glucuronyl-glucosamine-glycan-sulfate and Vascular-Diseases

To assess the clinical efficacy of sulodexide, including a comparison with venoactive drugs (VAD) (micronized purified flavonoid fraction, MPFF; hydroxy-ethyl-rutosides, HR; calcium dobesilate;Ruscus extract combined with hesperidin methyl chalcone and vitamin C, Ruscus+HMC+VitC; horse chestnut seed extract, HCSE) and pentoxifylline in patients with chronic venous disease.. We performed a literature search in MEDLINE, Embase, and Cochrane Library for randomized controlled trials (RCTs) and observational studies. Proportion of patients with complete venous ulcer healing was the primary outcome and lower leg volume, foot volume, ankle circumference and symptoms were the secondary outcomes. Bayesian network meta-analysis (NMA) was perfomed with random effects models using only RCTs. A meta-analysis of observational studies was performed for sulodexide because no RCT could be included in NMA for symptoms or signs.. Forty-five RCTs and eighteen observational studies were identified. Sulodexide was included only in a single NMA for the proportion of patients with complete ulcer healing and it showed to have the highest probability of being the best treatment (48%) compared with pentoxifylline (37%) and MPFF (16%). MPFF was the most effective treatment in reducing lower leg volume, CIVIQ-20 score and pain VAS scale while calcium dobesilate and Ruscus+HMC+VitC were the most effective in reducing foot volume and ankle circumference respectively.Meta-analyses of observational studies for sulodexide showed that it improves significantly the scoring of pain, feeling of swelling, heaviness and parasthesiae measured by Likert scales.. Sulodexide is at least as effective as pentoxifylline and more effective than MPFF in improving the rate of ulcer healing in patients with CVD. VADs are effective in improving venous symptoms and signs, as was also shown by sulodexide in the meta-analysis of observational studies. The relative effectiveness of sulodexide and VADs needs to be evaluated by an RCT in order to better inform clinical practice.

Topics: Glycosaminoglycans; Humans; Network Meta-Analysis; Pharmaceutical Preparations; Varicose Ulcer; Vascular Diseases

Sulodexide (SDX), a sulfated polysaccharide complex extracted from porcine intestinal mucosa, is a blend of two glycosaminoglycan (GAG) entities, namely a fast-moving heparin (HP) fraction and a dermatan sulfate (DS; 20%) component. The compound is unique among HP-like substances in that it is biologically active by both the parenteral and oral routes. A main feature of the agent is to undergo extensive absorption by the vascular endothelium. For this reason, in preclinical studies, SDX administered parenterally displays an antithrombotic action similar to that of HPs but associated with fewer alterations of the blood clotting mechanisms and tests, thus being much less conducive to bleeding risk than HPs. When given orally, SDX is associated with minimal changes in classic coagulation tests, but maintains a number of important effects on the structure and function of endothelial cells (EC), and the intercellular matrix. These activities include prevention or restoration of the integrity and permeability of EC, counteraction versus chemical, toxic or metabolic EC injury, regulation of EC-blood cell interactions, inhibition of microvascular inflammatory and proliferative changes, and other similar effects, thus allowing oral SDX to be considered as an endothelial-protecting agent. The best available clinical evidence of the efficacy of SDX administered orally with or without an initial parenteral phase is the following: alleviation of symptoms in chronic venous disease and especially acceleration of healing of venous leg ulcers; prevention of cardiovascular events in survivors after acute myocardial infarction; marked improvement of intermittent claudication in patients with peripheral occlusive arterial disease; and abatement of proteinuria in patients with diabetic nephropathy that may contribute to the amelioration or stabilization of kidney function. Although further clinical trials are warranted, SDX is presently widely accepted in many countries as an effective and safe long-term, endothelial-protecting drug.

