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PubMedDate not supplied

Effects of oral administration of purified micronized flavonoid fraction on increased microvascular permeability induced by various agents and on ischemia/reperfusion in diabetic hamsters.

The effects of a clinically used purified micronized flavonoid fraction (S5682) containing 90% diosmin and 10% hesperidin on increased microvascular permeability induced by histamine, bradykinin and leukotriene B4 (LTB4) were investigated by intravital microscopy in the cheek pouch preparation of diabetic hamsters. We also investigated the effects of S 5682 on macro- molecular permeability increase and leukocyte adhesion during ischemia-reperfusion using the same preparation. Diabetes was induced by an intraperitoneal injection of streptozotocin (50 mg/kg). S 5682, suspended in 10% lactose solution, or vehicle (10% lactose) was administered orally for 25 days at 20 mg/kg/day (10 mg/kg twice a day), starting 5 days after the streptozotocin injection. Fluorescein isothiocyanate-labelled dextran (molecular weight 150,000) was given intravenously, 30 min after completion of the cheek pouch preparation. The leukocytes were stained by continuous intravenous infusion of acridine orange (0.5 mg/ kg/min). Histamine (2 microMs), bradykinin (1 microM), and LTB4 (0.01 microM), applied topically for 5 min, increased the number of fluorescent vascular leakage sites in postcapillary venules. A temporary ischemia (duration: 30 min) with total circulatory arrest of the cheek pouch was obtained by clamping the neck of the everted pouch. The maximum number of leaky sites (per cm2 in the prepared area) which occurs either at 5 min after the beginning of each topical application or 10 min after the onset of reperfusion was quantified in UV light microscopy. The results from 60 animals divided into ten groups of 6 animals each are presented as means +/- SEM. In comparison with vehicle, S 5682 significantly inhibited the macromolecular permeability increasing the effect of histamine (343.8 +/- 18.5 vs. 91.0 +/- 8.2 leaks/ cm2; p > 0.001), bradykinin (347.0 +/- 14.6 vs. 110.3 +/- 8.5 leaks/cm2; p < 0.001) and LTB4 (323.0 +/- 15.5 vs. 161.3 +/- 13.8 leaks/cm2; p < 0.001). At reperfusion, after 30 min ischemia, S 5682 significantly decreased the observed macromolecular permeability (168.5 +/- 19.7 vs. 52.7 +/- 6.3 leaks/cm2; p < 0.01). Flavonoid-treated animals also tended to have a lower number of leukocytes adhering to the venular endothelium (104.8 +/- 11.0 vs. 75.8 +/- 9.7/6 mm2; p > 0.05). These results demonstrate that oral administration of S 5682 for 25 days at 20mg/kg body weight/day has a protective effect on leakage of macromolecules after application of permeability-increasing substances and during ischemia-reperfusion in the cheek pouch microvasculature of diabetic hamsters. In conclusion, the present data illustrating the inhibitory effect of a clinically relevant doses of S 5682 on the inflammatory processes induced in this in vivo model of microcirculation may serve as a rational basis to explain its clinical efficacy.

Administration, Oral↗
PubMed1995

Cellular basis of inflammation, edema and the activity of Daflon 500 mg.

Inflammation activates leukocytes causing the release of agents that disrupt the endothelial barrier to such an extent that retention of plasma protein is impaired. This phenomenon can be observed using microvascular methods in which ischemia-reperfusion-induced inflammation-like condition are analyzed in terms of the increased adherence of leukocytes to the venular endothelium. Pretreatment with Daflon 500 mg, a purified, micronized, flavonoid fraction consisting of 90% diosmin and 10% hesperidin, prior to the induction of 4 h of tourniquet ischemia significantly lowers the number of adherent leukocytes. This observation is linked to the protective effect of flavonoids in the treatment of edema, as decreased activation is also associated with a decreased platelet and complement system activation, leading to a lowered release of histamine and decreased leukocyte-dependent endothelial damage. It is proposed that attenuation of leukocyte adherence during ischemia-reperfusion is evidence of the protective endothelial effect of Daflon 500 mg and its ability to control edema in clinical situation.

