glucuronyl-glucosamine-glycan-sulfate and Venous-Insufficiency

Chronic venous disease (CVD) is a common condition associated with valvular dysfunction, venous hypertension and endothelial inflammation. Sulodexide facilitates the healing of venous ulcers and is frequently used in patients with CVD without ulcer. This review assessed the efficacy and safety of sulodexide for treatment of signs and symptoms of lower extremity CVD.. We searched MEDLINE, EMBASE, CINAHL and AMED as well as the Cochrane Central Register of Controlled Trials and the World Health Organisation (WHO) International Clinical Trials Registry Platform Search Portal. We also manually searched potentially relevant journals, conference proceedings and journal supplements. Any study monitoring any effect of sulodexide in patients with CVD at any stage of the disease, classified or non-classified, was considered. Treatment effects were estimated using standardised mean differences (SMDs), mean differences (MDs) and risk ratios (RRs), as appropriate. We calculated 95% confidence intervals (CIs) and heterogeneity (Q, tau and I. The search found 64 studies, but only 23 provided data on 7153 participants (mean age 55 years; 68% female). The 13 studies providing extractable quantitative information included 1901 participants (mean age 55.2 years; 65% female). Sulodexide decreased the intensity of pain, cramps, heaviness, oedema and total symptom score and reduced inflammatory mediators in patients with CVD. The risk of adverse events (AEs) was not different between sulodexide and placebo or heparan sulphate (RR 1.31, 95% CI 0.74-2.32; I. Sulodexide was found to have a beneficial venoactive effect on the major signs and symptoms of CVD such as pain, cramps, heaviness and oedema without increasing the risk of AEs. It is also likely to exert a systemic effect on the course of CVD by interfering with inflammatory chemokines.

Topics: Adult; Anticoagulants; Chronic Disease; Female; Glycosaminoglycans; Humans; Inflammation Mediators; Lower Extremity; Male; Middle Aged; Pain Measurement; Venous Insufficiency

Sulodexide is a glycosaminoglycan extracted from porcine intestinal mucosa. The purpose of this review is to discuss sulodexide's complex pharmacological profile and its clinical applications for venous disease. Sulodexide has wide-ranging biological effects on the vascular system, including antithrombotic, profibrinolytic, anti-inflammatory, endothelial protective and vasoregulatory effects. Sulodexide has emerged as a potential therapeutic option for the management of chronic venous insufficiency, including venous ulceration, and the prevention of recurrent venous thromboembolism, with a low rate of major bleeding complications. Sulodexide's pleiotropic vascular effects may facilitate the management of common venous disorders.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Blood Coagulation; Glycosaminoglycans; Humans; Inflammation Mediators; Recurrence; Secondary Prevention; Treatment Outcome; Varicose Ulcer; Veins; Venous Insufficiency; Venous Thromboembolism

Inflammation represents an important epiphenomenon in the etiopathogenesis of chronic venous disease, a worldwide debilitating condition affecting millions of subjects. The pathophysiology of chronic venous disease (CVD) is based on the hemodynamic abnormalities in conjunction to alterations in cellular and extracellular matrix biocompounds. The endothelial dysfunction results from early perturbation in the endothelium linked to glycocalyx injury and promoted by inflammatory cells and mediators (such as matrix metalloproteinases and interleukins), which lead to progressive dilation of the vein resulting in chronic venous insufficiency. Activated leukocytes during the inflammatory process release enzymes, free radicals, chemokines and inflammatory cytokines in the vessel microenvironment, which are responsible for the changes of the venous wall and venous valve, reflux and venous hypertension, and the development/progression of tissue destruction and skin changes. Sulodexide, a highly purified mixture of glycosaminoglycans composed by 80% fast moving heparin and 20% of dermatan sulphate, exhibits anti-thrombotic and profibrinolytic properties, restoring also the essential endothelial glycocalyx. Glycosaminoglycan sulodexide has been also characterized to reduce the release of inflammatory cytokines/chemokines and to inhibit the matrix metalloproteinases-related proteolytic cascades, counteracting endothelial dysfunctions. The pleiotropic effects of sulodexide set the basis for a very promising agent in treating the spectrum of CVD.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Chronic Disease; Cytokines; Glycosaminoglycans; Humans; Inflammation Mediators; Signal Transduction; Treatment Outcome; Varicose Veins; Veins; Venous Insufficiency

