[Calcium dobesilate in the treatment of primary venous insufficiency of the lower limbs. A controlled clinical study]. [Effect of 0-(beta-hydroxyethyl)-rutoside (Venoruton) on symptomatic venous insufficiency in the lower limbs]. Leg oedema protection from a buckwheat herb tea in patients with chronic venous insufficiency: a single-centre, randomised, double-blind, placebo-controlled clinical trial. A double-blind trial of calcium dobesilate in chronic venous insufficiency. Pycnogenol in chronic venous insufficiency. Efficacy and safety of a Butcher's broom preparation (Ruscus aculeatus L. extract) compared to placebo in patients suffering from chronic venous insufficiency. The efficacy and safety of a coumarin-/troxerutin-combination (SB-LOT) in patients with chronic venous insufficiency: a double blind placebo-controlled randomised study. Investigation of the efficacy of oxerutins compared to placebo in patients with chronic venous insufficiency treated with compression stockings. Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients. [On the therapy of so-called leg pains. Controlled double-blind study of the therapeutic efficacy of Daflon]. Are the phlebotonic properties shown in clinical pharmacology predictive of a therapeutic benefit in chronic venous insufficiency? Our experience with Daflon 500 mg. The effect of hydroxyethylrutosides after acute and chronic oral administration in patients with venous diseases. A double-blind study. The effect of hydroxyethylrutosides on capillary filtration in moderate venous hypertension: a double blind study. A randomised controlled trial of micronised purified flavonoid fraction vs placebo in patients with chronic venous disease. Hydroxyethylrutosides in elderly patients with chronic venous insufficiency: its efficacy and tolerability. [Centella asiatica extract in venous disorders of the lower limbs. Comparative clinico-instrumental studies with a placebo]. Clinical evaluation of a venotropic drug in man. Example of Daflon 500 mg. A double-blind trial of O-(beta-hydroxyethyl)-rutoside in patients with chronic venous insufficiency. [Clinical, placebo-controlled double-blind study of venoruton in the treatment of chronic venous insufficiency. Importance of the selection of patients]. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. General practice treatment of symptoms of venous insufficiency with oxerutins. Results of a 660 patient multicentre study in the UK. Double-blind clinical and plethysmographic study of calcium dobesilate in patients with peripheral microvascular disorders. PYCNOGENOL in chronic venous insufficiency. Doxium 500 in chronic venous insufficiency: a double-blind placebo controlled multicentre study.
Fourty patients with lower limb chronic venous insufficiency entered a randomised placebo controlled study with calcium dobesilate for one month. Clinical symptoms and plethysmographic parameters were evaluated before and after therapy in all patients. In the group of patients treated with calcium dobesilate we observed an improvement of clinical and instrumental parameters; no changes were found in the placebo group. We observed good tolerance to the drug and no side effects required withdrawal of treatment. Forty-three patients recruited from general practice with symptom-producing chronic venous insufficiency in the lower limbs participated in a randomized double-blind clinical trial with Venoruton (300 mg x 3) or a placebo for 28 days. Twenty-eight patients were treated with Venoruton and 19 with a placebo. None of the patients received other forms of treatment for chronic venous insufficiency. No differences were observed between the two groups as regards changes in symptoms (swelling, pain, heaviness, restlessness, itching and cramps) the subjective assessment of the discomfort in the extremities or the circumference of the limbs. Venoruton does not appear to have any effect on chronic venous insufficiency in the lower limbs. The efficacy of a buckwheat herb tea was determined in patients with chronic venous insufficiency (CVI) in a single-centre, randomised, double-blind, placebo-controlled clinical trial.
                Sixty-seven male and female patients (22-74 years) with CVI were randomly divided into two groups after a 2-week run-in period. They received either buckwheat herb tea (Fagopyrum esculentum) or a placebo tea for a period of 3 months. The main outcome measure was the lower leg volume determined by ultrasound. Subjective symptoms were assessed by a clinical symptom score system. The femoral vein diameters were measured by B-scan sonography. In a subgroup of patients capillary permeability was determined by cutaneous fluorescence angiography.
                Although the mean partial leg volume did not change in the treatment group (from 2041 to 2073 ml), it increased in the placebo group by 110 ml (from 1972 to 2082 ml) according to intent to treat. The difference between the groups was significant. The subjective clinical symptoms were significantly reduced in both groups. The mean diameters of the femoral veins were reduced and capillary permeability was improved, but neither change was statistically significant. No drug-related adverse effects were observed.
