COMMUNITY HERBAL MONOGRAPH ON
HARPAGOPHYTUM PROCUMBENS
D.C.
AND/OR
HARPAGOPHYTUM ZEYHERI
DECNE, RADIX
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
Harpagophytum procumbens
DC. and/or
Harpagophytum zeyheri
Decne, radix
(devil’s claw root)
i) Herbal substance
Cut dried tuberous secondary root
ii) Herbal preparations
Powdered herbal substance
Comminuted herbal substance
Liquid extract (1 : 1 ; 30% V/V ethanol)
Soft extract (2.5-4.0 : 1 ; 70% V/V ethanol)
Dry extract (1.5-2.5 : 1 ; water)
Dry extract (5-10 : 1 ; water)
Dry extract (2.6-4 : 1 ; 30% V/V ethanol)
Dry extract (1.5-2.1 : 1 ; 40% V/V ethanol)
Dry extract (3-5 : 1 ; 60% V/V ethanol)
Dry extract (3-6 : 1 ; 80% V/V ethanol)
Dry extract (6-12 : 1 ; 90% V/V ethanol)
Well-established use
Traditional use
Herbal substance or herbal preparation in solid or
liquid dosage forms or as herbal tea for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Ph. Eur. monograph (ref.:1095, current edition).
2
The declaration of the active substance(s) for an individual finished product should be in accordance with
relevant herbal quality guidance.
EMEA 2008
2/7
4.1.
Therapeutic indications
Well-established use
Traditional use
a) Traditional herbal medicinal product for relief
of minor articular pain.
b) Traditional herbal medicinal product used for
the relief of mild digestive disorders such as
bloating and flatulence and where there is loss
of appetite.
The product is a traditional herbal medicinal
product for use in specified indications
exclusively based on long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults
Indication a)
Daily dose
i) Herbal substance
Dried root : 4.5 g in 500 ml water as herbal tea
divided in 3 doses
ii) Herbal preparations
A)
Comminuted herbal substance: 4.5 g in
500 ml water as herbal tea divided in
3 doses
B)
Powdered herbal substance: 1.35 g
divided in 3 doses
C)
Liquid extract (1 : 1 ; 30% V/V ethanol):
15 ml
D)
Soft extract (2.5-4.0 : 1 ; 70% V/V
ethanol):
10 ml
E)
Dry extract (1.5-2.5 : 1 ; water): 300 mg
to 2.4 g divided in 2 to 3 doses
F)
Dry extract (5-10 : 1 ; water): 600 to
800 mg divided in 2 to 3 doses
G)
Dry extract (2.6-4: 1 ; 30% V/V ethanol):
460 mg up to 1.6 g divided in 2 to 4
doses
EMEA 2008
3/7
H)
Dry extract (1.5-2.1 : 1 ; 40% V/V
ethanol): 600 mg to 2.7 g divided in 2 to
3 doses
I)
Dry extract (3-5: 1 ; 60% V/V ethanol):
960 mg divided in 2 to 4 doses
J)
Dry extract (3-6 : 1 ; 80% V/V ethanol):
300 mg divided in 3 doses
K)
Dry extract (6-12 : 1 ; 90% V/V ethanol):
90 mg divided in 2 doses
Indication b)
Daily dose
i) Herbal substance
Dried root: 1.5 g in water divided in three
doses
ii) Herbal preparations
Soft extract (2.5-4.0 : 1 ; 70% V/V ethanol):
10 ml
Indications a) and b)
Not recommended for use in children and
adolescents under 18 years of age (see section 4.4
‘Special warnings and precautions for use’).
Duration of use
Indication a)
Note to be taken for more than 4 weeks.
Indication b)
Duration of use should be restricted to a
maximum of 2 weeks.
If the symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Method of administration
Oral use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
EMEA 2008
4/7
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under
18 years of age is not recommended because of
the lack of available experience.
Articular pain accompanied by swelling of joints,
redness or fever should be examined by a doctor.
As a general precaution, patients with gastric or
duodenal ulcer should not use devil’s claw root
preparations.
Caution should be taken when Harpagophytum is
administered to patients affected by
cardiovascular disorders.
If the symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
For liquid 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
Not known.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
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.
EMEA 2008
5/7
4.8.
Undesirable effects
Well-established use
Traditional use
Gastrointestinal disorders: diarrhoea, nausea,
vomiting, abdominal pain.
Central Nervous system disorders: headache,
dizziness.
Skin disorders: allergic skin reactions
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
No case of overdose has been reported.
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.
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 reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
EMEA 2008
6/7
Well-established use
Traditional use
Not applicable.
6 November 2008
EMEA 2008
7/7
Assessment Report
I. REGULATORY OVERVIEW
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ‘Not Known’
Member State
Regulatory Status
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Only fixed combination
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
No products
Finland
MA
TRAD
Other TRAD
Other Specify:
No products
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Healing products
Iceland
MA
TRAD
Other TRAD
Other Specify:
No products
Ireland
MA
TRAD
Other TRAD
Other Specify:
No products
Italy
MA
TRAD
Other TRAD
Other Specify:
Food supplements
Latvia
MA
TRAD
Other TRAD
Other Specify:
No products
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 products
Norway
MA
TRAD
Other TRAD
Other Specify:
No products
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
No products
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
No products
Á EMEA 2009
2/26
II.
ASSESSMENT REPORT
ON HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR
COMBINATIONS THEREOF WITH TRADITIONAL USE
Harpagophytum procumbens
DC. and/or
Harpagophytum zeheyri
Decne, radix
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
(TRADITIONAL USE)
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Harpagophytum procumbens
DC. and/or
Harpagophytum zeyheri
Decne, radix
Herbal preparation(s)
Dry extracts
Soft extracts
Liquid extracts
Powdered herbal substance
Comminuted herbal substance
Pharmaceutical forms
Herbal substance or herbal preparation in solid or
liquid dosage forms or as herbal tea for oral use.
Rapporteur
Antoine SAWAYA
Assessors
Pharmaceutical:
Jacqueline VIGUET POUPELLOZ
Non-Clinical:
Fabien LAVERGNE
Clinical (rheumatology):
Sylvain GUEHO
Pharmacovigilance:
Nathalie DELEAU
Interactions:
Beatrice SAINT-SALVI
Á EMEA 2009
3/26
II.1
INTRODUCTION
II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations
thereof
Herbal substance(s)
2,3
: Cut dried tuberous secondary root of
Harpagophytum
procumbens
DC. and/or
Harpagophytum zeyheri
Decne
Herbal preparation(s)
1,2
: Powdered herbal substance, comminuted herbal substance,
liquid extract (1 : 1 ; 30% V/V ethanol), soft extract (2.5-4.0 : 1 ; 70% V/V ethanol),
dry extract (1.5-2.5 : 1 ; water), dry extract (5-10 : 1 ; water), dry extract (2.6-4 : 1 ;
30% V/V ethanol), dry extract (1.5-2.1 : 1 ; 40% V/V ethanol), dry extract (3-5 : 1 ;
60% V/V ethanol), dry extract (3-6 : 1 ; 80% V/V ethanol), dry extract (6-12 : 1 ;
90% V/V ethanol)
The characteristic constituents are iridoid glucosides (0.5 – 3 %): harpagoside, harpagide,
8-(4-coumaroyl)-harpagide, procumbide, its 6
-4-coumaroyl ester and procumboside. The European
Pharmacopoeia prescribes no less than 1.2% of harpagoside.
Harpagoside
Harpagide
The other constituents are principally sugars (stachyose, raffinose and monosaccharides) and phenolic
glycosides (verbascoside and isoacteoside).
II.1.2 Information on period of medicinal use in the Community regarding the specified
indication
The first herbal medicinal product has been authorized in Germany in 1978. Some products are
marketed also in Belgium, in Denmark, in France, in Hungary and in Malta.
The different herbal medicinal products on the market are prepared with powder, aqueous extract or
ethanolic extracts (30 - 40% V/V, and 60 - 90% V/V)
II.2
NON-CLINICAL DATA
II.2.1 I
NTRODUCTION
Harpagophytum procumbens
belongs to the
Pedaliacea
family. This perennial herbaceous plant grows
naturally in the Kalahari desert and Namibian steppes region of south-west Africa. Its secondary
tuberised roots, commonly called “Devil’s claw” because of their shape, have been widely used in
2
According to “Guideline on quality of herbal medicinal products/traditional herbal medicinal products”
(CPMP/QWP/2819/00 Rev. 1)
3
According to “Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations
and herbal medicinal products/traditional herbal medicinal products” (CPMP/QWP/2820/00Rev.1)
Á EMEA 2009
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traditional medicine for various indications. In Europe, it is used for painful arthritis, tendinitis, loss of
appetite and dyspeptic complaint [
Baghdikian
et al.
1997
].
Studies quoted in this document were not performed in compliance with GLPs. Most of them were
conducted to evaluate the pharmacodynamics of
Harpagophytum procumbens
secondary roots extracts
referred to as “
Harpagophytum procumbens
extracts” in the following pages. Other non-clinical data
(pharmacokinetics, toxicology) are scarce.
II.2.2
P
HARMACODYNAMICS
II.2.2.1 Primary pharmacodynamics
II.2.2.1.1
Analgesic effect
Writhing test
An aqueous extract of
Harpagophytum procumbens
(containing 2.2% harpagoside) was tested for its
analgesic activity in the writhing test. It was administered intraperitoneally to male Swiss mice at the
following dose levels: 100, 400, 800 and 1200 mg/kg [
Baghdikian
et al.
1997
]. Acetylsalicylic acid
(Aspegic
Ò
) was used as a reference peripheral analgesic compound at the dose of 68 mg/kg. Control
animals received 0.9% NaCl solution under the same experimental conditions. Thirty minutes after
these administrations, the animals were injected a 1.2% acetic acid solution by intraperitoneal route.
Each animal was then isolated and observed for 30 minutes. During this period, the number of
writhings and stretchings was recorded. The percentage of protection against the acetic acid algic
effect was then calculated for each group.
The results indicated that
Harpagophytum procumbens
dose-dependently decreased the number of
writhings and stretchings from the 400 mg/kg dose (35% protection). The maximal effect was
observed at 1200 mg/kg, the percentage of protection reaching 62%. Comparatively, acetyl salicylic
acid (68 mg/kg) induced a protection of 59% [
Baghdikian
et al.
1997
].
