Community herbal monograph on
Ribes nigrum
L., folium
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
i) Herbal substance
Ribes nigrum
L. folium (blackcurrant leaf)
ii) Herbal preparations
a) Comminuted herbal substance.
b) Dry extract (DER 7:1), extraction solvent
water
Well-established use
Traditional use
Comminuted herbal substance as herbal tea for
oral use.
Herbal preparations in solid dosage forms.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Indication 1)
Traditional herbal medicinal product for relief of
minor articular pain.
Indication 2)
Traditional herbal medicinal product to increase
the amount of urine to achieve flushing of the
1
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
Community herbal monograph on
Ribes nigrum
L., folium
EMA/HMPC/142986/2009
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Well-established use
Traditional use
urinary tract as an adjuvant in minor urinary
complaints.
The product is a traditional herbal medicinal
product for use in the specified indication
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults, Elderly
Indication 1)
Comminuted herbal substance for infusion as
herbal tea preparation: 2 to 4 g per cup 3 times
daily.
Indication 1) and 2)
Dry extract (7:1, water) 169 mg 1 to 3 times
daily.
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
The herbal substance is traditionally used over a
period of 2 (indication 2) to 4 weeks (indication
1).
If the symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Method of administration
Oral use.
To ensure an increase of the amount of urine,
adequate fluid intake is required during treatment.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Condition was a reduced fluid intake is
recommended (e.g. severe cardiac or renal
disease).
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Ribes nigrum
L., folium
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4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under 18
years of age is not recommended.
If the symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
If complaints of symptoms such as fever, dysuria,
spasms or blood in the urine occur during the use
of the medicinal product, a doctor or a qualified
health care professional should be consulted.
Concomitant treatment with synthetic diuretics is
not recommended.
Articular pain accompanied by swelling of joints,
redness or fever, should be examined by a doctor.
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
None reported.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
None known.
If adverse reactions occur, a doctor or a
Community herbal monograph on
Ribes nigrum
L., folium
EMA/HMPC/142986/2009
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Well-established use
Traditional use
pharmacist should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c (1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c (1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
Well-established use
Traditional use
Not applicable.
6 May 2010
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Ribes nigrum
L., folium
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Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 4
1.3. Search and assessment methodology....................................................................
8
2. Historical data on medicinal use ........................................................................................ 8
2.1. Information on period of medicinal use in the Community ........................................
8
preparations and indications.......................................................................................
9
3. Non-Clinical Data ............................................................................................................... 9
preparation(s) and relevant constituents thereof ...........................................................
9
3.1.1. Assessor’s overall conclusions on pharmacology................................................. 1
2
preparation(s) and relevant constituents thereof ......................................................... 1
3
3.2.1. Assessor’s overall conclusions on pharmacokinetics ............................................ 1
3
preparation(s) and constituents thereof ..................................................................... 1
3
3.3.1. Assessor’s overall conclusions on toxicology ...................................................... 1
4
3.4. Overall conclusions on non-clinical data............................................................... 1
4
4. Clinical Data ..................................................................................................................... 14
4.1. Clinical Pharmacology ....................................................................................... 1
4
including data on relevant constituents ...................................................................... 1
4
4.1.1.1. Assessor’s overall conclusions on pharmacodynamics....................................... 1
4
including data on relevant constituents ...................................................................... 1
4
4.1.2.1. Assessor’s overall conclusions on pharmacokinetics ......................................... 1
4
4.2. Clinical Efficacy ................................................................................................ 1
4
4.2.1. Dose response studies.................................................................................... 1
4
4.2.2. Clinical studies (case studies and clinical trials).................................................. 1
4
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 1
4
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 1
4
5. Clinical Safety/Pharmacovigilance................................................................................... 15
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 1
5
5.2. Patient exposure .............................................................................................. 1
5
5.3. Adverse events ................................................................................................ 1
5
5.4. Serious adverse events and deaths..................................................................... 1
5
5.5. Laboratory findings .......................................................................................... 1
5
5.6. Safety in special populations and situations ......................................................... 1
5
5.6.1. Intrinsic (including elderly and children) /extrinsic factors ................................... 1
5
5.6.2. Drug interactions........................................................................................... 1
5
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5.6.5. Drug abuse................................................................................................... 1
5
5.6.6. Withdrawal and rebound................................................................................. 1
5
5.7. Overall conclusions on clinical safety ................................................................... 1
6
6. Overall conclusions .......................................................................................................... 16
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1.
