Dietary Support for Varicose Veins and Hemorrhoids
Mending Varicose Veins
You're so vain,
You probably think this song is about you.
You're so vain,
I'll bet you think this song is about you.
Don't you? Don't you? Don't you?
-- Carly Simon
anity is usually considered to be a bad thing, on a par with conceit, narcissism, and egotism. But to be vain also means to be concerned about one's appearance. There's nothing wrong with that, and when a negative appearance is an early warning of vascular disease, concern is both responsible and appropriate. Varicose veins - those abnormally enlarged, twisted veins that develop in our legs with age - are, in a manner of speaking, a vain thing, especially for women, who suffer the unsightly appearance of varicosity four times more than men.1
But until recently, the harsh choice was between doing nothing and submitting to injections or surgery, neither of which is without liabilities . . . neither of which produces reliable results . . . and neither of which gets to the root of the problem. Fortunately, there is now a good alternative, with the discovery that certain dietary nutrients, herbs, and phytonutrients can really make a difference in your life, not only for better appearance, but for better health.
WHAT IS THE VENOUS SYSTEM?
Essentially, the cardiovascular system is made up of the arterial system (the arteries) and the venous system (the veins). The arterial system delivers blood from the heart to the lungs, where it picks up oxygen and drops off certain waste products, such as carbon dioxide. The blood is then sent to the major arteries (via the heart again), arterioles (small arteries), and lastly, the capillaries. At the point of the capillaries, the nutrient- and oxygen-rich blood is fed to the body's cells. With this mission completed, the blood is carried back to the heart via the venous system (comprising the venules (small veins), and the veins) to repeat the cycle.
HOW DO NORMAL VEINS WORK?
Looking more closely at the veins, reveals that they have one-way valves that allow blood to travel in only one direction - toward the heart. If the valves are functioning properly, any tendency toward back-flow (away from the heart) immediately pushes the vein's valve leaflets (flaps) closed. The movement of venous blood is passive. Unlike the arterial system which actively pumps blood to all the cells of the body, venous blood returns to the heart primarily due to the contraction of muscles and inspiratory (breathing) movement, literally squeezing venous blood back to the heart. One of the most important muscle pumps is the calf muscle pump.
WHAT IS VENOUS INSUFFICIENCY?
As we age, our venous system progressively deteriorates and venous blood flow becomes impaired. Any impairment of venous blood flow towards the heart is often referred to as venous insufficiency. Venous insufficiency can occur in deep veins, superficial veins, or both. It can result from pump failure, obstruction (clot), or incompetent valves within veins. Another significant consideration is insufficient nutrients and other biomolecules that nourish and repair venous mechanisms are likely to create further deterioration and dysfunction.
Also, veins tend not to be as hearty as arteries. The weakest veins are the superficial veins which lie near the surface of the skin. This is why the first signs of venous insufficiency are often seen in the superficial veins as varicose veins.
WHY DO WE GET VARICOSE VEINS?
Incompetence of the valves of superficial veins, which manifests as varicose veins, is the most common form of venous disease. When the valves become compromised and no longer perform their usual function, backwards flow of blood through the vein occurs. The blood accumulates and pools, causing the vein to enlarge, stretch and widen. (See Figure.) This state can be seen as dark or blue tortuous veins and nodules at the surface of the skin called varicose veins. Similar pathology may be present deeper in the venous system but is not apparent to the eye; and may not be detected until severe enough to cause symptoms. By this time the disease state may be well-advanced.
Valve failure may have different causes, including prolonged pressure; for example, prolonged standing; phlebitis (inflammation of vessels); direct injury; or congenitally weak or abnormal walls. These problems are likely to be exacerbated by nutrient insufficiency which may instigate further dysfunction. The net result is venous insufficiency and unsightly veins, and as more evidence indicates, can lead to serious, even life-threatening conditions such as venous thrombosis (clot).
THE PROBLEMS OF VARICOSE VEINS
As varicose veins develop, so can pain. Feelings of drug-like heaviness, fatigue, burning, throbbing, and itching often ensue. Cramps are common. Edema (swelling) may follow prolonged standing. And it is not always possible to see the outward signs of varicose veins if they are not close to the surface of the skin.
Along this torturous road, there is always the possibility that varicose veins may lead to phlebitis, a serious inflammation of the veins in which the legs become hard and ultrasensitive to touch. Other possible serious problems, such as open ulcers could require medical attention.
