Horse Chestnut
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Aesculus hippocastanum L.
[Fam. Hippocastanaceae]
Overview
Europeans have used horse chestnut seeds for medicinal
purposes since at least the late 16th century when the plant was introduced
into Northern Europe from the Near East (Blumenthal et al., 2000; McCaleb et al.,
2000). Extracts from horse chestnut seeds were used in France in the early 1800s.
Publications from 1896 to 1909 report success in its use for hemorrhoids
(Schulz et al., 2000). Although horse
chestnut seed extract (HCSE) is relatively new to the U.S. botanical market, it
is gaining in popularity due to the significant quantity of clinical evidence
from Europe documenting its safety and efficacy as a treatment for varicose
veins, chronic venous insufficiency, and related vascular disorders. Horse
chestnut seeds can be toxic when unprocessed and are unrelated to sweet
chestnuts (Castanea sativa), a plant
in the family Fagaceae, which can be
eaten without precautions (McCaleb et al.,
2000). Standardized and purified preparations of horse chestnut seeds are
available. HCSE is the most widely prescribed oral remedy for venous edema in
Germany (Schulz et al., 2000).
Description
Horse chestnut preparations produced from the dried seed of Aesculus hippocastanum L. [Fam. Hippocastanaceae], containing not less
than 3% triterpene glycosides, calculated as anhydrous escin (also spelled
aescin), with reference to the dried seed (DAB, 1999). HCSE is a dry extract
manufactured from German pharmacopeia-grade horse chestnut seed and is normalized
to contain no less than 16%, and no more than 20%, triterpene glycosides,
calculated as anhydrous escin (DAB, 1999). The typical drug-to-extract ratio
for the native dry extract falls within the range of 5–8:1 (w/w), depending on the chemical
composition of the starting material, and the subsequent yield of soluble
extractive (Blumenthal et al., 2000).
Primary Uses
Internal
Venous insufficiency, chronic (Geissbühler and
Degenring, 1999; Shah et al., 1997;
Diehm et al., 1996; Rehn et al., 1996; Diehm et al., 1992; Erler, 1991; Pilz, 1990; Steiner, 1990; Steiner and
Hillemanns, 1990; Erdlen, 1989; Kalbfleisch and Pfalzgraf, 1989; Rudofsky et al., 1986; Lohr et al., 1986; Bisler et al.,
1986)
Note: The
German Commission E also approved HCSE for venous insufficiency, usually of the
legs, including pain and sensation of heaviness in the legs, nocturnal
systremma (cramps in the calves), pruritus, and swelling of the legs
(Blumenthal et al., 1998)
Varicosis, lower veins (Kreysel et al., 1983; Friederich et al.,
1978; Neiss and Böhm, 1976)
External
Blunt traumas, especially painful hematomas,
post-traumatic and postoperative soft tissue swelling (Schilcher, 1997)
Injuries with hematomas (Calabrese and
Preston, 1993)
Symptoms associated with varicose veins, such
as swollen legs (edema), pain and heaviness in the legs, and calf pain (Morant
and Ruppanner, 2001)
Other Potential Uses
Severe cranio-cerebral trauma (Put, 1979)
Prevention and treatment of postoperative
edema (Reynolds et al., 1989)
Traumatic head injury, intracranial
pressure, and edema (McCaleb et al.,
2000)
Hemorrhoids (Mills and Bone, 2000)
Leg ulcers (Weiss and Fintelmann, 2000)
Dosage
Internal
Crude Preparations
Tincture: 1:2.6 (w/v), 65 vol.-% alcohol, adult dose 20–30 drops (0.5–0.7 ml), with
water at meal times, 3 times daily (Morant and Ruppanner, 2001).
Standardized Preparations
Dry extract from dried seed:
5–8:1 (w/w), 16–20% triterpene
glycosides: 250–312.5 mg, 2 times daily in delayed-release form, corresponding
to 100 mg escin daily. One dose in the morning and another in the evening, with
ample liquids during meals (Blumenthal et
al., 1998).
Dry extract from fresh seed: 5.0–6.1:1
(w/w), adult dose:
2 enteric coated tablets containing 63–90 mg dry native extract each, 3 times
daily taken with water at mealtimes, corresponding to 120 mg escin daily. After
1–2 weeks reduced to 1 tablet, 3 times daily (Morant and Ruppanner, 2001).
Purified Escin (intravenous preparation in
the form of sodium escinate): 5.1 mg sodium escinate, 1–2 times
daily, maximum adult dose: 20 mg (Reynolds et
al., 1989; Weiss, 1988); children 3–10 years: 0.2 mg/kg body weight,
infants up to 3 years: 0.1mg/kg body weight (Weiss, 1988) (not available in the
U.S.).
