Horse Chestnut Seed Extract vs. Pycnogenol® for Chronic Venous Insufficiency

By Francis Brinker, ND

Chronic venous insufficiency (CVI) is a problem of the lower extremities for both youth and adults, affecting 20%-25% of women and 10%-15% of men. Though it can be more cosmetic than symptomatic, it often increases in severity until complications such as dermatitis, ulceration, or phlebitis result. Progressive etiology begins with weakness of the connective tissue and smooth muscle in the vessel wall, leading to damage to the endothelium and valves, which ultimately results in disturbed microcirculation and stasis. Hospitalization and surgery may be warranted when mechanical compressive therapy is inadequate. Therefore, botanical approaches with evidence of efficacy and safety deserve to be seriously considered as alternative or complementary therapies and potential preventive measures.

In 1984 the German Commission E approved the oral use of horse chestnut seed extract (HCSE) from Aesculus hippocastanum, supplying 100 mg/d of escin (a saponin mixture also spelled as "aescin"), for pathological conditions of veins. This approval was renewed in 1994 for CVI characterized by leg pains with associated itching, swelling, and/or a sense of heaviness, as well as nocturnal cramps in the calves.1 HCSEs are 5-8:1 (w/w) strength dry native extracts made from dried seeds, normally standardized to a 16%-20% triterpene saponin escin fraction, while containing flavonoids and other relatively minor constituents. The seeds contain at least 3% escin.2 HCSE is recommended clinically in conjunction with other prescribed non-invasive treatments including supportive elastic stockings, leg compresses, or cold water applications.1

In addition to HCSE, another botanical extract is gaining attention for positive effects observed in clinical trials for CVI. The French maritime pine bark extract from Pinus pinaster ssp. atlantica, in the form of the commercial product PycnogenolÒ, has been studied for this vascular disorder. This extract consists largely of oligomeric procyanidins and their monomeric catechin and epicatechin units, along with minor constituents such as taxifolin, phenolic acids, and their glucosides and glucose esters, respectively. The comparative usefulness of HCSE and Pycnogenol has become relevant as they may both provide suitable options for treating CVI, varicosities, and associated symptoms.2

Pharmacology of HCSE and its Saponins

Within the last decade, pre-clinical studies have documented several mechanisms that appear to be major contributors to HCSE’s beneficial effects. Ex vivo research demonstrated its independent contractile properties on isolated veins, increase in the contractile response to norepinephrine, and resultant increase in venous pressure. In a dose-dependent fashion it was found to decrease experimental edema and capillary hyperpermeability induced by inflammatory agents such as histamine and serotonin when given orally to rats. HCSE also inhibits free radical damage in vitro and in vivo in mice and rats.3

The escin components of the saponin fraction of the seeds given orally to rats likewise inhibited experimental edema and reduced vascular permeability induced by histamine and serotonin.4 The mechanisms involved in these effects include calcium ion channel sensitization to reduce vascular permeability and enhanced generation of prostaglandin F2a in the veins to increase venous tone. Additional inhibition of proteoglycan degradation in the capillary endothelium and extravascular matrix also may be involved.5 By inhibiting the enzyme hyaluronidase, escin may facilitate venous strengthening provided by perivascular connective tissue.6

Prior HCSE Reviews and Meta-Analyses

An excellent review of CVI treatment with HCSE by Szapary and Cirigliano published in this newsletter7 discussed a 1998 systematic review of 13 randomized controlled trials (RCTs) meeting suitable methodological criteria.8 The relative value of these isolated studies was limited by their small sizes (20-240 participants) and short durations (2-12 weeks). However, since HCSE compared favorably to other therapies (including one compression study and three studies with 500-2,000 mg/d oxerutin) and was found superior to placebo (eight studies) in 1,083 total participants, it has demonstrable clinical applicability.

