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PubMed2006

Physical growth patterns and dental caries in thalassemia.

This study was conducted to assess the effect of age, ferritin level, hemoglobin level and chelating agents on the physical growth in thalassemic children and to determine the prevalence of dental caries in thalassemic children. Weight, standing height, sitting height and subischial leg length were measured in 65 children attending the Thalassemia day care center at a tertiary hospital in Delhi. Their mean pre transfusion hemoglobin and ferritin levels over the previous two years were calculated. Dental caries indices, DMFT and DMFS were measured and compared with age matched controls. Weight, standing height, sitting height and subischial leg length expressed as percentage for age in children >or=10 y were significantly lower than those of children < 6 y, and those 6 to 10 y. Mean hemoglobin and ferritin did not affect growth significantly. Sitting height for age in children receiving Desferrioxamine alone or Desferrioxamine with Deferiprone was significantly lower than that of children receiving Deferiprone alone or no chelating agent. Dental caries were significantly higher in thalassemics.

Adolescent↗
PubMedDate not supplied

Iron transport and subcellular distribution in Hep G2 hepatocarcinoma cells.

Thalassemic patients with iron overload are presently treated with deferoxamine or the experimental chelator deferiprone. To understand how these agents remove iron from the liver, cultured human hepatoma cells loaded with iron were previously used as a model for hepatic iron overload. The present study was undertaken to characterize further the pathways of iron transport and distribution in these cells. The activation energy for Fe2+ transport is 19 kJ/mol greater than for Fe3+, and the rate of Fe2+ transport--but not that of Fe3(+)--decreases with temperature above 25 degrees C, suggesting distinct uptake processes for different redox states of iron. Iron loading, which promotes a greater rate of Fe3+ transport, also caused a proportionally greater deposition of iron in the microsomal and cytosolic compartments and specifically lowered the activities of succinate-cytochrome c reductase and 5'-nucleotidase, representative markers of the mitochondria and plasma membrane, respectively. Both deferiprone and deferoxamine decreased total cellular iron and iron in each fraction except cytosol, indicating mobilization of iron for clearance from the cell via the cytosol. This model may be useful in characterizing the determinants of effective chelation in patients.

5'-Nucleotidase↗
PubMed2002

The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro.

The hypusine biosynthetic steps represent novel targets for intervention in cell proliferation. Hypusine is a rare amino acid, formed posttranslationally in one cellular protein, eIF5A, and is essential for cell proliferation. Deoxyhypusine hydroxylase, the metalloenzyme catalyzing the final step in hypusine biosynthesis, and prolyl 4-hydroxylase, a non-heme iron enzyme critical for collagen processing, can be inhibited by small chelating molecules that target their essential metal atom. We examined the effects of 5 compounds (ciclopirox, deferiprone, deferoxamine, mimosine and 2,2'-dipyridyl) on these protein hydroxylases in HUVECs, on cell proliferation and on angiogenesis using 2 model assays: tube-like vessel formation on Matrigel and the chick aortic arch sprouting assay. These compounds inhibited cellular deoxyhypusine hydroxylase in a concentration-dependent manner, but their efficacy varied widely in the following order: ciclopirox--> deferoxamine-->2,2'-dipyridyl-->deferiprone-->mimosine (IC(50) 5-200 microM). Inhibition of DNA synthesis, following the same order (IC(50) 10-450 microM), correlated with G(1) arrest of the cell cycle. These compounds also inhibited proline hydroxylation and maturation of collagen in HUVECs and caused inhibition of angiogenesis in vitro. Of the compounds tested, ciclopirox was by far the most effective inhibitor of HUVEC proliferation and angiogenesis. The strong antiangiogenic activity of this readily available antifungal drug along with its antiproliferative effects suggests a new potential application for ciclopirox in the treatment of solid tumors.

Antifungal Agents↗
PubMed2006

Transport kinetics of iron chelators and their chelates in Caco-2 cells.

