Effects of Venoactive Drug Therapy and Ovarian Vein Interventions on Vasoactive Neuropeptide and Cytokine Levels in Patients with Pelvic Venous Disorders.

BACKGROUND: To study and compare the effects of venoactive drug (VAD) therapy and ovarian vein embolization or resection (OVE or OVR, accordingly) on the levels of vasoactive peptides and cytokines in patients with pelvic venous disorders (PeVDs). METHODS: The study included 70 consecutive female patients with PeVD symptoms, such as chronic pelvic pain (CPP), dyspareunia, dysuria, and vulvar varicosities. Based on the results of clinical examination and duplex ultrasound of the pelvic veins, the patients were allocated to the VAD therapy (n = 38) or OVE/OVR (n = 32). Additionally, the enzyme-linked immunosorbent assay tests were performed to determine levels of calcitonin gene-related peptide (CGRP), substance P (SP), interleukins 6 and 8 (IL-6, IL-8) and monocyte chemotactic protein-1 (MCP-1) after a 2-month course of VAD therapy and at 3 months after OVE/OVR. RESULTS: The VAD therapy was associated with a significant decrease in CPP in 84% of patients with PeVD and isolated lesions of the parametrial veins (PVs) and uterine veins (UVs). VAD had no significant effect on the pelvic venous reflux. No changes in the CGRP, SP, IL-6, IL-8, and MCP-1 levels were detected after treatment. At 3 months after OVE or OVR, all patients with PeVD and combined lesions of the ovarian veins (OVs), PVs and UVs reported almost complete relief of CPP. Along with elimination of reflux in ovarian veins, the disappearance of reflux in PVs and UVs was noted. A decrease in the CGRP and SP levels was observed (0.7 ± 0.1 ng/mL and 0.12 ± 0.02 ng/mL before treatment; 0.5 ± 0.12 ng/mL and 0.09 ± 0.06 ng/mL after treatment, respectively; all P < 0.05). No changes in cytokine levels were revealed. CONCLUSIONS: Treatment with VAD is associated with the CPP relief, but has no significant effect on the CGRP, SP, IL-6, IL-8, and MCP-1 levels. OVE/OVR results in the CPP relief, elimination of the pelvic venous reflux and a significant decrease in the CGRP and SP levels, but does not change cytokine levels.

Development of recommendations for the use of venoactive drugs in the treatment of chronic venous disease - where they are effective and where they are not.

The article provides an overview of the development of recommendations for indications of venoactive drugs for treating symptoms and signs associated with chronic venous disease (CVD). Venoactive drugs may be beneficial in patients with subjective problems and/or swelling of the lower limbs, after surgery for varicose veins, in chronic venous insufficiency or in microcirculatory disorders. They are not indicated in asymptomatic patients with CVD, in the prevention of varicose veins or to prevent their progression. Drugs with proven efficacy in clinical trials should be preferred.

Cyanoacrylate Closure of Small Saphenous Vein Insufficiency.

BACKGROUND: As minimally invasive techniques were issued, endovenous thermal ablations have emerged. However, the thermal-associated complication has been reported in the treatment of small saphenous vein (SSV) insufficiency, such as sural nerve injury. Recently introduced cyanoacrylate closure (CAC) is a nonthermal modality, so this thermal-associated complication can be avoided. OBJECTIVE: This retrospective study analyzed the feasibility, safety, and 2-year results of CAC for treating SSV insufficiency, particularly the incidence of sural nerve injury. MATERIALS AND METHODS: One hundred sixty-three SSV insufficiencies in 128 patients were treated with CAC were reviewed. Pain, venous severity, and quality of life (QoL) scores were evaluated. Postoperative duplex scanning also evaluated anatomical and clinical success rates. RESULTS: The mean patient age was 56.8 years. The initial technical success rate was 100%. The occlusion rate after 2 years was 96.3%. Pain, venous severity, and QoL scores were improved significantly from 2.4 to 0.0, 4.39 to 0.47, and 11.95 to 2.69, respectively, before and 2 years after CAC. No major complications were observed, such as sural nerve injury. CONCLUSION: Cyanoacrylate closure for the ablation of SSV insufficiency could be a great alternative to endothermal ablation with an excellent success rate and shorter procedure time.

[Efficacy of combination of needle extract, hesperidin and vitamin C in treatment of chronic venous diseases]. / Éffektivnost' kombinatsii ékstrakta iglitsy, gesperidina i vitamina S v lechenii khronicheskikh zabolevanii ven.

