Iron-chelation therapy

The high specificity of siderophore iron coordination has been extensively explored in iron-chelation therapy for various medical applications, including iron overload diseases, control of iron in specific brain tissues , arresting the growth and proliferation of malaria parasite within their host , as well as arresting the proliferation of cancer cells . Other directions for metal ligation involve enzyme inhibition, which have been demonstrated by the inhibition of urease by coordination of hydroxamate ligand to nickel ions and zinc coordination in matrix metalloprotease (MMP) inhibition by primary hydroxamates. ... 

C. Hershko, Iron Chelation Therapy, Kluwer Academic/Plenum, New York, 2002. 

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. 

Structures above show the iron complex ferrioxamine B and the related compound, ferrioxamine E, in which the chelate has a cyclic structure. Graph shows success of transfusions and Ironsfusions plus chelation therapy. [Crystal structure kinrty provided by M. Neu, Los Alamos National Laboratory, based on D. Van der Helm and M. Poling. J. Am. Chem. Soc. 1976, 98,82. Graph from R S. Dobbin and R. C. Hider, Iron Chelation Therapy." Chem. Br. 1990,26.565.]... 

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. 

Hershko C, Link G, Konijn AM, CabantchikZI. Objectives and mechanism of iron chelation therapy. Ann N Y Acad Sci 2005 1054 124-135. 

C. Hershko, G. Link, and A. M. Konijn, Cardioprotective Effect of Iron Chelators, in Iron Chelation Therapy , 1st edn., ed. C. Hershko, Kluwer Academic/Plenum Publishers, New York, 2002, Vol. 509, p. 77. 

Mariam, R., Aroslo, C., Pelucchi, S., Grisoli, M., Riga, A., Tromblnl, R, Plperno, A. Iron chelation therapy in aceruloplasminemia study of a patient with a novel missense mutation (case report). Gut 2004 53 756-758... 

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. 

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

Thuma PE, Weiss G, Herold M, Gordeuk, VR. Serum neopterin, interleuIcin-4, and interleukin-6 concentrations in cerebral malaria patients and the effect of iron chelation therapy. Am J Trop Med Hyg 1996 54 164-8. 

The structures of the three iron chelators which are currently approved for clinical use are presented in Figure 22.4. It is now well established that iron chelation therapy reduces the risk of death and improves patient survival during more than four decades of clinical experience with the current reference standard chelator, des-ferrioxamine (DFO). DFO is a hexadentate chelator (as we saw in Chapter 2). However, it is not active by oral... 

Current Status of Iron Chelation Therapy Robert W. Grady, Anthony Cerami U, 219... 

In order to retard or prevent this accumulation of iron, a powerful iron chelator, desferrioxamine-B, is administered either by injection or by intravenous infusion. This chelator is capable of forming a very stable complex with iron and then carrying the iron out of the body with the urine or stool. Iron chelation therapy greatly improves the well-being of the patient and extends the lifetime of the patient appreciably (3). 

Desferrioxamine-B (DFB) (I) is produced "In a fermentation process by Ciba Pharmaceutical Co. and is supplied as the methane sulfonate salt under the name Desferal. Although there are many excellent iron chelators known, DFB is the only one that not only works in humans, but is available in sufficient amounts to supply the need for iron chelation therapy. 

Several powerful iron chelators, some recently synthesized specifically for the Cooley s Anemia program, are being tested to ascertain their potential as drugs for use in iron chelation therapy for treating iron overload in Cooley s Anemia. Some of the more promising ones include ... 

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