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September 2009

Prevalence and risk factors of chronic venous insufficiency.

Venous disease in the legs occurs very commonly in the general population in Western countries. Around one third of women have trunk varices. A lower prevalence has been observed in men but some recent surveys have suggested that the occurrence in men may be comparable to that in women. The prevalence increases with age but the incidence of new cases appears to be constant throughout adult life. Open venous ulcers occur in about 0.3% of the adult population and a history of open or healed ulceration occurs in around 1%. The etiology of chronic venous disease in the legs is unknown. A genetic predisposition may be present but evidence for this and for a mode of inheritance is lacking. There is some suggestion that prolonged standing may be a risk factor but studies are open to considerable bias. In women, obesity and previous pregnancy has been associated with the presence of varicose veins but the evidence is inconsistent. There have been few well-conducted studies examining diet and bowel habit as a risk factor. The risk of ulceration is related to the severity of varicosities and venous insufficiency, and is increased following deep vein thrombosis. Much further research is required to investigate the cause of this common condition in the general population.

Angiology. 2001 Aug;52 Suppl 1:S5-15

Efficacy of a 6-month treatment with Daflon 500 mg in patients with venous leg ulcers associated with chronic venous insufficiency.

AIM: Epidemiological data show that standard compression therapy for leg ulceration in chronic venous insufficiency (CVI) often fails to effectively improve patients’ condition. This study assesses the contribution of Daflon 500 mg added to conventional therapy in the healing of hypostatic ulcers of CVI patients. METHODS: Patients of about 65 years were included, with ulcers > or = 2 and > or = 10 cm diameter on 1 or 2 limbs, Doppler ankle/arm pressure index > 0.9, and no recent history of skin graft. Controls (n=68) remained on compression alone while the tested group (n=82) also received Daflon 500 mg 2 tablets/day during 6 months. Treatment could be stopped as soon as the reference ulcer appeared fully healed. Primary endpoints were the rate of healed ulcers and the time to complete healing assessed by planimetry/photography and clinical examination. Variations of the ulcer surface, appearance of the skin, and clinical symptoms of CVI were the secondary criteria. RESULTS: Only 7% of Daflon 500 mg patients necessitated the full 6 month therapy. Whatever the lesion size, from W8 significantly more healed ulcers were observed under Daflon 500 mg (p=0.004), and the ulcer surface was more reduced (p=0.012). For large ulcers, the rate of healing was approximately 2-fold higher with Daflon 500 mg, and the percentage of ulcers healed before W24 was significantly higher (p=0.008). Heavy leg sensation was significantly improved by Daflon 500 mg from W4 (p < 0.05). No treatment-related side effects were reported and the acceptability was considered excellent by 85% of Daflon 500 mg patients. CONCLUSION: Six months of Daflon 500 mg in addition to compression significantly improve some clinical symptoms and accelerate the healing process in patients with ulcerous complications of CVI, with a good acceptability.

Int Angiol. 2003 Mar;22(1):24-31

Surgical correction of varicose vein disease under micronized diosmin protection (results of the Russian multicenter controlled trial DEFANS).

The paper presents the results of DEFANS trial (Detralex - assessment of efficacy and safety for combined phlebectomy). The study enrolled 245 patients with varicose vein disease, who underwent unilateral combined phlebectomy. The main group (n=200) received micronized diosmin (Detralex, 1,000 mg/day) for 2 weeks before and 30 days after the procedure; control group (n=45) did not receive Detralex in pre- and postoperative period. Pain severity by 10-point visual analog scale (VAS), an area of subcutaneous hemorrhage in the zone of femoral great saphenous vein resection (by original 12-point scale) and subjective feelings of limb heaviness and fatigability were evaluated 7, 14, and 30 days after the procedure. Subjective symptoms and the area of subcutaneous hemorrhage were significantly lower in the main group, then in control: 7 days after the procedure VAS score was 2.9 and 3.5, respectively; hemorrhage area - 3.4 and 4.6 points, respectively. The same trend was observed for limb heaviness and fatigability, evidencing the better exercise and orthostatic tolerance among patients of the main group in early postoperative period. Quality of life assessment by CIVIQ failed to reveal statistically significant difference between main and control groups in 4-weeks postoperative follow-up. Micronized diosmin in pre- and postoperative period after plebectomy helps to attenuate pain syndrome, to decrease postoperative haematomas and accelerate their resorption, to increase exercise tolerance in early postoperative period.