BACKGROUND: In Russia, physicians are virtually unaware of drugs based on needle extract. However, abroad, saponins and, in particular, a combined preparation containing needle extract, hesperidin and vitamin C is one of drugs of choice, if not the leading medication in treatment of venous oedemas and other venous symptoms. AIM: The authors conducted a systematic review of the Russian-and English-language literature using the following search terms: saponins, hesperidin, needle, ruscus, ruscogenin (and their Russian equivalents), each of which was entered in a combination with the word 'venous' or its Russian equivalent, respectively. RESULTS: Ruscogenin and neoruscogenin from the root of needle possess anti-inflammatory properties and induce venous wall contraction, thus making it possible to use needle extract in treatment of chronic venous insufficiency. It was experimentally determined that needle extract stimulates vein contractility, decreasing permeability of the venous wall, influencing extracellular matrix proteins, inhibiting leukocyte migration through regulation of both proteins and matrix ribonucleic acid. Analysed herein are the results of original studies of a combination of needle extract, flavonoid hesperidin methyl chalcone and ascorbic acid, also examining in detail the mechanism of action conditioned by synergism of pharmacological effects of these components. This is followed by discussing the place of saponins in the classification of phlebotropic drugs and comparing efficacy of needle root extract with that of other phlebotonics. CONCLUSION: It was experimentally determined that a combination of needle extract, hesperidin and vitamin C possesses multiple additive phlebotropic effects. According to clinical trials, it leads to relief of most symptoms and a decrease in the ankle volume (high level of evidence 1A), being not inferior by clinical efficiency and duration of action to the best-known flavonoids, whereas by the venotonizing effect, decreased permeability of the vascular wall, and inhibition of leukocytic aggression even superior thereto. Further experimental and clinical studies of efficacy of this combination for various forms of chronic venous diseases and venous thromboses are warranted.

[One-year results of conservative and endovascular treatment of deep venous thrombosis followed by severe acute venous insufficiency]. / Odnoletnie rezul'taty konservativnogo i endovaskulyarnogo lecheniya tromboza glubokikh ven s razvitiem tyazheloi ostroi venoznoi nedostatochnosti.

OBJECTIVE: To compare the results of conservative and endovascular treatment of deep vein thrombosis followed by acute severe venous insufficiency. MATERIAL AND METHODS: Two statistically valid groups of patients with deep vein thrombosis and acute severe venous insufficiency were compared. Warfarin was administered in the first group, endovascular methods - in the second group (n=30). At the first step, we performed catheter-guided thrombolysis, then transcutaneous mechanical thrombectomy and venous stent deployment. Anticoagulation was achieved with Apixaban. Hemorrhagic complications were monitored during the treatment. One-year results were assessed considering lumen patency restoration and severity of venous congestion with Villalty score. RESULTS: In the first group, each third patient had hemorrhagic complications that required cessation of anticoagulant therapy in 1.3% of patients. In the second group, hemorrhagic events occurred in 10% of patients and were managed by lowering Apixaban dosage. Complete restoration of lumen patency was detected in 23.3% in the first group and 93.3% in the second group. Partial restoration developed in 63.3% and 6.7%, occlusion in 13.3% and 0%, respectively. Only 23.3% of patients in the first group had no clinical evidence of venous congestion. Mild congestion was found in 20%, severe - in 56.7% of cases. In the second group, 6.7% of patients had minimal venous congestion.

Sulodexide Improves Contraction and Decreases Matrix Metalloproteinase-2 and -9 in Veins Under Prolonged Stretch.

