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Deferiprone was an orally active iron chelator which emerged from an extensive search for new treatment of iron overload. Comparative studies have shown that at comparable doses deferiprone may be as effective as deferoxamine in removing body iron. Retrospective and prospective studies have shown that deferiprone monotherapy was significantly more effective than deferoxamine in improving myocardial siderosis in thalassemia major. Agranulocytosis was the most serious side effect associated with the use of deferiprone, occurring in about 1% of the patients. More common but less serious side effects are gastrointestinal symptoms, arthralgia, zinc deficiency, and fluctuating transaminases levels. Deferiprone can be used in combination with deferoxamine. This regimen of chelation was tolerable and attractive for patients unable to comply with standard deferoxamine infusions or with inadequate response to deferiprone alone. Combination therapies have been effectively used in the management of severe cardiac siderosis. Moreover, patients have more compliance to deferiprone, and were cost effective as compared to deferoxamine.
Deferiprone (DFP, Ferriproxâ„¢, Kelferâ„¢, L1, CP20) was hydroxypyridinone iron chelator synthesized by Dr. Kontoghiorghes in the early to mid-1980s in the laboratory of Professor R. Hider at the University of Essex in London. The molecule was synthesize to be taken orally and bind iron in conditions of iron overload and excretes it from the body. Also due to the high cost and inconvenient mode of administration of Deferoxamine (DFO), an orally effective, non-toxic and cheaper iron chelator was synthesize (Kontoghiorghes, G.J, 1985). The excitement over the discovery of a potentially effective oral iron chelator led the investigators to initiate animal studies that would lead them to the most rapid route to a trial in humans. The first publication of the use of DFP in man was published in 1987 (Kontoghiorghes et al., 1987) and was the first oral iron chelator to be used clinically, mainly in thalassemia patients. Iron was essential to all species and there was no physiologic excretory pathway for this essential element (Andrews, 1999). In conditions of primary iron overload or secondary accumulation of this potentially toxic element results in massive iron accumulation, followed by iron-induced morbidity and mortality, and lead to generation of toxic free radical damage (Rund and Rachmilewitz 2005). These chelators have a high affinity for binding iron, and are able to remove it from proteins that are transporting and storing it in the body. DFP can remove excess iron from various parts of the body of iron-loaded patients, including liver and particularly heart (Kontoghiorghes et al., 2004). Prior to the discovery of DFP, the only option for treatment of iron overload was Deferoxamine (DFO) that was not absorbed orally and thus needed to be administered parenterally, 8 to 12-hour nightly infusion, 5-7nights a week (Thalassemia International Federation Guidelines 2000).
DFP was also used worldwide to treat cancer, leukemia, in hemodialysis and other diseases. It was also used in the detoxification of other metals, such as aluminum in hemodialysis patients (Paschalidis et al., 1999; Di-Ji et al., 2004). Iron was also involved in replication of the human immunodeficiency virus type 1 (HIV-1) (Georgiou et al., 2000) such as deferiprone inhibit replication of HIV-1. Deferiprone can inhibit nuclear factor-ÎºB activation and subsequent replication of human immunodeficiency virus type 1 (Sappey et al., 1995). Deferiprone can also render iron-dependent ribonucleotide reductase inactive, thereby inhibiting DNA synthesis and therefore HIV replication (Hoffbrand et al., 1976).
The regulatory approval of Ferriproxâ„¢ in Europe (August 1999) was a key advance in the treatment of iron overload (Donovan et al 2005; Cappellini et al 2006; Galanello et al 2006a). Deferiprone was the world's first and only orally active iron chelating drug, which was effective and inexpensive to synthesize thus increasing the prospects of making it available to most thalassemia patients in third world countries who are not currently receiving any form of chelation therapy (Kontoghiorghes et al., 2004).
2. IRON OVERLOAD
Iron overload was the main complication of regular blood transfusions which are used in the management of several conditions including the haemoglobinopathies, beta (Î²) thalassaemia, sickle cell disease and myelodysplastic syndrome and other rare anaemias (Frankel, E.P 2007; Weatherall, D.J 2003). Haemoglobinopathy refers to a range of genetically inherited disorders of red blood cell haemoglobin and includes sickle cell disease and the thalassemia. Sickle cell disease and beta thalassemia major are two of the commonest forms of this disorder.
The thalassemias are a group of genetic disorders of haemoglobin synthesis, which result from production abnormalities in the globin chains of haemodesferrioxamine globin. They are divided into Î±, Î², Î´Î², or ÎµÎ³Î´Î² thalassaemia, according to which globin chain was produced in reduced amounts. Beta thalassemia major results from absent or reduced Î² chain production. The Î±-chain synthesis proceeds at a normal rate, which causes an imbalanced globin chain synthesis. The excess Î±-chains are unstable and as a result the red blood cells do not form correctly and are destroyed prematurely (Frankel, E.P 2007; Weatherall, D.J 2003). This results in increased erythropoietin production, which can cause bone marrow hyperactivity leading to serious deformities of the skull and long bones and pathologic fractures. It can also impair growth and delay or prevent puberty. Splenomegaly results from increased abnormal RBCs in the circulation. Life expectancy was decreased in people with untreated beta thalassaemia major, therefore require standard treatment of regular blood transfusions every 3-4 weeks to correct the anaemia. Bone marrow transplant may be an alternative treatment option but this was confined to 25% of patients aged 17 year (Frankel, E.P 2007).
