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12.28.05 (2 years ago)
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Coumarin (Chemical Abstracts Service registry number 91-64-5; NSC 8774; systematic name 2H-1-Benzopyran-2-one, also referred to as 5,6-benzo-[a]-pyrone), is a compound that has been studied for the management of high-protein lymphedemas such as those associated with local and regional treatments for neoplastic diseases.[8,9]
BENZOPYRONES
Benzopyrones are a type of flavonoid; one of the main benzopyrones that has been of interest in relation to lymphedema is coumarin. This compound should not be confused with the powerful blood thinner coumadin, which is a derivative of coumarin; coumarin does not have the anticoagulant properties (see note following Table 3). The story of benzopyrones has been developed primarily by one individual: J.R. Casley-Smith. He has been publishing articles about lymphedema and its treatment for more than 40 years (10). He described the use of benzopyrones, coumarin and troxerutin, for this purpose in 1974 (11). In fact, there are 58 published articles (including published letters, editorials, and conference reports) on lymphedema by Casley-Smith. Most of the articles are either about, or include mention of, the benzopyrone treatments.
According to Casley-Smith, benzopyrones function by inducing macrophages, increasing both their number and their activity. These macrophages then lyse the proteins in the lymphatic fluid. The resulting smaller proteins can then be resorbed, with concurrent reduction in water volume of the affected area. Further, the benzopyrenes may aid in the movement of the collected lymphatic material by other mechanisms of cellular stimulation. The claim is that the benzopyrones begin acting within about 24 hours of ingestion but that the process of resolving lymphedema by their use can take several months. In one study using a mixture of flavonoids different than those relied on by Casley-Smith but, presumably, with the same action, improvements were said to be observed starting from the third month of treatment (12). The usual treatment time in clinical trials for lymphedema using benzopyrones is six months. While Casley-Smith indicates that the benzopyrones do not remove the cause of protein-rich edemas for which it is effective, the improvement is said to be very useful. Even topical application of the benzopyrones is said to be of benefit and combined topical and internal treatment is reported to yield the best results (13).
Coumarin, the benzopyrone claimed to be highly effective in relatively low dosage (about 400-800 mg/day), is commonly found in sweet clover (Melilotus officinalis) and tonka beans (Dipteryx odorata) which are the main natural sources for the lymphedema-resolving drug products that are available in several countries (but not the U.S.). Other flavonoids have been claimed to be effective, including diosmin, which is derived from citrus and is made into a drug product in Europe for vein problems that include edema. Aesculin, a related compound from horse-chestnut, has been recommended for treatment of venous insufficiency and is considered a potential treatment for lymphedema, especially of the legs. It is not known, at this time, what range of flavonoids are effective.
The degree of effectiveness of benzopyrones for lymphedema is not well-established; Casley-Smith describes the action as slow but safe, with the ability to change a gradually worsening condition into a gradually improving one. There is some research activity regarding the benzopyrones outside of the Casley-Smith facility of Australia
, especially in Italy.
Benzopyrone treatment has not been approved in the U.S. and a study that might have led to its use here yielded a negative result. The study was conducted at the Mayo Clinic and tracked 140 women taking either placebo or 200 mg of coumarin twice daily (total: 400 mg, the usual recommended dosage that is reported effective in other studies). No significant difference was noted, and a potential negative effect was observed: 6% of the women showed some evidence of liver toxicity (14). Casley-Smith has relayed Australian data that suggests a 3% incidence of liver toxicity from use of coumarin, and also mentions some cases of nausea or diarrhea from the treatment. In a study he published in the New England Journal of Medicine (5), benefits of the treatment were described in terms of reduction in volume of the affected limb. The lymphedema in arms was 46% above normal volume before treatment and reduced to 26% above normal volume after six months; in legs, the change was from 25% above normal to 17% above normal. In other words, the lymphedema was only partly reduced and required prolonged therapy. Therefore, while benzopyrones may have an effect on lymphedema, the search for other natural substances that might be of benefit should continue.
Coumarin occurs widely in the plant kingdom, but is usually present only in trace quantities. It is not found in significant amounts in herbal medicines, but other closely related compounds are found. It is interesting to note that the formulas of Gong Tingxian depicted in Table 1 always include one or more of the benzopyrone-containing herbs (see Table 3). Other herbs in the formula may contain active constituents different than the benzopyrones that could have an effect on edema.
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