PURPOSE: Caco-2 monolayers were used to contrast the bidirectional transport of iron chelators and their chelates and to estimate fundamental kinetics associated with their intestinal absorption. METHODS: Bidirectional transport was studied at 37 degrees C and pH 7.4 using 500-microM concentrations. Monolayer integrity was tested via transepithelial electrical resistance and sodium fluorescein permeability. Apical and basolateral analysis provided mass balance evidence. Apparent permeability coefficient (P(app)) served to rank and compare molecules and estimate in vivo bioavailability. Model-dependent rate constants defined cellular influx and efflux. RESULTS: 1) P(app) ranked in decreasing order for chelators from directional transport studies were CP363 > deferiprone> ICL670 > CP502 > deferoxamine (DFO). 2) Fe(CP502)(3), Fe(ICL670)(2), and FeDFO were not measurable in receiving chambers, whereas Fe(deferiprone)(3) and Fe(CP363)(3) were detected in both directions. 3) CP363 was transported significantly faster from the basolateral to the apical direction than the converse. 4) Mass balance of donor and receiver chambers gave approximately 100% recovery in all cases. 5) Kinetic analysis supports the view that the Caco-2 chelator efflux constants are generally greater than their influx constants. CONCLUSIONS: Caco-2 cells are useful in screening iron chelators and chelates and estimating bioavailabilities. Structure and distribution coefficients partially predict passive transport through Caco-2 monolayers.

Algorithms↗
PubMed2002

Iron regulation of hepatic macrophage TNFalpha expression.

Sustained TNFalpha induction is central to the pathogenesis of chronic liver disease including alcoholic liver disease (ALD). However, molecular understanding of this abnormality at the cellular level remains elusive. Redox regulation of NF-kappaB is critical in the transcriptional control of TNFalpha expression. Evidence supports that increased iron storage in hepatic macrophages (HM) is causally associated with accentuated and sustained NF-kappaB activation in these cells in ALD. Treatment of cultured HM with a lipophilic iron chelator (deferiprone) abrogates LPS-induced NF-kappaB activation. HM from an animal model of ALD have increased nonheme iron content accompanied by increased generation of EPR-detected radicals, NF-kappaB activation, and TNFalpha induction, all of which are normalized by ex vivo treatment of the cells with deferiprone. A moderate increase in the nonheme iron content in HM by erythrophagocytosis, promotes subsequent LPS-stimulated NF-kappaB activation in a hemeoxygenase-dependent manner. Recent evidence also suggests a role of intracellular low molecular weight iron in the early signal transduction for LPS-mediated NF-kappaB activation.

Animals↗
PubMed2004

Iron-chelation therapy: an update.

Chronically transfused patients develop iron overload that leads to organ damage and ultimately to death. The introduction of the iron-chelating agent, desferrioxamine mesylate, dramatically improved the life expectancy of these patients. However, the very demanding nature of this treatment (subcutaneous continuous infusion via a battery-operated portable pump) has been the motivation for attempts to develop alternative forms of treatment that would facilitate the patients' compliance. In this review, we describe the most important advances in iron-chelating therapy. In particular, we analyze a new method of administering desferrioxamine mesylate (twice daily subcutaneous bolus injections) and a novel, orally active iron chelator (ICL670A). We also present a meta-analysis of the largest trials on the oral iron chelator deferiprone and the results of combined therapy (deferiprone and desferrioxamine).

Clinical Trials as Topic↗
PubMed2006

Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences.

Labile iron in hemosiderotic plasma and tissue are sources of iron toxicity. We compared the iron chelators deferoxamine, deferiprone, and deferasirox as scavengers of labile iron in plasma and cardiomyocytes at therapeutic concentrations. This comprised chelation of labile plasma iron (LPI) in samples from thalassemia patients; extraction of total cellular iron; accessing labile iron accumulated in organelles and preventing formation of reactive-oxidant species; and restoring impaired cardiac contractility. Neonatal rat cardiomyocytes were used for monitoring chelator extraction of LCI (labile cell iron) as 59Fe; assessing in situ cell iron chelation by epifluorescence microscope imaging using novel fluorescent sensors for iron and reactive oxygen species (ROS) selectively targeted to organelles, and monitoring contractility by time-lapse microscopy. At plasma concentrations attained therapeutically, all 3 chelators eliminated LPI but the orally active chelators rapidly gained access to the LCI pools of cardiomyocytes, bound labile iron, attenuated ROS formation, extracted accumulated iron, and restored contractility impaired by iron overload. The effect of deferoxamine at therapeutically relevant concentrations was primarily by elimination of LPI. The rapid accessibility of the oral chelators deferasirox and deferiprone to intracellular labile iron compartments renders them potentially efficacious for protection from and possibly reversal of cardiac damage induced by iron overload.

Animals↗
PubMed2003

Emerging understanding of the advantage of small molecules such as hydroxypyridinones in the treatment of iron overload.