Pharmacotherapy is a mainstay of treatment for lower limb chronic venous disease (CVD) and its complications. However, therapeutic agents with evidence-based efficacy for the treatment of CVD are limited. Sulodexide (registered as Vessel Due F in Russia) has confirmed therapeutic efficacy in patients with moderately severe or late-stage CVD, but real-world evidence of its use in Russian patients with initial manifestations of chronic venous insufficiency (CVI) remains scarce.. Data concerning the use of sulodexide in Russian patients with CVD in routine clinical practice were collected and assessed within the framework of the ACVEDUCT program. This observational, prospective, non-controlled multicenter program included patients routinely prescribed sulodexide, as a solution for injections and/or soft capsules, by their physician in accordance with the registered Russian Federation instructions for use.. In total, 2263 patients took part in the program. The majority of patients were diagnosed as having CEAP class C3 (38.4%) or class C4 (35.6%) CVD. Sulodexide was associated with decreased symptom severity in 56.4% of patients and a decreased number of symptoms in 42.8%. Thus, improvements were observed in 99.2% overall, with the drug effects being apparent as early as 15-20 days after starting treatment. The highest rate of CVD symptom regression was observed in patients aged 30-40 years. There was a significant positive correlation between sulodexide efficacy and treatment duration and the use of capsules during follow-up. A negative correlation was found between treatment efficacy and patient age at diagnosis, CEAP class, the total number of symptoms, and a combination of risk factors.. Sulodexide was an effective, safe, well-tolerated, and pathogenetically substantiated pharmacologic agent for the treatment of patients with lower limb CVD, and therefore should be recommended in patients with early-stage CVD. Patients with venous trophic ulcers require higher doses and prolonged administration of the drug.

Topics: Adult; Aged; Anti-Inflammatory Agents; Duration of Therapy; Female; Glycosaminoglycans; Humans; Lower Extremity; Male; Middle Aged; Prospective Studies; Russia; Treatment Outcome; Venous Insufficiency

A multi-centre study was carried out in 476 patients with chronic venous insufficiency to compare the efficacy, tolerability and dose-effect relationship of sulodexide given orally as either capsules or as a new, enteric-coated tablet formulation. Three comparable groups of patients each with chronic venous insufficiency of thrombotic or varicose aetiology received during 60 consecutive days either sulodexide 250 LRU (= 25 mg) capsules twice daily, 50 mg sulodexide enteric-coated tablets twice daily or 100 mg sulodexide enteric-coated tablets once daily, according to a double-blind, double-dummy, randomized design. Doppler and echoduplex examinations, supine and standing peripheral venous pressure, specific symptoms and signs, peripheral haemodynamics and safety haematology and haematochemistry were monitored monthly. The results showed that peripheral venous pressure improved to a clinically relevant and statistically significant extent in all groups and symptoms and signs were rapidly and significantly relieved. These effects were dose-related, as in both cases the recovery was faster and greater with the 100 mg per day dose however administered. Both the thrombotic and varicose aetiologic sub-groups benefited from treatment to approximately the same extent. Mild to moderate gastro-intestinal adverse experiences occurred in 48 patients evenly split between groups but spontaneously disappeared within 72 hours, none leading to treatment withdrawal. No clinically relevant modifications of peripheral haemodynamics or of safety haematology and haematochemistry was observed. The haemocoagulation parameters failed to exhibit appreciable variations. While the known clinical usefulness of sulodexide 250 LRU (= 25 mg) capsules twice daily was confirmed in this trial, the enteric-coated tablets, 50 mg twice daily or 100 mg once daily, were shown to have greater efficacy and similar tolerability to the standard formulation and dose.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation Tests; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycosaminoglycans; Humans; Male; Middle Aged; Venous Insufficiency; Venous Pressure

