Aesculus – Horse-Chestnut Seed (Hippocastani semen)
|Latin name of the genus:||Aesculus|
|Latin name of herbal substance:||Hippocastani semen|
|Botanical name of plant:||Aesculus hippocastanum l.|
|English common name of herbal substance:||Horse-chestnut seed|
Latin name of the genus: Aesculus
Latin name of herbal substance: Hippocastani semen
Botanical name of plant: Aesculus hippocastanum L.
English common name of herbal substance: Horse-Chestnut Seed
- I.REGULATORY STATUS OVERVIEW1
- II.ASSESSMENT REPORT
- BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
- (WELL-ESTABLISHED USE)
- BASED ON ARTICLE 16D(1), ARTICLE 16F AND ARTICLE 16H OF DIRECTIVE 2001/83/EC
- AS AMENDED
- (TRADITIONAL USE)
- II.1 I
- II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
- Information on period of medicinal use in the Community regarding the specified indication
- Conclusions on traditional use
- II.2.1 Pharmacology
- II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- Primary pharmacodynamics
- Anti-inflammatory and anti-oedematous effect
- Effect on venous tone
- Effect on contractility of human veins
- Endothelium effects
- Effect on lysosymal enzymes
- Safety pharmacology
- Pharmacodynamic interactions
- II.2.1.2 Assessor’s overall conclusions on pharmacology
- II.2.2 Pharmacokinetics
- II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
- II.2.3 Toxicology
- II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- Single dose toxicity
- Sub-acute intravenous toxicity
- Chronic oral toxicity
- Blood toxicity
- II.2.3.2 Assessor’s overall conclusions on toxicology
- II.3.1 Clinical Pharmacology
- II.3.1.1 Pharmacodynamics
- II.126.96.36.199 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.188.8.131.52 Assessor’s overall conclusions on pharmacodynamics
- II.3.1.2 Pharmacokinetics
- II.184.108.40.206 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.220.127.116.11 Assessor’s overall conclusions on pharmacokinetics
- II.3.2 Clinical Efficacy4
- II.3.2.1 Dose response studies
- II.3.2.2 Clinical studies (case studies and clinical trials)
- II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
- II.3.2.4 Assessor’s overall conclusions on clinical efficacy
- II.3.3 Clinical Safety/Pharmacovigilance
- II.3.3.1 Patient exposure
- II.3.3.2 Adverse events
- II.3.3.3 Serious adverse events and deaths
- Assessors comment
- II.3.3.4 Laboratory findings
- II.3.3.5 Safety in special populations and situations
- II.18.104.22.168 Intrinsic (including elderly and children) /extrinsic factors
- II.22.214.171.124 Drug interactions
- II.126.96.36.199 Use in pregnancy and lactation
- II.188.8.131.52 Overdose
- II.184.108.40.206 Drug abuse
- II.220.127.116.11 Withdrawal and rebound
- II.18.104.22.168 Effects on ability to drive or operate machinery or impairment of mental ability
- II.3.3.6 Assessor’s overall conclusions on clinical safety
I.REGULATORY STATUS OVERVIEW1
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’
1This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
2Not mandatory field.
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
BASED ON ARTICLE 16D(1), ARTICLE 16F AND ARTICLE 16H OF DIRECTIVE 2001/83/EC
II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance(s) 3 : Aesculus hippocastanum L., semen. The dried seeds of Aesculus hippocastanum L., containing not less than 3.0% of triterpene glycosides, expressed as
anhydrous aescin (C55H86O24; Mr 1131) and calculated with reference to the dried drug (Ph. Eur. draft monograph 1995). A monograph is also available in DAB 10.
Herbal preparation(s): Hydroalcoholic extract
and not more than 20.0% of glycosides of triterpenes, expressed as anhydrous aescin (C55H86O24; Mr 1131) and calculated with reference to the dried extract (Ph. Eur. draft monograph 1996).
