COMMUNITY HERBAL MONOGRAPH ON
HYPERICUM PERFORATUM
L., HERBA
(WELL-ESTABLISHED MEDICINAL USE)
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10(a) of Directive
2001/83/EC as amended
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Hypericum perforatum
L., herba
(St. John’s Wort)
See document EMEA/HMPC/745582/2009
i) Herbal substance
Not applicable
A)
Dry extract (DER 3-7:1), extraction solvent
methanol (80% v/v)
B)
Dry extract (DER 3-6:1), extraction solvent
ethanol (80% v/v)
C)
Dry extract (DER 2.5-8:1), extraction
Well-established use
Herbal preparation in solid dosage forms for oral
use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
Traditional use
4.1.
Therapeutic indications
Well-established use
Traditional use
Indication 1
Herbal preparations A, B:
Herbal medicinal product for the treatment of
mild to moderate depressive episodes (according
to ICD-10).
1
The material complies with the Ph. Eur. monograph (ref. 01/2008:1438)
2
The declaraction of the active substance(s) for an individual finished product should be in accordance with the relevant herbal quality
guidance
3
The herbal preparations comply with the Ph. Eur. monograph (ref. 07/2008: 1874)
4
A narrow range of the DER to be specified for each product
© EMEA 2009
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Indication 2
Herbal preparation C:
Herbal medicinal product for the short term
treatment of symptoms in mild depressive
disorders.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults and elderly
Herbal preparation A:
Single dose: 300-600 mg
Dosage frequency: 1-3 times daily
Daily dose: 600-1800 mg
Herbal preparation B:
Single dose: 900 mg
Dosage frequency: 1 single daily dose
Daily dose: 900 mg
Herbal preparation C:
612 mg, once daily
or
Single dose: 250-650 mg
Dosage frequency: 2-3 times daily
Daily dose: 500-1200 mg
Children, adolescents
The use in children and adolescents under
18 years of age is not recommended (see section
4.4 ‘Special warnings and precautions for use’).
Duration of use
Indication 1
The onset of the effect can be expected within
4 weeks of treatment. If the symptoms persist
during the use of the medicinal product, a doctor
should be consulted.
Indication 2
6 weeks.
The onset of the effect can be expected within
4 weeks of treatment. If the symptoms persist
during the use of the medicinal product, a doctor
should be consulted.
Method of administration
Oral use.
© EMEA 2009
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4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Concomitant use with cyclosporine, tacrolimus
for systemic use, amprenavir, indinavir and other
protease inhibitors, irinotecan and warfarin (see
section 4.5 ‘Interactions with other medicinal
products and other forms of interaction’).
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
Indications 1 and 2
During the treatment intense UV-exposure should
be avoided.
Since no sufficient data are available, the use in
children and adolescents under 18 years of age is
not recommended.
4.5.
Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
Hypericum dry extract induces the activity of
CYP3A4, CYP2C9, CYP2C19 and
P-glycoprotein. The concomitant use of
cyclosporine, tacrolimus for systemic use,
amprenavir, indinavir and other protease
inhibitors, irinotecan and warfarin is
contraindicated
(see
section
4.3.
‘Contraindications’).
Special care should be taken in case of
concomitant use of all drug substances the
metabolism of which is influenced by CYP3A4,
CYP2C9, CYP2C19 or P-glycoprotein (e.g.,
amitriptyline, fexofenadine, benzodiazepines,
methadone, simvastatin, digoxin, finasteride),
because a reduction of plasma concentrations is
possible.
The reduction of plasma concentrations of oral
contraceptives may lead to increased
intermenstrual bleeding and reduced safety in
birth control. Women using oral contraceptives
should take additional contraceptive measures.
Prior to elective surgery possible interactions with
products used during general and regional
anaesthesia should be identified. If necessary the
herbal medicinal product should be discontinued.
© EMEA 2009
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The elevated enzyme activity returns within
1 week after cessation to normal level.
Hypericum dry extract may contribute to
serotonergic effects when combined with
antidepressants such as serotonin reuptake
inhibitors (e.g. sertraline, paroxetine,
nefazodone), buspirone or with triptans.
Patients taking other medicines on prescription
should consult a doctor or pharmacist before
taking Hypericum.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Animal studies have shown equivocal results. The
potential risk for humans is unknown. In the
absence of sufficient clinical 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 adequate studies on the effect on the ability to
drive and use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
Gastrointestinal disorders, allergic skin reactions,
fatigue and restlessness may occur. The frequency
is not known.
Fair-skinned individuals may react with
intensified sunburn-like symptoms under intense
sunlight.
If other adverse reactions not mentioned above
occur, a doctor or a pharmacist should be
consulted.
© EMEA 2009
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Well-established use
Traditional use
After the intake of up to 4.5 g dry extract per day
for 2 weeks and additionally 15 g dry extract just
before hospitalisation seizures and confusion have
been reported.
After ingestion of massive overdoses, the patient
should be protected from sunlight and other
UV-light sources for 1-2 weeks.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Pharmacotherapeutic group:
Other antidepressants
ATC code: N06AX
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
Hypericum dry extract inhibits the synaptosomal
uptake of the neurotransmitters noradrenaline,
serotonine and dopamine. Subchronic treatment
causes a down-regulation of
-
adrenergic
receptors; it changes the behaviour of animals in
several antidepressant models (e.g., forced
swimming test) similarly to synthetic
antidepressants. Napthodianthrones
(e.g. hypericin, pseudohypericin), phloroglucin
derivatives (e.g. hyperforin) and flavonoids
contribute to the activity.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
The absorption of hypericin is delayed and starts
about 2 hours after administration. The
elimination half-life of hypericin is about 20
hours, the mean residence time about 30 hours.
Maximum hyperforin levels are reached about
3-4 hours after administration; no accumulation
could be detected. Hyperforin and the flavonoid
miquelianin can cross the blood-brain-barrier.
Hyperforin induces the activity of the metabolic
enzymes CYP3A4, CYP2C9, CYP2C19 and PGP
dose-dependently via activation of the PXR
system. Therefore the elimination of other drug
substances may be accelerated, resulting in
decreased plasma concentrations.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
© EMEA 2009
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5.3.
Preclinical safety data
Well-established use
Traditional use
Studies on acute toxicity and repeated dose
toxicity did not show signs of toxic effects.
The weak positive results of an ethanolic extract
in the AMES-test (Salmonella typhimurium TA
98 and TA 100, with and without metabolic
activation) could be assigned to quercetin and are
irrelevant to human safety. No signs of
mutagenicity could be detected in further in-vitro
and in-vivo test systems.
Tests on reproductive toxicity revealed equivocal
results.
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 the carcinogenic potential have not been
published.
Phototoxicity:
After oral application of dosages of 1800 mg of
an extract per day for 15 days the skin sensitivy
against UVA was increased, and the minimum
dose for pigmentation was significantly reduced.
In the recommended dosage, no signs of
phototoxicity are reported.
Well-established use
Traditional use
Extracts should be quantified with respect to
flavonoids should be declared.
12 November 2009
5
Ph. Eur. monograph (ref. 01/2008:0765) Extracts.
© EMEA 2009
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Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW
........................................................................................ 4
ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
AND/OR TRADITIONAL USE
II.1
................................................................................................................. 5
I
NTRODUCTION
II.1.1
............................................................................................................................... 6
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
6
II.1.1.1
Herbal substance(s):
................................................................................................... 6
II.1.1.2
Herbal preparation(s):
................................................................................................ 7
II.1.1.3
Combinations of herbal substance(s) and/or herbal preparation(s)
........................... 9
II.1.1.4
Vitamin(s)
.................................................................................................................... 9
II.1.1.5
Mineral(s)
5
Information on period of medicinal use in the Community regarding the specified
indication
II.1.2.1
......................................................................................................................................... 9
Type of tradition, where relevant
................................................................................ 9
II.1.2.2
Bibliographic/expert evidence on the medicinal use
II.1.2.2.1
................................................... 9
Evidence regarding the indication/traditional use
................................................ 9
II.1.2.2.2
Evidence regarding the specified posology
........................................................ 14
II.2
II.2.1
.................................................................................................................. 15
Pharmacology
............................................................................................................... 15
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.1.1.1
.................................................................................................. 15
Effects associated with depression
..................................................................... 15
II.2.1.1.2
Antidepressant activity in animal models
........................................................... 17
II.2.1.1.3
Anxiolytic effects
............................................................................................... 18
II.2.1.1.4
Neuroprotection, memory impairment, nootropic effects
.................................. 19
II.2.1.1.5
Support in smoking cessation
............................................................................. 21
II.2.1.1.6
Treatment of alcoholism
..................................................................................... 22
II.2.1.1.7
Antibacterial activity
.......................................................................................... 22
II.2.1.1.8
Antiinflammatory activity
.................................................................................. 22
II.2.1.1.9
Wound healing
................................................................................................... 23
II.2.1.1.10
Pregnancy, lactation
......................................................................................... 23
II.2.1.1.11
Photodynamic therapy
...................................................................................... 23
II.2.1.1.12
Other effects
..................................................................................................... 23
II.2.1.2
Assessor’s overall conclusions on pharmacology
..................................................... 24
II.2.2
Pharmacokinetics
.......................................................................................................... 25
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.2.2
.................................................................................................. 25
Assessor’s overall conclusions on pharmacokinetics
................................................ 26
II.2.3
Toxicology
..................................................................................................................... 26
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
and constituents thereof
II.2.3.1.1
................................................................................................................. 26
Single-dose toxicity
............................................................................................ 26
II.2.3.1.2
Repeated-dose toxicity
....................................................................................... 26
II.2.3.1.3
Mutagenicity
....................................................................................................... 26
II.2.3.1.4
Carcinogenicity
.................................................................................................. 26
II.2.3.1.5
Phototoxicity
...................................................................................................... 26
II.2.3.1.6
Reproduction Toxicity
........................................................................................ 28
II.2.3.2
Assessor’s overall conclusions on toxicology
........................................................... 29
II.3
........................................................................................................................... 29
Clinical Pharmacology
.................................................................................................. 29
II.3.1.1
Pharmacodynamics
................................................................................................... 29
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II.
II.1.2
II.2.1.1
II.2.2.1
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal
preparation(s) including data on constituents with known therapeutic activity.
II.3.1.1.2
................... 29
Assessor’s overall conclusions on Pharmacodynamics
...................................... 29
II.3.1.2
Pharmacokinetics
II.3.1.2.1
...................................................................................................... 30
Overview of available data regarding the herbal substance(s)/herbal
preparation(s) including data on constituents with known therapeutic activity.
II.3.1.2.2
................... 30
Assessor’s overall conclusions on pharmacokinetics
......................................... 30
II.3.2
Clinical Efficacy
............................................................................................................ 30
II.3.2.1
Dose response studies
................................................................................................ 30
II.3.2.2
Clinical studies (case studies and clinical trials)
II.3.2.2.1
...................................................... 30
Studies on the treatment of depression
............................................................... 31
II.3.2.2.2
Somatoform disorders
........................................................................................ 53
II.3.2.2.3
Schizophrenia
..................................................................................................... 53
II.3.2.2.4
Nootropic effects
................................................................................................ 54
II.3.2.2.5
Cutaneous treatment
........................................................................................... 54
II.3.2.2.6
Premenstrual syndrome
...................................................................................... 54
II.3.2.2.7
Menopausal symptoms
....................................................................................... 55
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
........................... 55
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
................................................... 56
II.3.3
Clinical Safety/Pharmacovigilance
............................................................................... 56
II.3.3.1
Patient exposure
........................................................................................................ 56
II.3.3.2
Adverse events
........................................................................................................... 56
II.3.3.3
Serious adverse events and deaths
............................................................................ 61
II.3.3.4
Laboratory findings
II.3.3.4.1
................................................................................................... 61
Phototoxicity
...................................................................................................... 61
II.3.3.5
Safety in special populations and situations
II.3.3.5.1
.............................................................. 63
Intrinsic (including elderly and children) /extrinsic factors
............................... 63
II.3.3.5.2
Drug interactions
................................................................................................ 63
II.3.3.5.3
Use in pregnancy and lactation
........................................................................... 63
II.3.3.5.4
Overdose
............................................................................................................. 64
II.3.3.5.5
Drug abuse
.......................................................................................................... 64
II.3.3.5.6
Withdrawal and rebound
.................................................................................... 64
II.3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
64
II.3.3.6
Assessor’s overall conclusions on clinical safety
...................................................... 64
II.4
......................................................................................... 65
ANNEXES
III.1
....................................................................................................................................... 65
P
REPARATION
(
S
)
OR
C
OMBINATIONS THEREOF
>
......................................................................... 65
III.2
........................................................................................................... 65
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II.3.1.1.1
III.
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:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: no product
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify:
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:
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
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:
1
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products
in the MSs concerned.
2
Not mandatory field
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II.
ASSESSMENT REPORT
FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR
COMBINATIONS THEREOF WITH WELL-ESTABLISHED USE AND/OR
TRADITIONAL USE
Hypericum perforatum
L., herba
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
(WELL-ESTABLISHED USE)
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)
Whole or broken, dried flowering tops of
Hypericum perforatum
L., harvested during
flowering time.
Herbal preparation(s)
See section 2 of the draft monograph
Pharmaceutical forms
See section 3 of the draft monograph
Rapporteur
Reinhard Länger
EMEA 2008
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II.1
I
NTRODUCTION
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations
thereof
Hyperici herba consists of the whole or cut, dried flowering tops of
Hypericum perforatum
L.,
harvested during flowering time. It contains not less than 0.08% of total hypericins expressed as
hypericin calculated with reference to the dried drug.
Constituents
(Wichtl 2002; Bradley 2006, Hänsel
et al
2007)
Phloroglucinol derivates: 0.2-4%, depending on the age of the herbal drug, mainly hyperforin
and its homologue adhyperforin, furanohyperforin
Naphtodianthrones: 0.06-0.4%, mainly pseudohypericin and hypericin, protohypericin,
protopseudohypericin, cyclopseudohypericin, skyrinderivatives. The amount of pseudohypericin
is about 2-4 times higher than that of hypericin.
Flavonoids: 2-4%, mainly glycosides of the flavonol quercetin: hyperoside, rutin, isoquercitrin,
quercitrin; also biflavones (I3,II8-Biapigenin, Amentoflavone)
Procyanidines: e.g. procyanidine B
2
, tannins with catechin skeletal (6-15%)
Xanthones: in trace amounts
Essential oil: 0.1-0.25%; the essential oil of dried flowering tops contains as main compounds
2-methyloctane (16%) and α-pinene (10.6%). In the essential oil of leaves of Indian origin
58 components were identified, α-pinene (67%) being dominant; the other components included
caryophyllene, geranyl acetate and nonane (each about 5%)
Other constituents: include small amounts of chlorogenic acid and other caffeoylquinic and
p-coumaroylquinic acids, and also free amino acids.
OH
O H
OH
O H
OH
HO
CH
3
HO
HO
CH
3
HO
CH
3
OH
O
OH
OH
O
OH
Hypericin
Pseudohypericin
3
According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2) and the ‘Procedure for the preparation of Community
monographs for herbal medicinal products with well-established medicinal use (
EMEA/HMPC/182352/2005
Rev.2)
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O
OH
O
OH
O
O
O
O
Hyperforin
Adhyperforin
OH
OH
HO
O
H
O
O
OH
3
OH
OH
OH
H
8
HO
O
OH
OH O
HO
O
OH
OH O
OH
OH
Biapigenin
Procyanidin B
2
II.1.1.2
Herbal preparation(s):
St. John’s wort dry extract, quantified extract (Pharm. Eur. ref. 07/2008:1874)
Extraction solvents ethanol (50-80% v/v) or methanol (50-80% v/v). Content of total hypericins
(expressed as Hypericin) 0.10-0.30%, content of flavonoids (expressed as rutin) minimum 6.0%,
content of hyperforin maximum 6.0% and not more than the content stated on the label.
Herbal preparations with evidence of tradition according Dir. 2004/24:
A)
Dry extract, DER 4.6-6.5:1, extraction solvent ethanol 38% v/v. This type of extract is in
medicinal use since more than 30 years.
B)
Dry extract (DER 3.5-6:1), extraction solvent ethanol 60% (m/m): on the market in DE at least
since 1976
C)
Dry extract (DER 5-7:1), extraction solvent ethanol 70% (m/m): on the market in DE at least
since 1976
D)
Liquid extract (DER 1:4-20), extraction solvent vegetable oil (e.g. olive oil, sunflower oil,
linseed oil, wheat germ oil)
Preparation:
According to the German “Ergänzungsbuch” to the German Pharmacopoeia 6 (Erg.-B6. 1941):
The crushed fresh flowers of
Hypericum perforatum
(25 parts) are doused
with olive oil (100 parts) in
a white glass. The mixture is allowed to ferment at a warm place. After completion of the fermentation
the glass has to be sealed. It is then stored at a sunny place for about 6 weeks until the oil is bright red.
The herbal substance has to be pressed out, the oil is dried with sodium sulfate
(6 parts).
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According to the Swiss Pharmacopoeia (1999, Pharm. Helv. 8): The comminuted fresh flowering tops
of
Hypericum perforatum
are covered with 40.0 g refined sun flower oil. The mixture is reshuffled
frequently; extraction and fermentation take place at a temperature of 15-30 °C. After 50-80 days the
herbal substance is pressed out, the water layer is removed. It is allowed to dilute the oil to a
maximum of 80 g of sunflower oil, the content of hypericin is at least 0.001% (spectrophotometric
determination).
According to the company ‘Caelo’, Germany: the dried herbal substance (according to Pharm. Eur.) is
mazerated with olive oil in a DER of 1:20. The mixture is agitated under light exposure for at least
40 hours. The content of hypericin is at least 0.005% (spectrophotometric determination).
Constituents of Hyperici oleum
Hyperici Oleum does not contain hypericin. By using the sunlight maceration method described in the
supplement to DAB 6 (EB 6), lipophilic breakdown products of this compound are obtained which
lend the oil its red colour. The stability of hyperforin is limited; sufficient shelf-life could only be
achieved by hot maceration of dried flowers with eutanol G and storage in the absence of air. The
action of light during preparation of the oil led to a rise in the content of flavonoids (Maisenbacher
et
al
1992).
As a consequence the spectrophotometric determination used for the specification of the St. John’s
wort oils mentioned above detects primarily artifacts of hypericin.
Schempp
et al
(2000) used for the test of the influence of
Hypericum
extracts on skin sensitivity
Hypericum
oil containing 110 µg/ml Hypericin. It is not transparent, whether the authors determined
hypericin or the oil derivatives.
E)
Liquid extract (DER 1:13), extraction solvent maize oil: on the market in DE at least since 1976
F)
Tincture (DER 1:10), extraction solvent ethanol 45-50% v/v: The external use of a tincture (no
further details on DER and extraction solvent) is mentioned in Irion (1955) as an equivalent to
Hypericum
oil. Also Madaus (1938) mentions the use of a tincture, details about the DER are
lacking. A tincture with a DER of 1:10 (extraction solvent ethanol 45-50% v/v) is mentioned as
traditional herbal preparation in Barnes
et al
(2002) and Gruenwald
et al
(2004).
G)
Tincture (DER 1:5), extraction solvent ethanol 50% v/v: mentioned in Bradley (2006). The
evidence of tradition of this tincture has to be proved.
H)
Liquid extract DER 1:2, extraction solvent ethanol 50%
The product ‘Hyperforat-drops’, contains a liquid extract with DER of 1:2, extraction solvent
ethanol 50% (no details v/v or m/m). This is in contrast to details given in the review of Linde
(2007) with respect to the DER: Hyperforat is cited in the study with a DER of 5-7:1, which
would indicate a dry extract. This difference is due to obvious incorrect data in the German
“Rote Liste”. The first clinical study with this liquid extract is published 1979, therefore when
the monograph on
Hypericum
will be published, the extract is in medicinal use at least 30 years.
I)
Liquid extract 1:5-7, ethanol 50%. Trade name Psychotonin, since 1963 in medicinal use.
J)
Expressed juice from the fresh herb (DER 1.25-2.5:1): on the market in DE at least since 1976
K)
Comminuted herbal substance: cut herbal substance used for tea preparation; powdered herbal
substance in solid dosage forms for oral use on the market in DE at least since 1976
Further liquid extracts:
Since the edition 1993 of Hager’s Handbuch (Hänsel
et al
1993) a liquid extract with a DER 1:6,
extraction solvent ethanol 70% is mentioned. This type of extract is not mentioned in previous
literature. The period of 30 years of medicinal use is therefore not fulfilled.
The request for marketed products in the EU revealed that numerous further extracts are on the
market. However, they neither do fulfil the criteria for traditional use nor are supported by clinical
evidence.
EMEA 2008
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Influence of the extraction solvent on the composition of the extract:
When using extraction solvents containing more than 50% of ethanol or methanol in water the content
of hypericin in the extract seems to be very similar independent of the actual concentration of the
extraction solvent. In contrast the extraction of hyperforin and adhyperforin depends strongly on the
concentration of the extraction solvent. Best yield (60% of the hyperforin in the herbal substance, 45%
of adhyperforin in the herbal substance) is achieved with 70% (e.g. ethanol), while with 50% ethanol
only 20% of hyperforin and no adhyperforin are extracted (Meier 1999).