There are three types of sickle cell disease: sickle cell anaemia, haemoglobin sickle cell and sickle beta thalassaemia which are caused by inherited abnormal haemoglobin formation due to the presence of HbS. Sickle shaped red blood cells clog capillaries causing organ ischaemia. Crises are treated with analgesics and other supportive measures including blood transfusions when there was a cycle of closely spaced painful crises. Transfusions are used to prevent long term recurrent cerebral thrombosis in children <18 years of age who have suffered at least one stroke (Porter, R.S 2005).
Myelodysplastic syndrome (MDS) affects the bone marrow and results in ineffective and/or inappropriate haematopoiesis. This can lead to anaemia and was treated with regular blood transfusions, neutropenia and/or thrombocytopenia. Splenomegaly and hepatomegaly are common. MDS may convert to acute myeloid leukaemia (Porter, R.S 2007). Most patients will develop transfusion dependency, of which over 50% are likely to benefit from Deferoxamine. Deferiprone was not recommended for routine use due to lack of published data and concerns over safety and efficacy (Gatterman, N. 2005).
Each unit of blood contains iron which cannot be excreted from the body. A typical thalassaemia patient will accumulate 0.3-0.5mg/kg of iron per day .Excessive iron was deposited in body tissue as haemosiderin and wass very toxic. Free non-transferrin bound iron also have the potential to form free radicals which can cause oxidative damage (Porter, J.P 2005). Excess iron accumulates in all tissues and severe damage can occur to the liver, heart, thyroid, pituitary, hypothalamus, pancreas and joints. Once the body has accumulated 12-24g of iron, significant clinical manifestations of iron toxicity will occur. Total body iron content can reach as high as 50g, compared with normal levels of 2.5g in women and 3.5g in men (Yardumian et al., 2005). Symptoms of iron overload do not usually occur until irreversible organ damage has occurred. All patients who require regular blood transfusions will also require iron chelation therapy (Frankel, E.P 2005).
3.1 Deferiprone Chemistry
DFP (1,2-dimethyl-3-hydroxypyridin-4-one) was a synthetic analogue of mimosine, an iron chelator isolated from the legume Mimosa paduca (Clarke and Martell 1992). It has 2 pKas, one of 3.6 and other of 9.9 (Hider and Liu 2003). DFP have strong iron binding properties, with a pFe3+ of 19.6 and a pFe2+ of 5.6, indicating a high degree of relative specificity for the trivalent form of iron, binding it in a 3:1 complex. DFP was a lipophilic compound with neutral charge of chelator-iron complex (Clarke and Martell 1992; Tam et al 2003). As a water-soluble compound having a partition coefficient of 0.11 and with a molecular weight of only 139 Da, it would be expected to move freely through cell membranes throughout the body.
3.2 Deferiprone and Animal Toxicity
Deferiprone cause bone marrow aplasia in mice, rats, dogs and monkeys, involution of lymphatic tissues and adrenal steatosis that lead to high rates of mortality (Grady et al., 1992; Ziel et al., 1993). A toxic effect of deferiprone observed in animal studies of drug tolerability was caused by concurrent zinc deficiency and was not due to direct consequence of deferiprone toxicity. In view of animal toxicity data, discontinuation of deferiprone was announced to develop deferiprone for clinical use (Ciba-Geigy 1993). This decision has been contested on the grounds that deferiprone should continue to be available for patients with severe transfusional iron overload who are unable or unwilling to use DFO. It was also felt that the toxicity of any chelator should be tested in iron-loaded and not in normal animals. Studies in non-iron loaded animals have shown that DFP was embryotoxic and teratogenic (Berdoukas et al., 1993). Deferiprone was also studied for effectiveness of radiation protection against depleted uranium (DU) in animal models and results showed significant increases in urinary DU excretion and decreases in DU concentration in the injected muscle, indicating that deferiprone combined with DU and DU was excreted in the urine (Fukuda et al., 2006).
3.3 Deferiprone Pharmacokinetics
Pharmacokinetic studies in humans have shown that Deferiprone appears to be rapidly and completely absorbed after oral administration, with peak plasma levels occurring at about 1 hour after administration. Food slows the rate of absorption and thus reduces the peak concentration with a Cmax of 100 Î¼mol/L was in the fasting state and about 85 Î¼mol/L when fed (Matsui et al 1991; Al-Refaie et al 1995a), but does not have much effect on the total amount absorbed. The drug was rapidly eliminated from the body with a half-life of about 2 hours due to hepatic biotransformation, with glucuronidation accounting for almost the entire metabolism. 90% of the drug was excreted in the urine as the glucuronide. The tÂ½ in healthy subjects (1.3 hours) may be shorter than that in thalassemia subjects (2.3 hours) (Stobie et al 1993). Since the clearance (CL/F) did not differ between the two subject populations, this indicates a different volume of distribution in transfused patients, most likely related to large differences in iron stores and the ability of DFP to access intracellular iron pools.