Introduction
Handbooks as well as publications (PubMed & local journals) were used as sources. Keywords:
Ribes
nigrum
, blackcurrant, cassis.
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
•
Herbal substance(s)
Blackcurrant leaf consists of the dried leaves of
Ribes nigrum
L. (blackcurrant), belonging to the family
of the
Grossulariaceae
. The genus
Ribes
contains between 140 and 150 species. The leaves are
collected during or shortly after flowering (Pharm. Française 1996; Hänsel et al. 1994).
A dark green upper surface and a pale greyish green lower surface is characteristic for the slightly
wrinkled leaf fragments. Furthermore a widely spaced reticulate venation is particularly distinct on the
lower surface. Glands can be seen as scattering yellowish dots. In contrast with the fresh leaves, the
dried leaves have no odour or taste. There are no falsifications as the herbal substance is harvested
from cultivation (Wichtl 1994; Hänsel et al. 1994).
The dried
Ribes nigrum
leaf contains not less than 1.5% of
flavonoids
, expressed as rutin. The
material complies with the monograph of the Pharmacopée Française (1996) (ESCOP, 2003).
•
Phytochemistry
The most important secondary metabolites present in the herbal substance can be subdivided into
several groups of phytochemical compounds.
Polyphenolic substances, more particularly
flavonoid glycosides
: kaempferol, quercetin.
Hydroxycinnamic acid derivatives
: chlorogenic acid and chlorogenic acid derivatives (isochlorogenic
acid, neochlorogenic acid), caffeic acid, gallic acid, ferulic acid, coumaric acid, gentisinic acid
(Trajkovski, 1974a; Trajkovski 1974b).
Some substances can seasonally appear in the glands of leaves of
Ribes nigrum
.
Sakuranetin
is a
methylated flavanone aglycone (4’,5-diOH-7-methoxyflavanone). Its biosynthesis may be useful in the
protection against parasites like
Botrytis cinerea
Pers. ex Fr. (Atkinson & Blakeman, 1982).
OH
CH
3
O
O
OH
Figure 1: sakuranetin
Prodelphinidins
(
proanthocyanidines)
were identified in a methanolic extract of the leaves. They
may be responsible for the anti-inflammatory properties of the herbal preparations (Tits et al. 1992a;
Tits et al. 1992b).
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OH
OH
H
O
OH
OH
OH
OH
OH
H
O
OH
OH
OH
Figure 2: dimer prodelphinidin I
The presence of
glycerolipids
has been reported. The total fatty acid composition was unusual,
because the following unsaturated fatty acids were identified: linolenic acid (alpha-18:3), together with
cis-7, 10, 13-hexadecatrienoic acid (16:3) and lower amounts of stearidonic acid (18:4) and gamma-
linolenic acid (gamma-18:3). This makes the lipid composition type mixed: typical of 16:3 plants but
also partially typical for 18:4 plants (Dobson, 2000).
Ascorbic acid is present: between 100 and 270 mg per 100 g dried material (Hänsel et al. 1994).
•
Herbal preparation(s)
The essential oil of the leaves of
Ribes nigrum
contains mainly monoterpenic substances like alpha-
pinene, myrcene, p-cymene, limonene, beta-ocimene, beta-phellandrene, linalool, terpinen-4-ol,
geraniol, citronellylacetate. Furthermore the sequiterpenes caryophyllene and humulene were
identified, as well as methyl salicylate (Andersson et al. 1963).
The potassium-sodium ratios in the leaf of
Ribes nigrum
and decoctions of the leaves were 128:1 and
242:1 respectively. These ratios are considered as eventually contributing to the diuretic effect
(Szentmihályi et al. 1998).
1.2.
Information about products on the market in the Member States
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations.