Another experiment was performed according to the same protocol, to study the analgesic activity of a
standardized aqueous extract of
Harpagophytum procumbens
containing 1.8% harpagoside (50, 100,
200 and 400 mg/kg) and harpagoside (5 and 10 mg/kg). Acetylsalicylic acid (68 mg/kg) and morphine
sulphate (1.15 mg/kg) were used as reference peripheral/central analgesic compounds. The results
indicated that
Harpagophytum procumbens
dose-dependently decreased the number of writhings and
stretchings from the 100 mg/kg dose (47% protection). The maximal effect was observed at
400 mg/kg, the percentage of protection reaching 78%. Harpagoside exerted a protective effect against
the painful stimuli at the dose of 10 mg/kg only (10 mg harpagoside corresponding to twice the
harpagoside content of 400 mg extract) [
Lanhers
et al.
1994
].
The acid treatment of the extract and harpagoside (HCl 0.1 N (pH 1) during 3 hours at 38°C),
performed to reproduce the physico-chemical conditions found in the stomach, abolished their
analgesic activity in the writhing test [
Lanhers
et al.
1994
].
Hot plate test
The same authors evaluated the protection potential of the extract and harpagoside against heat-
induced pain [
Lanhers
et al.
1994
]. Male Swiss mice were placed in a glass flack bathing in water
whose temperature was maintained at 56°C. Reaction times of mice before any treatment were
recorded – time to obtain a response to heat stimuli, e.g. licking of the forepaws, jumping. Then, mice
were intraperitoneally injected the extract (200 and 400 mg/kg) or harpagoside (10 mg/kg).
Acetylsalicylic acid (68 mg/kg) and morphine sulphate (4.6 mg/kg) were used as reference substances.
The procedure to measure time reactions was repeated after 30 minutes. Each animal was its own
control.
In this test,
Harpagophytum procumbens
, harpagoside and acetylsalicylic acid did not increase the
reaction time of mice. On the contrary, morphine sulphate (4.6 mg/kg) exerted a significant protective
effect on heat-induced pain, as the reaction time was increased by 46% 30 minutes after its
administration.
Á EMEA 2009
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Assessor’s comments
Analgesic activity of Harpagophytum procumbens and harpagoside was evaluated in two murine
models. In these models, pain was induced either chemically by intraperitoneal injection of acetic acid
(writhing test), or thermally (hot plate test). In these experiments, test articles were administered by
intraperitoneal route.
Harpagophytum procumbens had a dose-dependant protective effect against the pain induced by
acetic acid. The lowest effective dose varied from 100 to 400 mg/kg, according to the extract used.
In the same animal model, harpagoside was only effective at the dose of 10 mg/kg, which represents
twice the harpagoside dose contained in 400 mg of the extract effective at 100 mg/kg. Therefore, the
authors concluded that other substances (than harpagoside) are involved in the analgesic activity of
Harpagophytum procumbens
[
Lanhers
et al.
1994
]
. However, these substances remain unknown.
Moreover, the extract and harpagoside were submitted to an acid treatment whose aim was to mimic
the physico-chemical conditions found in the stomach. The substances obtained were then evaluated
for their analgesic activity in the writhing test, according to the same protocol (i.p. route). The results
indicated that their protective effect against chemical-induced pain observed previously was
abolished. Although the gastric degradation of active substances involves other phenomena
(enzymatic action, absorption, intestinal resorption), this would suggest that Harpagophytum
procumbens is not effective in terms of analgesia when administered orally.
In the hot plate test, like acetylsalicylic acid, but contrary to morphine sulphate, Harpagophytum
procumbens was ineffective. Therefore, it does not possess any central analgesic properties.
In summary, Harpagophytum procumbens possesses peripheral analgesic properties after
intraperitoneal administration, as shown in the writhing test in mice. Studies performed with
harpagoside suggest that other unidentified substances are involved in this analgesic effect, but these
active substances remain unknown. Effective doses are not accurately defined, as they can change
according to the extract used. A study performed after the acid treatment of an extract suggested that
Harpagophytum procumbens could be ineffective by oral route in terms of analgesia.
II.2.2.1.2 Anti-inflammatory effect
II.2.2.1.2.1 Isolated substances (harpagoside, harpagogenin)
Three animal models of inflammation were used:
-
the carrageenan-induced mouse/rat paw oedema [
Lanhers
et al.
1994
;
Recio
et al.
1994
].
-
the TPA-induced mouse ear oedema [
Recio
et al.
1994
].
-
the granuloma pouch test [
Eichler
and Koch 1970
].
·
Carrageenan-induced mouse paw oedema [Recio
et al.
1994]
This study was designed to evaluate the anti-inflammatory activity of harpagoside (100 mg/kg) and
11 other iridoids administered orally to female Swiss mice. Control animals received the vehicle in the
same conditions. Indomethacin at the dose of 7 mg/kg was used as a reference product. Each group
was composed of 6 mice.
One hour after these administrations, each mouse was injected a 3% w/v suspension of carrageenan in
its right hind paw to induce oedema. The volumes of the injected and contra-lateral paws were
measured at 1, 3 and 5 hours after the induction of inflammation.
The values of the oedema volume and the oedema inhibition percentage were calculated for each
group. The authors considered that harpagoside administered orally did not exert a notable protective
effect in this test.
·
Carrageenan-induced rat paw oedema [Lanhers
et al.
1994]
Male OFA rats were administered harpagoside by intraperitoneal route at the doses of 5 and 10 mg/kg.
In the same conditions, indomethacin (2.5, 5 and 10 mg/kg) was used at a reference product and the
controls received 0.9% NaCl solution. Twelve rats per harpagoside group were used, as well as
Á EMEA 2009
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13 control rats and 10 rats per indomethacin group. Thirty minutes after these administrations, each rat
received a subplantar injection of a 1% carrageenan suspension in its right back paw.
The average volume of the back paws of each animal were measured before any treatment and at
different time points after the injection of the carrageenan suspension (30 min, 1, 2, 3, 4, 5, 6 and
24 hours). For each group, the following data were then calculated: average volumes of the back paws
before treatment and at the different time points, and percentages of variation (percentages of
oedema).
In control animals, a local oedema was observed 30 minutes after the injection of the carrageenan
suspension, and reached a maximal intensity after 3 or 4 hours (% of oedema = 56 to 67%). Then, the
oedema progressively decreased but still remained obvious after 24 hours. The intraperitoneal pre-
treatment with harpagoside did not induce an inhibitory effect on carrageenan-induced oedema,
contrary to indomethacin.
·
TPA-induced mouse ear oedema [Recio
et al.
1994]
Application of a single dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ears induces an
acute inflammatory reaction consisting of erythema, oedema and polymorphonuclear leukocyte
(PMN) infiltration. TPA was applied on the right ear of mice (2 groups, 6 per group).
Then, harpagoside was administered topically at the dose of 1 mg (right ear). The reference substance
was indomethacin, 0.5 mg (right ear). Left ears of the animals served as controls, and were applied
vehicle (EtOH) or acetone, which was used to dissolve TPA or harpagoside. After 4 hours, animals
were sacrificed and the swelling induced by TPA was assessed in terms of the increase in the weight
of the right ear biopsy over that of the left ear.
The results indicate that harpagoside 1 mg/kg induced an inhibition of 36.2 % of the oedema, as
compared to controls. This oedema inhibition percentage amounted to 87.1% with indomethacin
0.5 mg/kg. Therefore, it was concluded that harpagoside did not exert anti-inflammatory effects in this
model.
·
Granuloma pouch test [Eichler and Koch 1970]
In this test, an aseptic inflammation with large volumes of haemorrhage is induced. Here, croton oil
(0.5 ml, 0.5%) was used as irritant in Wistar rats. Harpagoside (20 mg/kg) and harpagogenin
(20 mg/kg) were tested following daily intraperitoneal administration for 12 days. Phenylbutazone
(40 mg/kg) was used as a reference substance.
The results indicated that harpagoside and harpagogenin induced a significant inhibition of exudate
production (respective values of 33.8% and 28.9%), of granuloma weight (respective values of 29.9%
and 24.5%) and of tissue granulation (respective values of 19.2% and 14.6%).
II.2.2.1.2.2 Aqueous extracts of Harpagophytum procumbens (secondary roots)
Various aqueous extracts of
Harpagophytum procumbens
have been evaluated for their anti-
inflammatory activity in mice and rats. Three main animal models of inflammation were used:
-
the carrageenan-induced rat paw oedema [
Baghdikian
et al.
1997
,
Lanhers
et al.
1994
,
McLeod
et al.
1979
,
Whitehouse
et al.
1983
,
Soulimani
et al.
1983
].
-
the adriamycine-induced rat paw oedema [
Jadot and Lecomte 1992
].
-
the adjuvant-induced arthritis in rats [
McLeod
et al.
1979
,
Whitehouse
et al.
1983
].
-
the granuloma pouch test [
Erdös
et al.
1978
].
·
Carrageenan-induced rat paw oedema
Aqueous extracts of
Harpagophytum procumbens
were tested in this model by intraperitoneal and oral
routes. Due to conflicting results, another study was undertaken to compare directly the anti-
inflammatory activity of
Harpagophytum procumbens
by intraperitoneal, oral and intraduodenal
routes.
Á EMEA 2009
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–
Intraperitoneal route
A standardised aqueous extract of
Harpagophytum procumbens
(containing 1.8% harpagoside) was
administered to rats (15 per group) at the following dose levels: 100, 200 and 400 mg/kg – doses
expressed in terms of dried plant material [
Lanhers
et al.
1994
]. As precised in the protocol described
above, a carrageenan suspension was injected thirty minutes after in the right back paw of each
animal. The average back paw volume of each rat was measured before any treatment and at different
time points after the injection of the inflammatory agent (up to 24 hours).
The results showed that the local oedema induced by the carrageenan suspension was reduced dose-
dependently by a pre-treatment by
Harpagophytum procumbens
from the dose of 100 mg/kg within
2-3 hours. The intensity of the anti-inflammatory effect was maximal 3 hours after carrageenan
injection. Then, it progressively declined, but still remained significant after 24 hours. The oedema
inhibition percentages were 38%, 63% and 72% at respectively 100, 200 and 400 mg/kg (3 hours).
Compared to indomethacin (2.5 to 10 mg/kg), whose effect reached a maximal intensity 30 minutes
after injection of the carrageenan suspension and remained steady for 5 hours, the anti-inflammatory
effect of
Harpagophytum procumbens
was more transient [
Lanhers
et al.
1994
].
The same test was performed to study the influence of acid treatment on the anti-inflammatory effect
of
Harpagophytum procumbens
. Therefore, the extract was treated to reproduce the physico-chemical
conditions found in the stomach (HCl 0,1 N (pH 1) during 3 hours at 38°C). At the unique dose of
400 mg/kg i.p. used, the anti-inflammatory effects of
Harpagophytum
previously observed were
abolished by this treatment [
Lanhers
et al.