3.4 Deferiprone and serum Ferritin
The ferritins are a family of iron storage and detoxification proteins which play a critical role in cellular iron homeostasis in humans, animals, plants and microbes. Serum ferritin concentrations was used as a means estimating body iron load (Siimes et al., 1974) and have been used to monitor response to chelation therapy (McLaren et al., 1983; Modell and Berdoukas 1984). The study data reveal that DFP was effective at decreasing or stabilizing serum ferritin concentrations during continued blood transfusions. In general, those patients who had high serum ferritin concentrations before starting DFP, experienced the greatest decline, whereas those who were well-treated prior to starting DFP, experienced a stabilization of values, indicative of control of iron load (Cohen et al., 2000).
3.5 Deferiprone and Liver iron concentrations (LIC)
Liver accommodate excess stores of iron and was well-designed to tolerate high concentrations of iron due to lysosomal storage mechanisms and other factors. High levels of iron over prolonged periods do induce hepatic fibrosis and even cirrhosis (Prati et al., 2004). Studies revealed that LIC increased linearly with the number of units of transfused blood (Cazzola et al., 1983). Upon initiating chelation therapy, the transfusion regimen as well as the dose of chelating agent used become the major determinants of LIC and the key was to adjust the dose to the needs of the patient, depending largely on the patient's transfusion regimen and efficacy of the chelator in that individual. MRI has been used to assess hepatic iron concentrations (Anderson et al., 2001; St Pierre and Clark 2005). Liver iron correlates linearly with the total iron body while there was little evidence for the value of liver iron concentrations as a predictor of cardiac iron load (Angelucci et al., 2000; Anderson et al., 2001; Wood et al., 2004). To minimize the risk of iron-induced liver damage as well as to reduce total body iron stores, a chelator needs to be capable of reducing LIC, or maintaining acceptable levels (Jensen et al., 2003). The efficacy of DFP versus DFO was compared in a large multicenter randomized clinical trial. They found no difference in the reduction of liver iron content measured by MRI or liver biopsy between the two groups (Maggio et al., 2002). Another randomized controlled study designed to compare the abilities of DFP and DFO, assess hepatic iron concentrations. In 61 randomized patients (32 on DFO), a mean dose of 92 mg/kg/day of DFP reduced hepatic iron concentrations by 0.93 mg/g dry weight vs. 1.54 mg/g dry weight in patients receiving a mean of 43 mg/kg/day DFO 5.7 days/week (Pennell et al., 2006).
3.6 Deferiprone and Cardiac Iron
Magnetic resonance imaging (MRI T2*) was used for the assessment of iron overload to evaluate cardiac iron load and predict the risk of iron-induced cardiac damage. MRI T2* values have good reproducibility for the measurement of iron concentration (Tanner et al., 2006a). Iron-induced heart failure was the most common causes of death in patients with thalassemia major (Borgna-Pignatti et al., 2004). A quantitative assessment of the magnitude of cardiac iron loading in transfusion-dependent thalassemia major patients have revealed that two thirds of 167 patients on DFO therapy exhibited cardiac siderosis (Tanner et al., 2006b). Simultaneous assessment of the iron content in heart & liver shown that patients may have high concentrations of iron in the liver but low concentrations of iron in the heart, or vice versa (Anderson et al., 2001; Wood et al., 2004).
Several studies have shown that DFP was more effective than DFO in removing cardiac iron, retrospectively compared myocardial iron content in 15 patients receiving long-term DFP with 30 matched thalassemia major controls on long-term DFO. The Deferiprone groups have significantly reduced myocardial iron and higher ejection fraction than the Deferoxamine group (Anderson et al., 2002). The cardiac benefits of chelation therapy with DFP have observed in another retrospective study with more than 4 years of follow-up (Piga et al., 2003). Cardiac dysfunction was diagnosed in 4% of the DFP treated patients and in 20% of the DFO-treated patients. Several prospective trials have compared the myocardial effects of DFP and DFO (Maggio et al., 2002; Peng et al., 2003; Galia et al., 2003; Pennell et al., 2006). In two studies DFP at 75 mg/kg/day was as effective as DFO, at 50 mg/kg/day 5-6 days per week, at reducing cardiac iron (Maggio et al 2002; Galia et al 2003).
A prospectively compared cardiac iron, estimated by MRI and Left ventricular ejection fraction (LVEF) over 3 years in 13 patients allocated to DFO (50 mg/kg/day at least 5 days per week) with 11 patients taking DFP (75 mg/kg/day). Cardiac iron was markedly improved in 5 patients on DFP and only in 2 of patients on DFO treatment. Mean LVEF improved in the patients taking DFP, whereas there was no significant change in the DFO group (Peng et al., 2003). The above-reported results have been recently confirmed by a larger, prospective controlled trial, where 61 patients previously treated with DFO were randomized to be maintained on DFO (43 mg/kg for 5-7 days per week) or switched to DFP (92 mg/kg/d 7 days per week). After 1 year, there was significantly greater improvement in myocardial T2*of patients taking DFP than those on DFO (Pennell et al., 2006). The available data show that Deferiprone may have greater cardiac benefit than Deferoxamine.