A subsequent meta-analysis considered, in addition to 13 RCTs of at least 20 days with HCSE (1,051 patients), three observational studies with compiled results from 10,725 patients with CVI.9 The quality of each study, assessed in a range from 0 (poor) to 6 (excellent), found the average was 5 for the RCTs and 3 for the observational studies. Compared to placebo in the RCTs, those patients taking HCSE had reductions in leg volume and ankle circumference. In two of the observational studies 84% more patients had improved edema, 91% had reduced pain, and 85% had improved leg fatigue and heaviness. The third study supported these findings but its results could not be pooled because of differences in reporting data. No severe adverse events were reported.

Pharmacology of Pycnogenol and its Procyanidin Polyphenols

The anti-inflammatory activity demonstrated in mice by Pycnogenol and its fractions correlated with free radical scavenging effects demonstrated in vitro.10 One potential mechanism of the anti-inflammatory effect of this polyphenolic-rich extract was shown in down-regulation of pro-inflammatory interleukin-1b gene expression and production in vitro.11 Pycnogenol’s protective effect as an antioxidant was demonstrated by increasing oxygen radical absorbance capacity in a six-week study of 25 healthy subjects taking 150 mg/d.12 When 60 patients with coronary artery disease were studied in a randomized, four-week, controlled, double-blind trial using 150 mg Pycnogenol three times daily, peri- pheral microcirculation improved as did myocardial ischemia.13 This may be due in part to increased nitric oxide production by vascular endothelium.10

Capillary fragility was reduced in rats with oral Pycnogenol comparable or superior to the effect of flavonoids given at higher doses.10 Oligomeric procyanidins as found in Pycnogenol have been shown to bind to elastin fibers and diminish their degradation in vitro and in vivo by the elastase enzymes that are released as part of inflammatory processes.14 Elastin fibers help maintain connective tissue integrity that is involved in vascular support. Procyanidins further protect connective tissue by their potent antihyaluronidase activity as demonstrated in vitro, while the Pycnogenol component taxifolin likewise has a mild antihyaluronidase effect.15

Review and Recent Clinical Studies with Pycnogenol for CVI

A 1999 review examined 15 clinical trials in which 595 of 784 patients were treated with Pycnogenol.10 This review included seven open studies (404 patients), five placebo-controlled, double-blind trials (149 patients), and three double-blind studies with placebo or reference drugs (231 patients). Overall, these clinical studies demonstrated clinical efficacy of Pycnogenol in patients with veno-capillary diseases, suggesting that oxidative processes have a role in venous diseases. A reduction in subcutaneous edema was associated with alleviation of the sensation of heavy legs. Reduced capillary permeability was observed, but not modification of venous blood flow.

One placebo-controlled trial with 40 patients found significant (P < 0.01) reduction on hydrostatic edema from sitting for one and two hours with 360 mg Pycnogenol daily for six days. In an unpublished controlled double-blind study with 40 patients, 300 mg daily for 60 days resulted in significant symptomatic improvement for Pycnogenol but not placebo, including reduced leg swelling (63%) and pain (67%). Another unpublished placebo-controlled study with 300 mg Pycnogenol daily involving 50 CVI and varicose vein patients found heaviness and edema steadily improved from baseline to 30 days (by 37%) and then from 30 to 60 days (by 36%) for a total reduction of 55%. In an active-medication controlled trial, Pycnogenol had no side effects and equivalent efficacy based on signs and symptoms when 240 mg for one week and 180 mg for five weeks were compared to 600 mg oxerutin for six weeks.10

A subsequent randomized, placebo-controlled, double-blind trial with 40 CVI patients studied 100 mg Pycnogenol three times daily for two months.16 Compared to placebo, significant reductions in subcutaneous edema (P < 0.01), heaviness (P < 0.01), and pain in the legs (P < 0.05) occurred after 30 and 60 days. After two months, 60% had complete disappearance of edema and pain. This was accompanied by a reduction of leg heaviness in almost all patients with its complete absence in about 33%. Placebo patients experienced no benefits; no effect on venous blood flow was observed in either group.

