Treatment of Iron Overload

The aim of treatment of iron overload is to remove all potentially toxic iron from the body. In hereditary haemochromatosis this can be achieved by weekly phlebotomies of 500 ml until the desired serum ferritin concentration (mostly <50 gg/1) or a normal transferrin iron saturation is reached (Brissot et ah, 2000). 

Fig. 30. Chemical structures of two siderophore mimic molecules presently in clinical use for treatment of iron overload, Exjade and Deferiprone.

Ponka et al. [372] showed that pyridoxal isonicotinoyl hydrazone (PIH, Figure 19.23) is an iron chelating agent. Numerous studies showed the possibility of using this chelator for the treatment of iron overload disease [373], In subsequent studies the antioxidant activity of PIN has been confirmed. For example, Hermes-Lima et al. [374,375] showed that PIN protected plasmid pUC-18 DNA and 2-deoxyribose against hydroxyl radical damage. 

Desferrioxamine (108) is the only clinically approved iron chelator. As well as being used for the treatment of iron overload diseases it is... 

Hydroxypyranones and hydroxypyridinones are promising candidates as chelating agents for the treatment of iron overload, since many are readily available, they form stable complexes with Fe, and some are permitted food additives. Hydroxypyridinones are to be preferred to hydroxypyranones as the former form the more stable complexes and are less readily metabolized. An extensive literature on synthetic iron chelators has been built up over the past 20 years -we can cite only a very small proportion here. In the 1980s it was established that hydroxypyridinones, usually in the form of... 

Iron(III) complexation by 5-nitrotropolone follows the usual mechanistic pattern, 4 at Fe +, at FeOH +aq. Dinuclear Fe2(OH)2 aq, like FeOH +aq, reacts by an mechanism. Curcumin (232) and its diacetyl derivative form complexes with Fe + whose stabilities approach that of Fe -desferrioxamine, hence their suggested use for treatment of iron overload—a topic which dominates the following section devoted to two specific classes of hydroxyketones, viz hydroxypyranones and hydroxypyridinones. ... 

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 ° . ... 

The oral iron chelator deferasirox is approved for treatment of iron overload. Deferasirox appears to be as effective as deferoxamine at reducing liver iron concentrations and is much more convenient. However, it is not clear yet whether deferasirox is as effective as deferoxamine at protecting the heart from iron overload. 

Erythropoietin has been used successfully to offset the anemia produced by zidovudine treatment in patients with HIV infection and in the treatment of the anemia of prematurity. It can also be used to reduce the need for transfusion in high-risk patients undergoing elective, noncardiac, nonvascular surgery to accelerate erythropoiesis after phlebotomies for autologous transfusion for elective surgery or for treatment of iron overload (hemochromatosis). 

Deferasirox is a tridentate chelator with a high affinity for iron and low affinity for other metals, eg, zinc and copper. It is orally active and well absorbed. In the circulation, it binds iron, and the complex is excreted in the bile. Deferasirox was recently approved for the oral treatment of iron overload caused by blood transfusions, a problem in the treatment of thalassemia and myelodysplastic syndrome. 

In cases where metals or metal ions can contaminate the products, reaction vessels fabricated from inert polymeric materials restrict that possibility. A significant example involved the reaction of maltol with aqueous methylamine to give l,2-dimethyl-3-hydroxypyrid-4-one. The product is a metal chelator employed for the oral treatment of iron overload. Consequently, it is an excellent metal scavenger but must be produced under stringent conditions that preclude metal complexation. Literature conditions involved heating maltol in aqueous methylamine at reflux for 6 h, the product was obtained in 50% yield, but required decolourisation with charcoal135. With the CMR, the optimal reaction time was 1.3 min, and the effluent was immediately diluted with acetone and the near colourless product crystallised from this solvent in 65% yield (Scheme 9.18). A microwave-based batch-wise preparation of 3-hydroxy-2-methylpyrid-4-one from maltol and aqueous ammonia was also developed. 

The ferrioxamines are a family of linear and cyclic siderophores built up from l-amino-5-(hydroxyamino)alkanes and succinic and acetic acids. Figure 47 shows ferrioxamine B, a linear trihydroxamic acid, which is probably the best-known example. The mesylate salt of the deferri form of ferrioxamine B is used in the clinical treatment of iron-overloaded patients. 

Eijgenraam FJ, Donckerwolcke RA. Treatment of iron overload in children and adolescents on chronic haemodialysis. Eur J Pediatr 1990 149(5) 359-62. 