Animals↗
PubMed1995

Effects of Daflon 500 mg on increased microvascular permeability in normal hamsters.

Daflon 500 mg1 (S 5682) is a purified, micronized, flavonoid fraction containing 90% diosmin and 10% hesperidin, which is currently used to treat chronic venous insufficiency and haemorrhoidal disease. In the present study, the effects of Daflon 500 mg on increased microvascular permeability induced by histamine, bradykinin and leukotriene B4 (LTB4) were investigated by intravital microscopy in the hamster cheek pouch preparation. Daflon 500 mg, suspended in 10% lactose solution, or vehicle (10% lactose) was administered orally to male hamsters for 10 days at a dose of 20 mg/kg/day (10 mg/kg twice daily). Fluorescein isothiocyanate-labeled dextran 150 was given intravenously, 30 min after completion of the cheek pouch preparation. Histamine, 2 mumol/l, bradykinin, 0.1 mumol/l, and LTB4, 0.01 mumol/l, applied topically for 5 min increased the number of fluorescent vascular leakage sites in postcapillary venules. The maximum number of leaky sites per cm2 in the prepared area that occurred 5 min after the beginning of each topical application was quantified by UV light microscopy. In comparison with vehicle, Daflon 500 mg significantly inhibited the macromolecular permeability-increasing effect of histamine (343.5 +/- 22.3 vs. 207.5 +/- 32.0; p < 0.01), bradykinin (345.2 +/- 19.0 vs. 206.2 +/- 21.6; p < 0.01) and LTB4 (353.3 +/- 27.5 vs. 242.7 +/- 33.6; p < 0.05). These results demonstrate that oral administration of Daflon 500 mg for 10 days at 20 mg/kg body weight/day has a protective effect against leakage of macromolecules after application of permeability-increasing substances in the cheek pouch microvasculature. These data, which illustrate the inhibitory effect of a clinically relevant dose of Daflon 500 mg on the inflammatory processes induced in this in vivo model of microcirculation, may serve as a rational basis to explain the clinical efficacy of Daflon 500 mg.

Animals↗
PubMed1995

Effect of Daflon 500 mg, a flavonoid drug, on neurological signs, levels of free radicals and electroretinogram in the gerbil after ischemia-reperfusion injury.

The effect of Daflon 500 mg1, purified, micronized flavonoid fraction (90% diosmin, 10% hesperidin) was studied on stroke index, levels of free radicals and electroretinography in the gerbil after ischemia-reperfusion injury. The drug was administered orally at doses of 200, 100 and 50 mg/kg, for 6 days before left carotid occlusion. Daflon 500 mg significantly reversed the increase of stroke index only at the dose of 100 mg/kg and significantly decreased levels of hydroxyl free radicals at all 3 doses with a maximum effectiveness for the dose of 100 mg/kg. Amplitude and latency of the b wave were disturbed after ischemia-reperfusion insult. Daflon 500 mg, 100 mg/kg for 6 days, significantly reversed these modifications. In conclusion, Daflon 500 mg could interact with hydroxyl free radicals, which have a deleterious effect in ischemic tissues, particularly in the retina.

Animals↗
PubMed1995

An original microhaemorheological approach to the pharmacological effects of Daflon 500 mg in severe chronic venous insufficiency.

