COMMUNITY HERBAL MONOGRAPH ON
PEUMUS BOLDUS
MOLINA, FOLIUM
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
Peumus boldus
Molina, folium (boldo leaf)
i)
Herbal substance
Whole or fragmented, dried leaf
ii)
Herbal preparations
Comminuted herbal substance
Dry extract (5:1, aqueous)
Well-established use
Traditional use
Herbal substance or herbal preparations for oral
use as herbal tea or 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
Traditional herbal medicinal product for
symptomatic relief of dyspepsia and mild
spasmodic disorders of the gastrointestinal tract.
The product is a traditional herbal medicinal
product for use in specified indications exclusively
based upon long-standing use.
1
The material complies with the Ph. Eur. monograph (ref. 04/2005: 1396)
2 The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal quality
guidance
Á EMEA 2009
2/5
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults and elderly
Comminuted herbal substance for tea preparation:
1–2 g of herbal substance.
To be taken 2-3 times daily.
Dry extract (5:1, aqueous): up to 400 mg 2 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
If the symptoms persist more than 2 weeks during
the use of the medicinal product, a doctor or a
qualified health care practitioner should be
consulted.
Method of administration
Oral use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Obstruction of bile duct, cholangitis, liver
disease, gallstones and any other biliary disorders
that require medical supervision and advice.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under 18
years of age is not recommended because data
are not sufficient and medical advice should be
sought.
If symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
practitioner should be consulted.
Á EMEA 2009
3/5
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 view of the pre-clinical
safety data (see section 5.3), the use during
pregnancy and lactation should be avoided.
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
Hypersensitivity (anaphylaxis) has been reported.
The frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
Á EMEA 2009
4/5
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
3
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 have been
performed with a dry ethanolic extract of boldo
leaf and boldine administered orally to pregnant
rats. Results showed anatomical alterations in the
fetus and a few cases of abortion at high doses.
Tests on genotoxicity and carcinogenicity have not
been performed with preparations of boldo leaf.
Well-established use
Traditional use
Not applicable.
14 January 2009
3
Where herbal preparations from boldo leaf are used, the total exposure to ascaridole should be considered from a safety
standpoint. The levels in herbal medicinal products should be quantified.
Á EMEA 2009
5/5
Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW .................................................................................... 3
II.
ASSESSMENT REPORT FOR
PEUMUS BOLDUS
MOLINA, FOLIUM WITH
TRADITIONAL USE ............................................................................................................................ 4
II.1
I
NTRODUCTION
......................................................................................................................... 5
II.1.1
Description of the herbal substance .................................................................................. 5
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication......................................................................................................................................... 5
II.2
N
ON
-C
LINICAL
D
ATA
................................................................................................................ 5
II.2.1
Pharmacology .................................................................................................................. 5
II.2.1.1
Overview of available data regarding boldo leaf and the major alkaloid, boldine........ 5
II.2.1.2
Assessor’s overall conclusions on pharmacology....................................................... 7
II.2.2
Pharmacokinetics ............................................................................................................. 7
II.2.2.1
Overview of available data regarding boldo leaf and the major alkaloid, boldine........ 7
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics.................................................. 8
II.2.3
Toxicology ........................................................................................................................ 8
II.2.3.1
Overview of available data regarding boldo leaf and the major alkaloid, boldine........ 8
II.2.3.2
Assessor’s overall conclusions on toxicology ............................................................ 9
II.3
C
LINICAL
D
ATA
...................................................................................................................... 10
II.3.1
Clinical Pharmacology ................................................................................................... 10
II.3.1.1
Pharmacodynamics ................................................................................................. 10
II.3.1.2
Pharmacokinetics .................................................................................................... 10
II.3.2
Clinical Efficacy ............................................................................................................. 10
II.3.2.1
Assessor’s overall conclusions on the traditional use ............................................... 12
II.3.2.2
Dose response studies duration of use...................................................................... 13
Duration of use:.......................................................................................................................... 13
II.3.2.3
Clinical studies (case studies and clinical trials)....................................................... 13
II.3.2.4
Clinical studies in special populations (e.g. elderly and children) ............................. 13
None reported............................................................................................................................. 13
II.3.2.5
Assessor’s overall conclusions on clinical efficacy .................................................. 13
II.3.3
Clinical Safety/Pharmacovigilance ................................................................................. 13
II.3.3.1
Patient exposure ...................................................................................................... 13
II.3.3.2
Adverse events........................................................................................................ 13
II.3.3.3
Serious adverse events and deaths ........................................................................... 13
II.3.3.4
Laboratory findings ................................................................................................. 13
II.3.3.5
Safety in special populations and situations ............................................................. 13
II.3.3.6
Assessor’s overall conclusions on clinical safety ..................................................... 14
II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
..................................................................................... 14
©
EMEA 2009
2/15
I. REGULATORY STATUS OVERVIEW
1
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
Comments
2
Austria
MA
TRAD
Other TRAD
Other Specify: Only combinations
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify: Only combinations
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify: Only combinations
Finland
MA
TRAD
Other TRAD
Other Specify: Only combinations
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify: Only combinations
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify: Only combinations
Ireland
MA
TRAD
Other TRAD
Other Specify: Only combinations
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify: Only combinations
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify: Only combinations
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify: Only combinations
Portugal
MA
TRAD
Other TRAD
Other Specify: Only combinations
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify: Only combinations
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify: Only combinations
United Kingdom
MA
TRAD
Other TRAD
Other Specify: Only combinations
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
©
EMEA 2009
3/15
II.