II.1.1.3
Not applicable
II.1.1.4
Not applicable
II.1.1.5
Not applicable
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
II.1.2.1
Type of tradition, where relevant
European tradition
II.1.2.2
Bibliographic/expert evidence on the medicinal use
II.1.2.2.1
Evidence regarding the indication/traditional use
Traditional indications for oral use of herbal teas liquid extracts (extraction solvent ethanol) and
dry extracts
Nervous system disorders, psychiatric disorders
Indication References
Psychovegetative disturbances Hamacher
et al
(2003), Hänsel (1993), Wichtl (2004),
Blaschek
et al
(2006), Hänsel
et al
(1993), Gruenwald
et al
(1998), Gruenwald
et al
(2004), Commission E monographs
(1998), Dingermann
et al
(2004), DAC (1991-1999)
Mood depression Hamacher
et al
(2003), Hänsel (1993), Bradley (2006), Irion
(1955), Blaschek
et al
(2006), Hänsel
et al
(1993), Auster
et
al
(1958), Gruenwald
et al
(1998), Gruenwald
et al
(2004),
Commission E monograpsh (1998), Dingermann
et al
(2004),
Hänsel
et al
(1988), DAC (1991-1999), Flamm
et al
(1940)
Mild depression Escop 2003
Anxiety and/or nervous restlessness Hänsel (1993), Wichtl (2004), Bradley 2006 (including
menopausal anxiety), Blaschek
et al
(2006), Hänsel
et al
(1993), Madaus (1938), Gruenwald
et al
(1998), Gruenwald
et al
(2004), Barnes
et al
(2002), Commission E monographs
(1998), Dingermann
et al
(2004), Hänsel
et al
(1988), DAC
(1991-1999), Martindale (2002) (particulary if associated
with the menopause)
4
According to the ‘Guideline on the clinical assessment of fixed combinations of herbal substances/herbal
preparations’ (EMEA/HMPC/166326/2005)
5
Only applicable to traditional use
EMEA 2008
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Insomnia
Gerlach (2008), Irion (1955), List
et al
(1976), Madaus
(1938), Barnes
et al
(2002), Hänsel
et al
(1988), Martindale
(2002)
Support of emotional balance
Gerlach (2008), ESCOP (2003)
‘Weak nerves’, vegetative dystonia
Gerlach (2008), Irion (1955),
Agitation, excitability, irritability
List
et al
(1976), Barnes
et al
(2002), Upton (1997)
After mental efforts
Madaus (1938)
Neuralgia, Neurasthenia
List
et al
(1976), Madaus (1938), Barnes
et al
(2002), Flamm
et al
(1940), WHO monographs (2002)
Traumatic damages of nerves,
paralysis
Madaus (1938)
Migraine, headache
Flamm
et al
(1940), WHO monographs (2002)
Sciatica
Barnes
et al
(2002), WHO monographs (2002)
Gastrointestinal disorders
Indication
References
Gastritis
Wichtl (2002), Blaschek
et al
(2006), Hänsel
et al
(1993),
Gruenwald
et al
(2004), Böhme (2006)
Ulcers, dyspepsia
WHO monographs (2002)
Unspecific catarrhs of the gastro-
intestinal tact
Gerlach (2008), Irion (1955), Flamm
et al
(1940), Hänsel
et
al
(1988)
Nervous gastric diseases
Gerlach (2008), Blaschek
et al
(2006), Hänsel (1993)
Abdominal pain
Madaus (1938)
Diarrhoea
Wichtl (1984), List
et al
(1976), Blaschek
et al
(2006),
Hänsel
et al
(1993), Madaus (1938), Gruenwald
et al
(2004),
Flamm
et al
(1940), Karsten
et al
(1962)
Haemorrhoids
Irion (1955), List
et al
(1976), Flamm
et al
(1940), WHO
monographs (2002)
Hepatobiliary disorders
Indication
References
Gallbladder diseases
Wichtl (2004), Irion (1955), List
et al
(1976), Blaschek
et al
(2006), Hänsel
et al
(1993), Madaus (1938), Gruenwald
et al
(2004), Böhme (2006), WHO monographs (2002)
As a choleretic
Blaschek
et al
(2006), Hänsel
et al
(1993)
Renal and urinary disorders
Indication
References
Nocturnal enuresis
Gerlach (2008), Wichtl (1984), Irion (1955), List
et al
(1976),
Blaschek
et al
(2006), Hänsel
et al
(1993), Madaus (1938),
Gruenwald
et al
(2004), Flamm
et al
(1940), Dingermann
et
al
(2004), Schneider (1990)
Kidney stones, bladder stones,
inflammations of the urogenital tract
Irion (1955), Flamm
et al
(1940), WHO monographs (2002)
Irritable bladder, incontinence
Hamacher
et al
(2003), WHO monographs (2002)
As a diuretic
Wichtl (1984), List
et al
(1976), WHO monographs (2002)
Respiratory, thoracic and mediastinal disorders
Indication
References
Cough, bronchitis, asthma
Irion (1955), Blaschek
et al
(2006) Hänsel
et al
(1993),
Madaus (1938), Gruenwald
et al
(2004), Flamm
et al
(1940),
WHO monographs (2002)
Common cold
WHO monographs (2002)
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Infections and infestations
Indication
References
Worm infestations
Blaschek
et al
(2006), Hänsel
et al
(1993), Gruenwald
et al
(2004), Flamm
et al
(1940), Zörnig (1911)
As an antimalaria agent
WHO monographs (2002)
Endocrine disorders
Indication
References
Polymenorrhoea, oligomenorrhoea,
dysmenorrhoea, endometritis
Madaus (1938), Irion (1955), Flamm
et al
(1940), Heinrich
et
al
(2004)
As emmenagogue
WHO monographs (2002)
Diabetes
Irion (1955), Auster
et al
(1958), WHO monographs (2002)
Musculoskeletal and connective tissue disorders
Indication
References
Rheumatism
Wichtl (1984), Blaschek
et al
(2006), Hänsel
et al
(1993),
Auster
et al
(1958), Gruenwald
et al
(2004)
Metabolism and nutrition disorders
Indication
References
Gout
Wichtl (1984), Blaschek
et al
(2006), Hänsel
et al
(1993),
Gruenwald
et al
(2004)
Metabolic disorders
List
et al
(1976)
Traditional indications for oral use of liquid extracts (extraction solvent vegetable oil):
Indication
References
Dyspepsia
Hamacher
et al
(2001), Blaschek
et al
(2006), Hänsel
et al
(1993), Gruenwald
et al
(1998), Gruenwald
et al
(2004),
Commission E monographs (1998), DAC (1991)
Nervous gastric diseases
Gerlach (2008), Blaschek
et al
(2006), Hänsel
et al
(1993)
As a choleretic
Blaschek
et al
(2006), Hänsel
et al
(1993)
Abdominal pain
Madaus (1938)
Discussion and assessment of traditional indications for oral use:
Since the
Hypericum
oil differs considerably in the nature of the constituents from aqueous and
ethanolic liquid extracts these types of herbal preparations are discussed separately.
a)
Aqueous extracts (herbal teas), liquid extracts prepared with ethanol, dry extracts, expressed juice:
Infusions prepared with water are widely used in the traditional medicine at least in Central Europe
(Gerlach 2008). The indication ‘depression’ is unknown in traditional medicine;
Hypericum
is used
in order to ‘strengthen the nerves’, to restore emotional balance, in Madaus (1983) it called ‘the
arnica of the nerves’. The wording which is found in literature reflects this fact, although put into
different words. This traditional indication is plausible because of the pharmacological and clinical
data which are available for isolated compounds and alcoholic extracts of
Hypericum perforatum
.
The numerous further traditional indications mentioned in the literature for these kinds of extracts
are not plausible.
Since for the indication of a traditional herbal medicinal product terms like ‘depression’ or
‘depressed mood’ are not suitable, particular attention is paid to the wording of the indication.
Proposals:
Somatoform disorders (ICD-10 F45.0):
The main feature is repeated presentation of physical symptoms together with persistent requests for
medical
investigations, in spite of repeated negative findings and reassurances by doctors that the
symptoms have no physical basis. If any physical disorders are present, they do not explain the
nature and extent of the symptoms or the distress and preoccupation of the patient.
EMEA 2008
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Neurasthenia (ICD-10 F48.0)
Considerable cultural variations occur in the presentation of this disorder and two main types occur
with substantial overlap. In one type, the main feature is a complaint of increased fatigue after
mental effort, often associated with some decrease in occupational performance or coping
efficiency in daily tasks. The mental fatiguability is typically described as an unpleasant intrusion of
distracting associations or recollections, difficulty in concentrating, and generally inefficient
thinking. In the other type, the emphasis is on feelings of bodily or physical weakness and
exhaustion after only minimal effort, accompanied by a feeling of muscular aches and pains and
inability to relax. In both types a variety of other unpleasant physical feelings is common such as
dizziness, tension headaches, and feelings of general instability. Worry about decreasing mental and
bodily well-being, irritability, anhedonia, and varying minor degrees of both depression and anxiety
are all common. Sleep is often disturbed in its initial and middle phases but hypersomnia may also
be prominent.
Adjustment disorders (ICD-10 F43.2)
States of subjective distress and emotional disturbance, usually interfering with social functioning
and performance, arising in the period of adaptation to a significant life change or a stressful life
event. The stressor may have affected the integrity of an individual's social network (bereavement,
separation experiences) or the wider system of social supports and values (migration, refugee
status), or represented a major developmental transition or crisis (going to school, becoming a
parent, failure to attain a cherished personal goal, retirement). Individual predisposition or
vulnerability plays an important role in the risk of occurrence and the shaping of the manifestations
of adjustment disorders, but it is nevertheless assumed that the condition would not have arisen
without the stressor. The manifestations vary and include depressed mood, anxiety or worry (or
mixture of these), a feeling of inability to cope, plan ahead, or continue in the present situation, as
well as some degree of disability in the performance of daily routine. Conduct disorders may be an
associated feature, particularly in adolescents. The predominant feature may be a brief or prolonged
depressive reaction, or a disturbance of other emotions and conduct.
All these three types of disorders reflect partly the traditional oral use
Hypericum
. The definition of
the somatoform disorders includes characteristics which are not suitable for THMPs. Particularly the
persistent request for medical investigation is in contrast to the concept that the products are intended
for use without medical supervision.
The traditional use seems to be covered in a most suitable way by the definition of neurasthenia.
The plausibility of the efficacy in this traditional indication is supported by an observational study
(Grube
et al
1996).
Hypericum
dry exctract LI 160 was administered corresponding to
900 µg hypericine daily (= approximately 540 mg extract) to patients with mild temporary depressed
mood.
Additionally the indication should be clearly different from the proposed health claims for food
supplements (contributes to emotial balance and general wellbeing; contributes to optimal relaxation;
helps to support relaxation and mental and physical wellbeing; helps to maintain a healthy sleep; helps
maintain a positve mood).
Proposed traditional indication (oral use, aqueous extracts, liquid ethanolic extracts, dry extracts)
Indication 1)
Traditional herbal medicinal product for the symptomatic relief of temporary mental exhaustion
(neurasthenia).
The product is a traditional herbal medicinal product for use in the specified indication exclusively
based upon long-standing use.
b)
Liquid extracts prepared with vegetable oil (Hypericum oil):
The indications mentioned in the references cannot be explained by the constituents of the
hypericum oil, data from pharmacological experiments are lacking. Therefore the mentioned
indications are not plausible. There is no traditional indication for the oral use of
Hypericum
oil.
EMEA 2008
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Traditional indications for cutaneous use of liquid extracts (extraction solvent vegetable oil):
Skin and subcutaneous tissue disorders
Indication
References
First degree burns,
sunburn
Gerlach (2008), Wichtl (1984), Wichtl (2004), Bradley (2006), Irion (1955),
Flamm
et al
(1940), Schneider (2004), Wagner
et al
(1999), Böhme (2006),
WHO monographs (2002), Hamacher
et al
(2001), Hamacher
et al
(2006),
Blaschek
et al
(2006), Hänsel
et al
(1993), Gruenwald
et al
(1998), Gruenwald
et al
(2004), Comission E monographs (1998), DAC (1991), DAC (1998)
Wound healing
Gerlach (2008), Wichtl (1984), Wichtl (2004), Bradley (2006), Irion (1955),
Hager (1878), Fischer
et al
(1902), Frerichs
et al
(1938), List
et al
(1976),
Auster
et al
(1958), Flamm
et al
(1940), Wagner
et al
(1999), Schneider (1990),
Karsten
et al
(1962), WHO monographs (2002), Hamacher
et al
(2001),
Hamacher
et al
(2006), Blaschek
et al
(2006), Hänsel
et al
(1993), Gruenwald
et
al
(1998), Gruenwald
et al
(2004), Comission E monographs (1998), DAC
(1991), DAC (1998), Madaus (1938)
Gingivits,
stomatitis
Gerlach (2008), Hänsel
et al
(1972)
Fibrositis
Barnes
et al
(2002)
Neurodermatitis
Wagner
et al
(1999)
Eczema
Irion (1955)
Prevention of
decubitus
Hänsel
et al
(1988), Hänsel
et al
(2007)
Shingles, viral
infections
Bradley (2006), WHO monographs (2002)
Musculoskeletal and connective tissue disorders
Indication
References
Myalgia
Hamacher
et al
(2001), Hamacher
et al
(2006), Länger
et al
(2001), Blaschek
et
al
(2006), Hänsel
et al
(1993), Gruenwald
et al
(1998), Gruenwald
et al
(2004),
Comission E monographs (1998), DAC (1991), DAC (1998), Flamm
et al
(1940), Wagner
et al
(1999)
Rheumatism
Gerlach (2008), Irion (1955), Flamm
et al
(1940), Hager (1878), Blaschek
et al
(2006), Hänsel
et al
(1993), Wagner
et al
(1999), Auster
et al
(1958)
Lumbago
Blaschek
et al
(2006), Hänsel
et al
(1993), Flamm
et al
(1940), Madaus (1938)
Ischialigia,
neuralgia
Irion (1955), Flamm
et al
(1940), Böhme (2006)
Articular pain
Gerlach (2008)
Sprains
Flamm
et al
(1940), Madaus (1938)
Bruises
Bradley (2006), Irion (1955), Flamm
et al
(1940)
Swellings
Bradley (2006), Flamm
et al
(1940), Madaus (1938)
Metabolism and nutrition disorders
Indication
References
Gout
Gerlach (2008), Irion (1955), Flamm
et al
(1940), Madaus (1938)
Traditional indications for cutaneous use of liquid extracts (extraction solvent ethanol):
Skin and subcutaneous tissue disorders
Wound healing
Gerlach (2008), Irion (1955)
Traditional indications for cutaneous use of liquid extracts (extraction solvent water):
Skin and subcutaneous tissue disorders
Wound healing
WHO monographs (2002)
EMEA 2008
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Discussion and assessment of traditional indications for cutaneous use:
The traditional use of liquid preparations of
Hypericum
for wound healing is supported by
pharmacological data. Antiinflammatory activity, analgesic activity, adstringent activity and
antibacterial activity are documented,
in vivo
data are poor, clinical data are lacking. In contrast the
traditional use for the treatment of symptoms caused by an injury or related to rheumatism is not yet
plausible. Antiviral effects are documented for several types of viruses, but not for Varicella zoster.
Therefore the traditional use in the treatment of shingles cannot be supported.
Proposed traditional indication (cutaneous use, liquid extracts, extraction solvents vegetable oil,
ethanol or water)
Indication 2)
Traditional herbal medicinal product for the symptomatic treatment of minor inflammations of the
skin (such as sunburn) and as an aid in healing of minor wounds.
The product is a traditional herbal medicinal product for use in the specified indication exclusively
based upon long-standing use.
II.1.2.2.2
Evidence regarding the specified posology
Oral administration
Comminuted herbal substance
The single dose for tea preparation is 1 teaspoon per cup, which is equivalent to 1.8 to 2 g of herbal
substance. The recommendation of the daily dose is 1-2 cups equivalent to 1.8 to 4 g of herbal
substance (Wichtl 2004, Hänsel
et al
1993, ESCOP 2003), only few references recommend higher
daily dosages (Duke 2002: up to 8 g; Madaus 1983: up to 7 g; Irion 1955 and Barnes
et al
2002: up to
12 g).
Proposal for the posology of the comminuted herbal substance for tea preparation:
Adults, elderly: single dose 2 g; daily dose 4 g
Children and adolescents: Since no data on the safe traditional use in children are available the use
in children and adolescents is not recommended.
The powdered herbal substance is in medicinal use in solid dosage forms longer than 30 years. The
proposed posology (single dose 300-500 mg, daily dose 900-1000 mg) reflects the posology of the
authorized products.
Herbal preparations:
Dry extracts: Traditionally dry extracts are administered in considerably lower doses than those used
for the treatment of mild to moderate depression. The herbal preparation type B was traditionally
administered in a single dose of 120 mg and a daily dose of 360 mg. A daily dose of 252 mg showed
no beneficial effects in the treatment of mild major depression compared to placebo. Therefore a
single dose of 60-180 mg and a daily dose of 180-360 mg of dry extracts are proposed for traditional
use.
Tincture (DER 1:5): 3-4.5 ml daily dose (Bradley 2006)
Tincture (DER 1:5) (= ESCOP 2003, posology with reference to a product from Steigerwald):
3-4.5 ml daily = equivalent to 0.6 – 0.9 g herbal substance.
Tincture (DER 1:10), 45% ethanol: 2-4 ml 3 x daily (Barnes
et al
2006, Duke 2002) = equivalent to
0.6 – 1.2 g herbal substance.
Tincture (DER 1:2): Single dose 0.8-1.2 ml, daily dose 2.4-3.6 ml.
Tincture (DER not given): 10-15 drops (= approximately 0.5-0.75 ml), 2-3 x daily (= 1-2.25 ml)
(Madaus 1938). Because of the lack of data of the DER this posology cannot be considered.
The posology of the further mentioned herbal preparations reflects the posology of the authorized
products.
Children and adolescents: Since no data on the safe traditional use in children are available the use in
children and adolescents is not recommended.
EMEA 2008
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Cutaneous administration
Strength of the preparations:
Hypericum
oil is administered undiluted.
Hypericum
tea prepared with a DER of 1:5 (WHO monographs 2002)
Children and adolescents: Since no data on the safe traditional use in children are available the use in
children and adolescents is not recommended.
II.2
N
ON
-C
LINICAL
D
ATA
II.2.1
Pharmacology
II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.1.1.1
Effects associated with depression
The mechanisms of action as well as the responsible compounds of
Hypericum
extracts are still under
discussion. Several actions contributing to a clinical efficacy are reported: blockade of the reuptake of
serotonin, noradrenalin and dopamine; upregulation of postsynaptic 5-HT
1
and 5-HT
2
receptors and of
dopaminergic receptors; increased affinity for GABAergic receptors. Constituents which contribute to
the activity are hypericin, pseudohypericin, flavonoids, and oligomeric procyanidins. The relevance of
hyperforin is discussed controversely. As a consequence the entire extract has to be considered as the
active substance.
Effects of constituents (
primarily according to a review from Butterweck
et al
2003
)
Flavonoids, Biflavonoids
In vitro
the flavonols inhibit the monoaminooxidase (MAO), a fraction rich in flavonols also inhibited
the catechol-O-methyltransferase (COMT). The concentrations which were necessary to achieve the
results were considerably higher than concentrations which could be expected in therapeutic dosages.
Amentoflavon, which occurs only in traces in the flowers, inhibits in very low concentrations the
binding of flumazenil on the benzodiazepine binding sites of the GABA receptor (Baureithel
et al
1997) as well as to the -subunit of the opioid receptor. I3,II8 biapigenin, which is present in much
higher concentrations, is not investigated up to now, because it is commercially not available.
A flavonoid fraction, free of hypericins and hyperforin, induced a reduction of the -receptors in the
frontal cortex of the rat brain in similar manner like imipramin.
It is not known whether the flavonoids or their metabolites are responsible for these effects.
Hyperosid directly stimulates the endocytosis of 1-receptors and reduces their lateral mobility
(Häberlein
et al
2008).
Quercetin (10 – 40 mg/kg) altered dose-dependently the pattern in an electropharmacogram of rats, the
changes resembled those of the MAO A inhibitor moclobemide and the MAO B inhibitor selegiline
(Dimpfel 2008).
Naphthodianthrones
Pure naphthodianthrones are only poorly soluble in water. The solubility is increased by compounds of
the extract. For example procyanidines are able to increase solubility in water 10-fold. Rutin and
hyperosid may also contribute to the better solubility of hypericin in extracts.
Hyperosid and the procyanidines increase the serum level of hypericin considerably.
Isolated hypericin has no influence on the MAO A and B.
In vitro
it inhibits the dopamine--
hydroxylase, it interacts with -adrenergic receptors and possesses a high affinity to the -receptor as
well as to the D
3
-receptor.
Hypericin alters the concentration of several neurotransmitters after 8 weeks of treatment comparable
to imipramine. 8 weeks treatment also increased the serotonin concentration in the hypothalamus,
while the concentration of metabolites of dopamine is reduced. Hypericin induces a reduction of the
-receptors in he frontal cortex of the rat brain, after 8 weeks of treatment a significant change could
be observed.
EMEA 2008
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Hypericin reduced, similar to imipramine, the expression of mRNA of the corticotrophin releasing
hormone in the hypothalamus as well as the ACTH and corticosterone levels in the plasma of rats.
An overview presenting chemical and biological properties of hypericin is published by Lavie
et al
(1995).
Phloroglucinol derivatives
Müller
et al
(1998) and Chatterjee
et al
(1998) revealed that hyperforin plays an important role in the
inhibition of neurotransmitter reuptake.
In vitro
the IC
50
value for the inhibition of the synaptosomal
reuptake of serotonin, dopamine, noradrenaline, GABA and glutamate caused by hyperforin is in the
range of 80 to 1234 nM. After a daily intake of 900 mg of
Hypericum
extract a blood level of 180 nM
of hyperforin was detected. Therefore it could be concluded that sufficient amounts of hyperforin for
the inhibition of the reuptake of some neurotransmitters could be achieved during therapy.
