Iron chelators thalassemia

Desferrioxamine (DFO-B), the natural siderophore initially isolated from Streptomyces pilosus, is the only iron chelator currently used for clinical treatment of iron-overload disease such as thalassemia, sickle cell anemia and hemochromatosis ° . ... 

It is an orally active iron chelator. It is useful in acute iron poisoning, iron overload in cirrhosis, transfusion siderosis in thalassemia patients. Adverse effects are anorexia, vomiting, altered taste, joint pain and neutropenia. 

Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy. One unit of blood can be removed every week or so until all of the excess iron is removed. Iron chelation therapy using parenteral deferoxamine is much less efficient as well as more complicated, expensive, and hazardous, but it may be the only option for iron overload that cannot be managed by phlebotomy, such as the iron overload experienced by patients with thalassemia major. 

Thalassemia Major. Transfusion-dependem thalassemia major patients liuvc abnormal growth and sexual maturation al puberty, presumably as a result of pituitary iron overload. Still poorly understood, this disorder is reported to respond well to deferoxamine iron chelation therapy, particularly if administered before the age of maturity. 

The treatment of thalassemia, as in other metal overload disorder, is chelation therapy. The chelating agent most widely nsed is deferoxamine administered subcutaneously. The search for an orally administered iron chelator has intensified in recent years, leading to cUnical trials of many potential new iron chelators snch as deferiprone(Ll). However, many issues regarding the nse of these drugs, such as dose-related toxicity and recommended age of initiation, remain unresolved. " ... 

Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McQelland RA, Burt AD, Fleming KA. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998 339(7) 417-23. 

Mazza P, Amurri B, Lazzari G, Masi C, Palazzo G, Spartera MA, Gina R, Sebastio AM, Suma V, De Marco S, Semeraro F, Moscogiuri R. Oral iron chelating therapy. A single center interim report on deferiprone (LI) in thalassemia. Haematologica 1998 83(6) 496-501. 

Adhikari D, Roy TB, Biswas A, Chakraborty ML, Bhattacharya B, Maitra TK, Basu AK, Chandra S. Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassemia and hemoglobin E-beta thalassemia. Indian Pediatr 1995 32(8) 855-61. 

Ohvieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis LM, Cameron RG, McClelland RA, Liu PP, Templeton DM, Koren G. Iron-chelation therapy with oral deferipronein patients with thalassemia major. N Engl J Med 1995 332(14) 918-22. 

Olivieri NF, Matsui D, Liu PP, Blendis L, Cameron R, McClelland RA, Templeton DM, Koren G. Oral iron chelation with l,2-dimethyl-3-hydroxypyrid-4-one (LI) in iron loaded thalassemia patients. Bone Marrow Transplant 1993 12(Suppl 1) 9-11. 

Olivieri. N.F. et al. (1995) Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N. Engl. J. Med.. 332,918-922. 

An orally effective iron chelator now under clinical investigation, deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one), may be of value in patients with thalassemia major who are unable or unwilling to receive deferoxamine. Combination therapy with deferoxamine also is under investigation. 

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 ]. 

In the past few decades, increasingly effective iron chelation regimens have dramatically improved the life expectancy of patients with 3-thalassemia. In particular, early death from cardiac dysfunction is preventable by long-term effective chelation, but up to 50% of patients are unable to adhere to treatment. 

Yesilipek MA, Karasu G, Kazik M, Uygun V, Ozturk Z. Posttransplant oral iron-chelating therapy in patients with beta-thalassemia major. Pediatr Hematol Oncol 2010 27(5) 374-9. 

Normally, most iron is stored as ferritin but with increasing iron overload hemosiderin increases. Hemosiderin is found in the parenchymal cells of the liver and this may result in hemosiderosis and even cirrhosis. Treatment is with the iron chelator desferrioxamine and small amounts of ascorbic acid. The effect of ascorbic acid upon iron transport has been reported for dietary iron overload and P-thalassemia. As a result of ascorbic acid administration, serum iron rapidly rises and its careful use in conjunction with the iron chelator desferrioxamine increases urinary iron excretion (O Brien, 1974 Nienuis et ai, 1976 Nienhuis, 1981 Murray, 1982). 

Adamson lYR, Sienko A, Tenenbein M (1993) Pulmonary toxicity of deferoxamine in iron-poisoned mice. Toxicol Appl Pharmacol 120 13-19 Aisen P (1992) Entry of iron into cells a new role for the transferrin receptor in modulating iron release from transferrin. Ann Neurol 32 S62-S68 Aksoy M, Birdwood GFB (eds) (1985) Hypertransfusion and iron chelation in thalassemia. Huber, Berne... 

Bronspigel-Weintrob N, Olivieri NF, Tyler B, Andrews DF, Freedman MH, Holland JF (1990) Effect of age at the start of iron chelation therapy on gonadal function in -thalassemia major. N Engl J Med 323 713-719... 

Jacobs A, Hoy T, Humphrys J, Perera P (1978) Iron overload in Chang cell cultures biochemical and morphological studies. Br J Exp Pathol 59 489-498 Kattamis C (ed) (1989) Iron overload and chelation in thalassemia. Huber Toronto Klopman G (1968) Chemical reactivity and the concept of charge- and frontier-controlled reactions. J Am Chem Soc 90 223-234 Kontoghiorghes GJ, Bartlett AN, Hoffbrand AV, Goddard JG, Sheppard L, Barr J, Nortey P (1990) Long-term trial with the oral iron chelator l,2-dimethyl-3-hydroxypyrid-4-one (LI). I. Iron chelation and metabolic studies. Br J Haematol 76 295-300... 

The effectiveness of iron chelators is illustrated by the tremendous improvements in both life expectancy and quality of life in patients with thalassemia, thanks to structured and rigorous diagnosis and treatment schemes, as for example in Cyprus. At the same time, the chronic use of chelators continues to pose major challenges, concerns regarding their best use, and scientific assessment of their long-term benefits and harms [1, 2 ]. 

Pradhan V, Badakere S, Ghosh K. Antihistone and other autoantibodies in beta-thalassemia major patients receiving iron chelators. Acta Haematol 2003 109(1) 35-9. 

MarseUa M, Borgna-Pignatti C. Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Hematol... 

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