ASSESSMENT REPORT FOR
PEUMUS BOLDUS
MOLINA, FOLIUM WITH
TRADITIONAL 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)
Peumus boldus
Molina, folium
(Whole or fragmented, dried leaf)
Herbal preparation(s)
Comminuted herbal substance
Dry extract (5:1, aqueous)
Pharmaceutical forms
Herbal substance or herbal preparations for oral use as
herbal tea or in solid dosage forms.
Rapporteur
Linda Anderson
©
EMEA 2009
4/15
II.1
I
NTRODUCTION
II.1.1
Description of the herbal substance
Boldo leaf
(Boldi folium) consists of the
whole or fragmented dried leaf of
Peumus boldus
Molina. It contains not less than 0.1% of total alkaloids, expressed as boldine
(C
19
H
21
NO
4
=327.4), calculated with reference to the anhydrous drug. [European
Pharmacopoeia]
Boldo leaf contains 2-4% of volatile oil. Major constituents reported as: ascaridole (16-38%),
1,8 cineole (11-39%) and
p
-cymene (9-29%) (Bradley, 2006).
Ascaridole is highly toxic (see Section II.2.3.1) and this raises concerns about the suitability
of boldo leaf in traditional herbal medicinal products.
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
Peumus boldus
Molina (Monimiaceae) is an evergreen shrub or small tree indigenous to
Chile and Peru. A detailed review on the pharmacognosy of
P. boldus
has been given by
Schindler (Schindler, 1957).
The dried leaves have been reported in medicinal usage since the 19
th
century in South
America against diseases of the liver and gallstones. In 1870, the leaves of
Peumus boldus
are
reported to have been introduced in Europe and first described by Bourgoin and Verne
(Lanhers
et al
., 1991).
Pharmacognostical texts, pharmacopoeias and handbooks list the therapeutic uses as
cholagogue, choleretic, digestive disturbances, diuretic, hepatic stimulant, stomachic,
sedative and anthelmintic (Grieve, 1931; British Herbal Compendium, 1992;
British Herbal
Pharmacopoeia, 1976; British Pharmaceutical Codex, 1934; The Complete German
Commission E Monographs, 1998; ESCOP, 2003; Hansel, 1991; Martindale Extra
Pharmacopoeia, 1924; Potter’s New Cyclopedia 1973; Benedum
et al,
2006). Boldo leaf has
also been reported as used for the treatment of headache, earache, toothache, rheumatism and
urinary tract inflammation (Spiesky and Cassels 1994).
Cholagogues and choleretics are well known in traditional herbal medicine: cholagogues are
reported to stimulate the release of bile that has already formed in the biliary system whilst
choleretics stimulate bile production by hepatocytes (Mills and Bone, 2000; Schulz
et al.,
1998).
II.2
N
ON
-C
LINICAL
D
ATA
II.2.1
Pharmacology
II.2.1.1
Overview of available data regarding boldo leaf and the major alkaloid, boldine.
Constituents
(Barnes
et al
., 2007; Bradley, 2006; ESCOP, 2003; Leung, 1996; Wichtl, 2004)
Alkaloids
Isoquinoline-type 0.25-0.7%. Boldine, isoboldine, 6a,7-dehydroboldine, isocorydine,
isocorydine-
N
-oxide, norisocorydine, laurolitsine, laurotetanine, N-methyllaurotetanine,
reticuline, (-)-pronuciferine, sinoacutine.
