight
,
fasting glucose level, insulin and lipid profile, visual analogue
scale scores of appetite/satiety and blood glucose and insulin levels
measured repeatedly after
a standardized breakfast.
Reported energy intake (REI) was determined with Enkal-Pro software, and total energy expenditure
(TEE) was calculated as basal metabolic rate (BMR) multiplied by physical activity level (PAL). Energy
intake was defined as a ratio REI/BMR<1.1.
Subjects
Thirty-nine healthy overweight male volunteers, aged 18-59 years (mean 38 years) completed this
study. All were of stable weight (mean weight 85.4 kg, range 75.2-105.5; mean body mass index
27.3 kg m
-2
; range 24.9-29.4). One subject among the 40 initially enrolled was withdrawn from the
study before the first administration of the drug due to partaking in a non-authorized treatment.
Assessor’s comment:
Referring to an hydro-alcoholic fenugreek containing medicinal product in France the dose received
would represent around twice the dose recommended in the posology section.
Results
Daily fat consumption
was significantly decreased by the higher dose of fenugreek seed extract
[3.73 vs. 4.51 MJ day(-1), -17.3% vs. placebo, 95% confidence interval (CI) -1.51 to -0.05, n = 12,
P = 0.038]. This specific reduction tended to lower the
total energy intake
(9.97 vs. 11.29 MJ day (-
1), -11.7% vs. placebo, 95% CI -2.91 to 0.26, n = 12,
P = 0.094
).
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Table 1
Comparison of fasting data of plasma glucose, serum insulin and lipid profile between healthy
overweight subjects receiving fenugreek seed extract 1176 mg/day and those receiving placebo
Main metabolic parameters
Fenugreek
Placebo
P
Fasting plasma glucose (mmol 1
-1
)
-Baseline
-Post-treatment
4.61±0.21
5.38±0.10
4.87±0.19
5.26±0.16
0.355
0.545
Fasting serum insulin (mU 1
-1
)
-Baseline
-Post-treatment
5.10±0.41
4.73±0.43
5.02±0.31
5.38±0.36
0.887
0.057
Fasting insulin/glucose ratio (Mu mmol
-1
)
-Baseline
-Post-treatment
1.17±0.13
0.89±0.09
1.07±0.08
1.06±0.10
0.708
0.044
Total cholesterol (mmol 1
-1
)
-Baseline
-Post-treatment
4.82±0.26
4.88±0.25
5.19±0.19
5.06±0.20
0.254
0.207
HDL-cholesterol (mmol 1
-1
)
-Baseline
-Post-treatment
1.27±0.05
1.30±0.05
1.22±0.08
1.17±0.07
0.555
0.067
Triglycerides (mmol 1
-1
)
-Baseline
-Post-treatment
1.25±0.15
1.27±0.16
1.15±0.11
1.41±0.14
0.732
0.148
Values are given at the mean ± standard error of the mean (SEM)
The ratio of fasting serum insulin/plasma glucose was significantly decreased in subjects treated with
fenugreek seed extract relative to the placebo group [0.89±0.09 (n=19) vs 1.06±0.10 (n=19) mUI
mmol-1, respectively. No effect on plasma lipid profile, antioxidant parameters and oxidative stress
markers were observed.
Authors’ conclusions
: The repeated administration of a fenugreek seed extract slightly but significantly
decreased dietary fat consumption in human volunteers in this short-term study.
Assessor’s comments:
According to the authors, the lower ratio of fasting serum insulin/plasma glucose may reflect an
improved insulin sensitivity. However, still as underlined by the authors, this property cannot be
regarded as established and specific investigations would be required. This is all the more disputable
that in this study FPG even increases from baseline to post-treatment (4.61 mmol/L to 5.38 mmol/L).
As regards the lipid parameters, the trend is rather towards an increase of total cholesterol and
triglycerides, the only “positive” trend being a slight and non-significant increase of HDL.