Information on period of medicinal use in the Community regarding the specified indication
The medicinal use of
Based on the survey of products avaliable in the Member states, A. hippocastanum containing products have been in use for at least 30 years:
Germany: Ointment (since 1976) containing 20% tincture (1:5; extraction solvent 50% ethanol v/v); traditionally used for the improvement of conditions in tired legs; apply
Austria: Ointment (since 1968) containing dry extract (extraction solvent: ethanol 50% v/v) corresponding to 760 mg aescin per 100 g ointment; pain in the legs, heavy legs, pruritus, varicosis; apply several times daily.
Conclusions on traditional use
Based on information obtained from Member states and data retreived from handbooks it can be concluded that the following extracts and uses of horse chestnut seed fulfil the criteria for traditional use:
Dry aqueous ethanol
Tincture (1:5; extraction solvent: 50% ethanol v/v), 20% in an ointment base, for cutaneous use.
A)Traditional herbal medicinal product to relieve of symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
B)Traditional herbal medicinal product for relief of symptoms of bruises, such as oedema and haematoma.
3According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal products’ (EMEA/HMPC/182320/2005 Rev.2) and the ‘Procedure for the preparation of Community monographs for herbal medicinal products with
A)Adults and elderly: Apply a thin layer on the affected area
B)Adolescents over 12 years, adults and elderly: Apply a thin layer on the affected area
II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
The seeds of Aesculus hippocastanum L. contain
All saponins have a trisaccharide group at
Structure of the main saponin in aescin
Three fractions of aescin, denoted as
Other constituents include flavonoids (0.3%), principally di- and triglycosides of quercetin and kaempferol, sterols, essential oil and a high proportion of starch (30 – 60%) (ESCOP 2003). Coumarin derivatives (aesculin and fraxetin) are present in other parts of Aesculum hippocastanum L., but not in the seeds or the seed shell (Hagers Handbuch 1992).
The literature on the pharmacodynamics of
Anti-inflammatory and anti-oedematous effect
The following information was retrieved from ESCOP (2003):
Similar results are reviewed by Hager (1992)
Lorenz (1960) performed an extensive investigation on several ethanol extracts of
no effect. The effect was
Effect on venous tone
The effects of extracts (no information on drug/extract ratio or solvent) from horse chestnut (Aesculus hippo- castanum) and of aescin were investigated on isolated veins (bovine Vena metacarpalis, human Vena saphena) which either were perfused or used as strips with isotonic recording. They produced in high doses (0.2 mg/ml and more) a slow and irreversible contraction in both experimental procedures. The contractions were very similar to those produced by the same doses of saponin, but dissimilar to those produced by much smaller doses of noradrenaline.
According to ESCOP (2003) similar effects on venous tone were observed with HCSE (alcoholic horse- chestnut seed extract) at
The following results were obtained with an extract (containing 75 % aescin, no other details given) contained in the commercial preparation Veinotonyl 75®. In the isolated canine saphenous vein, the extract induced
Aescin, in concentrations of
Other investigations showing venotonic effects of various alcoholic
Effect on contractility of human veins
In vitro, aescin contracted vein segments derived from normal vessels whereas no contraction was observed in segments from varicose vessels (Brunner 2001).
Human vascular endothelial cells (HUVECs) were exposed to CoCl2 as an in vitro model of hypoxia. Expression of
Effect on lysosymal enzymes
Aescin inhibited the enzyme hyaluronidase (IC50 = 149.9 μM) (Facino 1995).
No information except toxicity data presented in section II.2.3.
II.2.1.2 Assessor’s overall conclusions on pharmacology
Aqueous ethanolic extracts of Aesulus hippocastanum L., seed
Based on available preclinical data, it can be concluded that the mechanism of action of orally administered HCSE in connection with chronic venous insufficiency is not known. Concerning aescin, it has been shown that pure aescin (ca
II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Some pharmacokinetic studies have been performed on aescin, but compelling evidence that the pharmacological activity of HCSE can be ascribed to aescin has not been presented. At present, the pharmacokinetic data on aescin are of limited importance.
