rutin and Lymphedema

Lymphoedema is the accumulation of excess fluid in the body caused by obstruction of the lymphatic drainage mechanisms. It can be caused by a number of factors, including congenital predisposition, parasitic infection or surgery. Lymphoedema is chronic and progressive and affects a significant proportion of the population. The standard treatment regimes include compression hosiery, skin care and exercise. The use of drugs in treatment, particularly benzo-pyrones, has gained favour over the last ten years. Benzo-pyrones, originally developed for use in vascular medicine, are prescribed to reduce vascular permeability and thus the amount of fluid forming in the subcutaneous tissues. Advocates for this treatment method believe that, as a result of reducing filtration, the drugs have some beneficial effect on pain and discomfort in the swollen areas. Proponents also claim that these drugs increase macrophage activity, encouraging the lysis of protein, which in turn reduces the formation of fibrotic tissue in the lymphoedematous limb.. To assess the effectiveness of benzo-pyrones compared to placebo or to different benzo-pyrones in reducing limb volume, pain and discomfort in lymphoedematous limbs. To assess the effect of benzo-pyrones on the quality of affected tissues and on the patient's quality of life and, finally, to establish the incidence of adverse effects. We searched the Cochrane Breast Cancer Group register (September 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4,2003), MEDLINE, EMBASE, CINAHL, UnCover, PASCAL, SIGLE, reference lists produced by The British Lymphology Society, the National Research Register (NRR) and The International Society of Lymphology congress proceedings.. Types of studies considered for review were randomised controlled trials testing Paroven, coumarin, Venastat, Cyclo 3 Fort or Daflon versus placebo (with both groups having or not having standard physical treatment. Eligibility for inclusion was confirmed by two blinded reviewers who screened the papers independently using a checklist of criteria relating to the randomisation and blinding of the trial. Both reviewers extracted data from the eligible studies using a data extraction form.. Overall, 15 trials were included that evaluated the role of benzo-pyrones. Three trials of oxerutin were found. Each tested the drug over 6 months using the same dose of drug against placebo. Two were crossover trials and one a parallel group trial with a total number of 127 participants and data available for only 81 of them. There were insufficient data provided in any of the trials to calculate the per cent reduction or increase in baseline excess limb volume. Standard deviations or confidence intervals and the numbers in the groups at the different stages of the trial were missing for all the data in two of the reports and for much of the data in the third, making any attempt at meta-analysis impossible. One trial testing Cyclo 3 Fort (approved name) over 3 months was found and involved 57 patients but provided insufficient data to allow a proper analysis of its findings. A single trial of Daflon (approved name) was found, lasting 6 months and involving 104 participants; once again there was insufficient information provided in the report to reach a conclusion about the effectiveness of the drug. Three trials of coumarin combined with troxerutin were found and tested two different doses of the drug against each other with no placebo, however, numbers of participants in the trial groups and baseline data were not provided. Eight trials of coumarin were identified. Two of the reports were confirmed as reporting the same trial and a further trial potentially also referred to the same trial but this was unconfirmed. A further two papers appeared to refer to the same trial but this was not confirmed. Three trials involved the same researcher. Five studies were conducted in India or China and they added anti-filarial dia or China and they added anti-filarial drugs to the interventions tested. The numbers of participants withdrawn and the numbers included in the analyses in all these trials were not extractable; the reporting of outcome measures in most of the trials was not clear. Loprinzi's 1999 trial in the USA reported the conduct of the trial and its findings with more detail, however, its conclusions were very much at odds with the findings of the other trials, finding that no difference was observed between those on the active preparation (coumarin) and placebo in any of the outcomes under investigation. This trial also reported a case of hepato-toxicity in a patient receiving the active preparation.. Meta-analysis was not performed due to the poor quality of the trials. It is not possible to draw conclusions about the effectiveness of Benzopyrones in reducing limb volume, pain, or discomfort in lymphoedematous limbs from these trials.