1994
].
Another aqueous extract of
Harpagophytum procumbens
(containing 2.2% harpagoside) was
administered to rats at doses of 400, 800 and 1200 mg/kg – doses expressed in terms of dried plant
material [
Baghdikian
et al.
1997
]. Control animals received a 0.9% NaCl solution, and the reference
substance used was indomethacin 10 mg/kg. As in the previous study, a 1% carrageenan suspension
was injected in the right back paw (subplantar route) 30 minutes after these administrations. The
average volumes of each rat back paws were measured before any treatment and at different time
points after the injection of the inflammatory agent (up to 24 hours).
In controls, a local oedema was observed 1 hour after the injection of the carrageenan suspension, and
reached a maximal intensity after 3 or 4 hours and still remained obvious after 24 hours. The
carrageenan-induced oedema was dose-dependently decreased in animals pre-treated with
Harpagophytum procumbens
from 400 mg/kg. This inhibitory effect was significant 3 and 4 hours
after the injection of the phlogistic agent in the 400 mg/kg group (percentages of inhibition
respectively 43 and 30%); in the 800 and 1200 mg/kg groups, it was more marked and sustained
(significant from 1 to 5 hours), the maximal inhibition being reached 3 hours after induction of the
oedema (56 and 64% inhibition, respectively). The inhibitory effect of indomethacin was recorded as
soon as 1 hour after the injection of carrageenan and reached a maximum at 3 hours (58% inhibition).
Then, it remained steady for 5 hours. This effect was still significant after 24 hours [
Baghdikian
et al.
1997
].
–
Oral route
Thirty male Wistar rats were administered either an aqueous extract of
Harpagophytum procumbens
(1 g/kg), indomethacin as a reference substance (5 mg/kg), or 0.5% tragacanth. One hour after these
administrations, carrageenin 0.1% was injected into the rear right foot of each animal, and volumes of
both rear feet were then measured at hourly intervals. The peak reaction was observed 4 hours after
the injection of the phlogistic agent. At this time point, the anti-inflammatory effect of the extract and
indomethacin were evaluated taking into account the inhibition of the oedema intensity. Respective
inhibition percentages were 6% and 63%. Therefore, this extract of
Harpagophytum procumbens
did
not exert any anti-inflammatory effect in these conditions [
McLeod
et al.
1979
].
An extract of
Harpagophytum procumbens
was compared to acetylsalicylic acid (ASA) in terms of
inhibition of the oedema induced in male Sprague-Dawley rats injected a 1% solution of carrageenan
into the subplantar tissue of the right hind foot. The animals were pre-treated one hour before with
either
Harpagophytum procumbens
(20, 200, 2000, 6000 mg/kg, 6 rats per group) or ASA
(200 mg/kg, 4 rats) by gastric gavage. Volumes of the hind feet (right and left) were measured before
and 3 hours after carrageenan treatment. This study showed that
Harpagophytum
administered up to
Á EMEA 2009
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6000 mg/kg did not reduce the oedema consecutive to carrageenan injection (max. 20.3% inhibition,
2000 mg/kg) contrary to ASA (51.9% inhibition) [
Whitehouse
et al.
1983
].
–
Intraperitoneal/oral/intraduodenal routes
Harpagophytum procumbens
exerts an anti-inflammatory effect when administered by intraperitoneal
route but not by oral route. Furthermore, this effect is abolished after treatment of the extract in
conditions mimicking the physico-chemical conditions found in the stomach. Therefore, some authors
conducted a study to investigate the influence of the gastric passage on the anti-inflammatory activity
of
Harpagophytum procumbens
in rats [
Soulimani
et al.
1994
].
The extracts prepared had a total glucoiridoid content 2.72%, and an harpagoside content of 0.44%.
Extracts intended to be administered orally and intraduodenally were lyophilized with b-cyclodextrin
to promote its bioavailability. The general design of the study is listed below:
-
IP route: administration of the extract (100, 200 and 400 mg/kg in terms of dry material) or
NaCl 0.9% (controls) followed after 30 minutes by an injection of a 1% carrageenan
suspension into the back paw of each animal.
-
Oral route: administration of the extract (200, 400, 800, 1600 mg/kg in terms of dry material)
or water (controls) followed after 60 minutes by an injection of a 1% carrageenan suspension
into the back paw of each animal.
-
Intraduodenal route: ketamine anaesthesia followed by the administration of the extract (200,
400, 800, 1600 mg/kg in terms of dry material) or water (controls) and, after 60 minutes, by an
injection of a 1% carrageenan suspension into the back paw of each animal.
In control animals belonging to intraperitoneal and oral groups, a local oedema appeared 1 hour after
carrageenan injection; its intensity increased to reach a maximum at 3 hours. In control animals of the
intraduodenal groups, the local oedema was observed 2 to 3 hours after the injection of carrageenan
and reached a maximal intensity at 6-9 hours. This temporal shift was attributed to ketamine
administration. In all control groups, the oedema progressively decreased in intensity but remained
obvious 24 hours after its induction.
Three hours after intraperitoneal administration of the extract, significant inhibition of the
carrageenan-induced oedema was observed from the 100 mg/kg dose (36% inhibition of the oedema).
At 400 mg/kg, the effect is maximal (67% inhibition) and was significant from 2 hours to 6 hours after
oedema induction. Administered intraduodenally, the extract reduced the carrageenan-induced oedema
from the dose of 200 mg/kg 6 to 9 hours after the carrageenan injection (43% inhibition). The effect
was maximal at the dose of 400 mg/kg (60% inhibition). By oral route, no inhibitory effect was
observed on the carrageenan-induced oedema, whatever the dose of extract administered [
Soulimani
et al.
1994
].
·
Adriamycine-induced rat paw oedema
Harpagophytum procumbens
(powder in suspension in arabic gum, 3% glucoiridoids) was
administered daily for 5 days to male Wistar rats by oral gavage (0, 37, 370 and 3700 mg/kg/d). Then,
all animals were injected in the left hind paw (subplantar injection) 0.2 ml of a solution of adriamycine
chlorhydrate (0.5 mg). The volumes of the injected paw were measured before any administration, 1
hour and 5 days after administration of the inflammatory agent.
In a previous study, the authors showed that the injection of adriamycine chlorhydrate in the same
conditions caused, after 1 hour, a release of serotonin and histamine. After 5 days, lipid peroxidation
and free radicals were identified.
In the present study, one hour after having induced inflammation, the injected paw volume was
decreased in all treated groups, but the effect was maximal in the 37 mg/kg dose group (-48.07%).
After 5 days, the administration of
Harpagophytum procumbens
did not inhibit the formation of free
radicals, the injected paw volumes not significantly differing between control and treated animals.
Therefore, it is concluded that
Harpagophytum procumbens
, after 5 days of oral administration, exerts
an anti-inflammatory activity from the 37 mg/kg dosage but no anti-oxidant activity at any dose-level
[
Jadot
and
Lecomte
1992
].
Á EMEA 2009
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·
Adjuvant-induced arthritis in rats
Female Sprague-Dawley rats were induced adjuvant arthritis by injection of
Mycobacterium
tuberculosis
(0.1 ml, 1 mg/ml) into their rear right feet [
McLeod
et al.
1979
]. Then, the following
drugs were administered orally daily for 21 days:
Harpagophytum procumbens
dried aqueous extract
(100 mg/kg – 1 g/kg), indomethacin (3 mg/kg, used as a reference substance), or tap water (controls).
The number of animals involved in this experiment totalled 40. During the administration period, the
following parameters were measured: body weight and rear foot volumes.
The results of the study indicated that contrary to indomethacin,
Harpagophytum procumbens
administered orally did not produce a significant effect on either the primary or secondary
inflammatory reaction. Moreover, when given in the high-dose group (1 g/kg), the volumes of the
injected and uninjected feet were greater than controls. This unexpected effect was significant on day
7 (+16%). Therefore, the authors do not exclude the potential of
Harpagophytum procumbens
to
potentiate adjuvant arthritis in a manner similar to that seen with levamisole and penicillamine
[
McLeod
et al.
1979
].
In another experiment [
Whitehouse
et al.
1983
], male Sprague-Dawley rats were injected an oily
suspension of
Mycobacterium butyricum
(0.05 ml, 15 mg/ml) into the right hind paw (day 0). An
additional group (n = 6) served as a control group and was left uninjected. Oedema in the contra-
lateral foot was monitored in each animal. On day 11, all adjuvant-pre-treated animals exhibiting a
foot volume of 2 ml or more were randomly divided into 3 treatment groups (6 per group) and
received daily until day 17, by oral route, either:
-
Water (2 ml/kg).
-
Harpagophytum procumbens
extract (2 g/kg).
-
Indomethacin (3 mg/kg), reference substance.
Volumes of the feet were monitored on days 11, 15 and 17 and mean foot volumes were then
calculated. The results indicate that
Harpagophytum procumbens
was ineffective in this model of
inflammation after 6 days of treatment, whereas indomethacin completely alleviated the adjuvant-
induced arthritis after 4 days of treatment (day 15 of the experiment) [
Whitehouse
et al.
1983
].
·
Granuloma pouch test
An experiment similar to the one described above was performed with an aqueous extract containing
2.7% harpagoside given orally and daily for 11 days at the doses of 20 and 200 mg/kg. At the higher
dose-level, the granuloma weight was significantly decreased by 69%, as well as the exudate
production [
Erdös
et al.
1978
].
Assessor’s comments
In the carrageenan-induced paw oedema model, harpagoside administered either orally to mice at the
doses of 100 mg/kg or intraperitoneally to rats at doses up to 10 mg/kg did not prevent the
inflammation produced by the injection of the phlogistic agent. Moreover, it did not exert any anti-
inflammatory effect when tested in the TPA-induced mouse ear oedema model.
However, some anti-inflammatory effects were reported for harpagoside and harpagogenin in the
granuloma pouch test performed in rats, after intraperitoneal administration at higher dose-level
(20 mg/kg).
Aqueous extracts of Harpagophytum procumbens showed anti-inflammatory activity in the
carrageenan-induced rat paw oedema model after intraperitoneal administration. The lowest effective
dose was 100 mg/kg or 400 mg/kg, according to the extract used. When compared to indomethacine,
the reference substance, the effect was more transient.
By oral route, Harpagophytum did not exert any anti-inflammatory effect in the same animal model of
inflammation, as well as in another model, the adjuvant-induced arthritis (2 studies).