•
Sharma RD et al. Use of fenugreek seed powder in the management of non-insulin dependent
diabetes mellitus. Nutrition Research, 1996, 16:1331-1339
Study population
Sixty patients with mild (22), moderate (35) and severe (7) non insulin dependent diabetes mellitus
(NIDDM) were registered for the study. These patients were drawn from the outpatients diabetic
clinics, OPD and the Postgraduate Department of Medicine, S. N. Medical College, Agra (India). Of
these 45 were male patients and 15 female. Their ages ranged between 30 to 70 years.
According to body mass 21 were obese and 39 non-obese. Twenty six patients had multiple
complications. Twenty one patients had hypertension, 18 patients suffered from diabetic neuropathy, 2
were suffering from diabetic nephropathy, 2 showed retinopathy, 8 had angina and 8 developed
myocardial infarction.
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All patients registered had uncontrolled blood glucose levels. They were not taking adequate
medicine due to either poverty or ignorance
. Poor patients who could not afford adequate food
were given suboptimal doses of drugs. Initially, 18 patients took Dionil, 4.72 mg Glibenclamide daily.
Eight patients took Glycophage, 1.06 mg of Metform daily. A combination of both drugs i.e. Dionil +
Glycophage was taken by 5 severe diabetic patients, 17 mg of Glibenclamide + 1.7 mg Metform daily.
Nine patients took other drugs of Homeopathy treatment. Twenty patients did not take any medication
for diabetes.
Long-term data up to 24 weeks are available in this study.
A control group comprised of 10 subjects was also run simultaneously
. This group was drawn
from staff of S. N. Medical College, Agra. Of these, 7 were male and 3 females. Their ages, like study
group patients, ranged between 30 to 70 years.
In the beginning of the study, both control and diabetic subjects were put on a prescribed diet
comprising of 300 g carbohydrate for seven days of the control period. For the estimation of basal
parameters, glucose tolerance test with 75 g glucose load was initially performed for each subject.
For
the long-term follow up study diabetic patients were asked to continue to consume the
prescribed diet in addition to 25 g fenugreek seed powder divided into two doses at lunch
and dinner.
Glucose tolerance test (GTT) was performed for each subject at an interval of 4, 8, 12 and 24 weeks.
Results
Both control and experimental diets provided similar calories and had similar nutrient composition
except fibre content which was higher in the fenugreek seed powder diet.
The food and mean energy intake of diabetic subject during control and experimental periods were
almost similar and constant. The mean energy intake being 2056±289 kilo calories, of which 63±5.1%
was derived from carbohydrates, 18±2.8% from fat and 19.1±2.7% from protein.
There was no significant change in the body mass for these two groups.
A significant fall in serum levels were observed at ½ hr, 1 hr and 2 hr during GTT. Although fasting
levels of insulin remained unchanged, mean insulin area was reduced significantly (p<0.05).
Table1
Blood glucose and insulin levels and the area under the curve for diabetic subjects before and after
administration of fenugreek seed powder.
Time (hr)
Blood glucose (mmol/L)
Serum insulin (Mu/L)
Initial
24
th
week
Initial
24
th
week
0 hr
8.4±0.3@
6.2±0.3**
16.2±8.9
17.3±1.3
1/2 hr
11.9±0.4
6.9±0.9**
31.2±5.2
22.9±2.1*
1 hr
13.6±0.5
10.9±0.6**
40.3±3.9
33.4±2.8*
1.5 hr
14.6±0.5
10.7±0.6**
-
2 hr
14.6±0.6
9.5±0.6**
38.2±2.5
25.8±2.2*
Mmol/L/min
Mu/L/min
Area under the
curve
593.8±31.1
351±32.9**
2892.8±510.0
1786.4±188.5*
@ = mean ± S.E.
Level of significance for comparison of initial versus 24
th
week values.
In 10 diabetic patients, 24 hr urinary sugar was estimated at the beginning and at the 8
th
week after
fenugreek seed powder administration. A fall of 13% in urinary sugar was observed which was found to
be statistically significant (p<0.001) (table 2).
Glucosylated haemoglobin was also determined
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initially and at the end of 8
th
week
.