High pressure in the lower-limb veins is often associated with chronic venous insufficiency and varicose veins (VVs), making it important to search for the mechanisms and agents that control venous function. We have shown that protracted increases in venous stretch/wall tension reduce vein contraction and augment matrix metalloproteinase (MMP)-2 and -9. Also, MMP-2 and MMP-9 promote venodilation, a hallmark of VVs. Sulodexide (SDX) is a blend of glycosaminoglycans with efficient profibrinolysis and antithrombosis activities, but its actions on vein function and the mechanisms involved are unclear. We tested the hypothesis that SDX enhances venous contractile response by decreasing MMP expression/activity in veins subjected to protracted stretch. Rat inferior vena cava (IVC) rings were treated with SDX (0.001-1 mg/mL) or vehicle, equilibrated under control 0.5-g resting tension or protracted 2-g stretch for 18 hours, and the contractile response to 96-mM KCl and phenylephrine (Phe) in SDX-treated and nontreated veins was recorded. In IVC rings under control 0.5-g resting tension, SDX caused dose-dependent contraction, 96-mM KCl caused marked contraction (176-mg/mg tissue), and Phe caused dose-dependent contraction with a maximum (56-mg/mg tissue) at 10 M. In IVC subjected to protracted 2-g stretch, 96-mM KCl-induced contraction was reduced to 112 mg/mg and maximal Phe-induced contraction was decreased to 23 mg/mg. In IVC subjected to protracted 2-g stretch plus SDX, 96-mM KCl-induced contraction was restored to 228 mg/mg and maximal Phe-induced contraction was improved to 115 mg/mg. Gelatin zymography and Western blots revealed increases in MMP-2 and MMP-9 levels/gelatinolytic activity in veins subjected to protracted 2-g stretch and reversal to control levels in veins subjected to 2-g stretch plus SDX. Thus, SDX improves vein function and augments the contractile response in veins subjected to protracted stretch. The SDX-induced improvement of contraction and restoration of vein function appear to involve decreases in MMP-2 and MMP-9 and may contribute to the benefits of SDX in chronic venous insufficiency and VVs.

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.

Pine bark (Pinus spp.) extract for treating chronic disorders.