The inefficacy of Harpagophytum procumbens in these models when administered orally, compared to
its efficacy in the carrageenan-induced rat paw oedema model when administered intraperitoneally is
Á EMEA 2009
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amazing. Some studies have shown that this discrepancy could result from the gastric passage of the
extract. First, some authors showed that an extract submitted to an acid treatment whose aims was to
mimic the physico-chemical conditions found in the stomach abolishes its anti-inflammatory activity
previously reported. Secondly, other authors reported that the same extract protected rats against
carrageenan-induced paw oedema when given intraperitoneally or intraduodenally, but not orally.
Moreover, in rats injected a suspension of Mycobacterium butyricum to induce arthritis,
Harpagophytum procumbens was ineffective but authors evoked its ability to potentiate adjuvant
arthritis in a manner similar to that seen with levamisole and penicillamine.
Only two isolated studies reported an anti-inflammatory activity of Harpagophytum procumbens after
oral administration (granuloma pouch test and adriamycine-induced rat paw oedema model).
In summary, several points remain unresolved/unclear:
- Isolated compounds (mainly harpagoside) were not or were slightly, effective in animal model of
inflammation, whereas Harpagophytum extracts have shown anti-inflammatory activity in the
carrageenan-induced rat paw oedema model after intraperitoneal administration. Therefore,
harpagoside does not seem to be
the
active substance/the
unique
active substance involved in the anti-
inflammatory activity claimed for Harpagophytum procumbens. These substances should then be
identified.
- The influence of the gastric passage on Harpagophytum procumbens’s anti-inflammatory activity
should be clarified; presently, available preclinical studies do not support its potential to induce anti-
inflammatory effects after oral administration.
- The lowest effective dose should be accurately precised, as it varied according to the extract used
(intraperitoneal studies).
- The ability of Harpagophytum procumbens to potentiate adjuvant arthritis in a manner similar to
that seen with levamisole and penicillamine should be taken into consideration.
II.2.2.1.3 Mechanism of action
Four mechanisms of action were investigated either in
in vitro
or in
in vivo
studies in order to explain
the analgesic and anti-inflammatory activity of
Harpagophytum procumbens
reported in animal and in
man. Its possible influence on the arachidonic acid pathway was particularly studied.
·
Influence on arachidonic acid pathway
The effects of
Harpagophytum procumbens
on prostaglandin synthetase were examined
in vitro
.
Radiolabelled arachidonic acid and prostaglandin synthetase were incubated at 37°C for 4 minutes
with various concentrations of indomethacin, acetylsalicylic acid or
Harpagophytum procumbens
extract. The percentage of inhibition of the enzyme was then determined. IC
50
were then calculated
and amounted to 0.376 mg/ml for indomethacin and 437 mg/ml for acetylsalicylic acid. In comparison,
the concentration of
Harpagophytum procumbens
causing 50% inhibition of prostaglandin synthetase
was superior to 10
5
mg/ml. Therefore, it was concluded that the claimed anti-inflammatory activity of
Harpagophytum procumbens
is not mediated by the inhibition of the prostaglandin synthetase
[
Whitehouse
et al.
1983
].
Other authors have investigated the effects of
Harpagophytum procumbens
(aqueous extract) against
LPS-stimulated expressions of COX-2 and iNOS (inducible nitric oxide synthase) in murine fibroblast
cell line L929 [
Jang
et al.
2003
]. The following parameters were measured:
-
Cell viability (MTT assay).
-
COX-1, COX-2 and iNOS mRNAs expressions (RT-PCR).
-
PGE
2
biosynthesis (commercial competitive enzyme immunoassay kit).
-
NO biosynthesis (commercial NO detection kit).
Á EMEA 2009
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The results obtained did not indicate any cytotoxic effect of the extract tested towards L929 cells at
concentrations up to 1 mg/ml. In LPS-stimulated cells, compared to controls, the expressions of
COX-1, COX-2 and iNOS mRNAs were increased, as well as PGE
2
and NO synthesis. However,
when the cells were incubated with LPS and
Harpagophytum procumbens
(up to 1 mg/ml), these
parameters were increased compared to controls, but significantly reduced compared to
LPS-stimulated cells not incubated with
Harpagophytum procumbens
.
As shown by Salvemini
et al
(1993), NO modulates the activity of COX-2 in a cGMP-independent
manner and plays a critical role in the release of PGE
2
by direct activation of COX-2. Therefore, the
results obtained in murine cell line L929 suggest that
Harpagophytum procumbens
suppresses COX-2
and iNOS mRNAs expressions, resulting in inhibition of PGE2 synthesis. This mechanism could
explain its analgesic and anti-inflammatory activities [
Jang
et al.
2003
].
This possible inhibitory potential of COX-2 was further investigated
in vivo
in ICR mice. The animals
were applied a methanolic extract of
Harpagophytum procumbens
(200 and 400 mg) onto their shaven
back. After 30 minutes, TPA (12-O-tetradecanoylphorbol-13-acetate, a prototype tumour inducer) was
administered the same way to induce cutaneous COX-2 expression. As an underlying mechanism of
COX-2 inhibition, this extract reduced TPA-stimulated catalytic activity of extra-cellular signal-
regulated protein kinase (ERK), which is known to regulate the activation of eukaryotic transcription
factors mediating COX-2 induction. While TPA-induced activation of nuclear factor-kB remained
unaffected by the extract, it inhibited TPA-induced activation of activator protein-1 (AP-1) and
attenuated the expression of its key component c-Fos. Furthermore, pre-treatment with the same
extract abrogated the DNA binding of cyclic AMP response element binding (CREB) protein induced
by topical application of TPA [
Kundu
et al.
2005
].
Figure 1: Proposed molecular
mechanism of COX-2 down-
regulating effects of
Harpagophytum procumbens
[Kundu
et al
. 2005].
The methanol extract of
Harpagophytum procumbens
inhibited TPA-induced COX-2
expression in mouse skin
in
vivo
by blocking ERK kinase
activity (
j
), c-Fos expression
(
k
), AP-1 DNA binding (
l
)
and CREB DNA binding (
m).
The effects of different fractions of
Harpagophytum procumbens
extracts on ecosanoid biosynthesis
were evaluated on human whole blood
in vitro
[
Loew
et al.
2001
]. A crude aqueous ethanolic extract
(80% wt/wt), extract fractions prepared by liquid/liquid extraction with solvent of increasing polarity
and 2 other extracts were tested. These extracts were pre-incubated with human whole blood
(n=5 volunteers) for 15 minutes. Then, the Ca
2+
ionophore A23187 was added to stimulate the
biosynthesis of Cys-LT (cysteinyl-leukotriene) and TXB
2
(thromboxane B
2
) by blood cells. Control
Á EMEA 2009
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samples were not pre-incubated with any extracts. Cys-LT and TXB
2
were measured by
radioimmunoassay.
The results obtained with different fractions of the extract showed that the inhibition of A23187-
stimulated Cys-LT and TXB
2
biosynthesis is dependent on the harpagoside content in the extracts
(see table 1).
Table 1:
Effect of different
Harpagophytum
extracts and extract fractions on the ionophore
A23187-stimulated biosynthesis of Cys-LT and TXB
2
in vitro
in human whole blood
[Loew
et al.
2001].
This study also showed that the different extract fractions have different pharmacological properties.
For example, fraction E stimulates the synthesis of Cys-LT and TXB2 and consequently exerts
potentially a pro-inflammatory activity [
Loew
et al.
2001
].
·
Inhibition of TNF-a synthesis
This potential mechanism of action has been investigated by Fiebich
et al
2001. A
Harpagophytum
procumbens
extract was obtained after aqueous ethanolic extraction (60% v/v) and labelled SteiHap69
(Steiner
Harpagophytum procumbens
69). This extract was then purified from lipopolysaccharides of
bacterial origin to obtain PSH69 extract (Purified SteiHap 69). Studies were also conducted with
LPS-free harpagide and harpagoside.
Human monocytes were incubated with either PSH69, harpagide or harpagoside and then
LPS 10 ng/ml were added in the culture medium. After 24 hours, IL-1b, IL-6, TNF-a and PGE
2
concentrations were measured in the supernatants. Controls were only incubated with LPS 10 ng/ml.
The results show that the LPS-stimulated excretion of TNF-a is inhibited dose-dependently when cells
are pre-treated with PSH69 (IC
50
= 100 mg/ml). Furthermore, IL-1b, IL-6, and PGE
2
were decreased
with PSH69 concentrations superior to 100 mg/ml. On the contrary, pre-treating cells with harpagide
or harpagoside up to 10 mg/ml did not influence the TNF-a synthesis, compared to control.
Therefore, PSH69 inhibits inflammatory processes by preventing the release of TNF-a from human
monocytes
in vitro
. However, harpagide and harpagoside had no activity in the same pharmacological
model.
·
Inhibition of human leukocyte elastase
Boje
et al.
performed an
in vitro
study to evaluate the inhibiting activity of
Harpagophytum
procumbens
towards the elastase from human leukocytes [
Boje
et al.
2003
].
An aqueous extract (2.35% harpagoside) or 5 of the main components of
Harpagophytum procumbens
were incubated with human neutrophile elastase for 1 hour. At the end of the enzymatic reaction,
inhibition rates were calculated and corresponding IC
50
were then determined.
IC
50
of the aqueous extract was 542 mg/ml. The more potent active substances in this test were
6
-O-acetyllacteoside and isoacteoside, with respective IC
50
values of 47 and 286 mg/ml (70 and
286 mM). Other compounds, including harpagoside, had IC
50
greater than 500 mg/ml (800 mM).
Á EMEA 2009
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The elastase inhibiting potency of the aqueous extract
Harpagophytum procumbens
and its main
components, with IC50 > 50 mM, is mediocre [
Boje
et al.
2003
].
·
Anti-oxidant activity
An ethanolic extract (53% w/v) of
Harpagophytum procumbens
was administered to male
Wistar rats
by intraperitoneal route for 1, 7 or 14 days in doses of 100 and 200 mg/kg. Control animals received
NaCl 0.9% in the same conditions. Selegiline (Deprenyl
À
) 2 mg/kg was used intraperitoneally as a
reference substance.
At the end of the treatment period, the frontal cortex and the striatum were dissected out and the
following parameters were measured:
-
Super-oxide dismutase (SOD) activity.
-
Catalase (CAT) activity.
-
Glutathione peroxidase (GPX) activity.
-
Lipid peroxidation.
-
Protein estimation.
In animals pre-treated at least 7 days with either
Harpagophytum procumbens
or Selegiline, the
activities of SOD, CAT and GPX were dose-dependently increased, and lipid peroxidation was
decreased. The authors concluded that the extract tested exerts an anti-oxidant activity at the dosages
tested [
Bhattacharya
and
Bhattacharya
1998
].