Ribes nigri
folium only as
an excipient or in mixed
preparations
Belgium
MA
TRAD
Other TRAD
Other Specify: No preparations
registered or authorized
Bulgaria
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
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Member State Regulatory Status
Comments (not
mandatory field)
Cyprus
MA
TRAD
Other TRAD
Other Specify: No information
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Denmark
MA
TRAD
Other TRAD
Other Specify: Only food supplements
Estonia
MA
TRAD
Other TRAD
Other Specify: Can be used in food
supplements
Finland
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
France
MA
TRAD
Other TRAD
Other Specify: Registered preparations
for oral use
Germany
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Greece
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Hungary
MA
TRAD
Other TRAD
Other Specify: Only combinations
registered
Iceland
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Ireland
MA
TRAD
Other TRAD
Other Specify: Excipient in authorized
medicines (berries and
leaves)
Italy
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Latvia
MA
TRAD
Other TRAD
Other Specify: No information
Liechtenstein
MA
TRAD
Other TRAD
Other Specify: No information
Lithuania
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Luxemburg
MA
TRAD
Other TRAD
Other Specify: No information
Malta
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Norway
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Poland
MA
TRAD
Other TRAD
Other Specify: Herbal tea
Portugal
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Romania
MA
TRAD
Other TRAD
Other Specify: No information
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
Slovenia
MA
TRAD
Other TRAD
Other Specify: No authorized or
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Member State Regulatory Status
Comments (not
mandatory field)
registered preparations
Spain
MA
TRAD
Other TRAD
Other Specify: Comminuted herbal
substance in capsules
Sweden
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No authorized or
registered preparations
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’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
Marketing specifications
Country
Therapeutic indication
Details
Austria
One combination product is used as
an adjuvant in case of liver and bile
complaints.
The product is an oral solution containing
Ribes nigri folium
, apart from
Agrimonia
eupatoria, Achillea millefolium, Mentha
piperita, Rosa canina, Berberis vulgaris.
The
content of ethanol is 20%.
France
Traditionally used to support renal
and digestive elimination systems
Traditionally used to treat minor
articular pain.
Powdered herbal substance in hard
capsules: 340 mg per capsule
•
on the market since 1988
•
posology: 1 capsule 3x daily (maximally
5 capsules per day)
Dry extract (DER 7:1; extraction solvent
water) in hard capsules: 169 mg per
capsule
•
on the market since 1990
•
posology: 1 to 3 capsules daily
Ireland
Expectorant for the relief of chesty
coughs, nasal congestion and
catarrh
Listed as an excipient of a Chesty Cough
and Decongestant Oral Solution
Poland
Herbal medicinal product
traditionally used in minor
rheumatic complaints.
Topical use in minor skin
inflammations.
Herbal tea: 2-4 g 3x daily
There are 2 authorized products on the
market.
The herbal substance was described in the
Polish Herbal Compendium from 1978.
Spain
Traditionally used as a diuretic and
in minor rheumatic complaints
(Powdered) herbal substance in hard
capsules: 250 mg per capsule
•
on the market since 1991
•
posology: 1-2 capsules, 2-3x daily
Also in combination products:
Ribes nigrum
Combination products are used for
diuretic activity and as an adjuvant
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Country
Therapeutic indication
Details
in case of diets and for losing
weight.
with
Camellia sinensis
.
1.3.
Search and assessment methodology
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
Inflammatory conditions
Indications exclusively in folk medicine are: arthritis, rheumatic complaints, diarrhoea, spasmodic
cough. Rarely preparations were locally applied on wounds (Wichtl, 1994).
Ribes
has been traditionally
used as an infusion to cure joint complaints (traditionally classified as ‘rheumatism’) (Leclerc 1983;
Rombi 1991). The only indication mentioned in the ESCOP monograph is ‘adjuvant in the treatment of
rheumatic conditions’ (ESCOP, 2003).
Anti-inflammatory posology according to ESCOP (2003), Van Hellemont (1985) and Delfosse (1998):
•
Dried leaves as an infusion: from 1.5 to 4 g per cup (= 150 ml; 3-4 cups daily) to 20-50g per litre
(250 to 500 ml daily), infused during 15 minutes.
•
Fluid extract (1:1): 5 ml 2x daily. The extraction solvent is not specified.