There are no indications that toxic metabolites are formed from aescin.
II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
No information available on pharmacokinetic interactions. No information available on metabolites.
II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Single dose toxicity
The following data (LD50 mg/kg bw) on the extract contained in the preparation Venostasin retard (dry extract, DER 5:1, 50% aqueous ethanol, standardized to a content of 50 mg aescin in
For aescin the following data are available in Hager (1992): LD50 (mg/kg bw) intravenous: Mouse 9.3, rabbit 5.0, rat 16.8, guinea pig 9.1, pig 4, dog 3. By intraperitoneal administration an LD50 of 17 mg/kg was determined for rats (von Kreybig 1977)
Sub-acute intravenous toxicity
Chronic oral toxicity
Neither toxic effects, nor organ damage were observed after 34 week oral administration of the HCSE contained in Venostasin retard (see above) to dogs (2 male, 2 female per dose and control group) at 20, 40 or 80 mg/kg bw daily (5 days/week) and to rats (20 male, 20 female per dose and control group) at 100, 200 and 400 mg/kg bw daily. The highest dose level used in dogs corresponded to 8 times the usual therapeutic dose in humans. The highest dose studied in rats amounts to 40 times the human therapeutic dose (Liehn 1972).
SD rats were treated with different doses of aescin (15, 10 and 5 mg/kg, i.p.) once per day for 7 days. Hematology indices (white blood cell, red blood cell, platelet and hemoglobin) and blood coagulation indices (Prothrombin time, Thrombin time, activated part thromboplastin and coagulation time) were selected as observational indices. Comparing rats treated with aescin with the controls, the number of white blood cell was decreased (p < 0.05). The number of red blood cell and platelet, and the content of hemoglobin were enhanced markedly (p< 0.05, <0.01). At the same time, all the blood coagulation indices in rats treated with aescin 10 and 15 mg/kg shortened significantly (p < 0.05, <0.01), and in rats treated with 5 mg/kg, prothrombin time and thrombin time were reduced (p < 0.05, <0.01). Conclusion: There was significant blood toxicity to SD rats treated with high dose of aescin i.p. (Li 2006).
In the Ames mutagenicity test, using Salmonella typhimurium strain TA 98, a commercial dry extract (Caesar & Loretz) gave a negative response without activation, but a weekly positive response (factor
Following daily oral administration of the HCSE contained in Venostasin retard (see above) to rats and rabbits at 100 and 300 mg/kg bw, no significant effects compared to control animals were observed in teratogenicity studies. At 300 mg/kg bw to rabbits, a significant reduction (p<0.001) in the mean weight of the foetuses was observed. 300 mg/kg bw is approximately 30 times the recommended therapeutic dose for humans (Liehn 1972).
Juvenile rats were treated with 2 x 5 mg/kg aescin at age 32 days. After they had reached fertility, kidneys, testes and sperm were examined. The high dose of aescin used did not affect fertility and a nephrotoxic activity could not be detected (von Kreybig 1977).
II.2.3.2 Assessor’s overall conclusions on toxicology
With an LD50 ranging between 1 and 2.6 g/kg bw, the acute oral toxicity of HCSEs is low in all animals studied. The subacute studies were performed with IV administration and indicated that a daily dose amounting to ¼ of the IV LD50 has no untoward effects when given during 8 weeks. Also the data on oral chronic toxicity indicate a low toxicity of the extract. Data on teratogenic effects are incomplete. Equivocal results on mutagenic activity of HCSE have been reported.
II.3.1 Clinical Pharmacology
II.22.214.171.124 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
The effect of an extract (drug/extract ratio 5:1, 50% ethanol), contained in capsules with 240 to 290 mg of the extract, standardized to 50 mg aescin/capsule on
In the first study (Pauschinger 1953), oral administration of a single dose of the extract (300 mg, n =12) or placebo (n = 14) to healthy volunteers, produced a significantly lower capillary filtration coefficient in the extract group.