Assessor’s comments
Several in vitro and in vivo studies were conducted to investigate, on a mechanistic basis, the
analgesic and anti-inflammatory activities of Harpagophytum procumbens.
A first series of experiments explored its influence on the arachidonic acid pathway. Two studies
showed that Harpagophytum procumbens can interfere with arachidonic acid metabolism by acting
on the COX-2 mRNA expression. The first study was performed with an aqueous extract in vitro, and
the second with a methanol extract in mice, after cutaneous application.
In an in vitro model of A23187-stimulated biosynthesis of ecosanoids on human whole blood, it was
reported that a crude aqueous ethanolic extract inhibits the release of Cys-LT and TXB
2
. Assays
performed with different fractions of this extract showed that this activity depends on the harpagoside
content. However, a fraction stimulated the release of Cys-LT and TXB
2
, underlying the need of
standardized extracts. Another in vitro study showed that Harpagophytum procumbens does not act by
inhibiting the prostaglandin synthetase.
A LPS-free aqueous ethanolic extract of Harpagophytum procumbens prevented the in vitro release of
TNF-
a
from human monocytes. In the same experimental conditions, harpagide and harpagoside did
not exert any activity. Furthermore, other authors showed that an aqueous extract of Harpagophytum
procumbens and its main components have a mediocre elastase-inhibiting potency in human
leukocytes.
In rats, an ethanolic extract administered by intraperitoneal route exerted an anti-oxidant activity
after 7 and 14 days of treatment at 100 and 200 mg/kg. This result is not consistent those of a previous
study, which showed that an orally administered suspension of Harpagophytum procumbens (doses up
to 3700 mg/kg) did not induce any anti-oxidant activity 5 days after adriamycine injection. This raises
the previously highlighted question about Harpagophytum procumbens efficacy variability according
to the route of administration.
Therefore, some points remain unresolved/ unclear:
- Mechanistic studies were performed with aqueous, aqueous alcoholic or alcoholic extracts of
Harpagophytum procumbens. As qualitative and quantitative composition of the extracts differs
according to the extraction process, the relevance of these data is uncertain. For example, although
Á EMEA 2009
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a crude ethanolic extract exerted anti-inflammatory activity by inhibiting LPS-stimulated release of
Cys-LT and TXB2 in vitro, a fraction of this extract had the opposite effect.
II.2.2.2
Other studies
·
Cardiovascular activity [Circosta
et al.
1984]
The cardiovascular activity of
Harpagophytum procumbens
and harpagoside was evaluated in rats,
and in Langendorff preparations of rabbit heart.
Single doses of a methanolic extract (2.09% total glucoiridoids/1.70% harpagoside) or harpagoside
were administered either orally or intraperitoneally to conscious normotensive rats (5 per group).
By
i.p
. route, the extract was administered from 25 to 100 mg/kg and harpagoside at 5 and 10 mg/kg.
By oral route, the extract was administered from 100 to 400 mg/kg and harpagoside at 20 and
30 mg/kg. Controls received water in the same experimental conditions. Sixty minutes after these
administrations (30 minutes for
i.p.
route), anesthetized rats were injected a pro-arythmogenic drug
(either aconitine, CaCl
2
or epinephrine-chloroform) by
i.v.
route.
A dose-dependent bradycardic effect was reported after
Harpagophytum procumbens
administration.
At higher dose-levels (300-400 mg/kg oral and 75-100 mg
i.p
.), the effect became significant 30 and
15 minutes after the administration of the extract, by oral and
i.p
. routes respectively. It lasted up to
120 minutes. ECG records also showed P-wave changes (decreased voltage and long-lasting
increased) at these higher dose-levels. Moreover, a dose-dependant reduction of arterial blood pressure
was noted. Significant responses were obtained 15 minutes after an oral dose of 400 mg/kg and
i.p.
doses of 50 and 100 mg/kg. This hypotensive effect lasted 75 minutes. In experiments conducted with
harpagoside, the same effect on arterial blood pressure was noted by both routes of administration, and
was more long-lasting compared to the extract. However, the intensity of the effect is lower, compared
to the extract containing corresponding quantities of harpagoside. A protective effect of the extract
against chemically-induced arrhythmias was observed from 300 mg/kg oral and 25 mg/kg
i.p
. doses.
With harpagoside, a protective effect was reported too, but its intensity was lower than that of the
extract containing corresponding quantities of harpagoside.
Single doses of either the methanolic extract of
Harpagophytum procumbens
, harpagoside or
harpagide, were injected in the coronary circulation of rabbit hearts – Langendorff preparations.
Pro-arythmogenic drugs were added before, together with or after.
The results indicate that in this model,
Harpagophytum procumbens
caused a mild positive inotropic
effect at lower doses but a marked negative inotropic effect at higher dose, with a concomitant
decrease in coronary flow. A mild decrease in heart rate was also reported. In the same model, the
negative chronotropic and positive inotropic effects of harpagoside were comparatively higher than
that of the extract. Harpagide had slight negative chronotropic and considerable negative inotropic
effects. A protective effect of the extract against chemically-induced arrhythmias was observed.
From this study, it is concluded that the extract of
Harpagophytum procumbens
might interfere with
penetration of calcium into the myocardial cells – protection against arrhytmias induced by calcium
chloride. This could explain the anti-arrhythmic effects reported in this study, in two animal models
[
Circosta
et al.
1984
].
·
Effects on hyperkinetic ventricular arrhythmias (HVA) by reperfusion [de Pasquale
et al.
1985]
A methanolic extract of
Harpagophytum procumbens
(2.09% total glucoiridoids/1.70% harpagoside)
was evaluated for its protective potential against ischemic reperfusion-induced HVA in Langendorff
preparations of rat heart.
Isolated rat hearts were perfused by Langedorff method up to stabilization of ECG. Then, the coronary
flow was reduced to provoke an ischemic perfusion. After 30 minutes, the perfusion was brought to
basal conditions. In the same time, the extract and harpagoside were added to the perfusion medium
through a cannula connected to the aorta. Seven rat hearts per dose-level were used.
In control hearts, polytope extrasystoles occurred 1 minute after the reperfusion. One minute later
(2
nd
minute of reperfusion), ventricular tachycardia occurred. The treatment with
Harpagophytum
Á EMEA 2009
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procumbens
extract reduced the HVA observed in control animals from 1 mg (= 0.085 mg
harpagoside) but this protective effect was improved at the dose of 2 mg. With harpagoside,
a protective effect was reported too, at 0.170 mg. However, its intensity was lower than that of the
extract containing corresponding quantities of harpagoside (2 mg of extract).
The methanolic extract (2 mg) and harpagoside (0.170 mg) impeded the insurgence of hyperkinetic
arrhythmia set off by 100 mg digitoxin, limiting this latter’s toxic effects to disturbances of conduction
and of the repolarisation phase. It is hypothesized by the authors that
Harpagophytum procumbens
might inhibit HVA due to a verapamil-like mechanism (calcium antagonistic effect) [
de Pasquale
et
al.
1985
].
Assessor’s comments
These studies were conducted in the same laboratory and most of their authors took part in both
studies. Therefore, the methanolic extracts used, containing the same amount of total glucoiridoids
and harpagoside, are supposed to be identical.
This methanolic extract of Harpagophytum procumbens exerts hypotensive and bradycardic effects in
conscious rats. In isolated rabbit heart a marked negative inotropic effect with a concomitant
decrease in coronary flow was reported at the higher dose tested. Moreover, this extract had a
protective effect against chemically-induced arrhythmia in conscious rats and in isolated rabbit
hearts, and against HVA induced by reperfusion in isolated rat hearts. The effects were observed with
harpagoside, but their magnitude was lower than that of the extract containing corresponding
quantities of harpagoside. This suggests that harpagoside is not the unique active substance in the
extract of Harpagophytum procumbens, as previously underlined in various primary
pharmacodynamics studies.
From the results of these studies, it is also concluded that Harpagophytum procumbens could have a
verapamil-like mechanism on calcium currents. Therefore, caution should be taken and
Harpagophytum procumbens should not be administered to patients affected by cardiovascular
disorders.
In summary:
- Decreased heart rate and arterial blood pressure were reported in exposed conscious rats, and
marked negative inotropic effect with a concomitant decrease in coronary flow was noted in a model
of isolated rabbit heart. The authors hypothesized that it might have a verapamil-like effect on calcium
currents.
- The potential of Harpagophytum procumbens to induce QT prolongation is unknown.
- Potential pharmacodynamic interactions have not been investigated.
- Therefore, Harpagophytum procumbens should not be administered to patients affected by or treated
for cardiovascular disorders.
II.2.3
P
HARMACOKINETICS
Van Haelen conducted
in vitro
studies with harpagoside and harpagide to obtain the corresponding
genin resulting form acid hydrolysis (harpagogenin). Optimal conditions were: pH 2 and 6 hours
incubation in a saturated butanol-1 aqueous solution. Those conditions were chosen to mimic the
physico-chemical conditions found in the stomach. The author reports that harpagogenin has not been
isolated
in vivo
probably because of its high reactivity and of its high protein-binding rate [
van
Haelen
1983
].
Another study was performed to study the metabolism of 3 iridoid glycosids from
Harpagophytum
procumbens
by human intestinal bacteria: harpagoside, harpagide and 8-o-p-coumaroylharpagide.
Those iridoids were incubated aerobically at 37°C for 24 hours with either almond b-glucosidase or a
bacterial mixture from human faeces (18 strains). In these two tests, aucubinine B was obtained from
Á EMEA 2009
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the 3 iridoids, the amount recovered being higher with human intestinal bacteria than with
b-glucosidase. Seventeen of the 18 bacterial strains were involved in this reaction. Furthermore, the
highest formation rate was observed with harpagoside, as 12.5% harpagoside were converted to
aucubinine B by human bacterial mixture [
Baghdikian
et al.
1999
].
Assessor’s comments
Information about the pharmacokinetics of Harpagophytum procumbens is scarce. In vitro studies
showed that harpagoside and harpagide can be transformed into harpagogenin in physico-chemical
conditions mimicking those found in the stomach. However, harpagogenin has not been isolated in
vivo, so that the relevance of this data remains uncertain. In a in vitro second study, harpagoside,
harpagide and another iridoid (8-o-p-coumaroylharpagide) were metabolised to aucubinine B by a
bacterial mixture from human faeces. However, previous studies have shown that harpagoside could
be denatured in the stomach. As this transformation of iridoids to aucubinine B has not been shown in
vivo, the relevance of this data remains uncertain too.