                CVI is a very placebo-sensitive condition. The treatment with buckwheat herb tea is safe and could have a favourable influence on patients with CVI such that further oedema development is prevented. Calcium dobesilate was studied in a double-blind trial in 30 normal subjects and in 30 patients with chronic venous insufficiency (CVI). There were no significant alterations in the normal subjects. In patients with CVI the active drug gave significant improvements (p less than 0.01) in the measured volume of the foot and lower limb, in clinical tenderness (p less than 0.05), and in most of the symptoms (including feelings of heaviness, swelling, tiredness, and aching in the lower extremities). Even though the chronic venous insufficiency had existed for an average of fifteen years, a relatively short course of the drug caused considerable, and significant, improvements in a number of signs and symptoms of the disease. Forty patients with chronic venous insufficiency (CVI) and varices of the legs were selected and double-blindly randomly assigned to a treatment with Pycnogenol (French maritime pine bark extract), 100 mg x 3/day or a placebo for 2 months, according to a double-blind experimental design. The effects of the treatment were evaluated by scoring the symptomatology with a semi-quantitative scale, and the venous blood flow by means of a hand-held Doppler ultrasound. The tolerability was evaluated by recording the adverse effects and by means of hematology and blood chemistry parameters, before and at the end of the treatment. Pycnogenol treatment induced a significant reduction in subcutaneous edema as well as heaviness and pain in the legs, on both after 30 and 60 days, the evaluation time periods. Approximately 60% of patients treated with Pycnogenol(R) experienced a complete disappearance of edema (the most rapidly disappearing symptom) and pain at the end of the treatment, while almost all the patients reported a reduction in leg heaviness which disappeared in approximately 33% of patients. These changes were statistically significant. No effect was observed in the placebo-treated subjects. No effect on the venous blood flow was observed in either of the experimental groups. Extracts from Butcher's broom rhizome (Ruscus aculeatus) have been widely used in the oral treatment of lower leg edema in patients with chronic venous insufficiency. The aim of the present multi-center, double-blind, randomized, placebo-controlled trial was to confirm the efficacy and safety of a ruscus extract (Fagorutin Ruscus Kapseln) according to the latest scientific standards. 166 women suffering from chronic venous insufficiency (Widmer grade I and II, CEAP (Clinical signs, Etiological classification, Anatomic distribution, Pathophysiology) 3-4) were included. The data of 148 patients (30-89 years, 150-182 cm height, 49-97 kg body weight) with a mean disease duration of 14.6 years in the ruscus extract group and 15.1 years in the placebo group were eligible for the intent-to-treat-analysis. The primary parameter was the area under baseline of the leg volume changes over 12 weeks (AUB0-12). Secondary parameters were the changes in circumference of the lower leg and the ankle, changes in subjective symptoms and quality of life, the overall efficacy and tolerability and safety parameters. The study was carried out according to the guidelines for testing drugs for chronic venous insufficiency. There were significant differences between the treatment groups ruscus and placebo for the AUB0-12 (-827 ml x day), for the change of leg volume after 8 and 12 weeks of treatment (-16.5 ml and -20.5 ml), for changes in ankle and leg circumferences after 8 and 12 weeks of treatment, and for the changes in subjective symptoms, heavy tired legs and sensation of tension (week 12). For the changes in the symptoms heavy lower legs, sensation of tension, and tingling sensation a significant positive correlation with the changes in leg volume was shown. Overall assessment of efficacy was significantly better for ruscus extract compared to placebo. Overall tolerability for both treatments was assessed as good and very good. Of all 48 adverse events occurring in both treatment groups, 22 were reported in the ruscus group, one of them was considered to be related to the study medication (unlikely). Considering the study duration of three months it is concluded, that ruscus extract, in the recommended daily dosage according to the German monograph, is a safe and effective treatment for patients suffering from chronic venous insufficiency. The objective was to evaluate the oedema-protective effect of a vasoactive drug (coumarin/troxerutin [SB-LOT]) plus compression stockings in patients suffering from chronic venous insufficiency after decongestion of the legs as recommended by the new guidelines.
                231 patients were randomly assigned medical compression stockings plus SB-LOT (90 mg coumarin and 540 mg troxerutin per day) or medical compression stockings plus placebo for the first 4 weeks and SB-LOT or placebo for the second 12 weeks of the study. The primary efficacy endpoint was the lower leg volume measured by well-established water plethysmometry.
