Efficacy and safety of deferoxamine conjugated to hydroxyethyl starch.
The efficacy and safety of deferoxamine conjugated to hydroxyethyl starch (HES-DFO) was evaluated in an in vitro rat cardiac membrane lipid peroxidation (CMLP) assay and in a swine model of regional myocardial ischemia/reperfusion injury in comparison to DFO. The rat CMLP results demonstrate that HES-DFO is at least as potent as DFO (IC50 = 10 and 13 microM, respectively). HES-DFO given intravenously (i.v.) at the equivalence of 25 mg/kg and 100 mg/kg DFO in a swine model of regional myocardial ischemia [20-min left anterior descending coronary artery (LAD) occlusion followed by 60-min reperfusion] showed no significant changes in hemodynamics as compared with DFO at 25 mg/kg i.v. In addition, HES-DFO was at least as potent as DFO with regard to recovery of regional segment shortening function (%SS). Furthermore, both HES-DFO and DFO significantly reduced tissue water content (edema) in the area at risk (AAR). We conclude that conjugation of DFO to HES improves the safety without any interference in the efficacy of DFO.
Mousa
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Pharmaceuticals and Biotechnology Research Division, Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400.
Ritger
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Smith
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D000818:Animals; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology; D003676:Deferoxamine / Q000009:adverse effects / Q000494:pharmacology / Q000592:standards*; D004487:Edema / Q000188:drug therapy; D006439:Hemodynamics / Q000187:drug effects; D006895:Hydroxyethyl Starch Derivatives / Q000009:adverse effects / Q000494:pharmacology / Q000592:standards*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D013552:Swine; D016277:Ventricular Function, Left / Q000187:drug effects
D006895:Hydroxyethyl Starch Derivatives; C068460:hydroxyethyl starch-deferoxamine conjugate; D003676:Deferoxamine