Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1)
Section snippets
Iron imbalance
Iron is an essential trace element found in many proteins, which play a key role in the metabolic pathways involved in the growth and development of humans and almost all other organisms. Under normal conditions total body iron in adults is about 4.5 g and is uniformly distributed as haemoglobin (2.6 g), myoglobin (0.4 g), non-haem storage iron in tissues (1.4 g), smaller amounts as enzymes and minute amounts in plasma. About 1–4 mg of dietary iron is absorbed daily mainly from the duodenum and
Transfusional iron overload in thalassaemia and other conditions
Transfusional iron overload is the most common metal-related toxicity condition with the highest mortality rate worldwide. The risk is higher in those belonging in the category of the most common inherited disorder namely the haemoglobinopathies. It is estimated that 270 million people are heterozygotes of a haemoglobinopathy and at least 200 000 babies are born each year, half with sickle cell disease and the other half with thalassaemia [1], [2], [3]. About 73% of those born with thalassaemia
Iron toxicity mechanisms
In all the conditions of iron overload, iron toxicity may arise mainly from the incapacity of cells to store iron in a safe storage form, resulting in lysosomal rupture and subsequent cellular and tissue damage. Potentially toxic forms of iron in iron overload are the low molecular weight labile iron pool and haemosiderin found intracellularly and the low molecular weight non-transferrin bound iron (NTBI) found extracellularly. Iron could catalyse the oxidative breakdown of most biomolecules
Methods for the assessment of iron overload
Estimation of the body iron status and the progress of iron chelation therapy in iron-loaded patients could be achieved by a variety of methods, all of which have limitations and none of which could precisely predict total body iron and extent of iron toxicity. This is mainly because of variability in body and organ iron distribution, iron detection methods, iron estimation and extrapolation to all other body iron pools and other factors such as the diet, infection, inflammation, erythropoietic
Chelating drugs and their mode of action
A chelator (χηλη, Greek claw of a crab) is a naturally occurring or chemically designed molecule which has high specificity and affinity for a metal ion, forming a complex with it. An ideal chelator designed for the decorporation of a particular metal from the body should be able to bind, carry and remove the metal out of the body without causing any toxicity. The chelator dose protocol should be selected for each patient and aimed to achieve maximum efficacy in iron removal and minimum
Deferoxamine
DF has been the mainstay of iron chelation therapy in transfusional iron loaded patients in the last forty years. It is a generic drug and could be produced chemically or isolated from the fungus streptomyces pilosus. The development of chelation therapy with DF involved different stages of various application techniques and experimentation protocols over the last 40-year period, including various methods of administration in order to improve its overall efficacy. The prolonged subcutaneous and
The α-ketohydroxypyridines
Hundreds of potentially orally active chelators have been tested in vitro and in animals and only 16 reached the stage of clinical evaluation, with mostly disappointing results because of either ineffectiveness or toxicity in humans [15], [16], [17]. The α-ketohydroxypyridines (KHP) is the most promising group of chelators [18]. They were designed to mimic the naturally occurring chelators mimosine, tropolone and maltol which were previously shown to be orally active and effective in binding
Deferiprone
L1 is the first oral iron chelating drug to be used in thalassaemia and other iron-loaded patients [28], [29]. Progress in its development has been very slow because it was mostly undertaken through research-orientated projects and supported by non-profit establishments. Pharmaceutical companies only showed an interest on L1 after it became clear that it would be a profitable financial venture.
It is estimated that more than 6000 patients in 40 countries have received L1 since the initiation of
Clinical use of L1
Many centres have reported the results of clinical trials since the first reports of the iron removal effects of L1 in transfusional iron loaded patients in 1987, all confirming the original findings that L1 is an effective, non-toxic, orally active chelator [28], [29], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56]. Overall, L1 has so far been assessed in three different therapeutic areas of medicine, mainly for iron removal from iron-loaded patients,
Pharmacology of deferoxamine and deferiprone
DF is supplied in a vial as a freeze-dried solid of its mesylate salt, which is dissolved in water and administered with the aid of an electronic pump over an 8–12 h period. The rate of elimination of DF in blood is faster than L1 and depends on the route of administration. The half-life of elimination of i.v. DF is 5–10 min and im DF is 60 min. It is estimated that during the 8–12 h long s.c. DF administration, the elimination of DF is very fast and a plateau level in the plasma is achieved
Toxicity of deferiprone and deferoxamine
Most drugs have toxic side effects which may or may not be related to their pharmacological activity or toxicity findings in animals. A major aspect of toxicity in relation to iron chelation therapy is the removal or displacement of other essential metals. Two other iron chelating drugs namely DTPA and EDTA have been previously shown in iron-loaded patients to increase the excretion of Zn, Cu, Mn in addition to Fe resulting in toxic side effects. Increased excretion of Zn and Cu has also been
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