HBED ligand: preclinical studies of a potential alternative to deferoxamine for treatment of chronic iron overload and acute iron poisoning.
We have continued the preclinical evaluation of the efficacy and safety of the hexadentate phenolic aminocarboxylate iron chelator N, N'-bis(2-hydroxybenzyl) ethylenediamine-N, N'-diacetic acid monosodium salt (NaHBED) for the treatment of both chronic transfusional iron overload and acute iron poisoning. We examined the effect of route of administration by giving equimolar amounts of NaHBED and deferoxamine (DFO) to Cebus apella monkeys as either a subcutaneous (SC) bolus or a 20-minute intravenous (IV) infusion. By both routes, NaHBED was consistently about twice as efficient as DFO in producing iron excretion. For both chelators at a dose of 150 micromol/kg, SC was more efficient than IV administration. The biochemical and histopathologic effects of NaHBED administration were assessed. No systemic toxicity was found after either IV administration once daily for 14 days to iron-loaded dogs or after SC administration every other day for 14 days to dogs without iron overload. Evidence of local irritation was found at some SC injection sites. When the NaHBED concentration was reduced to 15% or less in a volume comparable to a clinically useful one, no local irritation was found with SC administration in rats. Because treatment of acute iron poisoning may require rapid chelator infusion, we compared the effects of IV bolus administration of the compounds to normotensive rats. Administration of DFO produced a prompt, prolonged drop in blood pressure and acceleration of heart rate; NaHBED had little effect. NaHBED may provide an alternative to DFO for the treatment of both chronic transfusional iron overload and of acute iron poisoning.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville 32610, USA. bergeron@mc.cop.ufl.edu
Wiegand
Jan
J
Brittenham
Gary M
GM
D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002428:Cebus; D002908:Chronic Disease; D003676:Deferoxamine / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D004195:Disease Models, Animal; D004285:Dogs; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D004492:Edetic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D007501:Iron / Q000506:poisoning*; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D019190:Iron Overload / Q000188:drug therapy*; D008297:Male; D011041:Poisoning / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013810:Therapeutic Equivalency
D007502:Iron Chelating Agents; C037740:N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid; D004492:Edetic Acid; D007501:Iron; D003676:Deferoxamine