Treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone (coumarin). Reduction of filaritic lymphoedema and elephantiasis by 5,6 benzo-alpha-pyrone (coumarin), and the effects of diethylcarbamazine (DEC). Treatment of secondary lymphedema of the upper limb with CYCLO 3 FORT. Efficacy of Daflon 500 mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer). Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. The effects of 5,6 benzo-[a]-pyrone (coumarin) and DEC on filaritic lymphoedema and elephantiasis in India. Preliminary results. Comparative study of the clinical efficacy of two different coumarin dosages in the management of arm lymphedema after treatment for breast cancer. The use of 5,6 benzo-[alpha]-pyrone (coumarin) and heating by microwaves in the treatment of chronic lymphedema of the legs. A double-blind, cross-over trial of O-(beta-hydroxyethyl)-rutosides (benzo-pyrones) in the treatment of lymphoedema of the arms and legs. [Benzo-pyrones in the treatment of chronic lymphoedema of the arms and legs]. Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone.
To study efficacy of treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone.
                Randomised, double blind, placebo controlled study with matching for grade and duration of disease, age, and sex. Treatment was given for 367 days, and subjects were followed up for another year.
                A town in Shandong Province, China.
                104 men and women with chronic unilateral filarial lymphoedema or elephantiasis of the leg: 64 were randomised to benzopyrone and 40 to placebo. By the end of the study 19 patients had dropped out of the treatment group and two out of the placebo group.
                Two 200 mg tablets of 5,6-benzo-alpha-pyrone or two placebo tablets given daily.
                Volumes of the affected and normal legs estimated every three months, and daily listing of any side effects.
                Benzopyrone reduced oedema for all grades of lymphoedema during the year of treatment (pW0.001) and the follow up year (p = 0.026). During treatment the mean monthly reductions in leg volume were 0.62% (95% confidence intervals 0.4% to 0.85%), 1.1% (0.71% to 1.6%), and 1.6% (0.89% to 2.3%) of the volume of the normal leg for grades 1, 2, and 3-5 (elephantiasis) of lymphoedema respectively. During follow up the mean monthly reductions were 0.18% (0.01% to 0.35%), 0.54% (0.27% to 0.82%), and 0.87% (0.51% to 1.2%). At the end of the trial the total reduction in oedema was 100%, 95%, and 45% for grades 1, 2, and 3-5. Symptoms and complications were considerably reduced, including attacks of secondary acute inflammation, while side effects were minor and disappeared after one month. In the placebo group there were no changes in the severity of lymphoedema.
                5,6-benzo-alpha-pyrone reduces the oedema and many symptoms of filarial lymphoedema and elephantiasis. It has few side effects, and its relatively slow action makes it ideal for use without compression garments. Chronic filaritic lymphoedema and elephantiasis, in India, were treated orally with 5,6 benzo-alpha-pyrone (56 BaP; 1,2 benzo-alpha-pyrone; coumarin) in a double-blind, randomized, matched-group trial. Each group finally contained 40-55 patients. Patients were observed for about 2 years (ranging from 6 to 45 months, with 75% completing the 2 years). The 56 BaP slowly, but very significantly (P < 0.0001), reduced all grades of lymphoedema and elephantiasis. Two thirds of the oedema was lost by grade 2 over 2 years. Grades 3 to 5 were reduced by a fifty over that time. The greater the initial oedema, the greater was its rate of resolution. A slowly worsening condition thus became a slowly improving one. Slowness has its advantages: compression stockings, that are impractical in hot, wet or dirty conditions, are not necessary. The slowly remodelling fibrous tissue, while lessening in amount, is still able to hold the tissues together. The 56 BaP considerably improved many symptoms and complications, particularly bursting-pains, inflammation and ulcers. It is cheap and of very low toxicity. Diethylcarbamazine (DEC) was studied with and without 56 BaP. DEC alone gave some reduction of the oedema, but this was much smaller than that with 56 BaP. It considerably worsened the reductions by 56 BaP, while 56 Bap slightly improved those by DEC and reduced the fever caused by DEC. Together, they reduced feelings of swelling and bursting-pain, fungal infections, lymphangitis and lymphadenitis more than when used alone. Fifty seven patients with secondary lymphedema of the upper limb after previous treatment for breast cancer were treated for 3 months with an extract of Ruscus + Hesperidin Methyl Chalcone (CYCLO 3 FORT) or placebo according to a double-blind protocol in the context of a controlled clinical trial. All patients also underwent manual lymphatic drainage twice a week for at least one month. With CYCLO 3 FORT, the reduction in volume of arm edema, the main assessment criteria, was 12.9% after 3 months of treatment as compared with a placebo (p=0.009). Decreased edema tended to be more marked in the forearm compared with the upper arm where excess fat deposition