Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from 'high' to 'moderate' because of risk of bias concerns, and further to 'low' because of imprecision. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base.

Antioxidant, anticancer activities and mechanistic studies of the flavone glycoside diosmin and its oxidovanadium(IV) complex. Interactions with bovine serum albumin.

The natural antioxidant flavonoid diosmin, found in citric fruits, showed low antioxidant properties among other flavonoids due to its structural characteristics and low cytotoxicity against lung (A549) and breast (T47D, SKBR3 and MDAMB231) cancer cell lines. The anticancer behavior has been improved by the metal complex generated with the flavonoid and the oxidovanadium(IV) ion. This new complex, [VO(dios)(OH)3]Na5·6H2O (VOdios), has been synthesized and characterized both in solid and solution states. The interaction of the metal ion through the sugar moiety of diosmin precluded the improvement of the antioxidant effects. However, the cell-killing effects tested in human lung A549 and breast T47D, SKBR3 and MDAMB231 cancer cell lines, were enhanced by complexation. The anti-proliferative effects on the human lung cancer cell line were accompanied by cellular ROS generation and an increase in cytoplasm condensation. The breast cancer cell lines did not produce caspase3/7 activation, mitochondrial potential reduction and ROS generation. Therefore, a non-apoptotic form of cell death in a caspase- and oxidative stress-independent manner has been proposed. The protein binding ability has been monitored by the quenching of tryptophan emission in the presence of the compounds using bovine serum albumin (BSA) as a model protein. Both compounds could be distributed and transported in vivo and the complex displayed stronger binding affinity and higher contributions to the hydrogen bond and van der Waals forces.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by valvular dysfunction with or without associated obstruction, usually in the lower limbs. It might result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is an update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: For this update, the Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (August 2015), as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7). The reference lists of the articles retrieved by electronic searches were searched for additional citations. We also contacted pharmaceutical companies and searched the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal for ongoing studies (last searched in August 2015). SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardised mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence interval (CIs) and percentage of heterogeneity (I(2)). Additionally, we performed sensitivity analyses. MAIN RESULTS: We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I(2) = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I(2) = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I(2) = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I(2) = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I(2) = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.

Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials.

BACKGROUND: Postthrombotic syndrome (PTS) is a frequent, chronic complication of DVT. The effectiveness and safety of available treatments are unknown. The objective of this study was to systematically review the literature to assess whether pharmacologic and compression therapies are effective and safe for the treatment of PTS. METHODS: We sought to identify randomized controlled trials (RCTs) via a search of PubMed, studies referenced in included publications, and studies that cited relevant literature. RESULTS: A total of 121 titles were reviewed, 12 full-text publications were assessed for inclusion, and seven RCTs, including 703 patients, were selected for inclusion. Four trials assessed the effectiveness of drugs, including rutosides, hidrosmin, and defibrotide, and four trials assessed compression therapies for treatment of PTS. Systems for the diagnosis and classification of PTS severity varied across studies. Three of four drug therapy trials reported moderate improvement in selected PTS symptoms, minor changes in calf and ankle circumference, and some effects on ulcer healing. Two studies of compression stockings did not report benefit. Two studies that assessed compression devices reported improvement in PTS symptoms scores; one of these reported an improvement in quality-of-life score. CONCLUSIONS: There is limited and low-quality evidence for the effectiveness of rutosides, hidrosmin, defibrotide, and compression stockings, but moderate-quality evidence that supports the use of intermittent compression to provide at least short-term relief from PTS. More rigorous studies are needed to assess the short- and long-term effectiveness and safety of PTS therapies.

A new flavonoid derivative, dosmalfate, attenuates the development of dextran sulphate sodium-induced colitis in mice.

In this study, we have evaluated the efficacy of dosmalfate, a new flavonoid derivative compound, for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Colitis was quantified by a clinical damage score, colon length, weight loss, stool consistency and rectal bleeding. Inflammatory response was assessed by neutrophil infiltration, determined by histology and myeloperoxidase (MPO) activity. Interleukin (IL)-1 beta, prostaglandins (PG)E(2) and (PG)D(2) concentrations in colonic tissue, histological and histochemical analysis of the lesions were also measured. Dosmalfate (400-800 mg/kg body weight, p.o.) ameliorated severe colitis reduced the degree of inflammation through reduction of neutrophil infiltration and IL-1 beta levels. (PG)E(2) and (PG)D(2) synthesis were significantly reduced in colitis control group and treatment with dosmalfate abolished the decrease in PG synthesis in colon mucosa. We conclude that dosmalfate is protective in acute DSS-induced colitis. The beneficial effects seem to be related to a decrease of neutrophil infiltration, absence of up-regulation of IL-1 beta and increase of PG production in colon mucosa.

Effects of dosmalfate, a new cytoprotective agent, on acute and chronic trinitrobenzene sulphonic acid-induced colitis in rats.

Activated neutrophils and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) are clearly involved in the pathogenesis of bowel disease. Increased expression of epidermal growth factor-receptor (EGF receptor) has been reported for the colon mucosa surrounding areas of ulceration, suggesting a pivotal role in mucosal defence and repair. In this study, we examined the effects of dosmalfate, a new flavonoid derivative compound (diosmin heptakis) with antioxidant and cytoprotective properties, on acute and chronic experimental trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. The inflammation response was assessed by neutrophil infiltration as evaluated by histology and myeloperoxidase activity. Mucosal TNF-alpha production and histological analysis of the lesions was also carried out. In addition, we studied the expression of the EGF receptor inmunohistochemically during the healing of TNBS-induced chronic colitis. A 2-day treatment with 400 or 800 mg/kg of dosmalfate ameliorated the colon damage score and the incidence of adhesions. It also significantly (P<0.05) decreased myeloperoxidase activity and colonic mucosal production of TNF-alpha. Chronic treatment (14 days) with 800 mg/kg/day of dosmalfate also had significant protective effects on TNBS-induced colitis which were reflected by significant attenuation (P<0.05) of the damage score while the inflammatory indicators were not improved. The chronic beneficial effect of dosmalfate was apparently related to the enhancement of EGF receptor expression. These findings confirm the protective effects of dosmalfate in acute and chronic experimental colitis.

