Age, sedentary lifestyle, and obesity favor chronic venous insuffi ciency (CVI)— all fac- tors with increasing importance in modern industrial societies. Primarily a vascular disease characterized by insuffi cient blood fl ow, edema, and heavy legs, CVI will cause itching, dark- ening, and hardening of lower leg skin and fi nally ulcera, thus entering the fi eld of dermatol- ogy. Physical training is regarded as the best therapy, but many older patients are limited in this respect. Compression stockings and diuretics may give some relief, but their effect is only symptomatic. Topically applied creams and ointments have, apart from short- time re- lief from itching or infl ammation, little effect beyond the physical massage pro cess and of- ten bear a risk of causing an allergic rush. There is, however, no convincing orally applied synthetic drug either.
Some botanicals reduce edema and infl ammation, display antioxidative and proteolytic effects, and are able to seal the capillaries in CVI. Furthermore, they increase the venous tone and enhance the lymphatic fl ow. Orally administered botanicals for the venous system are especially used in the case of insuffi ciency, contraindication, or intolerance of compres- sion therapy. Several botanicals are traditionally used to treat CVI and are fi rst- line treat- ments for this indication today.
Extracts from the seeds of the horse chestnut (Aesculus hippocastanum) with the major constituent escin, a complex mixture of biologically active triterpenes, have traditionally been used to treat patients with CVI and to alleviate associated symptoms, including lower leg swelling. The effi cacy of preparations containing horse chestnut seed extract is believed to be largely caused by an inhibitory effect on the catalytic breakdown of capillary wall proteo- glycans (75) [LOE- D]. More than a dozen placebo- or reference- controlled clinical trials have shown that horse chestnut extract is superior to placebo and as effective as reference medica- tions in improving objective symptoms of CVI like pain and leg volume (76) [LOE- A].
Flavonoid- containing drugs: Japa nese pagoda tree (Styphnolobium japonicum) extract
(77) [LOE- D]. The capacity of 1 to 2 g oxerutin (syn. 7- O-g- hydroxyethyl- rutosides) daily to improve symptoms of CVI stages I and II and to protect long- distance fl yers from edema with ankle swelling and pain was reported in several controlled clinical trials, for example, (78– 80) [LOE- A]. In a double- blind, randomized, placebo- controlled multicenter study, the effi cacy of oxerutin has been evaluated in 120 female patients suffering from stage II CVI. The patients received 1 g oxerutin daily over a treatment period of 12 weeks with a follow- up period of 6 weeks. It turned out that the oxerutin treatment combined with compression therapy was signifi cantly superior to compression therapy alone with regard to edema re- duction. Moreover, the therapeutic effect of oxerutin was per sis tent even after cessation of the treatment (81) [LOE- A].
Rutin derivatives (“fagorutin”) are also found in buckwheat (Fagopyrum esculentum); a randomized, double- blind, placebo- controlled clinical trial with 67 patients suffering from CVI found no change in leg edema during 12 weeks of treatment phase but a signifi - cant increase in the placebo group. Changes in other pa ram e ters were not signifi cant (82) [LOE- A].
Red wine leaf (Vitis viniferae folium) extract is an herbal medicine containing various fl avonoids, with quercetin- 3- O-beta- glucuronide and isoquercitrin (quercetin- 3- O-beta- glucoside) as the main components (83). Red wine leaf extract has been administered orally in once- daily doses of 360 mg and 720 mg in comparison to placebo in a 12- week, random- ized, double- blind, placebo- controlled, parallel- group, multicenter study in patients with stage I and incipient stage II CVI. The extract was safe and effective in a dose- related manner in the treatment of mild CVI, signifi cantly reducing edema and circumference of the lower leg and improving CVI- related symptoms to a clinically relevant extent. The edema reduction was at least equivalent to that reported for compression stockings and/or other edema- reducing agents (83) [LOE- A].
An extract from French maritime pine bark (Pinus maritima) (pycnogenolTM) standard- ized for oligomeric proanthocyanidins has been shown to be benefi cial at 150 mg daily in the treatment of CVI in a randomized, placebo- controlled, four- week trial with 39 patients; resting fl ux, rate of ankle swelling, edema, and a complex analogue scale for symptom rat- ing all showed signifi cant improvement versus start and versus placebo (84) [LOE- A]. In an open, controlled study with 40 patients comparing the effi cacy of 360 mg pycnogenol daily to 600 mg horse chestnut seed extract over a period of four weeks, both medications were equally well tolerated, but French maritime pine bark extract was superior to the horse chestnut seed extract (85) [LOE- B]. Diosmin, a fl avonoid glycoside found in citrus fruits, has also been shown in several randomized, controlled clinical studies to reduce edema and accelerate venous ulcer healing by anti- infl ammatory action in patients suffering from CVI (86, 87) [LOE- A].
Butcher’s broom (Ruscus aculeatus) is an orally used botanical medicine containing ste- roid saponines (ruscogenins) for the treatment of lower leg edema in patients with CVI. The effi cacy and safety of a Ruscus extract has been confi rmed in a multicenter, double- blind, randomized, placebo- controlled trial with 166 women suffering from CVI (88) [LOE- A].
Not directly aiming at CVI but nevertheless interesting, 400 mg daily of an extract of yel- low sweet clover (Melilotus offi cinalis) containing 8 mg coumarin has been shown to be ef- fective in reducing lymphedema of the upper arm caused by lymphadenectomy for breast cancer. A possible mode of action is the edema- preventing property of coumarines that results from the activation of macrophages and subsequent proteolysis in the tissue affected by chronic lymphedema (89) [LOE- C].
An uncontrolled clinical trial with a cream containing yellow sweet clover and Butcher’s broom revealed improvement of edema, pain, heaviness, and itch of patients suffering from CVI. The cream was well tolerated (90) [LOE- C]. Another comparative controlled study suggests mild effi cacy of the combination of a- tocopherol, rutin, Melilotus offi cinalis, and
Centella asiatica administered orally in patients with CVI (91) [LOE- A].
In summary, there are some botanicals that are widely used and intensively investigated in CVI. Design and conductance of virtually all clinical trials have been criticized repeat- edly, and clinical evidence for the use of oral botanicals in CVI was questioned (92). This, however, also applies to all other CVI therapies; high response to placebo may also be a reason why studies in venous insuffi ciency are diffi cult to perform (92). Nevertheless, the products are well accepted by the patients. Apart from minor or major shortcomings in in- dividual studies, the broad data basis for chestnut and fl avonoid drugs supports their use- fulness as experienced by patients and therapists.