Iron overload reduction

Treatment with iron chelators and a-tocopherol protect against lipid p>eroxidation and hepatocellular injury in iron-overloaded rats (Sharma etal., 1990). When hepatocytes are isolated from rats, which have been pretreated with a-tocopherol, there is a significant reduction in iron-induced lipid peroxidation and improvement in cell viability in vitro (Poli et al., 1985). Similar effects were seen when hepatocytes were incubated with iron chelators (Bacon and Britton, 1990). Treatment of moderately, but not heavily, iron-loaded rats with desferrioxamine in vivo inhibits the pro-oxidant activity of hepatic ultrafiltrates (Britton et al., 1990b). 

Conventional treatments for hemochromatosis and for nutritional iron overload include reduction of dietary iron and periodic removal of blood (phlebotomy) until iron stores are reduced. In transfusion siderosis, it is necessary to eliminate iron via the urine by the intravenous infusion of highly specific chelating agents such as desferral (see Iron Transport Siderophores). This process is painful, laborious, and costly. The development of new orally effective iron chelators is expected. 

Treatment of chronic iron overload, e.g. haemochro-matosis, patients who are transfusion-dependent due to chronic haemolytic anaemias, thalassaemia and refractory anaemias with transfusional iron overload (siderosis). The goal of therapy is the reduction and maintenance of body iron stores at normal or near-normal levels to avoid the tissue damage associated with iron overload. 

As described in Section 3, iron can promote peroxidation of biological macromolecules due to its reactions with ROS and, thus, is of high toxic potential for cells, if it is not kept in a toxicologi-cally inactivated form bound to specific proteins. Only when iron is tightly bound to a chelator is its capacity for promoting LPO minimal. Amongst synthetic chelators of iron, fois-(2-aminoethyl)-amine-A, N,A, N -penta-acetic acid, desferrioxamine, o-phenanthroline and bathophenanthroline are able to complex Fe + and, thus, slow down reduction of Fe to Fe + by reductants like ascorbic acid or (O2) in vitro, but EDTA is ineffective. Desferrioxamine was originally developed for the treatment of iron overload disease because it binds Fe +... 

While the bulk of literature on iron chelation concerns P-thalassemia, in patients with thalassemia intermedia abnormal regulation of iron homeostasis may lead to iron overload, even in the absence of transfusions. In an open study in 11 patients with thalassemia intermedia, deferasirox 10-20 mg/kg/day for 24 months was associated with significant reductions in liver iron content and serum ferritin concentrations in the first 12 months, which continued during the second part of the study no serious adverse events were recorded [9 ]. 

The combined use of deferoxamine with deferasrrox has been described in seven Asian patients with thalassemia and iron overload in a retrospective evaluation of alternating administration of deferoxamine (20-40 mg/ kg/day for 8-12 hours for 3 days, combined with vitamin C 100 mg/day) and deferasirox (20-30 mg/kg/day for 4 days) every week for 8-27 months [24 ]. There was a substantial reduction in serum ferritin concentrations and no adverse events were reported. 

In two patients with P-thalassemia in whom chelation with deferoxamine and deferiprone, alone and in combination, had been unsuccessful, daily alternating combination treatment with deferiprone and deferasirox orally maintained a low iron burden [25 ]. In one patient there was also a reduction in iron overload. In the other patient treatment was complicated by multiple hypersensitivity reactions, after subcutaneous deferoxamine had repeatedly led to systemic hypersensitivity reactions with a rash, fever, and pain, and the subsequent use of deferasirox was also complicated by a rash, which reappeared on two occasions after low-dose... 

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