glucuronyl-glucosamine-glycan-sulfate and Myocardial-Infarction

This report summarizes the results of some of the studies that have evaluated the pharmacokinetic, pharmacodynamic, anticoagulant, and antithrombotic properties of Sulodexide, which consists of a mixture of electrophoretically fast moving heparin (80% of the mass) and dermatan sulfate (the balance), with an average product (Mr) <8000. The low molecular weight (Mr) of the constituents of Sulodexide would predict that the product has the high bioavailability associated with low-Mr heparin and low-Mr dermatan sulfate. Given orally, subcutaneously, or by intravenous injection, Sulodexide exhibits antithrombotic and profibrinolytic properties in several animal models of venous and arterial thrombosis and has relatively high affinity for endothelial (and possibly other) cells. Additionally, in a large multicenter clinical trial involving 3986 patients who had recovered from acute myocardial infarction, oral Sulodexide was associated with a 32% reduction in death and a significant reduction of left ventricular thrombus formation. Compared with heparin, low-Mr heparin, and unfractionated and low-Mr dermatan sulfates, the doses of Sulodexide required for antithrombotic efficacy suggest that the combination of heparin and dermatan sulfate in Sulodexide provides a more effective antithrombotic mechanism than heparin/low-Mr heparins (which catalyze the antiprotease actions of antithrombin III) or dermatan sulfate/low-Mr dermatan sulfate (which catalyze thrombin inhibition by heparin cofactor II).

Topics: Animals; Anticoagulants; Biological Availability; Blood Coagulation; Carotid Artery Thrombosis; Clinical Trials as Topic; Dermatan Sulfate; Drug Administration Routes; Drug Evaluation, Preclinical; Endothelium, Vascular; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Humans; Molecular Weight; Multicenter Studies as Topic; Myocardial Infarction; Partial Thromboplastin Time; Rabbits; Rats; Thrombosis

This study was conducted to assess the efficacy of sulodexide, a glycosaminoglycan compound with antithrombotic properties, in preventing death and thromboembolic events after acute myocardial infarction.. Antithrombotic therapy has been found to play an important role in the prevention of cardiovascular events and death after acute myocardial infarction. Glycosaminoglycan-containing compounds, including sulodexide, show profibrinolytic and antithrombotic properties that render them suitable for use in patients after infarction.. A total of 3,986 patients who had recovered from acute myocardial infarction were randomized to receive either the standard therapy routinely administered at each study center, excluding antiplatelet and anticoagulant drugs (control group, 1,970 patients), or the standard therapy plus sulodexide (treated group, 2,016 patients). Between 7 and 10 days after the episode of acute myocardial infarction, sulodexide was administered as a single daily 600-lipoprotein-lipase-releasing unit (LRU) intramuscular injection for the 1st month, followed by oral capsules of 500 LRU twice daily. Patients were evaluated for > or = 12 months.. At the end of the study, 140 deaths (7.1%) were recorded in the control group and 97 (4.8%) in the sulodexide group (32% risk reduction, p = 0.0022, chi-square test). A total of 90 patients (4.6%) in the control group had a further infarction, compared with 66 (3.3%) in the sulodexide group (28% risk reduction, p = 0.035). Furthermore, a reduction in left ventricular thrombus formation (evaluated by echocardiography) was observed in the sulodexide group (n = 12; 0.6%), compared with values in the control group (n = 25; 1.3%) (53% risk reduction, p = 0.027). Sulodexide was well tolerated and devoid of significant adverse events. All significant results were confirmed by "actual treatment" analyses.. The study provides evidence that long-term therapy with sulodexide started early after an episode of acute myocardial infarction is associated with reductions in total mortality, rate of reinfarction and mural thrombus formation.

Topics: Aged; Cardiovascular Diseases; Cause of Death; Female; Glycosaminoglycans; Heart Diseases; Humans; Hypolipidemic Agents; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Recurrence; Thrombolytic Therapy; Thrombosis; Time Factors

Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10⁻⁷), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10⁻⁸). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10⁻¹⁵; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.

Topics: Adult; Age of Onset; Aged; Arteries; Coronary Artery Disease; Female; Genome-Wide Association Study; Glycosaminoglycans; Humans; Male; Matrix Metalloproteinase 12; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide

Several glycosaminoglycans (GAGs) have been demonstrated to protect the ischemic heart against reperfusion injury, in part, by modulating activation of the complement cascade. The present study assessed the cardioprotective effects of sulodexide (KRX-101), a mixture of GAGs composed of 80% low-molecular mass heparin and 20% dermatan sulfate. KRX-101 differs from other GAGs (e.g., heparin) in that it has limited anticoagulant efficacy and can be administered orally. The experimental protocol was designed to determine whether KRX-101 could protect the ischemic myocardium. Anesthetized New Zealand white rabbits underwent 30 min of coronary artery occlusion. Intravenous doses of KRX-101 (0.5 mg/kg, n = 10) or drug diluent (n = 10) were administered at the end of regional ischemia and at each hour of reperfusion. Infarct size, as a percentage of the area at risk, was calculated for both groups. Myocardial infarct size was 31.3 +/- 4.1% in the vehicle- and 17.3 +/- 3.2% in the KRX-101-treated animals (p < 0.05 versus vehicle). Activated partial thromboplastin times determined at baseline (preischemia) and at each hour of reperfusion (n = 4) were not significantly different between vehicle- and KRX-101-treated groups (p = N.S.). Myocardial injury was further assessed by measuring serum levels of cardiac-specific troponin I. KRX-101 administration significantly reduced (p < 0.05) the serum concentration of troponin I during reperfusion. The results suggest that KRX-101 may be an effective adjunctive agent in myocardial revascularization procedures, without the risk of increased bleeding.

Topics: Animals; Arachidonic Acid; Biomarkers; Blood Coagulation; Blood Platelets; Blood Pressure; C-Reactive Protein; Fluorescent Antibody Technique; Glycosaminoglycans; Heart; Heart Rate; Hemostasis; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Partial Thromboplastin Time; Rabbits; Thrombin

Topics: Aspirin; Ethics Committees; Glycosaminoglycans; Humans; Hypolipidemic Agents; Informed Consent; Myocardial Infarction; Randomized Controlled Trials as Topic