                226 patients were evaluated. After ceasing compression stockings, an edema protective effect was detected in the SB-LOT-group but not in the controls. Recurrence of leg volume increase was by 6.5 +/- 12.1 ml and by 36.7 +/- 12.1 ml in the SB-LOT and placebo group, respectively (p = 0.0402). The local complaint score and general aspects of quality of life were also superior for the SB-LOT-group (p = 0.0041). Significant differences were also observed with regard to clinical global impression and therapeutic effect. No serious adverse drug reaction or clinically relevant impairment of laboratory parameters occur.
                This study confirms the oedema-protective effect of SB-LOT in chronic venous insufficiency and provides a treatment option for patients who discontinue compression after a short time. The aim of this study was to investigate, if the the combined treatment of compression stockings and drug treatment with oxerutins (O-(beta-hydroxyethyl)-rutosides, Venoruton) provides additional benefit for patients with chronic venous insufficiency (CVI) compared to compression treatment alone. Oxerutins belong to the group of oedema protective agents and possess anti-exudative and membrane protective activity. A total of 133 female patients with CVI grade II participated in this double-blind, randomised, multi-centre, parallel-group study with two treatment groups. The whole study lasted for 19 weeks, and consisted of a one week placebo run-in phase, 12 weeks treatment phase, followed by a 6 weeks treatment-free follow-up period. All patients received a basis compression therapy that consisted of standard compression stockings. In order to standardise initial fitting of stockings in this multi-centre setting, stockings were fitted after one week of standard diuretics starting at baseline and then stockings were worn for the following 11 weeks. Patients were randomised to receive oxerutins (2 x 500 mg daily) or matching placebo. Leg volumes (water displacement) and associated subjective symptoms (visula analogue scale) were measured during a placebo run-in period at enrolment (week - 1) and half a week later (week - 1/2), at baseline week 0), at 4, 8, 12 weeks on treatment, and again after a 3- and 6-weeks treatment-free follow-up. The primary efficacy criterion, the area under the baseline from week 0 to week 18 (AUB0-18) of leg volume changes, as measurement of the global change of leg oedema during the study, resulted in a superior reduction of -5589 ml.d for the combined treatment with oxerutins compared to -2101 ml.d for placebo (p = 0.012). The mean change of leg volume compared to baseline after 12 weeks of treatment was -63.9 ml for stockings and oxerutins, and -32.9 ml for the patients who received stockings and placebo (p < 0.05). Oxerutins showed a prolonged effect in the follow-up phase compared to placebo, with mean AUB values for week 12 to week 18 of -1769 ml.d versus -133 ml.d (p < 0.01). The study demonstrated that the combined therapy of compression stockings and drug treatment with oxerutins is significantly superior in reducing leg oedema resulting from chronic venous insufficiency compared to compression treatment alone. 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. nan In 3 controlled clinical trials, double blind versus placebo, the activity of Daflon 500 mg, a new micronised flavonoid fraction, has been evaluated on venous tone using venous plethysmography. A double-blind, randomized cross-over Phase II pharmaco-clinical trial has shown that Daflon 500 mg is statistically more effective than placebo on pathological legs, as well as normal legs. In this study, which included 20 patients suffering from post-thrombotic syndrome, Daflon 500 mg decreased: 1) venous capacity (p less than 0.001); 2) venous distensibility (p less than 0.001); 3) venous outflow time, measured by the two parameters total emptying venous time (p less than 0.001) and T2p (p less than 0.001). These modifications have been observed 2 hours after administration without any significant change in T50 outflow, cardiad index, capillary filtration index, blood pressure, cardiac or respiratory rate. The same acute effect of increasing venous tone has been demonstrated in another pharmacoclinical trial, 1 and 2 hours after ingestion in 3 groups of 10 women suffering from venous insufficiency: group I without varicose, group II during pregnancy and group III with a post-thrombotic syndrome. Finally, in a Phase III clinical trial, in 2 parallel groups of 20 patients each with functional chronic venous insufficiency, Daflon 500 mg has been compared to placebo. It was then demonstrated after 1 and 2 months treatment an improvement in the functional symptoms and edema accompanied by a statistically significant increase of the venous tone. (ABSTRACT TRUNCATED AT 250 WORDS) nan The aim of this study was to evaluate the effect of hydroxyethylrutosides on capillary filtration in subjects with mild to