Blood, 15 April 2002, Vol. 99, No. 8, pp. 3019-3026
TRANSFUSION MEDICINE
HBED ligand: preclinical studies of a potential alternative to
deferoxamine for treatment of chronic iron overload and acute iron
poisoning
Raymond J. Bergeron,
Jan Wiegand, and
Gary M. Brittenham
From the Department of Medicinal Chemistry, University
of Florida, Gainesville, and the Departments of Pediatrics and
Medicine, Columbia University College of Physicians and Surgeons, New
York, NY.
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 µmol/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.
