Sulodexide: A Renewed Interest in This Glycosaminoglycan

Glycosaminoglycans (GAGs) are the most abundant group of heteropolysaccharides found in the body. These long unbranched molecules contain a repeating disaccharide unit. GAGs are located primarily in the extracellular matrix or on the surface of cells. These molecules serve as lubricants in the joints while at the same time providing structural rigidity to cells. Sulodexide is a highly purified glycosaminoglycan composed of a fast mobility heparin fraction as well as dermatan sulfate. Sulodexide differs from other glycosaminoglycans, like heparin, by having a longer half-life and a reduced effect on systemic clotting and bleeding. In addition, sulodexide demonstrates a lipolytic activity that is increased in comparison to heparin. Oral administration of sulodexide results in the release of tissue plasminogen activator and an increase in fibrinolytic activities. An increasing body of research has demonstrated the safety and efficacy of sulodexide in a wide range of vascular pathologies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73024/1/j.1527-3466.2006.00214.x.pd

Sulodexide attenuates myocardial ischemia/ reperfusion injury and the deposition of C-reactive protein in areas of infarction without affecting hemostasis

ABSTRACT 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% lowmolecular 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 ϭ 10) or drug diluent (n ϭ 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 Ϯ 4.1% in the vehicleand 17.3 Ϯ 3.2% in the KRX-101-treated animals (p Ͻ 0.05 versus vehicle). Activated partial thromboplastin times determined at baseline (preischemia) and at each hour of reperfusion (n ϭ 4) were not significantly different between vehicle-and KRX-101-treated groups (p ϭ N.S.). Myocardial injury was further assessed by measuring serum levels of cardiac-specific troponin I. KRX-101 administration significantly reduced (p Ͻ 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

Contemporary use of and outcomes associated with ultra‐low contrast volume in patients undergoing percutaneous coronary interventions

BackgroundThe risk of contrast‐induced acute kidney injury (CI‐AKI) increases in a nonlinear fashion with increasing volume of contrast media. Prior studies recommend limiting contrast volume to less than three times the estimated creatinine clearance (CC). Recently, a number of operators have reported successful percutaneous coronary intervention (PCI) using even lower volumes of contrast.ObjectivesTo evaluate the prevalence and outcomes associated with ultra‐low contrast volume among patients undergoing PCI.MethodsWe assessed the prevalence and outcomes associated with use of ultra‐low contrast volume among 75 393 patients undergoing PCI in Michigan between July 2014 and June 2017 in the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry. Ultra‐low contrast volume was defined as contrast volume less than or equal to the patient’s estimated CC. Patients receiving dialysis at the time of the procedure were excluded.ResultsUltra‐low contrast volume was used in 13% of procedures with the majority of these patients being at low risk of renal complications. Compared with patients who received a contrast volume between one and three times the CC, use of ultra‐low volume of contrast was associated with a significantly lower incidence of AKI (aOR 0.682, 95% CI 0.566–0.821, P < 0.001) and a lower incidence of need for dialysis (aOR = 0.341, 95% CI 0.165–0.704, P = 0.003). These benefits were most evident in the patients with a high baseline predicted risk of AKI.ConclusionsA small but clinically significant number of patients are treated with ultra‐low contrast volume. Ultra‐low contrast volume use is associated with a significant reduction in the incidence of AKI or need for dialysis. It may be prudent to consider this new threshold when performing PCI on patients who are at an increased risk of AKI.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147772/1/ccd27819.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147772/2/ccd27819_am.pd

The “One‐Step” approach for QT analysis increases the sensitivity of nonclinical QTc analysis

Abstract Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. First, the QT interval is corrected for the influence of rate and then statistical significance is tested. There is renewed interest in improving the sensitivity of nonclinical corrected QT interval (QTc) assessment with modern studies having greater data density than previously utilized. The current analyses examine the effects of moxifloxacin or vehicle on the QT interval in nonhuman primates (NHPs) using a previously described one‐step method. The primary end point is the statistical sensitivity of the assessment. Publications suggest that for a four animal crossover (4 × 4) in NHPs the minimal detectable difference (MDD) is greater than or equal to 10 ms, whereas in an eight animal crossover the MDD is ~6.5 ms. Using the one‐step method, the MDD for the four animal NHP assessments was 3 ms. In addition, the one‐step model accounted for day‐to‐day differences in the heart rate and QT‐rate slope as well as drug‐induced changes in these parameters. This method provides an increase in the sensitivity and reduces the number of animals necessary for detecting potential QT change and represents “best practice” in nonclinical QTc assessment in safety pharmacology studies

Sildenafil citrate for prophylaxis of nephropathy in an animal model of contrast-induced acute kidney injury.

