The seeds of horse chestnut, Aesculus hippocastanum, have long been used in Europe to treat venous disorders such as varicose veins. The saponin glycoside aescin from horse chestnut extract (HCE) inhibits the activity of lysosomal enzymes thought to contribute to varicose veins by weakening vessel walls and increasing permeability, which result in dilated veins and edema. In fact, recent research has shown that A hippocastanum inhibits only against hyaluronidase but not elastase, and this activity is linked mainly to the saponin escin. In animal studies, HCE, in a dose-dependent fashion, increases venous tone, venous flow, and lymphatic flow. It also antagonizes capillary hyperpermeability induced by histamine, serotonin, or chloroform. This extract has been shown to decrease edema formation of lymphatic and inflammatory origin. Horse chestnut extract has antiexudative properties, suppressing experimentally induced pleurisy and peritonitis by inhibiting plasma extravasation and leukocyte emigration, and its dose-dependent antioxidant properties can inhibit in vitro lipid peroxidation. Randomized, double-blind, placebo-controlled trials with HCE show are eduction in edema, measured using plethysmography.
In another recent randomized, placebo-controlled study, the efficacy and safety of class 2 compression stockings and dried HCE were compared. Both HCE and the compression stockings decreased lower leg edema after 12 weeks of therapy; the results showed an average 43.8-mL reduction with HCE and 46.7-mL with compression stockings, while the placebo group showed an increase of 9.8 mL. Both HCE and compression therapy were well tolerated, with no serious adverse effects. This study may indicate that both of these modalities are reasonable alternatives for the effective treatment of patients with chronic venous insufficiency. Also, HCE has been shown to markedly improve other symptoms associated with chronic venous insufficiency, such as pain, tiredness, itching, and tension in the swollen leg, in a case-observation study. Aside from effects on venous insufficiency, prophylactic use of HCE has been thought to decrease the incidence of thromboembolic complications of gynecological surgery. However, since this issue is still controversial, this does not appear to be the case.
Standardized HCE is prepared as an aqueous alcohol extract of 16% to 21% of triterpene glycosides, calculated as aescin. The usual initial dosage is 90 to 150 mg/d of aescin, which may be reduced to 35 to 70 mg/d if clinical benefit is seen. Standardized HCE preparations are not available in the United States, but nonstandardized products may be available.
Some manufacturers promote the use of topical preparations of HCE for treatment of varicose veins as well as hemorrhoids; however, at least one study has demonstrated poor aescin distribution at sites other than the skin and muscle tissues underlying the application site. Moreover, the involvement of arterioles and veins in the pathophysiology of hemorrhoids makes the effectiveness of HCE doubtful, since HCE has no known effects on the arterial circulation. For now, research studies have yet to confirm any clinical effectiveness of topical HCE preparations.
Although adverse effects are uncommon, HCE may cause gastrointestinal irritation. Parenteral aescin has produced isolated cases of anaphylactic reactions, as well as hepatic and renal toxic effects. In the event of toxicity, aescin can be eliminated via dialysis, with elimination dependent on protein-binding. Horse chestnut extract is also one of the components of venocuran, a drug marketed as a treatment for venous disorders. In 1975, venocuran was determined to cause a pseudolupus syndrome characterized by recurrent fever, myalgia, arthralgia, pleuritis, pulmonary infiltrates, pericarditis, myocarditis, and mitochondrial antibodies in the absence of nuclear antibodies after prolonged treatment. Venocuran has since been withdrawn from the market; however, the nature of its pathophysiologic action is still unknown.
Like A hippocastanum, Ruscus aculeatus (butcher's broom) is also known for its use in treating venous insufficiency. Ruscus aculeatus is a short evergreen shrub found commonly in the Mediterranean region. Two steroidal saponins, ruscogenin and neurogenin, extracted from the rhizomes of R aculeatus are thought to be its active components. In vivo studies on hamster cheek pouch reveal that topical Ruscus extract dose dependently antagonizes histamine-induced increases in vascular permeability. Moreover, topical Ruscus extract causes dose-dependent constriction of venules without appreciably affecting arterioles. Topical Ruscus extract's vascular effects are also temperature dependent and appear to counter the sympathetic nervous system's temperature-sensitive vascular regulation: venules dilate at a lower temperature (25°C), constrict at near physiologic temperatures (36.5°C), and further constrict at higher temperatures (40°C); arterioles dilate at 25°C, are unaffected at 36.5°C, and remain unaffected or constrict at 40°C, depending on Ruscus concentration. Based on the influence of prazosin, diltiazem, and rauwolscine, the peripheral vascular effects of Ruscus extract appear to be selectively mediated by effects on calcium channels and 1-adrenergic receptors with less activity at 2-adrenergic receptors. Also, R aculeatus exhibits strong antielastase activity and has little effect on hyaluronidase in direct contrast to A hippocastanum. This activity may contribute to their efficacy in the treatment of venous insufficiency since these enzyme systems are involved in the turnover of the main components of the perivascular amorphous substance.
Several small clinical trials using topical Ruscus extract support its role in treating venous insufficiency. One randomized, double-blind, placebo-controlled trial involving 18 volunteers showed a beneficial decrease in femoral vein diameter (median decrease, 1.25 mm) using duplex B-scan ultrasonography. The decrease was measured 2.5 hours after applying 4 to 6 g of a cream containing 64 to 96 mg of Ruscus extract. In another small trial (N = 18) it was shown that topical Ruscus extract may be helpful in reducing venous dilation during pregnancy. Oral agents may be useful as topical drugs for venous insufficiency, although the evidence is less convincing. Although capsule, tablet, ointment, and suppository (for hemorrhoids) preparations of Ruscus extract are available in Europe, only capsules are available in the United States. These capsules contain 75 mg of Ruscus extract and 2 mg of rosemary oil. Aside from occasional nausea and gastritis, adverse effects from using R aculeatus have rarely been reported, even in high doses. Nevertheless, one should be wary of any drug that has not been thoroughly tested. Although there is ample evidence to support the pharmacological activity of R aculeatus, there is still a relative deficiency of clinical data to establish its actual safety and efficacy. Until more studies are completed, no recommendations regarding dosage can be offered.
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