Coordination Chemistry Reviews
`184 (1999) 291–310
`
`Iron chelating agents in clinical practice
`
`Gavino Faa a,*, Guido Crisponi b
`a Dipartimento di Citomorfologia, Sezione di Anatomia Patologica, Via Porcell 2,
`I-09124 Cagliari, Italy
`b Dipartimento di Chimica e Tecnologie Inorganiche e Metallorganiche, Via Ospedale 72,
`I-09124 Cagliari, Italy
`
`Received 24 November 1998; accepted 16 February 1999
`
`Contents
`
`Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2. Iron overload and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3. Desferrioxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4. Development of non toxic oral iron chelators . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4.1 Deferiprone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5. New indications for iron-chelating therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5.1 Adult Respiratory Distress Syndrome (ARDS).
`. . . . . . . . . . . . . . . . . . . . . . . .
`5.2
`Iron chelators and myocardial ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5.3
`Iron chelators and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5.4 Iron chelators as antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
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`Abstract
`
`The relevance of iron chelators in medicine has increased in recent years. Iron is essential
`for life but it is also potentially more toxic than other trace elements. This is due to the lack
`of effective means to protect human cells against iron overload and to the role of iron in the
`generation of free radicals. To protect patients from the consequences of iron toxicity, iron
`chelating agents have been introduced in clinical practice. Unfortunately, the ideal chelator
`for treating iron overload in humans has not been identified yet. The aim of this review is to
`report the experience with desferrioxamine therapy in patients affected by b-thalassemia
`major according to: bioavailability; mechanism of interactions with hepatocellular iron:
`
`* Corresponding author.
`E-mail address: gfaa@vaxca1.unica.it (G. Faa)
`
`0010-8545/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
`PII: S 0 0 1 0 - 8 5 4 5 ( 9 9 ) 0 0 0 5 6 - 9
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`in
`impact of iron chelation on survival
`release of iron chelates and their excretion;
`thalassemia patients and side effects of prolonged therapy. Problems related to the develop-
`ment of non-toxic oral iron chelators are also discussed, with particular emphasis on the
`preliminary data on usefulness and safety of deferiprone (L1), recently evaluated in different
`clinical trials. Iron chelating therapy has been introduced, in recent years, even in the therapy
`of disorders not characterized by iron overload. Here the following new therapeutic
`indications are discussed: adult respiratory distress syndrome, myocardial ischemia, cancer
`and malaria. © 1999 Elsevier Science S.A. All rights reserved.
`
`Keywords: Iron-chelators; Desferrioxamine; Deferiprone; Thalassemia
`
`1. Introduction
`
`Iron chelators are used in medicine to protect patients from the consequences of
`iron overload and iron toxicity in organs and tissues. The ideal chelator for treating
`iron overload in humans should act as a selective depletor of iron, should be
`efficiently absorbed by the gastrointestinal tract, could not cross the blood–brain
`and placental barriers and should lack or have a low toxicity. Such a chelating
`agent has not been identified yet and this goal is at the basis of multiple research
`projects in this field. In this review, the experience with long-term iron chelating
`therapy in patients affected by chronic transfusion-dependent anemias will be
`summarized with particular emphasis on thalassemic patients who are the main
`target of iron-chelating drugs. The experience in thalassemia patients with the well
`established chelator desferrioxamine and with the orally active deferiprone will be
`outlined. This review is also intended to report the most recent development of new
`non-toxic and orally effective iron chelating agents and their possible application in
`clinical use. New indications for iron chelating therapy will also be explored, such
`as the use of iron chelation in oncology to prevent tumor cell growth by the
`inhibition of iron-dependent enzymes, the application of iron-chelating agents in
`the therapy of infectious disease with particular emphasis on their action as
`antimalarials,
`the experience of
`iron-chelating drugs in the therapy of adult
`respiratory distress syndrome and in the therapy of myocardial ischemia. Finally,
`the relevance of the dialogue among clinicians, pathologists, pharmacologists,
`biochemists, chemists, molecular biologists and other experts in metal toxicity in
`order to improve our knowledge on the relationship between the metabolism of
`iron and other trace elements will be discussed. This implies the final goal of
`prolonging survival and improving the quality of life of iron-loaded patients.