The second study (Bisler 1986), had a
In a study of venous tone, a single dose of 150 mg of extract was administered orally to 23 healthy young subjects. A further 14 subjects received either 80 mg of extract or identical placebo capsules in a crossover design. Plethysmographic measurements taken before and 2 hours after administration showed that the extract
Comparable results were obtained from a further study in which 12 healthy volunteers firstly received placebo and then a single oral dose of extract (360 mg, standardized to 90 mg of aescin). In contrast, intravenous administration of 20 mg of aescin had no effect on venous tone (Ehringer 1968).
II.126.96.36.199 Assessor’s overall conclusions on pharmacodynamics
An increase in venous tone has been reported for oral HCSE in clinical pharmacology studies, but pure aescin (i.v.) was reported not to have this effect. Furthermore, a decrease in capillary filtration coefficient has been reported for HCSE in human pharmacological studies. Both these effects (which probably are related) appear relevant in connection with chronic venous insufficiency.
A mechanism proposed for this effect, is that HCSE would prevent the action of enzymes which catalyze the breakdown of proteoglycans, constituting part of the capillary walls. It has been proposed that this effect would not be via direct inhibition of the enzymes, but by a protective action on the lysosomal membrane that is the site of enzyme release. However, it appears unlikely that a saponin containing extract would stabilize membranes.
At present, the mechanism of action of HCSE in chronic venous insufficiency cannot be considered clarified, but it seems to involve an influence on the venous tone and capillary filtration rate. The effect does not seem to be due to aescin.
II.188.8.131.52 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
After intravenous administration, the pharmacokinetics of aescin was found to correspond to an open three compartment model. With an intravenous dose of 5 mg of aescin (infusion rate: 718 µg/min) the elimination
Several clinical studies have been published comparing the bioavailability of aescin in a prolonged release formulation (Venostasin retard®,
In single dose experiments (Schrader 1995; Dittgen 1996 and Oschmann1996), HCSE (Venostasin retard®) contataining 50 mg aescin resulted in Cmax values ranging from
In repeated dose experiments (Oschmann 1996; Schrödter 1998; Kunz 1998), HCSE (Venostasin retard®) contataining 50 mg aescin resulted in Cmax values ranging from
In all the published clinical studies the same RIA, under identical conditions, in the same laboratory, was employed. The immuno assay had been validated for a specific batch of aescin, and for this particular batch of aescin it was reported to work satisfactorily. However,
II.184.108.40.206 Assessor’s overall conclusions on pharmacokinetics
There is no compelling evidence that aescin is the therapeutically active substance in HCSE, so the pharmacokinetic data available are of very limited value.
Some data on the pharmacokinetic parameters of the marker substance aescin have been reported in the literature. The absolute figures of the parameters are not reliable for analytical methodological reasons (Loew 2000; Bässler 2003). They are thus not suitable for adjusting a dosing regimen of HCSE in clinical practice.
II.3.2 Clinical Efficacy4
II.3.2.1 Dose response studies
II.3.2.2 Clinical studies (case studies and clinical trials)
A systematic review of 29 randomised controlled clinical trials assessing oral
4 In case of traditional use the
A total number of 1443 patients participated in the trials. The number of patients varied between the studies from 20 to 286. Eleven studies comprised less than 50 participants. The majority of the included studies diagnosed the patients according to the classification by Widmer (Widmer 1978). Fourteen trials reported inclusion criteria for CVI patients relating to this classification.
Leg pain: Leg pain was assessed in seven
Oedema: Oedema was assessed in six
Pruritus: Pruritus was assessed in eight
Leg volume: Leg volume was assessed in seven
Significant beneficial effects for CVI patients were reported in trials which administered HCSE standardised to
Circumference: Circumference at calf and ancle was assessed in seven
The authors of the systematic review conclude that HCSE appears to be effective and safe as a symptomatic,
II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
No information available.