Several mechanisms for these effects are in discussion: inhibition of calcium channels of the P-type, a
reserpin-like action, increase of the intracellular sodium concentration.
Isolated hyperforin did not influence the density of -receptors in rats, while an extract rich in
hyperforin induced a down-regulation of the -receptor density.
Hyperforin directly causes the endocytosis of 1-receptors and reduces their lateral mobility
(Häberlein
et al
2008).
Xanthones
Due to the low content of xanthones in the herbal substance (about 0.0004%) it is not likely that the
experimentally documented inhibition of MAO A and B is of clinical relevance.
Effects of extracts (examples of publications)
The results on MAO inhibition are controversial. At concentration of 10
-4
to 10
-3
mol/l of a methanolic
extract (Bladt
et al
1994) and of a methanolic extract (Thiede
et al
1994) MAO could be inhibited up
to 82%. In a later study a methanolic extract exhibited a rather weak potency as MAO inhibitor
in
vitro
(Müller
et al
1997).
The inhibition of synaptosomal reuptake of several neurotransmitters could be demonstrated for
different kinds of extracts (different extraction solvent, different amounts of hypericin, hyperforin).
Long-term treatment of rats with a methanolic extract (500 mg/kg p.o.) significantly increased the
5-HT levels in the hypothalamus of rats; the 5-HT turnover was significantly lowered in hippocampus
and hypothalamus (Butterweck
et al
2002).
Misane
et al
(2001) found that an ethanolic extract given in high doses affects the neuronal 5-HT
uptake more like tricyclic antidepressants than SSRIs.
Calapai
et al
(2001) investigated an extract standardised to 50% flavonoids, 0.3% hypericin and 4.5%
hyperforin. After acute oral administration (250 – 500 mg/kg) dose-dependently the contents of 5-HT
and 5-hydroxyindolacetic acid (5-HIAA) were significantly enhanced in all brain regions examined.
Noradrenalin and dopamine levels were significantly increased in the diencephalon; in the brainstem
only noradrenalin was significantly enhanced.
The down regulation of -receptors could be demonstrated with an ethanolic extract (0.2% hypericin)
dose dependently (Kientsch
et al
2001).
A methanolic extract (4.5% hyperforin) interacted with a GABA A receptor, an extract rich in
hyperforin did not show an interaction. Data on the inhibition of specific bindings to the dopamine
transporters indicate that the hyperforin content cannot explain effects of extracts on receptors (Gobbi
et al
2001).
A methanolic extract could also inhibit the binding of flumazenil to the benzodiazepine binding site of
the GABA A receptor
in vitro
.
Simbrey
et al
(2004) used quantitative radioligand receptor binding studies to examine the effects of
short-term (2 weeks) and long-term (8 weeks) administration of different
Hypericum
extracts and
constituents on -adrenergic binding in rat frontal cortex. The effects were compared to those of the
standard antidepressants imipramine and fluoxetine. A lipophilic CO2 extract decreased beta-AR-
binding (13%) after two weeks and slightly increased the number of -receptors after 8 weeks (9%).
Short-term treatment with the methanolic
Hypericum
extract decreased -receptor-binding (14%), no
effects for this extract were observed after 8 weeks. Treatment with hypericin led to a significant
EMEA 2008
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down-regulation (13%) of -receptors in the frontal cortex after 8-weeks, but not after 2 weeks, while
hyperforin (used as trimethoxybenzoate), and hyperoside were ineffective in both treatment
paradigms. Compared to the
Hypericum
extracts and single compounds the effect of imipramine on
-receptor-binding was more pronounced in both treatment paradigms.
Teufel-Mayer
et al
(1997) could demonstrate that a methanolic extract significantly increased the
numbers of 5-HT receptors, whereas the affinity of these receptors remained unchanged.
Hypericum
extract inhibited the binding of naloxone to the µ- and -opioid receptor (IC
50
values
25 and 90 µg/ml). Isolated flavonoids like quercetin, kaempferol as well as quercitrin did not inhibit
naloxone binding. The authors suggest that this inhibition may contribute to the anti-depressant
activity (Simmen
et al
1998).
II.2.1.1.2
Antidepressant activity in animal models
Forced swimming test (FST)
In the FST pure naphthodianthrones were active in high concentrations only, after addition of a
fraction rich in procyanidines (which is itself inactive in the FST) was hypericin active in a
concentration of 0.009 mg/kg (Butterweck
et al
1998).
Hyperosid, isoquercitrin and miquellianin showed activity in low concentrations (0.6 mg/kg) in the
FST. Rutin, when administered as isolated compound, has no activity in the FST. However, extracts
with a low content of rutin show only a weak activity in the FST, but when pure rutin is added to the
extract, an activity could be demonstrated. Unfortunately the contents of the naphthodianthrones were
not presented in the study (Butterweck
et al
2000).
Daily administration of 3 mg/kg isorhamnetin, a main metabolite from quercetin, for 9 days induced a
statistically significant decrease in the immobility time in the forced swimming test (Paulke
et al
2008).
Noldner
et al
(2002) found that an ethanolic extract (doses 30-300 mg/kg, 7 days oral treatment)
shortened the spent time immobile in a dose dependent manner, while a methanolic extract was
inactive. After addition of rutin to the methanolic extract a strong effect comparable to the ethanolic
extract could be demonstrated.
Beijamini
et al
(2003) investigated the same methanolic extract. The rats received 150 to 500 mg/kg
extract in 3 portions starting 24 hours before the experiment. All doses significantly reduced the
immobility time.
Two different hydroethanolic extracts (4.5% and 0.5% hyperforin) and a stable salt of hyperforin were
tested in the forced swimming test by Cervo
et al
(2002). All test substances caused a significant
reduction of immobility; the effect was more pronounced in the extract containing more hyperforin.
The authors therefore conclude that hyperforin plays an important role in the antidepressant-like
activity.
Calapai
et al
(2001) found that an extract standardised to 50% flavonoids, 0.3% hypericin and 4.5%
hyperforin was able to reduce the immobility time by about 30-40% compared to control. The effect
was antagonised by the coadministration of sulpiride and metergoline. The effect was also
significantly ower in animals pre-treated with 6-hydroxydopamine, which destroys noradrenergic
neurons. The authors suggest that the action is probably mediated by serotonergic, noradrenergic and
dopaminergic system activation.
Learned-helplessness paradigm
Chatterjee
et al
(1998) compared an ethanolic extract (4.5% hyperforin) and a supercritical CO
2
extract (38.8% hyperforin). Oral doses of 300 mg/kg/day of the ethanolic extract and 30 mg/kg/day of
the CO
2
extract were almost equieffective to 10 mg/kg/day of imipramine (52% reduction).
Model of escape deficit
Usai
et al
(2003) compared 2 hydroethanolic extracts (4.5% hyperforin, 7.47% hyperforin). Both
extracts exhibit a strong protective effect to prevent the development of escape deficit in rats. The
extract with 4.5% hyperforin was effective in doses 8 times lower than of the other extract.
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II.2.1.1.3
Anxiolytic effects
Kumar
et al
(2000) reported anxiolytic effects of a
Hypericum
extract (ethanol 50%) of Indian origin
in animal models, the dosage was relatively high (100 and 200 mg/kg p.o.).
Flausino
et al
(2002) investigated the effects of acute and chronic oral treatment with
Hypericum
perforatum
L. (HP LI 160, 62.5-500 mg/kg) in rats submitted to different anxiety models: the elevated
T-maze (for inhibitory avoidance and escape measurements), the light/dark transition, and the cat odor
test. These models were selected for their presumed capacity of evidencing specific subtypes of
anxiety disorders as recognized in clinical practice. The results showed that acute HP (125 mg/kg)
impaired elevated T-maze inhibitory avoidance, an anxiolytic effect, without altering escape
performance. Chronic HP (250 mg/kg) enhanced avoidance latencies only in animals that were
preexposed to the open arms of the maze. Preexposure shortens escape latency, improving it as an
escape index. Differently from the reference drug imipramine (IMP, 15 mg/kg), chronic HP did not
impair escape from the open arms of the maze. On the other hand, similarly to IMP, the extract
increased the number of transitions between the two compartments in the light/dark transition model.
Treatment regimens with HP and IMP did not alter behavioral responses of rats to a cloth impregnated
with cat odor. These observations suggest that HP LI 160 exerts anxiolytic-like effects in a specific
subset of defensive behaviors, particularly those related to generalized anxiety.
The aim of a study from Beijamini
et al
(2003) was to evaluate the putative antipanic/anxiolytic effect
of a standardised
Hypericum perforatum
extract (LI 160) on rats. It was tested in the elevated T-maze,
an animal model of innate (panic) and learned (generalised) anxiety, at doses that exhibit
antidepressant-like activity.
Hypericum perforatum
(150, 300 and 500 mg/kg, administered orally 24,
18 and 1h before the test) decreased the immobility time in the forced swim test. Rats were treated
orally with
Hypericum perforatum
(150 or 300 mg/kg) or paroxetine (5mg/kg) 24, 18, and 1h before
being tested in the elevated T-maze (subacute treatment). Immediately after this test, the animals were
submitted to the open field to evaluate locomotor activity. Paroxetine was used as a positive control.
Other groups of animals were submitted to the same drug treatment for 7 days (subchronic treatment).
Paroxetine (5mg/kg) impaired inhibitory avoidance after subacute treatment, while subchronic
administration increased one-way escape latency. Subacute treatment with
Hypericum perforatum
(300 mg/kg) exerts a partial anxiolytic-like effect in the inhibitory avoidance task. Repeated
administration of
Hypericum perforatum
(300 mg/kg) induced an anxiolytic effect (decreased
inhibitory avoidance) and an antipanic effect (increased one-way escape). No effect on locomotor
activity was found with any treatment. Thus, the results suggest that
Hypericum perforatum
extract
could exert an anxiolytic and antipanic effect.
Grundmann
et al
(2006) used exposure to an open field (OF) as inescapable stressor to mice. Exposure
of male BL6/C57J mice to OF stress significantly increased body temperature (DeltaT = 1.8 +/- 0.13
degrees C, p < 0.05). Anxiolytic drugs (the benzodiazepine diazepam; 5 mg/kg, and the 5HT (1A)
receptor agonist buspirone; 10 mg/kg) significantly reduced DeltaT, whereas antidepressants
(imipramine and fluoxetine) had no effect on DeltaT. Oral administration of
Hypericum
extract
significantly reduced DeltaT in doses of 250 and 500 mg/kg. Higher (750 and 1000 mg/kg) as well as
a lower dose (125 mg/kg) did not affect DeltaT after stress, indicating a U-shaped dose-response
curve. Hypericin (0.1 mg/kg, p. o.) administered 60 min prior to testing significantly decreased DeltaT
(p < 0.05) whereas hyperforin (1 - 10 mg/kg, p. o.) had no effect in this test paradigm. The flavonoids
hyperoside, isoquercitrin and quercitrin (all at 0.6 mg/kg, p. o.) and rutin (1 mg/kg, p. o.) only partially
blocked OF-induced hyperthermia. If compared to all other flavonoids, the quercetin 3-O-glucuronide
miquelianin (1.2 mg/kg, p. o.) was the most potent compound tested in this experimental design. From
the biflavonoids in
Hypericum
, only amentoflavone decreased SIH-induced hyperthermia in a dosage
of 0.1 mg/kg. These findings could be interpreted as putative anxiolytic effects of
Hypericum
extract
and single consituents.
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II.2.1.1.4
Neuroprotection, memory impairment, nootropic effects
Kaltschmidt
et al
(2002) analyzed the effect of hypericin on NF-B activation. Hypericin alone was
able to induce short-time activation of NF-B, which declined to basal levels after 24 h. Cell death
was induced by hypericin at a concentration of 10 µM. A profound synergistic action in inducing
apoptosis was detected in co-treatment of hypericin together with FeSO
4
. In contrast, hypericin in low
concentrations was able to partly prevent cell death induced by amyloid-beta-peptide (Abeta).
Hypericin (10 µM) synergistically enhanced Abeta neurotoxicity. The data describe NF-B in the
same primary neuronal culture as stimulus-dependent, anti-apoptotic, or pro-apoptotic factor.
Extracts of
Hypericum perforatum
exhibited upgrading and significant protective effects on the trauma
of PC12 cells induced by 200 µM H
2
O
2
in a dose-dependent manner within 24-hour treatment (Lu
et
al
2004). Cell viability was assessed by the MTT method, and in situ cellular hydrogen peroxide
(H
2
O
2
)-induced oxidative stress was examined by measurement of reactive oxygen species (ROS)
formation using CDCFH procedures. Intra- and extra-cellular ROS levels decreased significantly to
71.9% and 50.0% of the control at a moderate concentration of 20 µg/ml, respectively, suggesting that
Hypericum
extract could easily enter the cells and play important roles in reducing ROS levels. The
results were proved by detection of DNA fragmentation and inspection of cell morphology of PC12
cells.
Hypericum
extract can obviously block DNA fragmentation and prevent the cells from shrinking
and turning round of H
2
O
2
-induced apoptosis in PC12 cells at concentrations of 10 approximately 100
µg/ml. The authors conclude that
Hypericum
extracts may be a candidate for application in
neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.
Genovese
et al
(2006) evaluated the effect of
Hypericum perforatum
(given at 30 mg/kg) in an
experimental animal model of spinal cord injury, which was induced by the application of vascular
clips to the dura via a four-level T5 through T8 laminectomy. The degree of (a) spinal cord
inflammation and tissue injury (histological score), (b) nitrotyrosine, (c) poly(adenosine diphosphate-
ribose), (d) neutrophils infiltration, and (e) the activation of signal transducer and activator
transcription 3 was markedly reduced in spinal cord tissue obtained from
Hypericum perforatum
extract-treated mice. It could be demonstrated that
Hypericum perforatum
extract significantly
ameliorated the recovery of limb function.
Froestl
et al
(2003) studied the effect of hyperforin on the processing of the amyloid precursor protein
(APP) in rat pheochromocytoma PC12 cells, stably transfected with human wildtype APP. The authors
observed transiently increased release of secretory APP fragments upon hyperforin treatment. Unique
features, like a strong reduction of intracellular APP and the time course of soluble APP release,
distinguished the effects of hyperforin from those of alkalizing agents and phorbol esters, well known
activators of secretory processing of APP. Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone
(FCCP), a protonophore, induced an almost identical decrease in intracellular pH in PC12 cells as does
hyperforin. Despite this, FCCP induced a less pronounced release of soluble APP fragments and only
slightly reduced intracellular APP levels. These results suggest that hyperforin is an activator of
secretory processing of APP.
Silva
et al
(2004) assessed the neuroprotective role of a
Hypericum perforatum
ethanolic extract and
obtained fractions in amyloid-beta peptide (Abeta (25-35))-induced cell death in rat cultured
hippocampal neurons. Lipid peroxidation was used as a marker of oxidative stress by following the
formation of TBARS in rat cortical synaptosomes, after incubation with ascorbate/Fe2+, alone or in
the presence of EC97 effective concentrations of
Hypericum perforatum
fractions. Induced lipid
peroxidation was significantly inhibited by fractions containing flavonol glycosides, flavonol and
biflavone aglycones, and by a fraction containing several phenols, mainly chlorogenic acid-type
phenolics (21%, 77% and 98%, respectively). Lipid peroxidation evaluated after incubation with 25
µM Abeta(25-35), was significantly inhibited by
Hypericum perforatum
extract. Cell viability was
assessed by use of the Syto-13/PI assay. The total ethanolic extract (TE) and fractions containing
flavonol glycosides, flavonol and biflavone aglycones, reduced Abeta(25-35)-induced cell death (65%,
58% and 59%, respectively). These results were further supported by morphological analysis of cells
stained with cresyl violet. Peptide beta-amyloid(25-35) induced a decrease in cell volume, chromatin
condensation and nuclear fragmentation, alterations not evident in the presence of the TE and fractions
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containing hypericins (hypericin concentration = 11.02 µM), or fractions containing flavonoids
(quercetin concentration = 21.13 µM). Dendritic lesion, an evidence of neurodegeneration, was
observed by neuronal staining with cobalt following insult with Abeta(25-35), but prevented after
exposure to the peptide plus the fractions referred above. The results suggest that
Hypericum
perforatum
extracts may be endowed with neuroprotective compounds able to prevent Abeta(25-35)-
induced toxicity.
The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid beta-
peptide (Abeta). Dinamarca
et al
(2006) have determined the effect of hyperforin on Abeta-induced
spatial memory impairments and on Abeta neurotoxicity. Hyperforin decreases amyloid deposit
formation in rats injected with amyloid fibrils in the hippocampus, decreases the neuropathological
changes and behavioral impairments in a rat model of amyloidosis, and prevents Abeta-induced
neurotoxicity in hippocampal neurons both from amyloid fibrils and Abeta oligomers, avoiding the
increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained
by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner
and to decrease Abeta aggregation and amyloid formation.
Acute administration of
Hypericum
extract (4.0, 8.0, 12.0, and 25.0 mg/kg i.p.) in mice before retrieval
testing increased the step-down latency during the test session. The same doses of
Hypericum
extract,
on the other hand, failed to reverse scopolamine-induced amnesia of a two-trial passive avoidance
task. Pretreatment of the animals with serotonergic 5-HT1A receptor antagonist (-)-pindolol (0.3, 1.0,
and 3.0 mg/kg), serotonergic 5-HT2A receptor blocker spiperone (0.01, 0.03, and
0.1 mg/kg), alpha adrenoceptor antagonist phentolamine (1, 5, and 10 mg/kg), beta receptor antagonist
propranolol (5, 7.5, and 10 mg/kg), dopaminergic D1 receptor antagonist SCH 23390 (0.01, 0.05, and
0.1 mg/kg), and dopaminergic D2 receptor antagonist sulpiride (5, 7.5, and 10 mg/kg) revealed the
involvement of adrenergic and serotonergic 5-HT1A receptors in the facilitatory effect of
Hypericum
extract on retrieval memory. It is concluded that
Hypericum
extract may be a better alternative for
treatment of depression commonly associated with dementia than other antidepressants known to have
anticholinergic side effects causing delirium, sedation and even exacerbating already existing impaired
cognition (Khalifa 2001).
The effects of a
Hypericum
extract and hyperforin sodium salt were evaluated in rat and mouse
avoidance tests by Klusa
et al
(2001). In a conditioned avoidance response (CAR) test on the rat, oral
daily administration of hyperforin (1.25 mg/kg/day) or of the extract (50 mg/kg/day) before the
training sessions considerably improved learning ability from the second day onwards until the day 7.
In addition, the memory of the learned responses acquired during 7 consecutive days of administration
and training was largely retained even after 9 days without further treatment or training. The
observations made using different doses indicate that these learning-facilitating and/or memory-
consolidating effects by the agents follow inverse U-shaped dose-response curves in dose ranges lower
than (for hyperforin) or equal to (for
Hypericum
extract) their effective dose in the behavioral despair
test for antidepressants. In a passive avoidance response test on the mouse, a single oral dose
(1.25 mg/kg) of hyperforin not only improved memory acquisition and consolidation, but also almost
completely reversed scopolamine-induced amnesia. The single
Hypericum
extract dose tested
(25 mg/kg) did not reveal any significant effects in the passive avoidance response (PAR) test on the
mouse. These observations suggest that the
Hypericum
extract could be a novel type of antidepressant
with memory enhancing properties, and indicate that hyperforin is involved in its cognitive effects.
Pure hyperforin seems to be a more potent antidementia agent than an antidepressant.
Kumar
et al
(2000, 2002) found that orally administered extracts of
Hypericum perforatum
of Indian
origin (doses 100 mg and 200 mg /kg) to rats showed effects which could be interpreted as possible
nootropic action.
Widy-Tyszkiewicz
et al
(2002) investigated the effects of long-term
Hypericum perforatum
treatment
on spatial learning and memory in rats. A
Hypericum
powder (HP) standardized to 0.3% hypericin
content was administered orally for 9 weeks in doses of 4.3 and 13 µg/kg corresponding to therapeutic
dosages in humans of 0.3 and 0.9 mg of total hypericins daily. A Morris water maze paradigm was
used. The mean escape latency over 4 d for the Control group (21.9 s) and HP 4.3 group (21.7 s) was
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significantly greater than the latency of the HP 13 group (15.8s). In the probe trial on day 5, the HP 13
group crossed the correct annulus in the SE quadrant more often (4.5) than the other groups: Con (2.4)
and HP 4.3 (3.1). After completion of the behavioural experiment, the regional brain concentrations of
monoamines and metabolites were estimated in selected brain regions, i.e. prefrontal cortex,
hippocampus and hypothalamus. Significant differences in the content of monoamines and metabolites
between the treatment groups compared to the control were detected. The increased
5-hydroxytryptamine (5-HT) levels in the prefrontal cortex correlated positively with the retention of
spatial memory. These findings show that the long-term administration of
Hypericum perforatum
can
improve learning and spatial memory with significant changes in the content of monoamines in several
brain regions.
Administration of
Hypericum perforatum
(350 mg/kg daily for 21 days) significantly enhanced recall
of passive avoidance behavior (PAB), but had no effect on the acquisition of conditioned avoidance
responses (CARs). Rats stressed chronically (2 h daily for 21 days) displayed diminished recall of the
PAB and this effect was abolished by St John's wort. Chronic administration of the "equivalent" to the
stress dose of exogenous corticosterone (5 mg/kg daily for 21 days) also impaired recall of PAB, and
this effect was also reversed by
Hypericum perforatum
. None of the treatments produced significant
motor coordination impairments as tested in a 'chimney' test. It appears that
Hypericum perforatum
prevents stress-induced deterioration of memory in rats (Trofimiuk
et al
2005, 2006).