`
`2. Iron overload and toxicity
`
`Iron is essential for life: all living cells, whether prokaryotic or eukaryotic, need
`a supply of iron for reduction of oxygen (respiration), reduction of carbon dioxide
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`(photosynthesis), reduction of dinitrogen or other fundamental biological processes
`[1]. Excessive amounts of iron may become very toxic to the human body and,
`eventually, is fatal for vital cell structures [2].
`Iron overload may be defined as an excess in total body iron stores. The normal
`iron concentration in the human body ranges between 40 and 50 mg/kg of body
`weight [3]. Most of this iron is present in hemoglobin and in myoglobin: all the rest
`is stored as ferritin or as its less accessible form, hemosiderin. Only a few hundred
`milligrams of iron are stored in enzymes such as cytochrome c oxidase which,
`however, are essential to human life [1]. Humans have very limited capacity for
`excretion of excess iron: in particular they lack any effective means to protect cells
`and tissues against iron overload. As a consequence, any increase in iron intake
`may cause in a short time an increase in body iron stores [4]. Iron balance is
`normally regulated by controlling iron absorption in the proximal small intestine
`[5]. In women, losing iron in the menstrual cycle could protect against excess iron
`toxicity and it is considered to be, at least in part, responsible for their greater
`longevity than men [1]. The major regulators of mucosal iron absorption are the
`amount of body iron stores and the level of erythropoiesis [6]. Iron overload may
`be caused by two different factors:
`1. parenteral administration of iron, as in chronic transfusion therapy;
`2. increase in iron absorption from the diet, that may be genetically determined
`like in hereditary hemochromatosis [7] or caused by dietary iron overload [8].
`When the accumulation of iron in organs exceeds the body capacity for safe
`storage, potentially lethal tissue damage results [9]. The severity of iron toxicity
`seems to be related to the amount of body iron burden. Recent studies in patients
`with thalassemia major found that the magnitude of the body iron burden was the
`major determinant of the risk of clinical complications and of early death [10,11].
`Target organs for iron-induced injury are the liver, pancreas and heart [12].
`In the category of patients affected by chronic anaemia, who need regular blood
`transfusions in order to sustain their normal growth and development during
`childhood, b-thalassemia major (BTM) constitutes one of the most serious public
`health problems in the Mediterranean area [13], in the Middle East, in the Indian
`subcontinent, in Southeast Asia [14] and, in particular, in the island of Sardinia
`[15]. BTM is an autosomal recessive disease, characterized by absent or decreased
`synthesis of the b globin gene: the number of thalassemic children requiring regular
`blood transfusions and a program of iron chelation has been estimated to be
`100 000 world-wide. In patients with thalassemia major, iron contained in trans-
`fused red cells inexorably accumulates if a concomitant regular chelation therapy is
`not programmed [16]. The major pathological manifestations observed in patients
`with BTM are related to iron overload: chronic liver disease, characterized by
`hepatocytic and Kupffer cell iron storage, fibrosis and, eventually, cirrhosis [17,18];
`dilatative cardiomyopathy with congestive heart failure is nowadays the most
`common cause of death in patients affected by BTM who reach adolescence and
`adulthood [19,20]. Even cardiomyopathy is related to cardiac hemosiderosis: a
`preferential accumulation of iron in the interventricular septum and in the left
`ventricle wall has been observed [21]. The toxic effects of iron overload has been
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`demonstrated in cultured heart cells: incubation of rat heart cell cultures with iron
`concentrations from 20 up to 80 g/ml resulted in a marked decrease in amplitude
`and rate of contractions and in gross abnormality in rhythmicity [22].
`
`3. Desferrioxamine
`
`Desferrioxamine is the only chelating agent to have been extensively used in
`clinical practice [23] after its discovery more than 30 years ago. It is a siderophore
`produced by Streptomyces pilosus [24], discovered by the team of Prelog and his
`co-workers Zahner and Keberle.