In the more advanced stages of chronic venous insufficiency, stasis in the skin microcirculation is associated with a decreased red blood cell velocity and an increase in packed cell volume related to the red blood cell piling phenomenon. Although the main factor determining blood viscosity is packed cell volume, the direct relationship between this variable, viscosity and velocity is no longer valid at the microcirculatory level (sigma effect). Viscosity is influenced by blood composition and red blood cell deformability. The aim of this open pilot study was to verify the variations in capillary packed cell volume in comparison with the velocity in 24 patients with third-stage chronic venous insufficiency before (day 1) and after (day 28) a 28-day treatment with Daflon 500 mg, a micronized purified flavonoid fraction consisting of diosmin, 450 mg, and hesperidin, 50 mg, per tablet, 1 g/day, and then 14 days (day 42) after cessation of treatment. Ankle skin microcirculation was evaluated by dynamic capillaroscopy. Values of relative capillary packed cell volume were calculated by a densitometric method, and red blood cell velocity was calculated using the cross-correlation simplified method. Relative capillary packed cell volume (mean +/- SD) significantly (p = 0.001) increased from day 1 (64.10 +/- 9.34%) to day 28 (72.89 +/- 5.74%) and then decreased until day 42 (66.84 +/- 7.48%). In the same patients, red blood cell velocity (mean +/- SD) significantly (p = 0.041) increased from day 1 (0.26 +/- 0.14 mm/sec) to day 28 (0.35 +/- 0.11 mm/sec) and then remained stable until day 42 (0.33 +/- 0.16 mm/sec). Two possible explanations can account for this apparent discrepancy: first, dissociation between viscosity and velocity due to the Fahraeus-Lindqvist effect (sigma effect); and secondly, increased deformability of red blood cells leading to an increased red blood cell velocity despite an increased packed cell volume. It can be concluded that Daflon 500 mg seems to have a beneficial haemorheological effect, resolving the stasis with an increase in red blood cell velocity. A concomitant increase in relative packed cell volume and red blood cell velocity after therapy suggests an improvement of the flexibility of red blood cells.

Adult↗
PubMed1997

Effects of Daflon 500mg on postischemic macromolecular leak syndrome in striated skin muscle of the hamster.

We have recently shown that the purified micronized flavonoid fraction (90% diosmin and 10% hesperidin) Daflon 500 mg attenuates reperfusion injury in the striated skin muscle of the hamster. Herein, we report on the action of Daflon 500 mg on postischemic macromolecular leakage of FITC-dextran 150 kD provoked by tourniquet ischemia. Intravital fluorescence microscopy was used for analysis of macromolecular leakage in the microcirculation model of the hamster. A tourniquet ischemia of 4 h duration was induced followed by reperfusion. Animals were treated by gavage of Daflon 500 mg (n = 6) for 8 days at a daily dose of 30 mg kg(-1) body weight. Control animals received equivalent volumes of the vehicle (5% Arabic gum solution, n = 6). Measurements of the microcirculatory parameters were made before induction of ischemia and at 0.5, 2 and 24 h of reperfusion. After induction of ischemia, macromolecular leakage from postcapillary venules was significantly enhanced in vehicle-treated animals. Treatment with Daflon 500 mg significantly attenuated macromolecular leakage of FITC-dextran 150 kD. Preliminary data from a histomorphometric analysis (n = 3/experimental group) indicated that the number of emigrated (extravascular) leukocytes after ischemia reperfusion was markedly reduced in Daflon 500 mg-treated animals as compared to controls. These data indicate that Daflon 500 mg prevents leakage of the macromolecular tracer FITC-dextran 150 kD from postcapillary venules after postischemic reperfusion, presumably through an inhibitory action on the emigration of activated leukocytes.

Animals↗
PubMed2001

Therapeutic approach to chronic venous insufficiency and its complications: place of Daflon 500 mg.

Early manifestations of chronic venous insufficiency (CVI) are edema, hyperpigmentation, and lipodermatosclerosis. Late complications are cutaneous ulceration and delayed healing. The specific hallmarks of this inflammation include CD68-positive infiltration into the dermal tissue, monocytes, and lymphocytes and enhanced endothelial permeability. This may lead to "fibrin cuff" formation. In addition, membrane adhesion molecules are present and cytokine expression is seen. In one experimental model of mesenteric venous hypertension, the inflammatory process was detected in its earliest stages. This was evident in the form of neutrophilic leukocyte adhesion to venular endothelium as well as migration of cells across the endothelium and basement membrane into the interstitial space. Simultaneously, parenchymal cell death was detected. This suggests that the mechanism that triggers the inflammatory reaction is venous hypertension. This may cause venous distension and a shift in fluid shear stress. Our observations suggest that patients with venous insufficiency demonstrate circulatory humoral stimulators for leukocyte activation. Otherwise, there is evidence that the inflammatory reaction is limited to the region of the venous ulceration or at least to the skin areas with severe microangiopathy. It may be that activated leukocytes traverse perivascular cuffs and release active transforming growth factor-beta1 (TGF-beta1) which has been found to be elevated exclusively in areas of clinically active CVI. Surgical intervention markedly decreases the number of dysfunctional vein segments and allows pharmacologic agents to protect normal structures from continuing damage. Daflon 500 mg, the purified micronized flavonoid fraction containing 90% diosmin and 10% hesperidin, acts favorably in venous ulcer treatment by inhibiting the synthesis of prostaglandins and free radicals. It decreases bradykinin-induced microvascular leakage and may act favorably to inhibit leukocyte activation, trapping, and migration. Clinically, edema is reduced, ulcer healing is accelerated, and leukocyte trapping diminished. The action of micronized purified flavonoid fraction is beginning to be better understood, and as further knowledge is gained, better pharmacologic control of CVI is a tantalizing promise.