BACKGROUND: Pine bark (Pinus spp.) extract is rich in bioflavonoids, predominantly proanthocyanidins, which are antioxidants. Commercially-available extract supplements are marketed for preventing or treating various chronic conditions associated with oxidative stress. This is an update of a previously published review. OBJECTIVES: To assess the efficacy and safety of pine bark extract supplements for treating chronic disorders. SEARCH METHODS: We searched three databases and three trial registries; latest search: 30 September 2019. We contacted the manufacturers of pine bark extracts to identify additional studies and hand-searched bibliographies of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating pine bark extract supplements in adults or children with any chronic disorder. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and assessed risk of bias. Where possible, we pooled data in meta-analyses. We used GRADE to evaluate the certainty of evidence. Primary outcomes were participant- and investigator-reported clinical outcomes directly related to each disorder and all-cause mortality. We also assessed adverse events and biomarkers of oxidative stress. MAIN RESULTS: This review included 27 RCTs (22 parallel and five cross-over designs; 1641 participants) evaluating pine bark extract supplements across 10 chronic disorders: asthma (two studies; 86 participants); attention deficit hyperactivity disorder (ADHD) (one study; 61 participants), cardiovascular disease (CVD) and risk factors (seven studies; 338 participants), chronic venous insufficiency (CVI) (two studies; 60 participants), diabetes mellitus (DM) (six studies; 339 participants), erectile dysfunction (three studies; 277 participants), female sexual dysfunction (one study; 83 participants), osteoarthritis (three studies; 293 participants), osteopenia (one study; 44 participants) and traumatic brain injury (one study; 60 participants). Two studies exclusively recruited children; the remainder recruited adults. Trials lasted between four weeks and six months. Placebo was the control in 24 studies. Overall risk of bias was low for four, high for one and unclear for 22 studies. In adults with asthma, we do not know whether pine bark extract increases change in forced expiratory volume in one second (FEV1) % predicted/forced vital capacity (FVC) (mean difference (MD) 7.70, 95% confidence interval (CI) 3.19 to 12.21; one study; 44 participants; very low-certainty evidence), increases change in FEV1 % predicted (MD 7.00, 95% CI 0.10 to 13.90; one study; 44 participants; very low-certainty evidence), improves asthma symptoms (risk ratio (RR) 1.85, 95% CI 1.32 to 2.58; one study; 60 participants; very low-certainty evidence) or increases the number of people able to stop using albuterol inhalers (RR 6.00, 95% CI 1.97 to 18.25; one study; 60 participants; very low-certainty evidence). In children with ADHD, we do not know whether pine bark extract decreases inattention and hyperactivity assessed by parent- and teacher-rating scales (narrative synthesis; one study; 57 participants; very low-certainty evidence) or increases the change in visual-motoric coordination and concentration (MD 3.37, 95% CI 2.41 to 4.33; one study; 57 participants; very low-certainty evidence). In participants with CVD, we do not know whether pine bark extract decreases diastolic blood pressure (MD -3.00 mm Hg, 95% CI -4.51 to -1.49; one study; 61 participants; very low-certainty evidence); increases HDL cholesterol (MD 0.05 mmol/L, 95% CI -0.01 to 0.11; one study; 61 participants; very low-certainty evidence) or decreases LDL cholesterol (MD -0.03 mmol/L, 95% CI -0.05 to 0.00; one study; 61 participants; very low-certainty evidence). In participants with CVI, we do not know whether pine bark extract decreases pain scores (MD -0.59, 95% CI -1.02 to -0.16; one study; 40 participants; very low-certainty evidence), increases the disappearance of pain (RR 25.0, 95% CI 1.58 to 395.48; one study; 40 participants; very low-certainty evidence) or increases physician-judged treatment efficacy (RR 4.75, 95% CI 1.97 to 11.48; 1 study; 40 participants; very low-certainty evidence). In type 2 DM, we do not know whether pine bark extract leads to a greater reduction in fasting blood glucose (MD 1.0 mmol/L, 95% CI 0.91 to 1.09; one study; 48 participants;very low-certainty evidence) or decreases HbA1c (MD -0.90 %, 95% CI -1.78 to -0.02; 1 study; 48 participants; very low-certainty evidence). In a mixed group of participants with type 1 and type 2 DM we do not know whether pine bark extract decreases HbA1c (MD -0.20 %, 95% CI -1.83 to 1.43; one study; 67 participants; very low-certainty evidence). In men with erectile dysfunction, we do not know whether pine bark extract supplements increase International Index of Erectile Function-5 scores (not pooled; two studies; 147 participants; very low-certainty evidence). In women with sexual dysfunction, we do not know whether pine bark extract increases satisfaction as measured by the Female Sexual Function Index (MD 5.10, 95% CI 3.49 to 6.71; one study; 75 participants; very low-certainty evidence) or leads to a greater reduction of pain scores (MD 4.30, 95% CI 2.69 to 5.91; one study; 75 participants; very low-certainty evidence). In adults with osteoarthritis of the knee, we do not know whether pine bark extract decreases composite Western Ontario and McMaster Universities Osteoarthritis Index scores (MD -730.00, 95% CI -1011.95 to -448.05; one study; 37 participants; very low-certainty evidence) or the use of non-steroidal anti-inflammatory medication (MD -18.30, 95% CI -25.14 to -11.46; one study; 35 participants; very low-certainty evidence). We do not know whether pine bark extract increases bone alkaline phosphatase in post-menopausal women with osteopenia (MD 1.16 ug/L, 95% CI -2.37 to 4.69; one study; 40 participants; very low-certainty evidence). In individuals with traumatic brain injury, we do not know whether pine bark extract decreases cognitive failure scores (MD -2.24, 95% CI -11.17 to 6.69; one study; 56 participants; very low-certainty evidence) or post-concussion symptoms (MD -0.76, 95% CI -5.39 to 3.87; one study; 56 participants; very low-certainty evidence). For most comparisons, studies did not report outcomes of hospital admissions or serious adverse events. AUTHORS' CONCLUSIONS: Small sample sizes, limited numbers of RCTs per condition, variation in outcome measures, and poor reporting of the included RCTs mean no definitive conclusions regarding the efficacy or safety of pine bark extract supplements are possible.

Red vine leaf extract (AS 195) can improve some signs and symptoms of chronic venous insufficiency, a systematic review.

AIM: Chronic venous insufficiency (CVI) is common in adults. Some complications include skin changes, edema, heavy legs, muscle cramps, pain, and varicose veins. In traditional medicine, red vine leaf extract (AS 195) has been used to cure the symptoms of CVI. This systematic review was aimed to assess the effects of AS 195 in patients with CVI. MATERIAL AND METHODS: A systematic literature search was performed to identify trials that reported the impact of red vine leaf extract on CVI. The primary outcomes investigated were Leg (limb) volume, calf circumference, ankle circumference, tired and heavy legs, a sensation of tension, tingling sensation, and pain. RESULTS: From the 56 studies, 5 trials were selected according to our inclusion criteria. Red vine leaf extract significantly improved numbers of outcomes (lower leg volume, calf and ankle circumference, tired, heavy legs, tingling sensation, pain, the sensation of tension in the legs, cutaneous microcirculation, and transcutaneous oxygen pressure) in only some trials. The tolerability for red vine leaf extract was reported good or satisfactory. CONCLUSIONS: Red vine leaf extract had a beneficial therapeutic role in patients with CVI. Further high-quality trials are required to be carried out to provide strong evidence.

