O. Shalev et al., DEFERIPRONE (L1) CHELATES PATHOLOGICAL IRON DEPOSITS FROM MEMBRANES OF INTACT THALASSEMIC AND SICKLE RED-BLOOD-CELLS BOTH IN-VITRO AND IN-VIVO, Blood, 86(5), 1995, pp. 2008-2013
Red blood cell (RBC) membranes from patients with the thalassemic and
sickle hemoglobinopathies carry abnormal deposits of iron presumed to
mediate a variety of oxidative-induced membrane dysfunctions. We hypot
hesized that the oral iron chelator deferiprone (L1), which has an enh
anced capacity to permeate cell membranes, might be useful in chelatin
g these pathologic iron deposits from intact RBCs. We tested this hypo
thesis in vitro by incubating L1 with RBCs from 15 patients with thala
ssemia intermedia and 6 patients with sickle cell anemia. We found tha
t removal of RBC membrane free iron by L1 increased both as a function
of time of incubation and L1 concentration. Thus, increasing the time
of incubation of thalassemic RBCs with 0.5 mmol/ L L1 from 0.5 to 6 h
ours, enhanced removal of: their membrane free iron from 18% +/- 9% to
96% +/- 4%, Dose-response studies showed that incubating thalassemic
RBC far 2 hours with L1 concentrations ranging from 0.125 to 0.5 mmol/
L resulted in removal of membrane free iron from 28% +/- 15% to 68% +/
- 11%. Parallel studies with sickle RBCs showed a similar pattern in t
ime and dose responses. Deferoxamine (DFO), on the other hand, was ine
ffective in chelating membrane free iron from either thalassemic or si
ckle RBCs regardless of dose (maximum, 0.333 mmol/L) or time of incuba
tion (maximum, 24 hours). In vivo efficacy of L1 was shown in six thal
assemic patients whose RBC membrane free iron decreased by 50% +/- 29%
following a 2-week course of L1 at a daily dose of 25 mg/kg. As the d
ose of L1 was increased to 50 mg/kg/d (n = 5), and then to 75 mg/kg/d
(n = 4), 67% +/- 14% and 79% +/- 11%, respectively, of their RBC membr
ane free iron was removed. L1 therapy-both in vitro and in vivo-also s
ignificantly attenuated the malondialdehyde response of thalassemic RB
C membranes to in vitro stimulation with peroxide. Remarkably, the hem
e content of RBC membranes from L1-treated thalassemic patients decrea
sed by 28% +/- 10% during the 3-month study period. These results indi
cate that L1 can remove pathologic deposits of chelatable iron from th
alassemic and sickle RBC membranes, a therapeutic potential not shared
by DFO. Furthermore, membrane defects possibly mediated by catalytic
iron, such as lipid peroxidation and hemichrome formation, may also be
alleviated, at least in part, by L1. (C) 1995 by The American Society
of Hematology.