Animals↗
PubMed2001

Clinical benefits of Daflon 500 mg in the most severe stages of chronic venous insufficiency.

Chronic venous insufficiency (CVI) affects a large number of people in Western countries, and is responsible for considerable inconvenience, discomfort, suffering, and costs. Micronized purified flavonoid fraction (MPFF, 450 mg diosmin plus 50 mg hesperidin-Daflon 500 mg) is a potent venotropic drug used in the treatment of venous insufficiency. Pharmacological and clinical studies demonstrated the comprehensive mode of action of Daflon 500 mg: it increases venous tone, it improves lymph drainage, and it protects the microcirculation. Clinical international, prospective, multicenter, randomized, controlled studies versus placebo studies documenting the effects of Daflon 500 mg in CVI at advanced stages with edema, skin changes, and venous leg ulcer are reviewed. In edema, one of the most frequent complaints of patients, Daflon 500 mg brings about a significant reduction in leg circumference, thanks to its capacity to inhibit inflammatory reactions and to decrease capillary hyperpermeability. The rationale for the use of Daflon 500 mg for treatment of skin disorders and venous leg ulcer is its action on the microcirculation-damaging processes. Regarding skin changes, Daflon 500 mg has been shown to improve venous trophic disorders, like gravitational (stasis) dermatitis, and dermatofibrosclerosis. In venous leg ulcer, Daflon 500 mg's clinical efficacy has been demonstrated in addition to standard treatment or versus standard treatment alone. Daflon 500 mg, thanks to its comprehensive mode of action on the veins, lymphatics, and microcirculation, is the method of choice not only in the early stages of CVI treatment, but also in the severe stages of this condition, in combination with compression treatment, sclerotherapy, and surgery if appropriate.

Diosmin↗
PubMedDate not supplied

Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids.

Chronic venous insufficiency (CVI) results in considerable morbidity and may seriously affect patients' quality of life. The RELIEF (Reflux assEssment and quaLity of life improvEment with micronized Flavonoids) Study was a prospective controlled study designed to assess differences in the severity and in the evolution of symptoms and signs of CVI according to presence or not of venous reflux. Patients were thus separated into 2 comparative groups: those presenting venous reflux and those without venous reflux. The design of the study was multicentric and international, carried out in 23 countries over 2 years, in which 5,052 symptomatic patients assigned to classes C0 to C4 (on the basis of CEAP clinical classification) were enrolled. Patients were treated with micronized purified flavonoid fraction (MPFF), consisting of 450 mg of micronized diosmin and 50 mg of flavonoids expressed in hesperidin over 6 months. In order to document changes in the quality of life of these patients during MPFF treatment, a new validated Quality of Life Questionnaire specific to CVI (CIVIQ) was used. The study also set out to gather epidemiologic data including the prevalence of venous reflux in symptomatic patients. The RELIEF study provided important information about the epidemiology and clinical manifestations of CVI. Of particular interest was the observation that venous reflux was found to be absent in 57% of patients diagnosed as suffering from CVI belonging to CEAP classes C0 to C4. A positive relationship between symptoms of CVI (pain, leg heaviness, sensation of swelling, and cramps) and presence of venous reflux was found in the RELIEF study: symptoms were more frequent and more severe at presentation in patients with venous reflux. Moreover, during MPFF treatment, all symptoms showed a greater decrease in the group without venous reflux compared with the other group. This difference in the evolution of symptoms between the 2 groups was significant for pain, sensation of swelling, and cramps. Regarding leg heaviness and signs such as edema (assessed by leg circumference), patients improved equally independently of the presence or not of venous reflux. The significant and progressive improvement in the signs of CVI was reflected in significant changes in the clinical class of the CEAP classification, ie, from more severe to less severe stages. Continuous clinical improvement was found throughout the study and after treatment with MPFF for 6 months, the clinical scores of all symptoms and signs had significantly decreased (p=0.0001 versus DO) in both groups. This improvement was also associated with a significant and continuous progression in the quality of life scores of all patients. Age of patients, average time since diagnosis, and presence of venous reflux increased with the severity of the disease. The relationship shown in this study between these parameters and clinical CEAP classification reflects the progressive nature of CVI. Despite obvious symptoms of CVI, a very low percentage (21.8%) of the "intention-to-treat" (ITT) population had previously been treated. This was the case whether venous reflux was present or not.

