title: High-dose iron-chelator therapy during reperfusion with deferoxamine-hydroxyethyl starch conjugate fails to reduce canine infarct size.
abstract: Iron catalyzes reactions during ischemia and reperfusion that contribute to myocardial injury. The iron-chelator deferoxamine blocks these reactions, but undesirable side effects limit the clinical potential of deferoxamine to decrease injury. We tested whether intravenous (i.v.) administration of high doses of a well-tolerated deferoxamine-hydroxyethyl starch (DEFHES) iron-chelator during the last 10 min of ischemia and the first 10 min of reperfusion would decrease canine infarct size. Fourteen chloralose-anesthetized mongrel dogs were randomized to therapy in a blinded fashion with deferoxamine conjugate (75 mg/kg deferoxamine) or hydroxyethyl starch (HES) vehicle alone. Nine other untreated dogs served as controls. Infarct size as a percentage of area at risk (MI/RISK) was not reduced by therapy with deferoxamine conjugate. The deferoxamine dose was five times greater than the maximally tolerated dose of free deferoxamine. Arterial deferoxamine concentrations in the deferoxamine-conjugate group were 0.69 +/- 0.09 mM at onset of reperfusion and 1.37 +/- 0.05 mM at 10 min of reperfusion. Area at risk, ischemic collateral blood flow, and heart rate-blood pressure (HR/BP) product were similar in the groups. Chelation of intravascular iron at the time of reperfusion does not reduce myocardial necrosis in an in vivo model of myocardial ischemia-reperfusion injury.
authors.affiliation: Division of Cardiology, University of Colorado Health Sciences Center, Denver.
authors.forename: E J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.forename: B E
authors.initials: BE
authors.lastname: Hedlund
authors.forename: P E
authors.initials: PE
authors.lastname: Hallaway
authors.forename: L D
authors.initials: LD
authors.lastname: Horwitz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003676:Deferoxamine / Q000008:administration & dosage*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D005609:Free Radicals; D006895:Hydroxyethyl Starch Derivatives; D007262:Infusions, Intravenous; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D009336:Necrosis; D011897:Random Allocation
chemical_list: D005609:Free Radicals; D006895:Hydroxyethyl Starch Derivatives; D003676:Deferoxamine