A more recent published study with 40 CVI patients treated 20 in an open phase and 20 in a double-blind phase with 100 mg Pycnogenol three times daily for two months.17 In the open phase there was significant reduction of heaviness and swelling after 30 days (P < 0.05) and 60 days (P < 0.01) compared to baseline. The double-blind phase found significant reductions for swelling after 30 days (P < 0.05), and in both parameters after 60 days (P < 0.05), compared to placebo. Venous pressure was significantly reduced after 60 days (P < 0.001) for those using Pycnogenol but not for placebo.

Comparative Study of HCSE and Pycnogenol

In 2002 Koch published the results of an open trial using the two botanical extracts with 20 CVI patients each over a four-week period.18 There were no significant differences between the two groups in their conditions or previous treatments. The relative doses were three 40 mg tablets of Pycnogenol three times daily (360 mg) or one capsule with 300 mg HCSE standardized to 50 mg escin twice daily (600 mg HCSE = 100 mg escin/d). Baseline parameters (leg circumference and symptoms scores) were re-measured at two-week intervals. Symptoms subjectively evaluated included pain, cramps, nighttime swelling, heaviness, and skin reddening. HCSE moderately, but not significantly, decreased leg circumference and reduced symptoms scores compared to baseline values. On the other hand, Pycnogenol significantly reduced leg circumference (P < 0.01) and subjective scores for pain, cramps, nighttime swelling, heaviness (P < 0.01), and reddening (P < 0.05) after two and four weeks. Both therapies were well tolerated. Unlike HCSE, Pycnogenol also significantly decreased cholesterol and LDL values by the end of the trial (P < 0.001).

Bioavailability and Relative Doses

Knowledge of the pharmacokinetics of escin in HCSE is based on studies using radioimmunoassays of b-escin, the major active component in the saponin mixture. Two HCSE tablet products standardized to 50 mg escin were compared in a randomized, open, crossover study with 18 healthy subjects through two 24-hour dosing cycles.5 The two products proved bioequivalent, with maximum b-escin serum concentrations from 16-18 ng/mL and the average concentration about 10 ng/mL. The second dosing cycle produced lower maximum (10-11 ng/mL) and average (7 ng/mL) levels. Effective adult HCSE doses in clinical studies provide the equivalent of 50-150 mg escin daily, with a typical dose of 300 mg extract (50 mg escin) every 12 hours.2,19

HCSE has been empirically used externally for symptoms associated with varicose veins, including leg swelling, pain, and heaviness and/or calf pain. The gel is standardized to 2% escin and usually applied to the affected area twice daily.2 Escin was shown to be absorbed after cutaneous application and to significantly reduce experimentally induced exudation by 19.9% (P < 0.005).20

Bioavailability of Pycnogenol is assumed on the basis of its clinical efficacy. None of its known components are excreted unchanged, but metabolites appear in the urine after oral ingestion. Taxifolin and ferulic acid are excreted as esters of glucuronic acid or sulphuric acid after four hours. The procyanidin metabolites are active valerolactones that are excreted as sulphates or glucuronides after 12-14 hours.21 Effective daily doses of Pycnogenol for CVI range from 100 mg to 360 mg, with 100 mg three times daily as the typical dosing schedule.2,18

Safety Issues with HCSE and Pycnogenol

The German Commission E monograph notes that itching, nausea, and gastric complaints have occurred in isolated cases after oral use of HCSE.1 Adverse drug reactions as documented in eight studies included GI symptoms, dizziness, nausea, headache, and itching, with a reported frequency between 0.9% and 3.0%. Three studies found no greater frequency than with placebo.8 This extract is not recommended for use in children, since no data support its use in this population. Children have been poisoned after consuming the raw seeds.19 No embryotoxic or teratogenic effects were found in rats or rabbits after intravenous doses of 30 mg/kg HCSE or oral doses of 100 or 300 mg/kg in rats. Only the 300 mg/kg dose in rabbits produced an undesirable effect: a mildly reduced average weight of the fetuses.22 Though not generally recommended for pregnant or nursing women, a controlled double-blind study using 600 mg HCSE (100 mg escin) daily with 52 pregnant women found no serious adverse effects after two weeks.19