In summary:
- The pharmacokinetic profile of Harpagophytum procumbens or its main constituents has not been
established.
- In particular, the outcome of the gastric passage could be of interest as pharmacodynamics studies
have shown that Harpagophytum procumbens extract exerts anti-inflammatory and analgesic
activities by i.p. route, but not after oral administration.
II.2.4 T
OXICOLOGY
II.2.4.1 Single-dose toxicity
The acute oral LD
0
and intravenous LD
0
in mice of aqueous, methanolic and butanolic extracts of
Harpagophytum procumbens
were greater than 4.6 g/kg and 1.0 g/kg, respectively. A purified extract
containing 85% harpagoside showed an acute oral LD
0
greater than 4.6 g/kg and acute and LD
50
of
395 mg/kg and 511 mg/kg, respectively [
Erdös
et al.
1978
]. The intraperitoneal LD
50
of harpagoside
in mice amounted to 1 g/kg, whereas the LD
50
of harpagide was greater than 3.2 g/kg in the same
conditions [
van Haelen
1983
].
In another study, the LD
0
of an extract of
Harpagophytum procumbens
was superior to 13.5 g/kg.
However, the mode of extraction was not described by the authors [
Whitehouse
et al.
1983
].
Assessor’s comments
Oral LD
0
of Harpagophytum procumbens were determined in mice with extracts obtained by various
modes of extraction. The results show that their acute toxicity in mice is low.
II.2.4.2 Repeated-dose toxicity
In male Wistar rats, no significant haematological or gross pathological findings were evident
following 21 days of sub-acute oral treatment with 7.5 g/kg of
Harpagophytum procumbens
.
No hepatotoxic effects were observed with respect to liver weight or levels of microsomal protein and
six liver enzymes after 7 days of oral treatment with 2 g/kg [
Whitehouse
et al.
1983
].
Á EMEA 2009
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Assessor’s comments
The relevance of this study remains uncertain. Indeed, it is briefly described in the publication of
Whitehouse et al.
1983.
The aim of this paper was to report studies exploring the anti-inflammatory
activity of Harpagophytum procumbens. Therefore, very few details are given about the 21- and
7- day toxicity studies. The nature of the extracts, the materials and methods, and detailed results of
this study are not described. Therefore, no conclusion can be drawn from these data.
II.2.4.3
Genotoxicity
No data.
II 2.4.4
Carcinogenicity
No data.
II 2.4.5
Reproduction toxicity
No data.
II.2.4.6 Local tolerance
No data.
II.2.4.7 Other studies
No data.
Assessor’s comments on toxicology
Harpagophytum procumbens has a low toxic potential after a single administration in mice. However,
its toxicological profile after repeated administrations is not established, as studies are lacking.
Moreover, its genotoxic potential has not been investigated and its toxic potential to reproduction has
not been studied.
Therefore, in view of the toxicological data available, the safety of Harpagophytum procumbens in
human is not guaranteed.
II.2.5
A
SSESSOR
’
S OVERALL CONCLUSIONS ON NON
-
CLINICAL DATA
Harpagophytum procumbens
is claimed to exert analgesic and anti-inflammatory activities in humans.
Several pharmacodynamics studies were performed in animals to support these assumptions.
In the writhing test,
Harpagophytum procumbens
showed peripheral analgesic properties after
intraperitoneal administration. Unfortunately, similar studies were not performed by the oral route.
In various animal models of inflammation (carrageenan-induced rat paw oedema, adjuvant-induced
arthritis),
Harpagophytum procumbens
showed anti-inflammatory properties when administered by
intraperitoneal route only. However, this activity was abolished in the same models after oral
administration. The inefficacy of
Harpagophytum procumbens
by oral route is amazing. Some authors
have hypothesized that this discrepancy could result from the gastric passage of the extract. Indeed,
the acid treatment of an extract, whose aims was to mimic the physico-chemical conditions found in
the stomach, was reported to abolish its anti-inflammatory activity previously reported by
i.p
. route.
Other authors reported that the same extract protected rats against carrageenan-induced paw oedema
when given intraperitoneally or intraduodenally, but not orally.
Most of these studies included the testing of the supposed active substances of
Harpagophytum
procumbens
, harpagoside or harpagide. Harpagoside exerted a peripheral analgesic activity (
i.p.
route)
at a dose level representing twice the harpagoside dose contained in the dose of extract needed to
obtain a maximal analgesic effect. Therefore, the authors concluded that other substances are involved
in the analgesic activity of
Harpagophytum procumbens
. In the carrageenan-induced paw oedema
model, harpagoside administered either orally to mice or intraperitoneally to rats did not prevent the
inflammation produced by the injection of the phlogistic agent. Moreover, it did not exert any anti-
Á EMEA 2009
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inflammatory effect when tested in the TPA-induced mouse ear oedema model. Some anti-
inflammatory effects were reported for harpagoside and harpagogenin in the granuloma pouch test
performed in rats, after intraperitoneal administration.
Several
in vitro
and
in vivo
studies were conducted to investigate, on a mechanistic basis, the analgesic
and anti-inflammatory activities of
Harpagophytum procumbens
. Two studies showed that
Harpagophytum procumbens
can interfere with arachidonic acid metabolism by acting on the COX-2
mRNA expression. One was conducted in vitro and the other
in vivo
after cutaneous application. A
LPS-free aqueous ethanolic extract of
Harpagophytum procumbens
prevented the
in vitro
release of
TNF-a from human monocytes. In the same experimental conditions, harpagide and harpagoside did
not exert any activity. In addition, an ethanolic extract administered to rats by intraperitoneal route
exerted an anti-oxidant activity after 7 and 14 days of treatment. This result is not consistent those of a
previous study, which showed that an orally administered suspension of
Harpagophytum procumbens
did not induce any anti-oxidant activity 5 days after adriamycine injection.
Studies conducted with a methanolic extract have shown that
Harpagophytum procumbens
could have
a verapamil-like mechanism on calcium currents.
Scarce information is available on the pharmacokinetics and toxicology of
Harpagophytum
procumbens
.
Therefore, the assessor’s current opinion on the subject is:
1.
Toxicological data available do not guarantee the safety of
Harpagophytum procumbens
in
humans. In particular, adequately conducted repeated-dose toxicity studies, genotoxicity
studies and reproduction toxicity studies are lacking.
2.
Decreased heart rate and arterial blood pressure were reported in exposed conscious rats,
and a marked negative inotropic effect with a concomitant decrease in coronary flow was
noted in a model of isolated rabbit heart. It has been hypothesized that
Harpagophytum
procumbens
might have a verapamil-like effect on calcium currents. Its influence on QT
prolongation remains unknown and potential pharmacological interactions have not been
investigated. Therefore, it may be relevant to include a warning for patients affected by or
treated for cardiovascular disorders especially with drugs known to prolong QT interval.
3.
Available studies were performed with extracts differing in their mode of preparation,
qualitative and quantitative composition. Extracts are not adequately standardised.
4.
Harpagophytum procumbens
has been shown to possess peripheral analgesic and anti-
inflammatory properties after intraperitoneal administration. However, effective dose
(i.p
. route) differs from one study to another and is not accurately defined.
5.
When administered intraperitoneally, harpagoside exerted analgesic effects at high-dose levels.
The results concerning its anti-inflammatory properties are conflicting. Various authors
suggested that other substances present in the extract are involved in its claimed activities.
However, these compounds are not identified.
6.
Neither
Harpagophytum procumbens
, nor harpagoside, possessed any analgesic or anti-
inflammatory activity by oral route in animal models of inflammation. It seems that the gastric
passage inactivates some compounds present in the extract. However, pharmacokinetic data are
lacking and the influence of the gastric passage on
Harpagophytum procumbens
activity is not
clarified.
7.
The ability of
Harpagophytum procumbens
to potentiate adjuvant arthritis in a manner similar
to that seen with levamisole and penicillamine should be taken into consideration
[McLeod
et
al.
, 1979
].
8.
Mechanistic studies were performed with aqueous, aqueous alcoholic or alcoholic extracts of
Harpagophytum procumbens
. As the qualitative and quantitative composition of the extracts
differs according to the extraction process, the relevance of these data is uncertain. For example,
Á EMEA 2009
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although a crude ethanolic extract exerted anti-inflammatory activity by inhibiting
LPS-stimulated release of Cys-LT and TXB2
in vitro
, a fraction of this extract had the opposite
effect.
II.3
CLINICAL DATA
II.3.1
C
LINICAL
E
XPERIENCE
The assessment is based on the documentation provided by the European Scientific Cooperative on
Phytotherapy (ESCOP) and the Association of the European Self-Medication Industry (AESGP).
Different kind of preparations of
Harpagophytum procumbens
were traditionally used for the
treatment of various diseases, mostly musculoskeletal complaints.
Harpagophytum
products were
various: powder, aqueous and ethanolic extracts.
The monograph of the ESCOP recommends
Harpagophytum procumbens
preparation for painful
osteoarthritis and low back pain. The assessment is therefore focused on the potential effectiveness of
Harpagophytum
products in both pathologies. No other rheumatic disease has been examined.
For
Harpagophytum
products, the ESCOP monograph recommends that the daily dose should contain
up to 100 mg of the coactive constituent harpagoside, twice the dose recommended by the German
Monograph.
Based on the empirical recommendations of the ESCOP monograph for
Harpagophytum
clinical use,
study selection was made in the field of osteoarthritis and low back pain. In order to establish a
sufficient scientific basis, clinical trials should met criteria of randomisation. For safety, open label
studies are acceptable.
For a well-established concept, herbal medicine must do embracing the formalities and the
technicalities of the current “state of the art” for these pathologies. The chosen bibliographical
documentation is therefore focused on clinical trials in recent years (last past decade).
II.3.2
A
SSESSMENT OF EFFICACY AND SAFETY
II.3.2.1
Dose finding studies
The recommended daily dose of harpagoside is not supported by clinical evidence.
According to the provided literature references, no dose-finding studies have been conducted in the
treatment of osteoarthritis or low back pain. The choice of daily doses of
Harpagophytum
/harpagoside
is mainly empirical.
It should be mentioned that a detailed clinical trial by Chrubasik
et al.
1999 compares two doses of
Harpagophytum
(600 mg and 1200 mg, containing 50 and 100 mg of harpagoside, respectively) but no
conclusion about a dose related effect resulted.
II.3.2.2
Randomised Controlled clinical trials
Effectiveness of
Harpagophytum procumbens
in treatment of acute low back pain.[Chrubasik
et al.