Other indications
Leaves of
Ribes nigrum
were mainly used in folk medicine as a diuretic, eliminating uric acid. The
preparations mentioned are aqueous decoctions (Decaux, 1930; Hänsel et al. 1994).
Some authors mention the use of tea preparations containing
Ribes nigrum
,
Fraxinus excelsior
and
Ulmaria officinalis
.
The essential oil of
Ribes nigrum
should stimulate the renal epithelium and enhance diuresis (Garnier
et al. 1961; Rombi 1991).
Leaves were applied on the head against migraine (Decaux, 1930).
Justification for acceptance of herbal preparations in the monograph
•
Herbal tea (2-4 g up to 3 times daily) has been used since 1978 in Poland for minor rheumatic
complaints and can be accepted according to the 30 years of use stipulated in Directive
2001/83/EC [article 16b paragraph (c)].
•
Powdered herbal substance in capsules has been marketed in France (since 1988) and in Spain
(since 1991) in different posologies (France: 340 mg up to 5 capsules per day; Spain: 250 mg up
to 6 capsules per day). The period of use covers 15 years in Europe but is not fulfilling the 30
years of traditional use as stipulated in Directive 2001/83/EC [article 16b paragraph (c)]. The
company provided evidence for a market introduction of a capsule containing 260 mg of ‘cassis’
powder in 1983. This would mean that the preparation could be included in the monograph from
2013 on.
•
Dry extract (7:1; extraction solvent water) is marketed in France as capsules (169 mg per capsule;
posology: up to 3 capsules daily) meets the 15 year tradition in Europe and does not comply with
the 30 years of traditional use as stipulated in Directive 2001/83/EC [article 16b paragraph (c)].
Nevertheless during its meeting of 12 January 2010 the MLWP decided to accept this preparation
based upon the following justification:
•
- The extract is made with water, a procedure close to herbal tea preparations.
•
- The drug-extract ratio is 7 to 1 and 169 mg is taken as a single dose up to 3 times a day. One
capsule corresponds to 1183 mg of herbal substance. For herbal tea 2 to 4 g herbal substance is
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infused; virtually, more material can be extracted by preparing the herbal tea. The number of daily
doses is similar for the extract and the infusion.
•
Topical use is not granted, because there are no preparations and posology specified (cf. Poland).
2.2.
Information on traditional/current indications and specified
substances/preparations
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
In vitro
- Biosynthesis and release of prostaglandins
Rabbit heart
The experimental model was the isolated heart of the rabbit with arachidonic acid as substrate (100
µg). The preparation consisted of purified flavonoid substances, but no further data about the exact
composition are available.
The prostaglandins released in the heart effluent were detected by means of bioassay, using the rat
stomach strip.
Total flavonoids extracted from the leaves of
Ribes nigrum
,
inhibited both biosynthesis and
release of PG-like substances
. They were more active than rutin and isoquercitin. The IC
30
were
respectively 1.03 + 0.24 mg/ml, 3.76 + 0.24 mg/ml and 2.31 + 0.40 mg/ml (Chanh et al. 1986).
Chondrocytes and COX
The experimental model consisted of cultured human chondrocytes from cartilage isolated after
surgery and cyclo-oxygenase-1 (COX-1) from ram seminal vesicles and cylco-oxygenase-2 (COX-2)
from sheep placenta.
The herbal preparation consisted of leaf extract made with acetone (70% v/v in water). The resulting
condensed tannins were purified using reversed phase and Sephadex LH20 column chromatography.
The proanthocyanidines were purified to 95%. Purification yielded among others catechin,
gallocatechin, gallocatechin-gallocatechin and gallocatechin-epigallocatechin.
Several effects of these purified fractions were evaluated on the cultivated chondrocytes:
•
A positive effect on the production of proteoglycans with concentrations from 1 to 100 µg/ml.
•
A positive effect on type II collagen production with concentration from 1 to 100 µg/ml.
•
An
inhibitory effect on the prostaglandin E2 (PGE2) production
mainly with concentrations
from 10 to 100 µg/ml.
Isolated prodelphinidines had an inhibitory effect on the biosynthesis of prostaglandins catalyzed by
COX-1 and COX-2. A concentration of 10
-4
M of gallocatechin and its dimer inhibited the formation of
prostaglandins to the same extent as indomethacin 10-5M: 53%, 57% and 67% respectively (Garbacki
et al. 2002).