Deferiprone, a hydroxypyridin-4-one, is effective at facilitating iron removal from iron overloaded patients, when administered orally. Some problems associated with deferiprone are discussed. Hydroxypyridinone analogues with improved distribution, metabolism and affinity for iron are described. In particular the "high pFe(3+)" hydroxypyridin-4-ones possess considerable clinical potential.

Animals↗
PubMed1997

Iron-chelating therapy and the treatment of thalassemia.

Iron-chelating therapy with deferoxamine in patients with thalassemia major has dramatically altered the prognosis of this previously fatal disease. The successes achieved with deferoxamine, as well as the limitations of this treatment, have stimulated the design of alternative strategies of iron-chelating therapy, including orally active iron chelators. The development of the most promising of these, deferiprone, has progressed rapidly over the last 5 years; data from several trials have provided direct and supportive evidence for its short-term efficacy. At the same time, the toxicity of this agent mandates a careful evaluation of the balance between risk and benefit of deferiprone in patients with thalassemia, in most of whom long-term deferoxamine is safe and efficacious therapy.

Animals↗
PubMed1997

Effect of nitric oxide on iron-mediated oxidative stress in primary rat hepatocyte culture.

An iron-mediated oxidative stress caused by an increase of the intracellular pool of low molecular weight complex of iron (LMWC) can be observed with iron overloading or ethanol metabolism. The aim of this study was to determine whether nitric oxide (NO) behaved as a pro-oxidant or an antioxidant in such an iron-mediated oxidative stress in rat hepatocytes. The cells were set up in primary cultures and incubated with lipopolysaccharide (LPS) and gamma-interferon (IFN) for 18 hours to induce NO synthase and to trigger NO production. Then 20 micromol/L iron or 50 mmol/L ethanol were added. Oxidative stress was evaluated by measuring lipoperoxidation using two markers: malondialdehyde (MDA) and conjugated dienes. Simultaneously, NO production was followed by the quantitation of nitrites in the culture medium, dinitrosyl iron complexes (DNICs) and mononitrosyl iron complexes (MNICs) in intact hepatocytes. DNIC and MNIC, evaluated by electron paramagnetic resonance (EPR), corresponded to NO bound to iron-containing molecules and to free NO, respectively. In cultures preincubated with LPS and IFN before iron or ethanol addition, a net decrease of lipid peroxidation induced by either NO, iron, or ethanol was noted. Moreover, an elevation of iron-bound NO and a decrease of free NO were observed in these cultures compared with the cultures incubated with only LPS and IFN. These data support the idea that there is a relationship between the changes of NO pool and the inhibition of oxidative stress. In addition, using N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, NO was shown to be involved in the inhibition of oxidative stress induced by iron or ethanol. Addition of the chelator of LMWC iron, deferiprone, was followed by the inhibition of the increase of iron-bound NO and the reincrease of lipid peroxidation extent, which was as high as in cultures incubated only with LPS and IFN. Thus LMWC iron appeared to be involved also in the inhibition of oxidative stress induced by NO. All the results favor the conclusion that NO acts as an antioxidant in iron-mediated oxidative stress in rat hepatocytes. NO reacted with LMWC iron to form inactive iron complexes unable to induce oxidative stress in rat hepatocytes. Thus NO played a critical role in protecting the liver from oxidative stress.

Animals↗
PubMedDate not supplied

Present status and future prospects of oral iron chelation therapy in thalassaemia and other diseases.

In the last few years we have witnessed the emergence of oral chelation which is a new form of therapy for transfusional iron-loaded patients in thalassaemia and other refractory anaemias. The need for a cheap, non-toxic, orally effective iron chelator is paramount because it could potentially save the lives of many thousands of patients. At present, less than 10% of the patients requiring iron chelation therapy worldwide receive the widely used chelating drug desferrioxamine (DF) because of its high cost, oral inactivity and toxicity. The most promising oral iron chelator is 1, 2-dimethyl-3-hydroxypyrid-4-one (L1 or INN: Deferiprone), which has so far been taken by over 450 patients in 15 countries, and in some cases daily for over 4 years with very promising results. L1 was shown at 50-100 mg/kg/day to be effective in bringing patients to negative iron balance. It increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in multi-transfused iron-loaded patients. Toxic side effects were mainly encountered at high doses (80-100 mg/kg/day) and include transient agranulocytosis (5 cases), transient musculoskeletal and joint pains (10-20%), gastric intolerance (2-6%) and zinc deficiency (1%). The incidence of these toxic side effects was reduced by using lower doses of 50-75 mg/kg/day. The overall efficacy and toxicity of L1 is comparable to that of DF in animals and humans. Further work is required for identifying susceptible individuals to L1 toxicity, and also optimum dose protocols of L1 which can maximise iron excretion and minimise the incidence of toxic side effects.