Note:
Unprocessed horse chestnut seeds should not be eaten or made into tea because
they contain toxins, including esculin, which are removed in processing
(McCaleb et al, 2000).
External
Standardized Preparations
Gel: 1 g
contains 54–177 mg dry extract standardized to 2% escin. Applied to affected
area 2 times daily (Morant and Ruppanner, 2001).
Ointment:
Contains aqueous extract. Applied to affected area. The type of ointment base
contributes to efficacy, as does the use of occlusive dressings (Schilcher,
1997).
Purified Escin Preparation
Escin gel NRF:
23.1 (Aescini mucilago), 1%
water-soluble escin, a thin layer applied to skin, several times daily as
needed. Not for use on open wounds (NRF 3, 1986) (not available in the U.S.).
Duration of Administration
Internal
There is little scientific information about the long-term
use of horse chestnut; however, one clinical trial administered horse chestnut
for 56 weeks without adverse effect (Put, 1979). HCSE is widely used for
long-term therapy in German clinical practice, without reports of adverse events
(Schulz et al., 2000).
Chemistry
Horse chestnut seed contains 3–6% of a complex mixture of
triterpenoid saponins collectively referred to as escin (aescin) (Morgan and
Bone, 1998), including the triterpene oligoglycosides escins, Ia, Ib, IIa, IIb,
and IIIa (Yoshikawa et al., 1996);
the acylated polyhydroxyoleanene triterpene oligoglycosides escins IIIb, IV, V,
and VI, and isoaescins Ia, Ib, and V (Yoshikawa et al., 1998); 0.2–0.3 % flavonoids (Wagner, 1967), including
flavonol oligosaccharides (Hübner et al.,
1999); coumarin derivatives (esculetin and esculin) (Fugmann et al., 1997); sterols (stigmasterol, a-spinasterol, and b-sitosterol); and fatty acids
(linolenic, palmitic, and stearic acids) (Leung and Foster, 1996). The
sapogenols hippocaesculin and barringtogenol-C are produced by hydrolysis
(Konoshima and Lee, 1986).
Pharmacological Actions
Human
Anti-edemic (Geissbühler and Degenring, 1999, Shah et al., 1997, Diehm et al.,
1996); reduces transcapillary filtration (Blumenthal et al., 1998; Schilcher, 1997); venoactive (BHP, 1996).
Animal
Anti-edemic (Guillaume and Padioleau, 1994); improved vein
compliance; inhibits vasodilation (Guillaume and Padioleau, 1994);
anti-inflammatory (Guillaume and Padioleau, 1994; Matsuda et al., 1997; Tsutsumi and Ishizuka, 1967); antioxidant
(Bombardelli and Morazzoni, 1996); diminished cutaneous capillary
hyperpermeability (Guillaume and Padioleau, 1994); isolated escin demonstrated
anti-exudative and vasoconstricting effects (Blumenthal et al., 1998).
In vitro
Antitumor (Konoshima and Lee, 1986); isolated hippocaesculin
and barringtogenol-C-21-angelate have antitumor activity (Chandler, 1993; De
Meirsman and Rosselle, 1980); isolated escin, and to a lesser extent escinol,
inhibits activity of hyaluronidase (Facino et
al., 1995); antioxidant (Bombardelli and Morazzoni, 1996);
anti-inflammatory and immunomodulatory (Brokos et al., 1999).
Mechanism of Action
Human
HCSE reduced lysosomal enzyme activity
(Kreysel et al., 1983) elevated in
chronic pathological conditions of the veins, thereby preventing breakdown of
glycocalyx (mucopolysaccharides) in the region of the capillary wall. Through a
reduction of vascular permeability, the filtration of small molecule proteins,
electrolytes, and water into the interstitium is inhibited (Blumenthal et al., 1998).
Inhibited experimentally induced leg edema in
patients with chronic venous insufficiency by reducing transcapillary
filtration (Pauschinger, 1987).
In vitro
Decreased free radical generation by
granulocytes, thereby indicating potential anti-inflammatory activity (Brokos et al., 1999).
Inhibited lipid peroxidation in vitro (Guillaume and Padioleau,
1994).
Lowered the rate of lymphocyte
proliferation while recruiting lymphocytes to mitotic cycle (Bronkos, 1999).
Elevated B and NK cells influencing the
induction/suppression-balance in the immune system (Bronkos, 1999).
Contraindications
Internal
Not recommended for children (Morant and Ruppanner, 2001;
ESCOP, 1999) or with chronic renal failure (Morant and Ruppanner, 2001). An
authoritative clinical review found no clinical basis for contraindications
(Schulz et al., 2000).