Adult↗
PubMedDate not supplied

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.

Diosmin↗
PubMedDate not supplied

Daflon 500 mg: symptoms and edema clinical update.

Patients suffering from any class of the Clinical, Etiological, Anatomical, Pathophysiological (CEAP) classification of chronic venous disease (CVD) may be symptomatic (C0s-C6s). Leg heaviness, discomfort, itching, cramps, pain, paresthesia, and edema (C3) are the most frequent manifestations of CVD and a major reason for medical consultation. Daflon 500 mg (micronized purified flavonoid fraction [MPFF]) is an effective treatment for symptoms and edema in CVD as demonstrated in several randomized controlled studies. A 2-month, double-blind study in 40 patients established the superiority of Daflon 500 mg over placebo with regard to symptoms and objective signs. This was confirmed in another double-blind, placebo-controlled trial (2 months' treatment, 160 patients), and in the Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids (RELIEF) study. The latter included 5,052 patients in 23 countries, using a visual analog scale for evaluating pain, leg heaviness, cramps, and a sensation of swelling. All symptoms showed significant and progressive improvement. The quality-of-life results (scores on the ChronIc Venous Insufficiency quality of life Questionnaire [CIVIQ]) paralleled those of symptoms. The decrease in the ankle and calf circumferences was significantly greater (p < 0.001) in the group of patients treated with Daflon 500 mg in two studies, and correlated well with the improvement in the sensation of swelling (p < 0.001). This was confirmed with more sophisticated measurement techniques as in the RELIEF study or in a trial assessing edema with an optoelectronic volumeter in 20 patients. A further double-blind, randomized, controlled study established a statistically significant difference in favor of Daflon 500 mg in comparison with diosmin, both on symptoms and edema. The therapeutic efficacy of Daflon 500 mg on CVD symptoms and edema has been demonstrated in double-blind, randomized, controlled studies. Further studies using a new approach may define the most precise and validated methodology for application in future research in phlebology.

Chronic Disease↗
PubMedDate not supplied

Venoruton vs Daflon: evaluation of effects on quality of life in chronic venous insufficiency.