Topics: Anticoagulants; Benzopyrans; Coumarins; Diosmin; Extremities; Humans; Hydroxyethylrutoside; Lymphedema; Plant Extracts; Randomized Controlled Trials as Topic

The benzo-pyrones reduce all high-protein oedemas, including lymphoedema and elephantiasis, by increasing the numbers of macrophages and their normal proteolysis. Thus they remove the excess protein, and thereby the oedema which is caused by it. They also remove the stimulus it provides for chronic inflammation and fibrosis, and its action as a culture medium for bacteria. Coumarin (5,6 benzo-[alpha]-pyrone, 56 BaP) and oxerutins (HR, O(beta-hydroxy-ethyl)-rutosides) have been used in many clinical trials on a variety of high-protein oedemas. Four such trials are summarised here: on lymphoedema and elephantiasis (from many causes in Australia, and filaritic in India and China). The drugs reduced these much more slowly than adequate physical therapy, but they did reduce them. About half the excess volume was removed over six months in the Australian trials. In India and China similar rates were achieved with lymphoedema, but elephantiasis reduced at a slower rate. The benzo-pyrones convert a slowly worsening condition into a slowly improving one. No compression garments are necessary. In addition, the drugs considerably reduce the number of attacks of secondary acute infection, reduce the deformities of elephantiasis and considerably improve the patients' comfort and mobility. They may be taken orally, or applied topically, have very low toxicities and only few, minor side-effects. They are useful in many other forms of high-protein oedema, and improve the results of physical therapy for lymphoedema.

Topics: Administration, Cutaneous; Administration, Oral; Anticoagulants; Arm; Australia; China; Combined Modality Therapy; Coumarins; Double-Blind Method; Elephantiasis; Humans; Hydroxyethylrutoside; India; Leg; Lymphedema; Multicenter Studies as Topic; Physical Therapy Modalities; Randomized Controlled Trials as Topic; Time Factors

The pathogenesis of lymphedema is briefly reviewed. Swelling secondary to lymphostasis shares the common deleterious effects of other edemas, especially those of chronic high protein edema, namely chronic inflammation with excess tissue fibrosis. Benzo-pyrones are the only known drugs which reduce the excess protein in the tissues with high protein edema including lymphedema. Once excess tissue protein is resorbed, edema subsides and the fibrosis slowly resolves by remodeling. Two of these benzo-pyrone drugs have been shown to reduce postmastectomy and primary lymphedema in randomized, double-blind, cross-over, placebo-controlled trials. One of these drugs (which is also inexpensive) has also been shown to reduce filaritic lymphedema and elephantiasis in a similar trial in India. The bigger the leg initially, the more rapid is the reduction. In this extreme condition about a 20% lessening of the excess volume occurs each year. The benzo-pyrones do not work rapidly, but they do convert a rapidly worsening condition into a slowly improving one. In addition, they have extremely low toxicity and are effective orally. They also seem to reduce the incidence of secondary acute inflammation.

Topics: Clinical Trials as Topic; Coumarins; Diosmin; Elephantiasis, Filarial; Flavonoids; Humans; Hydroxyethylrutoside; Lymphedema; Rutin

Using previously presented data, from an open multi-centered trial, the Medians and Third Quartiles were calculated for the overall edema reductions the "average" patient received from an "average" therapist using Complex Physical Therapy (CPT) on 628 lymphedematous limbs. These data provide therapists and patients a general guideline as to the minimal reductions which can be expected in three quarters of patients from average therapists, using CPT with or without the administration of benzo-pyrones. Benzo-pyrones were considered separately: oral (given for three months before and for 11 months after the course of CPT) and topical (during and after CPT). Depending on which measure of edema and its alterations were used, these reductions increased those from CPT alone from 130% to 200% and, after one year, between 150% to 300%. Whereas the effects of oral and topical benzo-pyrones were not statistically different, their combined usage was more effective than use of either alone.

Topics: Administration, Oral; Administration, Topical; Anticoagulants; Arm; Combined Modality Therapy; Coumarins; Humans; Hydroxyethylrutoside; Leg; Lymphedema; Physical Therapy Modalities; Treatment Outcome

As overall conclusions from this study, and the two preceding comparable trials in which TcPO2 was measured in patients with (8) and without (7) stockings, we propose that: All patients with symptoms and oedema of CVI should be advised to wear suitable compressive stockings (this study); if they do wear stockings, then additional benefit may be derived from treatment with HR (8); for patients who are reluctant to wear stockings, for a variety of reasons, or in whom stockings may be contraindicated (e.g. mixed arterio-venous disease), then HR is an acceptable alternative (7 and this study).