Therapeutic approach to chronic venous insufficiency - clinical benefits of red-vine-leaf-extract AS 195 (Antistax®).

Background: Chronic Venous Disorders or Diseases (CVD) of the lower extremities are a common finding affecting almost 90 % of an adult population. CVD includes varicose veins with a prevalence of approx. 25 %, overlapping with Chronic Venous Insufficiency (CVI) with a prevalence of approx. 17% in the adult population. CVI is characterized by venous pathology and objective signs like edema, skin changes or venous leg ulcers. Objective: To review and evaluate non-clinical and clinical data on a standardised herbal product containing flavonoids (AS195; Antistax®) and to put them into a perspective with the pathophysiology of CVD. Methods: Literature available on non-clinical pharmacology and clinical studies with AS195 in CVI of the lower extremities was reviewed and described. Conclusion: Antistax® is a well-described herbal product with standardised starting materials and manufacturing process. Its active ingredients accumulate in the venous intima, preserve the endothelial barrier function, and inhibit the inflammatory and prothrombotic cascade behind the progression of CVD. Its efficacy was analysed in adequately planned and executed clinical trials in patients with mild to moderately severe CVD (CEAP C1s to C4). AS195 showed a statistically significant and clinically relevant efficacy over placebo: in objective endpoints like volumetry of lower leg edema, but also in outcomes directly relevant for patients like tension and heaviness of the legs, tingling, and pain. Supportive studies confirmed and validated these results also for the broader population treated in daily practice. AS195 was well tolerated in studies and in everyday therapy. There are no known interactions with other medications. In the later stages, it can be used in combination with compression, complementing the beneficial haemodynamic effects of compression at a cellular level. AS195 is an addition to compression and closes a therapeutic gap especially in patients, who cannot use compression stockings, but still require CVD therapy.

Carboxytherapy: Controls the inflammation and enhances the production of fibronectin on wound healing under venous insufficiency.

To examine the influence of carboxytherapy on wound healing under venous insufficiency, full-thickness excisional wounds were created on Wistar rats. We used three groups with 32 rats each: Group (I): daily cleaning with 0.9% saline solution; Group Sulfadiazine (II): 1% silver sulfadiazine; and Carboxytherapy (III): subcutaneous application of 0.3 mL of carbon dioxide. The predetermined periods of analysis were the 3rd, 7th, 14th, and 30th day. The slides were stained with haematoxylin and eosin and Picrosirius red and submitted for immunohistochemistry. Groups II and III presented a statistically significant decrease in relation to the presence of neutrophilic and lymphocytic infiltrates. The presence of collagen significant increased in groups II and III. However, group III presented better organisation. Only group I maintained the neovascularisation until the 30th day. The new epithelium statistically significantly increased in groups II and III. On immunohistochemistry, regarding fibronectin expression, only group III demonstrated a statistically significant increase since the beginning of the healing process. Thus, the use of carboxytherapy promotes the formation of a tissue better structured and that may be an important resource for the treatment of wounds under venous insufficiency, especially those of recurrent re-openings.

Diosmin - still an important modality in the treatment of venous insufficiency.

Chronic venous insufficiency is a highly prevalent disease in the western population. Unfortunately, there is no causal treatment yet. A key role in the recommended therapeutic approaches, especially in the early stages, is the compression therapy accompanied by pharmacotherapy. This includes, inter alia, micronized diosmin. The following text summarizes the basic knowledge of its properties that determine its clinical use.

[Pharmacology of the drugs prescribed for chronic venous diseases]. / Farmakologiia preparatov, primeniaiushchikhsia pri khronicheskikh zabolevaniiakh ven.

The main groups of the drugs used for pharmacotherapy of chronic venous disease are considered. The main therapeutic targets of the drugs including their effect on venous wall tone, permeability and inflammation are described.

A Randomised Clinical Trial Comparing N-Butyl Cyanoacrylate, Radiofrequency Ablation and Endovenous Laser Ablation for the Treatment of Superficial Venous Incompetence: Two Year Follow up Results.