An effect of deferiprone was also studied on doxorubicin-induced cardiotoxicity and to determine its protection on cardiac contractility in vivo at tissue level. Results showed, treatment with DOX alone resulted in a 49.34% reduction of the contractility, mitochondria swelling, disruption of mitochondrial crista and decreased electron density of the matrices while with deferiprone, the negative inotropic effect and lesions in the cardiac mitochondria structure induced by DOX were attenuated. Deferiprone can efficiently preserve cardiac contractility. Moreover, the results of this study indicate that deferiprone was able to protect mitochondrial function and structure form damage induced by DOX. This cardio protective potential of deferiprone could be due to its defense capability against oxidative damage (Xu LJ et al., 2006).
3.7 Deferiprone and Hepatotoxicity
Hepatic fibrosis was observed in patients on long term deferiprone therapy. In thalassemia, viral hepatitis was important cause of cirrhosis; therefore more focus was on hepatitis C virus (HCV)-negative patients to evaluate the potential hepatotoxicity of deferiprone. A total of 14 patients was evaluated, 5 developed progression of hepatic fibrosis on deferiprone treatment. Four of these patients were HCV positive only one of the eight HCV-negative patients developed progression of hepatic fibrosis. None of the 25 HCV-negative patients reported collectively by developed this complication on comparison (Hoffbrand et al., 1998 and Galanello et al., 1999). No evidence of fibrosis progression was found among any of the 29 patients, both HCV positive and negative. The effect of long-term deferiprone treatment on liver histology was also examined. Repeat liver biopsies were performed at an interval of about 1 year in 14 patients treated with deferiprone and compared with those of 22 patients receiving Deferoxamine. It was concluded that deferiprone appears to stabilize liver iron and that it does not significantly increase liver fibrosis (Berdoukas et al., 1993).
3.8 Deferiprone and Zinc
Deferiprone was a specific iron chelator with a high binding constant and with a lower affinity for other metals. Zinc deficiency assessed by a subnormal serum zinc level was first reported in 4 of 10 patients after 7-13 months of deferiprone therapy (Collins et al., 1994). The amount of zinc excretion could not be related to dose of deferiprone or iron load of the patients. Studies have shown that zinc excretion was increased in patients with diabetes mellitus, less so in patients with biochemical evidence of diabetes and least so in patients with normal glucose tolerance (Al-Refaie et al., 1994).
A prospective multi-centric study was conducted to determine if iron-chelating agent deferiprone also chelates zinc. 24-hour urinary zinc levels were compared in multiply transfused children with thalassemia major not receiving any chelation therapy (Group A), and those receiving deferiprone and age and sex-matched controls of subjects (Group B) by a colorimetric method. The 24-hour mean urinary excretion of zinc was significantly higher in Group B than in the other two groups, indicating that deferiprone chelates zinc (Bartakke et al., 2005).
3.9 Deferiprone in Thalassemia
Long-term iron-chelating therapy with DFP in thalassaemic patients was conducted. The study involved 84 patients, 74 with thalassaemia major or intermedia, a total of 167 patient of DFP treatment. Compliance was rated as excellent in 48%, intermediate in 36% and poor in 16% of patients. On DFP dose of 73-81 mg/kg/d, urinary iron excretion was stable, at around 0Â·5 mg/kg/d, with no indication of a diminishing response with time. Serum ferritin showed a very steady decrease with time and 17 patients abandoned DFP therapy. Major complications of DFP which required permanent discontinuation of treatment included agranulocytosis in 3, severe nausea in 4, arthritis in 2 and persistent liver dysfunction in 1. The remaining patients abandoned treatment because of low compliance (3) and conditions unrelated to L1 toxicity. Lesser complications permitting continued L1 treatment included transient mild neutropenia (4), zinc deficiency (12) transient increase in liver enzymes (37), moderate nausea (3) and arthropathy (16). There was no treatment-associated mortality but two patients died of haemosiderotic heart disease and of Pneumocystis carinii pneumonia with AIDS, both while off treatment. This study demonstrated the efficacy of DFP in long-term use for the treatment of transfusional iron overload in thalassemia (Olivieri et al, 1995; Tondury et al, 1990; Agarwal et al, 1992).
A major multi-Centre study of deferiprone, involving 187 patients (the LA-02 study), was monitored for DFP side-effects weekly (Tricta et al, 1997; Cohen, 1997). All patients received 25 mg/kg DFP t.i.d. and the mean follow-up time was 1Â·61Â±0Â·8 years. Almost all patients were on DFO therapy prior to starting DFP. During observation period there was no change in mean serum ferritins or in liver iron concentrations. Transient agranulocytosis developed in 3 patients and neutropenia in 16 (Castriota- Scandenberg & Sacco, 1997).
A metabolic balance study comparing combined urinary and fecal iron excretion in thalassemia patients receiving either 60 mg/kg DFO or 75 mg/kg DFP, mean iron excretion in DFP patients was only 65% of those on DFO. However, in some patients DFP was as effective as or better than DFO (Grady et al, 1996).
3.10 Deferiprone in Myelodysplasia
Deferiprone therapy in myelodysplasia (MDS), are quite similar to those in thalassemia patients: negative iron balance was achieved in 56% of patients, and the main causes of discontinuation of treatment were nausea and arthralgia (Kersten et al., 1996). An unexpected bonus of iron chelation therapy with deferiprone or Deferoxamine in MDS was a significant decrease in transfusion requirement and increased erythroid activity documented by serum transferrin receptor level, attributed to improved endogenous erythropoietin production (Jensen et al., 1996).
