Aesculus – Horse-chestnut bark (Hippocastani cortex)

Latin name of the genus:Aesculus
Latin name of herbal substance:Hippocastani cortex
Botanical name of plant:Aesculus hippocastanum l.
English common name of herbal substance:Horse-chestnut bark
1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
Loading...

Latin name of the genus: Aesculus
Latin name of herbal substance: Hippocastani cortex
Botanical name of plant: Aesculus hippocastanum L.
English common name of herbal substance: Horse-chestnut bark

Aesculus - Horse-chestnut bark - Aesculus hippocastanum L.

Table of Contents

1. Introduction

The aim of this report is to assess the available preclinical and clinical data on Hippocastani cortex (horse chestnut bark) for preparing a Community herbal monograph.

1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof

Herbal substance(s)

Horse chestnut bark. The bark is obtained from the young branches and dried.

The composition of horse chesnut bark is complex. The most characteristic compounds are coumarin derivatives (up to 7%) (Wichtl et al. 2003):

– Glucosides:

Esculin (6-(β-D-glucopyranosyloxy)-7-hydroxy-2H-1-benzopyran-2-one, or 6,7- dihydroxycoumarin 6-glucoside), a glucoside of esculetin (6,7-dihydroxy-2H-1-benzopyran-2- one, or 6,7-dihydroxycoumarin).

Fraxin (8-(β-D-glucopyranosyloxy)-7-hydroxy-6-methoxy-2H-1-benzopyran-2-one, or 7,8- dihydroxy-6-methoxycoumarin-8-β-D-glucoside), a glucoside of fraxetin (7,8-dihydroxy-6- methoxy-2H-1-benzopyran-2-one, or 7,8-dihydroxy-6-methoxycoumarin);

Scopolin (7-(β-D-glucopyranosyloxy)-6-methoxy-2H-1-benzopyran-2-one), a glucoside of scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one, or 7-hydroxy-6-methoxy- coumarin)

– Aglycones: esculetin, fraxetin and scopoletin

Other constituents are: tannins (up to 2 %) (Fournier 1948; Paris & Moyse 1981), flavonoids, anthocyanins (Bombardelli et al. 1996, catechins derivatives (Bombardelli et al. 1996; Wichtl et al. 2003), traces of aescin (Wichtl et al. 2003; Schneider 1978).

Herbal preparation(s) Powdered herbal substance

Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.

Not applicable

1.2. Information about products on the market in the Member States

Horse chestnut bark as single herbal substance is authorised in France, Poland and Spain.

The active substance is present on the market as:

Herbal substance

Dried bark for decoction preparation for cutaneous use (Poland, over 15 years).

Herbal preparation

Powder (France, 1982; Spain, 1991).

Dry extract (solvent water, DER 5-6:1) (France, 1994).

Regulatory status overview

MA: Marketing Authorisation TRAD: Traditional Use Registration

Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’

This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.

1.3. Search and assessment methodology

Online database were used to research available pharmaceutical, non-clinical and clinical data on horse chestnut bark or its relevant constituents.

2. Historical data on medicinal use

2.1. Information on period of medicinal use in the Community

Aesculus hippocastanum L. belongs to the Hippocastanaceae family. Native to Western India, today the horse chestnut is widely distributed all over the world and it grows in Iran, Northern India, Asia Minor, Europe and USA (Bombardelli et al. 1996). It is a 25-30 m high tree (Bézanger-Beauquesne et al.

1980). Different plant parts have been used, only the bark is described in this assessment report.

Horse chestnut bark has been traditionally used for the capillary weakness and the venous system (varicose veins and haemorrhoids) (Bézanger-Beauquesne et al. 1975).

It was described for the first time in 1565 by Mathiole and it appeared in France in 1615. During the 18th century, it spread into most parts of Europe (Bombardelli et al. 1996; Fournier 1948; Leclerc 1976).

It was used in 1720 as febrifuge, as substitute for cinchona and as astringent for diarrhoea. It was used for external use in decoction (50 g/1000 g) as antiseptic for ulcers and gangrenous wounds (Fournier 1948).

The bark has been used (Fournier 1948):

as tonic: as decoction (30 to 50 g/l, 1 to 2 cups a day) or as powder (1 to 4 g)

as febrifuge: powder: 15 to 50 g

for haemorrhoids: medicinal wine: 30 to 60 g/l of white wine; tincture 250 g/l of alcohol (1 tablespoon /day)

Horse chestnut bark was mentioned in the French Pharmacopoeia in 1866.