Boldine is usually the major alkaloid (reported as 14-36% of total alkaloids). However, some
sources of leaf are reported to have boldine as a minor alkaloid (0.28-0.32% total alkaloids)
(Bradley, 2006).
©
EMEA 2009
5/15
Flavonoids
:
flavonols (e.g. isorhamnetin) and their glycosides.
Volatile oil
:
2.0-2.6% (Vogel
et al
1999). Major constituents reported as: ascaridole
(16-38%), 1,8 cineole (11-39%) and
p
-cymene (9-29%) (Bradley, 2006).
Vogel
et al.
1999 have shown that the principal components of the oil are determined
genetically and have reported levels: ascaridole (34.6%),
p
-cymene (3.9%), 1,8-cineole
(0.5%). Other constituents include:
α
α
-terpineol and methyl eugenol (Opdyke, 1982).
Other constituents
: coumarin, resin, tannin.
Choleretic effects – studies with boldo leaf extracts
Early studies in rats have reported choleretic effects with extracts of boldo (full details not
available) (Bohm, 1959; Pirtkien
et al
., 1960; Borkowski
et al
., 1966; Levy-Appert-Collin
and Levy, 1977).
Subsequent experiments in rats, however, failed to demonstrate choleretic activity after oral
administration of 400 or 800 mg/kg aqueous ethanolic extract, intraduodenal administration
of 200 or 800 mg/kg, or after intravenous administration of a dry ethanolic extract (4:1)
corresponding to boldo leaf at 125- 500 mg/kg (Lanhers
et al
., 1991).
Laxative effect: studies with boldo leaf extracts
A laxative effect has been reported in rats following oral administration of a hydroethanolic
extract at 400 or 800 mg/kg daily for 8 weeks (Magistretti, 1980).
Spasmolytic effect: studies with boldine
Boldine had a concentration-dependent smooth muscle relaxing effect on the acetylcholine-
induced contraction of isolated rat ileum via a competitive antagonist mechanism (Speisky
et
al
., 1991a).
Antioxidant activity: studies with boldo leaf extracts and boldine
A large number of studies have been carried out on boldo extracts and isolated boldine
showing potent free radical-scavenger and antioxidant activity. These studies have been
reviewed in detail (O’Brien
et al.,
2006).
A hydroethanolic extract (corresponding to 0.5 and 1 mg of dried leaf per ml) and boldine
(33 µg/ml) showed a hepatoprotective effect against
tert
-butyl hydroperoxide-induced
hepatotoxicity in isolated rat hepatocytes (Lanhers
et al
., 1991).
Antioxidant activity: studies with boldine
Boldine inhibited rat liver microsomal lipid peroxidation by 50% at a concentration of
0.015 mM (Cederbaum
et al
., 1992).
Boldine inhibited the peroxidative (accumulation of thiobarbituric acid reactive substances)
and lytic damage (trypan blue exclusion and lactate dehydrogenase leakage) to isolated rat
hepatocytes induced by
tert
-butyl hydroperoxide (Bannach
et al
., 1996).
Boldine concentration-dependently prevented the haemolytic damage induced by the free
radical initiator 2,2’-azobis-(2-amidinopropane)(AAPH) (Jimenez
et al
., 2000).
Boldine reduced the lethal effect induced by stannous chloride on the survival of
Escherichia
coli
cultures. In addition, the structural confirmation of the plasmid pUC 9.1 was not
©
EMEA 2009
6/15
-pinene, camphene, β-pinene, sabinene, ∆
3
-carene,
terpinolene, limonene, γ-terpinene, , 2-nonanone, fenchone, 1-methyl-4-isopropenylbenzene,
camphor, , α-fenchol, terpinen-4-ol,
modified by stannous chloride in the presence of boldine. These effects were considered to be
due to the antioxidant activity of boldine (Reiniger
et al
., 1999).
The antioxidant properties of boldine have been demonstrated by the prevention of rat brain
homogenate autoxidation, the 2,2’-azobis-(2-amidinopropane)(AAPH)-induced lipid
peroxidation of red cell plasma membranes and the AAP-induced inactivation of lysozyme.
These results indicate that boldine acts as an antioxidant in biological systems susceptible to
free radical-mediated reactions (Speisky
et al
., 1991b).
Boldine prevented the ferric-ATP catalysed peroxidation of human liver microsomes and
inactivation of cytochrome P450E1 (Kringstein and Cederbaum, 1995).