VARICOSE VEINS AND VENOUS DEGENERATIVE DISEASE
Diseases of the venous system (veins) can be serious. Following heart attack and stroke, venous thromboembolism (vein blockage by a clot) is the third most common cardiovascular disease in the United States, responsible for between 300,000 and 600,000 hospitalizations and up to 100,000 deaths annually.2 Chronic venous insufficiency with skin ulceration is a clinical manifestation of venous thromboembolism, affecting up to 500,000 individuals per year. This is just the tip of the iceberg. The number of individuals affected by varicose veins of the lower extremities and the anus (hemorrhoids, another form of varicosity) rises rapidly with age.3 By the age of 50, 50% of all adults are believed to be affected.4 In Western societies, venous insufficiency represents a substantial portion of age-related disablement (morbidity). The cost of care is huge. In fact, in many countries, "varicose veins are probably the commonest disorder presenting to general surgeons."5 Nursing venous ulcers absorbs up to 30% of all monies expended on outpatient care; varicose veins or leg ulceration inflict persistent discomfort with concomitant disability that can extend over long periods of time.
Despite the high cost of treating chronic venous insufficiency, little epidemiological research has been carried out on venous disease, perhaps partly because of society's perception that it is not a major problem and is not normally a cause of death. More recently, however, efforts have been made to conduct structured epidemiological studies to identify risk factors and to clarify the geographical variations. Recent findings using duplex scanners indicate that the frequency of venous thrombosis appears to be increased in patients with varicose disease.6 Yet it is amazing to realize that surgeons who remove varicose veins are at a loss to understand their recurrence.7
RISK FACTORS YOU CAN CONTROL
Posture can have a positive or negative influence on your body, and not always in the way that you think it might. Standing can increase the pressure in the veins several-fold versus lying down. Data show that the incidence of varicose veins is increased in people whose occupations require them to stand. Obesity - or just being overweight - can raise intra-abdominal pressure, which in turn can impede blood flow in the veins causing pressure buildup and varicosities in the associated veins.
THE DECLINE OF THE VEIN'S WALL
One theory that has been tested holds that a decline in circulating endothelial cells from the walls or linings of veins is instrumental in the development of varicose veins, chronic venous insufficiency, and, ultimately, venous thromboembolism.8 Researchers using a combination of ginkgo biloba extract, troxerutin (a bioflavonoid used in the treatment of disorders of the venous and microcirculatory systems), and heptaminol in a double-blind, placebo-controlled, clinical trial found that circulating endothelial-cell levels could be increased by a factor of two over placebo in just four weeks, confirming that changes in the endothelium are involved in the development of varicose veins. The data further suggest a potential beneficial action of venotropic (affecting the veins) supplements on the venous wall.
VARICOSE VEINS AND PREGNANCY
Varicose veins are strongly associated with pregnancy and menopause. In fact, as many as 70-80% of pregnant women develop varicose veins during the first trimester. Pregnancy causes an increase in hormone levels and blood volume, which in turn causes veins to enlarge. In the later stages of pregnancy, the enlarged uterus causes increased pressure on the veins in the pelvis, inducing or exacerbating varicose veins. Fortunately, approximately 60-70% of varicose veins due to pregnancy disappear within a few months of delivery. In a double-blind, placebo-controlled study, troxerutin was found to be helpful for venous insufficiency that manifested either during the premenstrual syndrome or during pregnancy from the fourth month onward.9 There was marked improvement with a dosage of 4 g/day of troxerutin.
WHAT CAN INCREASE MY RISK OF GETTING VARICOSE VEINS?
While varicose veins tend to be more common in some families and are thus attributable to the legacy of our genes, stress also plays an important role, as does lack of exercise, menopause, oral contraceptives, pregnancy, estrogen-replacement drugs, and, last but not least, aging. Curiously, there is evidence that exposure to sunlight is associated with an increased tendency to form varicose veins.10 Fortunately, there is good evidence that varicose veins, and far worse, venous problems can be prevented, contained, and possibly even reversed.
RELIEF ATTRIBUTED TO FLAVONOIDS AND OTHER PHYTONUTRIENTS
Europeans were out of the gate early in taking varicose veins seriously. Indeed, an extract of the seeds of horse chestnut (Aesculus hippocastanum) has been in nearly continuous use since 1565 in treating varicose veins as well as hemorrhoids. In modern times, it has acquired scientific respectability, because researchers have isolated escin, the active compound in this extract, and confirmed its traditional role in the treatment of venous conditions.