2.2. Information on traditional/current indications and specified substances/preparations

The current indications are:

– In France [Cahiers de l’Agence n°3 (AFSSAPS 1998)]:

Traditionally used in the symptomatic treatment of functional disorders of cutaneous capillary fragility, such as ecchymosis, petechias, etc.

Traditionally used in subjective signs of venous insufficiency, such as heavy legs.

Traditionally used in haemorrhoidal symptoms.

– In Spain:

Relief of symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.

Relief of the symptoms associated with haemorrhoids.

– In Poland:

Adjuvant in oedemas, small bruises, limited skin and subcutaneous tissue inflammations.

2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications

Posology for “traditional herbal medicines”:

Oral use:

Powder: 300 mg 2 times daily (Spain)

275 mg 3-6 capsules (= 1650 mg) daily, if necessary (France)

Dry extract (solvent water, DER 5-6: 1): 200 mg of extract 2 times daily

Cutaneous use:

Warm compresses (decoction 4 g in 400-500 ml of water) (Poland)

3. Non-Clinical Data

Non-clinical strategy

Online databases were used to research the available non-clinical data on extract of bark of horse chestnut or its relevant constituents. Only few articles about the non-clinical properties (pharmacology, pharmacokinetics, toxicology) of ‘horse chestnut bark extract’ were found in Medline.

3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

Pharmacodynamics

The main pharmacological activity of horse chestnut bark is its venotonic activity (Leung & Foster 1996; Fleurentin 2008). It can increase the vascular resistance and decrease the capillary permeability (Fleurentin 2008; Ollier 2000; Girre 1997; Bézanger-Beauquesne et al. 1980). It is also reported to have an anti-inflammatory activity (Leung & Foster 1996).

The pharmacodynamic properties of horse chestnut bark extract or some of its constituents were investigated in the published literature (see Table 1).

Table 1: Summary of pharmacodynamics studies

Additionally, data from reviews are also available:

Bombardelli published a review in 1996 where pharmacological properties of some of horse chesnut extract constituents were extensively reported.

Proanthocyanidin A2 exerts a venotonic activity normalising conditions of impaired capillary permeability and fragility. It increased capillary resistance in comparison to control and trihydroxyethylrutoside-treated rats.

Proanthocyanidin A2 was demonstrated to stimulate the processes of healing; it had a stimulating activity on the healing process by measurement of wound scar resistance in mice. It also showed wound healing activity in prednisone-treated rats after a topical or oral administration.

It also has antioxidant and antienzymatic activity. In vitro, it was able to inhibit all the stages of the peroxidative phenomenon in a dose-dependent manner. It inhibited the activity of some proteolytic enzymes (β-glucuronidase, elastase, collagenase) (Bombardelli et al. 1996).

Esculin has vasoprotective effects. It improves capillary permeability and capillary fragility. The capillary resistance was increased in guinea pigs treated with 1 mg/day of esculin compared to those on a diet of gray oats plus ascorbic acid.

It inhibits enzymes like hyaluronidase and collagenase.

In mice and rats, esculin and esculetin showed analgesic and antipyretic activities. Esculin also possesses an anti-inflammatory activity in the UV-induced erythema in animals and humans (Bombardelli et al. 1996).

Esculetin is known as a 5-lipoxygenase inhibitor that inhibits the production of leukotrienes and 5- hydroxyeicosatetraeinoic acid through lipoxygenase pathway. It shows scavenging activity against ROS and inhibits lipoperoxidation in rat liver (Kaneko et al. 2003).

Esculetin and esculin in a lesser extent exhibited suppressive effect on the formation of 8- oxodeoxyguanosine (8-oxodG) (Kaneko et al. 2003).

Safety pharmacology

No data about safety pharmacology are available.

Herb-Drug interactions

Herbs with coumarins, salicylate or with antiplatelet properties are suspected to potentially interfere with warfarin because of a theoretical risk of potentiation of anticoagulant activity. No direct experimental or clinical evidence is available. However, it has been recommended that patients taking horse chestnut extracts concurrently with medications that have anticoagulant effects, such as warfarin, should be closely monitored for signs of symptoms of bleeding (Heck et al. 2000).

No clinical cases have been reported.

3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

No information about pharmacokinetics of horse chestnut bark extract is available.