1996]
This trial can be considered as a starting point in the assessment of the efficacy of
Harpagophytum
in
patients with low back pain and it was a four-week randomised double-blind study. Patients between
18 and 75 years of age were recruited when they had experienced at least six months of low back pain
that could not be attributed to identifiable causes. 118 patients were randomised in the treatment and
placebo groups. Patients in the treatment group received two tablets of
Harpagophytum
400 mg, three
times daily, corresponding to harpagoside consumption of 50 mg.
The only rescue medication allowed was tramadol. In fact, cumulative requirements for tramadol, over
the last three weeks of the study period, were taken as the principal outcome measure of efficacy.
Secondary end-points, were the number of pain-free patients and global assessment with the Arhus
low back pain index.
Á EMEA 2009
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No difference was observed in the analgesic rescue medication sparing measurement between placebo
and treatment groups. A greater number of pain-free patients were observed in the treatment group,
than in placebo group but that difference did not show statistical significance.
Overall, negative clinical results as compared to placebo were observed in this clinical study.
The conclusion of the authors, was the need of further clinical trials. Future studies may also assess the
effect of dose in order to obtain clinical dose-response if applicable.
Effectiveness of
Harpagophytum
extract WS 1531 in the treatment of exacerbation of low back
pain: a randomised, placebo-controlled, double-blind study. [Chrubasik
et al.
1999]
This second trial is in direct line with the previous one. The design of the study is identical, but two
doses of
Harpagophytum
(600 and 1200 mg daily containing 50 and 100 mg of harpagoside,
respectively) were assessed
versus
placebo. The principal outcome measure was the proportion of
patients free of pain, without rescue medication (tramadol) for at least 5 days, in the fourth week.
Secondary outcome measure use Arhus Index to assess pain and functional disability. Of the 197
included patients, 183 completed the trial.
The number of patients free of pain in the last week of treatment (primary analysis) was small.
A greater number of responders was significantly observed (p = 0.027) in the treatment groups
(9% and 15% for 600 mg and 1200 mg respectively) than in the placebo group (5%) However,
inconsistency in the direction of any dose related effect was observed between primary and secondary
analyses, in particular for the pain component. Stratification tends to indicate that only some
subgroups (shorter exacerbations, less pain, no radiation) could be improved by the treatment. Due to
the contradictory results, no clear conclusion could be drawn regarding the efficacy of
Harpagophytum
in the treatment of low back pain.
Efficacy and tolerance of
Harpagophytum procumbens
versus Diacerhein in treatment of
osteoarthritis. [Chantre
et al.
2000]
Harpagophytum procumbens
in the treatment of knee and hip osteoarthritis. Four-month results
of a prospective, multicenter, double-blind trial versus Diacerhein. [Leblan
et al.
2000]
A four month clinical trial, published two times in different journals but in similar terms, assessed the
efficacy of
Harpagophytum
in the symptomatic treatment of osteoarthritis. This was a double blind,
randomised, parallel group, multicentre trial. Patients were recruited with radiologically proven
osteoarthritis of the knee or the hip; the clinical criteria of the activity of the disease was a
spontaneous pain of at least 50 mm on a 100 mm Visual Analogue Scale (VAS). The Lequesne Index
was also used to assess activity.
The clinical study compared the efficacy of
Harpagophytum
capsule (435 mg of powder containing
50 mg of harpagoside) to another active medication, diacerrhein, considered as a symptomatic slow
acting drug for osteoarthritis. There was no placebo group. Rescue medications allowed were
acetaminophen associated with caffeine and, if response was inadequate, diclofenac.
Primary efficacy endpoint was defined by the level of spontaneous pain using VAS. Primary analysis
was to demonstrate the non-inferiority of both treatments after 4 months of treatment.
Lequesne Index, functional disability of movement assessed on a VAS, amount of taken rescue
medication were used as secondary efficacy endpoints. Overall 122 patients were randomised and
92 patients completed the trial in accordance with the protocol. No differences were found between
both treatment in terms of pain relief and algo-functional parameters. The relevance of this clinical
trial is nevertheless very limited; the absence of a placebo group is questionable as it is necessary for
the design of a non-inferiority study and all the more regrettable as diacerrhein is not a reference drug
in the treatment of osteoarthritis.
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A randomised double-blind pilot study comparing Doloteffin
®
and Vioxx
®
in the treatment of
low back pain. [Chrubasik
et al.
2003]
A 1-year follow-up after a pilot study with Doloteffin
®
for low back pain [Chrubasik
et al.
2005]
The initial clinical trial is a double-blind study comparing an aqueous extract of
Harpagophytum
(containing 60 mg of harpagoside) and rofecoxib (12.5 mg per day) in the symptomatic treatment of
chronic low back pain. The aim of the exploratory study was to estimate effect sizes for a number of
outcome measures (number of pain-free patients, decrease in averaged daily pain score, percentage
change from baseline in Arhus Low Back Pain index, requirement for rescue medication, etc.).
Patients were recruited when they had experienced at least six months of low back pain that could not
be attributed to identifiable causes and with current exacerbation that had lasted for at least 8 weeks. A
score of 5 out of 10 on a visual analogue scale was needed. Patients were allowed to take tramadol as a
rescue medication up to 400 mg per day. 88 patients were randomised in the two groups of treatment.
There was no placebo group. The number of pain-free patients without taking rescue medication
increased progressively during the course of treatment and more or less in both groups.
No statistically significant difference was observed between the two treatments neither for pain-free
patients, nor for Arhus Low Back Pain and Health Assessment Questionnaire.
The interest for this clinical trial is very limited, in particular for efficacy assessment. The absence of a
placebo group is questionable as for the choice of active comparator. Rofecoxib can not be considered
as a reference in the treatment of chronic low back pain. In the European Union, rofecoxib was
principally indicated for symptomatic relief in osteoarthritis and rheumatoid arthritis, and for some
countries in the relief of pain and the treatment of dysmenorrhoea. Furthermore, the number of
patients was small. No definitive clinical conclusions can be drawn from this study.
Remaining patients from the pilot study (79 of the initial 88 patients) were invited to participate in a
follow-up study. The aim of the study was to assess the long-term effectiveness and safety of a
one-year treatment with the aqueous extract of
Harpagohytum
. 73 patients were included in the trial.
The clinical measures to be evaluated were the Arhus Index and Health Assessment Questionnaire.
The tolerability of the treatment was assessed with a verbal rating scale. Any additional analgesic
treatment was allowed. A total of 30 patients dropped out before the 54 weeks of the follow-up study.
Thirteen did so because of insufficient pain relief. As stated previously, the small number of patients
and the open design of the study preclude any conclusion on the efficacy and safety of
Harpagophytum
.
A randomised, active-controlled, mono-centric study of the herbal drug Devil’s claw
(
Harpagophytum procumbens
) (ALLYA
®
tablets), Voltaren
®
and Vioxx
®
indicates equal efficacy
in the treatment of patients with unspecific lumbar pain.
[Lienert A
et al.
2005]
There is only a meeting abstract of the 54
th
annual conference of the north German orthopaedic
organisation available with poor information. This study does not seem to have been published. The
authors themselves conclude to an equivalent efficacy of the three treatments (ethanolic extract of
devil’s claw, Voltaren, Vioxx), but small sample size and data variability make a definitive
interpretation difficult. Furthermore, it is not sure whether the North American Spine Society (NASS)
Instrument (German version) is valid to show change for the factor “impairment” for a study duration
of six weeks.
A stepweise scheme in coxarthrosis: Double-blind study with
Harpagophytum
.
[Frerick
et al.
2001]
In this randomised double-blind study in a group of 46 patients with activated coxarthrosis, the
successive reduction of an ibuprofen dose of 400 mg twice daily was investigated over a period of
20 weeks, under the concomitant treatment with either
Harpagophytum
extract Lo-Har-45
(flexi-loges) or placebo. The WOMAC (Western Ontario and McMaster Universities) Arthrosis Index
fell from a score of 5.01 to 3.61 in the
Harpagophytum
group and from 4.39 to 3.31 in the placebo
group. An increase in pain score by a maximum of 20% in the period without ibuprofen (which was
Á EMEA 2009
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regarded as a clinically relevant response) was fulfilled by 70.8% of patients of the
Harpagophytum
group, but by only 40.9% of patients in the placebo group. This paper gives some suggestions on a
possible mild therapeutic effect of
Harpagophytum
in coxarthrosis patients, however the low number
of patients (22 to 24 per group) and the study design in which
Harpagophytum
was given just as an
add-on therapy to decreasing doses of ibuprofen precludes further conclusions on the proof of clinical
efficacy.
II.3.2.3
Open Studies
Efficacy and tolerance of
Harpagophytum
Extract LI 174 in patients with chronic non-radicular
back pain [Laudahn and Walper, 2001]
This open-label, multicentre study was to assess the clinical effectiveness and safety of
Harpagophytum
extract on a period of 8 weeks. This was a non comparative trial – there was no
placebo or standard medication group to compare with. Patients were recruited with lumbar pain at
rest and on motion over a period of at least 6 months. Rescue medication in the form of
acetaminophen was allowed for the first 4 weeks. Multidimensional Pain Scale and Arhus Back Pain
Index were used as outcome clinical measure. Pain and mobility improvement were observed during
the overall period of the study. This trial could only be supportive for safety due to its open design. As
mentioned by the authors, further rigorous studies (i.e. against placebo, active treatment) will be
needed to clarify the therapeutic value of
Harpagophytum
for chronic back pain patients.
Comparison of outcome measures during treatment with the proprietary
Harpagophytum
Extract Doloteffin
®
in patients with pain in the lower back, knee or hip. [Chrubasik
et al.
2002]
This open study was conducted to examine various outcome measures of effect during treatment with
aqueous extract of
Harpagophytum
(containing 60 mg of harpagoside). Patients were recruited on the
basis of non specific low back pain or osteoarthritic pain in the knee or hip with current exacerbations,
requiring at least 8 weeks of symptomatic treatment. Patients were allowed to continue their
concomitant treatments and to supplement
Harpagophytum
with other analgesics as necessary.
Assessment of pain and disability included established instruments (Arhus Low Back Pain Index,
WOMAC,) and other non-validated measures. This trial could only be supportive for safety due to its
open design. The effectiveness of the herbal product was not the primary endpoint of the study.
Harpagophytum
-Extrakt LI 174 (Teufelskralle) bei der Behandlung unspezifischer
Rûckenschmerzen. [Göbel
et al.
2001]
The study population was an inhomogeneous group. Subpopulations were not evaluated. The results
show a significant improvement of muscle pain in the verum group in comparison to the placebo
group, but the results of the placebo group are not in accordance with other references and therefore
these results seem to be doubtful. In summary, the study is insufficient to prove the efficacy of devil’s
claw (ethanolic extract) in the treatment of low back pain.