`
`Desferrioxamine, earlier recognized as an antagonist of the antibiotic ferrimycin,
`was successively identified as an iron chelating agent [25]. It is a trihydroxamic acid
`with three residues of 1-amino-5-N-hydroxy aminopentane, two of succinic acid
`and one of acetic acid organized in a linear array; the free amino group explains its
`very high water solubility. Although it has been synthesized the use of the natural
`product is more economic.
`Initially used in the therapy of acute iron poisoning [26], desferrioxamine was
`later introduced in thalassemia treatment, giving a fresh chance to more than
`100 000 thalassemic patients requiring iron chelating therapy. The widespread use
`of desferrioxamine was firmly established, thanks to British investigators such as
`Berry, Modell, Pippard and Hoffman and to Italian clinicians such as Cao. The
`relevance of desferrioxamine in clinical practice and its role in the progress of the
`therapy of thalassemia patients has been underlined on the occasion of the 1991
`Pharmaceutical of the Year price, awarded to desferrioxamine by the Munchener
`Medizinische Wochenschrift [27]. In order to better understand the value of this
`award, it is useful to observe that it had been previously given to aspirin, cortisone
`and penicillin. Desferrioxamine is the only iron-chelating agent approved for
`clinical use [28]. In the following, we shall focus on
`“ the bioavailability;
`“ the mechanism whereby it interacts with hepatocellular iron, with iron stored in
`macrophages and with iron in transit;
`“ the release of its iron chelates and their subsequent biliary or urinary excretion;
`“ the impact of iron chelation on survival in thalassemia patients;
`“ the side effects of prolonged therapy.
`Bioavailability is defined by Hider [29] as the percentage of absorbed dose of a drug
`which reaches the systemic blood circulation. It depends on the absorption of the
`drug from the gastrointestinal tract and from the extraction by hepatocytes from
`the portal blood supply. Low or high bioavailability may be requested in iron
`chelators, depending on the clinical setting and on the main target of chelating
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`therapy. Thus, when a general systemic action of a chelator is required, a high
`bioavailability is ideal. On the contrary, when liver is the target of iron chelation,
`an efficient absorption of the chelator by hepatocytes and, consequently, a low
`bioavailability is ideal. Two major factors influence the absorption of iron chelators
`from the gastrointestinal tract: the oil/water distribution coefficient [30] and the
`molecular weight. To achieve 70% absorption of an iron chelator, its molecular
`weight [31] needs to be B300. A 70% absorption of the dose is mandatory for iron
`chelators: 50% absorption could leave in the lumen such a level of the chelator that
`might disturb the microbiological flora [29]. Most siderophores, including desfer-
`rioxamine, have a molecular weight from 500 to 900 Da which effectively excludes
`hexadentate ligands, such as desferrioxamine, from consideration as orally active
`chelators. In contrast deferiprone and 1,2-diethyl-3-hydroxy-4-pyridinone, two lig-
`ands of molecular weight 139 and 167 Da, respectively, are both efficiently
`absorbed in man [32]. Since desferrioxamine given orally is poorly absorbed, to be
`effective it must be administered subcutaneously [33], intramuscularly [34] or by
`intravenous infusion with a small portable syringe pump, ideally for 9–12 h each
`day [35]. This difficult regimen of desferrioxamine parenteral treatment easily
`explains why only part of thalassemic patients comply with iron chelating therapy,
`in spite of the knowledge that the advent of treatment with desferrioxamine has
`changed the gloomy prognosis of thalassemia patients [36]. On entering blood by
`intravenous injection, desferrioxamine plasma clearance [37] is generally considered
`rapid, with half life of 5 to 10 min, also if a longer half life (3.0591.30 h) has been
`estimated in a recent study [38]. While only a small part of desferrioxamine is
`inactivated within human plasma, the major part undergoes uptake by hepatocytes.