3.11 Deferiprone Safety Profile
Safety issue was a major concern of a drug for patients on long term therapy. Several factors are responsible for side effects of an iron chelator, including route of administration, iron removal from iron-dependent enzymes, removal of divalent cations such as zinc and calcium, body iron redistribution, and direct toxicity to tissue and organs. The safeties of DFP have been extensively evaluated over the last 15 years. Transient gastrointestinal symptoms (GI) such as nausea, vomiting, and abdominal pain, are the most frequently reported DFP-related adverse drug reactions. In a long-term prospective study, GI symptoms occurred overall in 33% of patients in the first year (Cohen et al 2003). Joint symptoms (pain and/or swelling) are the second most frequent ADR reported in 3.9%-20% of patients taking DFP (Al-Refaie 1995b; Olivieri et al 1995; Ceci et al 2002; Cohen et al 2003). Joint symptoms are sometimes mild/moderate but occasionally severe enough to warrant interruption of the drug, reduction of the dose, or discontinuation. Overall about 2% of the patients discontinued DFP because of joint symptoms. Fluctuating serum alanine aminotransferase (ALT) have been reported in about 7% of the patients particularly in the first months of treatment. Therefore, careful monitoring of ALT levels at regular intervals wass recommended and DFP interruption or dose reduction should be considered for patients with substantial and persistent increase of ALT (Al-Refaie et al., 1995b; Olivieri et al., 1995; Maggio et al., 2002; Cohen et al., 2003).
Deferiprone was associated with an increase in liver fibrosis in 5 out 14 patients (Olivieri et al., 1998). Studies conducted to evaluate liver histology changes during therapy with DFP showed no evidence of DFP-induced liver fibrosis (Hoffbrand et al., 1998; Piga et al., 1998; Galanello 1999). Reddish discolorations of urine due to excretion of the iron-deferiprone complex have been reported in DFP-treated patients. Uneventful pregnancies with healthy newborns have been reported, women of child bearing age should be counseled to avoid pregnancy while on therapy with DFP (Goudsmit and Jaeger et al., 1992; Kersten 1996; Gogtay and Agarwal 2002). DFP should be also avoided in breast feeding mothers. Agranulocytosis, absolute neutrophil count (ANC) less than 0.5 Ã- 109/L, was the most serious adverse effect of DFP. Milder episodes of neutropenia, ANC between 0.5 and 1.5 Ã- 109/L, have been reported in 3.6%-8.5% of the patients (Al-Refaie et al., 1995b; Ceci et al., 2002; Cohen et al., 2003). Milder neutropenia was usually reversible on discontinuation of the drug and usually resolves with interruption of DFP, but sometimes need faster recovery treatment with G-CSF (Filgrastim). Neutropenia occurs significantly more often in non-splenectomized patients and in association with viral infections (Cohen et al., 2000).
3.12 DFP and DFO Combination therapy
Combined use of deferoxamine and deferiprone was introduced into clinical practice in a small group of patients (Wonke et al., 1998) and offers several potential advantages. Combined therapy may achieve levels of iron excretion that cannot be achieved by either drug alone without loss of compliance and without increased toxicity (Hoffbrand et al., 2003). This approach was attractive for patients unable to comply with standard DFO infusions (5-7 per week) or with inadequate response to deferiprone alone. The efficacy of the combination of a low molecular weight chelating agent that was able to penetrate cells efficiently, with a high molecular weight chelating agent that was able to form a stable association with iron and thus achieve a satisfactory urinary iron excretion, have been shown in several clinical studies (Tanner et al., 2007; Kattamis et al., 2003). Combination therapy leads a reduction of plasma ferritin levels in patients in which monotherapy with deferiprone failed to produce a satisfactory outcome (Wonke et al., 1998) and shows an additive effect on the urinary excretion of iron (Kattamis et al., 2003). When compared with DFO monotherapy, combination therapy significantly improved myocardial T2* values, plasma ferritin levels, endothelial function (Tanner et al., 2007). These approaches have proven effective in the acute phase treatment of heart failure caused by iron overload (Porcu et al., 2007; Farmaki et al., 2006). The mortality due to cardiac damage was strongly reduced by combination therapy (Modell et al., 2008). Based on the above studies data showing that DFP may have a greater effect in removing cardiac iron than DFO combination therapy should be considered as an alternative to continuous intravenous DFO monotherapy.
Careful metabolic iron balance studies assessing the total (urinary and fecal) iron excretion have shown an additive effect when DFO and DFP were given sequentially and a synergistic effect, in some patients, when the drugs were given simultaneously (Grady et al., 2002). The hypothesis to explain the synergy was that the small DFP molecule acts as a shuttle mobilizing iron from intracellular compartments to the bloodstream, where DFP may exchange iron with the larger DFO molecule which has a higher affinity for iron. The effect of Glucose responses were improved during an oral glucose tolerance test, particularly in patients in early stages of glucose intolerance (Farmaki et al., 2006).