A recent study reviewing the electronic database literature, and other double-blind, randomized, controlled studies, focused on the use of horse chestnut for chronic venous insufficiency.11 Without exception, horse chestnut's superiority over placebo was found in all placebo-controlled studies, for the following benefits:
- Decrease of lower-leg volume (i.e., reduced swelling)
- Lessening of leg pain and itching
- Alleviation of fatigue and tenseness
An examination of five comparative trials against a reference medication found that horse chestnut
were equally effective. There was even a trial that indicated a therapeutic equivalence of horse chestnut and compression therapy (the wearing of tight stockings to alleviate varicose swelling).12
Overall, there were few, mild, and infrequent adverse effects.
HORSE CHESTNUT SEALS FLUIDS IN
One of the mechanisms by which horse chestnut's active ingredient escin is thought to work is through its ability to seal the walls of veins. When tested in rats, escin was found to inhibit fluid loss from veins.13 Similar results were found in a study with rabbits.
In a study involving 22 patients with chronic venous insufficiency, the effect of horse chestnut was assessed by measuring the permeability of capillaries and the intravascular volume (reflecting swelling) of the lower leg.14 Three hours after taking 100 mg of escin, fluid was inhibited from seeping out of veins therefore minimizing or preventing edema in the surrounding tissue. With placebo there was an increase in leakage. The researchers concluded that escin inhibits edema by decreasing leakage.
In a similar study assessing the effects of horse chestnut on venous circulatory disorders of the leg under everyday conditions, leg pain, skin lesions, circumference of the ankle, and diuretic action (induced urination) were measured. When 34 subjects were given the equivalent of 150 mg of escin per day in a double-blind trial, its effects were found to be significantly superior to a placebo of identical appearance.15
HORSE CHESTNUT AND TROXERUTIN PROVIDE CONTINUITY OF BENEFITS
HELPFUL FOR OTHER AREAS OF THE BODY
Varicose veins also occur in other parts of the body, where they are called:
- Hemorrhoids (in the anus)
- Esophageal varices (varicose veins in the esophagus), which are associated with excessive alcohol intake and cirrhosis
- Varicoceles (in the scrotum). A varicocele is a clump of varicose veins. It has the look and feel of "a bag of worms" - a wonderfully descriptive though unattractive analogy. Infertility due to low sperm counts is a problem in some men with varicoceles.
When horse chestnut
were tested against each other, troxerutin was proved to be equivalent or better at reducing leg volume at 500 mg/day compared to 600-1,000 mg/day
of horse chestnut.16
Administered for 12 weeks and observed in the follow-up for an additional 6 weeks, both horse chestnut and troxerutin were found to continue providing benefits even after they were stopped.
HORSE CHESTNUT AND DEEP VEIN PROTECTION
At the University of Heidelberg, Germany, researchers conducted a randomized, placebo-controlled, parallel, double-blind study on 40 patients suffering from venous edema in chronic deep-vein incompetence.17 Compared with placebo, horse chestnut significantly reduced edema, as determined by measurements of leg volume and leg circumference under aggravated conditions. With measurements of leg volume before and after provoking edema, the clinical benefits of horse chestnut appeared to be present in all everyday situations, whether in movement or in sitting or standing.
In a study that focused on horse chestnut's active ingredient, 50 mg of escin was found to be effective in the treatment of venous insufficiency. Given that higher-quality horse chestnut extract is standardized to 20% escin,18 the effective amount of the extract is 250 mg, usually taken twice per day. While horse chestnut's mechanisms of action are not clearly understood, its ability to lessen the effect of certain destructive enzymes, such as lysosomal proteoglycan, may be of value. These enzymes are typically increasingly active in patients with chronic venous insufficiency.
TROXERUTIN AS PREVENTATIVE
At the Technical University of Munich, after a two-week placebo run-in period (all subjects took placebo), 16 healthy volunteers were given 500 mg of troxerutin twice daily for three more weeks, in a double-blind, parallel study.19 At the beginning and once every week thereafter, the subjects were edema-provoked by standing motionless for 1 hour, before and after which leg volume was measured. There were no changes during the run-in period, and none in the placebo group, but those taking troxerutin had a progressive reduction in the volume of induced edema. Because the volunteers were healthy, with no prior indication of venous insufficiency, these results indicated a protective effect of troxerutin.