External
The gel or ointment should not be applied to broken or
ulcerated skin (NRF 3, 1986). Contraindicated in cases of thrombosis or risk of
embolism and for application to open wounds or mucous membranes (Morant and
Ruppanner, 2001).
Pregnancy and Lactation: There are no known restrictions
according to the Commission E (Blumenthal et
al., 1998). HCSE has been used in some clinical studies involving pregnant
women, with some studies excluding those in the third trimester. No adverse
effects have been reported (ESCOP, 1999).
Adverse Effects
The Commission E noted that in rare cases, pruritus, nausea,
and gastric complaints may occur after oral intake (Blumenthal et al., 1998). In rare cases, irritation
of the gastric mucous membranes and reflux may occur. Escin Ib isolated from horse chestnut might partially delay or
even inhibit gastric emptying. The inhibition of gastric emptying might be
mediated by capsaicin-sensitive sensory nerves (CPSN), stimulation of the
synthesis and/or release of dopamine, or through the central dopamine2
receptor, which in turn causes the release of prostaglandins (Matsuda and
Yoshikawa, 2000). This possible adverse effect can be minimized by taking the
extract in an enteric-coated, time-release tablet with the main meal (Morant
and Ruppanner, 2001). After intravenous
administration of isolated escin,
anaphylactic shock, toxic nephropathy, and renal failure have been reported
(Leung and Foster, 1996; Grasso and Corvaglia, 1976), but these reactions are
not associated with oral ingestion of the chemically complex HCSE preparations.
One case report (Comaish and Kersey, 1980) linking horse chestnut with contact
dermatitis has been documented, but this does not pertain to HCSE in internal
dosage forms.
Drug Interactions
Some sources have theorized that horse chestnut extractives
may interfere with the effects of anticoagulants (Ernst, 2000), specifically
escin (Madaus AG, 2000). However, another source suggests that this activity
pertains to the compound esculetin, found in the bark, not the seeds (Brinker, 2001). Escin, the main saponin
component in horse chestnut, binds to plasma protein and may affect the binding
of other drugs (speculative) (Newall et
al., 1996).
American Herbal Products Association (AHPA) Safety Rating
No rating. Note:
The herbs evaluated by AHPA in its Botanical
Safety Handbook were based on an earlier AHPA publication (Foster, 1992)
listing the names of approximately 550 of the most commonly-sold herbs in U.S.
commerce during the early 1990s (McGuffin et
al., 1997). Horse chestnut preparations were not readily available in the
U.S. at that time.
Regulatory Status
Canada: Horse
chestnut is listed in Appendix II of the “List of Herbs Unacceptable as
Non-medicinal Ingredients in Oral Use Products” (Health Canada, 1995b) and is
also listed in Appendix I of the “Herbs that are Restricted or not Accepted as
Medicinals in Traditional Herbal Medicines” (Health Canada, 1995a). However, it
is permitted as a component of homeopathic drugs (Health Canada, 2000).
France: Official in the French Pharmacopoeia (ESCOP, 1999; Ph.Fr. X, 1982–1996).
Nonprescription drug used in self-medication for circulatory stabilization
(Goetz, 1999; Noël, 1997).
Germany: HCSE is an approved drug in the German
Commission E monographs (Blumenthal et al.,
1998). Dried seed containing not less than 3.0% triterpene glycosides and HCSE
containing 16–20% triterpene glycosides are official in the German Pharmacopoeia (DAB, 1999).
Escin-Gel is an official preparation in the German
Formulary (NRF 3, 1986). Fresh-peeled seeds, the mother tincture, and
liquid dilutions are official preparations of the German Homeopathic Pharmacopoeia (HAB 1, 1978–1985).
Spain:
Official in the Spanish Pharmacopeia
(Newall et al., 1996; Reynolds et al., 1989).
Sweden: As of January 2001, no
horse chestnut products have been listed in the Medical Products Agency (MPA)
“Authorised Natural Remedies” (MPA, 2001).
Switzerland:
Positive classification (List D) by the Interkantonale
Konstrollstelle für Heilmittel (IKS) and corresponding sales category D
with sale limited to pharmacies and drugstores, without prescription (Morant
and Ruppanner, 2001; WHO, 1998). One horse chestnut Anthroposophical preparation,
19 phytomedicines preparations, and 5 mainly-botanical combination preparations,
are listed in the Swiss Codex 2000/01
(Ruppanner and Schaefer, 2001).
U.K.:
Medicinal product specified in the General
Sale List, Schedule 1 (subject of full Product License), Table B (external
use only) (GSL, 1994).
U.S.:
Oral preparations regulated as dietary supplement (USC, 1994).