Therapie der unspezifischen Lumbalgie mit Teufelskrallenwurzelextrakt – Ergebnisse einer
klinischen Studie. Effectiveness of
Harpagophytum
procumbens
in treatment of unspecific low
back pain. [Schmidt
et al.
2005]
This open prospective study shows no significant advantage of a mono therapy or a combination
therapy of
Harpagophytum procumbens
(ethanolic extract) with conventional therapy. Without further
information these data are insufficient to support a well-established indication like unspecific low back
pain.
Treatment of patients with arthrosis of hip or knee with an aqueous extract of Devil’s Claw
(
Harpagophytum procumbens
DC).[Wegener and Lüpke 2003]
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The aim of this open study is to assess the efficacy of a coated tablet containing 400 mg of an aqueous
extract in the osteoarthritis of the knee or hip. However, the results of this study can not support a
well- established indication.
Patient-perceived benefit during one year of treatment with Doloteffin [Chrubasik
et al.
2007]
This open study was conducted to examine various outcome measures of effect during treatment with
aqueous extract of
Harpagophytum
(containing a daily dose of 60 mg of harpagoside). 114 patients
were recruited on the basis of non-specific low back pain or osteoarthritic pain in the knee or hip. All
patients received four-week prescriptions of Doloteffin renewable at four-weekly assessment visits
until week 12, and then at six-weekly intervals for up to 54 weeks. Six 400 mg tablets of Doloteffin
per day contain a total of 2400 mg of aqueous extract of
Harpagophytum procumbens
. This is
equivalent to 4.5 g of crude drug per day (1.5-2.5:1). Patients were allowed to supplement
Harpagophytum
with other analgesics as necessary. Initially, and at each subsequent visit, the
assessments consisted of a series of established and non-validated measures. Of the 15 patients that
dropped out, 9 did so because of insufficient pain relief. About a third of the 114 patients used
additional analgesic medications.
This trial could only be supportive of safety due to its open design. As there was no placebo control
group, the documented improvements cannot be attributed confidently to the designated treatment
Doloteffin.
Rivoltan (Li 174) zur Behandlung von Patienten mit degenerativen Erkrankungen des
Bewegungsapparates [Engel 2000]
This open study was conducted to assess the clinical effectiveness and safety of
Harpagophythum
extract (480 mg twice/day) on a period of 6 weeks.
Patients with degenerative disease of the musculoskeletal system were recruited. Rescue medications
(analgesics) and physical therapies were allowed. Pain and mobility improvement were observed
during the overall period of the study.
This study could only be supportive for safety due to its open design and absence of control group.
Harpagophytum procumbens
ist effizient bei degenerativen Erkrankungen des
Bewegungsapparates [Müller
et al.
2000]
This open prospective study aimed to assess the clinical effectiveness of
Harpagophythum
extract
(400 mg 3 times/day) on a period of 4 weeks.
Patients with non acute diseases of the musculoskeletal system were enrolled.
An average improvement of symptoms was reported to be 45% but only minor anti-oedematous and
anti-inflammatory effects were found. The ratio of adverse events was reported to be 0.9% and
5 patients suffered from severe adverse effects (abdominal symptoms).
This open study with no control group is insufficient to prove the efficacy of
Harpagophytum
extract.
Behandlung chronisch aktivierter Schmerzen am Bewegungsapparat
[Ribbat and. Schakau
2001]
The study population was an inhomogeneous group. The results of the treatment (480 mg of
Harpagophytum
dry extract once or twice/day up to 8 weeks) show an improvement in the examined
parameters of all symptoms. Five treatments were stopped because of adverse events.
This open study is insufficient to prove the efficacy of
Harpagophytum
extract due to the absence of a
control group and to the subjective estimation of the degree of the pain and of the efficacy by the
patients and the physicians.
Arthrose-Therapie: Verträglich geht es auch [Schendel 2001]
This open prospective study was conducted with patients suffering from arthrosis of the knee or the
hip. A twice daily dose of 480 mg of
Harpagophytum
extract was tested over a period of 8 weeks.
Á EMEA 2009
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The aim of the study was to examine whether Non-steroidal anti rheumatics (NSAR) can be replaced
by
Harpagophytum
.
Therefore patients were told that they will be able to and should reduce or even discontinue the intake
of NSAR.
At the end of the study 27.9% of the patients had reduced their daily intake of NSAR while 61.4% of
the patients had discontinued the treatment with NSAR. An improvement of 52.5% in the intensity of
pain and an improvement of 49.68% in the rigidity was reported.
Six cases of adverse events were reported. No severe adverse events occurred.
This study is not conclusive due to its open design and the absence of a control group.
Analgetische Wirkung eines Teufelskrallenwurzel [Schmelz
et al.
1997]
This placebo-controlled pilot study was conducted to assess the effectiveness of
Harpagophytum
root
(3 times/day equivalent to a 4.92 g daily dose) over a period of 30 days. The results of this study can
not support a well-established use due to the three different indications assessed with a small number
of patients per group, the lack of statistical interpretation and the assessment of symptoms by patients
in a completely subjective way. The authors interpret the outcome of the study as a hint for a possible
antiphlogistic and analgesic activity which should be confirmed by further studies.
Wirksamkeit und Wirtschaftlichkeit von Teufelskrallenwurzelextrakt bei Rückenschmerzen:
Erste Ergebnisse einer therapeutischen Kohortenstudie [Chrubasik
et al.
1997]
This open prospective study was conducted to evaluate the effectiveness and economy of
Harpagophytum
extract (equivalent to 30 mg harpagoside/day) in the treatment of acute low back
pain.
The results of this study cannot support a well-established medication. The authors state that due to its
efficacy and economy the oral administration of
Harpagophytum
extract should gain more importance
in the treatment of acute low back pain. They also conclude that however an equivalence study has to
be performed to confirm these results.
Review
Harpagophytum procumbens
for osteoarthritis and low back pain: a systematic review
[Gagnier
et al.
2004]
The quality of twenty studies of treatment with various
Harpagophytum
products for exacerbations of
chronic musculoskeletal pain was examined.
Among the twenty, ten were double-blind, randomised controlled comparisons. The conclusion of this
systematic review is that further clinical trials are needed, to properly define the place of
Harpagophytum
preparations in the treatment of osteoarthritis and low back pain. Numerous questions
remain on the potential efficacy, the safety (in particular for long-term) and the doses. None of the
studies contribute to make categorical recommendation for treatment with
Harpagophytum
products.
II.3.2.4 Other properties
Like other bitter herbals,
Harpagophytum
is used for loss of appetite and mild digestive disorders.
Several EU Member States validate such indications for
Harpagophytum
based on the long-standing
use. Moreover, the above-mentioned properties are the oldest known in Europe for H
arpagophytum
;
its use in articular pain is more recent. The link between bitterness of herbals (including
Harpagophytum
) and their use as appetite stimulating agent and to relieve digestive disorders is
described in several references in literature [
Hänsel
et al.
1993
;
Zimmerman
,
1976
;
Schilcher H
1999
;
Braun and Frohne
1987
;
Czygan
1987
;
Bisset
1994
;
Weiss
1991
].
II.3.3
O
VERALL
C
ONCLUSION ON CLINICAL DATA
There is not sufficient evidence of any consistent clinically relevant effect, especially pain relief, as
can be judged from selected studies. The provided evidence of efficacy and safety in osteoarthritis and
Á EMEA 2009
25/26
low back pain is thus insufficient to implement marketing authorisations for a well-established use for
Harpagophytum
products.
Despite the lack of adequately conducted toxicological studies the safety of the use of
Harpagophytum
products is, however, reassuring based on safety data in the clinical trials and lack of serious signals
on pharmacovigilance. No clear conclusion of efficacy in osteoarthritis and low back pain can be
drawn from the varying doses and kind of
Harpagophytum
extract.
This is based on the following considerations:
•
The numbers of patients included in randomised clinical trials were too small for any definitive
conclusion about clinical significant efficacy in the treatment of osteoarthritis or low back pain
and the safety.
•
The studied populations and the chosen endpoints are variable from one study to another, which
makes comparison difficult. Endpoints are generally not in line with those used at present time
for assessing clinical efficacy in the treatment of osteoarthritis or low back pain,
•
Information on the safety of
Harpagohytum
product is very sparse and limited, in particular for
long-term treatment.
•
There are inconsistent results when
Harpagohytum
is compared with placebo. For some
comparative clinical trials, the absence of placebo group is highly questionable.
•
Therapeutic effects are very doubtful as there is no direct comparison between
Harpagophytum
products and the known reference therapy (NSAIDs, acetaminophen) in the symptomatic
treatment of osteoarthritis or low back pain.
•
Analysis of therapeutic efficacy over time (during the first days/weeks) is not presented,
therefore, the onset of response cannot be assessed (all studies). This is especially relevant for
the target population that needs rather quick pain relief.
•
Proper dose-finding studies are still needed to find the minimal dose required for efficacy.
Based on the requirements given in the clinical guidance for the treatment of osteoarthritis, there is no
sufficient scientific basis to recommend a well-established use for
Harpagophytum
products.
II.3.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
During some clinical studies, data on gastric or duodenal side effects have been reported [
Chantre
et
al.
2000
], [
Chrubasik
et al.
1999
], [
Frerick
et al.
2001
].
Harpagophyti radix is contraindicated in
case of gastric or duodenal ulcer in the British Herbal Compendium, in the ESCOP monograph and by
the German Commission E [
Blumenthal
et al.
2000
].
On the basis of non clinical data,
Harpagophytum
might have a verapamil-like effect on calcium
currents. Consequently, a special warning should be included in the corresponding section of the
monograph.
II.3.5
DRUG INTERACTIONS
Among clinical data available for
Harpagophytum
, we could not find any study or reported cases
suggesting an interaction between
Harpagophytum
and oral anticoagulants, or sulfonylureas for
instance.
Harpagophutym
was sometimes quoted as part of phytotherapy in general reviews but no specific
publications examined its interactive potential so far. Additionally, no signal, even weak, has emerged
from the literature to date [
Izzo
et al.
2005
;
Heck
et al.
2000
].
II.4. ASSESSOR’S OVERALL CONCLUSIONS
The clinical data are not sufficient to support a well-established use whether it is in low back pain
treatment or in osteoarthritis treatment. A monograph for traditional herbal medicinal products is
proposed, based on the existing herbal products in the European Countries and the ESCOP
monograph.
Á EMEA 2009
26/26
Source: European Medicines Agency
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