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Background: 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., Methods: 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., Results: 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., Conclusions: Sulodexide was effective and well tolerated in the treatment of CVD.

Arteries, veins and capillaries share the feature of hosting the "endothelial organ", an ubiquitous structure lining the surface of the entire circulatory tree. Endothelial cells and their supporting elements as the basement membrane, the intracellular matrix, and the surface covering glycocalyx, although displaying significant regional differences, maintain a common response to injury and to pharmacological stimuli. Sulodexide (SDX), a highly purified extractive glycosaminoglycan (GAG), shows many biological actions indicating effectiveness in arterial disorders and diseases. In fact, SDX besides inhibiting experimental arterial thrombogenesis displays, especially by the oral route, a number of vascular protective actions that are largely independent of those affecting blood coagulation. Among the activities relevant to arterial disorders, the agent provides restoration of damaged glycocalyx and of degraded intracellular matrix, as well as antiproliferative, antinflammatory, antioxidant, anti-proteolytic and anti-ischemic activities. Among the latter properties, the inhibiting effect on the enzyme family of matrix metalloproteinases (MMPs), and especially on the expression of MMP9 and its precursor, seems of crucial importance given the role of these matrix degrading enzymes in the pathogenesis and progression of atherothrombosis in coronary, carotid and peripheral arteries. These important biological data, many of them very recent, supply clues for the interpretation of a number of previous clinical trials in arterial diseases. Studies published in the years 1990-2005, showing significant reduction of cardiovascular events after a myocardial infarction, as well as a marked improvement in the walking ability in patients with peripheral arterial disease, deserve today an active re-appraisal likely conducive to new clinical research protocols in the field of primary and secondary prevention of cardiovascular disease of atherothrombotic nature.

Since its introduction, sulodexide has been used on and off for several indications. More recently this agent has become revitalized and tested in newer indications. Sulodexide is composed of glycosaminoglycan that includes a mixture of fast-moving heparin and dermatan sulfate. It exerts its anticoagulant and antithrombotic action through interactions with both AT and HCII. Sulodexide has been proven to have effects on the fibrinolytic system, platelets, endothelial cells, inflammation and more recently metalloproteases. The administration of sulodexide results in the release of lipoprotein lipase and has been shown to reduce the circulating level of lipids. It has also shown to decrease the viscosity of both whole blood and plasma. Sulodexide differs from heparin in its oral bioavailability and longer half-life. There is also less bleeding associated with sulodexide. In addition, oral administration of sulodexide does not interfere with the pharmacologic actions of commonly used agents. Similar to heparin, sulodexide releases TFPI which contributes to its antithrombotic effect and anti-inflammatory properties. Sulodexide has been proven to be effective in peripheral arterial thrombosis and venous thrombosis. It is also clinically active in the treatment of venous leg ulcers and intermittent claudication. More recent data suggest that sulodexide can be used in tinnitus and in vascular vertigo. Additional studies in these indications are required. Sulodexide was generally safe and well tolerated in the clinical trials, without any severe bleeding complications. Therefore sulodexide appears to be a good treatment for all arterial and venous diseases and for the prevention of progression of disease.

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.

Treatment of vascular diseases should be based on established pathophysiological concepts, and this also applies to chronic venous disease (CVD). On the basis of the latest research in this field, this paper summarizes the most advanced pathophysiological knowledge regarding the hemodynamics of the large veins and of the microcirculation, the endothelial function and inflammation, and the use of sulodexide in the treatment of CVD. The emerging theories on the pathophysiology of CVD consider inflammation, endothelial glycocalyx dysfunction, and the consequent changes in the extracellular matrix to play key roles in the development of CVD, and support a renewed interest in the research and application of sulodexide. As part of active approach to the treatment of CVD including edema and trophic venous alterations, sulodexide could help to alleviate progressive signs and symptoms of disease in any clinical CEAP class of CVD, from C1 to C6.