Clinical Review
Twenty-three studies are outlined in the following table,
“Clinical Studies on Horse Chestnut,” including a total of 4,339 participants.
All of the 20 studies that investigated the use of HCSE in venous disorders
demonstrated positive effects. Of the 20 studies, four were randomized,
double-blind, placebo-controlled, parallel group (R, DB, PC, PG), studies
(Diehm et al., 1992; Lohr et al., 1986; Pilz, 1990; Rudofsky et al., 1986), five were R, DB, PC,
cross-over (CO) studies (Bisler et al.,
1986; Friederich et al., 1978; Neiss
and Böhm, 1976; Steiner, 1990; Steiner and Hillemanns, 1990), four were R, DB,
comparison, PG design studies (Erdlen, 1989; Erler, 1991; Kalbfleisch and
Pfalzgraf, 1989; Rehn et al., 1996),
one was a R, PC single-blind design (Diehm et
al., 1996), another was a DB, PC, multicenter (MC) study (Shah et al., 1997), one was an uncontrolled,
multicenter study with 71 participants (Geissbühler and Degenring, 1999), one
was a DB design (Kreysel et al., 1983), three were surveillance studies (Masuhr
et al., 1994; Knoche and Knoche,
1978; Rossi et al., 1977). The main
outcome measure for most studies was reduced leg volume or ankle circumference.
A systematic review of 13 R, DB clinical trials from 1976–1996, using HCSE in
the treatment of venous disorders, and involving nearly 1,100 patients,
concluded that HCSE was superior to placebo (Pittler and Ernst, 1998). HCSE was
as effective as rutosides (the conventional treatment in Europe) in five
studies. Adverse effects were mild and infrequent.
A R, CO study found bioequivalence (phytoequivalence) in two
different forms of HCSE (Oschmann et al.,
1996). A R, DB, PC study of 70 subjects using HCSE topical gel, showed
significant reduction in tenderness with experimentally induced hematomas
(Calabrese and Preston, 1993). Subjects with severe cranio-cerebral trauma
regained consciousness more quickly and experienced reduced intracranial
pressure with purified escin i.v., followed by HCSE tablets, compared to
placebo (Put, 1979).
Branded Products*
Aesculaforce® Venen-Gel: Bioforce AG / CH-9325
Roggwil TG / Switzerland / Tel: +41 71 454 61 61 / Fax: +41 71 454 61 62 /
www.bioforce.com / Email: info@bioforce.ch. One g of gel contains 54–117 mg dry
extract prepared from fresh horse chestnut seed (Hippocastani semen recent
extr. Sicc. 5.0–6.1:1) standardized to contain 2% escin.
Aesculaforce® Venen-Tabletten: Bioforce AG.
Film-coated tablets (to prevent gastric irritation) contain 63–90 mg dry
extract prepared from fresh horse chestnut seed (Hippocastani semen extr. Sicc.
5.0–6.1:1), corresponding to 20 mg escin. Extraction solvent: 60% (m/m) ethanol.
Reparil® Dragées: Madaus AG / Ostermerheimer
Strasse 198 / Köln / Germany / Tel: +49-22-18-9984-76 / Fax: +49-22-18-9987-21
/ Email: b.lindener@madaus.de. One coated tablet contains 20 mg escin
amorphosed with adjuvants: polyvidone, magnesium stearate, talc, gum arabic,
polyethyl acrylate, methacrylic acid, Macrogol 8000, sodium hydoxide,
carmellose sodium, triethyl citrate, dimethicone, titanium dioxide, lactose,
colloidal silicon dioxide, sucrose, natural waxes.
Venoplant® retard S: Dr. Willmar Schwabe
Pharmaceuticals / International Division / Willmar Schwabe Str. 4 / D-76227
Karlsruhe / Germany / Tel: +49-721-4005 ext. 294 / www.schwabepharma.com /
Email: melville-eaves@schwabe.de. Each sustained-release tablet contains 263.2
mg dry extract from horse chestnut seeds (4.5–5.5:1), adjusted to 50 mg
triterpene glycosides, calculated as anhydrous aescin; extraction agent:
ethanol 50% (w/w).
Venostasin® Retardkapsel: Klinge Pharma GmbH /
Postfach 80 10 63 / D-81610 Munich / Germany / Tel: +089 45 44 – 01 / Fax: +089
45 44 - 13 29 / www.klinge.com, www.fujisawa.com. Each 300 mg capsule contains
240–290 mg native dry extract normalized to contain 50 mg triterpene
glycosides, calculated as escin. Extract is standardized by diluting with 10–60
mg dextrin.
*American equivalents, if any, are found in the Product
Table beginning on page 398.
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