Contrast-induced acute kidney injury (CIAKI) is one of the commonest complications associated with contrast media (CM). Although the exact etiology of CIAKI remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIAKI. In this study we evaluated the protective effects of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil citrate, in a rabbit model of CIAKI. New Zealand white rabbits were used due to their susceptibility to CIAKI. To evaluate the effects of sildenafil, the drug was administered before CM infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o.). Animals were sacrificed after 48 hours and kidneys were prepared for histological evaluation. Intravenous administration of CM produced marked kidney injury. Serum creatinine concentrations were elevated within two hours of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the CM were dose dependent. Treatment with sildenafil was associated with lesser degree of histological injury, attenuation in markers of acute kidney injury (48 hour creatinine 1.54±0.21 versus 4.42±1.31 mg/dl, p<0.05) and reduction in electrolyte derangement (percent change in serum K+ at 48 hours 2.55±3.80% versus 15.53±4.47%, p<0.05; serum Na+ at 48 hours -0.14±0.26% versus -1.97±1.29%, p = 0.20). The results suggest a possible role for PDE5 inhibitors in the treatment of CIAKI and warrant further evaluation to determine the exact mechanism of protection

Kidney to body weight ratio analysis in rabbits subjected to CIAKI.

<p>The kidney to body weight ratio was measured as the average weight of both kidneys per 100 g body weight. (a) Kidney to body weight ratio for animals treated with increasing doses of CM. (b) Kidney to body weight ratio for animals pretreated with sildenafil citrate (6.0 mg/kg; single dose or q8 h).</p

Representative histological lesions in kidneys from rabbits subjected to CIAKI.

<p>Renal cortex from rabbits treated with (A) 2.5 g I/kg CM, (B) 10.0 g I/kg CM, or (C) 5.0 g I/kg CM and sildenafil citrate (6.0 mg/kg, q8 h). In a rabbit treated with 2.5 g I/kg there were no histological alterations in the cortex. (A, summary pathology score  = 0) In a rabbit treated with 10.0 g I/kg there was severe tubular necrosis (arrows) affecting >50% of the cortical tubules. (B, summary pathology score  = 7). In a rabbit treated with 5.0 g I/kg CM and sildenafil citrate there was tubular necrosis affecting a much smaller percentage of cortical tubules (C, summary pathology score  = 3). Higher magnification of tubular necrosis from a rabbit in the 10.0 g I/kg group shows details of tubular necrosis, (arrows) evidenced by loss of cellular detail in the tubules, nuclear loss or condensation, and sloughing of necrotic cell debris into the tubule lumen. (D). A similar area in a rabbit treated with 2.5 g I/kg CM shows no alterations in the tubules (E). Hematoxylin and eosin stain. Original magnifications for A, B, C = ×200; bars  = 100 µm; for D, E  = ×600, bar  = 20 µm.</p

Repeated treatment with sildenafil citrate prevents hyponatremia and hyperkalemia in animals exposed to CM.

<p>(A) Percent change (t = 0 vs. 48 h) in plasma Na⁺ concentrations in animals administered intravenous ioxilan (5.0 g I/kg) with/without simultaneous sildenafil therapy. (B) Percent change (t = 0 vs. 48 h) in plasma K⁺ concentrations in animals administered intravenous ioxilan (5.0 g I/kg) with/without simultaneous sildenafil therapy. Values are presented as mean ± SEM; n = 3–5. † indicates p<0.05 versus 5.0 g I/kg by one-way ANOVA and Dunnett's multiple comparisons test.</p