A highly significant reduction was observed with a
percentage decrease of 12.5% as compared to initial values (table 2)
Table 2
Urinary sugar and glycosylated haemoglobin levels in diabetic subject before and after administration
of fenugreek seed powder
Weeks
Urinary (mmol/24 hr)
Serum glycosylated haemoglobin
(%)
Initial
76.7±1.7
@
9.6±1.9
8 weeks
43.3±4.3**
8.4±1.4**
@ = mean ± S.E
Level of significance initial versus 8th week (** p<0.001)
The degree of glycaemic control was assessed by measuring 2 hr post-prandial blood sugar levels
initially and at the 24
th
week of fenugreek seed powder ingestion. At the end of this study, 46.7% of
these patients showed full glycaemic control, 33.3% showed moderate glycaemic control, and 20%
exhibited minimal glycaemic control (table 3).
Table 3
Percent distribution of patients according to glycaemic control at the initial and 24
th
week of fenugreek
seed powder administration to NIDDM patients
Postprandial blood sugar
(mg/ml)
Initial study (%)
24
th
week study (%)
>140 (full glycaemic control)
5
46.7
140-180 (moderate glycaemic
control)
21.7
33.3
< 180 (minimal glycaemic
control)
20.0
Assessor’s comments:
As compared to other literature data, this study presents the interest of providing long-term data as
well as data on glycosylated haemoglobin. Unfortunately, there are critical limitations precluding any
reliable interpretation. The sample size is limited and the population is heterogeneous. It is unclear to
what extent the control group can be regarded as a valid control group for adequately estimating the
true contribution of fenugreek in the patient’s diet in terms of glycemic control. It is very unlikely that
the significant (1.2%!) change in glycosylated haemoglobin could be put at the credit of fenugreek.
Indeed, these patients badly controlled for their diabetes before the study entry, appear to have
benefit from standard treatments after inclusion. It is unclear whether both the experimental and
control groups have received superimposable therapeutic, biological and clinical monitorings for
enabling an adequate assessment of the fenugreek effect.
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No clinical data are available in children.
4.3.
Overall conclusions on clinical pharmacology and efficacy
When scrutinizing the published literature to substantiate the clinical efficacy of fenugreek in the
adopted indications, it has to be acknowledged that the data are scarce and of poor relevance
.
The effect of fenugreek then more relies on a traditional use than on a well-established use.
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5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
•
The safety and efficacy of
Trigonella foenum-graecum
extract was investigated by Abdel-Barry et al
in 20 male volunteers aged 20-30 years. They were randomly treated with either 40 mg/kg
aqueous extract powder in 10 ml distilled water or 10 ml distilled water in which coffee simulated
the extract. A significant reduction of 14.1% was observed in potassium levels. No significant
alteration in serum cholesterol, total serum protein and blood urea occurred. Approximately one-
third experienced feelings of hunger, increased micturition frequency or dizziness during the 24
hours after ingestion. The authors concluded that the hypokalaemic effect of fenugreek merits
further investigation.
•
Adverse events including transient diarrhoea and flatulence have been reported in studies
evaluating the effects of fenugreek on blood glucose (Sharma RD et al., 1996).
•
Some patients developed dyspepsia and mild abdominal distension after fenugreek seeds intake in
one double blind placebo controlled study Gupta et al, 2001) evaluating the effects of
Trigonella
foenum-graecum
seeds on glycaemic control and insulin resistance. Twenty-five patients were
enrolled, and 12 received 1 mg/d hydro-alcoholic extract of fenugreek seeds. The 13 other patients
received usual care (dietary control, exercise) and placebo. Duration of the study was 2 months.
Assessor’s comments:
It should be pointed out that the number of patients included in these studies is very limited. However,
the administration of fenugreek seems to be potentially associated
with digestive disorders,
dizziness, and increase in micturition frequency
. We agree that no conclusions can be drawn with
regards to the reduction of potassium levels observed in the first study.
5.2.
Patient exposure
Not applicable.
5.3.