`The rapid loss of circulating activity of desferrioxamine after intravenous injection
`is the main reason why prolonged infusion results in more efficient iron chelation
`[39]. After injection of desferrioxamine, both fecal and urinary iron excretion are
`observed. Probably the two excretion pathways reflect two different actions of the
`drug. Fecal excretion could only arise through iron chelation within the hepato-
`cytes, followed by excretion in the bile of the iron–desferrioxamine complex [39].
`The source of urinary iron remains more controversial: urinary excretion could
`derive from iron chelation within Kupffer cells and within other monophagocytic
`cells like spleen macrophages [40,41]. A further source to the urine is likely to be
`any nontransferrin bound iron in plasma of patients with a fully saturated plasma
`trasferrin, this kind of iron is reduced by desferrioxamine treatment [42]. The
`picture emerges that the major source of iron excreted through faeces by desferriox-
`amine is iron within hepatocytes, while urinary excretion could reflect an additional
`pathway of chelation, predominantly extracellular, regarding plasma nontransferrin
`bound iron, membrane-related iron of hepatocytes and iron in macrophages [39].
`The mechanism by which desferrioxamine is effective in removing intra and
`extracellular iron is not yet completely understood. To further the understanding of
`how desferrioxamine, as well other chelators, exert their effects on cells, many
`animal [43] and cellular models [44] have been proposed. Experiments on hepato-
`cytes have shown that the hepatocyte plasma membrane possesses a number of
`facilitated transport processes which are particularly efficient for the absorption of
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`small peptides as well as of desferrioxamine [29]. Once entered into the hepatocytes,
`the targets of desferrioxamine are the different pools of iron. Ferritin, whose major
`function is the storage of iron, is a protein of molecular weight 450 000 Da which
`can contain ca. 4500 iron atoms [45]. Desferrioxamine has been shown in vitro to
`be able of removing Fe(III) from ferritin: however, iron release requires chelator
`concentrations much higer than expected [45]. Probably the interaction of desfer-
`rioxamine with ferritin-bound iron is indirect. Ferritin is continuosly metabolized
`within lysosomes; the iron released in lysosomes enters a low molecular weight pool
`of iron which is the principal source of iron for desferrioxamine [46], whose main
`target is probably the pool of chelatable free iron in lysosomes. Another possible
`source of iron for desferrioxamine is trasferrin-bound iron. Transferrin is a glyco-
`protein, with a molecular weight of about 80 000 Da, which transports iron from
`the sites of absorption to those of storage and utilization. Desferrioxamine is
`generally unable to remove iron from transferrin; it may chelate transferrin-bound
`iron only in the presence of organic pyrophosphates, whose presence facilitates
`release of iron from transferrin [47]. Once in contact with the cellular membrane of
`hepatocytes, transferrin attaches to specific receptors and it is internalized by
`hepatocytes enclosed within endocytic vesicles in which iron is released. Iron
`released inside endocytic vesicles enters a labile intracellular transit iron pool
`consisting of low molecular iron complexes which may be chelated by desferrioxam-
`ine. A contribution to this intracellular transit iron pool may even derive by
`degradation of iron rich ferritin. Hepatocytes contain, in their cellular membrane,
`receptors for ferritin utilized for the uptake of ferritin released by Kupffer cells,
`following phagocytosis of erythrocytes [48,49]. The ingested ferritin is degraded
`within hepatocytic lysosomes and the released iron enters the chelatable transit iron
`pool, sensitive to the action of desferrioxamine. In patients affected by severe iron
`overload, when complete saturation of transferrin occurs, a low molecular weight
`iron pool, not associated to transferrin, is always present even in plasma. This
`plasmatic fraction of nontransferrin-bound iron may be bound to albumin or
`complexed by amino acids, citrate or sugars. Even this pool is a main target for
`chelation by desferrioxamine. The iron overload observed in hepatocytes from
`patients affected by congenital atransferrinemia [50] has demonstrated the existence
`of systems for the uptake of nontransferrin-bound iron. In vitro studies have shown
`that desferrioxamine may act even at this level, inhibiting the transferrin receptor-
`independent iron uptake systems [51]. Desferrioxamine acts even on macrophages
`and, particularly, on Kupffer cells. An important function of Kupffer cells is
`phagocytosis of senescent erythrocytes. Iron derived from hemoglobin enters a
`labile transit pool which is either returned to plasma transferrin or retained in
`ferritin [45]. Likely desferoxamine competes with apotransferrin for this pool of
`iron, which is on its way out of Kupffer cells and it is considered the major source
`of urinary iron excreted during desferrioxamine therapy [40]; fecal iron excretion on
`the contrary reflects the action of desferrioxamine on the chelatable iron pool
`present in the cytoplasm of the hepatocyte. The intimate mechanism of action of
`desferrioxamine is probably similar to that typical of the majority of iron chelators.