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Endothelial cells
The experimental model consisted of an LT2 cell line originating from human umbilical vein
endothelium cells.
A proanthocyanidin-enriched fraction was obtained from leaves from
Ribes nigrum
with acetone
extraction (70% v/v in water). Purification was done on reversed phase chromatography.
A significant inhibition of TNF-
α
(Tumor Necrosis Factor) stimulated ICAM-1 (Intercellular Adhesion
Molecule 1) expression was obtained with proanthocyanidins in concentrations starting from 10 µg/ml
on (Garbacki et al. 2005).
- Antilipoperoxidative effects
Methanolic crude extracts of fruits, leaves and buds of
Ribes nigrum
were tested in rat hepatic
microsomes. The extracts contained between 818 to 997 mg polyphenols per 100g leaves. The
oxidative mixture consisted of a Fe
++
(FeSO
4
) and ADP mixture in the presence of ascorbic acid.
Antilipoperoxidative effects were measured by quantifiying the amount of malondialdehyde. The IC50
of the extracts varied between 9.31 and 6.44 µg/ml (Costantino et al. 1993).
In vivo
- Anti-inflammatory and analgesic effects
Reference Experimental model
Intervention
Outcome
Declume
(1989)
Rats
Carrageenan paw
oedema
Extract of Rn in 14%
ethanol PO 30 minutes
prior to carrageenan
PO acute
(1) Rn 1 and 10 ml/kg
(2) Indo 2.5 and 5 mg/kg
(3)Nifl 25 and 50 mg/kg
PO subacute: 21 days
(4) Rn 0.33, 1 and 10
ml/kg
(5) Indo 1,66 mg/kg
(6) Nifl 12.5 mg/kg
Reduction paw oedema (after
4 hours)
(1) - 30% and - 54%
(2) - 63% and - 66%
(3) - 19% and - 70%
Reduction paw oedema
(4) - 30%, -42.5% and -46%
(5) - 49%
(6) - 53%
Mongold
(1993)
Rats
Maceration of Rn in 15%
ethanol: lyophylizate
Model 1
Carrageenan paw
oedema
Model 2
Cotton-pellet induced
granuloma test: 2 cotton
pellets intradorsally
implanted
Model 3
Freund’s adjuvant-
induced arthritis test:
Mycobacterium
butyricum
injected in
tail: paw oedema
resulting
Model 1
:
IP acute: paw oedema
(1) Rn 100 and 200 mg/kg
(2) Indo 5 and 10 mg/kg
Model 2
IP daily for 7 days
(3) Rn 150 mg/kg
(4) Indo 3 mg/kg
Model 1
Paw oedema (after 3 hours)
(1) - 70% (100 mg/kg)
(2) - 77%
(1) and (2) P<0.01 (vehicle)
Model 2
Weight of granuloma (day 8)
(3) - 18.6 %
(4) - 24 %
(3) and (4) P<0.001(vehicle)
Model 3
Paw volume
(5) - 18.7 and - 34.6%
(6) - 37.7%
(5) and (6) P<0.01 (vehicle)
Model 3
IP daily for 14 days
(5) 100 and 200 mg/kg
(6) Indo 3 mg/kg
Tits et al.