Due to their content of the antiplatelet coumarin derivative esculetin, the potentially toxic whole seeds or tea should not be consumed. HCSE does not contain this component and is considered safe with oral HCSE dosing unless a patient has a rare allergic sensitivity to it or its components. HCSE should not be used with hypoglycemic agents such as insulin, sulfonylureas, or metformin.19 The escin fraction from the seeds has shown oral hypoglycemic activity in rats after a single 200 mg/kg dose, while its major components were active at 100 mg/kg.23 Some speculate that since escin binds to plasma protein it may affect the binding of other drugs.2

Aside from reductions in cholesterol measurements12,18 and platelet aggregation,13,24 no significant differences in physiological, hematological, or biochemical parameters have been observed in clinical studies with Pycnogenol.13,16,17 Pycnogenol has been associated with gastric upset, diarrhea, and constipation, so it is recommended that it be taken with meals. Based on reports from 2,000 patients, frequency of adverse drug effects including headaches and dizziness is 1.6% and is unrelated to dose or duration of treatment. It is not recommended during the first three months of pregnancy, though no mutagenic or teratogenic effects, perinatal toxicity, or antifertility effects have been shown in safety pharmacological studies.2

No drug interactions have been reported with Pycnogenol. However, it is recommended that combinations with antiplatelet drugs be avoided,2 for when 60 patients were studied in a randomized, four-week, controlled, double-blind trial using 150 mg Pycnogenol three times daily, platelet aggregation and adhesion decreased compared to placebo.13 On the other hand, this effect can provide beneficial consequences in regular tobacco use as seen in a series of studies with smokers. The smoking-induced increase in platelet aggregation was prevented with single doses of 500 mg aspirin = 100 mg < 150 mg < 200 mg Pycnogenol. While aspirin significantly increased bleeding time in the smokers, Pycnogenol did not.24


Chronic venous insufficiency is a common and progressive problem of the lower extremities that can lead to significant morbidity. Treatment with pharmaceutical grade botanical extracts has been shown to significantly improve clinical outcomes. Reduction of symptoms, such as heavy sensation, swelling, and pain in the legs, and objective decreases in leg volume and ankle circumference, have been documented after using standardized HCSE and Pycnogenol. Both appear to impact both causes and effects of inflammation as they act as free radical scavengers and inhibit enzymatic degradation of connective tissue. Consequently, they are able to reduce vascular permeability. In addition, the horse chestnut extract enhances vascular tone by influencing ion channel sensitization and prostaglandin production, while Pycnogenol improves microcirculation.

Reviews of multiple clinical trials indicate that each of these botanical products has been shown to be clinically safe and effective. In a comparative study with CVI, 40 patients using the standard HCSE daily dose (600 mg = 100 mg escin) and a relatively high Pycnogenol dose (360 mg), the Pycnogenol group experienced significant symptom relief and greater beneficial clinical outcomes than those using HCSE.


Pycnogenol appears to be the optimal first choice when instituting an oral phyto-pharmaceutical therapeutic trial to assist in the management of CVI and it sequellae. Often a single therapeutic approach is not completely effective on its own, and individual patient response ultimately determines which product will prove preferable. The focus thus far on botanical extract clinical studies has been the mono-treatment of patients having well-established pathologies. The possibility of combining Pycnogenol with HCSE, internally and/or topically, to improve therapeutic outcome is worthy of investigation. Regular walking and/or aquatic exercise help reduce distal fluid retention. Mechanical support from elastic stockings is an obvious useful adjunct. Other passive means such as tonic (cold water) hydrotherapy, massage, and postural elevation techniques for the lower extremities also can be considered.

One would expect the greatest benefit from employing a combination of internal and external medication together with patient-appropriate exercise and physical therapy, especially for patients with severe symptomatology who otherwise face the probability of surgical intervention. For those whose conditions have not reached such an extreme degree, prevention of pathological progression by the use of one or another of these botanical extracts along with physical adaptations remains a benefit well worth pursuing.

Dr. Brinker is an Instructor at the Program in Integrative Medicine at the University of Arizona, Tucson.


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