Topics: Animals; Cerebrovascular Disorders; Clinical Trials as Topic; Diabetic Nephropathies; Endothelial Cells; Glycosaminoglycans; Humans; Peripheral Arterial Disease; Vascular Diseases; Venous Thrombosis

Chronic venous disease encompasses a range of venous disorders, including those involving the lower limbs resulting from venous hypertension. The spectrum of chronic venous disease signs and symptoms shows variable severity, ranging from mild (aching, pain, and varicose veins) to severe (venous ulcers). The pathophysiology of chronic venous disease is characterized by venous hypertension, which triggers endothelial dysfunction and inflammation leading to microcirculatory and tissue damage, and eventually to varicose veins and venous ulcers. Sulodexide is an orally active mixture of glycosaminoglycan (GAG) polysaccharides with established antithrombotic and profibrinolytic activity. The agent is used in the treatment of a number of vascular disorders with increased risk of thrombosis, including intermittent claudication, peripheral arterial occlusive disease and post-myocardial infarction. Sulodexide differs from heparin because it is orally bioavailable and has a longer half-life and a smaller effect on systemic clotting and bleeding. An increasing body of preclinical evidence shows that sulodexide also exerts anti-inflammatory, endothelial-protective, and pleiotropic effects, supporting its potential efficacy in the treatment of chronic venous disease. Clinical studies of sulodexide have shown that the agent is associated with significant improvements in the clinical signs and symptoms of venous ulcers, and is therefore a recommended therapy in combination with local wound care and bandages for patients with persistent venous leg ulcers. Preliminary evidence supports the use of sulodexide in the prevention of recurrent deep venous thrombosis. Sulodexide was generally safe and well tolerated in clinical trials, without hemorrhagic complications. Sulodexide therefore appears to be a favorable option for the treatment of all stages of chronic venous disease and for the prevention of disease progression.

Topics: Animals; Chronic Disease; Clinical Trials as Topic; Disease Progression; Fibrinolytic Agents; Glycosaminoglycans; Humans; Varicose Ulcer; Vascular Diseases

The authors studied efficacy of using sulodexide (Vessel Due F) in treatment of patients with clinical class C6 chronic venous disease (CVD) and type 2 diabetes mellitus (DM). The study included a total of sixty-two 18-to-75-year-old patients of both sexes suffering from class C6 CVD and type 2 DM. The patients were randomly assigned to either the Study Group (Group I) and Control Group (Group II) in the ratio of 1:1. The Study Group patients received treatment with sulodexide according to the standard regimen during 50 days. The study included taking case history, examination by a phlebologist and endocrinologist, measuring the malleolar volume, body weight, ultrasound examination of lower-limb vessels, clinical and biochemical blood analyses, coagulogram, planimetry of trophic ulcers, microbiological and cytological study. The primary end point was epithelialization of trophic ulcers after 1 month. Secondary endpoints were ulcer healing after 2 months and dynamic alterations during epithelialization. The Study Group patients as compared to the Control Group patients were found to have statistically significant improvement of the composite index of clinical assessment of VSCC severity, decrease in the malleolar volume, positive dynamics of speed velocity parameters of venous outflow and improvement of quality of life according to the SF-36 questionnaire. After 30 days, epithelialization was achieved in 11 (33.5%) cases in the Study Group and in 6 (19.4%) cases in the Control Group (p<0.05). After 60 days, epithelialization was achieved in 27 (87.1%) and 15 (48.4%) patients of the Study and Control Groups, respectively. The time to complete epithelialization in Group I and II patients amounted to 49.8 ± 1.4 and 76.6 ± 2.4 days, respectively (p<0.05). A conclusion was drawn that administration of sulodexide (Vessel Due F) is effective and pathogenetically substantiated in treatment of patients presenting with class C6 CVD and type 2 DM.. Изучена эффективность применения препарата сулодексид (Вессел Дуэ Ф) при лечении пациентов с хроническими заболеваниями вен (ХЗВ) С6 клинического класса и сахарным диабетом (СД) 2 типа. В исследование включены 62 пациента обоего пола в возрасте от 18 до 75 лет с ХЗВ С6 класса и СД 2 типа. Больные рандомизированы в основную (І) и контрольную (ІІ) группы в соотношении 1:1. Пациенты основной группы получали лечение препаратом сулодексид по стандартной схеме в течение 50 дней. При исследовании производили: сбор анамнеза, осмотр флеболога и эндокринолога, измерение маллеолярного объема, массы тела, ультразвуковое исследование сосудов нижних конечностей, клинический и биохимический анализы крови, коагулограмму, планиметрию трофических язв, микробиологическое и цитологическое исследование. Первичная конечная точка исследования – эпителизация трофических язв через 1 месяц. Вторичные конечные точки – заживление язв через 2 месяца и динамические изменения в процессе эпителизации. В основной группе по сравнению с контрольной выявлены статистически значимое улучшение суммарного показателя по клинической оценке тяжести заболевания VSCC, уменьшение маллеолярного объема, положительная динамика скоростных показателей венозного оттока и улучшение показателей качества жизни по опроснику SF-36. Через 30 дней эпителизация достигнута в 11 (33,5%) наблюдениях в основной и в 6 (19,4%) наблюдениях в контрольной группе (р<0,05). Через 60 дней эпителизация достигнута у 27 (87,1%) и 15 (48,4%) больных в основной и контрольной группах соответственно. Время полной эпителизации у пациентов І и ІІ групп соответственно составило 49,8±1,4 и 76,6±2,4 суток (р<0,05). Сделан вывод, что применение сулодексида (Вессел Дуэ Ф) является эффективным и патогенетически обоснованным при лечении пациентов с ХЗВ С6 класса и СД 2 типа.