`Desferrioxamine promotes the ferric form of iron and suppresses excellently iron
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`toxicity, inhibiting the formation of hydroxyl radicals and lipid peroxidation [52] by
`its ferroxidase activity [53]. A strong ferroxidase activity is also exerted by transfer-
`rin and by ceruloplasmin, a 132 kDa a-2-glycoprotein containing a trinuclear
`copper cluster responsible for its oxidase activity and radical scavenging [54]. The
`report that patients affected by dietary or genetic deficiency of ceruloplasmin show
`severe accumulation of iron in liver [55] as well in other organs [56] is at the basis
`of recent studies on the relevance of ceruloplasmin in iron metabolism, both in
`physiologic and in iron overloaded patients. One of the multiple functions of
`ceruloplasmin is to aid the release of iron from the hepatocyte to plasma transfer-
`rin. Ceruloplasmin is probably localized inside the endoplasmic reticulum, where it
`acts as a ferroxidase on Fe(II) mobilised from intracellular ferritins which may
`initiate free radical reactions [57]. This is a crucial step in iron release; in fact,
`transferrin may only bind Fe(III) [58]. The relevance of ceruloplasmin in iron
`excretion has been confirmed by the demonstration that infusion of ceruloplasmin
`may rapidly enhance iron release from liver in patients with congenital aceruloplas-
`minemia [55]. In Wilson’s desease, characterized by low plasma levels of ceruloplas-
`min, we have reported high iron levels in the liver in an autoptic case [59] and in
`a percentage of liver biopsies (G.Faa et al., unpublished data). A severe iron
`deposition has been moreover reported in the liver of LEC rats [60], an animal
`model in Wilson’s desease. To our knowledge, the correlation between ceruloplas-
`min status and desferrioxamine has not been extensively studied. On the basis of the
`crucial role of ceruloplasmin in iron release from hepatocytes, a deficiency in
`ceruloplasmin could explain why some thalassemic patients, in spite of their good
`compliance in desferrioxamine therapy, show massive iron storage in the liver and
`in the heart.
`An interesting property of desferrioxamine is that it is not only an excellent iron
`chelator, thereby decreasing the free-radical generating reactions [61], but can also
`directly scavenge some radical species [62].
`Although desferrioxamine has been demonstrated to be a safe drug when
`administered in the presence of an elevated body iron burden [63], serious compli-
`cations may arise as a consequence of long term chelation, mainly in young patients
`with low body iron stores. At the basis of desferrioxamine toxicity is the fact that,
`like other chelators, desferrioxamine is not completely iron-selective. The most
`frequent complications of long-term desferrioxamine treatment are growth retarda-
`tion, described in patients with thalassemia major [64,65]. Other complications
`described include bone changes [66], visual and auditory neurotoxicity [67]. Severe
`limb and metaphyseal deformities have been reported in patients who began
`chelation in the first year of life [64]. Other adverse effects of desferrioxamine, noted
`in patients receiving continuous 24-h infusions, are impairment of vision, with
`defective dark adaption and peripheral field loss [68]. Hearing and vision abnormal-
`ities may occur more readily in patients with low iron stores, but the relationship
`is still not entirely clear and other factors may play a role [69]. Different hypotheses
`have been postulated to explain the adverse effects of desferrioxamine treatment:
`1. depletion of other trace elements, such as zinc, copper, manganese, cobalt;
`2. a direct toxic effect of free desferrioxamine;
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`3. depletion of iron from critical iron-dependent enzymes, such as cytochrome c
`oxidase [39].