Another double-blind, placebo-controlled study has shown that troxerutin, when combined with compression therapy, is significantly superior to compression therapy alone (133 subjects).20 Another study involving 85 subjects found troxerutin to have favorable effects on mechanisms that are injurous to veins, such as those that increase damage to the vein linings, that cause leakage, that disrupt homeostasis, and that prevent nutrient distribution - all of which can be complications of chronic venous insufficiency.21
RESTLESS LEG IMPROVEMENT
A study designed to measure the effects of troxerutin on edema of the ankle and foot, as well as on paresthesia (abnormal sensations such as burning or prickling), found significant benefit at 1 g/day for four weeks.22 In a longer-range study, elderly subjects (over 65) given 900 mg/day of troxerutin for six months obtained symptomatic relief from leg cramps, heavy legs, and restless legs (102 subjects).23 A significant reduction was also seen in ankle and calf circumferences. Significant edema of the leg and eczema of the leg also improved impressively more than in the control group.
FOR EYES TOO
In a study designed to measure the effect of troxerutin on retinal vein occlusion, 57 subjects were shown to sharpen visual acuity, reduce macular edema, and alleviate other problems related to indications of visual decline.24 Furthermore, those taking troxerutin had slower progression of ischemia and decreased tendency of red blood cells to clump together compared with controls. It was thought that the results owed in part to reduced blood viscosity.
TROXERUTIN HELPFUL FOR HEMORRHOIDS
Hemorrhoids is a disorder of the anal canal characterized by recurrent, self-resolving acute episodes entailing pain, bleeding, exudation, and itching. In Indonesia, 97 women with first-, second-, or third-degree hemorrhoids during pregnancy were given either 1000 mg/day of troxerutin or placebo to assess its effect.25 For both subjective and objective signs (bleeding, inflammation, and dilation of the hemorrhoidal plexus), after two and four weeks of treatment, troxerutin was found to be superior when compared with placebo. Side effects were mild and transient, and no drug-related problems in the pregnancy or delivery were observed. The results suggest that troxerutin can provide a safe and effective treatment for women with hemorrhoids of pregnancy.
The recurrence of venous ulcers was found to be less likely when 1000 mg/day of troxerutin was used in conjunction with compression therapy over a three-month period (138 subjects).26 Another study with pregnant women, carried out for 30 days with 4 g/day of troxerutin, found a reduction in red blood cell aggregation (clumping) making for less viscous blood and thus improving venous blood flow during pregnancy.27
HESPERIDIN AND DIOSMIN FOR HEMORRHOIDS
There is a strong suggestion that the antioxidant capabilities of troxerutin (a flavonoid) are at least in part responsible for its positive effects on varicose veins, venous insufficiency, and hemorrhoids. Studies employing free-radical quenchers such as allopurinol and dimethylsulfoxide (DMSO) for the topical treatment of venous ulcers have been shown to be helpful, supporting the idea that free radicals are involved.28 Other flavonoids, including hesperidin and diosmin, have been shown to be remarkably effective against vasicose veins, especially hemorrhoids.
Treatment with 1350 mg of diosmin and 150 mg of hesperidin for four days, followed by 900 mg of diosmin and 100 mg of hesperidin for three days, produced marked relief.29 Of 100 subjects suffering from an acute hemorrhoidal attack, 50 received the flavonoids and 50 received placebo. Anal discomfort, pain, and anal discharge diminished to a greater extent in the flavonoid group, as did inflammation, congestion, edema, and prolapse. Furthermore, self-evaluation found the severity and duration to be less than in previous episodes, and there was a major reduction in the use of topical medications and analgesics among the flavonoid users. Without any doubt, the flavonoids provided quicker, more pronounced relief of the symptoms of acute hemorrhoids than did placebo.
In another study, 120 subjects (54 men, 66 women) suffering from acute and chronic recurrent hemorrhoids were divided into two groups and given either placebo or 900 mg of diosmin and 100 mg of hesperidin each per day for a period of two months.30 During this trial, about 40% in the flavonoid group had a hemorrhoid attack compared to the placebo group, about 70% of which had an attack. Placebo takers were 75% more likely to have an attack, which was likely to be 77% longer and 45% more severe. At the end of the study, using an overall rating system of the severity of hemorrhoids, placebo users barely improved, versus flavonoid users who at the end of the study had virtually no symptoms.
Horse chestnut, troxerutin, diosmin, and hesperidin should be avoided by anyone with liver or kidney disease. Their internal use is also contraindicated during pregnancy and lactation. Topically, horse chestnut has been associated with rare cases of allergic skin reactions. Since circulatory disorders and trauma associated with swelling may indicate a serious condition, a health care professional should be consulted before self-treating with horse chestnut.