Angiol Sosud Khir. 2007;13(2):47-55

Evaluation of clinical efficacy of a venotonic drug: lessons of a therapeutic trial with hemisynthesis diosmin in “heavy legs syndrome.”

Venous-type symptoms, i.e. painful sensation of heavy, swollen or restless legs, influenced by orthostatism and warm environment, significantly alters quality of life of a large proportion of women. Although the condition is frequently associated with chronic venous insufficiency, no demonstrable hemodynamic abnormality of the superficial as well as deep venous systems of the lower limbs can be found in many patients. The pathogenesis of this syndrome remains unknown, and there is no objective measurement of any biological nor hemodynamic parameters that can be used for its assessment. Diosmine and other flavane derivatives have been shown beneficial in this condition using various discomfort indexes. The aim of this work was to compare the therapeutic efficacy of two formulations of the same compound diosmine. In the analysis, particular attention was paid to the signification and usefulness of discomfort scales. This study was a double-blind, placebo-controlled therapeutic trial, comparing the efficacy of a new formulation, hemisynthesis diosmine 600 mg, one tablet per day taken in the morning, versus the usual tablet formulation of 300 mg taken twice a day (morning and evening). Treatment blindness was assured by the double placebo method. Two parallel groups were treated 28 days with one or the other treatment. Randomization was performed with stratification by center. The main evaluation criteria were a composite scale of venous type symptoms (i.e. the sum of individual score 0-4 of each symptom), and a visual analog auto-evaluation scale quoted each week by the patient. The global opinion of the physician on treatment adequacy to the clinical situation, and the degree of patient satisfaction (four grade scales) were used as subsidiary criteria. In order to increase the homogeneity of the study sample, inclusion was restricted to non-menopaused women aged 18 years and over, having given written informed consent, complaining of distressing sensation of heavy legs, without history of venous thrombosis, varicose veins, superficial or deep venous reflux at the duplex-scan examination. Patients with other causes of pain in the lower limbs, taking analgesic medications or requiring elastic stocking were not included. 255 patients participated in the trial. Eighteen withdrew, equally distributed in both groups (6 lost, 5 interfering diseases, and two dropouts for side effects, namely headache and gastric pain). Twenty additional patients complained of detrimental events not requiring treatment withdrawal, equally distributed between both groups, and mainly involving digestive functions. The results confirmed a similar efficacy of the two drug regimens, and a small but significantly better improvement of the patients’ auto-evaluation of their discomfort on the analogic scale (p = 0.021) for hemisynthesis diosmine 600 mg, mainly during the first two weeks; for all four criteria, the gamma risk showed that the once-a-day 600 mg preparation at least as effective as 300 mg twice daily (p < 0.001). On a methodological point of view, the comparison of evaluation criteria showed that the composite scale, although giving the feeling of a comprehensive and quantitative appraisal of the discomfort in the legs, was almost equivalent to a standard four grade rating of heaviness, which appeared as the central symptom of this condition. Auto-evaluation through an analogic scale proved to be more informative, more sensitive, less influenced by the physician’s feelings and allow easier assessment of the time-course of the drug’s effects. Global evaluations by the patient and the physician did not give additional information but could be used as quality criteria, assessing the coherence of the results obtained with the scales. This study demonstrated a similar efficacy of the two drug regimens, with a more rapid effectiveness of the 600 mg preparation taken once a day.

J Mal Vasc. 1998 Apr;23(2):106-12

Activity of purified diosmin in the treatment of hemorrhoids.

Several theories on the etio-pathogenesis and physio-pathology of hemorrhoids have been up to now proposed. From the fisio-pathological viewpoint, particular importance is retained by the vascular factor, which in its turn is influenced by mechanical and sphinceric factors, that impair the venous back-flow. In the evidence of an hemorrhoidal crisis, characterized by local oedema, pain and bleeding, the use of bioflavonoid drugs is deemed to be the first choice. We investigated the use of purified diosmin, given at a dose of two 450 mg tablets bid for the first 7 days, then at 1 tablet bid for up to 2 months, in a group of 66 patients suffering from primitive hemorrhoids of grade 1-4. Our results confirmed diosmin efficacy in decreasing both pain and bleeding: reduction rates of 79% and 67%, respectively, were reached in the first treatment week. In the second week, figures were 98% and 86%, respectively. Diosmin tolerability was excellent: this characteristic makes the drug very easy to handle by the general practitioner and also useful to the proctologist in the preparation of patient to further treatments.