3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof

Acute toxicity

Acute toxicity of esculetin (6,7-dihydroxycoumarin) extracted from the bark of Aesculus hippocastanum was tested in mouse after an intraperitoneal and oral administration. The intraperitoneal LD50 was 1450 mg/kg and the oral LD50 was > 2000 mg/kg (Tubaro et al. 1988). Acute toxicity of esculin was tested intraperitoneally in mice. The LD50 was 1900 mg/kg (RTECS 2010).

Repeat toxicity

No data available.

Genotoxicity

Esculin was screened on 6 Ames strains (TA92, TA94, TA97, TA98, TA100 and TA102) at 4 concentrations ranging from 0.2 to 500 µg/plate with or without S9. It was not mutagenic (Uwaifo 1984).

It should be pointed out that, in the quoted study, esculin was extracted from a Nigerian medicinal plant, Afraegle paniculata (Uwaifo 1984). Therefore, the relevance of this study for the safe use of horse chestnut bark preparation is doubtful.

Carcinogenicity

No conventional carcinogenicity study is available.

3.4. Overall conclusions on non-clinical data

Very few studies about horse chestnut bark preparations were found in the literature. No representative preparation can be defined.

Pharmacology

Effects on blood vessels

Horse chestnut bark has a venotonic activity. It produces a dose-dependent contraction of veins and arteries but its action is more pronounced on veins, possibly through an action on 5-HT2A receptors. It increases vascular resistance and decreases capillary permeability. This activity can be due to proanthocyanidin A2 and esculin.

Anti-inflammatory activity

In vivo, horse chestnut bark exerted an anti-inflammatory activity in the rat paw oedema model after oral administration of a petrol extract.

Esculetin extracted from horse chestnut bark demonstrated an activity in the croton oil ear test in mice and the acetylcholine-writhing test in mice.

Esculin is reported to have an anti-inflammatory activity in the UV-induced erythema.

The anti-inflammatory activity may be due to the inhibiting properties of esculetin and esculin toward lipoxygenase.

Effects on platelet aggregation

Horse chestnut extract decreases ADP-induced platelet aggregation but the experiment was conducted with a single concentration of horse chestnut bark. Therefore, the specificity of the reaction is doubtful.

It could be linked to the inhibition of lipoxygenase. Esculetin induced a stimulation cycloxygenase activity at low concentrations and inhibition at higher concentration. The mechanism remains unclear.

Anti-oxidant and anti-enzymatic activity

Constituents of horse chestnut bark preparation (proanthocyanidin A2, esculetin and esculin) are reported to have anti-oxidant properties through inhibition of the peroxidation and some enzymes activity (β-glucuronidase, elastase, collagenase, hyaluronidase, 5-lipoxygenase) or a scavenging activity against ROS.

Effects on healing

Proanthocyanidin A2 was demonstrated to have a trophic activity on muscle and to stimulate healing process.

No safety pharmacology data were available.

Pharmacokinetics

No pharmacokinetics data about horse chestnut bark preparation were available.

Toxicology

The acute toxicity of esculin and esculetin is low.

No other toxicity data was available.

In conclusion, the literature about non-clinical studies with horse chestnut bark preparation is sparse.

However, based on the data found, the venotonic activity of horse chestnut bark seems to be established.

No relevant non-clinical safety data are available.

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 pharmacodynamic data are available.

4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents

No clinical pharmacokinetic data are available.

4.2. Clinical Efficacy

The clinical efficacy is supported by the traditional use of the preparation. No clinical study or case study reports can be found to illustrate the clinical efficacy.

4.2.1. Dose response studies

No data available.

4.2.2. Clinical studies (case studies and clinical trials)

No clinical data are available. Only the use in folk medicine is mentioned in published literature.

Use as febrifuge:

Horse chestnut bark was used in 1720 by 3 physicians with a posology of 8 g 3 or 4 times daily. More than 20 cases of intermittent fever recovery were published in 1763. However, its use as substitute of cinchona was ruled out (Cazin 1868).

The minor efficacy as febrifuge, with a high dosage of 15 to 50 g of powder /day as it was used in 1809, has been mentioned (Fournier 1948).

Use in venous circulatory disorders:

Horse chestnut bark was effective for varicose veins, phlebitis and haemorrhoids, due to its vitamin properties, and it was used for capillary fragility (Boullard 2001).

Horse chestnut bark was very effective for the treatment of varicose veins and haemorrhoids. It soothed pain and stopped to spit blood from the internal varicose veins (Fournier 1948).