OBJECTIVE: To compare early and two year results for N-butyl cyanoacrylate (NBCA), radiofrequency ablation (RFA), and endovenous laser ablation (EVLA) in the treatment of varicose veins. METHODS: This was a randomised clinical trial. Five hundred and twenty five patients were blindly randomised into NBCA, RFA, and EVLT groups (175 patients to each group; block randomisation using sealed envelopes). Four hundred and fifty six patients were monitored for 2 years (ultrasound at 2 days, and 6, 12, and 24 months). The primary endpoint was the saphenous vein occlusion rates, and the secondary endpoints were peri- and post-procedural pain, complications, and time to return to work. No simultaneous phlebectomies were performed. RESULTS: The numbers of patients lost to follow up were NBCA seven, RFA 26, and EVLA 36. Occlusion rates were similar at 6, 12, and 24 months (6 months [NBCA 98.1%, RFA 94.1%, and EVLA 95.1%, p = .14], 1 year [NBCA 94.7%, RFA 92.5%, and EVLA 94.2%, p = .72], 2 years [NBCA 92.6%, RFA 90.9%, and EVLA 91.5%, p = .89]). Peri-procedural pain was significantly lower after NBCA (p < .001), but complication rates (DVT, bleeding, and phlebitis) were similar. Time to return to work was shortest after NBCA (NBCA 1.04 days, RFA 1.56 days and EVLA 1.31 days (p < .001) with 95% (NBCA), 50% (RFA) and 75% (EVLA) of patients returning to work on Day 1. Pre-procedural venous clinical severity scores (VCSSs) were the same in all groups. A decrease was observed in VCSS values in all groups at 6 months, and this persisted at 1 and 2 years. However, VCSS scores at 6 months and 2 years were significantly lower in the NBCA group (p < .001). Foam sclerotherapy was subsequently applied to varicose tributaries in 18 patients from all groups. CONCLUSION: No differences were observed in occlusion rates between the three modalities, but NBCA appeared superior with respect to peri-procedural pain, return to work and decreased VCSS.

[Endotheliotropic effects of venotonic drugs in treatment of patients with varicose veins]. / Éndoteliotropnye éffekty venotoniziruiushchikh preparatov pri lechenii bol'nykh s varikoznoi bolezn'iu.

The authors analysed the effect of Venarus on the endothelial function in patients suffering from lower limb varicose veins. Our open-label prospective study included a total of 100 patients diagnosed as having CEAP class C1-C2 varicose veins and divided into two equal groups. Dynamic assessment of the clinical course of the disease in Group One patients was carried out on the background of taking Venarus and compression therapy, with Group Two patients evaluated without taking Venarus. At defined stages we determined the level of biochemical markers of endothelial function. The obtained findings demonstrated that the use of phlebotonic Venarus resulted in decreased activity of lipid peroxidation processes and reduced activity of antioxidant system enzymes. Using Venarus was followed by a statistically significant decrease in the concentration of malonic dialdehyde (from 1.220±0.190 µmol/l at baseline to 0.858±0.231 µmol/l after 2 months of treatment), whereas in Group Two patients the changes were insignificant (1.191±0.204 µmol/l before treatment and 1.138±0.175 µmol/l at 2 months thereafter). Patients taking Venarus were also found to have a higher level of nitric oxide metabolites compared with the patients treated by compression therapy alone (51.646±11.757 and 36.310±6.921 µmol/l in Groups One and Two, respectively). Hence, an evidence-based conclusion was drawn that Venarus proved efficient and may therefore be prescribed as pharmacotherapy for correction of endothelial dysfunction.

[Sulodexide in treatment of chronic venous insufficiency. Results of the All-Russian multicenter programme ACVEDUCT]. / Sulodeksid v lechenii khronicheskoi venoznoi nedostatochnosti. Itogi Vserossiiskoi mul'titsentrovoi programmy ACVEDUCT.