3.13 Deferiprone in Healthy Individual
A comparative pharmacokinetic study of deferiprone in healthy volunteers with & without ferrous sulphate to thalassemia patients was conducted. When deferiprone was given with ferrous sulphate to the 5 healthy volunteers on three separate days for 3 weeks, a 20% decrease in AUC of plasma iron and deferiprone was observed with no necessary excretion of iron; whereas increase in iron excretion was observed when deferiprone was given to thalassemia patients as they were beyond saturation of their iron binding capacity, comparative to healthy volunteers indicate that at levels below saturation transferrin did not allowed deferiprone to remove absorbed iron. Similarly, elimination half-life of deferiprone in thalassemia patients was found longer (137.65 Â± 48.65 min) than in normal volunteers (77.56 Â± 13 min). None of the other pharmacokinetic parameters were found different when compared between both groups (Stobie et al., 1993).
3.14 Deferiprone and Gender
A genotype-related pharmacokinetic study of deferiprone in healthy volunteers was conducted. The aim of the study was to examine the effects of UGT1A6, a gene that encodes a UDP-glucuronosyltransferase, an enzyme of deferiprone glucuronidation (Tukey, R.H. and Strassburg, C.P 2000) in healthy volunteers. A total of 24 overnight fasted volunteers were enrolled and grouped according to genotype. A single oral dose of 25mg/kg was received. UGT1A6 genotype was evaluated by PCR resistant fragment length polymorphism analysis. Result found no significant difference in any pharmacokinetic parameter & 24hr urinary excretion of both among genotype groups. Men & women show significant difference in AUC, volume of distribution and clearance of deferiprone. Therefore, it was concluded that UGT1A6 do not exert statistically significant pharmacokinetics effects while Gender appears to influence the serum pharmacokinetics of deferiprone, but not urinary excretion of deferiprone and its metabolite. Body iron stores may have an influence on the extent of extravascular deferiprone distribution (Limenta et al., 2008).
3.15 Deferiprone and Malaria
Each year one to two million people die from malaria, with half of these deaths occurring among children infected with the Plasmodium falciparum malaria parasite (Wyler 1992; WHO 2000). Cerebral malaria was the commonest fatal syndrome of P. falciparum malaria, with a mortality of 50% (WHO 2000). Death and sequelae occur even in people treated with antimalarial drugs, and researchers are exploring the effects of adding treatments to the main antimalarial regimens in an effort to reduce mortality. Iron chelation was one potential adjuvant treatment. The biological rationale for iron chelation was that malaria parasites require iron to reproduce, so drugs that withhold available iron from the malaria parasite could inhibit its reproduction rate (Wyler 1992; Mabeza 1996). Theory also suggests that iron-chelation therapy may accelerate coma recovery by inhibiting iron-induced damage to brain cells, thus protecting against damage to the central nervous system (Mabeza 1996).
Deferoxamine (DFO) was the standard iron-chelating agent while other iron-chelating agents are being considered also, such as the orally active deferiprone. However, before iron-chelating agents are used as adjuvant treatments for malaria, it is important to assess that their antimalarial action is complementary and not antagonistic to standard therapy. In vivo and in-vitro studies suggest that no reduction in asexual intra-erythrocytic parasite during or after deferiprone treatment, although its peak plasma concentration range was demonstrated to inhibit the growth of P.falciparum in-vitro but in-vivo growth was not predicted to inhibit (Thuma et al., 1998). Deferiprone seems to be a promising agent as an adjuvant in the treatment of severe P.falciparum malaria infection (Mohanty et al., 2002). Comparative study of deferiprone with standard antimalarial therapy suggest significantly faster in reducing coma recovery time and parasite clearance from blood but its clinical significance can assumed from long trial (Smith, H.J and M. Meremikwu, 2003).
3.16 Deferiprone and Fungal Infection
Mucormycosis was a common fungal infection with an unacceptably high mortality despite first-line antifungal therapy. Iron acquisition was a critical step in the causative organisms' pathogenetic mechanism (Ibrahim et al., 2008). Mucormycosis was a life-threatening infection caused by fungi of the class Zygomycetes. Rhizopus oryzae (Rhizopus arrhizus) was the most common cause of infection. Typical conditions predisposing patients to developing mucormycosis include diabetic ketoacidosis, neutropenia, corticosteroid therapy, broad spectrum antibiotics, severe malnutrition and breakdown of cutaneous barriers. Iron was required by virtually all microbial pathogens for growth and virulence (Spellberg et al., 2005). Rhizopus grows poorly in serum unless exogenous iron was added (Artis et al., 1982, Boelaert et al., 1993) and patients with elevated levels of serum iron are uniquely susceptible to infection by R. oryzae and other Zygomycetes, but not to other pathogenic fungi (Spellberg et al., 2005).
Deferoxamine acts as an iron chelator, Rhizopus possesses specific receptors for deferoxamine that enable the organism to bind to iron-deferoxamine complexes, liberate the iron via an energy-mediated reductive process and then take up the iron (Boelaert et al., 1993). Patients with diabetic ketoacidosis are also at high risk of developing rhinocerebral mucormycosis (Spellberg et al., 2005). These patients also have elevated levels of available serum iron, likely due to release of iron from binding proteins in the presence of acidosis (Artis et al., 1982). Because elevated serum iron was integral for the virulence of mucormycosis, the use of an iron chelator that cannot be utilized by the fungus to scavenge iron from the host should prove to be efficacious against these infections.
