Heparins with reduced anti-coagulant activity reduce myocardial reperfusion injury

Recent Pat Cardiovasc Drug Discov. 2011 May;6(2):148-57. doi: 10.2174/157489011795933855.

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 250µg/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 Ca(2+) 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 Ca(2+) loading by reducing Ca2(+) influx via Na/Ca exchange, thus reducing Ca(2+) - 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.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / pharmacology
  • Anticoagulants / adverse effects
  • Anticoagulants / pharmacology*
  • Disease Models, Animal
  • Dogs
  • Heparin / adverse effects
  • Heparin / analogs & derivatives*
  • Heparin / pharmacology
  • Humans
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / physiopathology
  • Patents as Topic
  • Swine

Substances

  • Anti-Inflammatory Agents
  • Anticoagulants
  • heparin, O-desulfated
  • Heparin