seemed to dominate over excess fluid accumulation. CYCLO 3 FORT was well tolerated with minimal adverse reaction. To assess the activity of a purified, micronized, flavonoidic fraction (Dios; Daflon 500 mg*) on upper limb lymphedema occurring after breast cancer therapy, a monocenter, randomized, double-blind, parallel group vs placebo (Plac) trial was carried out. One hundred and four women with lymphedema were included; 94 completed the study (46 Dios, 48 Plac). A subset of 24 patients with more severe lymphedema (10 Dios, 14 Plac) was subjected to a separate analysis. Treatment consisting of Dios or Plac was given two tablets daily over a six-month period. A radionuclide lymphoscintigraphy using technetium-99m was performed at inclusion and at the end of the treatment. The upper limb volume was measured every two months. In the overall population the evolution of parameters was not different between Dios and Plac. In the 24 patients with a more severe lymphedema, the lymphoscintigraphic parameters (m +/- sd) were as follows: lymphatic migration speed was significantly improved by Dios in comparison with Plac (delta Speed cm/minute: 0.84 +/- 0.6 vs 0.14 +/- 0.26, P = 0.005). The half-life of the colloidal compound was significantly improved over time in the Dios group (delta half-life = 10.3 +/- 13.07 minute, P = 0.034) but not in the Plac group (delta half-life = 0.53 +/- 15.51 minute, P = 0.086). The change over time of colloidal clearance was close to significance in the Dios group (delta clearance microL/minute: 2.18 +/- 3.10, P = 0.054) but not in the Plac group (0.11 +/- 2.26, P = 0.86). No significant difference was found for evolution of lymphedema volume, despite a tendency in favor of Dios. This can be related to wide distribution of volume values and small numbers of patients. In conclusion, these results suggest a beneficial therapeutic activity of Dios at the usual dose of two tablets/day in patients affected with more severe lymphedema. The clear improvement of the lymphatic speed illustrates its known lymphokinetic activity. Further studies with a higher dosage could confirm the beneficial activity of this drug in secondary lymphedema. Lymphedema of the arms can be a serious consequence of local and regional therapy in women with breast cancer. Coumarin has been reported to be effective for the treatment of women with lymphedema; we undertook a study in which we attempted to replicate those findings.
                We studied 140 women with chronic lymphedema of the ipsilateral arm after treatment for breast cancer. The women received 200 mg of oral coumarin or placebo twice daily for six months and then the other treatment for the following six months. The end points of the study consisted of the volume of the arm (calculated from measurements of hand and arm circumference) and the answers on a questionnaire completed by the patient about symptoms potentially related to lymphedema.
                The volumes of the arms at 6 and 12 months, were virtually identical, regardless of whether coumarin or placebo was given first. After six months, the average volume of the affected arm increased by 21 ml during placebo treatment and 58 ml during coumarin treatment (P=0.80). In addition, answers to patient-completed questionnaires were similar in the two treatment groups. After six months only 15 percent of the women in the coumarin group and 10 percent of those in the placebo group reported that the study medication had helped a moderate or large amount (P=0.19). Coumarin was well tolerated, except that it resulted in serologic evidence of liver toxicity in 6 percent of the women.
                Coumarin is not effective therapy for women who have lymphedema of the arm after treatment for breast cancer. A randomized double-blind, placebo-controlled, trial of 5,6 benzo-[alpha]-pyrone (coumarin, '56 BaP') and of diethylcarbamazine (DEC) is being performed on patients with filaritic lymphoedema and elephantiasis over two years, using matched groups. In 169 patients there were significant (1% level) reductions in the amounts of oedema for the patients taking 56 BaP. The excess limb volumes were reduced from 40 to 25% over two years. A similar, but less significant (5% level), improvement was found for the circumference measurements. The rate of reduction was increased when the initial amount of oedema was greater. This therapy, while much slower than many other methods of treatment, does convert a slowly worsening condition into a slowly improving one. There were no significant reductions in the amount of oedema following DEC treatment. In a randomized, double-blind, parallel group study, we compared the clinical efficacy of coumarin 90 mg/day (Group A) with 135 mg/day (Group B) in 77 women (age 35-65 years) with lymphedema of the upper limb secondary to surgery and irradiation for treatment of breast cancer. During 12 months of coumarin therapy, the arm volume of lymphedema and a clinical score (degree of arm edema, heaviness, hardness, and neuralgia/dysesthesia) were determined. In both groups, the volume of arm lymphedema decreased (14.9% in Group A and 13.2% in Group B) (N.S.), the overall clinical score improved (12.9 +/- 