Recently considerable effort has been devoted to the synthesis of natural siderophores, enantiomeric siderophores, and completely synthetic siderophore analogs. These compounds have been prepared as potential drugs in the treatment of iron overload, as potential antibiotics, and as probes for the stereospecific recognition and uptake of siderophore complexes by microbes. In addition, octadentate analogs have been prepared as actinide-specific sequestering agents 24). 

Penicillamine, a chelating agent, solubilizes copper and other heavy metals and promotes their excretion in urine, analogous to the use of deferoxamine in the treatment of iron overload (Chapter 29). Long-term treatment with penicillamine increases the requirement for pyridoxine. Iron supplements should also be given, on a schedule... 

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 +... 

The selection and evaluation of new chelating agents for the treatment of iron overload. J. Pharmacol, and Exper. Therap. 1979, 208, 12-18. 

The Design of Chelating Agents for the Treatment of Iron Overload... 

Jetsrisuparb A, Komvilaisak P, Wiangnon S, Jetsrisuparb C. Retrospective study on the combination of desferrioxamine and deferasirox for treatment of iron-overloaded thal-assemic patients first evidence of more... 

The hydroxamic acid derivative known as Desferrioxamine B methane sulphonate (DFOA), a selective chelator for iron which has been widely used for the treatment of iron overload in man, is effective, either alone or in combination with NajCaDTPA, for the removal of plutonium from rats. However, the compound is ineffective for the removal of americium and the effectiveness for the removal of plutonium was limited to very short times after injection [see Taylor 1991 for references]. 

Kark RA, Poskanzer DC, Bullock JD, Boylen G (1971) Mercury poisoning and its treatment with A -acetyl-D,L-penicillamine. N Engl J Med 285 10-16 Kontoghiorghes GJ, Aldouri MA, Sheppard L, Hoffbrand AV (1987) 1,2-Dimethyl-3-hydroxypyrid-4-one, an orally active chelator for treatment of iron overload. Lancet 1 1294-1295... 

Grootveld M, Bell JD, Halliwell B, Aruoma OI, Bomford A, Sadler PJ (1989) Nontransferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy. J Biol Chem 264 4417-4422 Gyparaki M, Porter JB, Huehns ER, Hider RC (1986) Evaluation in vivo of hydro-xypyrid-4-one iron chelators intended for the treatment of iron overload by the oral route. Biochem Soc Trans 14 1181-1181 Hallaway PE, Eaton JW, Panter SS, Hedlund BE (1989) Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers. Proc Natl Acad Sci USA 86 10108-10112... 

Huehns ER, Porter JB, Hider RC (1988) Selection of hydroxypyridin-4-ones for the treatment of iron overload using in vitro and in vivo models. Hemoglobin 12 593-600... 

McLeod C, Fleeman N, Bagust A, Boland A, Chu P, Dickson R, Dundar Y, Greenhalgh J, Modell B, Olujohhungbe A, Teller P, Walley T. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfu-sional haemosiderosis) in patients suffering with chronic anaemia a systematic review and economic evaluation. Health Technol Assess 2009 13(1) iii-iv, ix-xi, 1-121. 

A Cochrane Database of Systematic Reviews meta-analysis of 22 trials including 2187 participants of deferoxamine mesylate for the treatment of iron overload in people with transfusion-dependent thalassaemias was performed [47 ]. Adverse events were recorded in 18 trials. Five trials reported a total of seven deaths, three in patients with defroxamine alone and two in patients who received deferoxamine and deferiprone. Seven trials reported cardiac function or liver fibrosis in end organ damage. The authors concluded that there is a need for adequately powered, high-quality trials comparing the overall clinical efficacy and long-term outcomes of deferiprone, deferasirox and deferoxamine. 

A review in 2014 provides arguments for and against treatment of iron overload in sickle cell patients with hydroxyurea and discusses all previous literature [62 ]. The review highlights several important studies, briefly summarised here. An annotated bibliography provides commentary on the importance of various studies in that review. 

In the case of hemochromatosis, excess iron can be removed from patients bodies by venesection. On the other hand, removal of iron using an iron chelator is the only effective way to relieve iron overload in patients with y0-thalasemia or sickle cell anemia [52,53]. Neither of these therapies are optimum for the treatment of these diseases. The current standard of care for iron chelation therapy is desferrioxamine (Scheme 7), which is the only approved iron chelator for the treatment of iron overload conditions in the USA. Desferrioxamine has reportedly been associated with several drawbacks. It has a narrow therapeutic window and due to lack of oral bioavailability, it requires administration for 8-12 h per day by parenteral infusions [54]. Thus, there is a clear need for the discovery and development of a new generation of orally active iron-chelating agents for the treatment of iron overload conditions. 

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