`A pulmonary syndrome, characterized by diffuse lung infiltration and restrictive
`dysfunction, has been rarely observed in patients with thalassemia major receiving
`intravenous high doses of desferrioxamine [70]. Local skin reaction at the site of
`subcutaneous injection of desferrioxamine is also common, in the form of acute
`inflammation or of subcutaneous nodules persisting for several days [23]. Another
`complication occurring during chronic treatment with desferrioxamine is oppor-
`tunistic Yersinia infection [71]. This complication of desferrioxamine treatment
`probably occurs since the virulence of Yersinia is enhanced by the presence of a
`membrane receptor which binds desferrioxamine [72]. Desferrioxamine toxicity may
`be controlled or prevented: the majority of all the reported adverse effects may be
`reduced or prevented by avoiding high doses and over-early commencement, and by
`long-term clinical monitoring once the overload is significantly reduced [23].
`In conclusion, there is no doubt that desferrioxamine, with all its limitations, has
`changed the quality of life and life expectancy of many patients affected by
`thalassemia [13], by preventing the complications of iron overload [73].
`
`4. Development of non toxic oral iron chelators
`
`Despite the well-acknowledged successes of desferrioxamine in the medical
`treatment of iron overload in thalassemic patients, long-term compliance with a
`regimen of prolonged nightly infusion may be problematic for many patients in the
`developed world [63], while in developing countries such a regimen is impractical
`and unaffordable [28]. On this basis, the search for an orally-active iron chelator as
`an alternative to desferrioxamine in the treatment and prevention of chronic iron
`overload has continued in recent years. To this end, chemists have used their
`knowledge to synthesize a wide variety of chelators often borrowing from examples
`of nature [44]. Desirable properties for an oral iron chelator are:
`1. specificy and affinity for iron;
`2. molecular weight lower than 400 Da, for gastrointestinal absorption;
`3. sufficient lipophilicity for gastrointestinal absorption and intracellular chelation;
`4. sufficient hydrophilicity, to limit liver absorption.
`In the past 20 years a large variety of ligands with oxygen binding groups, above
`all those containing hydroxamates, catechols and hydroxypyridinones has been
`systematically tested as potential orally active drugs. Some of these do not present
`proper pM values for iron chelation (pM was defined by Harris et al. [74] as the
`negative logarithm of free iron(III) concentration in a solution that is 10 mM in
`ligand and 1 mM in metal at pH 7.4. The pM concept is now of common use to
`evaluate the strength of chelates taking into account proton competition). Other
`ligands, while promising from a chemical point of view later proved toxic and could
`not be introduced in clinical practice. Many authors first focused on catecholate
`sequestering agents, which resulted in stronger iron chelators than desferrioxamine
`[75]. Unfortunately, no catechol ligands were found to be orally active and some of
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`them strongly promoted the growth of pathogenic microorganisms, precluding
`designs based on these ligands [76]. Among the molecules showing the more
`interesting properties as oral chelators are HBED [77] ant its derivative dimethyl-
`HBED [78], pyridoxal isonicotinoyl hydrazone [79], desferrithiocin [80] and hydrox-
`ypyridinones [81].
`
`HBED, an analogue of EDTA with two phenolate replacing two carboxylate
`groups shows a log K value much higher than EDTA (36.7 with respect to 25.1);
`nevertheless this value is mitigated by its strong affinity for hydrogen ion resulting
`in a pM 26.74 with respect to 22.3 for EDTA. While it is well absorbed orally and
`it is effective in rodent assays its response in primates and in patient trials was
`remarkably less effective [82]; its dimethyl derivative is now under clinical trials [83].
`
`Due to the high activity of PIH [79] and of its analogues in mobilising iron, their
`chelating properties were extensively studied by Vitolo et al. [84]: the pM values for
`these ligands indicate that they are thermodynamically able to mobilise transferrin-
`bound iron, but a kinetic barrier however inhibits their exchange properties. At any
`rate the response in clinical tests was discouraging under different points of view
`[82].