moderate venous incompetence--superficial varicose veins and/or deep venous disease and ankle oedema--using the vacuum suction chamber (VSC) device applied to the internal perimalleolar region and the wheal vanishing (WV) time. Subjects entered in to the study were randomised to receive either hydroxyethylrutosides (1 g twice daily for 4 weeks) or placebo for four weeks. The two groups entering and completing the study were comparable. Microcirculatory parameters (laser-Doppler resting flux, the venoarteriolar response, transcutaneous PO2 and PCO2) remained constant during the four week study in both groups. The WV time, which was comparable in the two groups at the beginning of the study decreased significantly [from a median 55 min (interquartile 955 min), to a median 45 minutes (interquartile 65-40 min) in the treated group, p < 0.01]. No change was observed in the WV time in the placebo group. Subjective symptoms measured with an analogue scale improved following treatment with hydroxyethylrutosides [foot oedema (p < 0.005), ankle oedema (p < 0.001), and paraesthesia (p < 0.01)]; only night cramps were reported less in patients receiving the placebo (p < 0.05). In conclusion, the WV time can be used to assess the beneficial effect of therapy on capillary filtration in subjects with mild-moderate venous hypertension, even after a short period of treatment, and before other microcirculatory parameters change. Furthermore, the changes observed in WV time correlate well with an improvement in patients symptoms. to evaluate the efficacy of a micronised purified flavonoid fraction (MPFF) in the treatment of chronic venous disease (CVD).
                prospective double blind, randomised, control study. PATIENTS and
                one hundred and one patients with symptomatic CVD were randomly allocated to treatment for 60 days with either MPFF (51 patients) or placebo (50 patients) 500 mg twice daily. There were 28 men and 73 women, aged 22-65 years (mean age 48 years). No difference regarding age, gender, clinical class or duration of symptoms was recorded between the treatment and placebo groups. A global score for evaluation of symptoms was used. Patients were investigated with plethysmography (foot-volumetry) and duplex-ultrasonography before and after the treatment period. For statistical comparison Cochran-Mantel-Haenszel test, two-sided Student t-test and covariance analysis were used and p<0.05 was regarded significant.
                improvement of the global score of symptoms was reported by 21 patients in the MPFF group and by 16 in the placebo group (N.S.). For the whole groups, no significant differences were recorded before and after treatment regarding foot-volumetric or ultrasonographic parameters. On the other hand, in patients with edema (20 in the MPFF group, 23 in the placebo group) ultrasonographic reflux time was significantly reduced for those in the treatment group (p=0.03). This finding did not correlate to clinical symptoms.
                in this study, MPFF did not change the symptoms of CVD, except night cramps. A secondary finding was reduced reflux times in patients with oedema, although no ultrasonographic or foot-volumetric parameters changed significantly for the whole group. The role of MPFF in treatment of patients with CVD needs to be further analysed in a large population.
                Copyright 2002 Harcourt Publishers Limited. The efficacy and tolerability of O-(beta-hydroxyethyl)-rutosides (HR) in elderly patients (aged over 65 years) with chronic venous insufficiency or varicose veins was studied in a multicentre, double-blind, randomised, placebo-controlled trial. Of the 104 patients entered into the trial, data from 102 were available for analysis of tolerability and from 86 for efficacy. Treatment was for 6 months, with monthly examinations. Three different dosages were used due to slight differences in the registered dosage in various countries: (1) 250 mg 4 times daily (1 g/day), UK, n = 19 patients; (2) 300 mg 3 times daily (900 mg/day), FRG and Belgium, n = 55, and (3) 300 mg 4 times daily (1,200 mg/day), The Netherlands, n = 30. Each centre had its own placebo control group. The HR-treated group (n = 41) showed a significantly greater reduction in the total symptom score, 5.7 +/- 2.4 to 2.3 +/- 1.8, than in the placebo group, 4.4 +/- 3.0 to 3.0 +/- 2.4 (p < 0.01). Of the 5 studied symptoms there was also a significant (p < 0.05) improvement in leg cramps, heavy legs and restless legs. No significant differences between the two groups were seen for aching pains and paraesthesia. A small reduction was also seen in ankle and calf circumferences, which became significant at the end of the trial (p < 0.05). Pitting oedema of the leg (p < 0.01) and eczema of the leg (p < 0.05) also improved significantly greater than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS) nan Chronic venous insufficiency (CVI) of the lower limbs is a complex and fluctuating