[The effects of a benzopyrone derivative in experimental brain edema due to cold in the rabbit]. / Efectos de un derivado benzopirónico en el edema cerebral experimental por frío en el conejo.

On this study, parenchymal changes during a cerebral edema caused by thermic injury (cool) on the rabbit, are analyzed. The work was based on the ultrastructural findings obtained by transmission electronic microscopy and on the effects produced by a benzopironic derived (F-117 Hydrosmina). The injury was produced with solid CO2, previous a craniectomy, on the dura mater of the left hemisphere. Forty rabbits were included into the study, the animals were distributed into five groups (n = 8): a control group and 4 treatment groups. One of the groups received treatment without previous cerebral injury. The group of rabbits with doses of 50 mg/Kg of weight showed focal and diffuse areas of edema alternating with less damaged areas, the edema was evident on the white substance. This group also showed a dissociation of the myelinic fibers and an intracytoplasmatic tumefaction into the glial cells. These findings contrast with the histopathological findings obtained from the rabbits (V), the extracellular edema was poor, the myelinic fiber disorganization was minimal with no vacuolar degeneration and no structural mitochondrial changes had been showed. The discontinuance of the hematoencephalic barrier caused by the cool could be a possible mechanism that causes the opening of the endothelial unions from the capillary vessels, changing their membranes and resulting in a free penetration of the molecule into the cerebral parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermal behavior and elastic properties of phospholipid bilayers under the effect of a synthetic flavonoid derivative, LEW-10.

We have investigated the effect on phospholipidic bilayers of LEW-10, a synthetic flavonoid, derivative of diosmin. Two optical techniques, Quasi-elastic Light Scattering (QLS) and Fourier Transform Infrared Spectroscopy (FT-IR) were used. The results show that in the presence of LEW-10, the phase transition of the bilayers is lowered and that the elastic modulus is decreased. The FT-IR results indicate interactions in the aqueous interface regions of the bilayers. We also discuss LEW-10 comparatively with another derivative, LEW-7/S1, whose effect has been previously studied.

Therapeutic effects of hidrosmin on chronic venous insufficiency of the lower limbs.

A double-blind, placebo-controlled trial was carried out to assess the effectiveness of a new synthetic bioflavonoid, hidrosmin, in patients with chronic venous insufficiency of the lower limbs. Fifty-seven patients, showing varicose veins and ankle swelling and suffering from local pain and heaviness of the legs, were allocated at random to receive treatment for 45 days with 1 capsule 3-times daily of either 200 mg hidrosmin (30 patients) or placebo (27 patients). Pain and heavy legs were assessed using rating scales; swelling was assessed by a photographic method. The results showed that hidrosmin produced a significant clinical improvement in all of the parameters evaluated; compared with placebo, there was a marked reduction in the main subjective symptoms accompanied by a 10% reduction in swelling. Apart from 1 patient who complained of epigastric pain, there were no reports of adverse events during the study period.

[The therapeutic action of hidrosmin in chronic lymphedema]. / Acción terapéutica de hidrosmina en el linfedema crónico.

During three months, 20 women, diagnosed of primary (n = 7) or secondary (n = 13) lymphoedema, were treated with hidrosmin, 400 mg t.i.d. The volume of the extremities was measured before and after therapy by projection of shadows with optoelectronic data collection; characteristics of oedema were also evaluated by means of an scoring scale including data on severity and consistency of oedema, pain, loss of function and trophic changes. The volume of the affected extremity was 2784 +/- 972 cc before treatment and was reduced to 2597 +/- 819 cc after it, the mean reduction being 5.8% +/- 9.0% (p less than 0.001). The overall scoring for clinical parameters was 4.2 +/- 1.4 before treatment and 3.5 +/- 1.5 after (p less than 0.05). The drug was well tolerated. The authors have considered hidrosmin as an important therapeutical options for the treatment of chronic lymphoedema.

[A double-blind study comparing the clinical efficacy of the preparation F-117 (hidrosmin) versus diosmin in the treatment of patients with peripheral venous disorders]. / Estudio doble ciego comparando la eficacia clínica del preparado F-117 (hidrosmina) versus diosmina en el tratamiento de pacientes con trastornos venosos periféricos.

A controlled double-blind clinical trial was performed comparing therapeutic efficacy of hidrosmin versus diosmin in patients suffering from chronic venous insufficiency with varicose symptomatology in the inferior limbs. Ten patients were treated with hidrosmin and other 10 with diosmin randomly. The controls carried out during the trial were as follows; basal control before the beginning of the trial and therapeutic controls on days 15, 30, 60 and 90 of the study. With that aim clinical examinations and different explorations were performed: physical exam, phlebography, electrocardiogram, ophthalmological examination and biochemical analyses (hemogram, globular sedimentation rate, platelet counts, etc.). The clinical therapeutic efficacy of hidrosmin in the treatment of chronic venous insufficiency of inferior limbs was superior to the diosmin in most of the studied parameters even though a lower posology was employed. From a clinical point of view the clinical improvement in the subjective symptomatology (heaviness, local tenderness, cramps, paresthesias, etc.) was very superior to the one obtained with the objective signs (phlebography, skin trophism, evolution of the edema, etc.). No significative adverse reactions appeared.