Clin Ter. 2000 Sep-Oct;151(5):341-4

Diosmin therapy alters the in vitro metabolism of noradrenaline by the varicose human saphenous vein.

We have previously shown that diosmin 30-100 mumol/l reduces the metabolism of noradrenaline (NA) in fragments of varicose saphenous veins obtained at surgery. Since diosmin is widely used in patients with chronic venous insufficiency we decided to test if the drug, administered in therapeutic doses to patients, would affect NA metabolism in the veins of the individuals so treated. Sex- and age-matched patients in which surgery was indicated were allocated in the order of admission to control (n = 5) or treated groups (n = 6; 600 mg twice a day, orally, during 10 days). Fragments of saphenous vein were incubated with [3H]NA 0.2 mumol/l during 60 min; the interval between operation and incubation was less than 30 min. Column chromatography and liquid scintillation counting were used to measure [3H]NA and its metabolites. In the treated group, accumulation of [3H]NA was significantly reduced and the formation of metabolites approximately halved. The present results show that oral administration of diosmin has evident effects on the in vitro metabolism of noradrenaline by the varicose tissue.

Pharmacol Res. 1991 Oct;24(3):253-6

Diosmin pretreatment affects bioavailability of metronidazole.

OBJECTIVE. To screen for inhibitory effects of diosmin on cytochrome P(450)-mediated metabolism of metronidazole in healthy volunteers. DESIGN. Before/after non-blinded investigation conducted in healthy male volunteers. METHODS. After an overnight fast, metronidazole (two 400 mg tablets) was administered to 12 volunteers, either alone or after a 9-day pretreatment period with a once-daily dose of diosmin 500 mg tablets under direct observation. Serum concentrations of metronidazole up to 48 h postdose and urinary concentrations of metronidazole and its two major metabolites up to 24 h postdose were measured using reversed-phase high-performance liquid chromatography. RESULTS. Metronicazole plasma AUC((0- infinity )) and C(max) were significantly higher after diosmin pretreatment by (mean) 27% and 24%, respectively. However, time to reach peak concentration (t(max)) was not affected significantly. Urinary excretion of acid and hydroxy metabolites in urine was decreased significantly, while excretion of unchanged metronidazole was increased. CONCLUSION. Diosmin pretreatment significantly altered the metabolism of metronidazole, as demonstrated by changes in plasma pharmacokinetics as well as by urinary recovery of both parent drug and its major metabolites. This may be caused by the inhibition of cytochrome P(450) enzymes.

Eur J Clin Pharmacol. 2003 Apr;58(12):803-7

Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and hemorrhoids.

Micronised purified flavonoid fraction (MPFF) [Daflon 500 mg], an oral phlebotropic drug consisting of 90% micronised diosmin and 10% flavonoids expressed as hesperidin, improves venous tone and lymphatic drainage, and reduces capillary hyperpermeability by protecting the microcirculation from inflammatory processes. The absorption of diosmin is improved by its micronisation to particles with a diameter <2 microm. Compared with placebo, MPFF 500 mg twice daily significantly decreased ankle or calf circumference, and improved many symptoms of chronic venous insufficiency (CVI) and plethysmographic parameters in two randomised, double-blind, 2-month studies. Improvement in symptoms was parallelled by an improvement in health-related quality of life in a nonblind, 6-month trial. Significantly more venous leg ulcers </=10 cm in diameter completely healed with MPFF 500 mg twice daily plus standard management (compression and local treatment) for 2-6 months than with standard management alone or with placebo in a nonblind and a double-blind trial. The addition of MPFF to standard management was cost effective in a retrospective pharmacoeconomic analysis of the 6-month trial. Compared with placebo, the duration and/or intensity of individual symptoms of grade 1 or 2 acute internal haemorrhoids improved significantly with 3 tablets of MPFF 500 mg twice daily for 4 days then 2 tablets of MPFF 500 mg twice daily for 3 days. Two tablets of MPFF 500 mg daily for 60 or 83 days reduced the frequency, duration and/or severity of acute haemorrhoidal symptoms and improved the overall signs and symptoms of chronic (recurrent) haemorrhoids compared with placebo. Compared with a control group, MPFF significantly reduced the risk of secondary bleeding after elective haemorrhoidectomy. In clinical trials, MPFF had a tolerability profile similar to that of placebo; the most frequently reported adverse events were gastrointestinal and autonomic in nature. In conclusion, MPFF is a well established and well tolerated treatment option in patients with CVI, venous ulcers, or acute or chronic internal haemorrhoids. MPFF is indicated as a first-line treatment of oedema and the symptoms of CVI in patients in any stage of the disease. In more advanced disease stages, MPFF may be used in conjunction with sclerotherapy, surgery and/or compression therapy, or as an alternative treatment when surgery is not indicated or is unfeasible. The healing of venous ulcers </=10 cm in diameter is accelerated by the addition of MPFF to standard venous ulcer management. MPFF may reduce the frequency, duration and/or intensity of symptoms of grade 1 or 2 acute internal haemorrhoids, and also the severity of the signs and symptoms of chronic haemorrhoids.