Mohanasundari
et al
(2006, 2007) tested the effect of an extract of
Hypericum perforatum
in
chemically induced Parkinson’s disease in mice. Treatment with
Hypericum perforatum
extract
resulted in an inhibition of monoamine oxidase-B activity and reduced astrocyte activation in striatal
area. The effects were more pronounced when
Hypericum
was combined with bromocriptine.
Sanchez Reus
et al
(2007) designed a study to investigate the pro-oxidant activity of rotenone, the
protective role of standardized extract of
Hypericum perforatum
(SHP), as well as the mRNA levels of
antioxidant enzymes, in brain homogenates of rats following exposure to rotenone and SHP extract.
Quercetin in liposomes, one active constituent, was tested in the same experimental conditions to serve
as a positive control. The animals received pretreatment with SHP (4 mg/kg) or quercetin liposomes
(25 and 100 mg/kg) 60 min before of rotenone injection (2 mg/kg). All treatments were given
intraperitoneally in a volume of 0.5 ml/kg body weight, for 45 days. SHP extract exerted an
antioxidant action which was related to a decrease of MnSOD activity and mRNA levels of some
antioxidant enzymes evaluated. One possible mechanism of action of SHP extract may be related to
quercetin in protecting neurons from oxidative damage.
El-Sherbiny
et al
(2003) investigated the effect of acute administration of
Hypericum perforatum
extract (4.0, 8.0, 12.0, and 25.0 mg/kg ip) on the brain oxidative status of naive rats treated with an
amnestic dose of scopolamine. The results showed that the administration of 1.4 mg/kg of
scopolamine impaired the retrieval memory of rats. Pretreatment of the animals with
Hypericum
extract (4, 8, and 12 mg/kg) resulted in an antioxidant effect through altering brain malondialdehyde,
glutathione peroxidase, and/or glutathione level/activity.
II.2.1.1.5
Support in smoking cessation
Catania
et al
(2003) investigated the effects of an extract of
Hypericum perforatum
(Ph-50) on
withdrawal signs produced by nicotine abstinence in mice. Nicotine (2 mg/kg, four injections daily)
was administered for 14 days to mice. Different doses of Ph-50 (125-500 mg/kg) were administered
orally immediately after the last nicotine injection. In another experiment, Ph-50 (500 mg/kg) was
orally administered in combination with nicotine, i) starting from day 8 until the end of the nicotine
treatment period, or ii) during nicotine treatment and after nicotine withdrawal, or iii) immediately
after the last nicotine injection. The locomotor activity reduction induced by nicotine withdrawal was
abolished by Ph-50, which also significantly and dose-dependently reduced the total nicotine
abstinence score when injected after nicotine withdrawal.
Mannucci
et al
(2007) investigated the possible involvement of 5-HT in the beneficial effects of
Hypericum perforatum
on nicotine withdrawal signs. With the aim to induce nicotine dependence,
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nicotine (2 mg/kg, four intraperitoneal injections daily) was administered for 14 days to mice (NM).
After nicotine withdrawal the measurement of 5-HT metabolism in the cortex showed a reduction of
the 5-HT content while animals treated only with
Hypericum
extract showed a significant reduction of
total abstinence score compared to controls. A selective 5-HT receptor antagonist inhibited the
reduction of total abstinence score induced by
Hypericum perforatum
. Moreover, 5-HT1A expression
has been evaluated 30 days after nicotine withdrawal. The results show a significant increase of
cortical 5-HT content in NM treated with H. perforatum, with a concomitant significant increase of 5-
HT1A receptor.
II.2.1.1.6
Treatment of alcoholism
Several studies were performed in order to investigate the influence of
Hypericum
extracts on alcohol
intake in animals (Rezvani
et al
1999, Perfumi
et al
1999, Perfumi
et al
2005, Perfumi
et al
2005a,
Coskun
et al
2006). All studies report beneficial effects on ethanol withdrawal symptoms, additionally
a reduction of alcohol intake in alcohol preferring animals was observed.
Hypericum
extracts and
opioid receptor antagonists act synergistically (Perfumi
et al
2003).
The changes in the alcohol drinking behaviour may be caused by hyperforin (Perfumi
et al
2001,
Wright
et al
2003). In contrast, De Vry
et al
(1999) reported a reduction in alcohol preference after
administration of an extract with very low hyperforin content. Clinical data are missing (Uzbay 2008).
II.2.1.1.7
Antibacterial activity
Gibbons
et al
(2002) screened extracts of 34 species and varieties of the genus
Hypericum
for activity
against a clinical isolate of methicillin-resistant Staphylococcus aureus, which in addition possessed a
multidrug efflux mechanism conferring a high level of resistance to therapeutically useful antibiotics.
Thirty-three of the 34 chloroform extracts showed significant activity in a disk diffusion assay, and
five extracts had minimum inhibitory concentrations of 64 µg/ml.
II.2.1.1.8
Antiinflammatory activity
Schempp (2000) investigated the alloantigen presenting function of human epidermal cells (EC)
exposed to
Hypericum
ointment
in vivo
in a mixed EC lymphocyte reaction (MECLR). The effect of
Hypericum
ointment was compared with the immunosuppressive effect of solar-simulated radiation
(SSR). Subsequently, the authors tested purified hyperforin
in vivo
and
in vitro
in a MECLR to
evaluate its possible contribution to the effect of the
Hypericum
ointment. Furthermore, the effect of
hyperforin on the proliferation of peripheral blood mononuclear cells (PBMC)
in vitro
was assessed.
Compared with untreated skin, treatment with
Hypericum
ointment resulted in a significant
suppression of the MECLR (P </= 0.001) that was similar to the effect of SSR. The combination of
Hypericum
ointment plus SSR was not significantly different from either treatment alone. EC isolated
from skin treated with the hyperforin containing ointment also showed a reduced capacity to stimulate
the proliferation of allogeneic T cells (P </= 0.001). Similarly,
in vitro
incubation of EC with
hyperforin suppressed the proliferation of alloreactive T cells (P </= 0.001). Furthermore, hyperforin
inhibited the proliferation of PBMC in a dose-dependent manner, without displaying pronounced toxic
effects as determined by Trypan blue staining. The results demonstrate an inhibitory effect of
Hypericum
extract and of its metabolite hyperforin on the MECLR and on the proliferation of T
lymphocytes that may provide a rationale for the traditional treatment of inflammatory skin disorders
with
Hypericum
extracts.
Three preparations of
Hypericum perforatum
L. (a hydroalcoholic extract, a lipophilic extract and an
ethylacetic fraction) and the pure compounds hypericin, adhyperforin, amentoflavone, hyperoside,
isoquercitrin, hyperforin dicyclohexylammonium (DHCA) salt and dicyclohexylamine were evaluated
for their topical anti-inflammatory activity (Sosa
et al
2007).
Hypericum perforatum
preparations
provoked a dose-dependent reduction of Croton-oil-induced ear oedema in mice, showing the
following rank order of activity: lipophilic extract > ethylacetic fraction > hydroalcoholic extract
(ID50 220, 267 and >1000 microg cm
-2
, respectively). Amentoflavone (ID50 0.16 micromol cm
-2
),
hypericin (ID50 0.25 micromol cm
-2
), hyperforin DHCA salt (ID50 0.25 micromol cm
-2
) and
adhyperofrin (ID50 0.30 micromol cm
-2
) had anti-inflammatory activity that was more potent or
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comparable to that of indometacin (ID50 0.26 micromol cm
-2
), whereas isoquercitrin and hyperoside
were less active (ID50 about 1 micromol cm
-2
). As dicyclohexylamine alone was inactive, the effect of
hyperforin DHCA salt can be attributed completely to the phloroglucinol moiety. The pharmacological
activity and phytochemical profile of the tested extracts and fraction suggest that different constituents
are involved in the topical antiphlogistic property of
Hypericum perforatum
in vivo
.
Eckert
et al
(2001) tested the effects of hyperforin on the fluidity of crude brain membranes from
young guinea pigs. Hyperforin modifies specific membrane structures in different ways. It decreases
the flexibility of fatty acids in the membrane hydrocarbon core, but fluidizes the hydrophilic region of
membrane phospholipids. Relatively low concentrations of hyperforin (0.3 µmol/l) significantly
decreased the annular fluidity of lipids close to membrane proteins. These findings are remarkable, as
inhibition of several neurotransmitter-uptake systems and modulation of several ionic conductance
mechanisms by hyperforin occur in the same concentration range. However, bulk fluidity was
unchanged by this low hyperforin concentration. The results emphasise a physicochemical interaction
of hyperforin with specific membrane structures that probably contribute to its pharmacological
properties.
II.2.1.1.9
Wound healing
The wound-healing effect of St. John's Wort (
Hypericum perforatum
L.) extract was evaluated by
comparing with dexpanthenol and titrated extract of Centella asiatica (TECA) on cultured chicken
embryonic fibroblasts (Ozturk
et al
2006). Chicken embryonic fibroblasts from fertilized eggs were
incubated with the plant extract, dexpanthenol and TECA. The wound-healing activity of
Hypericum
perforatum
extract seems to be mainly due to the increase in the stimulation of fibroblast collagen
production and the activation of fibroblast cells in polygonal shape, which plays a role in wound repair
by closing damaged area. The findings demonstrated the wound-healing activity of
Hypericum
perforatum
, which has previously been based on ethnomedical data.
II.2.1.1.10
Pregnancy, lactation
Rayburn
et al
(2001) investigated the cognitive impact of prenatal exposure to
Hypericum
in CD-1
mice.
Hypericum
(182 mg/kg/day) or a placebo was consumed in food bars for 2 weeks before mating
and throughout gestation. The hypericin content in the
Hypericum
formulation was in the middle range
of standardized
Hypericum
products. One offspring per gender from each litter (
Hypericum
13,
placebo 12) was tested on each of the following tasks: juvenile runway with adult memory, adult
Morris maze, adult passive avoidance, or adult straight water runway followed by a dry Cincinnati
maze. Learning occurred in both genders in all tasks (P<0.003) with no significant differences between
treatments at the final trial. Female offspring exposed to
Hypericum
, rather than to a placebo, required
more time to learn the Morris maze task (P<.05). Postlearning sessions did not show any significant
differences. In conclusion, prenatal exposure to a therapeutic dose of
Hypericum
did not have a major
impact on certain cognitive tasks in mice offspring.
II.2.1.1.11
Photodynamic therapy
Hypericin is considered as potential agent in the photodynamic therapy of cancer (Agostinis
et al
2002). However, since only isolated hypericin and not extracts have been tested, this approach is out
of the scope of this assessment.
II.2.1.1.12
Other effects
Capasso
et al
(2005) evaluated the effect of
Hypericum
on rat and human vas deferens contractility.
Hypericum
extract (1 to 300 microM) decreased in a concentration dependent manner the amplitude of
electrical field stimulation and agonist induced contractions with the same potency, suggesting direct
inhibition of rat vas deferens smooth muscle. Of the chemical constituents of
Hypericum
extract tested
hyperforin but not hypericin or the flavonoids quercitrin, rutin and kaempferol inhibited phenylephrine
induced contractions.
Hypericum
extract and hyperforin also inhibited phenylephrine induced
contractions in human vas deferens. These results might explain delayed ejaculation described in
patients receiving
Hypericum
extract.
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Effects of different extracts of
Hypericum perforatum
L. on the kindling epileptic discharges were
analyzed by Ivetic
et al
(2002). The experiment was carried out on Chinchilla rabbits with chronically
implanted electrodes in cortical structures and hippocampus. Water, n-butanol and ether fractions
(mass concentrations 0.1 g/ml) of crude ethanol extract of
Hypericum perforatum
were used. The
particular extracts were given intramuscularly in single dose of 1 ml/kg BW. The bioelectric activity
was registered before and after applications of each extracts. The obtained results show that the effect
depends on the constituents present in particular fractions. Most polar constituents that remained in
water fraction exerted highest antiepileptic activity in all (100%) animals tested. Substances present in
butanol fraction repressed the epileptic manifestations in 40% of animals with kindling epilepsy,
whereas lipid-soluble constituents in ether fraction potentiated the epileptic activity.
Hypericin, pseudohypericin and hyperforin at doses as low as 2.5 µmol/l are potent antioxidants in the
LDL oxidation systems used. These results indicate that these derivatives have possible
antiatherogenic potential (Laggner
et al
2007). An extract rich in flavonoids lowered serum levels of
total cholesterol, total triglycerides and LDL (Zou
et al
2005).
Free radical scavenging and antioxidant activities of a standardized extract of
Hypericum perforatum
were examined for inhibition of lipid peroxidation, for hydroxyl radical scavenging activity and
interaction with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH) by Benedi
et al
(2004). The
results suggest that
Hypericum
extracts shows relevant antioxidant activity both
in vitro
and in a cell
system, by means of inhibiting free radical generation and lipid peroxidation.
Antioxidative and radical scavenging effects are also reported for the flavonoid fraction of
Hypericum
perforatum
(Zou
et al
2004) and for several commercially available formulations (Hunt
et al
2001).
The antioxidative properties protect human neuroblastoma cells against induced apoptosis (Jang
et al
2002).
Genovese
et al
(2006) evaluated the effect of
Hypericum perforatum
extract on acute pancreatitis
induced by cerulein administration in male CD mice. The degree of pancreatic inflammation and
tissue injury (histological score), expression of ICAM-1, the staining for nitrotyrosine and PAR, and
myeloperoxidase activity was markedly reduced in pancreatic tissue sections obtained from cerulein-
treated mice administered
Hypericum perforatum
extract (30 mg/kg, suspended in 0.2 mL of saline
solution, o.s.). Moreover, the treatment with
Hypericum perforatum
extract significantly reduced the
mortality rate 5 days after cerulein administration.
Following the traditional use of
Hypericum perforatum
against viruses of the Herpes family in Greece
Axarlis
et al
(1998) found antiviral activity of a methanolic extract against Human Cytomegalovirus.
Panossian
et al
(1996) concluded that the antiviral, antiinflammatory and antitumroal effects of
hypericin may result from the inhibition of the PKC-mediated signalling pathway demonstrated in
human leukocytes, which influences the arachidonic acid metabolism and the interleukin-1-alpha
production resulting in an immunosuppressive effect.
II.2.1.2
Assessor’s overall conclusions on pharmacology
There are numerous pharmacological findings published which propose a similar pharmacology to
established synthetic antidepressant drugs. However, the discussion on the responsible compounds in
the extract is still ongoing. Since several hydroethanolic and hydromethanolic extracts with different
contents of hypericin and hyperforin are positively tested it could be concluded that the
naphthodianthrones and the phloroglucine derivatives are of minor relevance for the antidepressant
activity.
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II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
Wurglics
et al
(2006) published a review on pharmacokinetic data of compounds of
Hypericum
extracts. The hyperforin plasma concentration in humans was investigated in a small number of
studies. The results of these studies indicate a relevant plasma concentration, comparable with that
used in
in vitro
tests. Furthermore, hyperforin is the only ingredient of
Hypericum perforatum
that
could be determined in the brain of rodents after oral administration of alcoholic extracts. The plasma
concentrations of the hypericins were, compared with hyperforin, only one-tenth and, until now, the
hypericins could not be found in the brain after oral administration of alcoholic
Hypericum perforatum
extracts or pure hypericin.
The intestinal absorption characteristics of protohypericin were studied and compared with those of
hypericin by Kamuhab
et al
(1999). The Caco-2 model was used as a model of the intestinal mucosa
to assess transepithelial transport and cell uptake. Following application of the individual compounds
(80-200 microM) to the apical side of the monolayers, the appearance in the basolateral compartment
was found to be very low (<0.5%/5 h), but was comparable for both compounds. A lag-time of 2-3 h
was observed, suggesting gradual saturation of binding sites on the membrane or inside the cells.
Uptake experiments of protohypericin and hypericin by Caco-2 cells revealed a very significant
cellular accumulation (4-8%); uptake was characterised by saturation after 3 h. The findings of this
study suggest that protohypericin has comparable absorption characteristics as hypericin.
Investigations by Sattler
et al
(1997) indicate that a significant accumulation of hypericin in the cell
membrane and the cell nucleus membrane of Caco-2-cells takes place. The authors conclude that
hypericin is absorbed through the intestinal epithelium by passive transcellular diffusion and that
increasing its solubility by cyclodextrin appears as a promising approach to increase its oral
bioavailability for pharmaceutical formulations.
Plasma levels of hypericin in rats in the presence and absence of procyanidin B2 or hyperoside were
determined by reversed phase HPLC using fluorimetric detection (Butterweck
et al
2003). Both
compounds increased the oral bioavailability of hypericin by ca. 58% (B2) and 34% (hyperoside).
Procyanidin B2 and hyperoside had a different influence on the plasma kinetics of hypericin; median
maximal plasma levels of hypericin were detected after 360 min (C
max
: 8.6 ng/mL) for B2, and after
150 min (C
max
: 8.8 ng/mL) for hyperoside. It can be speculated that, when administered together with
these compounds, a significant accumulation of hypericin in rat plasma in the presence of both
polyphenols might be responsible for the observed increased
in vivo
activity.
Juergenliemk
et al
(2003) examined the pathway of miquelianin (quercetin 3-O-beta-D-
glucuronopyranoside), a flavonoid with antidepressant acitivity, from the small intestine to the central
nervous system. The permeability coefficient of miquelianin (Pc = 0.4 +/- 0.19 x 10(-6) cm/sec) was in
the range of orally available drugs assuming sufficient absorption from the small intestine. The
permeability coefficients (blood-brain-barrier: Pc = 1.34 +/- 0.05 x 10(-6) cm/sec; blood-CSF-barrier:
Pc = 2.0 +/- 0.33 x 10(-6) cm/sec) indicate the ability of miquelianin to cross both barriers to finally
reach the CNS.
Paulke
et al
(2008) suggested that not the genuine flavonoid glycosides reach the plasma. After oral
uptake they are deglycosylated in the small intestine, after absorption the quercetin aglycone is
glucuronidated (yielding e.g. miquelianin). Further methylation is possibly leading to isorhamnetin
and tamarixetin. These metabolites have the ability to penetrate the blood-brain-barrier. Moreover, a
significant accumulation of these metabolites in the CNS tissue is observed. After a single dose of a
Hypericum
extract (1600 mg/kg rat) the quercetin plasma level increased rapidly and reached the
maximum of about 700 ng/ml after 4 hours. After 24 hours, 50% of the C
max
was still measurable. In
contrast the concentration level of isorhamnetin/Tamarixetin increase much slower, the maximum was
reached after 24 hours with a C
max
of 903 ng/ml. Repeated doses of 1600 mg/kg rat yielded a
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continuous increase in the plasma levels of quercetin and isorhamnetin for 5 days, after that time the
concentration ermained constant.
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics
The few data on pharmacokinetics do not allow a final conclusion about absorption, distribution,
metabolism and excretion of constituents. Additionally it is not clear whether putative active
constituents of
Hypericum
extracts reach the brain tissue in sufficient concentration.
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
and constituents thereof
II.2.3.1.1
Single-dose toxicity
For a methanolic extract (DER 3-6:1) the following data are publis
hed in the SPC:
Species
Application
LD
50
(mg/kg BW)
Mouse
oral
≥ 5000
Rat
oral
≥ 5000
Mouse
intraperitoneal
1780
Rat
intraperitoneal
1000
Intravenous application of hypericin was well tolerated by rhesus monkeys in a dose of 2 mg/kg, at
5 mg/kg transient severe photosensitivity rash occurred (Fox
et al
2001). The amount of hypericin
administered daily in usual therapeutic dosages is not more than 3 mg for adults (= 0.04 mg/kg).
II.2.3.1.2
Repeated-dose toxicity
Studies on long-term toxicity (900 mg/kg and 2700 mg/kg extract per day (LI 160), 26 weeks
treatment) in rats and dogs revealed only minor non-specific symptoms (weight loss, minor
pathological changes in liver and kidney). All changes reverted to normal when treatment was stopped
(Leuschner 1996, Greeson
et al
2001). The dosages were approximately 70 and 200 times the mean
therapeutic dosage. Therefore the therapeutic dosage of 13 mg/kg per day (= 900 mg extract) can be
regarded as safe from that perspective.
II.2.3.1.3
Mutagenicity
The genotoxicity testing of ethanolic extracts showed weak positive results in the AMES-test
(Salmonella typhimurium TA 98 and TA 100, with and without metabolic activation). After
chromatographic separation the effect could be assigned to quercetin (Poginsky
et al
1988, Schimmer
1988).
Okpanyi
et al
(1990) tested an ethanolic extract (DER 1:5-7, 0.2-0.3% hypericin, 0.35 mg/g quercetin)
in several
in vivo
(mammalian spot test in mice, chromosome aberration test in Chinese hamsters) and
in vitro
test systems (HGPRT hypoxanthine-guanine-phosphoribosyl-transferase etst, UDS
unscheduled DNA synthesis test, cell transformation test). The authors could not detect signs of a
mutagenic potential of the extract.
II.2.3.1.4
Carcinogenicity
No data available
II.2.3.1.5
Phototoxicity
In order to estimate the potential risk of phototoxic skin damage during antidepressive therapy, Bernd
et al
(1999
)
investigated the phototoxic activity of hypericin extract using cultures of human
keratinocytes and compared it with the effect of the well-known phototoxic agent psoralen.
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The absorbance spectrum of the
Hypericum
extract revealed maxima in the whole UV range and in
parts of the visible range. Human keratinocytes were cultivated in the presence of different
Hypericum
concentrations. The determination of the bromodeoxyuridine incorporation rate showed a
concentration- and light-dependent decrease in DNA synthesis with high hypericin concentrations
(≥ 50 µg/mL) combined with UVA or visible light radiation. In the case of UVB irradiation a clear
phototoxic cell reaction was not detected. The authors found phototoxic effects even with 10 ng/mL
psoralen using UVA with the same study design as in the case of the
Hypericum
extract. These results
confirm the phototoxic activity of
Hypericum
extract on human keratinocytes. However, the blood
levels that are to be expected during antidepressive therapy are presumably too low to induce
phototoxic skin reactions.