A double-blind, placebo-controlled study was carried out in 36 patients, aged 30 to 50 years, to evaluate the effectiveness of oral sulodexide in the treatment of chronic venous insufficiency due to idiopathic varices. Patients were allocated at random to receive either oral sulodexide as 2 capsules (each containing 250 lipoproteinolipase releasing units) twice daily or 2 identical placebo capsules twice daily over a period of 45 days. Using strain gauge plethysmographic data, assessments were made of the microcirculatory effects of treatment by calculating the coefficient of capillary filtration from measurements made on both legs of each patient on entry and after 30 and 45 days of treatment. The coefficient is derived from the transmembranous flow values at the occlusive pressures of 60 and 40 mmHg, the difference between the two occlusive pressures examined and a corrective factor to calculate the capillary pressure based on the pressure in the venous circulation. Statistical analysis of the results showed that sulodexide produced a significant mean reduction from baseline values of the coefficient at both the 30 and 45 day examinations whereas the coefficient increased in the placebo group. The difference between the two groups was also statistically significant. These findings suggest that sulodexide has a positive influence on capillary permeability.

Topics: Administration, Oral; Adult; Chronic Disease; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Middle Aged; Plethysmography; Venous Insufficiency

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.

Topics: Animals; Down-Regulation; Glycosaminoglycans; In Vitro Techniques; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Proteolysis; Rats, Sprague-Dawley; Varicose Veins; Vasoconstriction; Vasoconstrictor Agents; Vena Cava, Inferior; Venous Insufficiency

Topics: Adult; Aged; Aged, 80 and over; Cell Line; Chronic Disease; Endoglin; Female; Glycosaminoglycans; Humans; Male; Middle Aged; Protein Isoforms; Transforming Growth Factor beta; Varicose Ulcer; Venous Insufficiency; Wound Healing

Sulodexide is a glycosaminoglycan approved for the treatment of chronic venous disease (CVD). It has been available in Mexico since 2012. The aim of the study was to understand the clinical experience of primary care physicians in the treatment of CVD with sulodexide.. Clinical data collection forms were distributed among general practitioners. Data was collected for up to four follow-up consultations. All signs and symptoms were rated with the Likert Scale at each examination: 0 to 5 (where 0 means none, and 5 very severe). Both the patient's and the physician's opinions of the effects of the treatment were recorded.. Data were collected from 1599 patients at different clinical stages of CVD, 52% of which were at advanced stages (C4-C6). A total of 434 cases were followed up with four examinations (median of thirty days between each examination). In these cases, the overall sign and symptom score decreased significantly at each examination (P<0.01). At the fourth examination, 98.9% of the patients felt better or much better than at the first examination, and 99.7% were better or much better in the physician's opinion (P<0.01). The only adverse effect was nausea, reported in two cases.. Sulodexide was effective and well tolerated in the treatment of CVD.

Topics: Adolescent; Adult; Aged; Chronic Disease; Female; Glycosaminoglycans; Humans; Male; Mexico; Middle Aged; Nausea; Practice Patterns, Physicians'; Primary Health Care; Severity of Illness Index; Surveys and Questionnaires; Venous Insufficiency; Young Adult