The aim of this independent study was to investigate differences in efficacy between oxerutins (Venoruton) and 500 mg micronized diosmin + hesperidin (D+H) (Daflon) in patients with chronic venous insufficiency (CVI), evaluating venous-related quality of life (Ve-QOL). A first group of 90 patients with severe venous hypertension (CVI, ankle swelling) was randomized to treatment with oxerutins or D+H. The oxerutins group received oral oxerutins (2 g/day); the D+H group received 3 (500 mg) tablets daily every 8 hours for 8 weeks. A second group of 122 comparable patients was included in a registry following the same study format. The 2 treatments were administered with the same methods and procedures. Clinical conditions were comparable. All patients completing 8 weeks of treatment were included in a registry. Specialists or general practitioners included patients when they considered that clinical conditions were compatible with treatment indications using 1 of the 2 treatments on the basis of their evaluation and experience. When cases were compatible with the registry, the prescribing physician communicated the case to our monitoring center. Patients were evaluated without interfering with their treatment. The main target of evaluation for this study was the change in Ve-QOL (range, 0-100) induced by treatment. A specific Ve-QOL questionnaire was used for this study. Ve-QOL score is a specific expression of the changes in QOL induced by CVI in patients between 35 and 75 years old (defined in our population studies) in which no other significant clinical disease is present (as a confounding factor affecting QOL). Two hundred twelve patients completed the 2 parts of the study. The 2 treatment groups were comparable for age and gender distribution. The mean age was 42 years (SD +/-5.5) in the oxerutins group and 41.5 (SD +/-6) in the D+H group. There were no differences in the severity of CVI between the treatment groups at inclusion. A significant decrease (46.8%, p <0.05) in Ve-QOL score; that is, improvement, was observed in the oxerutins group. The change in Ve-QOL was significantly less in the D+H group (15.5%). In conclusion, CVI, venous microangiopathy, and edema were significantly improved by the treatment with oxerutins; the improvement in QOL was significantly greater in the oxerutins group. The comparison with D+H indicates that oxerutins is comparatively more effective on Ve-QOL and on signs/symptoms of CVI.

Administration, Oral↗
PubMed1994

Flavonoids. A review of the pharmacology and therapeutic efficacy of Daflon 500 mg in patients with chronic venous insufficiency and related disorders.

Daflon 500 mg consists of 450 mg diosmin and 50 mg flavonoid expressed as hesperidin. The authors describe its effects on the microcirculation in chronic venous insufficiency: improvement of venous tone, inhibition of prostaglandin synthesis, protection against free radicals, activation of the complement system, and increased lymphatic drainage. The authors summarize studies of its therapeutic efficacy in reducing venous capacitance, distensibility, and emptying time; reducing capillary permeability; and increasing capillary resistance.

Animals↗
PubMed1994

Safety and security of Daflon 500 mg in venous insufficiency and in hemorrhoidal disease.

Daflon 500 mg is a new flavonoid vasoprotector venotonic agent whose active principle is micronized and contains 90% diosmin and 10% flavonoids expressed as hesperidin. In animal studies, the safety of Daflon 500 mg is shown by an LD50 (lethal dose 50) of more than 3 g/kg, ie, 180 times the daily therapeutic dose, as well as by the absence of any toxic effect after repeated oral dosing for thirteen and twenty-six weeks, using a dose representing 35 times the daily dosage, in the rate and primate. Daflon 500 mg has no mutagenic action nor any significant effect on reproductive function. Gastrointestinal tolerance is good when administered orally in the rat. Transplacental passage and passage into breast milk are minimal. In the rat, 0.003% of the administered dose has been found in each fetus and 1% in breast milk. Clinical trials fulfill international scientific requirements and have collected more than 2850 patients treated with Daflon 500 mg at the dosage of two tablets per day for six weeks to one year. The proportion of patients with side effects (10% of those treated), essentially of a gastrointestinal or autonomic nature and leading to a rate of only 1.1% trial dropouts, is less than described in 225 patients given a placebo (13.9%) in controlled trials. Satisfactory clinical acceptability already confirmed in the short term was equally found in long-term treatment. Hemodynamic parameters (systolic and diastolic blood pressure) as well as laboratory parameters (hematology, liver and renal function, metabolic) were uninfluenced even by prolonged treatment for one year at the dosage of two tablets per day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Microvascular reactivity after ischemia/reperfusion in the hamster cheek pouch: beneficial effects of different oral doses of S-5682 (Daflon 500 mg).