Adverse events and serious adverse events and deaths
Three publications highlight the risk of allergy after fenugreek ingestion, inhalation or external
application:
•
The first publication (Patil SP et al, 1997) reports two cases of immediate allergy following
inhalation, and external application of fenugreek seed powder. In the first case, inhalation of the
fenugreek seed powder resulted in rhinorrhoea, wheezing, and fainting. The second case was of a
patient with chronic asthma who developed numbness of head, facial angioedema, and wheezing
after application of fenugreek paste to her scalp as a treatment for dandruff. Skin scratch test was
performed with fenugreek and revealed strong sensitivity to fenugreek and chickpeas.
Immunoblots demonstrated binding of specific IgE from the patients' sera with the protein from
extracts between 20 kD to 70 kD bands.
•
The second one reports one case of bronchospasm after inhalation of curry powder (Ohuma et al,
1998).
•
The last case report involves one patient having used fenugreek powder orally as an appetite
stimulant and topically as a healing agent (Bessot et al, 1996). He experienced asthma and
rhinitis. The prick test performed with fenugreek powder was strongly positive.
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Three publications report a false diagnosis of maple syrup urine disease owing to ingestion
of herbal tea:
•
The first case (Sewell et al, 1999) involved a five-week old Egyptian infant had a 10-minute
episode of unconsciousness
while drinking bottled tea. He recovered spontaneously, but
the
parents nevertheless sought medical attention. On admission,
the child was in good clinical
condition and alert, and the
physical examination was unremarkable. The child exuded a
specific aroma
and a spontaneously voided urine sample
had a similar aroma. This observation
initiated emergency evaluations
of metabolic amino acids and organic acids to rule out maple
syrup urine disease; the results of all tests were normal. The
parents mentioned that they had
given their child an herbal
tea (Helba tea) to reduce flatulence and prevent fever. This
tea
contains seeds of fenugreek (
Trigonella foenum-graecum
L
.
).
Analysis of the infant's urine by
enantioselective multidimensional
gas chromatography and mass spectrometry revealed the
presence
of sotolone, the compound responsible for the aroma in maple
syrup urine disease.
The tea prepared from fenugreek seeds
was found to contain sotolone.
•
Two similar reports were published earlier in 1981 (Bartley et al) and 2001 (Korman et al).
One publication reports one case of aplastic anaemia in one 51 year-old woman having taken 3 dietary
supplements (during a 30-day herbal program). The product packaging listed a total of 39 plant-based
products, including fenugreek. The woman received transfusions of red blood cells and platelets and
was later discharged feeling well (Smereck et al, 2009).
Assessor’s comments:
According to these data, the local application as well as inhalation or ingestion of fenugreek have been
associated with
allergic reactions, sometimes serious
. Positive skin scratch test and prick test in
two of the three case-reports demonstrate the responsibility of fenugreek.
The risk of false
diagnosis of maple syrup urine disease and potential unnecessary investigations in young
children will not be introduced
in the monograph as fenugreek is not recommended for children
and adolescents under 18 years of age because of incomplete safety data.
5.4.
Laboratory findings
N/A
5.5.
Safety in special populations and situations
Drug interactions
An interaction between fenugreek and warfarin has also been retrieved in 2 publications, including one
case report (Heck et al, 2000 and Lambert et al, 2001). The case report involved a patient who was
treated with warfarin for atrial fibrillation. During treatment, an increase in international normalized
ratio (INR) and the patient’s admission that she was taking a variety of natural products, to include
boldo and fenugreek, led the authors to suspect that some of these natural products could alter the
effect of warfarin. When the patient stopped the herbal products, the INR returned to normal after 1
week. The herb-drug interaction was observed a second time, after both products were reintroduced a
few days later. The imputability of this interaction to both natural products, as determined by the
Naranjo algorithm, suggests a probable association between boldo-fenugreek and increased bleeding
time in patients treated with warfarin. No undesirable reaction was reported during telephone
discussions with the patient. Nevertheless, the authors recommend that clinicians treating patients
with anticoagulant therapy be vigilant when patients also take herbal agents.
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Assessor’s comments :
The data regarding a possible interaction with oral anticoagulants are definitely too sparse, and the
evidence is very weak.