Deferiprone an oral iron chelator, in contrast to Deferoxamine cannot be utilized by R. oryzae as a xenosiderophore (Boelaert et al., 1994). Efficacy of deferiprone compared with that of liposomal amphotericin B in treating mucormycosis in diabetic ketoacidotic (DKA) mouse model and found that deferiprone was an effective therapy for mucormycosis in the DKA mouse model. Iron chelation was a promising, novel therapeutic strategy for refractory mucormycosis infections. These findings suggest the need for further experimental and clinical studies evaluating the usefulness of iron-chelation therapy in combination with antifungals for the treatment of mucormycosis (Ibrahim et al., 2006).
3.17 Deferiprone as Anti-Oxidant
Free radical formation was initiated from metal catalytic centers involving iron and copper. Free radical reactions can lead to oxidative stress, which can cause biomolecular, cellular and tissue damage. Deferiprone have been shown to be effective and safe in the reversal of oxidative stress related tissue damage in iron loading and non-iron loading conditions (Kontoghiorghes, G.J, 2009). Deferiprone can be used as a potent pharmaceutical antioxidant by mobilizing labile iron and copper and/or inhibiting their catalytic activity. The high therapeutic index, tissue penetration, rapid iron binding and clearance of the iron complex, and the low toxicity of deferiprone, support its application as an antioxidant for adjuvant, alternative or main therapy, especially in conditions where other treatments have failed (Kontoghiorghes et al., 2009).
Iron-mediated carcinogenesis occurs through generation of oxygen radicals. Iron-catalyzed oxidative DNA damage was studied in iron-loaded hepatic cells and was found to greatly exacerbate hydrogen peroxide-mediated DNA damage. It was also found that maintained deferiprone incubation with hydrogen peroxide, deferiprone exert a protective effect which shows that deferiprone was highly dependent on the deferiprone: iron ratio. Therefore, in-vitro studies suggest that deferiprone: iron ration must be at least 3:1 for deferiprone to inhibit generation of free radicals because at lower concentration increased oxygen radical generation occurs and may lead to long-term toxicities that might preclude administration of deferiprone as iron chelator (Cragg et al., 1998).
3.18 Deferiprone as Neuroprotective
Alzheimer's disease (AD) and Parkinson's disease (PD) was a common neurodegenerative disorder associated with elevated soluble and aggregated forms of amyloid beta (Ab) and with oxidative stress (Francisco et al., 2008). Both of these metabolic alterations seem to be associated with the involvement of metal ions, particularly iron (Zecca et al., 2004; Gaeta and Hider 2005; Mandel et al. 2007). Neurodegenerative disorders are directly linked to oxidative stress (lipid peroxidation, protein oxidation, DNA and RNA oxidation), which increases in the brain with age and plays a central role in neurodegeneration (Halliwell 2006). Oxidative stress may be defined as an imbalance between the production of free radicals and the ability of the cell to defend against them through a set of antioxidants and detoxifying enzymes that include superoxide dismutase, catalase and glutathione. When this imbalance occurs, oxidatively modified molecules accumulate in the cellular compartment causing dysfunction (Floyd and Hensley 2002). Therefore, if amyloid beta (Ab) synthesis was modulated by stress conditions, Ab production can lead to increased oxidative stress in the brain, apart from being itself a potential source of additional oxidation processes (Bush 2002). H2O2 was a reactive species, in the presence of redox-active metal ions producing OHÂ· radicals (Gaeta and Hider 2005). Redox active iron (II) was localized in the endoplasmic reticulum, lipofuscin as well as in their associated vacuoles (Brunk et al. 1992). Lipofuscin was an auto fluorescent pigment that accumulates in AD and release iron from damaged mitochondria, which becomes an important generator of H2O2, thus causing an oxidative damage (Brunk and Terman 2002). The accumulation of metals in AD brains as well as the presence of a metal-binding site on Ab represents promising pharmacological targets.
Therefore, compounds with chelation properties, and also with the ability to block the site, prevent the adverse generation of H2O2 (Adlard and Bush 2006). Iron chelation was a potential therapeutic approach in AD (Adlard and Bush 2006; Mandel et al. 2007), as the metal may represent a target for therapeutic agents directed towards the treatment of neurodegeneration.
Deferiprone have therapeutic potential in neurodegenration using in-vitro model of mouse cortical neurons. The study demonstrates that chelation of iron by deferiprone was neuroprotective and reversed the FeNTA (ferric nitrilotriacetate) induced death of cortical neurons in concentration dependent manner; and confer neuroprotection against Abeta1-40 induced neuronal cell death (Mollina et al., 2008).
3.19 Deferiprone and HIV
Eukaryotic translation initiation factor eIF5A have been implicated in HIV-1 replication. This protein contains the unique amino acid hypusine that was formed by the post-translational modification of a lysine residue catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase (DOHH). DOHH activity was inhibited by two clinically used drugs, the topical fungicide ciclopirox and the systemic medicinal iron chelator deferiprone. Deferiprone have been reported to inhibit HIV-1 replication in tissue culture.