Schempp
et al
(2002) assessed the phototoxic and apoptosis-inducing capacity of pseudohypericin
(PH) compared to hypericin (H) in a cell culture model with human leukemic lymphoma cells (Jurkat).
Treatment with both photoactivated H and PH resulted in a dose-dependent inhibition of cell
proliferation, whereas not photoactivated H and PH had no effect at the concentrations tested. The
half-maximal inhibitory concentration (IC50) of H was lower (100 ng/mL) as compared to PH
(200 ng/mL) (p < 0.05). In an apoptosis assay the authors found a dose-dependent increase of DNA
fragmentation after treatment with both photoactivated H and PH. The cytotoxic potential of PH
should be taken into account during systemic therapy with
Hypericum
extracts, since PH is about two
times more abundant than H in
Hypericum perforatum
.
Wilhelm
et al
(2001) investigated the phototoxic potential of 3
Hypericum perforatum
extracts from
different sources as well as some of its main constituents.
Hypericum perforatum
extracts
demonstrated cytotoxicity and photocytotoxicity in a dose and UVA-dose dependent manner.
Hypericine itself also evoked severe phototoxic effects and was thus identified as the main phototoxic
constituent. Among the tested flavonoids quercitrin was found to be cytotoxic, while rutin
unexpectedly demonstrated phototoxicity whereas quercitrin was effective to control the phototoxic
activity of
Hypericum perforatum
extracts.
Clinical evidence suggests that administration of
Hypericum perforatum
(Hp) extracts containing the
photo-activated hypericin compounds may cause fewer skin photosensitization reactions than
administration of pure hypericin. Schmitt
et al
(2006) conducted a study to determine whether the
phototoxicity of hypericin in HaCaT keratinocytes could be attenuated by
Hypericum perforatum
extracts and constituents. Two extracts, when supplemented with 20 microM hypericin: (1) an ethanol
re-extraction of residue following a chloroform extraction (denoted ethanol(-chloroform))
(3.35 microM hypericin and 124.0 microM total flavonoids); and (2) a chloroform extract (hypericin
and flavonoids not detected), showed 25% and 50% (p<0.0001) less phototoxicity than 20 microM
hypericin alone. Two
Hypericum perforatum
constituents, when supplemented with 20 microM
hypericin: (1) 10 microM chlorogenic acid; and (2) 0.25 microM pyropheophorbide, exhibited 24%
(p<0.05) and 40% (p<0.05) less phototoxicity than 20 microM hypericin alone. The peroxidation of
arachidonic acid was assessed as a measure of oxidative damage by photo-activated hypericin, but this
parameter of lipid peroxidation was not influenced by the extracts or constituents. However alpha-
tocopherol, a known antioxidant also did not influence the amount of lipid peroxidation induced in this
system. These observations indicate that hypericin combined with
Hypericum perforatum
extracts or
constituents may exert less phototoxicity than pure hypericin, but possibly not through a reduction in
arachidonic acid peroxidation.
Schmitt
et al
(2006a) examined the cytotoxicity of Hp extracts prepared in solvents ranging in
polarity, fractions of one extract, and purified compounds in three cell lines. All extracts exhibited
significant cytotoxicity; those prepared in ethanol (no hyperforin, 3.6 microM hypericin, and
134.6 microM flavonoids) showed between 7.7 and 77.4% cell survival (p < 0.0001 and 0.01),
whereas the chloroform and hexane extracts (hyperforin, hypericin, and flavonoids not detected)
showed approximately 9.0 (p < 0.0001) and 4.0% (p < 0.0001) survival. Light-sensitive toxicity was
observed primarily with the ethanol extracts sequentially extracted following removal of material
extracted in either chloroform or hexane. The absence of light-sensitive toxicity with the Hp extracts
suggests that the hypericins were not playing a prominent role in the toxicity of the extracts.
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A study by Traynor
et al
(2005) used HaCaT keratinocytes to investigate the photoclastogenic ability
of hypericin on irradiation with UVA. The results show that although the combination of hypericin
and UVA light increased the genotoxic burden, when all factors are taken into account, the risk of
significant photogenotoxic damage incurred by the combination of
Hypericum
extracts and UVA
phototherapy may be low in the majority of individuals.
Phototoxicity to the eye
To determine if hypercin could be phototoxic to the eye, He
et al
(2004) exposed human lens epithelial
cells to 0.1-10 microM hypericin and irradiated them with 4 J/cm
2
UV-A or 0.9 J/cm
2
visible light.
Neither hypericin exposure alone nor light exposure alone reduced cell viability. In contrast, cells
exposed to hypericin in combination with UV-A or visible light underwent necrosis and apoptosis.
The ocular antioxidants lutein and N-acetyl cysteine did not prevent damage. Thus, ingested
Hypericum extract is potentially phototoxic to the eye and could contribute to early cataractogenesis.
Lens alpha-crystallin, isolated from calf lenses, was irradiated in the presence of hypericin (5 x 10(-5)
M, 10 mM ammonium bicarbonate, pH 7.0) and in the presence and absence of light (> 300 nm,
24 mW/cm
2
). Hypericin-induced photosensitized photopolymerization as assessed by sodium
dodecylsulfate-polyacrylamide gel electrophoresis. Further analysis of the oxidative changes occurring
in alpha-crystallin using mass spectrometry showed specific oxidation of methionine, tryptophan and
histidine residues, which increased with irradiation time. Hypericin did not damage the lens protein in
the dark. Damage to alpha-crystallin could undermine the integrity of the lens directly by protein
denaturation and indirectly by disturbing chaperone function. Therefore, in the presence of light,
hypericin can induce changes in lens protein that could lead to the formation of cataracts. The authors
conclude that appropriate precautions should be taken to protect the eye from intense sunlight while on
this antidepressant medication (Schey
et al
2000).
Wahlman
et al
(2003) found that the total accumulated protein leakage was positively correlated
(r = 0.9) with variability in focal length. Lenses treated with hypericin and irradiated with UVB had an
increase in focal length variability as compared with the lenses that were only UVB-irradiated. Lenses
without UVB irradiation had much lower focal length variability than irradiated lenses. For non-
hypericin-treated lenses, UVB-irradiated lenses had a larger variability (4.58 mm) than the
unirradiated lenses (1.78 mm). The lenses incubated in elevated glucose concentrations had a focal
length variability (3.23 mm) equivalent to that of the unirradiated hypericin-treated lenses (3.54 mm).
The authors conclude that photooxidative damage by hypericin results in changes in the optical
properties of the lens, protein leakage and finally cataract formation. In contrast to this, high
concentrations of glucose induced protein leakage but not changes in optical properties or the opacity
associated with a cataract. This work provides further evidence that people should protect their eyes
from intense sunlight when taking St. John's Wort.
To determine if hypericin might be phototoxic to the human retina, Wielgus
et al
(2006) exposed
human retinal epithelial cells to 10(-7) to 10(-5) M hypericin. Fluorescence emission detected from the
cells (lambda(exc) = 488 nm; lambda(em) = 505 nm) confirmed hypericin uptake by human RPE.
Neither hypericin exposure alone nor visible light exposure alone reduced cell viability. However
when irradiated with 0.7 J/cm(2) of visible light (lambda > 400 nm) there was loss of cell viability as
measured by MTS and LDH assays. The presence of hypericin in irradiated hRPE cells significantly
changed the redox equilibrium of glutathione and a decrease in the activity of glutathione reductase.
Increased lipid peroxidation as measured by the TBARS assay correlated to hypericin concentration in
hRPE cells and visible light radiation. Thus, ingested
Hypericum
extract is potentially phototoxic to
retina and could contribute to retinal or early macular degeneration.
II.2.3.1.6
Reproduction Toxicity
Ondrizek
et al
(1999) incubated zona-free hamster oocytes for 1 hour in St. John's wort (
Hypericum
perforatum
), or control medium before sperm-oocyte interaction. The DNA of herb-treated sperm was
analyzed with denaturing gradient gel electrophoresis. Pre-treatment of oocytes with 0.6 mg/mL of
St. John's wort resulted in zero penetration. A lower concentration (0.06 mg/mL) had no effect.
Exposure of sperm to St. John's wort resulted in DNA denaturation. Sperm exposed to 0.6 mg/mL of
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St. John's wort showed mutation of the BRCA1 exon 11 gene. The data suggested in the view of the
authors that St. John's wort at high concentrations damage reproductive cells. St. John's wort was
mutagenic to sperm cells. Since the concentrations used were several orders of magnitude higher than
considered as therapeutically relevant these effects should be considered with caution (Greeson
et al
2001).
Rayburn
et al
(2001) examined the influence of 180 mg/kg daily of a
Hypericum
extract on long-term
growth and physical maturation of mouse offspring for 2 weeks before conception and throughout
gestation. No differences between the
Hypericum
group and the placebo group could be detected.
Assessor’s comment:
Details on the type of extract are missing.
The purpose of a study of Gregoretti
et al
(2004) was to investigate the effects of a treatment with
Hypericum
administered prenatally and during breastfeeding (from 2 weeks before mating to 21 days
after delivery) in Wistar rats. Two doses of the extract were chosen, 100 mg/kg per day, which, based
on surface area, is comparable to the dose administered to humans, and 1000 mg/kg per day.
A microscopical analysis of livers, kidneys, hearts, lungs, brains, and small bowels was performed.
A severe damage was observed in the livers and kidneys of animals euthanized postnatally on day
0 and 21. The lesions were more severe with the higher dose and in animals that were breastfed for
21 days; however, an important renal and hepatic damage was evident also with the dose of 100 mg/kg
per day. In addition, similar serious hepatic and renal lesions were evident also in animals that were
exposed to
Hypericum
only during breastfeeding. In particular, a focal hepatic damage, with
vacuolization, lobular fibrosis, and disorganization of hepatic arrays was evident; in the kidney, a
reduction in glomerular size, disappearance of Bowman's space, and hyaline tubular degeneration were
found. The results obtained in this study indicate that further, appropriate histological studies should
be performed in other animal species to better evaluate the safety of
Hypericum
extracts taken during
pregnancy and breastfeeding.
Borges
et al
(2005) treated inseminated rats orally with a methanolic extract of
Hypericum
perforatum
. A dosage of 36 mg/kg was given on days 9-15 of pregnancy (= period of organogensis).
No clinical signs of maternal toxicity were found. In the administered dose
Hypericum
extract did not
interfere with the progress of gestation during organogenesis in rats.
II.2.3.2
Assessor’s overall conclusions on toxicology
The few data available on acute and subchronic toxicity do not reveal signs of a risk to the patient. The
weak positive outcome of tests on mutagenicity of ethanolic extracts is explained with the presence of
quercetin in the extracts. Tests on reproduction toxicity demonstrated no differences between
Hypericum
extract (108 mg/kg) and placebo in mice. Numerous publications deal with the potential
phototoxicity of hypericin and
Hypericum
extracts. Extracts exert less phototoxicity than pure
hypericin. Considering the outcome of clinical test on phototoxicity herbal preparations of
Hypericum
perforatum
can be considered as safe when administered in the proposed dosage. The data on
reproduction toxicology are contradictory. For safety reasons the oral use of
Hypericum
during
pregnancy and lactation should not be recommended.
II.3
C
LINICAL
D
ATA
II.3.1
Clinical Pharmacology
II.3.1.1
Pharmacodynamics
II.3.1.1.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
II.3.1.1.2
Assessor’s overall conclusions on Pharmacodynamics
To be completed
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II.3.1.2
Pharmacokinetics
II.3.1.2.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Biber
et al
(1998) investigated the pharmacokinetics of hyperforin after oral administration of 300,
600 and 1200 mg of two different ethanolic extracts (5% and 0.5% hyperforin). Maximum plasma
levels of hyperforin were reached after 2.8 to 3.6 hours. The 5% extract yielded a total AUC
0-∞
of
1336, 2215 and 3378 h x ng/ml. The hyperforin pharmacokinetics were linear up to 600 mg of the
extract, higher dosages resulted in a lower concentration than linear extrapolation would expect. The
plasma concentrations of hyperforin after administration of the other extract were considerably lower.
In a repeated dose study no accumulation of hyperforin could be detected, the steady state plasma
concentration after 3 x 300 mg/day of the extract was approximately 100 ng/ml.
The objective of two open phase I clinical trials (Schulz
et al
2005) was to obtain pharmacokinetic
data of hypericins, hyperforin and flavonoids from a
Hypericum
extract containing tablet. Each trial
included 18 healthy male volunteers who received the test preparation, containing 900 mg dry extract
of St John's wort (STW 3-VI, Laif 900), either as a single oral dose or as a multiple once daily dose
over a period of 14 days. After single dose intake, the key pharmacokinetic parameters were
determined as follows: Hypericin: Area under the curve (AUC
0-∞
) = 78.33 h x ng/ml, maximum
plasma concentration (C
max
) = 3.8 ng/ml, time to reach C
max
(t
max
) = 7.9 h, and elimination half-life
(t
1/2
) = 18.71 h; pseudohypericin: AUC
0-∞
= 97.28 h x ng/ml, C
max
= 10.2 ng/ml, t
max
= 2.7 h, t
1/2
=
17.19 h; hyperforin: AUC
0-∞
= 1550.4 h x ng/ml, C
max
= 122.0 ng/ml, t
max
= 4.5 h, t
1/2
= 17.47 h.
Quercetin and isorhamnetin showed two peaks of maximum plasma concentration separated by about
3-3.5 h. Quercetin: AUC
0-∞
= 417.38 h x ng/ml, C
max
(1) = 89.5 ng/ml, t
max
(1) = 1.0 h, C
max
(2) = 79.1
ng/ml, t
max
(2) = 4.4 h, t
1/2
= 2.6 h; isorhamnetin: AUC
0-∞
= 155.72 h x ng/ml, C
max
(1) = 12.5 ng/ml,
t
max
(1) = 1.4 h, C
max
(2) = 14.6 ng/ml, t
max
(2) = 4.5 h, t
1/2
= 5.61 h. Under steady state conditions
reached during multiple dose administration similar results were obtained.
A study from Johne
et al
(2004) evaluated the influence of cimetidine and carbamazepine on the
pharmacokinetics of hypericin and pseudohypericin. In a placebo-controlled, double blind study,
33 healthy volunteers were randomized into three treatment groups that received
Hypericum
extract
extract (LI160) with different comedications (placebo, cimetidine, and carbamazepine) for 7 days after
a run-in period of 11 days with
Hypericum
extract alone. Hypericin and pseudohypericin
pharmacokinetics were measured on days 10 and 17. Between-group comparisons showed no
statistically significant differences in AUC
0-24
, C
max
, and t
max
values for hypericin and
pseudohypericin. Within-group comparisons, however, revealed a statistically significant increase in
hypericin AUC
0-24
from a median of 119 (range 82-163 microg h/l) to 149 microg h/l (61-202 microg
h/l) with cimetidine comedication and a decrease in pseudohypericin AUC
0-24
from a median of 51.0
(16.4-102.9 microg h/l) to 36.4 microg h/l (14.0-102.0 microg h/l) with carbamazepine comedication
compared to the baseline pharmacokinetics in each group. Hypericin and pseudohypericin
pharmacokinetics were only marginally influenced by comedication with the enzyme inhibitors and
inducers cimetidin
e and carbamazepine.
II.3.1.2.2
Assessor’s overall conclusions on pharmacokinetics
Pharmacokinetic data on the most compounds which are considered to contribute to the activity are
available. The long elimination half-life has to be considered after overdose. The possible role of
metabolites is not addressed yet.
II.3.2
II.3.2.1
Dose response studies
II.3.2.2
Clinical studies (case studies and clinical trials)
6
In case of traditional use the long-standing use and experience should be assessed.
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II.3.2.2.1
Studies on the treatment of depression
Extract LI 160
Extract
LI 160
Extraction solvent
80% methanol
DER
3-6:1, initially 4-7:1
Hypericin
0.12-0.28%
Hyperforin
~ 4.5% (Mueller
et al
2006)
Flavonoids
~ 8.3% (Mueller
et al
2006)
From several notes in publications it can be assumed that the content of hyperforin is in the range 3-
6%.
Study
Bjerkenstedt
et al
2005
Indication
mild to moderate major Depression (DSM-IV: 296.31, 296.32); minimum of a
total score of 21 on the 21-item Hamilton Depression scale
Duration of use
4 weeks
Daily dosage
900 mg
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
20 mg fluoxetine
multicentre
n=15
number of patients
163
Outcome
HAMD reduction:
LI 160: from 24.9±4.5 to 15.0±8.4 (-9.9±8.1)
Fluoxetine: from 23.8±3.7 to 14.9±8.4 (-8.9±8.0)
Placebo: from 25.2±4.6 to 15.5±6.7 (-9.7±7.0)
Conclusion: LI 160 and fluoxetine are not more effective in short-term treatment
in mild to moderate depression than placebo.
Hypericum
is better tolerated than fluoxetine
Comment
Short time of treatment; high number of drop-outs in all groups (
Hypericum
start
n=59, end n=38; fluoxetine start n=57, end n=37; placebo start n=58, end n=40)
Study
Fava
et al
2005
Indication
major depressive disorder (HAMD-17 ≥ 16)
Duration of use
12 weeks
Daily dosage
900 mg
Single dosage
300 mg
Relapse
-
randomized
yes
double blind
yes
placebo-controlled
yes
reference-controlled
20 mg/d fluoxetine
multicentre
Studydesign
n=2
number of patients
135
Outcome
HAMD reduction (ITT-analysis):
LI 160: -38%, from 19.6± 3.5 to 10.2 ± 6.6
Fluoxetine: -30%, from 19.6 ± 3.1 to 13.3 ± 7.3
Placebo: -21%, from 19.9 ± 2.9 to 12.6 ± 6.4
EMEA 2008
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Conclusion: LI 160 is significantly more effective than fluoxetine and superior
to placebo. It is well tolerated and safe.
Comment
Sample smaller than originally planned; the lack of efficacy of fluoxetine is
explained by the fixed-dose approach.
Study
Brenner
et al
2000
Indication
mild to moderate depression (HAMD: ≥ 17, according to DSM IV)
Duration of use
7 weeks
Daily dosage
600 mg (1
st
week)
900 mg (6 weeks)
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no?
reference-controlled
50 mg sertraline (1
st
week)
75 mg sertraline (6 weeks)
multicentre
no
number of patients
30
Outcome
HAMD reduction:
LI 160: -40% ± 30%; from 21.3 ± 3.2 to 12.7 ± 6.7)
Sertraline: -42% ± 24%, from 21.7 ± 2.7 to 12.5 ± 5.6)
Conclusion:
LI 160 is as effective as sertraline in the treatment of mild to moderate
depression.
Comment
Small number of patients, relatively high drop out rate.
In the chapter ‘Study medication’ placebos are mentioned. However, no
placebo group in table of results.
Study
HDTSG 2002
Indication
moderately severe major depressive disorder (according to DSM-IV; HAM-D ≥
20; GAF ≤ 60)
Duration of use
8 weeks
Daily dosage
900-1800 mg (3 x 300- 3 x 600 mg)
Single dosage
300–600 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
50-150 mg sertraline
multicentre
n=12
number of patients
340
Outcome
HAMD reduction/response rate:
Placebo: -9.20/-31.9%
LI 160: -8.68/-23.9%
Sertraline: -10.53/-24.8%
Conclusion: No efficacy of LI 160 and of sertraline in treatment of moderately
severe major depression. Possible reason: low assay sensitivity.
Comment
No efficacy despite of increase of dosage during study
EMEA 2008
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Study
Montgomery
et al
2000
Indication
mild to moderate depression (DSM-IV)
Duration of use
12 weeks
Daily dosage
900 mg
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=18
number of patients
248
Outcome
Conclusion:
There is no statistically significant difference between placebo and LI 160.
(HAMD-score after 6 weeks). Negative Outcome
Study
Vorbach et al 1997
Indication
severe mild to moderate major depression according to ICD-10 F 33.2,
recurrent, without psychotic symptoms
Duration of use
6 weeks
Daily dosage
1800 mg
Single dosage
600 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
reference-controlled
150 mg/d imipramine
multicentre
n=20
number of patients
209
Outcome
HAMD (17 items) reduction:
LI 160:from 25.3±4.7 to 14.4±6.1
Imipramine: from 26.1±4.8 to 13.4±5.9
Conclusion:
Efficacy not statistically equivalent, equivalence only in subgroups with more
than 33% and 50% reduction of the HAMD total score. Superiority for LI 160
in adverse events.
Study
Wheatley 1997
Indication
mild to moderate major depression (HAMD-17 score: 17-24; according to
DSM-IV)
Duration of use
6 weeks
Daily dosage
900 mg
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
75 mg/d amitriptyline
multicentre
n=19
number of patients
165
Outcome
HAMD reduction:
LI 160: from 20 to 10
Amitriptyline: from 21 to 6
EMEA 2008
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Conclusion:
No statistically significant difference between LI 160 and amitriptyline;
Hypericum
is better tolerated.
Study
Harrer
et al
1994
Indication
moderately severe depressive episodes, according to ICD-10, F 32.1 (HAMD
17-items >- 16)
Duration of use
4 weeks
Daily dosage
900 mg/d
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
Maprotiline (3 x 25 mg)
multicentre
n=6
number of patients
102
Outcome
HAMD reduction:
LI 160: 20.5 -> 12.2, no statistically significant difference compared to
maprotiline.