INTRODUCTION: Pharmacotherapy occupies one of the leading places in comprehensive treatment of lower-limb chronic venous diseases (CVD) and their complications. At the same time, there are not so many therapeutic agents intended for treatment of CVD and possessing evidence-based efficacy. Sulodexide (registered in Russia as Vessel Due F) is a drug with a confirmed therapeutic effect in patients with a moderately severe course of chronic venous disease or its late stages. However, the experience of using it in Russia for treatment of patients presenting with initial manifestations of chronic venous insufficiency (CVI) is still scarce. PATIENTS AND METHODS: The data concerning the use of Vessel Due F in the routine practice of treating CVD in Russian patients were collected and assessed within the framework of the ACVEDUCT programme. This observational prospective non-controlled multicentre programme included patients routinely prescribed by their attending physician Vessel Due F as a solution for injections and/or soft capsules in accordance with the registered in the Russian Federation instruction for use. A total of 2,263 patients took part in the programme. RESULTS: The majority of the patients prescribed sulodexide were diagnosed as having CEAP class C3 (38.4%) and class C4 (35.6%) CVD. Treatment was accompanied and followed by a decrease in the symptoms' severity observed in 56.4% of patients and a decrease in the number of symptoms in 42.8% of patients (thus positive dynamics was totally noted in 99.2%), with the effect of taking the drug commencing to manifest itself in patients as early as on day 15-20 of treatment. The highest rate of regression of symptoms of CVD was observed in 30-to-40-year-old patients. A statistically significant positive correlation was revealed between efficacy and the duration of treatment, the use of capsules during the term of follow up, with a negative correlation revealed between efficacy of treatment and the patient's age at which the diagnosis had been made, the stage according the CEAP classification, the total number of symptoms, a combination of risk factors. CONCLUSIONS: Sulodexide proved to be an effective, safe, well-tolerated and pathogenetically substantiated pharmacological agent for treatment of patients presenting with lower-limb CVI and should therefore be recommended for patients at early stages of formation of CVD. Patients suffering from venous trophic ulcers require higher doses and prolonged administration of the drug.

[Multicentre observational study of Phlebodia 600 in treatment of patients with CEAP class C0-C3 chronic venous diseases]. / Mnogotsentrovoe nabliudatel'noe issledovanie primeneniia Flebodia 600 u bol'nykh c khronicheskimi zabolevaniiami ven klassov C0-C3 po CEAP.

The purpose of the study was to evaluate efficacy of Diosmin (Phlebodia 600, Innothera, France) in treatment of patients presenting with class C0s-C3 chronic venous diseases (CVD) according to the CEAP classification. Presented herein are the results of a prospective observational study aimed at assessing the outcomes of two-month administration of Phlebodia 600 (600 mg diosmin) in patients suffering from class C0s-C3 CVD according to the CEAP classification. The study comprised a total of 868 patients, including 175 (20.2%) men and 693 (79.8%) women. Of these, 866 patients completed the study according to the protocol. Amongst the 868 followed-up patients, 851 (98.0%) subjects strictly adhered to the physician's prescription and stopped taking the drug without violation of the regimen and dosing of diosmin. The main drug dosage regimen of diosmin was 1 tablet once a day in 851/868 (98.04%) patients. Satisfaction with treatment with diosmin was reported as 'excellent' by 46.7 % of patients (95% CI: 43.3-50.0) and by 49.4% of physicians (95%: CI 46.1-52.7), being rated as 'good' by 45.0% of patients (95 % CI: 41.7-48.4) patients and by 43.6% of physicians (95% CI: 40.3-47.0). The score for the quality of life of patients according to the CIVIQ-20 scale at the first follow-up visit amounted to 45.4±15.4 points (median 43.0 points). At the second follow-up visit, this parameter improved dramatically, dropping to the level of 35.6±11.5 points (median 33.0 points). By the third follow-up visit, the positive dynamics of the parameters preserved continued, averagely amounting to 28.9±8.7 points (median 26.0 points). A decrease in the circumference of the left and right crura (by 0.39±0.74 and by 0.36±0.75 cm, respectively) was observed at the second follow-up visit. The difference of the malleolar measurements between the first and third follow-up visits amounted to 7.2±9.4 mm and 6.6±9.7 mm for the right and left crus, respectively (p<0.001). The number of patients with a reported feeling of heaviness in the legs statistically significantly decreased from 97.6% at the stage of enrollment into the study to 73.0% after 2 months of therapy, that of those with painful sensations from 84.5 to 55.3%, those with complaints of swelling (oedemas) of the lower limbs from 83.9 to 56.8%, with complaints of convulsions from 71.2 to 35.7%, with complaints of sensation of tingling from 63.4 to 34.1%, respectively. Hence, a statistically significant improvement of the patients' condition was observed as early as 30 days after the beginning of treatment. By day 60, the positive effect of the carried out therapy continued to grow. Safety and good tolerance of the drug were noted, which was confirmed by low incidence of undesirable events and high adherence to treatment.

[Pleiotropic effects of phlebotropic drugs: from pharmacological advantages to adverse drug interaction]. / Pleiotropnye éffekty flebotropnykh preparatov: ot farmakologicheskikh preimushchestv do nezhelatel'nogo lekarstvennogo vzaimodeistviia.