II.3.2.4 Assessor’s overall conclusions on clinical efficacy
Of particular importance is the study by Diehm (1996) where HCSE was compared both with placebo and with standard treatment with compression stockings, which showed that the reduction of leg volume after 12 weeks of treatment was equal between HCSE and compression stockings and significantly (p< 0.005 and 0.002, respectively) different from placebo. The oedema volume in the leg of a patient with chronic venous insufficiency has been estimated to approximately 220 ml (Diehm 1996). The oedema reduction obtained in this study was ca 55 ml (for both HCSE and compression stockings), i.e. an effect size of approximately 25%, which is considered clinically relevant.
The effects on subjective symptoms, such as pain and pruritus have also been found to be significantly reduced by HCSE compared to placebo, although the data are less convincing.
II.3.3 Clinical Safety/Pharmacovigilance
II.3.3.1 Patient exposure
The controlled studies evaluated in the
II.3.3.2 Adverse events
Fourteen studies in the
According to Hitzenberger (1989) the preparation Venostasin retard was used in 895 362 500 single doses (= 447 681 250 daily doses) between 1968 and 1988. Only 15 cases of mild adverse effects were reported.
II.3.3.3 Serious adverse events and deaths
A serious safety issue was raised more than 25 years ago, i.e. the risk of acute renal failure, when patients, who had undergone cardiac surgery, were given high doses of horse chestnut extract i.v. for
18 healthy volunteers. Ten were administered 10 mg i.v. daily for 3 days, eight were given 20 mg i.v. for 6 days;
12 patients with cerebral oedema and normal renal function, who were given a massive i.v. dose on the day of surgery (49.2 ± 19.3 mg) and 15.4 + 9.4 mg daily for the following 10 days;
13 patients with impaired renal function due to glomerulonephritis or pyelonephritis, who were given
In all studies renal function was monitored daily resorting to the usual tests of renal function: BUN, serum creatinine, creatinine clearance, urin analysis. In a selected number of cases
As the bioavailabillity of orally administered aescin is only about 1.5% of the given dose (see II.220.127.116.11), there are no safety concerns in this aspect when HCSE is given orally in the normal dose.
II.3.3.4 Laboratory findings
II.3.3.5 Safety in special populations and situations
II.18.104.22.168 Intrinsic (including elderly and children) /extrinsic factors
II.22.214.171.124 Drug interactions
It has been stated that aescin could increase the effect of
II.126.96.36.199 Use in pregnancy and lactation
Pregnant women participated in one clinical trial (Steiner 1990). No adverse events were reported.
II.188.8.131.52 Drug abuse
II.184.108.40.206 Withdrawal and rebound
II.220.127.116.11 Effects on ability to drive or operate machinery or impairment of mental ability
II.3.3.6 Assessor’s overall conclusions on clinical safety
Only mild adverse events were reported in the 17 clinical trials evaluated in a
Only oral administration is foreseen for treatment of chronic venous insufficiency.
The clinical efficacy and safety of an extract (1:5, 50% aqueous ethanol, standardized to contain 50 mg of aescin in
During the meetings of the MLWP and at the public consultation several items were discussed. The following points led to amendments in the monograph:
The data in support of aescin as responsible for the therapeutic effect of HCSE is very weak, but the extracts used in most clinical trials appear to be produced as extracts standardised on aescin. It can thus be debated whether HCSE should be classified as a standardised or a quantified extract in the sense of Ph. Eur. In the final discussion of the MLWP, the notation “standardised extract” was considered most appropriate. A consequence of classifying HCSE as a standardised extract, is that it is reasonable to widen the span of ethanol content of the extraction solvent as long as the dose of the HCSE corresponds to 50 mg aescin 2 times daily.
Due to the uncertainty of the analytical data available for the pharmacokinetics of aescin, precise figures of the pharmacokinetic parameters should not be given in the monograph. However, the data seem to allow the conclusion that there is virtually no difference in bioavailability of aescin between retarded and
5Prepared according to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal products’ (EMEA/HMPC/182320/2005 Rev.2)
6Prepared according to the ‘Procedure for the preparation of Community monographs for herbal medicinal products with