Iron continued overload

Araujo A, Kosaryan M, MacDowell A, et al, A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload, BrJ Haematol 1996 93 835-837. 

The continued absorption of iron causes its deposition in various tissues starting with liver and spleen and followed by myocardium. Deposition of iron in the myocardium usually results in death by intractable cardiac failure. Patients suffer from hypoparathyroidism and hypogonadism. Patients with the severe form of thalassemia are more susceptible to bacterial infection, possibly due to the increase in serum iron, which may favor bacterial growth. Iron overload is less common in the adult forms of Q -thalassemia. This is most likely the result of a fundamental difference between a and -thalassemia. As mentioned, the excess of Q -globin chains cannot form viable tetramers and causes red-cell destruction. The excess jS-chains present in a-thalassemia are able to form solnble homodimers and do not precipitate in the bone marrow. This is paralleled in the fetal state when excess y-chains form solnble homodimers. Hence, a-thalassemia is characterized by a severe degree of inefficient erythropoiesis and a milder degree of anemia. 

Intravenous deferoxamine can be indicated in gross iron overload, serious cardiomyopathy, or intolerance of or non-adherence to subcutaneous administration. The results of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in 17 patients (25 intravenous lines) have been presented (154). The doses of deferoxamine were calculated with reference to the serum ferritin concentration, with a view to maintaining the therapeutic index (mean daily dose in mg/kg divided by the serum ferritin concentration in ng/ml) below... 

Cianciulli P, Sorrentino F, Maffei L, Amadori S. Continuous low-dose subcutaneous desferrioxamine (DFO) to prevent allergic manifestations in patients with iron overload. Ann Hematol 1996 73(6) 279-81. 

Recombinant erythropoietin, recently produced in large quantities by innoculat-ing the erythropoietin gene into the Chinese hamster ovary, has been used to treat the anemia of chronic renal failure with dramatic results (E6, E7, H5, L13, W8). Anemia is corrected in most patients, and there is a greater sense of well being and exercise tolerance (Mil). Iron overload from previous blood transfusions improves and serum ferritin levels fall as treatment with erythropoietin is continued. 

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 ]. 

While chemical principles can be used to design chelators that form stable and specific Fe chelates, uncertainty about the nature and location of the chelatable iron pool and constraints on delivery of suitable chelators to the site of action have determined that iron chelator design is still dominated by empirical testing of structure-function relationships. This in itself adds a new challenge in that there is no perfect animal model for the human iron overload syndromes. Pitt (1981) has pointed out that rodents Fe-loaded with heat-damaged erythrocytes have been used most frequently to assess the ability of chelators to remove iron by the fecal (biliary) and urinary routes and lower parenchymal (liver) and RES (splenic) stores. He reviews LD50 and iron-removal data on many natural and synthetic hydroxa-mates, phenols, catechols, tropolones, salicylates, benzoates, azines, and carboxylates. No clear picture emerges and the search for the ideal iron chelator continues. 

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