(1991)
Rats
Carrageenan paw
IP acute
Prodelphinidins
Reduction paw oedema:
(1) - 18%, - 40%, - 55% and
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Reference Experimental model
Intervention
Outcome
oedema
(1) 5, 10, 40 and 60
mg/kg
(2) Indo 4 mg/kg
(3) ASA 200 mg/kg
- 57%
(2) - 44%
(3) - 47%
Mongold
(1993)
Mice
Model 1
Acetic acid induced
writhing test
Maceration of Rn in 15%
ethanol: lyophylizate:
given 30 prior to acetic
acid
Model 2
Hot-plate (55°C)
response
with Rn lyophilizate
Model 1
IP acute
(1) Rn lyophilizate
(2) paracetamol
Model 1
Reduction of writhing
(1) ED
50
= 61.5 mg/kg
(2) ED
50
= 132 mg/kg
Therapeutic index = LD
50
/ED
50
(1) 17.7
(2) 3.8
Model 2
Time to escape
(1) not significant (vehicle)
(2) > vehicle: P < 0.001
Model 2
IP acute
(1) Rn lyophilizate: 200
mg/kg
(2) Morphine 4 mg/kg
Garbacki
(2004)
Male Wistar rats
Model 1
Carrageenin induced paw
oedema: injection of of
carrageenin 30 minutes
after the test substances
Model 2
Carrageenin-induced
pleurisy: injection of
carrageenin in the right
pleural cavity 30 minutes
after the test substances
Test substances = PACs
of Rn by extraction in
acetone 70% (v/v in
water) + purification by
RP
Model 1
(1) IP injection: one dose
PACs: 10, 30, 60 or 100
mg/kg
(2) Saline
Paw oedema evaluated after:
1 hour: PACs = saline
2 hours:,PACs (60 and 100
mg/kg) < saline (P<0.05)
4 hours: PACs (all doses) <
saline (P<0.05)
Model 2
Volume of exsudate
PACs (30, 60 and 100 mg/kg)
and indo < saline (P<0.05)
Infiltration of PMNs
PAC (all doses) and indo <
saline (P<0.05)
TNFα release
PACs (30 mg/kg) and indo <
saline (P<0.05)
Release of IL-6 and IL-10
PACs: no influence
Indo < saline (P<0.05)
Release of CINC-1
PACs (30 mg/kg) and indo <
saline (P<0.05)
NOx formation
PACs (30 mg/kg) < saline
(P<0.05)
Indo ≈ saline
Model 2
IP injection: one dose of:
(1) PACs: 10, 30, 60 or
100 mg/kg
(2) Indomethacin 10
mg/kg
Pleural cavity opened after
4 hours
Garbacki
(2005)
Male Wistar rats
Carrageenin-induced
pleurisy: injection of
carrageenin in the right
pleural cavity 30 minutes
IP injection: one dose
(1) PACs: 10, 30 or 60
mg/kg
(2) Saline
Pleural cavity opened after
Production of cytokines by
PMNs
CD11a: no influence
CD11b: stimulation with 60
mg/kg
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Reference Experimental model
Intervention
Outcome
after the test substances
PACs of Rn by extraction
in acetone 70% (v/v in
water) + purification by
RP
4 hours
CD49d:
inhibition with 10 mg/kg
stimulation with 60 mg/kg
CINC-I = cytokine-induced neutrophil chemoattractant-I
ED
50
= effective dose in 50% of animals
Indo = indomethacin
IP = intraperitoneal
LD
50
= lethal dose in 50% of animals
Nifl = niflumic acid
PACs = proanthocyanidines
PMNs = polymorphonuclear leukocytes
PO = peroral
Rn =
Ribes nigrum
RP = reversed phase (chromatography)
- Diuretic activity
The model used was a salidiuretic action. The intervention consisted of oral administration of a fluid
extract (1:1) of blackcurrant leaf. The diuretic action of an equivalent of 1500 mg dried leaf/kg was
comparable to the effect of furosemide at 50 mg/kg
(Rácz-Kotilla & Rácz 1977).
- Antihypertensive effects
The model used was the antihypertensive effect on cats. Doses liquid extract (1:1) equivalent to of 400
mg dried blackcurrant leaf/kg were compared to tolazoline 0.75 mg/kg and 1.0 mg/kg. The
antihypertensive effects of both were comparable
, but the effect of the leaf extract lasted for 20
minutes as compared to 5 minutes for tolazoline (Rácz-Kotilla & Rácz 1977).
In another study normotensive rats were used. An infusion of blackcurrant leaf (20g/L) was
administered intravenously at a dose equivalent to 360 mg dried leaf per kg. There was a
45% fall in
blood pressure
, which after 30 minutes was still 30% (Laserre et al. 1983).
3.1.1.
Assessor’s overall conclusions on pharmacology
Most of the experimental in vivo pharmacology with
Ribes nigrum
herbal preparations was done on
models of inflammation: carrageenin paw oedema, cotton pellet granuloma test and carrageenin
induced pleurisy. Rats were the species used. The preparations consisted mainly of alcoholic liquid
extracts which were mostly lyophilized. They were administered perorally as well as intraperitoneally.