PREVENTING VENOUS WALL BREAKDOWN
It is believed that flavonoids are able to inhibit the breakdown of proteins by enzymes that weaken the walls of veins, thus rendering them porous and causing them to lose collagen content.31 Collagen is an important component providing structural integrity in vein walls. Another substance associated with weakening the walls of veins is hyaluronic acid which increases wall edema. Some flavonoids, such as diosmin and hesperidin, protect the venous wall matrix and smooth muscle integrity.
As we age, pathological changes may cause venous stasis (the stoppage of blood flow in the veins). The result is hypoxia (diminished oxygen supply) causing damage to tissues. The cells of the inner vein walls are altered, releasing certain inflammatory substances. Free radicals and enzymes are released that degrade the linings of the veins. Together, these cascades ultimately render the vein walls vulnerable to protein-destroying enzymes, causing connective and muscle tissue in the vein walls to deteriorate.
By restoring the smooth muscle tone of the linings of the veins, horse chestnut increases the vein's ability to contract dynamically to the correct size for any required venous pressure. Horse chestnut also helps to correct the increase in capillary permeability, thereby decreasing leakage. As well, by reducing hypoxia, horse chestnut prevents decreases in ATP (the energy molecule of the cell) and reduces inflammatory activity.
In tandem with flavonoids such as troxerutin, diosmin, and hesperidin, horse chestnut counteracts the damaging effects of free radicals, thereby stabilizing connective tissue and preserving the integrity of the extracellular matrix. The stability and function of the veins' connective tissue are preserved because the degradation enzymes are inhibited.
THE POWER OF RARE FLAVONOIDS AND OTHER PHYTONUTRIENTS
All together, horse chestnut, troxerutin, diosmin and hesperidin demonstrate a variety of venotonic (helpful to veins) actions, including:
- Anti-edemic (anti-swelling)
Not only do these phytonutrients provide protective benefits, they also provide relief from the symptoms of venous insufficiency, such as tension or heaviness in the legs, pain, and a sense of tiredness. And important for our vanities, they significantly help reduce the unsightliness of varicose veins and the aggravation of hemorrhoids.
- Madar G, Widmer LK. Varicose veins and chronic venous insufficiency - minor disorder or disease? A critical review of the literature. Z Lymphol 1990 Aug;14(1):36-46.
- Hooper WC, Evatt BL. The role of activated protein C resistance in the pathogenesis of venous thrombosis. Am J Med Sci 1998 Aug;316(2):120-8.
- Center for Disease Control. Vital and Health Statistics, Series 10, No. 199 (10/98);p.83.
- Van den Oever R, Hepp B, Debbaut B, Simon I. Socio-economic impact of chronic venous insufficiency. An underestimated public health problem. Int Angiol 1998 Sep;17(3):161-7.
- Evans CJ, Fowkes FG, Hajivassiliou CA, Harper DR, Ruckley CV. Epidemiology of varicose veins. A review. Int Angiol 1994 Sep;13(3):263-70.
- Guex JJ. Thrombotic complications of varicose veins. A literature review of the role of superficial venous thrombosis. Dermatol Surg 1996 Apr;22(4):378-82.
- Creton D. 125 reinterventions for recurrent popliteal varicose veins after excision of the short saphenous vein. Anatomical and physiological hypotheses of the mechanism of recurrence. J Mal Vasc 1999 Feb;24(1):30-6.
- Janssens D, Michiels C, Guillaume G, Cuisinier B, Louagie Y, Remacle J. Increase in circulating endothelial cells in patients with primary chronic venous insufficiency: protective effect of Ginkor Fort in a randomized double-blind, placebo-controlled clinical trial. J Cardiovasc Pharmacol 1999 Jan;33(1):7-11.
- Marhic C. Clinical and rheological efficacy of troxerutin in obstetric gynecology. Rev Fr Gynecol Obstet 1991 Feb 25;86(2 Pt 2):209-12.
- Engel A, Johnson ML, Haynes SG. Health effects of sunlight exposure in the United States. Results from the first National Health and Nutrition Examination Survey, 1971-1974. Arch Dermatol 1988 Jan;124(1):72-9.
- Pittler MH, Ernst E. Horse-chestnut seed extract for chronic venous insufficiency. A criteria-based systematic review. Arch Dermatol 1998 Nov;134(11):1356-60.
- Neumann HA, van den Broek MJ. A comparative clinical trial of graduated compression stockings and O-(beta-hydroxyethyl)-rutosides (HR) in the treatment of patients with chronic venous insufficiency. Z Lymphol 1995 Aug;19(1):8-11.