Maprotiline: 21.5 -> 10.5
Responder rate: 61% in
Hypericum
, 67% in maprotiline
Onset of effects up to the second week of treatment. After 2 weeks of treatment
more pronounced effect with maprotiline, after 4 weeks both groups similar.
Study
Shelton
et al
2001
Indication
major depression (HAMD: ≥ 20 for more than 2 years, according to DSM-IV:
major depression disorder, single episode or recurrent, without psychotic
features)
Duration of use
8 weeks
Daily dosage
900 mg/d for 4 weeks, in case of not adequate response increase to 1200 mg/d
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=11
number of patients
200
Outcome
Response rate in the ITT-analysis:
LI 160: 26.5% (for statistical significance 36.1% is needed)
Placebo: 18,6%
In
Hypericum
group a significant greater proportion of remissions.
Conclusion: LI160 is not effective in treatment of major depression; good
compliance: only adverse effect: headache.
Comment
High number of patients with chronic depression. Sponsoring by Pfilzer
EMEA 2008
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Study
Hänsgen
et al
1996
Indication
mild to moderate major depression, according to DSM-III-R (HAMD >- 16)
Duration of use
4 weeks (+2 weeks)
Daily dosage
900 mg/d
Single dosage
300 mg
Relapse
-
Studydesign
randomized
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=17
number of patients
102
Outcome
HAMD reduction:
LI 160: 21.0 -> 8.9, statistically significant compared to placebo.
Placebo: 20.4 -> 14.4
Responder rate: 70% in
Hypericum
, 24% in placebo
Further 2 weeks of verum-treatment in both groups: similar improvement in the
former placebo-group like in the first 2 weeks of treatment in the verum group.
Study
Hänsgen
et al
1994
Indication
mild to moderate major depression, according to DSM-III-R (HAMD >- 16)
Duration of use
4 weeks (+2 weeks)
Daily dosage
900 mg/d
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=11
number of patients
67
Outcome
HAMD reduction:
LI 160: 21.8 -> 9.2, statistically significant compared to placebo.
Placebo: 20.4 -> 14.7
Responder rate: 81% in
Hypericum
, 26% in placebo
Further 2 weeks of verum-treatment in both groups: similar improvement in the
former placebo-group like in the first 2 weeks of treatment in the verum group.
Study
Sommer
et al
1994
Indication
Depressive symptoms according ICD-09 300.4 (neurotic depression) and 309.0
(brief depressive reaction).
Duration of use
4 weeks
Daily dosage
900 mg/d
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=3
number of patients
105
Outcome
Only graphical presentation of data; improvement under
Hypericum
after 4
weeks significant at a 1% level compared to placebo.
Responder rate: 67% in
Hypericum
, 28% in placebo
EMEA 2008
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Metanalaysis of clinical studies with LI 160 (Linde 2007)
Conclusion:
Reference controlled studies: all studies included patients with major depression; similar or
insignificant less efficacy compared to standard antidepressants; in some studies no difference
between
Hypericum
, reference medication and placebo. Only one study (Vorbach
et al
1997) was
designed for proof of equivalence.
Placebo controlled studies: tendency that in older studies (published before 2000) better outcome for
Hypericum
; modern studies also with negative outcome.
Studies including patients with more severe depressive episodes (daily dosage up to 1800 mg extract)
do not show sufficient efficacy.
Extract WS 5570:
Extract
WS 5570
Extraction solvent
80% methanol
DER
4-7:1
Hypericin
0.12-0.28%
Hyperforin
3-6%
The extraction solvent and the declared amount of hypericine of this extract are identical with that of
LI 160.
Study
Anghelescu
et al
2006
Indication
moderate to severe depression according to DSM-IV criteria: 296.22, 296.23,
296.32 and 296.33 (HAMD 17-item: ≥ 22)
Duration of use
6 weeks of acute treatment
Daily dosage
900 mg or 1800 mg; dose increase in week 2 in patients with HAMD
improvement <20%
Single dosage
300 mg or 600 mg
EMEA 2008
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Relapse
Patients with a HAM-D total score decrease of >=50% during the 6 weeks of
acute treatment were asked to continue the treatment for another 16 weeks
(n=133)
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
20/40 mg/d paroxetine; dose increase in week
2 in patients with HAMD improvement <20%
multicentre
n=21
number of patients
133
Outcome
HAMD reduction:
WS 5570: .from 25.3+/-2.5 to 4.3+/-6.2
Paroxetine: from 25.3+/-2.6 to 5.2+/-5.5
During maintenance treatment alone 61.6% of the
Hypericum
group and 54.6%
of the paroxetine group showed additional reduction of HAMD score.
Remission occurred 81.6% in the
Hypericum
group and 71.4% in the paroxetine
group. 3 Patients under
Hypericum
and 2 patients under paroxetine showed an
increase in HAMD score of >5 during continuation treatment
Conclusion: WS 5580 an paroxetine are similarly effective in preventing relapse
in a continuation treatment after recovery from an episode of modeate to severe
depresssion
Study
Szegedi
et al
2005
Indication
moderate to severe major depression (HAMD 17-item: ≥ 22; DSM-IV: 296.22,
296.23, 296.32, 296.33)
Duration of use
6 weeks
Daily dosage
900 mg-1800 mg; dose increase in week 2 in patients with HAMD improvement
<20%
Single dosage
300 mg-600 mg
Relapse
Responders (decrease in total HAMD score ≥ 50%) were invited to participate in
a four month double blind maintenance phase
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
20 mg-40 mg/d paroxetine; dose increase in
week 2 in patients with HAMD improvement
<20%
multicentre
n=21
number of patients
251
Outcome
HAMD recuction/% responder:
WS 5570: -14.4 / 71%
Paroxetine: -11.4 / 60%
Conclusion: WS 5570 is as effective as paroxetin in the treatment of moderate to
severe major depression
Comment
The results of the maintenance phase will be published elsewhere.
EMEA 2008
37/65
Study
Lecrubier
et al
2002
Indication
mild to moderate major depression (single or recurrent episode, DSM-IV code:
296.21, 296.22, 296.32, HAMD 17-item: 18-25)
Duration of use
6 weeks
Daily dosage
900 mg
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=26
number of patients
375
Outcome
HAMD reduction/Responders
WS 5570: -9.9/52.7%
Placebo: -8.1/42.3% (The difference is significant)
Conculusion: WS 5570 is safe and more effective than placebo in the treatment
of mild to moderate major depression
Study
Kasper
et al
2006
Indication
mild or moderate major depressive episode (single or recurrent episode, DSM-
IV criteria: 296.21, 296.31, 296.21, 296.22, 296.31, 296.32; HAMD 17-item: ≥
18, “depressive mood” ≥ 2)
Duration of use
6 weeks
Daily dosage
600-1200 mg
Single dosage
600 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=16
number of patients
332
Outcome
More patients in the WS 5570 1200 mg group met the criterion of remission
(HAMD: ≤ 7 at treatment end)
HAMD reduction:
WS 5570 600 mg: -11.6 ± 6.4
WS 5570 1200 mg: -10.8 ± 7.3
Placebo: -6.0 ± 8.1
Conclusion: WS 5570 is safe and more effective than placebo in treatment of
mild to moderate depression.
EMEA 2008
38/65
Study
Kasper
et al
2008
Indication
recurrent episode of moderate major depression; HAMD 17-item: ≥ 20, ≥ 3
previous episodes in 5 years (ICD-10 F33.0. F33.1, DSM-IV 296.3)
Duration of use
6 weeks single blind acute treatment, then 26 weeks double blind continuation
treatment, then 52 weeks double blind maintenance treatment
Daily dosage
900 mg
Single dosage
300 mg
Relapse
+
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
yes
number of patients
426
Outcome
Relapse rates:
Hypericum
18.1%; placebo 25.7%
Average time to relapse:
Hypericum
177 days; placebo 163 days
Conclusion: WS 5570 showed a beneficial effect in preventing relapse after
recovery from acute depression. Tolerability in continuation and long-term
maintenance treatment was on the placebo level.
Conclusion:
All studies are well designed. All studies report superiority compared to placebo or non-
inferiority compared to standard medication.
Comparison with LI 160:
In contrast to the recent studies published for LI 160 all modern studies for WS 5570 demonstrated a
positive outcome for
Hypericum
. Since the extracts LI 160 and WS 5570 are very similar in their key
parameters, it seems to be justified to combine the results. It can be concluded that the efficacy of this
type of extract in the treatment of mild to moderate severe depression is well documented.
EMEA 2008
39/65
Extract Ze 117:
Extract
Ze 117
Extraction solvent
There are differing informations on the extraction solvent: 50% ethanol or
ethanol 49% m/m : 2-propanol (97.3 : 2.7)
DER
4-7:1
Hypericin
0.2%
Hyperforin
nearly free of hyperforin
Information on the refinement of the extract in order to reduce the content of hyperforin are not
available.
Study
Schrader 2000 (=Friede
et al
2001?)
Indication
mild to moderate depression (ICD-10; F 32-0 and F 32-1, HAMD scale (21-
item) 16-24)
Duration of use
6 weeks
Daily dosage
500 mg
Single dosage
250 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
20 mg fluoxetine
multicentre
n=7
number of patients
240
Outcome
HAMD reduction:
Ze 117: from 19.65 to 11.54/-7.25
Fluoxetine: from 19.50 to 12.20/-8.11
Conclusion:
Hypericum
and fluoxetine are equipotent. Ze 117 safety was superior to
fluoxetine.
Comment
Contact of patients with investigators only at the beginning of the study and
after 6 weeks in order to minimize the placebo effect.
Nearly identical data in the publication compared to Friede
et al
2001.
However, no coincidence of the authors and the sponsor.
Study
Friede
et al
2001 (=Schrader 2000?)
Indication
mild to moderate depressive episodes (ICD-10: F 32.0, F 32.1; HAMD range:
16-24)
Duration of use
6 weeks
Daily dosage
500 mg
Single dosage
250 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
20 mg fluoxetine
multicentre
n=7
number of patients
240
Outcome
HAMD reduction/responder rate:
Ze 117: from 19.7 to 11.5/60%
Fluoxetine: from 19.5 to 12.2/40%
EMEA 2008
40/65
Conclusion:
Ze 117 is equipotent to fluoxetine in the treatment of mild to moderate
depression
Comment
There was a marked decrease of depressive agitation (pre-post comparison:
46%) and anxiety symptoms (44%) during the therapy with St. John's wort.
Depressive obstruction (44%) and sleep disorders (43%) were reduced during
the treatment.
Nearly identical data in the publication compared to Schrader
et al
2000.
However, no coincidence of the authors and the sponsor.
Study
Woelk 2000
Indication
mild to moderate depression (ICD-10 codes F32.0, F33.0, F32.1, F 33.1;
HAMD score (17-item) > 17)
Duration of use
6 weeks
Daily dosage
500 mg
Single dosage
250 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
150 mg/d imipramine
multicentre
n=40
number of patients
324
Outcome
HAMD reduction:
Ze 117: from 22.4 to 12.0
Imipramine: from 22.1 to 12.75
Conclusion: Ze 117 and imipramine are therapeutically equivalent in the
treatment of mild to moderate depression. In the treatment of depression with
anxiety
Hypericum
has more benefit. There are fewer adverse events in the Ze
117 group.
Comment
The dosage of imipramine is relatively high, which could be the reason the high
number of drop outs in the reference group.
Study
Schrader
et al
1998
Indication
mild to moderate depression (ICD-10; F 32-0 and F 32-1)
Duration of use
6 weeks
Daily dosage
500 mg (corresponding to 1 mg hypericin daily)
Single dosage
250 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=16
number of patients
162
Outcome
HAMD (21-item) reduction /% responder:
Ze 117: from 20.13 to 10.53 / 56%
Placebo: from 18.76 to 17.89 / 15%
Conclusion: ZE 117 is significantly superior compared to placebo and safe in
treatment of mild to moderate depression
Comment
Contact of patients with investigators only at the beginning of the study and
after 6 weeks in order to minimize the placebo effect.
EMEA 2008
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Conclusion:
The superiorioty of the extract ZE 117 against placebo and the non-inferiority against
imipramin and fluoxetin could be demonstrated. Compared with the results obtained with the extracts
LI 160 and WS 5570 it can be concluded that the content of hyperforin in the extract is not correlated
with clinical efficacy. The extract is according to the manufacturer at least since 1996 in Germany on
the market. Therefore the minimum of 10 years of medicinal use is fulfilled.
Liquid extract
Extract
Hyperforat drops
Extraction solvent
50% ethanol
DER
0.5:1
Hypericin
2 mg / ml
Hyperforin
not specified
Study
Hoffmann
et al
1979
Indication
mild to severe forms of depression
Duration of use
6 weeks
Daily dosage
90 drops (= 3.6 ml = 7.2 mg hypericin)
Single dosage
30 drops
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
-
multicentre
-
number of patients
60
Outcome
Not standardised symptom score with 47 items; improvement under
Hypericum
after 6 weeks of 61.4%, in placebo group of 16.8%.
Responder:
Hypericum
: 80%
Placebo: 33%
Comment
Lack of statistical evaluation; inadequate study design
Conclusion:
An old study (inadequate study design) shows superiority against placebo. No data are
available on comparison to synthetic antidepressants.
EMEA 2008
42/65
Extract STW 3
Extract
STW 3
Extraction solvent
50% ethanol
DER
5-8:1
Hypericin
mean 0.21%
Hyperforin
mean 3.3%
Flavonoids
mean 7.11%
Study
Gastpar
et al
2005
Indication
moderate depressive disorder (according to ICD-10 criteria: F32.1 or F33.1;
HAMD 17-items: 20-24)
Duration of use
12 weeks
Daily dosage
612 mg
Single dosage
612 mg
Relapse
after 12 weeks additional treatment for 12 weeks of n=161
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
50 mg sertraline
multicentre
n=18
number of patients
241
Outcome
HAMD reduction: (week 12/week 24)
STW 3: from 22.0 to 8.3/5.7
Sertraline: from 22.1 to 8.1/7.1
Conclusion: STW 3 is therapeutically equivalent to sertraline in moderate
depression and it is well tolerated.
Comment
Single daily dose
Conclusion:
an adequate study demonstrates non-inferiority compared to sertraline (50 mg).
Esbericum capsules:
Daily dosage: 213-252 mg extract;
Extract
Esbericum
Extraction solvent
60% ethanol
DER
2-5,5:1
Hypericin
0.1%
Hyperforin
not specified
Flavonoids
not specified
EMEA 2008
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Study
Bergmann
et al
1993
Indication
mild to moderate depression (ICD-10 F32.0, F32.1, F33.0, F33.1)
Duration of use
6 weeks
Daily dosage
213-252 mg extract (Corresponding to 0.75 mg hypericin)
Single dosage
Relapse
-
randomized
Studydesign
yes
placebo-controlled
yes
reference-controlled
30 mg amitriptylin/day
multicentre
n=1
number of patients
80
Outcome
HAMD reduction /% responder:
Esbericum: from 15.82 to 6.43 / 84.2%
Amitriptylin: from 15.26 to 6.65 / 73.7%
From the fact that the low dosage of amitriptylin was effective it can be
assumed that only patients with mild depression were included.
Comment
Low dosage of amitriptylin; study design insufficient
Conclusion
: The results do not allow the conclusion, that this type of extract in the chosen posology is
suitable for the treatment of mild or moderate depression.
Extract STEI 300:
Extract
STEI 300
Extraction solvent
60% ethanol
DER
5-7:1
Hypericin
0.2-0.3%
Hyperforin
2-3%
Flavonoids
not specified
Study
Philipp
et al
1999
Indication
moderate depression according to ICD-10 (codes F32. 1 and F33.1) (HAMA
score > 18)
Duration of use
8 weeks
Daily dosage
1050 mg
Single dosage
350 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
100 mg/d imipramine (titrated within 4 days
from 50 mg)
multicentre
n=18
number of patients
263
EMEA 2008
44/65
Outcome
HAMD reduction /% responder:
STEI 300: 22.7-> 7.3 / 76%
Placebo: 22.7-> 10.6 / 63%
Imipramine: 22.2-> 8.0 / 66.7%
Conclusion: STEI 300 is as effective as imipramine and more effective than
placebo in the treatment of moderate depression and it is safe.
Comment
Study of high methodological quality
Conclusion
: superiority against placebo and non-inferiority against imipramine (100 mg) could be
demonstrated.
Extract LoHyp-57:
Extract
LoHyp-57
Extraction solvent
60% ethanol
DER
5-7:1
Hypericin
0.2-0.3%
Hyperforin
2-3%
Flavonoids
not specified
Extract identical to STEI 300, but different dosage form and posology.
Study
Harrer
et al
1999
Indication
mild to moderate major depression according to ICD 10 (F32.0, F32.1)
Duration of use
6 weeks
Daily dosage
800 mg
Single dosage
400 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
20 mg fluoxetine (= 22.4 mg fluoxetine HCl)
multicentre
n=17
number of patients
149
Outcome
HAMD (17-items) reduction:
LoHyp 57: from 16.60 to 7.91 (mild: from 14.21 to 6.21; moderate: from 18.73
to 9.43)
Fluoxetine: from 17.18 to 8.11 (mild: from 15.21 to 7.46; moderate: from 19.10
to 8.75)
Responder rate:
LoHyp 57: 71.4% (mild subgroup: 81.8%; moderate subgroup: 62.2%)
Fluoxetine: 72.2% (mild subgroup: 76.9%; moderate subgroup: 67.5%)
EMEA 2008
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Conclusion: LoHyp 57 is equivalent to fluoxetine in treatment of mild to
moderate major depression particularly in elderly patients.
Comment
No confidence intervals shown in the publication, therefore the non-inferiority
is formally not demonstrated; patients 60-80 years
Conclusion
: 800 mg of LoHyp-57 is equivalent to 20 mg fluoxetine in the treatment of mild to
moderate major depression.
Extract STW3-VI:
Extract
STW3-VI
Extraction solvent
80% ethanol
DER
3-6:1
Hypericin
mean 0.26%
Hyperforin
mean 3.0%
Flavonoids
mean 7.17%
Study
Gastpar
et al
2006
Indication
moderate depression (HAMD 17-items score: 20-24, ICD-10. F32.1, F33.1,
according to DSM-IV major depressive episode and recurrent major
depression)
Duration of use
6 weeks
Daily dosage
900 mg
Single dosage
900 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
20 mg citalopram
multicentre
n=21
number of patients
388
Outcome
HAMD reduction /% responder:
Hypericum
: 21.9 -> 10.3 / 54.2%
Citalopram: 21.8-> 10.3 / 55.9%
Placebo: 22.0 -> 13.0 / 39.2%
Conclusion:
The
Hypericum
group was statistically non-inferior to citalopram and
significantly superior to the placebo.
Comment
Study of high methodological quality
EMEA 2008
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Study
Uebelhack
et al
2004
Indication
moderate depressive disorders (ICD-10 F32.1, F33.1) and HAMD (17-items)
score : 20-24
Duration of use
6 weeks
Daily dosage
900 mg
Single dosage
900 mg
Relapse
Studydesign
randomized
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=1
number of patients
140
Outcome
HAMD reduction /% responder:
STW3-VI: 22.8 -> 11.8 / 58.6%
Placebo: 22.6 -> 19.2 / 5.7%
Conclusion: STW3-VI in a single daily dose is superior to placebo.
Comment
Conspicuously low responder rate under placebo. This is explained by the
authors that primarily patients with moderate depression were included, while
other studies included also a higher number of patients with mild depression.
Conclusion
s: superiority against placebo and non-inferiority against citalopram (20 mg) could be
demonstrated.
Extract WS 5572:
Extract
WS 5572
Extraction solvent
60% ethanol
DER
25-5:1
Hypericin
not specified
Hyperforin
4-5% (Rychlik
et al
2001, Lackmann
et al
1998)
15% (Kalb
et al
2001)
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Study
Rychlik
et al
2001
Indication
mild to moderate depression (based on CGI)
Duration of use
7 weeks
Daily dosage
600 mg/1200 mg
Single dosage
600 mg
Relapse
-
randomized
Studydesign
no
double blind
no
placebo-controlled
no
reference-controlled
comparison of 600 mg and 1200 mg daily
multicentre
n=446
number of patients
2166
Outcome
Responder:
600 mg: 83.7%
1200 mg: 86.9%
Conclusion: Good effectiveness and tolerability of WS 5572
Comment
Observational study
Study
Kalb
et al
2001
Indication
mild to moderate major depressive disorder (according to DSM-IV criteria)
(DSM-IV code: 296.21, 296.31, 296.22, 296.32, HAMD (17-items): ≥ 16)
Duration of use
6 weeks
Daily dosage
900 mg
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
no
multicentre
n=11
number of patients
72
Outcome
HAMD reduction /% responder:
WS 5572: 19.7 -> 8.9 / 62.2%
Placebo: 20.1 -> 14.4 / 42.9%
Conclusion: superior compared to placebo
Comment
Efficacy was already statistically significant at day 28
Adaptive 2-stage design
Study
Laakmann
et al
1998
Indication
mild or moderate depression according to DSM-IV criteria, HAMD ≥ 17
Duration of use
6 weeks
Daily dosage
900 mg
Single dosage
300 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
yes
reference-controlled
900 mg WS 5573
multicentre
n=11
number of patients
147
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Outcome
HAMD reduction /% responder:
WS 5572: 20.9 -> 10.7 / 49.0%
WS 5573: 20.3 -> 11.8 / 38.8%
Placebo: 21.2 -> 13.3 / 32.7%
Conclusion:
WS 5572 (5% hyperforin) was superior to placebo
WS 5573 (0.5% hyperforin) and placebo were descriptively comparable
The therapeutic effect depends on the content of hyperforin.