Anti-inflammatory effects: studies with boldo extracts
An aqueous alcoholic extract showed anti-inflammatory activity in the rat-paw carrageenann-
induced oedema test following intraperitoneal administration but boldine was negative in the
test at doses of 10 and 20 mg/kg (Lanhers
et al
., 1991, 1992).
Anti-inflammatory effects: studies with boldine
Oral administration of boldine was shown to exhibit a dose-dependent anti-inflammatory
activity in the rat-paw carrageenann-induced oedema test with an ED
50
of 34 mg/kg
(Backhouse
et al
., 1994).
Intrarectal administration of boldine (100 mg/kg) to rats with colitis resulted in significantly
reduced colonic neutrophil infiltration. Boldine also protected against acid-induced oedema
as shown by decreased total colon weight (Gotteland
et al
., 1997).
Antipyretic effects: studies with boldine
Oral administration of boldine (60 mg/kg) was shown to reduce bacterial pyrogen-induced
hyperthermia in rabbit (Backhouse
et al
., 1994).
II.2.1.2
Assessor’s overall conclusions on pharmacology
Most investigations have been carried out using the isolated alkaloid, boldine. Limited
information is available on herbal preparations of boldo leaf and where studies have been
reported, details of the preparations are usually lacking. The choleretic effects of boldo leaf
have not been confirmed.
II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data regarding boldo leaf and the major alkaloid, boldine.
Studies with boldo extracts
Boldine was found in the urine of rats after oral administration of a hydroethanolic extract
(no further details recorded) of boldo at 400 and 800 mg/kg (Magistretti, 1980)
.
Studies with boldine
In vitro experiments
Addition of boldine at 200 µM to a suspension of isolated rat hepatocytes was followed by a
time-dependent disappearance of boldine from the extracellular medium and accumulation
within the cells. Boldine was also concentration-dependently removed from the extracellular
medium when boldine was portally perfused through isolated rat livers
(Jimenez and Spiesky, 2000).
©
EMEA 2009
7/15
In vivo experiments
Absorption of boldine was rapid following oral administration to rats at 25, 50 or 75 mg/kg
with maximum plasma concentration reached within 15-30 minutes. Boldine was found to be
preferentially concentrated in the liver (Jimenez and Spiesky, 2000).
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics
Limited data are available on pharmacokinetics.
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding boldo leaf and the major alkaloid, boldine
Single/repeat dose toxicity: studies with boldo extracts
Oral administration of a hydroethanolic extract (no further details recorded) of boldo to rats
in single doses up to 3 g/kg body weight caused no deaths or toxic symptoms (Magistretti,
1980).
The intraperitoneal LD
50
in mice of an ethanolic extract of boldo (80%; no further details
recorded) was found to be equivalent to 6 g/kg (Levy-Appert-Collin and Levy, 1977).
Oral administration of a dry ethanolic extract of boldo (92.8%; no further details recorded)
or of boldine to rats daily for 90 days at 200 mg/kg/day caused significant reductions in blood
levels of cholesterol, aspartate aminotransferase (AST), total bilirubin, glucose and urea,
although cholesterol and AST were raised after 30 and 60 days. There were no significant
changes in creatinine levels. Doses of 50 mg/kg/day did not produce any significant changes
over the 90-day period. Neither the boldo extract nor boldine caused any overt signs of
toxicity in the heart or kidneys but steatosis was observed in two animals at doses of
800 mg/kg (De Almeida
et al
., 2000).
Single/repeat dose toxicity: studies with boldine/total alkaloids
When boldine was administered orally, doses of 500 and 1000 mg/kg were required to cause
death of mice and guinea pigs, respectively (Kreitmar, 1952).
The intraperitoneal LD
50
values of total alkaloids and of boldine in mice were reported to be
420 and 250 mg/kg, respectively (Levy-Appert-Collin and Levy, 1977).
Total alkaloids from boldo administered by sub-cutaneous injection to dogs produced
vomiting, diarrhoea and epileptic symptoms with recovery after 50 minutes (Kreitmar, 1952).
Genotoxicity: studies with boldo extracts
No studies were located using herbal preparations of boldo leaf.
Genotoxicity: studies with boldine
Boldine did not show genotoxic activity in the SOS chromotest with
Escherichia coli
or in
the Ames test using
Salmonella typhimurium
strains TA100, TA98 and TA102. Furthermore,
it did not induce point and frameshift mutations in haploid
Saccharomyces cerevisiae
cells.