Topics: Adult; Aged; Chronic Disease; Cytoprotection; Diabetes Mellitus, Type 2; Drug Monitoring; Endothelium, Vascular; Female; Fibrinolytic Agents; Glycosaminoglycans; Humans; Hypoglycemic Agents; Lower Extremity; Male; Middle Aged; Severity of Illness Index; Treatment Outcome; Ultrasonography, Doppler, Duplex; Vascular Diseases

Thirty patients with Stage II peripheral vascular disease were treated with sulodexide, a new, medium molecular weight glycosaminoglycan, and placebo using a double-blind, crossover study design. After a 1-month wash-out period, patients were treated for 1 month with one or other trial medication and then crossed over to the alternative preparation for a further month. Measurements were made at baseline and at the end of each treatment period of serum, plasma and whole blood viscosities (at various shear rates), fibrinogen levels and red cell filterability. Tolerance parameters were also assessed at the same times. The results showed that there were statistically significant reductions in plasma and whole blood viscosity and in fibrinogen levels after sulodexide, but not after placebo. Neither treatment had any marked effect on red blood cell filterability. Local and systemic tolerance of the treatment was excellent, and some patients reported an improvement in symptoms whilst they were taking sulodexide; this, however, could not be quantified in this study. It is suggested that the viscosity and fibrinogen reducing effect of sulodexide make it a useful form of treatment in patients with atheromatous vascular diseases of the lower limbs.

Topics: Adult; Aged; Blood Viscosity; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Middle Aged; Vascular Diseases

Topics: Aged; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Randomized Controlled Trials as Topic; Regional Blood Flow; Vascular Diseases

Thirty vasculopathic subjects with hyperlipoproteinemia (18) and/or diabetes (22) underwent a clinical double-blind study in order to evaluate the effect of sulodexide on lipid and hemorheologic parameters. The experimental design consisted of a first 20-day i.m. therapeutic period with either sulodexide (300 Lipasemic Units twice daily via intramuscular route) or placebo and the following 70 days with the active compound for both groups at the same posology. Results obtained demonstrated that sulodexide yields a hypotriglyceridemic effect on type IV hyperlipoproteinemia and hypofibrinogenic effect, as well. Moreover, this compound exerted a beneficial effect on HDL Cholesterol levels and on the antithrombin III activity by increasing both parameters significantly. Signs and symptoms were alleviated, particularly in the most severe cases of peripheral vascular disease. Insignificant and slight changes were observed at the end of treatments as regards the efficacy of the two administration routes, the i.m. one being more efficacious on lipid parameters and faster acting. No side effects or intolerance were observed during the different periods of the trial.