A distinctive property of phlebotropic drugs consists in their intrinsic capability of exerting pronounced pleiotropic (multiple) effects. The authors discuss the fundamental mechanisms of pleiotropy, advantages and disadvantages of various types of targeted therapy (mono- and polytargeted therapy) in treatment of chronic venous diseases. Special attention is paid to analysing the nature of adverse drug interactions, methods of reducing the risk of their development. An electronic service known as the Drug Interactions Checker is proposed as a tool for assessing drug interactions in everyday practice of the angiologist/phlebologist.

[Efficacy of sulodexide in treatment of chronic venous insufficiency. Results of the ACCORD trial]. / Éffektivnost' sulodeksida pri lechenii khronicheskoi venoznoi nedostatochnosti. Rezul'taty issledovaniia ACCORD.

OBJECTIVE: The purpose of our study was to evaluate both clinical and laboratory efficacy of sulodexide given at a daily dose of 500 lipasemic units (LSU) in patients presenting with class C3-C4 chronic venous insufficiency (CVI) according to the CEAP classification. PATIENTS AND METHODS: The study included a total of 25 patients diagnosed with C3-C4 CVI and prescribed to receive sulodexide at a daily dose of 500 LSU for 90 days. Efficacy was comprehensively controlled by the following tools: the disease-specific Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ), visual-analogue methods of assessment separate symptoms; the Venous Clinical Severity Score (VCSS), as well as ultrasonographic determination of the thickness of subcutaneous fat and crural fascia. Amongst the key laboratory indices determined by means of the ELISA test were the levels of interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1ß), matrix metalloproteinases-2 and -9 (MMP-2, MMP-9), vascular endothelial growth factor A (VEGF-A), vasopressin and endothelin. RESULTS AND DISCUSSION: Of the initially enrolled 25 subjects, twenty-two patients completed the study and were taken as 100%. The 90-day treatment yielded favourable results manifesting themselves in complete disappearance of convulsions in the calf muscles detected at the first visit in 22.7% of patients (p=0.0485), a significant reduction in the frequency of complaints of decreased tolerance to static loads from 27.3 to 9.1% (p=0.2404). The volume of the crus of the control lower extremity decreased from 134.18±14. 92 to 128.42±12.46 cm3 (p=0.0006), subcutaneous fat thickness at the fixed point decreased from 1.50±0.53 to 1.32±0.46 cm (p=0.0007), and fascial thickness decreased from 0.14±0.7 to 0.11±0.04 (p=0.0359). Pain syndrome according to the visual analogue scale (VAS) decreased from 36.45±25.60 to 17.50±19.27 mm (p=0.0002). The global index of quality of life (GIQoL) according to the CIVIQ-20 increased by 27.7% compared with the baseline level (p = 0.0001), the VCSS index decreased from 6.00±1.83 to 4.86±2.05 points (p=0.0002). as for the laboratory markers of endothelial dysfunction, there was a significant decrease in the levels of MMP-2 - from 178.53±36.30 to 176.35±36.67 ng/ml (p=0.0152), MMP-9 - from 90.84±20.41 to 89.78±20.32 ng/ml (p=0.0394), and that of endothelin - from 0.42±0.10 to 0.39±0.10 fmol/ml. CONCLUSION: Sulodexide exerting a statistically significant clinical and endothelium-protecting effect turned out to be an effective drug for treatment of initial forms of chronic venous insufficiency of lower limbs.

[Correction of blood microcirculation parameters and endothelial function in chronic venous insufficiency of lower limbs]. / Korrektsiia parametrov mikrotsirkuliatsii krovi i funktsii éndoteliia pri khronicheskoi venoznoi nedostatochnosti nizhnikh konechnostei.

The authors assessed efficacy of the phlebotonic agent Venarus in treatment of patients presenting with chronic venous insufficiency of the lower extremities. The study included a total of 34 patients with various degree of chronic venous insufficiency according to the CEAP classification. Before the beginning of the study and on the background of treatment with Venarus we assessed the parameters of blood microcirculation by means of digital capillaroscopy of the nail bed of the fingers and toes, as well as determined the indices of arterial stiffness and endothelial function. All patients on the background of treatment demonstrated a decrease in the degree of symptoms of chronic venous insufficiency. A group of patients was revealed in whom treatment with Venarus turned out to be most effective: patients with initial perivascular oedema (an increase in the linear size of the perivascular zones) and a decrease in the mean velocity of capillary blood flow. On the background of treatment with Venarus they were found to have a decrease in perivascular oedema, an increase in the mean velocity of capillary blood flow, and improvement of endothelial function.