Boldine did, however, induce mitotic recombinational events in diploid yeast cells and
cytoplasmic ‘petite’ mutation in haploid yeast cells (Moreno
et al
., 1991).
Boldine did not induce a statistically significant increase in the frequency of chromosome
aberrations or sister-chromatid exchanges when tested
in vitro
on human peripheral blood
lymphocytes or
in vivo
using mouse bone marrow cells (Tavares and Takahashi, 1994).
Boldine administered intra-peritoneally at sub-lethal doses induced no signs of genotoxicity
in mouse bone marrow as assessed by the micronucleus test (Spiesky and Cassels, 1994).
©
EMEA 2009
8/15
Carcinogenicity
No studies were located using herbal preparations of boldo leaf or boldine.
Reproductive and development toxicity: studies with boldo extracts and boldine
Pregnant rats treated orally with a dry ethanolic extract of boldo (92.8%; no further details
recorded) or with boldine at 500 or 800 mg/kg body weight on days 1-5 or days 7-12 of
pregnancy showed anatomical alterations in the fetus at the higher dose. Incidents of
blastocystotoxic-antizygotic action and a few cases of abortion were also observed in both
treated groups at 800 mg/kg body weight. Daily doses of 500 mg/kg body weight did not
produce teratogenic or abortifacient activity but reduced fetal weight by 28-40%. The authors
concluded at 800 mg/kg/day the boldo extract and boldine had adverse effects at the
beginning of egg production and also during implantation (De Almeida
et al
., 2000).
Toxicity of boldo leaf volatile oil
Boldo leaf is reported to contain 2-4% of volatile oil. The major components are ascaridole
(16-38%), 1,8 cineole (11-39%) and
p
-cymene (9-29%) (Bradley, 2006).
Boldo leaf oil is stated to be one of the most toxic oils due to the presence of ascaridole
(Tisserand, 1995) and the oil should not be used internally or externally.
Ascaridole is a bicyclic monoterpene with a bridging peroxide functional group. It is the main
constituent (90%) of Chenopodium oil (
Chenopodium ambrosioides
L
.
, American Wormseed
oil) and renders this oil one of the most toxic known. Chenopodium oil has been used in the
past as an anthelmintic but has been superseded by safer treatments. The anthelmintic activity
is due to the ascaridole content.
Acute toxicity boldo oil
An acute oral LD
50
value for boldo oil has been given as 0.13 g/kg body weight in rats, with
doses of 0.07 g/kg causing convulsions (Opdyke, 1982). The acute dermal LD
50
in rabbits
was between 0.625 and 1.25 g/kg.
Toxicity of Chenopodium oil
Human toxicity and fatal poisoning have been reported with Chenopodium oil (Opydyke
1982). Toxic effects include skin and mucous membrane irritation, headache, vertigo, nausea,
vomiting, constipation, tinnitus, temporary deafness, diplopia and blindness, transient
stimulation followed by depression of the CNS leading to delirium and coma, occasional
convulsions, circulatory collapse due to vasomotor paralysis and sometimes pulmonary
oedema. Chenopodium oil is also toxic to the kidneys, liver and haematuria, albuminuria and
jaundice have been observed. Several cases of fatal poisoning have been reported in children.
In view of the known toxicity, boldo oil should not be used internally or externally. Where
boldo leaf is used, the total exposure to ascaridole should be considered from a safety
standpoint. The levels in herbal preparations and herbal medicinal products should be
quantified.
II.2.3.2
Assessor’s overall conclusions on toxicology
Most investigations have been carried out using boldine. Limited information is available on
herbal preparations of boldo leaf and where studies have been reported, details of the
preparations are usually lacking. There are no reported genotoxicity or carcinogenicity
studies with herbal preparations of boldo leaf. Abortifacient and teratogenic effects in rats
were observed with high doses of a dry ethanolic extract and boldine.
©
EMEA 2009
9/15
In view of the known toxicity, boldo oil should not be used internally or externally. Where
boldo leaf is used, the total exposure to ascaridole should be considered from a safety
standpoint. The levels in herbal medicinal products should be quantified. No data was
located comparing levels of ascaridole in preparations derived from boldo leaf. In view of the
low solubility of ascaridole in water the use of aqueous extracts including herbal tea could be
accepted. However, the levels of ascaridole in the herbal preparations and herbal medicinal
products should be quantified. The use of ethanolic extracts of boldo leaf is not considered
acceptable for traditional herbal medicinal products in view of the potentially higher levels
of the toxic ascaridole constituent.