disease by its pathogenic mechanisms and its clinical symptoms. Although symptoms are subjective, they affect the quality of life and socio-professional activity of many patients. This is why convincing demonstration of therapeutic activity of a venotropic drug should be carried out according to strict methodology. Only randomized double-blind controlled trials versus placebo (no reference drugs being available) could demonstrate the activity on condition that they are set up in a protocol, the statistical design of which, is adapted and defined "a priori". Inclusion, non inclusion and judgement criteria must be rigorous, taking into account many exogenous and endogenous factors which could have influence on the severity or the change in CVI and on the comparability of groups at the beginning and at the end of the study. Thus, the main risk factors of CVI (heredity, obesity, obstetrical and gynecological history, estroprogestogen treatment, profession, environment, etc.) and the season when the patient is recruited should be taken into account. With respect to all these restraints on methodology, the venotrotopic activity of a flavonoid Daflon 500 mg (2 tablets daily) was demonstrated in 200 patients (174 women, 26 men) with organic CVI (n = 83) or functional CVI (n = 117) treated for two months in two double-blind randomized trials versus placebo. The venotropic activity of Daflon 500 mg, was shown by a significant reduction of CVI signs and symptoms, whether organic or functional, and a significant improvement in venous hemodynamics according to plethysmographic parameters. Good acceptability was observed after medium and long term trials. nan nan Ninety-four patients suffering from venous insufficiency of the lower limbs participated in a multicenter, double-blind versus placebo study. After randomization, they were allotted for a treatment period of two months to one of three groups: TECA 120 mg/day, TECA 60 mg/day, or placebo. A significant difference (p less than 0.05) in favor of TECA was shown for the symptoms of heaviness in the lower limbs and edema, as well as for the overall evaluation by the patient. The venous distensibility measured by a mercury strain gauge plethysmograph at three occlusion pressures was improved for the TECA groups but aggravated for the placebo group. nan nan The aim of out study was to investigate the efficacy of Pycnogenol - a French maritime pine bark extract - in the treatment of chronic venous insufficiency (CVI). The study consisted of a double-blind phase - in which 20 patients were recruited and randomly treated with placebo or Pycnogenol (100 mg 2 3/day for 2 months) - and an open phase - in which other 20 patients were treated with Pycnogenol at the same dose schedule. In total, 40 patients were enrolled; 30 of them were treated with Pycnogenol and 10 with placebo. Pycnogenol significantly improved the legs' heaviness and subcutaneous edema; the venous pressure was also significantly reduced by the Pycnogenol treatment, thus adding further clinical evidence to its therapeutic efficacy in patients with CVI. Pycnogenol was effective, probably by either stabilizing the collagenous subendothelial basal membrane or scavenging the free radicals, or by a combination of these activities. Clinically, capillary leakage, perivascular inflammation and subcutaneous edema were all reduced. The safety of use of Pycnogenol is demonstrated by the lack of side effects or changes in blood biochemistry and hematologic parameters. Pycnogenol can be therefore recommended both for prevention and treatment of CVI and related veno-capillary disturbances. The aim of this double-blind placebo-controlled study was to evaluate the therapeutic efficacy of Doxium in chronic venous insufficiency (CVI). 225 patients were treated randomly for 4 weeks with 1.5 g (3 capsules/day) of Doxium or placebo. The evolution of the leg oedema was determined by measuring calf and ankle circumferences. Pain and discomfort were assessed by visual analogue scale. The results show that at the end of the trial, all the examined parameters (leg oedema, pain, day and night cramps, discomfort, heavy legs, paresthesia and restless legs) were significantly more improved in the Doxium group than in the placebo group: the leg volume was diminished by 3.8% in the Doxium group compared to 1.2% in the placebo (p less than 0.005). The overall assessment by the physicians showed an improvement in 82% of the Doxium-treated patients compared to 42% of the placebo group (p less than 0.0001). The tolerance of the treatment was comparable in both groups.
There is not enough evidence to globally support the efficacy of phlebotonics for chronic venous insufficiency. There is a suggestion of some efficacy of phlebotonics on oedema but this is of uncertain clinical relevance. Due to the limitations of current evidence, there is a need for further randomised, controlled clinical trials with greater attention paid to methodological quality.