Topics: Adult; Aged; Antithrombin III; Cholesterol, HDL; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Double-Blind Method; Female; Fibrinogen; Glycosaminoglycans; Humans; Hyperlipidemias; Male; Middle Aged; Triglycerides; Vascular Diseases

Thirty patients suffering from peripheral vascular disease (stage-II according to Fontaine) were included in a double-blind study aimed at assessing the efficacy of a high-dose glycosaminoglycan (GAG) (Sulodexide) both in terms of laboratory parameters, such as lipid metabolism and blood coagulation components, and instrumental procedures (strain-gauge plethysmography). Compared with the fifteen control patients (treated with placebo), the fifteen patients treated with Sulodexide showed a significant decrease in blood triglycerides and fibrinogen as well as a significantly increased HDL-cholesterol, and positive instrumental changes: at the end of treatment Peak and Rest Flow values--and consequently also Winsor's index--were significantly increased only in patients treated with Sulodexide.

Topics: Aged; Arteriosclerosis; Cholesterol, HDL; Clinical Trials as Topic; Double-Blind Method; Female; Femoral Artery; Fibrinogen; Glycosaminoglycans; Humans; Intermittent Claudication; Male; Random Allocation; Triglycerides; Vascular Diseases

Topics: Chronic Disease; Glycosaminoglycans; Humans; Vascular Diseases

According to previous studies, sulodexide suppresses intravascular inflammation when used in patients with chronic venous disease (CVD). In the current study, we tested the effect of prolonged in vitro exposure of human venous endothelial cells to the serum from patients with CVD, examining the function of these cells and how it is modified when these cells are simultaneously exposed to sulodexide.. Human umbilical venous cells (HUVEC) were cultured in standard medium (control), in medium supplemented with 5% serum pooled from CVD patients (CVD-serum) or in medium from CVD patients who were treated with sulodexide (CVD-serum-SUL). The synthesis of interleukin-6 (IL-6), monocyte chemoattractant protein -1(MCP-1) and soluble intercellular adhesion molecule - 1 (s-ICAM-1) were studied at the beginning of incubation and were measured after 9 and 15 days of exposure to the studied media. The concentration of IL-6 after cell stimulation by interleukin -1 (IL-1) was also measured. In a subsequent part of the experiment, the effect of the studied sera on the in vitro replicative ageing of HUVEC was evaluated. A total of 15 passages of the cell culture were performed and both the PDT (population doubling time) and the cell hypertrophy were assessed.. The concentrations of Il-6, MCP-1, and ICAM-1 gradually increased in the supernatants containing 5% CVD serum compared with the control medium. In the supernatants obtained after cell incubation with serum from sulodexide treated patients, the increase in concentrations of IL-6, MCP-1 and ICAM-1 was significantly less than the control. Release of IL-6 after stimulation with IL-1 (100 pg/mL) was the highest in the CVD-serum group: 3540±670 pg/105 cells vs. 1850±540 pg/105 cells in the control (P<0.01 vs. CVD-serum) and 2320 ±430 pg/105 cells in CVD-serum-SUL (P<0.02 vs. CVD-serum). PDT was significantly longer in the cells incubated with CVD serum compared with the control group, and PDT was reduced when serum from sulodexide treated patients was used. The cells became senescent in the presence of CVD serum, but the cells obtained from patients at the end of 8 weeks of treatment with sulodexide showed a much weaker inflammatory phenotype than the CVD group.. Chronic in vitro exposure of HUVEC to medium supplemented with CVD patient serum induces an inflammatory phenotype. Sulodexide treatment significantly reduces that effect and slows HUVEC senescence in the milieu of CVD serum.

