Horse Chestnut

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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