Daflon 500 mg (S-5682) is a purified, micronized flavonoid fraction containing 90% diosmin and 10% hesperidin that is currently used to treat chronic venous insufficiency and hemorrhoidal disease. Thus, it seemed of interest to evaluate the effects of S-5682 on ischemia/reperfusion, ie, the changes in mean internal diameter and blood flow of arterioles and venules and the functional capillary density (FCD) during reperfusion after ninety minutes of total ischemia in the hamster cheek pouch microvasculature. Different doses of S-5682 (5, 20, 80, and 160 mg/kg body weight/day), suspended in 10% lactose solution or vehicle (10% lactose) were administered orally to male hamsters for ten days twice a day. The cheek pouch preparation was placed under an intravital microscope coupled to a closed-circuit TV system. A ninety-minute local ischemia was obtained by a cuff mounted around the neck of the everted pouch where it left the mouth of the hamster. Mean arteriolar and venular internal diameters were determined by means of an image-shearing device, IPM model 907; red blood cell (RBC) velocity was measured by the dual-slit photometric technique; microvessel volume flow was calculated from diameters and RBC velocities; and FCD was defined as the number of red-cell-perfused capillaries per observation field. During reperfusion, placebo-treated animals showed significant vasodilatation concomitant with a decrease in blood flow and FCD compared with preischemic values and an impairment of the myogenic response. In S-5682-treated animals, there was a significant dose-dependent improvement in all these parameters including the myogenic tonus. These results clearly demonstrated that oral administration of different doses of S-5682 for ten days improved the microvascular reactivity and FCD after ischemia/reperfusion in a dose-dependent fashion in the hamster cheek pouch microvasculature.

Animals↗
PubMed1997

Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients.

The objective of this study was to evaluate the efficacy of Daflon 500 mg (Dios)* in venous ulcers. A multicenter, double-blind, randomized, controlled versus placebo (Plac) trial was conducted, with stratification according to the size of ulcer (< or = 10 cm and > 10 cm). The protocol called for a two-month treatment with Dios (one tablet = 450 mg micronized purified Diosmin) or a placebo, two tablets/day, in addition to compression therapy. Evaluations were performed every fifteen days, from D0 to D60. The primary endpoint, in accordance with Alexander House group requirements were: percentage of patients with complete ulcer healing, ie, comparison between Dios and Plac group at D60, and comparison of survival curves in each group between D0 and D60 (log rank test). Secondary endpoints included ulcer surface area assessed by computerized planimetric measurements, qualitative evaluation of ulcers, and symptoms. The patients were 105 men and women ranging in age from eighteen to eighty-five years, with standard compression stocking, who were undergoing standardized local care of ulcer and had no significant arterial disease (ankle/arm systolic pressure index > 0.8). Fifty-three patients received Dios, and 52 received Plac. The 2 groups were well matched for age (m +/- 1 SD = seventy-one +/- eleven years), gender, ulcer size, and associated disorders. Among patients with ulcer size < or = 10 cm (Dios = 44, Plac = 47) a significantly larger number of patients had a complete ulcer healing at two months in the Dios group (n = 14) in comparison with the Plac group (n = 6) (32% vs 13%, P = 0.028) with a significantly shorter time duration of healing (P = 0.037). No difference was shown for the secondary criteria, except for sensation of heavy legs (P = 0.039) and a less atonic aspect of ulcer (P = 0.030) in favor of Dios. Among the 14 patients with ulcer size > 10 cm (Dios = 9, Plac = 5), subjected to a descriptive analysis only, no ulcer healed. This study showed that a two-month course of Daflon 500 mg at a daily dose of two tablets, in addition to conventional treatment, is of benefit in patients with venous ulcer < or = 10 cm by accelerating complete healing.

Adolescent↗
PubMed1997

Effects of oral administration of purified micronized flavonoid fraction on increased microvascular permeability induced by various agents and on ischemia/reperfusion in the hamster cheek pouch.