Comment
WS 5572 and WS 5573 are produced with the identical manufacturing process
(identical DER, extraction solvent), the only difference between the extracts
relates to the content of hyperforin. The fingerprint chromatograms of the two
extracts are except for hyperforin identical. It is not mentioned how the
differences in the conbtent of hyperforin are achieved.
The negative outcome for the extract with low content of hyperforin is in
contrast to the positive findings with the extract ZE 117, which is said to be
nearly free of hyperforin.
Conclusion
: WS 5572 is superior to placebo in the treatment of mild to moderate major depression.
Extract Calmigen:
Extract
Calmigen
Extraction solvent
not specified
DER
not specified
Hypericin
0.3%
Hyperforin
not specified
Study
Behnke
et al
2002
Indication
mild to moderate depression (ICD-10 F32), HAMD (17-items) score 16-24
Duration of use
6 weeks
Daily dosage
300 mg
Single dosage
150 mg
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
40 mg fluoxetin
multicentre
n=446
number of patients
70
Outcome
HAMD reduction /% responder;
Calmigen: 20.0 -> 10.0 / 55%
Fluoxetin: 20.7 -> 8.7 / 66%
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Comment
Number of patients too small for comparison of efficacy.
Not to be confused with Calmigen capsules (300 mg
Hypericum
extract,
extraction solvent methanol 80%, 0.3% hypericin, authorized in DK)
Extract Hyperiforce:
Extract
Hyperiforce
Extraction solvent
not specified
DER
4-5:1 (shoot tips)
Hypericin
0.5%
Hyperforin
not specified
Study
Lenoir
et al
1999
Indication
mild to moderate depression (ICD-10)
Duration of use
6 weeks
Daily dosage
corresponding 0.17 mg, 0.33 mg or 1 mg hypericin
Single dosage
Relapse
-
randomized
Studydesign
yes
double blind
yes
placebo-controlled
no
reference-controlled
comparison of different dosaged
multicentre
n=38
number of patients
348
Outcome
Reduction in HAMD score from initially 16-17 to 8-9 in all groups. Resonder
rate 62%-68%. The extract was effective on all three dosages.
Comment
No placebo group
Psychotonin (Liquid extract, DER 1: 5-7, extraction solvent ethanol 50%)
All studies performed with this type of extract (Harrer
et al
1991, Osterheider
et al
1992, Quandt
et al
1993, Schlich
et al
1987, Schmidt
et al
1989) are not convincing from the current point of view. The
methodology is inadequate, the number of included patients is small, the drop-out-rate is considerably
high. The studies do not fulfil the criteria for well-established use.
Overall metanalysis
Roder
et al
(2004) published a meta-analysis of effectiveness and tolerability of treatment of mild to
moderate depression with
Hypericum
extracts.
The results demonstrate a significant superiority of
Hypericum
extracts over placebo (mean response:
Hypericum
: 53.3% and placebo: 32.7%). Compared to standard antidepressive
Hypericum
is similar
effective for the treatment of depression (mean response:
Hypericum
: 53.2%, synthetic antidepressive:
51.3%). In the sub group of mild to moderate depression
Hypericum
showed better results against the
standard antidepressive group (mean response: 59.5%/52.9%) and a better side-effect profile. The fail-
safe-N-test indicates that 423 studies with no effect would be needed to negate the presented result for
placebo studies.
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Werneke
et al
(2004) came to similar results. They found that the effect sizes in recent studies were
smaller than those resulted form earlier studies.
Linde
et al
(2005) concluded that the available data for major depression is confusing. While
Hypericum
has minimal benefical effects over placebo, other trials suggest that
Hypericum
and
standard antidepressives are equal.
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Assessor’s conclusion:
Overview of extracts with predominately positive study outcome (Superiority against placebo,
equivalence to reference medication):
ICD-10 F32.0: mild depressive episode
ICD-10 F32.1: moderate depressive episode
ICD-10 F33.0: recurrent depressive disorder, current episode mild
ICD-10 F33.1: recurrent depressive disorder, current episode moderate
DSM-IV 296.21: major depressive disorder, single episode, mild
DSM-IV 296.22: major depressive disorder, single episode, moderate
DSM-IV 296.23: major depressive disorder, single episode, severe without psychotic features
DSM-IV 296.31: major depressive disorder, recurrent, mild
DSM-IV 296.32: major depressive disorder, recurrent, moderate
DSM-IV 296.33: major depressive disorder, recurrent, severe without psychotic features
single episode
recurrent
single
recurrent
mild
moderate
mild
moderate
severe
severe
ICD-10
F32.0
DSM-
IV
296.21
ICD-10
F32.1
DSM-
IV
296.22
ICD-10
F33.0
DSM-
IV
296.31
ICD-10
F33.1
DSM-IV
296.32
DSM-IV
296.23
DSM-IV
296.33
A: LI 160
x
x
x
B: WS 5570
x
x
x
x
C: STW3-VI
x
x
D: STEI 300
x
x
E: LoHyp-57
x
x
F: WS 5572
x
x
x
x
G: STW3
x
x
H: ZE 117
x
x
x
x
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DER
extraction solvent
% hypericin
% hyperforin
% flavonoids
daily dosage duration
A: LI 160
3-6:1
methanol 80%
0.12-0.28
app. 4.5%
app. 8.3%
900 mg
4-12 weeks
B: WS 5570 4-7:1
methanol 80%
0.12-0.28
3-6%
not specified
600-1800 mg 6/26 weeks
relapse +
C: STW3-VI 3-6:1
ethanol 80%
0.26% (mean)
3.0% (mean)
7.17% (mean)
900 mg
6 weeks
D: STEI 300 5-7:1
ethanol 60%
0.2-0.3%
2-3%
not specified
1050 mg
8 weeks
E: LoHyp-57 5-7:1
ethanol 60%
0.2-0.3%
2-3%
not specified
800 mg
6 weeks
F: WS 5572
2.5-5:1
ethanol 60%
not specified
4-5%
not specified
600-1200 mg 6-7 weeks
G: STW3
5-8:1
ethanol 50%
0.21% (mean)
3.3% (mean)
7.11% (mean)
612 mg
12 weeks
H: ZE 117
4-7:1
ethanol 50%
0.2%
nearly free
not specified
500 mg
6 weeks
Pharm.Eur.
not
specified
ethanol 50-80%
methanol 50-80%
0.10-0.30%
< 6.0%
> 6.0%
It is proposed to include the extracts types A-G into the monograph under well-established use with
the indication ‘mild to moderate depressive episodes’. Since the informations on the extraction solvent
of the extract of type H are inconsistent, it could not be included in the monograph.
II.3.2.2.2
Somatoform disorders
Volz
et al
(2002) conducted a multicentre, randomised, placebo controlled, 6-week trial comparing the
efficacy of LI 160 (600 mg/day) and placebo in 151 out-patients suffering from somatization disorder
(ICD-10: F45.0), undifferentiated somatoform disorder (F45.1), or somatoform autonomic
dysfunctions (F45.3). The primary outcome measure was the decrease of the Hamilton Anxiety Scale,
subfactor somatic anxiety (HAMA-SOM), during the trial period. The
Hypericum
extract was superior
effective concerning the primary outcome criterion HAMA-SOM [decrease from 15.39 (SD 2.68) to
6.64 (4.32) in the
Hypericum
group and from 15.55 (2.94) to 11.97 (5.58) in the placebo group
(statistically significant difference, P=0.001)]. This was corroborated by the result of a statistically
significant superior efficacy in the outcome criteria additionally used such as Clinical Global
Impression, HAMA-total score, HAMA, subscore psychic anxiety, Hamilton Depression Scale, Self-
Report Symptom Inventory 90 items - revised (SCL-90-R), and SCL-90-R, subscore somatic anxiety.
The efficacy of LI 160 was preserved after splitting the population in those with and those without
mild depressive symptoms [corrected]. Tolerability of LI 160 was excellent. The efficacy is
independent of an existing depressive mood.
In a prospective, randomized, placebo-controlled, and double-blind parallel group study,
184 outpatients with somatization disorder (ICD-10 F45.0), undifferentiated somatoform disorder
(F45.1), and somatoform autonomic dysfunction (F45.3), but not major depression, received either
300 mg of
Hypericum
extract extract LI 160 twice daily or matching placebo for 6 weeks (Muller
et al
2004). Six outcome measures were evaluated as a combined measure by means of the Wei Lachin test:
Somatoform Disorders Screening Instrument--7 days (SOMS-7), somatic subscore of the HAMA,
somatic subscore of the SCL-90-R, subscores "improvement" and "efficacy" of the CGI, and the
global judgment of efficacy by the patient. In the intention to treat population (N=173), for each of the
six primary efficacy measures as well as for the combined test, statistically significant medium to
large-sized superiority of
Hypericum
extract treatment over placebo was demonstrated (p<0.0001). Of
the
Hypericum
extract patients, 45.4% were classified as responders compared with 20.9% with
placebo (p=0.0006). Tolerability of
Hypericum
extract treatment was equivalent to placebo.
II.3.2.2.3
Schizophrenia
Hypericum
extract LI160 has demonstrated a ketamine-antagonising effect. Therefore Murck
et al
(2006) examined whether LI160 reverses changes of a low dose ketamine on auditory evoked
potentials (AEP) in healthy subjects. The authors performed a double-blind randomized treatment with
either 2 x 750 mg LI 160 or placebo given one week, using a crossover design, in 16 healthy subjects.
A test-battery including AEPs, the oculodynamic test (ODT) and a cognitive test were performed
before and after an infusion with 4 mg of S-ketamine over a period of 1 hour. S-ketamine led to a
significant decrease in the N100-P200 peak to peak (ptp) amplitude after the placebo treatment,
whereas ptp was significantly increased by S-ketamine infusion in the LI160 treated subjects. The
ODT and the cognitive testing revealed no significant effect of ketamine-infusion and therefore no
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interaction between treatment groups. Provided that ketamine mimics cognitive deficits in
schizophrenia, LI160 might be effective to treat these symptoms.
II.3.2.2.4
Nootropic effects
A study from Elis
et al
(2001) aimed to examine whether acute administration of standardized
Hypericum
extract could exert a nootropic effect in normal human subjects. The study employed a
double-blind, crossover, repeated-measures design. Twelve healthy young subjects completed the
Cognitive Drug Research (CDR) memory battery, following administration of placebo, 900 mg and
1800 mg
Hypericum
(Blackmore's Hyperiforte). The findings suggested that
Hypericum
does not have
an acute nootropic effect in healthy humans at these doses. However, there was some evidence for an
impairing effect on accuracy of numeric working memory and delayed picture recognition at the
higher dose. This observed impairment could be due to a sensitivity of these specific tasks to
modulation by neurotransmitters that have been noted to have memory-impairing effects (e.g. y-
aminobutyric acid (GABA), serotonin).
In a randomized, double-blind, cross over study of 12 healthy male volunteers received capsules with
255-285 mg St John's wort extract (900 µg hypericin content), 25 mg amitriptyline and placebo three
times daily for periods of 14 days each with at least 14 days between (Siepmann
et al
2002). The doses
of amitriptyline and St John's wort extract are comparable with respect to their antidepressant activity.
Neither St John's wort extract nor amitriptyline had an influence on cognitive performance such as
choice reaction, psychomotor coordination, short-term memory and responsiveness to distractive
stimuli. Amitriptyline but not St John's wort extract decreased self rated activity (P < 0.05). Both drugs
caused significant qEEG changes. St John's wort extract increased theta power density. Amitriptyline
increased theta as well as fast alpha power density.
II.3.2.2.5
Cutaneous treatment
In a half-side comparison study Schempp
et al
(2003) assessed the efficacy of a cream containing
Hypericum
: extract standardised to 1.5% hyperforin (verum) in comparison to the corresponding
vehicle (placebo) for the treatment of subacute Atopic Dermatitis. The study design was a prospective
randomised placebo-controlled double-blind monocentric study. In twenty one patients suffering from
mild to moderate Atopic Dermatitis (mean SCORAD 44.5) the treatment with verum or placebo was
randomly allocated to the left or right site of the body, respectively. The patients were treated twice
daily over a period of four weeks. Eighteen patients completed the study. The severity of the skin
lesions on the left and right site was determined by means of a modified SCORAD-index (primary
endpoint). The intensity of the eczematous lesions improved on both sites of treatment. However, the
Hypericum
-cream was significantly superior to the vehicle at all clinical visits (days 7, 14, 28)
(p < 0.05). Skin colonisation with Staphylococcus aureus was reduced by both verum and placebo,
showing a trend to better antibacterial activity of the
Hypericum
-cream (p = 0.064). Skin tolerance and
cosmetic acceptability was good or excellent with both the
Hypericum
-cream and the vehicle
(secondary endpoints).
II.3.2.2.6
Premenstrual syndrome
19 women with premenstrual syndrome who were in otherwise good physical and mental health and
not taking other treatments for premenstrual syndrome were investigated in a prospective, open,
uncontrolled, observational pilot study (Stevinson
et al
2000
)
. The participants took
Hypericum
tablets
for two complete menstrual cycles (1 x 300 mg
Hypericum
extract per day standardised to 900 µg
hypericin). Symptoms were rated daily throughout the trial using a validated measure. The Hospital
Anxiety and Depression scale and modified Social Adjustment Scale were administered at baseline
and after one and two cycles of treatment. There were significant reductions in all outcome measures.
The degree of improvement in overall premenstrual syndrome scores between baseline and the end of
the trial was 51%, with over two-thirds of the sample demonstrating at least a 50% decrease in
symptom severity. Tolerance and compliance with the treatment were encouraging.
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Hicks
et al
(2004) performed a randomized, double-blinded, placebo-controlled trial, with two parallel
treatment groups. After a no-treatment baseline cycle, volunteers were randomized to either
Hypericum
extract or placebo for a further two menstrual cycles. 169 normally menstruating women
who experienced recurrent premenstrual symptoms were recruited onto the study. 125 completed the
protocol and were included in the analysis. Study medication: 600 mg of
Hypericum
extract
(standardized to contain 1800 µg of hypericin) or placebo (containing lactose and cellulose).
A menstrual diary was used to assess changes in premenstrual symptoms. The anxiety-related
subgroup of symptoms of this instrument was used as the primary outcome measure. After averaging
the effects of treatment over both treatment cycles it was found that there was a trend for
Hypericum
extract to be superior to placebo. However, this finding was not statistically significant.
II.3.2.2.7
Menopausal symptoms
In a drug-monitoring study Grube
et al
(1999) investigated 12 weeks of treatment with St. John's
Wort, one tablet three times daily (900 mg
Hypericum
, Kira), in 111 women from a general medical
practice. The patients, who were between 43 and 65 years old, had climacteric symptoms
characteristic of the pre- and postmenopausal state. Treatment outcome was evaluated by the
Menopause Rating Scale, a self-designed questionnaire for assessing sexuality, and the Clinical Global
Impression scale. The incidence and severity of typical psychological, psychosomatic, and vasomotor
symptoms were recorded at baseline and after 5, 8, and 12 weeks of treatment. Substantial
improvement in psychological and psychosomatic symptoms was observed. Climacteric complaints
diminished or disappeared completely in the majority of women (76.4% by patient evaluation and
79.2% by physician evaluation). Of note, sexual well-being also improved after treatment with St.
John's Wort extract.
In a double-blind randomized, placebo-controlled, multicenter study (Chung
et al
2007), 89 peri- or
postmenopausal women experiencing climacteric symptoms were treated with St. John's wort and
black cohosh extract (Gynoplus), Jin-Yang Pharm., Seoul, Korea) or a matched placebo for 12 weeks.
Climacteric complaints were evaluated by the Kupperman Index (KI) initially and at 4 and 12 weeks
following treatment. Vaginal maturation indices, serum estradiol, FSH, LH, total cholesterol, HDL-
cholesterol, LDL-cholesterol, and triglyceride levels were measured before and after treatment. From
the initial 89 participants, 77 completed the trial (42 in the Gynoplus group, 35 in the placebo group).
Results: Baseline characteristics were not significantly different between the two groups. Mean KI
scores and hot flushes after 4 and 12 weeks were significantly lower in the Gynoplus group.
Differences in superficial cell proportion were not statistically significant. HDL levels decreased in the
control group from 60.20 +/- 16.37 to 56.63 +/- 12.67, and increased in the Gynoplus group from
58.32 +/- 11.64 to 59.74 +/- 10.54; this was statistically significant (p=0.04). Conclusion: Black
cohosh and St. John's wort combination was found to be effective in alleviating climacteric symptoms
and might provide benefits to lipid metabolism.
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
Depression in children
Hübner
et al
(2001) investigated a
Hypericum
extract in children under 12 years with symptoms of
depression and psychovegetative disturbances.
Study design: multi-center, post-marketing surveillance study; n=101 children under 12 years, dosage:
300 to 1800 mg per day.
Based on the data available for analysis, the number of physicians rating effectiveness as 'good' or
'excellent' was 72% after 2 weeks, 97% after 4 weeks and 100% after 6 weeks. The ratings by parents
were very similar. There was, however, an increasing amount of missing data at each assessment point
with the final evaluation including only 76% of the initial sample. Tolerability was good and no
adverse events were reported. The results of this study suggest that
Hypericum
is a potentially safe and
effective treatment for children with symptoms of depression.
Findling
et al
(2003) conducted an open-label prospective outpatient pilot study of St. John's wort in
juvenile depression.
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Youths 6 to 16 years of age meeting DSM-IV criteria for major depressive disorder, prospective,
open-label, outpatient study; dosage: 3 x 150-300 mg. The extract is not further specified.
33 children with a mean age of 10.5 (2.9) years were enrolled. After 4 weeks of St. John's wort
therapy, 22 youths had their dose increased to 900 mg/day. Twenty-five of the patients met response
criteria after 8 weeks of treatment. Overall, St. John's wort was well tolerated. The authors conclude
that
Hypericum
may be an effective treatment for youths diagnosed with major depressive disorder.
Attention deficit, hyperactivity disorder
In a randomized, double-blind, placebo controlled study (Weber
et al
2008) 54 children aged 6 to
17 years received 300 mg
Hypericum
extract (containing 0.3% Hypericine) 3 times daily for 8 weeks.
All participants met the diagnostic criteria for ADHD.
Hypericum
did not improve the symptoms.
Assessor’s conclusion on the use in the paedriatic population:
The only relevant study is that performed by Hübner
et al
(2001) with the extract LI 160. However,
this study was performed as post-marketing surveillance study and not as prospective phase III clinical
trial. The efficacy and safety of the medication were assessed using very coarse rating scales but not
generally accepted scales like HAMD-score. The data support the safety of a potential use in children
but not the efficacy which is necessary for well-established use. Therefore the use in children and
adolescents is not recommended.
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
Dry extracts prepared with ethanol (50-80%) or methanol (50%) demonstrated clinical efficacy in the
treatment of depression (ICD-10 F32.0: mild depressive episode; F32.1: moderate depressive episode;
F33.0: recurrent depressive disorder, current episode mild; F33.1: recurrent depressive disorder,
current episode moderate).
The evidence of long-term efficacy in order to prevent of relapse seems to be at the moment not
sufficient. Therefore the proposed indication for well-established use is restricted to mild depressive
episodes.
There are several new therapeutical approaches (smoking cessation, treatment of alcolohism,
menopausal symptoms …) published. However, the clinical evidence is at the moment insufficient to
be considered in a community monograph.
The clinical data of the hyperforin cream demonstrate a great potential. However, the herbal
preparation is less than 10 years in medicinal use; therefore well-established use is not yet justified in
the monograph.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
II.3.3.2
Adverse events
A randomized, double-blind, crossover study was performed in healthy male volunteers aged 22 to
31 years (25 +/- 3 years; mean +/- SD) years by Siepmann
et al
(2004). Subjects orally received
capsules with 255 to 285 mg St. John's wort extract (900 µg hypericin content), 25 mg amitriptyline,
and placebo 3 times daily for periods of 14 days each with at least 14 days between. Vasoconstrictory
response of cutaneous blood flow (VR) and skin conductance response (SR) following a single deep
inspiration were employed as parameters of autonomic function. St. John's wort extract had no effect
on VR and SR.
Stevinson
et al
(2004) reviewed systematically the clinical evidence associating
Hypericum
extract
with psychotic events. Seventeen case reports associated the use of
Hypericum
extract with psychotic
events. In 12 instances, the diagnosis was mania or hypomania. Causality is in most cases possible. In
no case was a positive rechallenge reported. These case reports raise the possibility that
Hypericum
extract may trigger episodes of mania in vulnerable patients.
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Linde performed in his meta-analysis (Linde
et al
2005) also an analysis of safety. There was a trend
towards lower probability of dropping out because of adverse effects in the
Hypericum
groups
compared to standard therapy.