II.3
C
LINICAL
D
ATA
II.3.1
Clinical Pharmacology
No data available.
II.3.1.1
Pharmacodynamics
Twelve healthy volunteers treated daily with either 2.5 g of a dry extract of boldo (ethanol
60% v/v) containing 0.4% of total alkaloids and 0.12% of boldine showed prolongation of
intestinal transit time compared to placebo (Gotteland
et al
., 1995).
Assessor’s overall conclusions on pharmacodynamics
Due to lack of data no conclusions can be drawn
.
II.3.1.2
Pharmacokinetics
No data available.
Assessor’s overall conclusions on pharmacokinetics
Due to lack of data no conclusions can be drawn.
II.3.2
Clinical Efficacy
No clinical studies were located with mono-preparations containing boldo. Therefore it is
concluded that there are no data to support boldo as a well-established medicinal product
with recognised efficacy and acceptable safety.
The following traditional uses have been recorded for boldo leaf:
A Modern Herbal
(Grieve, 1931)
Medicinal action and uses: Tonic, antiseptic, stimulant. Useful in chronic hepatic torpor. The
oil in 5-drop doses has been found useful in genitor-urinary inflammation. Tincture of boldo
used as a diuretic.
Dosage
: Tincture of boldo BPC, 10-40 minims (0.6-2.4 ml).
Duration of use
: No information.
The Complete German Commission E Monographs
( Blumenthal, 1998).
Mild spasmodic disorders of gastrointestinal tract; dyspeptic complaints.
Daily oral dose:
3 g. Equivalent
amount of preparations.
Duration of use:
No information.
Herbal Medicine
.
Expanded Commission E Monographs (
Blumenthal, 2000).
Dosage:
Unless otherwise prescribed: 3 g per day of cut herb.
Infusion: 3 g in 150 ml water. Fluid extract 1:1 (g/ml): 3 ml. Tincture 1:5 (g/ml): 15 ml.
Duration of use:
No information.
©
EMEA 2009
10/15
British Herbal Compendium
(Bradley, 1992)
Actions: Choleretic, liver stimulant, hepatoprotective, anti-inflammatory, mildly laxative,
antimicrobial. Increases secretion of gastric juice and stated to be diuretic, urinary tract
antiseptic and sedative.
Traditional uses: Mild spasmodic disorders of the gastrointestinal tract, especially functional
disorders of the bile duct, gall-stones, liver or gall bladder pains, dyspeptic complaints,
urinary tract inflammation including cystitis, rheumatism.
Dosage:
British Herbal Pharmacopoeia
: Three times daily: dried leaf, 60-200 mg, or as an infusion;
liquid extract (1:1 in 45% alcohol) 0.1-0.3 ml; tincture (1:10 in 60% alcohol) 0.5 – 2 ml.
Germany
: Daily dose: dried leaf 3 g; 1-2 g as infusion in 150 ml water 2-3 times daily.
British Herbal Pharmacopoeia
(1976)
Gall-stones, Pain in liver or gall bladder. Cystitis. Rheumatism. Specific: Cholelithiasis with
pain.
Dosage:
(3 times daily): 0.25-1 g (powder or infusion); 0.5-1 ml liquid extract (1:1 in 25%
alcohol); 0.5-2 ml tincture (1:8 in 45% alcohol).
Duration of use:
No information.
British Pharmaceutical Codex
(1934)
Boldo possesses diuretic and stimulant properties. Leaves are employed in Chile and other
South American countries for chronic hepatic congestion and as an aromatic tonic and
diuretic in gonorrhoea, and in cystitis and other bladder affections. Boldo leaf is principally
used as a diuretic and supposed liver stimulant.
Dosage
: Tincture of boldo 1:10 in 60% alcohol, 0.6-2 ml.
Duration of use:
No information.
Encyclopedia of common natural ingredients
(Leung, 1980)
Reported to have choleretic, diuretic, stomachic and cholagogic properties.
Daily oral dose:
No information.
Duration of use
: No information.
ESCOP Monograph
(2003)
Minor hepatobiliary dysfunction, symptomatic treatment of digestive disturbances.
Daily dose:
2-5 g of the drug as a tea infusion.
0.2-0.6 g of the drug or equivalent hydroethanolic extract.
Tincture (1:5, ethanol 80% v/v) 1-3 ml.
Fluid extract (1:1 ethanol 80% v/v) 0.5-1 ml.
Duration of use:
not more than 4 weeks.