Only one clinical case is available (Lambert JP, Cormier A in Pharmacotherapy, 2001:21:509-12). The
patient showed slight increases of her INR values, usually comprised between 2 and 3, and which
increased to 3.1 after one week of the combination and to 3.4 after two weeks.
Firstly, these increases are to be considered slight. Moreover, the patient seemed to present with
memory disorders (“
It was difficult to make a precise list of OTC and natural products consumed
because the patient has some memory confusion”
). Moreover the authors themselves appear
disbelieving (“
we did experience some difficulty in obtaining the exact name of the various OTC
products the woman consumed. It is not impossible that she may have omitted or forgotten to mention
some change in nutrition such as decreased consumption of food rich in vitamin K or excessive
consumption of alcohol
”).
The French Pharmacovigilance Database with 22 reports of patients receiving fenugreek as an active
substance did not reveal any case sustaining this hypothesis.
Taking into account all these elements, it is considered not suitable to add a specific warning in the 4.5
section of the monograph as regards this putative, poorly documented, far not proven interaction.
Use in pregnancy and lactation
In one study, both water and alcoholic extracts of fenugreek exerted a stimulating effect on the
isolated guinea pig uterus, especially during late pregnancy. As a result, the authors concluded that
fenugreek may possess abortifacient effects
, and is not recommended for use in doses higher
than those found in foods during pregnancy (Abdo et al, 1969)
Assessor’s comments:
No data are available in humans regarding pregnancy and lactation. As a precautionary measure, the
use of fenugreek should not be recommended in this population.
Overdose, Drug abuse
No data available.
Withdrawal and rebound
No data available.
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.6.
Overall conclusions on clinical safety
Data from the literature have enabled to identify mainly two kinds of adverse effects after fenugreek
intake:
digestive disorders and allergic reactions
. Other adverse effects have however been
reported in some studies: dizziness and increase of micturition frequency.
The risk of false diagnosis of maple syrup urine disease and potential unnecessary investigations
underlined in young children will not be introduced in the monograph as fenugreek is not
recommended for children and adolescents under 18 years of age because of incomplete safety data.
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Taking into account all the elements mentioned above regarding the potential risk of interaction
between fenugreek and anticoagulants (page 40/41), it is considered not suitable to add a specific
warning in the 4.5 section as regards this putative, poorly documented, far not proven interaction.
6.
Overall conclusions
Fenugreek containing preparations are reported as being on the EU market for more than 30 years in
products for oral use in lack of appetite (Poland and France) and in products for external use for skin
inflammation treatment (Poland). Only the preparations which have been used for at least 30 years are
described in the monograph.
Nevertheless, when scrutinizing the published literature to substantiate the clinical efficacy of
fenugreek in the first indication, it has to be acknowledged that the data are scarce and of poor
relevance in adults.
The clinical data are of poor relevance in adolescents. In children, no efficacy data are available,
clinical experience is sparse and mainly through case reports of adverse events.
The literature data appear to be relatively more abundant as concern the hypoglycaemic and
hypolipemiant
properties
of fenugreek, however, due to significant methodological deficiencies and
inconsistencies, still without providing adequate demonstration of their
clinical impact
.
Finally, the cutaneous clinical use of fenugreek for skin inflammation is not substantiated in the
literature data.
Consequently, the effect of fenugreek is plausible and relies on a traditional use (data
cannot substantiate a well-established use).
As regards the safety profile of fenugreek, it is mainly characterized by
digestive disorders and
allergic reactions
.
The use of fenugreek in pregnant women should be avoided, in view of the uncertainties surrounding a
beneficial effect of this plant on one hand and the uterine stimulant properties reported in animal
studies (even justifying an historical use as an abortifacient) on the other hand.
The use in children and adolescents under 18 years of age is not recommended because of incomplete
data on safety.
Available genotoxicity data do not allow the inclusion of Trigonellae foenugraeci semen in the list of
herbal substances, preparations and combinations thereof for use in traditional herbal medicinal
products.
Annex
List of references
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