Drugs. 2003;63(1):71-100

A double-blind, placebo-controlled trial of a new veno-active flavonoid fraction (S 5682) in the treatment of symptomatic capillary fragility.

The efficacy and safety of a new veno-active flavonoid fraction (S 5682) consisting of micronized diosmin (90%) and hesperidin (10%) have been studied in 100 patients with symptomatic capillary fragility in a double-blind, randomized, placebo-controlled trial. Treatment lasted 6 weeks and consisted of 2 daily tablets of either S 5682 or placebo. Patients were examined at weeks 0, 2, 4, and 6. Compared to placebo, capillary resistance, assessed by the negative suction cup method, was significantly higher in the S 5682 group at week 4 (219 +/- 10 mmHg versus 159 +/- 8 mmHg; p < 0.001) and week 6 (261 +/- 12 mmHg versus 163 +/- 9 mmHg; p < 0.001). This resulted in a significant improvement of symptoms of capillary fragility (spontaneous ecchymosis, epistaxis, purpura, petechiae, gingivorrhagia, metrorrhagia and conjunctival haemorrhage) in S 5682 treated patients (p < 0.001). S 5682 was well tolerated. The rate of side-effects spontaneously volunteered by the patients was similar in both groups. We, therefore, conclude that S 5682 increases to a large extent the capillary resistance in patients with abnormal capillary fragility without significant side-effects.

Int Angiol. 1993 Mar;12(1):69-72.

From symptoms to leg edema: efficacy of Daflon 500 mg.

This article reviews the mechanisms by which micronized purified flavonoid fraction (MPFF; Daflon 500 mg) acts on symptoms as well as on edema in patients with chronic venous disease, in the light of new advances in the understanding of the pathophysiology of this chronic condition. Deterioration of venous wall tone followed by valve dysfunction leading eventually to varicose veins are the key pathophysiologic features that produce venous hypertension. Both mechanical and biological factors are responsible for the deterioration of the venous wall in large veins. These are decreased shear stress and hypoxia of the media and of the endothelium, which act as triggering factors for biochemical reactions leading to inflammation. There is a body of evidence that inflammation in chronic venous insufficiency (CVI) plays a role right from the early stages of venous dysfunction and venous valve restructuring. The whole process of venous wall stretching and dilation is painful and may present as leg heaviness, a sensation of swelling, and paresthesia. Daflon 500 mg relieves symptoms, edema, and red blood cell aggregation, which cause paresthesia and restless legs. At the level of the microcirculation, dysfunction of microvessels is observed, characterized by an increase in capillary permeability followed by skin changes. The earliest manifestation of microcirculatory disorder is edema. At this level, Daflon 500 mg acts favorably on microcirculatory complications by normalizing the synthesis of prostaglandins and free radicals. It decreases bradykinin-induced microvascular leakage and inhibits leukocyte activation, trapping, and migration. Its efficacy in decreasing CVI edema and ankle swelling has been proven in rigorous studies that are reviewed in this paper. Daflon 500 mg, a well-established oral flavonoid that consists of 90% micronized diosmin and 10% flavonoids expressed as hesperidin, may be prescribed from the very beginning of the disease for the relief of pain and edema, and in any CVI patient presenting with symptoms as well. Daflon 500 mg is thus the first-line treatment for edema and symptoms of CVI at any stage of the disease. At advanced disease stages, Daflon 500 mg may be used in conjunction with sclerotherapy, surgery, and/or compression therapy or as an alternative treatment when other treatments are not indicated or not feasible.

Angiology. 2003 Jul-Aug;54 Suppl 1:S33-44