Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 370-375
HBED: The Continuing Development of a Potential Alternative to
Deferoxamine for Iron-Chelating Therapy
Raymond J. Bergeron,
Jan Wiegand, and
Gary M. Brittenham
From the Department of Medicinal Chemistry, University of Florida,
Gainesville, FL; and the Department of Medicine, MetroHealth Medical
Center, Case Western Reserve University, Cleveland, OH.
To further examine the potential clinical usefulness of the
hexadentate phenolic aminocarboxylate iron chelator
N,N
-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) for the chronic treatment of transfusional iron
overload, we performed a subchronic toxicity study of the HBED
monosodium salt in rodents and have evaluated the iron excretion in
primates induced by HBED. The HBED-induced iron excretion was
determined for the monohydrochloride dihydrate that was first dissolved
in a 0.1-mmol/L sodium phosphate buffer at pH 7.6 and administered to
the primates either orally (PO) at a dose of 324 µmol/kg (149.3 mg/kg, n = 5), subcutaneously (sc) at a dose of 81 µmol/kg (37.3 mg/kg, n = 5), sc at 324 µmol/kg (n = 5), and sc
at 162 µmol/kg (74.7 mg/kg) for 2 consecutive days for a total dose
of 324 µmol/kg (n = 3). In addition, the monosodium salt of HBED in
saline was administered to the monkeys sc at a single dose of 150 µmol/kg (64.9 mg/kg, n = 5) or at a dose of 75 µmol/kg every
other day for three doses, for a total dose of 225 µmol/kg (n = 4).
For comparative purposes, we have also administered deferoxamine (DFO) PO and sc in aqueous solution at a dose of 300 µmol/kg (200 mg/kg). In the iron-loaded Cebus apella monkey, whereas the PO
administration of DFO or HBED even at a dose of 300 to 324 µmol/kg
was ineffective, the sc injection of HBED in buffer or its monosodium
salt, 75 to 324 µmol/kg, produced a net iron excretion that was
nearly three times that observed after similar doses of sc DFO. In
patients with transfusional iron overload, sc injections of HBED may
provide a much needed alternative to the use of prolonged parenteral
infusions of DFO. Note: After the publication of our previous
paper (Blood, 91:1446, 1998) and the completion of the studies
described here, it was discovered that the HBED obtained from Strem
Chemical Co (Newburyport, MA) that was labeled and sold as a
dihydrochloride dihydrate was in fact the monohydrochloride
dihydrate. Therefore, the actual administered doses were 81, 162, or
324 µmol/kg; not 75, 150, or 300 µmol/kg as was previously
reported. The new data have been recalculated accordingly, and the data
from our earlier study, corrected where applicable, are shown in
parentheses.