Chronic venous disease (CVD) of the lower limbs is a common problem. It is more prevalent in women than in men and has a significant impact on patients' quality of life (QoL) and on the healthcare system. The aim of this study was to evaluate the efficacy of sulodexide in adult patients with CVD of the lower limbs and its effect on patients' QoL.. Patients with CVD were treated with sulodexide [250 LSU (lipasemic units) twice daily] for 3 months in a setting of real-life clinical practice. The endpoints of this observational non-comparative, open-label prospective study were the clinical efficacy of sulodexide (evaluated by scoring objective and subjective symptoms with a Likert-type scale) and the impact of sulodexide therapy on patients' QoL [assessed using the chronic venous insufficiency quality of life questionnaire (CIVIQ)].. The study included 450 patients (mean age 46.9 ± 10.5 years, range 17-78 years). A greater percentage of patients were female (65.4%). Three months of treatment with sulodexide significantly improved all objective and subjective symptoms (p < 0.0001). Overall, patients reported a significant improvement in all QoL scores (p < 0.0001). Adverse events were spontaneously reported by two patients (one case of epigastric pain and one of gastric pain with vomiting).. Oral sulodexide significantly improves both objective and subjective symptoms, as well as functional and psychological aspects of QoL in patients with CVD.. No funding or sponsorship was received for this study. Sponsorship for article processing charges and open access fees was provided by Alfa Wassermann.

Topics: Adult; Anticoagulants; Chronic Disease; Female; Glycosaminoglycans; Humans; Lower Extremity; Male; Middle Aged; Prospective Studies; Quality of Life; Surveys and Questionnaires; Treatment Outcome; Tunisia; Venous Insufficiency

According to previously performed studies, inflammation plays a crucial role in vein wall and leg tissue injury related to chronic venous insufficiency (CVI) development. Sulodexide (SUL) is a balanced mix of glycosaminoglycans with potential anticoagulant and profibrinolytic activity, also protecting endothelial cells and suppressing inflammatory reactions in various vascular disease-related conditions. The goal of the present study was to evaluate the anti-inflammatory action of SUL in patients with CVI.. The study was performed on a group of 11 patients with chronic venous disease (stage C5 according to CEAP classification). The mean age of the patients was 58.4±7.7 years, and none of them were diabetic. The patients were treated for 8 weeks with orally-administered SUL (2 x 500 LSU/day). Blood samples were collected at the start and at the end of the study for measurement of MMP-9, IL-6 and monocyte chemoattractant protein-1 (MCP-1). Additionally, the effect of the obtained serum samples on the function of human venous endothelial cells (HVEC) in in-vitro culture was evaluated.. After treatment with SUL, the serum concentration of MMP-9 (ng/mL) decreased from 6.50±3.48 to 5.41±1.36, P<0.05, and the concentration of IL-6 (pg/mL) decreased from 11.5±3.4 to 10.1±2.3, P<0.005. There was also a trend of decreased serum MCP-1 (pg/mL) from 31.3±23.0 before treatment to 27.1±10.7 at the end. Intracellular generation of oxygen-derived free radicals in HVEC maintained in in-vitro culture was lower in the serum samples collected after treatment with SUL: 3.09±0.35 abs/μg protein vs. 3.63±0.32 abs/μg protein, at the start, P<0.05. Synthesis of IL-6 was lower in HVEC exposed in vitro to serum collected at the end of SUL treatment: 1.02±0.31 ng/μg cell protein vs. 1.32±0.41 ng/μg cell protein before SUL treatment. The proliferation rate of HVEC was similar in serum collected at the beginning and at the end of SUL treatment.. We conclude that treatment with SUL in patients with CVI reduces intravascular inflammation and is protective for the endothelial cells and for the extracellular matrix changes related to metalloproteinase expression.

Topics: Aged; Anti-Inflammatory Agents; Anticoagulants; Chemokine CCL2; Chronic Disease; Endothelial Cells; Female; Glycosaminoglycans; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 9; Middle Aged; Treatment Outcome; Venous Insufficiency

Topics: Cardiovascular Agents; Chronic Disease; Glycosaminoglycans; Humans; Treatment Outcome; Varicose Veins; Venous Insufficiency