Horse chestnut bark contains flavonoids and coumarins (esculin); these constituents are active on capillary fragility (Paris & Moyse 1981).

Horse chestnut bark was very used as venous tonic and for the prevention of vascular disease (Paris & Moyse 1981).

Horse chestnut had an important vitamin P activity due to the presence of coumarins (esculin) (Bézanger-Beauquesne et al. 1980).

Use in diarrhoea:

Horse chestnut bark was used for the treatment of diarrhoea due to its tannins content (powder 1 to 4 g daily, decoction, wine 30 to 60 g/l) (Garnier et al. 1961).

4.2.3. Clinical studies in special populations (e.g. elderly and children)

No data available.

4.3. Overall conclusions on clinical pharmacology and efficacy

Assessor’s comment:

The clinical efficacy of Aesculus hippocastanum bark preparation relies only on the traditional use. No pertinent clinical efficacy data can be found in the literature to support the claimed indications. Only few publications mention the use of horse chestnut bark in folk medicine and contribute to demonstrate the plausibility of the traditional use given the link between its constituents and the attributed indications.

5. Clinical Safety/Pharmacovigilance

5.1. Overview of toxicological/safety data from clinical trials in humans

No data available.

5.2. Patient exposure

No data available.

5.3. Adverse events and serious adverse events and deaths

In terms of using horse chestnut in general by oral or intravenous route, three main types of side effects have been reported:

Kidney failure: Kidney failure has been documented in children and adults after receiving injections of escin, and in adults after taking high doses of escin (Chandler 1993; Hellberg et al. 1975; Klose & Pistor 1976)

Liver damage: Liver damage has been documented in one person after the intramuscular injection of a product containing horse chestnut (Tagegoshi et al. 1986)

Allergic reactions: An allergic reaction has been documented in one person after the rectal administration of a product for the treatment of haemorrhoids that contained esculin (Comaish & Kersey 1980)

There is one report of a person experiencing a severe allergic reaction (anaphylactic shock) after the injection of a horse chestnut extract (Farah et al. 2000)

Aesculin poisoning in humans is manifested by symptoms of muscle weakness, lack of coordination, dilated pupils, diarrhoea and vomiting, paralysis and stupor (Nagy 1973).

5.4. Laboratory findings

No data available.

5.5. Safety in special populations and situations

No specific data are available on use in pregnancy and lactation, overdose, drug abuse, withdrawal and rebound, effects on ability to drive or operate machinery or impairment of mental ability. However, as safety during pregnancy and lactation, and in children and adolescents has not been established, the use of horse chestnut bark in these special populations should be avoided.

5.6. Overall conclusions on clinical safety

The specific safety of Aesculus hippocastanum bark preparation cannot be established due to the lack of published data. Due to the presence of aesculin in the bark, it could be assumed that the described adverse events with the different preparations could apply. However, the long term traditional use of oral forms is in favour of their good tolerance in the target population and in the recommended range of dose.

Clinical safety data are very limited. However, no safety problems concerning the traditional use of horse chestnut or its preparations have been reported.

In addition, due to lack of data, the use during pregnancy and lactation, and in children and adolescents under 18 years of age is not recommended.

In other situations, horse chestnut bark preparations are not harmful when used in the recommended dosages for the specified indications.

6. Overall conclusions

In conclusion, due to its long-standing use and based on the available documentation, only a traditional use can be granted for horse chestnut bark. Only the preparation which has been used for at least 30 years including at least 15 years in the European Union is described in the monograph.

To be in compliance with the wording validated in other monographs (e.g. monographs on Aesculus hippocastanum L., semen; Melilotus officinalis L., herba; Hamamelis virginiana L., folium; Ruscus aculeatus L., rhizoma), the monograph information should remain limited to the traditional use to “relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances” and “for symptomatic relief of itching and burning associated with haemorrhoids”.

As there are no clinical studies conducted with horse chestnut bark in children and adolescents under the age of 18 years, horse chestnut bark should not be used in this target population and should be limited to adults and elderly.

Given that no reproductive toxicity studies have been conducted and there are no data from the use of horse chestnut bark in pregnant women, section 4.6 of the monograph is adapted accordingly and in compliance with the wording validated in other monographs.

The therapeutic area of the two indications is: venous circulatory disorders.

Due to the lack of genotoxicity testing, a Community list entry cannot be established.

Annex

List of references

Comments