Ribes nigrum
performed qualitatively and quantitatively well as compared to non steroidal anti-
inflammatory substances like indomethacin, nifluminic acid and acetylsalicylic acid. Several
inflammatory parameters were significantly reversed, especially the formation of oedema and the
cellular components as illustrated by reduced exsudate, infiltration of polymorphonuclear leukocytes,
release of interleukins and cytokines and the formation NO-components.
Apart from the anti-inflammatory activity there was also an analgesic activity demonstrated in the
acetic acid induced writhing test and the hot-plate response with mice. Alcoholic extracts were
intraperitoneally administered. The therapeutic index in the writhing test was about 5 times better than
the one of paracetamol. On the contrary,
Ribes nigrum
was not effective in the hot plate response as
compared to vehicle and morphine.
Assessment report on Ribes nigrum L., folium
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In vitro experiments confirmed the anti-inflammatory actions seen in vivo. Flavonoids extracted from
Ribes nigrum
inhibited the biosynthesis of prostaglandins in whole organs (rabbit heart) as did
concentrated proanthocyanidines in COX-1 preparations (from ram seminal vesicles) and COX-2
preparations (sheep placenta). The effect was comparable to indomethacin.
Additional properties emerged from in vitro experiments with human chondrocytes. Purified
proanthocyanidins stimulated the biosythesis of proteoglycans and collagen. This can be considered as
an activity complementary to the treatment of inflammation. Furthermore proanthocyanidins inhibited
the formation of tumor necrosis factor α and the intracellular adhesion molecule in human endothelial
cells. Finally antilipoperoxydase effect can be added to this large scope of activities.
As a conclusion, an overview of the experimental pharmacology of
Ribes nigrum
preparations opens
perspective for further clinical investigations in human subjects.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data with regard to absorption, distribution, metabolism, elimination and pharmacokinetic
interactions with other medicinal products are available.
3.2.1.
Assessor’s overall conclusions on pharmacokinetics
Not applicable.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
- Acute toxicity
Mice were used as animal species.
Ribes
nigrum leaf was administered intraperitoneally as liquid
extract (1:1). The intraperitoneal LD
0
and LD
50
were 22 and 49 g/kg respectively. The LD
100
was
estimated at 90 g/kg (ESCOP, 2003).
In another study with mice a lyophilizate obtained by maceration of 100 g leaf per litre 15% ethanol
was administered. Intraperitoneal LD
50
was 1.09 g/kg. Oral doses up to 3 g/kg did not show overt
toxicity (ESCOP, 2003; Mongold 1993).
- Subacute toxicity
Rats were used as animal species.
Ribes nigrum
leaf was administered as a lyophilized 15% ethanolic
extract (1 g of extract was equivalent to 1.8 g of leaf). The extract was administered orally in daily
doses of 2 g/kg/day (21 days) and 1.34 g/kg/day (28 days) respectively. No signs of toxicity or gastric
ulceration were observed (ESCOP, 2003).
Rats were used as animal species.
Ribes nigrum
leaf was administered as a lyophilizate obtained by
maceration of 100 g leaf per liter 15% ethanol. The extract was administered orally during 10 days
without specification of the dose. No change in feeding pattern, fluid consumption or body weight was
seen. Blood analysis and histopathological evaluation of 14 organs did not reveal any abnormalities
(ESCOP, 2003, Mongold 1993).
- Chronic toxicity
Feeding mice with a daily dose of 3 g/kg of dried leaves during 6 months did not reveal any toxicity
(Hänsel et al. 1994).
Assessment report on Ribes nigrum L., folium
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3.3.1.
Assessor’s overall conclusions on toxicology
No signs of major toxicity can be seen. In contrast of what could be expected from preparations able to
inhibit cyclo-oxygenase, no gastric damage could be detected.
3.4.
Overall conclusions on non-clinical data
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No clinical data available.
4.1.1.1.
Assessor’s overall conclusions on pharmacodynamics
Not applicable.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data available.
4.1.2.1.
Assessor’s overall conclusions on pharmacokinetics
Not applicable.