4.3 to 5.7 +/- 3.5 in Group A and from 11.7 +/- 3.7 to 4.7 +/- 3.9 in Group B) (N.S.), and the overall efficacy of coumarin was similarly good or excellent (71.9% in Group A and 68.6% in Group B) (N.S.). Only mild to moderate side effects of drug therapy were recorded. Coumarin prevents a spontaneous trend toward an increase in arm lymphedema after treatment of breast cancer, decreases the severity of local symptoms, and overall improves the quality of life. No difference was found between the apparent benefits of coumarin at 90 mg/day compared with 135 mg/day. Sixty patients with leg lymphedema from a variety of etiologies were divided into randomized two groups, matched by Grade, duration, age, sex, and cause of lymphedema. Using a double-blind format, one group received 5,6 benzo-[alpha]-pyrone (coumarin 1,2 benzopyrone, 400 mg/day) for six months; the other received a placebo. For the next six months, both groups received a standardized regimen of heat (using microwaves) coupled with compression garments. Benzopyrone produced approximately 20% reduction in the volume (p = 10(-4)) and improvement in circumferences and tonometry (p = 10(-5) and 10(-7)). Symptoms (feelings of swelling, pain, heaviness and loss of mobility) were also significantly improved (p = 0.03 to 10(-7)). During the second six months, when microwave heat therapy was added to drug therapy, the patients who had previously received the placebo showed significant improvement (p = 0.03 to 10(-9)) in signs and symptoms of lymphedema. Some, but not all, of the group that was receiving benzopyrones were also significantly improved by heat therapy (p = 0.8 to 0.002). Taking benzopyrones for 12 months plus heat treatment for six months was significantly better, for some criteria, than the placebo plus heat therapy (p = 0.7 to 0.04). On the other hand, heat plus either placebo or benzopyrone was often significantly better than either the active or inactive drug without heat (p = 0.8 to 10(-9)). A randomised, double-blind, cross-over trial was performed on 26 patients with postmastectomy lymphoedema of the arm, and 14 with lymphoedema of the leg. For 6 months, patients took 0-(beta-hydroxyethyl)-rutosides (oxerutin; "Paroven", "Venoruton", Zyma) in doses of 3 g/day, or the placebos; then they took the reverse. Measurements (volume, circumferences, tonometry and skin temperature) were made monthly. The active drug reduced the volumes of the limbs (p less than 0.05 to 0.01) and their circumferences (p less than 0.05 to 0.001). It increased the softness of the limbs, as shown by the increases in the tonometry values (p less than 0.01 to 0.001). There was a lowering of the elevated skin temperatures (p less than 0.05 to 0.001). Patients reported increased comfort and freedom of movement, a lessening of their bursting pains, heaviness and tension (p less than 0.05 to 0.01), and an increased mobility of their limbs (p less than 0.0001). Most patients (70%) preferred the active drug (p less than 0.0001). An increase in general well-being was reported by 97% of patients when taking the active drug compared with 4% for placebo (p less than 0.0001). nan Benzopyrones can reduce the volume of high-protein edema fluid by stimulating proteolysis. These compounds provide a method for removing excess protein and its consequent edema and reduce its clinical sequelae, such as chronic inflammation and secondary infections.
                We conducted a randomized, double-blind, placebo-controlled, crossover trial of 5,6-benzo-[alpha]-pyrone in 31 patients with postmastectomy lymphedema of the arm and 21 patients with lymphedema of the leg of various causes (this agent, also known as 56 BaP, 1,2-benzopyrone, or coumarin, is not an anticoagulant). The patients received 400 mg of the active drug or placebo, each for six months.
                During the placebo period, lymphedema often worsened, especially in the arms. Measurements of limb volume showed that the active drug reduced the mean amount of edema fluid in the arms from 46 percent above normal to 26 percent above normal (P < 0.001) and the amount in the legs from 25 percent to 17 percent above normal (P < 0.001). The circumference of the arms was reduced from 17 percent to 13 percent above normal, and the circumference of the legs from 11 percent to 7 percent above normal (P < 0.001). The softness of the limb tissue was increased (P < 0.001), and elevated skin temperatures were reduced (P < 0.001). There were fewer attacks of secondary acute inflammation (P = 0.01). Bursting pains and feelings of hardness were decreased, as were feelings of tightness, tension, swelling, and heaviness; limb mobility also improved. The active drug was preferred to the placebo by 93 percent of the patients (P < 0.001). Side effects--mild nausea or diarrhea--occurred in seven patients taking the active drug. None withdrew from the trial, and the side effects disappeared after the first month of therapy.
                5,6-Benzo-[alpha]-pyrone results in slow but safe reduction of lymphedema of the extremities.
It is not possible to draw conclusions about the effectiveness of Benzopyrones in the management of lymphoedema from the current available trials.