Topics: Adult; Aged; Bandages; Blood Gas Monitoring, Transcutaneous; Female; Humans; Hydroxyethylrutoside; Lymphedema; Male; Middle Aged; Venous Insufficiency

Pregnancy is a critical risk for development of varicosis, therefore early detection and treatment are strongly recommended. In our study we examined 51 patients subdivided into three groups. One group underwent physical therapy (cold foot-baths in the morning an in the evening), the other group was administered beta-hydroxyethyl rutosides, and the patients of the third group had appeared only once for examination. Leg circumference and diameter of vein (by sonography) were measured, and the subjective criteria evaluated. In the group of patients who were additionally given drugs, a significant reduction of all parameters was found: leg circumference was reduced by 3% and diameters of veins were reduced by 15% on average, the reduction of the subjective criteria was by 34%. Provided the veins were prevented from further extension through progressive varicosis, apparent beneficial clinical effects can be achieved by administration of beta-hydroxyethyl rutosides.

Topics: Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hydroxyethylrutoside; Infant, Newborn; Lymphedema; Physical Therapy Modalities; Pregnancy; Pregnancy Complications, Cardiovascular

Topics: Anticoagulants; Capillary Permeability; Humans; Hydroxyethylrutoside; Lymphedema

The evaluation of the effects of venoactive drugs and particularly of Venoruton may be performed using microcirculatory parameters. Laserdoppler flowmetry may be used in association with PO2/PCO2 measurements. In this study we combined the microcirculatory evaluation with foot and leg volumetry to evaluate the effects of Venoruton in 15 patients with deep (popliteal vein) incompetence and venous hypertension, treated for 6 weeks. A control group of 20 patients was also evaluated. All these subjects were studied and selected according to ambulatory venous pressure measurements (AVP) and duplex scanning. Measurements were made at the internal perimalleolar region in constant temperature condition (23 degrees C). No variations of AVP or duplex scanning findings were observed after 6 weeks in both treated and untreated patients. Laserdoppler flowmetry showed a significant decrease of the resting flow (which was increased in all patients at the beginning of the study). An increased efficacy of the venoarteriolar response was also recorded together with an increased response of skin flow after increase of temperature in the perimalleolar region in patients treated with Venoruton. This was also associated with an increase of skin PO2 and with a decreased PCO2. In the control group no significant variations of these parameters were observed. Leg volume was also significantly decreased in the patients treated with Venoruton while no changes were observed in controls. In conclusion this study showed the efficacy of Venoruton in improving parameters altered in venous hypertension and the possibility of application of this microcirculatory model to study venoactive drugs used for treating venous hypertension.

Topics: Anticoagulants; Blood Gas Monitoring, Transcutaneous; Clinical Trials as Topic; Female; Humans; Hydroxyethylrutoside; Lasers; Leg; Lymphedema; Male; Microcirculation; Middle Aged; Postphlebitic Syndrome; Random Allocation; Rutin; Venous Insufficiency; Venous Pressure

The antioedematous effect of 0-(beta-Hydroxylethyl)-rutoside (HR)-drinking solutions with 600, 900, 1200 and 1500 mg active substance was tested in a randomized double-blind study against placebo with 30 female patients in the change of life. The decrease of the oedemas was measured by recording the change in the leg volume. The patients valued the symptoms "tired and heavy legs", "tenseness" and "tingling sensation". After 3 months the daily taking of HR-drinking solutions showed a significant decrease of leg volume. At the end of the treatment there was no significant difference between the four verum groups.