Adverse events reported from clinical trials:
Study
Extract
Daily dose
Adverse events
Lecrubier
et al
(2002)
WS 5570
3 x 300 mg
n=21 of 186
Nausea (4.8%)
Headache (1.6%)
Dizziness (2.2%)
Abdominal pain (1.1%)
Insomnia (1.6%)
Kalb
et al
(2001)
WS 5572
3 x 300 mg
Sinusitis
Bronchitis
Common cold
Schrader
et al
(1998) Ze 117
2 x 250 mg
n=6 of 81 (7.4%)
Abdominal pain (2) Moderate
Diarrhoea (1) Moderate
Melancholia (1) Moderate
Acute deterioration (1) Moderate
Dry mouth (1) Mild
Schrader (2000)
Ze 117
2 x 250 mg
8%
only GI disturbances (5%) with an incidence
greater than 2%
Randlov
et al
(2006)
PM235,
(
Cederroth
International AB,
Sweden)
3 x 270 mg
mild, mainly headache, gastrointestinal
symptoms
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Anghelescu
et al
(2006)
WS 5570
900 mg or 1800 mg 26.8% of 71
no “typical adverse events (except: 1 allergic
reaction to sunlight → early study termination)
0.006 AE/d
Woelk (2000)
Ze 117
2 x 250 mg
62 of 157 (39%)
Dry mouth (13)
Headache (3)
Sweating (2)
Asthnia (2)
Nausea (1)
Philipp
et al
(1999)
STEI 300
3 x 350 mg
0.5 events per patient (22%)
most frequently reported adverse event: Nausea
Gastpar
et al
(2005) STW3
612 mg
9.8% related to study medication
Diarrhea (1)
Serious adverse events (3): shoulder blade after
falling down the stairs, somatic disorder,
cerebral hemorrhage)
Bjerkenstedt
et al
(2005)
LI 160
3x 300 mg
Adverse events: 38
Patients with adverse events: 35.1%
Adverse events possibly related to study
medication: 24
Body as a wohole (13)
Gastro-intestinal system disorders (6)
Autonomic nervous system disorders (10)
Central & peripheral nervous system disorers
(10)
Skin and appendages disorders (9)
Psychiatric disorders (2)
Others (5)
Kasper
et al
(2006)
WS 570
600 mg or 1200 mg
(2 x 600 mg)
All adverse events. 49 (39.8%)
Serious events 1 (tendon rupture attributable to
accidental injury)
Ear and labyrinth disorders 3 (2.4%)
Gastrointestinal disorders 24 (19.5%)
General disorders and administraion site
conditions 2 (1.6%)
Infection and infestatons 7 (5.7%)
Injury, poisoning and procedural complications
1 (0.8%)
Investigations 1 (0.8%)
Metabolism and nutrition disorders 1 (0.8%)
Musculosceletal and connective tissue disorder
1 (0.8%)
Nervous system disorder 6 (4.9%)
Psychiatric disorders 2 (1.6%)
Renal and unrinary disorders 1 (0.8%)
Reproductive system and breast disorders 1
(0.8%)
Respiratory, thoracic and mediastinal disorders
4 (3.3%)
Skin and subcutaneous disorders4 (3.3%)
Vascular disorders 1 (0.8%)
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Fava
et al
(2005)
LI 160
3 x 300 mg
n=90
most common adverse events.
Headache (42%)
Dry mouth (22%)
Nausea (20%)
Gastrointestinal upset (20%)
Sleepiness (18%)
Shelton
et al
(2001)
LI 160
900 mg/d for 4
weeks, after this
period no adequat
response, new dose
1200 mg/d
Headache (41%)
Abdominal pain (≥ 10%)
Hypericum
Depression Trial
Study Group (2002)
LI 160
900 to 1500 mg
(3-5 x 300 mg)
Diarrhea (21%)
Nausea (19%)
Anorgasmia (25%)
Forgetfulness (25%)
Frequent urination (27%)
Sweating (18%)
Swelling (19%)
Szegedi
et al
(2005) WS 5570
900 mg (3 x 300
mg) – 1800 mg (3 x
600 mg)
adverse events per day
WS 5570 900 mg (0,029)
WS 5570 1800 mg (0,039)
Upper abdominal pain (9.6%)
Diarrhoea (9.6%)
Dry mouth (12.8%)
Nausea (7.2%)
Fatigue (11.2%)
Dizziness (7.2%)
Headache (10.4%)
Sleep disorder (4%)
Increased sweating (7.2%)
highest incidence:
Gastrointestinal disorders (59 events in 42
patients)
Nervous system disorders ( 35 events in 29
patients)
2 serious adverse events (psychic
decompensation attributable to social problems,
hypertensive crisis), both not caused by
Hypericum
van Gurp
et al
(2002) ?
900 to 1800 mg/d
Sleep disturbance (54.8%)
Anxiety (42.9%)
Sexual problems (11.9%)
Headaches (42.9%)
Dizziness (11.9%)
Tremor (19.1%)
Sweating (16.7%)
Dry mouth (38.1%)
Muscle spasms (11.9%)
Muscle or joint stiffness (19.1%)
Urinary problems (16.7%)
Difficulty digesting (19.1%)
Nausea or vomiting (9.5%)
Diarrhea (23.8%)
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Lack of appetite (23.8%)
Heart palpitations (9.5%)
Fatigue (45.2%)
Pain (11.9%)
Blurred vision (14.3%)
1 serious adverse reaction (acute manic
reaction)
Laakmann
et al
1998 WS 5573
WS 5572
3 x 300 mg
WS 5573 (28.6% of 49 patients)
WS 5572 (28.6% of 49 patients)
Bronchitis (3/1)
Influenza-like symptoms (2/0)
Cough (2/0)
Infection (1/0)
Schrader 2000
Ze 117
2 x 250 mg
8%
Hypericum
GI disturbances (5%)
Lenoir
et al
1999
Hyperiforce
(provided by
Biofroce AG,
Roggwil,
Switzerland)
3 x 1 tablet
(standardised to
either 0.17 mg,
0.33 mg, or 1 mg
total hypericin per
day)
There is no difference in AE with possible or
probable causality in the three treatment-groups.
Probable/Possible realation to study medication:
Skin (0/3)
Nerves (2/5)
Psyche (1/1)
Gastrointestinal tract (4/0)
Oranism as a whole (0/2)
Harrer
et al
1999
LoHyp 57
2 x 400 mg
n=12 (For this reason withdrawn: 6)
Volz
et al
2000
D-0496
2 x 250 mg
n=18 at 17% patients
Influenza-like symptoms (7)
Gastrointestinal tract (2)
Skin (3)
Infection of the urinary tract (1)
Others (5)
Gastpar
et al
2006
STW3-VI
900 mg
17.2%
Total AE´s. 58
Related: 10
Gastrointestinal disorders (6)
Ear and labyrinth disorders (1)
Skin and subcutaneous tissue disorders (1)
Wheatley 1997
LI 160
3 x 300 mg
37% of the patients
Dry mouth (5%)
Drowsiness (1%)
Sleepiness (2%)
Dizziness (1%)
Lethargy (1%)
Nausea/Vomiting (7%)
Headache (7%)
Constipation (5%)
Pruritus (2%)
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Vorbach
et al
1997
LI 160
3 x 600 mg
23% of the patients
n=37
Dry mouth (3)
Gastric symptoms (5)
tiredness/sedation (5)
Restlessness (6)
Tremor (2)
Dizziness (5)
Allergic skin reaction (1)
Rychlik
et al
2001
WS 5572
600 mg/1200 mg
17 patients
n=21 (13 with relation to
Hypericum
)
AE´x frequency < 1%
Skin irritation, pruritus
Allergic exanthema
Nervousness, restlessness
Gastrointestinal disorders (4)
Diarrhoe
Insomnia
According to the review by Greeson
et al
(2001) the overall incidence of ADR is in the range of 2%.
The most commonly reported side effects were gastrointestinal irritations (0.6%), allergic reactions
(0.5%), fatigue (0.4%) and restlessness (0.3%). In comparison, the overall ADR incidence for SSRIs is
between 20% and 50%, including more serious side effects.
Additional case reports:
Acute neuropathy after taking 500 mg of
Hypericum
powder per day and exposure to sunlight
(Bove 1998)
II.3.3.3
Serious adverse events and deaths
Several case reports document psychotic side effects like mania and psychosis (review in Hammerness
et al
2003). The majority of the affected persons had histories of affected illness, in most cases
Hypericum
was combined with other psychopharmaceuticals. The symptoms remitted after
discontinuation of the medication. As a precaution
Hypericum
extracts should not be taken by persons
with a history of mania or psychosis. Seizures are reported after overdose only (Karalapillai &
Bellomo 2007).
II.3.3.4
Laboratory findings
II.3.3.4.1
Phototoxicity
Hypericin
Schempp
et al
(1999) describe the HPLC detection of hypericin and semiquantitative detection of
pseudohypericin in human serum and skin blister fluid after oral single-dose (1 x 6 tablets) or steady-
state (3 x 1 tablet/day, for 7 days) administration of the
Hypericum
extract LI 160 in healthy
volunteers (n = 12). Serum levels of hypericin and pseudohypericin were always significantly higher
than skin levels (p </= 0.01). After oral single-dose administration of
Hypericum
extract the mean
serum level of total hypericin (hypericin + pseudohypericin) was 43 ng/ml and the mean skin blister
fluid level was 5.3 ng/ml. After steady-state administration the mean serum level of total hypericin
was 12.5 ng/ml and the mean skin blister fluid level was 2.8 ng/ml. These skin levels are far below
hypericin skin levels that are estimated to be phototoxic (>100 ng/ml).
Dry extracts
In a prospective randomized study Schempp
et al
(2003) investigated the effect of the
Hypericum
extract LI 160 on skin sensitivity to ultraviolet B (UVB), ultraviolet A (UVA), visible light (VIS) and
solar simulated radiation (SIM). Seventy two volunteers of skin types II and III were included and
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were divided into six groups, each consisting of 12 volunteers. In the single-dose study the volunteers
(n = 48) received 6 or 12 coated tablets (5400 or 10 800 microgram hypericin). In the steady-state
study the volunteers (n = 24) received an initial dose of 6 tablets (5400 microgram hypericin), and
subsequently 3 x 1 tablets (2700 microgram hypericin) per day for 7 days. Phototesting was performed
on the volar forearms prior to medication and 6 h after the last administration of
Hypericum
extract.
The erythema-index and melanin-index were evaluated photometrically using a mexameter. After both
single-dose and steady-state administration, no significant influence on the erythema-index or
melanin-index could be detected, with the exception of a marginal influence on UVB induced
pigmentation (p = 0.0471) in the single-dose study. The results do not provide evidence for a
phototoxic potential of the
Hypericum
extract LI 160 in humans when administered orally in typical
clinical doses up to 1800 mg daily. This is in accordance with previous pharmacokinetic studies that
found hypericin serum and skin levels after oral ingestion of
Hypericum
extract always to be lower
than the assumed phototoxic hypericin threshold level of 1000 ng/mL.
The objective of a study by Schulz
et al
(2006) was to investigate the effect of two different
Hypericum
extracts (STW 3, STW 3-VI) on photosensitivity with respect to minimal erythema dose
(MED) after 14 days treatment. Both open, multiple-dose, one-phase studies were conducted in
20 healthy men, receiving one tablet per day. MED values were determined prior to
Hypericum
extract
administration (baseline) and after 14 days treatment using an erythem tester emitting a light very
similar to sun light (main emission spectrum: 285-350 nm). Skin reactions with respect to MED were
evaluated 12 h, 24 h (primary endpoint), 48 h and 7 days after irradiation. All volunteers reached
steady-state of hypericin/pseudohypericin plasma concentrations before study day 14, when the
irradiation under treatment conditions took place. In all subjects MED was measurable under baseline
and under
Hypericum
treatment conditions. With respect to the primary endpoint, in both studies,
mean MED (24 h) were not significantly different between baseline and after 14 days
Hypericum
treatment. However, individually photosensitivity of the skin could increase under treatment
conditions, just as well photosensitivity could decrease or remain unchanged. There were no clinically
relevant changes in the laboratory parameters, the vital signs, physical findings and other observations
related to safety during the examinations. In one study (STW 3), two adverse events were reported,
both described as hypersensitivity to light in mild intensity. The two studies showed that treatment
with the two
Hypericum
extracts under steady state and under prescribed conditions were safe
medications without significant increases of photosensitivity.
Hypericum
oil
Schempp
et al
(2000) investigated the effects of
Hypericum
oil (hypericin 110 microg/mL) and
Hypericum
ointment (hypericin 30 microg/mL) on skin sensitivity to solar simulated radiation. Sixteen
volunteers of the skin types II and III were tested on their volar forearms with solar simulated
radiation for photosensitizing effects of
Hypericum
oil (n=8) and
Hypericum
ointment (n=8). The
minimal erythema dose (MED) was determined by visual assessment, and skin erythema was
evaluated photometrically. With the visual erythema score, no change of the MED could be detected
after application of either
Hypericum
oil or
Hypericum
ointment (P>0.05). With the more sensitive
photometric measurement, an increase of the erythema-index after treatment with the
Hypericum
oil
could be detected (P< or =0.01). The results do not provide evidence for a severe phototoxic potential
of
Hypericum
oil and
Hypericum
ointment, detectable by the clinically relevant visual erythema score.
However, the trend towards increased photosensitivity detected with the more sensitive photometric
measurement could become relevant in fair-skinned individuals, in diseased skin or after extended
solar irradiation.
Assessor’s comment:
The mentioned content of hypericin is in contrast to investigations from Maisenbacher
et al
(1992),
these authors found only artefacts of hypericin.
From traditional use of Hypericum oil it is known that the exposure to sunlight of treated parts of the
skin would lead to skin irritations. In traditional medicine it is recommended to protect treated skin
from sunlight.
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II.3.3.5
Safety in special populations and situations
II.3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors
II.3.3.5.2
Drug interactions
The extent of induction of CYP3A varies among St. John's wort products and depends on hyperforin
dose (Mueller
et al
2006, Gutmann
et al
2006). Products that do not contain substantial amounts of
hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction (Madabushi
et
al
2006). Hypericin may be assumed to be the P-glycoprotein inducing compound, although the
available evidence is less convincing (Mannel 2004).
Several meta-analyses are published on the pharmacokinetic interactions of
Hypericum
with the
cytochrome-P450 enzyme complex and P-glycoprotein (Pal
et al
2006, Madabushi
et al
2006, Whitten
et al
2006, Zhou
et al
2004, Mills
et al
2004, Izzo 2004, Henderson
et al
2002): Results from clinical
studies and case reports indicate that self-administered
Hypericum
extract reduce steady state plasma
concentrations of alprazolam, amitriptyline, cyclosporine, tacrolimus, digoxin, fexofenadine,
amprenavir, indinavir, lopinavir, ritonavir, saquinavir, benzodiazepines, methadone, nevirapine,
simvastatin, theophyline, irinotecan, midazolan, triptans and warfarin.
Hypericum
has been also
reported to cause bleeding and unwanted pregnancies when concomitantly administered with oral
contraceptives. When combined with serotonin reuptake inhibitor, antidepressants (e.g. sertaline,
paroxetine, nefazodone) or buspirone,
Hypericum
extracts can cause serotonergic syndrome. Whitten
et al
(2006) concluded that in three studies, where the daily exposure to hyperforin was less than 4 mg,
no significant effect on CYP3A4 could be detected. Brattström (2005, unpublished data, cited in
Whitten
et al
2006) tested the extract ZE117 in 16 females in a dose of 500 mg daily for 14 days. The
women started 3 months prior to the study taking 20 µg ethinyl oestradiol and 150 µg desogestrel
daily. Pharmacokinetic testing on days 7 and 22 after the treatment with ZE 117 revealed no
significant differences in ethinyl estradiol or 3-ketodesgestrel (active metabolite). It is not known
whether a longer treatment with ZE117 would induce CYP3A4. Arold
et al
(2005) report from a
pharmacokinetic interaction study with 240 mg
Hypericum
extract daily containing 3.5 mg
Hyperforin. After treatment for 11 days no siginifcant changes in the primary kinetic parameters of
alprazolam, caffeine, paraxanthine, tolbutamide, 4-hydroxytolbutamide and digoxin were observed.
CYP1A2 appears to be induced by
Hypericum
extract only in females, the activities of CYP2D6,
NAT2, and XO were not affected by
Hypericum
extract (Wenk
et al
2004).
The causality of some of the published interactions is questioned by Schulz (2005), particularly the
combinations with serotonin reuptake inhibitors and digoxin.
The elevated activity of CYP3A returns to basal level approximately 1 week after termination of
Hypericum
administration (Imai
et al
2008). Therefore the warning in the monograph is justified that
Hypericum
administration should be discontinued at least 10 days prior to elective surgery.
II.3.3.5.3
Use in pregnancy and lactation
Five mothers who were taking 300 mg of St. John's wort 3 times daily (LI 160 [Jarsin]) and their
breastfed infants were assessed by Klier at al (2006). Thirty-six breast milk samples (foremilk and
hindmilk collected during an 18-hour period) and 5 mothers' and 2 infants' plasma samples were
analyzed for hyperforin levels. Hyperforin is excreted into breast milk at low levels. However, the
compound was at the limit of quantification in the 2 infants' plasma samples (0.1 ng/mL). Milk/plasma
ratios ranged from 0.04 to 0.13. The relative infant doses of 0.9% to 2.5% indicate that infant exposure
to hyperforin through milk is comparable to levels reported in most studies assessing anti-depressants
or neuroleptics. No side effects were seen in the mothers or infants. The authors conclude that these
results add to the evidence of the relative safety of St. John's wort while breast-feeding found in
previous observational studies.
In a review Dugoua
et al
(2006) searched 7 electronic databases and compiled data according to the
grade of evidence found. The authors found very weak scientific evidence based on a case report that
St Johns wort is of minimal risk when taken during pregnancy. There is
in vitro
evidence from animal
studies that St John's wort during pregnancy does not affect cognitive development nor cause long-
term behavioral defects, but may lower offspring birth weight. There is weak scientific evidence that
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St. John's wort use during lactation does not affect maternal milk production nor affect infant weight,
but, in a few cases, may cause colic, drowsiness or lethargy. There is weak scientific evidence that
St. John's wort induces CYP450 enzymes, which may lower serum medication levels below
therapeutic range; this may be of concern when administering medications during pregnancy and
lactation. Caution is warranted with the use of St John's wort during pregnancy until further high
quality human research is conducted to determine its safety. St John's wort use during lactation
appears to be of minimal risk, but may cause side effects. Caution is warranted when using
medications along with St. John's wort.
Karalapillai & Bellomo (2007) reported a case of overdose in suicidal intention of a 16-year-old girl. It
has been reported that the girl had taken up to 15 tablets per day for 2 weeks and 50 tablets just before
hospitalisation. Seizures and confusion were diagnosed, after 6 days the EEG was normal, no further
seizures occurred in the following 6 months. The published data on the composition of the tablets are
not clear (‘300 µg tablets’).
Assessor’s comment:
In a pesonal communication the author confirmed that there is a typing error in the publication. The
product contained 300 mg extract per tablet. These symptoms occurred therefore after ingestion of
4500 mg extract per day over a period of 2 weeks (approximately the 5-fold therapeutic dose) and an
additional dose of 15000 mg extract (approximately the 17-fold therapeutic dose).
II.3.3.5.5
Drug abuse
II.3.3.5.6
Withdrawal and rebound
Beckman
et al
(2000) conducted a telephone survey of 43 subjects who had taken
Hypericum
extract
to assess demographics, psychiatric and medical conditions, dosage, duration of use, reason for use,
side effects, concomitant drugs, professional consultation, effectiveness, relapse, and withdrawal
effects. Most subjects reported taking
Hypericum
extract for depression, and 74% did not seek medical
advice. Mean dosage was 475.6+/-360 mg/day (range 300-1200 mg/day) and mean duration of therapy
was 7.3+/-10.1 weeks (range 1 day-5 yrs). Among 36 (84%) reporting improvement, 18 (50%) had a
psychiatric diagnosis. Twenty (47%) reported side effects, resulting in discontinuation in five (12%)
and one emergency room visit. Two consumers experienced symptoms of serotonin syndrome and
three reported food-drug interactions. Thirteen consumers experienced withdrawal symptoms and two
had a depressive relapse. These data suggest the need for greater consumer and provider awareness of
the potential risks of
Hypericum
extract in self-care of depression and related syndromes.
Assessor’s comment:
Details on the type of products used are missing. Data from a telephone survey should be assessed
reluctantly.
II.3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
II.3.3.6
Assessor’s overall conclusions on clinical safety
The adverse events observed in clinical trials, which are most probably linked to the study medication
are in general mild, the frequency is, compared to synthetic antidepressants considerably lower. The
induction of CYP3A4 is well documented; the amount is directly correlated with the content of
hyperforin in the herbal preparation. Pharmacokinetic interactions are documented for several drug
substances metabolised via CYP3A4 with a narrow therapeutic range.
Hypericum
extracts should not
be used concomitantly with these substances. Adequate studies with extracts low in hyperforin ,which
could justify exemptions in the wording of the contraindications, special warnings and interactions
sections of the monograph, are missing. Nevertheless, the risk / benefit assessment favours the benefits
of the
Hypericum
dry extracts.
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The induction of the CYP3A4 is reversible within approximately 10 days after stopping ingestion of
Hypericum
extracts. Therefore the administration should be discontinued at least 10 days prior to
surgery.
The only risk of the cutaneous application of
Hypericum
oil seems to be the phototoxicity when
treated skin is exposed to intense sunlight. A special warning should inform the patient.
II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
Dry extracts of
Hypericum perforatum
demonstrated in several controlled clinical trials superiority
over placebo and non inferiority against standard medication in mild to moderate depressive episodes.
Therefore these types of extracts are proposed for ‘well-established use’.
The orally administered herbal tea and other extracts, mostly liquid, have a long tradition in folk
medicine for the treatment of ‘weak nerves’, therefore the indication ‘mental exhaustion
(neurasthenia) is proposed. Provided that the duration of use is restricted to several days, this
traditional use of such herbal preparations can be accepted. The cutaneous application of oil
preparations is plausible based on pharmacological tests.
III.
ANNEXES
III.1
C
OMMUNITY HERBAL MONOGRAPHS FOR
H
YPERICUM PERFORATUM
L.,
HERBAL
III.2
L
ITERATURE
R
EFERENCES
7
According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2)
8
According to the ‘Procedure for the preparation of Community monographs for herbal medicinal products
with well-established medicinal use’ (EMEA/HMPC/182352/2005 Rev.2)
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Source: European Medicines Agency
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