Médicaments à base de plantes
(Ministère de la Santé et de L’action Humanitaire, 1990)
Traditionally used to facilitate urinary and digestive elimination functions. Traditionally used
as a choleretic or cholagogue.
Daily oral dose:
No information.
Duration of use
: No information.
French Pharmacopoeia
8
th
edition 1965; 9
th
edition 1979
Boldo tincture (1:5, ethanol 80% v/v) 1-3 ml.
Fluid extract (1:1 ethanol 80% v/v) 0.5-1 ml
.
Handbook of Medicinal Herbs
(Duke, 2002)
Leaves used as a mild diuretic especially in liver complaints like jaundice. Also stated to be
anodyne, antiseptic, choleretic, hepatotonic, hypnotic, stimulant, tonic and vermifuge. Used
for dyspepsia, gout, hepatosis, rheumatism, syphilis and worms. Infusion of leaves used for
stomach and liver troubles.
Daily oral dose:
2 – 8 g.
Duration of use:
No information.
©
EMEA 2009
11/15
Herbal Drugs and Phytopharmaceuticals
(Wichtl, 2004)
Primarily used as a cholagogue.
Daily dose
: 1-2 g as infusion in 150 ml water 2-3 times daily.
Duration of use:
No information.
Herbal Medicines. A guide for healthcare professionals
(Barnes
et al
., 2007)
Stated to possess cholagogue, liver stimulant, sedative, diuretic, mild urinary demulcent, and
antiseptic properties. Used for mild digestive disturbances, constipation, gall-stones, pain in
liver or gall bladder, cystitis, rheumatism and specifically cholelithiasis with pain.
Martindale Extra Pharmacopoeia
(1924)
For dyspepsia, liver affections, rheumatism and as a diuretic for atony of the bladder.
Dosage
: Dried leaf: 0.06-0.18 g; Tincture (1 in 5) 90% alcohol: 0.6 –1.2 ml.
Duration of use:
No information.
Martindale Extra Pharmacopoeia
(1941)
For dyspepsia, liver affections, rheumatism and as a diuretic for atony of the bladder.
Dosage:
Dried leaf: 0.06-0.18 g; Tincture (1 in 10) 60% alcohol: 0.6 – 2 ml.
Duration of use:
No information.
Martindale Extra Pharmacopoeia
(1967)
Boldo is employed in herbal medicine as a diuretic, for hepato-biliary disorders and for
gastrointestinal disorders such as constipation.
Dosage
: Single dose: liquid extract (1 in 1): 0.5-1 ml; tincture (1 in 5): 0.5-2 ml.
Duration of use:
No information.
Potter’s New Cyclopedia of Botanical Drugs and Preparations
(1973)
Boldo is used as a cholagogue, liver stimulant and diuretic; used for the treatment of gall-
stones and cystitis and as an aid to slimming.
Dosage
: Liquid extract (1:1) 0.5 – 2ml.
Duration of use
: No information.
II.3.2.1
Assessor’s overall conclusions on the traditional use
Traditional medicinal use of,
Peumus boldus
Molina leaf, in the form of powdered herbal
drug, herbal tea or ethanolic extracts is well documented in a number of bibliographic sources
for mild digestive disturbances which would be suitable for self- medication. The
requirement of medicinal use for at least 30 years (including at least 15 years within the
Community) according to Directive 2004/24/EC is considered fulfilled.
The following indication, in accordance with the Commission E monograph is considered
acceptable for traditional registration subject to appropriate contra-indications, warnings etc.:
Traditional herbal medicinal product for symptomatic relief of dyspepsia and mild spasmodic
disorders of the gastrointestinal tract.
In view of the potential presence in herbal preparations and herbal medicinal products of the
toxic ascaridole constituent, only herbal teas and aqueous extracts are considered acceptable.
However, the levels of ascaridole in the herbal preparations and herbal medicinal products
should be quantified.
The use of ethanolic extracts of boldo leaf is not considered acceptable for traditional herbal
medicinal products in view of the potentially higher levels of the toxic ascaridole constituent.
©
EMEA 2009
12/15
II.3.2.2
Dose response studies/duration of use
There are no dose response studies available.
Duration of use:
Limited information is available. Continuous long-term use is not recommended in some
sources (Hansel, 1991; Blumenthal, 2000). Based on the German Commission E monograph,
boldo leaf preparations should not be taken for more than 2 weeks. If the symptoms persist
for more than 2 weeks, a doctor or a qualified health care practitioner should b
e
consulted.