Topics: Administration, Oral; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Lymphedema; Middle Aged; Randomized Controlled Trials as Topic; Rutin; Venous Insufficiency

The pathogenesis of lymphedema is briefly reviewed. Swelling secondary to lymphostasis shares the common deleterious effects of other edemas, especially those of chronic high protein edema, namely chronic inflammation with excess tissue fibrosis. Benzo-pyrones are the only known drugs which reduce the excess protein in the tissues with high protein edema including lymphedema. Once excess tissue protein is resorbed, edema subsides and the fibrosis slowly resolves by remodeling. Two of these benzo-pyrone drugs have been shown to reduce postmastectomy and primary lymphedema in randomized, double-blind, cross-over, placebo-controlled trials. One of these drugs (which is also inexpensive) has also been shown to reduce filaritic lymphedema and elephantiasis in a similar trial in India. The bigger the leg initially, the more rapid is the reduction. In this extreme condition about a 20% lessening of the excess volume occurs each year. The benzo-pyrones do not work rapidly, but they do convert a rapidly worsening condition into a slowly improving one. In addition, they have extremely low toxicity and are effective orally. They also seem to reduce the incidence of secondary acute inflammation.

Topics: Clinical Trials as Topic; Coumarins; Diosmin; Elephantiasis, Filarial; Flavonoids; Humans; Hydroxyethylrutoside; Lymphedema; Rutin

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).

Topics: Arm; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Leg; Lymphedema; Male; Mastectomy; Middle Aged; Postoperative Complications; Random Allocation; Rutin; Skin Temperature

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Lymphedema; Middle Aged; Rutin; Venous Insufficiency

Topics: Adult; Aged; Coumarins; Double-Blind Method; Drug Combinations; Female; Humans; Hydroxyethylrutoside; Ischemia; Leg; Lymphedema; Male; Middle Aged; Postoperative Complications; Rutin

A new reversible complex between troxerutin and phosphatidylcholine (85-90mg/kg per day), in the form of a liposome-like water microdispersion, was topically applied to the rat thigh in an experimental counterpart of acute lymphedema. After four days there was 75% less hindlimb edema (mean decrease 40% of normal compared to control 10% of normal) in the treated compared with the untreated rats. These findings suggest that this drug preparation may be useful to minimize acute peripheral lymphedema in patients.

Topics: Administration, Topical; Animals; Drug Carriers; Hindlimb; Hydroxyethylrutoside; Liposomes; Lymphedema; Phosphatidylcholines; Rats

The effect of O-(beta-hydroxy-ethyl)-rutosides (HR), injected subcutaneously, was investigated on experimental acute lymphoedema in rat thighs. The oedema was reduced from a 30% increase over the normal weight, to one of 13%. When the macrophages were destroyed by the intraperitoneal injection of silica (for eight days before the initiation of lymphoedema) the oedema of the thigh increased to 41% - thus showing the importance of these cells in limiting high-protein oedemas. When HR was given to animals treated with silica the oedema was no longer reduced (42%). Thus HR reduces a high-protein oedema substantially via the macrophages.

Topics: Animals; Hindlimb; Hydroxyethylrutoside; Lymphedema; Macrophages; Male; Proteins; Rats; Rats, Inbred Strains

Topics: Adult; Chemical and Drug Induced Liver Injury; Coumarins; Drug Combinations; Female; Humans; Hydroxyethylrutoside; Jaundice; Lymphedema; Rutin; Turner Syndrome

Lymphoedema of the arm is a disabling complication of surgery for cancer of the breast. It occurs in a significant proportion of patients and tends to occur later after the operation. Radiation increases the incidence. It needs to be differentiated for tumour recurrence and venous obstruction. Aetiology may include surgical technique, radiation and infection. Prevention is important as treatment is difficult. Treatment may include drugs, particularly benzopyrones, and enzymes, physiotherapy, elastic sleeves and surgery.

Topics: Arm; Breast Neoplasms; Coumarins; Diuretics; Drug Combinations; Female; Humans; Hydroxyethylrutoside; Lymph Node Excision; Lymphedema; Mastectomy; Physical Therapy Modalities; Radiotherapy; Surgical Wound Infection

Topics: Benzopyrenes; Coumarins; Diuretics; Drainage; Humans; Hydroxyethylrutoside; Leg; Lymphatic System; Lymphedema; Vascular Surgical Procedures; Veins