DEFERIPRONE (L1) CHELATES PATHOLOGICAL IRON DEPOSITS FROM MEMBRANES OF INTACT THALASSEMIC AND SICKLE RED-BLOOD-CELLS BOTH IN-VITRO AND IN-VIVO

Citation
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
Citations number
28
Categorie Soggetti
Hematology
Journal title
BloodACNP
ISSN journal
00064971
Volume
86
Issue
5
Year of publication
1995
Pages
2008 - 2013
Database
ISI
SICI code
0006-4971(1995)86:5<2008:D(CPID>2.0.ZU;2-M
Abstract
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.