The effects of a clinically used purified micronized flavonoid fraction (S 5682) containing 90% diosmin and 10% hesperidin on increased microvascular permeability induced by histamine, bradykinin, and leukotriene B4 (LTB4) were investigated by intravital microscopy in the hamster cheek pouch preparation. The authors also investigated the effects of S 5682 on macromolecular permeability increase and leukocyte adhesion during ischemia-reperfusion by using the same preparation. S 5682, suspended in 10% lactose solution, or vehicle (10% lactose) was administered orally to male hamsters for ten days at 20 mg/kg/day (10 mg/kg twice a day). Fluorescein isothiocyanate (FITC)-labeled dextran (mol wt 150,000) was given intravenously, thirty minutes after completion of the cheek pouch preparation. The leukocytes were stained by continuous IV infusion of acridine orange (0.5 mg/kg/minute). Histamine (2 microM), bradykinin (1 microM), and LTB4 (0.01 microM), applied topically for five minutes, increased the number of fluorescent vascular leakage sites in postcapillary venules. A temporary ischemia with total circulatory arrest of the cheek pouch was obtained by clamping the neck of the everted pouch. The maximum number of leaky sites (per cm2 in the prepared area) that occurred either at five minutes after the beginning of each topical application or ten minutes after the onset of reperfusion was quantified in ultraviolet light microscopy. The results from 60 animals divided into 10 groups of 6 animals each are presented as means +/- SEM. In comparison with vehicle, S 5682 significantly inhibited the macromolecular permeability increasing effect of histamine (343.5 +/- 22.3 versus 207.5 +/- 32.0 leaks/cm2; P < 0.01), bradykinin (345.2 +/- 19.0 versus 206.2 +/- 21.6 leaks/cm2; P < 0.01), and LTB4 (353.3 +/- 27.5 versus 242.7 +/- 33.6 leaks/cm2; P < 0.05). At reperfusion, after thirty minutes of ischemia, S 5682 significantly decreased the observed macromolecular permeability (103.6 +/- 15.4 versus 42.6 +/- 9.3 leaks/cm2; P < 0.01). Flavonoid-treated animals also displayed a statistically significant lower number of adhering leukocytes to the venular endothelium (83.5 +/- 9.5 versus 48.4 +/- 12.3 per 6 mm2; P < 0.05). These results demonstrate that oral administration of S 5682 for ten days at 20 mg/kg body weight/day had a protective effect against leakage of macromolecules after application of permeability-increasing substances and during ischemia-reperfusion in the cheek pouch microvasculature. Since firm leukocyte attachment to the endothelial wall and subsequent emigration of leukocytes into the interstitium is a mechanism for tissue damage during inflammation, attenuation of this phenomenon during conditions of ischemia-reperfusion can in part explain previous observations that this purified micronized flavonoid fraction decreases edema formation. The present data illustrating the inhibitory effect of a clinically relevant dose of S 5682 on the inflammatory processes induced in this in vivo model of microcirculation may serve as a rational basis to explain its clinical efficacy.

Administration, Oral↗
PubMed2002

HR (Venoruton1000, Paroven, 0-[beta-hydroxyethyl]-rutosides) vs. Daflon 500 in chronic venous disease and microangiopathy: an independent prospective, controlled, randomized trial.

OBJECTIVES: The aim of this study was to demonstrate whether and how HR (Venoruton(1000), Paroven, 0-[beta-hydroxyethyl]-rutosides) and Daflon (diosmin, 500 mg) were comparatively effective in improving the microcirculation in venous hypertension and microangiopathy. METHODS: A group of 90 patients with severe venous hypertension due to chronic venous insufficiency, ankle swelling, and lipodermatosclerosis were included. After informed consent, patients were randomized into a Venoruton and a Daflon (DF) group: patients in the Venoruton group received oral HR (2 g/day for 8 weeks); those in the Daflon group received three 500-mg tablets daily every 8 hours. The two groups were comparable for age and sex distribution. The mean age was 41 years (SD +/- 11) in the Venoruton group (46 patients) and 41.3 (SD +/- 12) in the DF group (44 patients). RESULTS: There were no differences in microcirculatory parameters between the Venoruton and DF treatment groups at inclusion. There was no significant change between inclusion and measurements at 8 weeks in the DF group. In comparison, a significant decrease (P < .05) in RF (resting skin flux) and RAS (rate of ankle swelling) was observed in the Venoruton group (P < .001). The decrease in capillary filtration was associated with improvement in signs and symptoms (measured by an analogue scale line) (P < .05). Symptomatic improvement was clinically and statistically significant and important only in the Venoruton group. No side effects and no drop-outs were observed. CONCLUSION: Venous microangiopathy was improved by the treatment with Venoruton. The comparison with Daflon indicates that HR is comparatively more effective both on microcirculatory parameters and on signs and symptoms.

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