Physiopathologie et prise en charge de la surcharge en fer transfusionnelle: Etat actuel de la therapeutique chelatrice du fer

Although the iron chelating compound deferoxamine (DF) has been available for treating transfusional iron overload since the early 1960s, the era of modern and effective iron chelating therapy started only 20 years ago with the introduction of subcutaneous DF infusions by portable pumps, with a major impact on well-being and survival. Most of the improvement in survival is attributed to a decrease in cardiac mortality. In addition to preventing cardiac complications, vigorous DF treatment is also able to reverse symptomatic myocardiopathy. Because of the inconvenience of continuous subcutaneous DF infusion, many patients are unable or unwilling to cope with the rigorous requirements of such treatment. In view of these considerations, there is a great need for the development of alternative, orally effective iron chelating drugs. At present only deferiprone (L1) has been used in a substantial number of thalassemic patients to allow preliminary clinical evaluation. Although L1 is able to induce a negative iron balance, its use is associated with significant toxicity, the most important of which is agranulocytosis. However, recent observations also raise concerns regarding the ability of L1 to induce sufficient depletion of tissue iron to offer protection from critical organ damage in a substantial fraction of patients. Among the other new chelators that may be suitable for clinical use. HBED and dimethyl-HBED are presently being evaluated. Iron balance studies performed in a small number of thalassemic patients treated with HBED showed excretion that was only to 48% of the amounts required for achieving negative iron balance. Because the prodrug dimethyl-HBED showed improved absorption and bioavailability in animal studies, this compound is now regarded as a promising candidate for clinical evaluation. Another promising new chelator is IRC011, a substituted cyclic polyaza compound, with preferential interaction with the toxic non-transferrin plasma iron (NTBI) released from RE cells. Safety and efficacy are major considerations in the selection of new chelators. These are determined by the nature on their interaction with iron. Thus, hexadentate chelators would be always preferable to bidentate or tridentate chelators. The partition coefficient determines ability to cross lipid membranes and lipophilic compounds penetrate cells with relative ease. Prodrugs can be made less polar than their active derivative and their intestinal absorption may improve markedly. Because of their gradual release and absorption, their overall effect may be improved several fold. Better understanding of the pathophysiology of iron toxicity and the mechanism of iron chelation is vital for the development of improved strategies of iron chelating therapy.