`
`Desferrithiocin, isolated from S. antibioticus, is one of the few siderophores not
`belonging to hydroxamate or catecholate classes and it forms a stable 2:1 complex
`[85] with iron (K=4×1029 M − 1). This compound proved effective in iron mobili-
`sation both in rat and in primate models but animals exposed to it presented with
`nephrotoxicity [86]. In any case because of the strong chelating properties of
`desferrithiocin investigation is yet performed on its analogues [87].
`Despite their favourable iron binding properties none of the molecules presented
`above has proven completely satisfactory.
`Considering both their binding properties and the results of biological trials
`hydroxypyridinones appear to be the most promising oral chelators; their func-
`tional group was isolated in siderophores from a culture of Pseudomonas alcaligenes
`in 1979 by Barker et al. [88]. Among 1-hydroxy-2-pyridinone, 3-hydroxy-2-pyridi-
`
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`none and 3-hydroxy-4-pyridinone studied by Scarrow [81] with pM values 22.3,
`21.2 and 25.7, respectively,
`
`the third presents the most interesting properties and its 1,2-dimethyl derivative,
`known as deferiprone (L1 or CP20) is at the present the orally active iron chelating
`agent with the broadest clinical experience [63].
`
`4.1. Deferiprone
`
`Deferiprone [29] is a member of the family of hydroxypyridinones, of molecular
`weight 139 Da. By virtue of its low molecular weight, deferiprone possesses high
`absorption efficiency and it is efficiently absorbed from the human intestinal tract
`[32].
`
`Deferiprone was originally synthesized by Robert Hider and his colleagues at Essex
`University, patented in 1982 as an alternative to desferioxamine in the treatment of
`iron overload [89] and the early biological assessments were performed at Univer-
`sity College Hospital in London [36]. Deferiprone, in common with all hydrox-
`ypyridinones, forms 5-membered chelate rings in which iron is bound by two
`oxygen atoms [76]. Little is known about mobilization of iron stored in hepatocytes
`and in Kupffer cells by deferiprone. Deferiprone,
`in common with other low
`molecular weight iron chelators, likely removes Fe(III) from ferritin by penetration
`of the protein shell [90]. In other studies, it has been shown that deferiprone may
`mobilize iron even from hemosiderin, lactoferrin and from transferrin [91]. De-
`feriprone, like other bidentate hydroxypyridones, forms a 3:1 complex with iron; its
`efficiency in chelating iron, determined in iron-loaded monkeys, is significantly less
`than that observed in the same animals with parenteral administration of desfer-
`rioxamine [82]. Deferiprone is metabolized in the liver, where it undergoes rapid
`conversion to nonchelating metabolites. The major metabolite of deferiprone in
`man is the glucuronide which, as a result of conjugation of the 3-hydroxyl function,
`is unable to bind iron [92]. The majority of deferiprone–iron complex is excreted in
`the urine (70%), while little iron is excreted in the feces [93]. Although deferiprone,
`such as other bidentate ligands, has a clear advantage over desferrioxamine with
`respect to oral viability,
`it is potentially more toxic. In fact, by virtue of its
`relatively low molecular weight,
`it may easily penetrate most cell membranes,
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`10 of 20
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`301
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`blood–brain barrier and placental barrier. The efficacy of deferiprone in inducing
`and maintaining a negative iron balance in iron loaded transfused patients has been
`demonstrated by the first long-term trials. Iron chelation therapy with deferiprone
`in a large series of subjects affected by thalassemia intermedia showed a reduction
`of liver iron stores and a normalization of serum ferritin levels [94]. This observa-
`tion was followed by the report of a significant decline in liver iron concentration
`in patients affected by thalassemia major, during a 5-year treatment with de-
`feriprone [95]. In b-thalassemic patients who reach adolescence and adulthood, the
`heart has become the core of medical interest, since the main cause of death in adult
`b-thalassemia patients