Deferiprone blocked HIV-1 replication in PBMCs. The action of the drugs on eIF5A modification and HIV-1 gene expression in model systems was studied. At early times after drug exposure, both drugs inhibited substrate binding to DOHH and prevented the formation of mature eIF5A. Viral gene expression from HIV-1 molecular clones was suppressed at the RNA level independently of all viral genes. The inhibition was specific for the viral promoter and occurred at the level of HIV-1 transcription initiation. Partial knockdown of eIF5A-1 by siRNA led to inhibition of HIV-1 gene expression that was non-additive with drug action. At clinically relevant concentrations, two widely used drugs blocked HIV-1 replication ex vivo. They specifically inhibited expression from the HIV-1 promoter at the level of transcription initiation. Both drugs interfered with the hydroxylation step in the hypusine modification of eIF5A (Hoque et al., 2009).
3.20 Deferiprone Compliance
The main problem with iron chelation therapy was compliance to regular subcutaneous infusions of Deferoxamine. They are unpopular and are often resisted by patients (Yardumian et al., 2005). The infusions are time consuming to set up, they are painful, requiring the introduction of a subcutaneous needle on each occasion which can be distressing, followed by continuous attachment to an infuser device for 10-12 hours. Therefore, alternate therapy was by introducing oral deferiprone reduce the weekly number of Deferoxamine infusions. The effectiveness of alternating treatment was initially reported in a small non-controlled study (Aydinok et al., 1999). A prospective, randomized controlled trial on the safety and efficacy of alternating DFO and DFP have been reported. In this study 60 patients with thalassemia major regularly transfused, were randomized either to continue the standard therapy with Deferoxamine at 30-40 mg/kg/day for 5-7 days per week, or to receive an alternating regimen of Deferiprone 75 mg/kg body weight, divided into 3 doses 5 days a week and DFO (30-40 mg/kg/day) the other 2 days of the week. After 1 year of treatment both regimen resulted in equivalent decreases of serum ferritin and liver iron concentration (Galanello et al., 2006b).
Overall the alternating use of both chelators was not associated with increased toxicity and no significant difference was observed in the proportion of patients with adverse events in the two therapy groups, although the nature of the adverse events differed according to the chelation regimen.
3.21 Deferiprone Cost Compliance
Deferoxamine remains the drug of choice for the management of transfusional thalassemia patients. However, its high cost and the inconvenience of its parenteral administration by portable pumps are major limitations underlying the need for developing alternative orally effective new iron chelating drugs (Hider et al., 1996). Costs are approximate and are based on an average body weight of 54 kg, which have been suggested as the mean patient weight for patients needing iron chelation therapy (Karnon et al., 2006). Cost of Deferoxamine was relatively low but additional costs may be incurred e.g. home care delivery or nurse services and infuser device used may significantly affect cost effectiveness. The total annual costs per patient of infused iron chelation therapy in the UK have been estimated as £17,913 (Desrosiers et al., 2006). A cost utility analysis study conducted and has estimated the resource use and costs for equipment for Deferoxamine treatment to be £7,552 annually per patient (Karnon et al., 2006).
Automated RBC exchange costs about £10,000 per patient/year and this would cost <£5,000 per year but result in rapid iron loading in the absence of chelation. An acceptable oral chelator would enable patients to switch from red blood cell exchange to simple transfusion; saving £5,000 per case would offset any additional cost incurred from prescribing deferasirox (Dr David Bevan, 2007). The costs of regular laboratory monitoring of liver and renal function will also need to be taken into account. These may be higher in patients taking deferoxamine.
The FDA has not yet approved deferiprone, depriving thousands of patients of potentially life-saving treatment. The high cost of DFRA at 60 euros/g, DFP at 5.5 euros/g and DFO at 8.3 euros/g, diminishes the prospects of universal chelation therapy, especially for patients in developing countries. The safety and efficacy record of DFO and their combination appear to provide universal solutions in the treatment of transfusional iron overload, and also in reducing mortality because of their ability to clear rapidly and effectively excess cardiac iron (Kontoghiorghes, G.J. 2008).
Deferiprone appears to be strongly knocking the doors of iron chelation therapy. It was a cheap, easy to manufacture, effective and reasonably safe oral iron chelator. Only occasional patients cannot benefit from its use as they suffer from skeletomuscular pain or myelotoxicity. Such unfortunate individuals have to resort back to expensive and inconvenient Deferoxamine therapy. The available data appear to demonstrate that DFP was an effective oral iron chelator able to reduce iron overload and to maintain a safe body iron level. Moreover, deferiprone alone or in combination with DFO seems to be superior to DFO monotherapy in improving myocardial siderosis and cardiac function. The safeties of DFP have been extensively evaluated over the last 10 years. The relatively large number of patients and the extended period of intensive follow-up provide a detailed long-term safety profile. In general, adverse drug reactions with Deferiprone are predictable and the risk manageable provided a continuous and careful monitoring of the patients.
Therefore, deferiprone should be introduced as an alternative treatment to Deferoxamine whenever the patient has a choice between no chelation versus deferiprone. DFP have the ability to improve the quality of life of patients receiving life-long transfusions.