4.2.1.
Dose response studies
No dose response studies available.
4.2.2.
Clinical studies (case studies and clinical trials)
No clinical studies reported.
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No clinical studies in special populations reported.
4.3.
Overall conclusions on clinical pharmacology and efficacy
Not applicable.
1
In case of traditional use the long-standing use and experience should be assessed.
Assessment report on Ribes nigrum L., folium
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5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
No data collected.
5.2.
Patient exposure
No data available.
5.3.
Adverse events
No data available.
5.4.
Serious adverse events and deaths
None reported.
5.5.
Laboratory findings
None reported.
5.6.
Safety in special populations and situations
Oedema due to heart failure or renal insufficiency is mentioned as a possible contra-indication without
any further specification (Hänsel et al. 1994).
5.6.1.
Intrinsic (including elderly and children) /extrinsic factors
No data available.
5.6.2.
Drug interactions
No data available.
5.6.3.
Use in pregnancy and lactation
No data available.
No data available.
5.6.5.
Drug abuse
No data available.
5.6.6.
Withdrawal and rebound
No data available.
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5.6.7.
Effects on ability to drive or operate machinery or impairment of
mental ability
No data available.
5.7.
Overall conclusions on clinical safety
Not applicable.
6.
Overall conclusions
There is a lot of interesting experimental work done in vitro as well in vivo with preparations of
Ribes
nigrum
. The results of these studies substantiate the traditional use of blackcurrant leaves in
inflammatory conditions. There is experimental evidence for an additional analgesic activity. No signs
of general or gastro-intestinal toxicity are seen.
As a consequence the clinical perspective of
Ribes nigrum
leaves and its preparations may be
promising. Up to now clinical data are totally absent which means that the herbal drug and herbal
preparations thereof can only be considered as traditionally used.
6.1.
Benefit-risk assessment
•
Quality issues
The herbal medicinal substance is not yet described in the European Pharmacopoeia, but there are
other standard references as the quality of the raw material is concerned (French Pharmacopoeia,
Hagers Handbuch and ESCOP). By these descriptions a clear definition of the raw material can be
guaranteed. The herbal substance can be identified without too much difficulty. Moreover, there is a
characteristic smell due to the essential oil content.
•
Safety issues
There are no published reports on serious side effects when taking therapeutic doses or after
(in)voluntary intoxications with the herbal substance or herbal preparations thereof. Secondary
metabolites of
Ribes nigri
folium have a polyphenolic character and can be considered as antioxidants.
Acute or chronic preclinical toxicity investigations are no subject to any major concerns. Nevertheless,
polyphenols can be harmful in high concentrations and high daily intake in concentrated form. There is
still a need for the investigation of genotoxic, mutagenic and cancerogenic properties in order to
facilitate a list entry.
•
Therapeutic issues
The pathological conditions for which
Ribes nigri
folium is used are mostly symptomatically
approached. There are no conditions when they should be avoided. In inflammatory conditions a
symptomatic approach is made. When comparing the herbal substance with the medicines actually in
use, the effectiveness of the former is only preclinically documented. Nevertheless, the use of
Ribes
nigri
folium and preparations thereof seems safer concerning side effects, more particularly gastro-
intestinal side effects. Actually the possible therapeutic consequences of a hypothesized diuretic action
of
Ribes nigri
folium cannot be compared with the clinical significance of the actual diuretics used in
cardiovascular prevention and treatment. It is not recommendable to use the herbal substance or
preparations thereof in this therapeutic context.
2
Benefit-risk assessment. Annex to comment on concept paper benefit-risk: EMEA HMPC 2008.
Assessment report on Ribes nigrum L., folium
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There are no concerns of possible drug interactions. The use is not recommended in children and
during pregnancy and lactation. This precaution is because safety data is lacking: there are no real
indications for use in these groups at risk.
The herbal substance has been on the market for more than 30 years in some European countries. As
the plant belongs to the European fauna of the mixed climate zone and the berries have been well
Annex
List of references
3
The use of leaves has already been mentioned by Rembertus Dodonaeus in his ‘Herbarius ofte Cruydt-Boeck’, Antwerpen
1608 p. 1264.
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Source: European Medicines Agency
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