II.3.2.3
Clinical studies (case studies and clinical trials)
There are no studies reported with single ingredient products containing boldo leaf.
II.3.2.4
Clinical studies in special populations (e.g. elderly and children)
None reported.
II.3.2.5
Assessor’s overall conclusions on clinical efficacy
There are no clinical investigations with single ingredient products containing boldo leaf.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
No data available.
II.3.3.2
Adverse events
No data available.
II.3.3.3
Serious adverse events and deaths
None reported.
See II.3.3.5.1.
II.3.3.4
Laboratory findings
No data available.
II.3.3.5
Safety in special populations and situations
No data available.
Use in children and adolescents is not recommended because data are not
sufficient and medical advice should be sought.
Boldo leaf is contraindicated where there is obstruction of the bile duct, severe liver diseases.
Medical advice is recommended in cases of gall-stones (Blumenthal, 2000; ESCOP, 2003).
II.3.3.5.1 Intrinsic (including elderly and children) /extrinsic factors
Limited data available. One case report of anaphylaxis following intake of a boldo leaf
infusion has been located (Monzon
et al
., 2004). The patient, who had a history of allergic
rhinoconjunctivitis related to grass pollen suffered an acute and generalized urticaria, facial
angioedema, dysphagia, dysphonia and dyspnea. The reaction was confirmed by positive
oral challenge. Hypersensitivity to boldo leaf should be included as a contraindication.
©
EMEA 2009
13/15
II.3.3.5.2 Drug interactions
Limited data available. A single case report has been located of a potential interaction
between warfarin and two herbal products resulting in an increase in INR (Lambert and
Cormier, 2001). The herbal products were a liquid preparation of boldo leaf (no details
provided) and capsules containing Fenugreek (no details provided). The INR returned to
normal once the patient stopped taking the herbal products. No information is available using
the individual products thus it is not possible to conclude if only one or both products
contributed to the increased bleeding time.
II.3.3.5.3 Use in pregnancy and lactation
No data available. Most sources recommend contra-indication in pregnancy and lactation.
Tests on reproductive toxicity have been performed with a dry ethanolic extract of boldo leaf
and boldine administered orally to pregnant rats. Results showed anatomical alterations in the
fetus and a few cases of abortion at high doses (see section II.2.3.1).
Safety during pregnancy and lactation has not been established. In view of the findings in the
studies on reproductive toxicity , use during pregnancy and lactation should be avoided.
II.3.3.5.4 Overdose
Limited data available. One source reports emetic effect and spasms with very high doses
(Braun, 1981).
II.3.3.5.5 Drug abuse
No data available.
II.3.3.5.6 Withdrawal and rebound
No data available.
II.3.3.5.7 Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
II.3.3.6
Assessor’s overall conclusions on clinical safety
Limited data are available. Use in children and adolescents is not recommended because the
available data are not sufficient and medical advice should be sought. boldo leaf should be
avoided during pregnancy or lactation. Use is contraindicated where there is obstruction of
the bile duct, cholangitis, or liver disease. Medical advice is needed in cases of gall-stones or
other biliary disorders. Duration of use should be limited to 2 weeks and if symptoms persist
medical advice should be sought.
II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
Sufficient data are available to develop a Community herbal monograph on the traditional use
of
Peumus boldus
Molina
,
folium provided the indications are suitable for self-medication.
The proposed indications are in accordance with the Commission E monograph (Blumenthal,
2000):
Traditional herbal medicinal product for symptomatic relief of dyspepsia and mild spasmodic
disorders of the gastrointestinal tract.
Duration of use should be limited to 2 weeks.
Use of boldo leaf is not recommended in children and adolescents and should be avoided
during pregnancy and lactation. Boldo leaf is contra-indicated where there is obstruction of
©
EMEA 2009
14/15
the bile duct, cholangitis liver disease, gallstones or any other biliary disorder that would
require medical supervision.
The use of comminuted herbal substance as such and of ethanolic extracts of boldo leaf are
not considered acceptable for traditional herbal medicinal products in view of the potential
risks associated with the toxic ascaridole constituent.
As the minimum required data on mutagenicity (Ames’ test) are not available for herbal
preparations of boldo leaf, an inclusion to the Community list of herbal substances,
preparations and combinations thereof for use in traditional herbal medicinal products is not
recommended.
©
EMEA 2009
15/15
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/boldi_folium_herbal.html
Copyright © 1995-2021 ITA all rights reserved.