Heparins with Reduced Anti-Coagulant Activity Reduce Myocardial Reperfusion Injury

Author(s): William H. Barry, Thomas P. Kennedy.

Journal Name: Recent Patents on Cardiovascular Drug Discovery (Discontinued)

Volume 6 , Issue 2 , 2011

Abstract:

Heparin which is desulfated at the 2-O and 3-O positions (ODSH) has reduced anti-coagulant properties, and reduced interaction with heparin antibodies. Because of the reduced anti-coagulant effect, ODSH can be safely administered to animals and humans intravenously at doses up to 20 mg/kg, resulting in a serum concentration of up to 250 μg/ml. Administration of ODSH causes a 35% reduction in infarct size in dogs and pigs subjected to coronary artery occlusion and reperfusion when given 5 min before reperfusion. ODSH has anti-inflamatory effects, manifest as a decrease in neutrophil infiltration into ischemic tissue at high doses, but this effect does not entirely account for the reduction in infarct size. ODSH decreases Na+ and Ca2+ loading in isolated cardiac myocytes subjected to simulated ischemia. This effect appears due to an ODSH-induced reduction in an enhanced Na+ influx via the Na channel in the membrane of cardiac myocyes caused by oxygen radicals generated during ischemia and reperfusion. Reduction in Na+ influx decreases Ca2+ loading by reducing Ca2+ influx via Na/Ca exchange, thus reducing Ca2+ - dependent reperfusion injury. ODSH does not appear to interact with antibodies to the heparin/platelet factor 4 complex, and does not cause heparin-induced thrombocytopenia. Because of these therapeutic and safety considerations, ODSH would appear to be a promising heparin derivative for prevention of reperfusion injury in humans undergoing thrombolytic or catheter-based reperfusion for acute myocardial infarction. The review article discussed the use of heparin and the discussion of some of the important patents, including: US6489311; US7478358; PCTUS2008070836 and PCTUS2009037836.

Keywords: Calcium, heparin, myocardium, reperfusion injury, sodium, Anticoagulant, sodium calcium exchange, O-desulfated heparin, glycation end products, Calcium Loading

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Article Details

VOLUME: 6
ISSUE: 2
Year: 2011
Page: [148 - 157]
Pages: 10
DOI: 10.2174/157489011795933855
Price: $100

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