Topics: Aged; Cells, Cultured; Chemokine CCL2; Chronic Disease; Endothelial Cells; Glycosaminoglycans; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Middle Aged; Vascular Diseases

Topics: Fibrinolytic Agents; Glycosaminoglycans; Humans; Thrombin; Vascular Diseases

We evaluated the effects of the glycosaminoglycan sulodexide (SDX; antithrombotic/profibrinolytic drug) on the activity and release of matrix metalloproteinases (MMPs) in human blood. This was a prospective non-randomized study, analyzing by zymography and ELISA the in vitro effects of SDX on pro-enzyme, complexed, and active MMP forms in plasma and serum from 60 healthy donors, and in U-937 leukemia cell line. The levels and zymographic profile of MMP-2 did not show significant changes among samples and during SDX treatments. However, pro- and complexed forms of MMP-9 were strongly affected by SDX treatment (P<0.001), with significant decrease of MMP-9 secretion from white blood cells in a dose-dependent fashion (P<0.0001), without any displacement of MMP prodomains. The mechanism of reduced release of MMP-9 forms from leukocytes and inhibition of proteolytic activity due to SDX treatment may support the hypothesis that drugs based upon inhibitors of MMP-9 activity may provide a therapeutic tool for the underlying pathological destruction of extracellular matrix, and offering novel pharmacologic applications for chronic inflammatory vascular diseases, including varicose vein and chronic venous diseases associated with enhanced MMP activation in blood and limbs.

Topics: Adult; Chronic Disease; Collagen; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Glycosaminoglycans; Humans; In Vitro Techniques; Leukemia; Leukocytes; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Middle Aged; Prospective Studies; U937 Cells; Vascular Diseases

Streptozotocin-induced diabetes leads to the development of endothelial dysfunction, as evidenced by decreased expression of endothelial nitric oxide synthase (eNOS) and increased expression of endothelin-1 as specific markers of endothelial disorders. All test substances showed endotelioprotective activity by increasing the concentration of eNOS and reducing the level of endothelin-1. With respect to the degree of impact on the eNOS and endothelin-1 levels, the compounds studied can be rated as follows: sulodexide > meksidol.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Endothelin-1; Endothelium; Glycosaminoglycans; Immunohistochemistry; Male; Nitric Oxide Synthase Type III; Picolines; Rats; Vascular Diseases

Endothelium-protective properties of pharmacological agents may be assessed by using different experimental models of endothelial dysfunction or injury. The model of endothelial dysfunction induced by vessel perfusion with polymorphonuclear leukocytes (PMN) was used for evaluation of pentoxifylline (PTX) effects on vasoconstrictor responses to noradrenaline (NA) in the rabbit renal artery. Addition of PMN into the perfusion solution significantly increased the responses to NA at all doses. PTX administration (10(-5) mol x l(-1)) significantly diminished the constrictor responses to NA in vessels perfused with PMN+PTX when compared to the responses in PMN-perfused vessels (at dose 0.1 microg: 32.25 vs. 14.25, at dose 1 microg: 51 vs. 27.75 (p<0.01), at dose 10 microg 74.25 vs. 39.75 (p<0.05), all values expressed as median of perfusion pressure in mm Hg). The model of endothelial damage induced by repeated NA administration in 5 doses (10-50 microg of NA) was used for evaluation of the endothelium-protective effect of sulodexide (SLX). It was found that SLX (120 U/l) significantly decreased the number of desquamated endothelial cells (EC) compared to the control group (controls: 131.4+/-20.1 EC, +SLX: 83.3+/-13.8 EC, p<0.01). These results confirmed the favorable endothelium-protective effects of pentoxifylline and sulodexide in the two experimental models.

Topics: Animals; Endothelium, Vascular; Female; Femoral Artery; Glycosaminoglycans; Male; Neutrophils; Norepinephrine; Pentoxifylline; Rabbits; Renal Artery; Vascular Diseases; Vasoconstriction; Vasodilator Agents

Topics: Aged; Cerebrovascular Disorders; Female; Glycosaminoglycans; Humans; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type IV; Hyperlipoproteinemias; Hypolipidemic Agents; Male; Middle Aged; Placebos; Vascular Diseases

Topics: Blood Viscosity; Fibrinogen; Glycoproteins; Glycosaminoglycans; Humans; Hypolipidemic Agents; Sclerosis; Vascular Diseases