- Rothkopf M, Vogel G. New findings on the efficacy and mode of action of the horse chestnut saponin escin. Arzneimittelforschung 1976 Feb;26(2):225-35.
- Bisler H, Pfeifer R, Kluken N, Pauschinger P. Effects of horse-chestnut seed extract on transcapillary filtration in chronic venous insufficiency. Dtsch Med Wochenschr 1986 Aug 29;111(35):1321-9.
- Neumann-Mangoldt P. Experiences in the use of Essaven capsules in the treatment of venous leg diseases. Results of a double-blind study. Fortschr Med 1979 Dec 1;97(45):(2117-9).
- Rehn D, Unkauf M, Klein P, Jost V, Lucker PW. Comparative clinical efficacy and tolerability of oxerutins and horse chestnut extract in patients with chronic venous insufficiency. Arzneimittelforschung 1996 May;46(5):483-7.
- Diehm C, Vollbrecht D, Amendt K, Comberg HU. Medical edema protection - clinical benefit in patients with chronic deep vein incompetence. A placebo controlled double blind study. Vasa 1992;21(2):188-92.
- Hitzenberger G. The therapeutic effectiveness of chestnut extract. Wien Med Wochenschr 1989 Sep 15;139(17):385-9.
- Rehn D, Hennings G, Nocker W, Diebschlag W. Time course of the anti-oedematous effect of O-(beta-hydroxyethyl)-rutosides in healthy volunteers. Eur J Clin Pharmacol 1991;40(6):625-7.
- Unkauf M, Rehn D, Klinger J, de la Motte S, Grossmann K. Investigation of the efficacy of oxerutins compared to placebo in patients with chronic venous insufficiency treated with compression stockings. Arzneimittelforschung 1996 May;46(5):478-82.
- Boisseau MR, Taccoen A, Garreau C, Vergnes C, Roudaut MF, Garreau-Gomez B. Fibrinolysis and hemorheology in chronic venous insufficiency: a double blind study of troxerutin efficiency. J Cardiovasc Surg (Torino) 1995 Aug;36(4):369-74.
- Renton S, Leon M, Belcaro G, Nicolaides AN. The effect of hydroxyethylrutosides on capillary filtration in moderate venous hypertension: a double blind study. Int Angiol 1994 Sep;13(3):259-62.
- MacLennan WJ, Wilson J, Rattenhuber V, Dikland WJ, Vanderdonckt J, Moriau M. Hydroxyethylrutosides in elderly patients with chronic venous insufficiency: its efficacy and tolerability. Gerontology 1994;40(1):45-52.
- Glacet-Bernard A, Coscas G, Chabanel A, Zourdani A, Lelong F, Samama MM. A randomized, double-masked study on the treatment of retinal vein occlusion with troxerutin. J Ophthalmol 1994 Oct 15;118(4):421-9.
- Wijayanegara H, Mose JC, Achmad L, Sobarna R, Permadi W. A clinical trial of hydroxyethylrutosides in the treatment of haemorrhoids of pregnancy. J Int Med Res 1992 Feb;20(1):54-60.
- Wright DD, Franks PJ, Blair SD, Backhouse CM, Moffatt C, McCollum CN. Oxerutins in the prevention of recurrence in chronic venous ulceration: randomized controlled trial. Br J Surg 1991 Oct;78(10):1269-70.
- Lefebvre G, Lacombe C. Venous insufficiency in the pregnant woman. Rheological correction by troxerutin. Rev Fr Gynecol Obstet 1991 Feb 25;86(2 Pt 2):206-8.
- Salim AS. The role of oxygen-derived free radicals in the management of venous (varicose) ulceration: a new approach. World J Surg 1991 Mar-Apr;15(2):264-9.
- Cospite M. Double-blind, placebo-controlled evaluation of clinical activity and safety of Daflon 500 mg in the treatment of acute hemorrhoids. Angiology 1994 Jun;45(6 Pt 2):566-73.
- Godeberge P. Daflon 500 mg in the treatment of hemorrhoidal disease: a demonstrated efficacy in comparison with placebo. Angiology 1994 Jun;45(6 Pt 2):574-8.
- Drubaix I, Viljanen-Tarifa E, Robert AM, Robert L. Role of glycosoaminoglycans in venous disease. Mode of action of some flavonoid drugs. Pathol Biol (Paris) 1995 May;43(5):461-70.
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