Animals↗
PubMed2004

Bone mass and metabolism in thalassemic children and adolescents treated with different iron-chelating drugs.

We evaluated bone mineral density (BMD) and bone turnover in 22 homozygous prepubertal beta-thalassemic patients treated with desferrioxamine. Ten patients underwent treatment with desferrioxamine for the whole study period, while 12 patients stopped desferrioxamine and were then treated with deferiprone (L1). Lumbar and femoral BMD and bone metabolism markers were examined at baseline and after 1 and 3 years of follow up. All patients were prepubertal at baseline and they all became pubertal over the 3 years of follow up. At baseline, the mean lumbar Z score value was -2.048 SD +/- 0.75; the Z score was less than -2 SD in 13 children, within -1 and -2 SD in 6, and within 0 and -1 SD in only 3 subjects. A significant BMD increase (P < 0.0001) was observed at both the lumbar (+8.466%/year) and the femoral level (average of +3.46%/year at neck and +5.83%/year at the intertrochanteric region) after 3 years, without any significant difference being shown between patients treated with desferrioxamine and those treated with L1. The mean Z score SD values increased to -1.957 +/- 0.975 at 1 year (not significantly different from baseline) and to -1.864 +/- 1.221 at 3 year follow up (P < 0.05 vs baseline); an increase in bone turnover was also observed. These findings show that low BMD, a hallmark of beta-thalassemia, improves significantly when puberty begins; this increase involves different skeletal sites, regardless of pharmacological treatment with different iron-chelating drugs.

Adolescent↗
PubMed2005

Bifunctional 3-hydroxy-4-pyridinone derivatives as potential pharmaceuticals: synthesis, complexation with Fe(III), Al(III) and Ga(III) and in vivo evaluation with 67Ga.

A series of extra-functionalized 3-hydroxy-4-pyridinone chelators of hard metal ions, containing different side-chains with peptidomimetic groups, was studied to assess the effect of those groups on the physico-chemical properties, the metal-chelating affinity and the in vivo behaviour of the compounds, in view of their potential pharmaceutical applications. Besides the synthesis of the chelators, the study of their properties in aqueous solution alone and in the presence of M (3+) (M = Fe, Ga and Al) was performed by potentiometric/spectroscopic techniques. The octanol/water partition coefficient values of these hydroxypyridinone derivatives cover ca. 3 orders of magnitude (1.1 > log P > -2). They all form very stable tris-chelated M(III) complexes, the pFe and pGa values ranging up to five orders of magnitude. The in vivo studies showed the effect of the ligands on the biodistribution of (67)Ga citrate and also of (67)Ga-complexes in mice, in view of the potential use of the ligands or complexes as metal decorporating or as imaging agents, respectively. Although almost all these peptidomimetic hydroxypyridinone derivatives present very rapid clearance rate from most organs, the L-ornithine derivative (H(2)L(9)) shows to be superior to the others and as good as Deferiprone as metal decontaminant of Ga. Concerning the (67)Ga complexes, the benzyl-propylamine (H(2)L(3)) shows considerable bone retention, thus suggesting its potential application as imaging agent.

Aluminum↗
PubMed1996

The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethly-, 1,2 diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat.

The 3-hydroxypyridin-4-ones (HPs) are iron and aluminum chelators. Their ability to enter the brain had not previously been directly determined. To determine whether they cross the blood-brain barrier (BBB), three HPs possessing a wide range of lipophilicity were examined: 1-[ethan-1'ol]-2-methyl-HP (CP40), 1,2-dimethyl-HP (CP20, L1, deferiprone), and 1,2-dimethyl-HP (CP94, EL1NEt). Their pharmacokinetics were determined in rats to establish dosing parameters for microdialysis studies of BBB permeation. Studies were then conducted with microdialysis probes in the blood, frontal cortex, and lateral ventricle to determine the rate and extent of HP BBB permeability. All three HPs were detectable in brain dialysate samples collected 0-7 min after HP injection, demonstrating rapid entry into the brain. The extent of unbound distribution (an indicator of the mechanism of BBB permeation) was 0.9 and 1.2 for the frontal cortex and lateral ventricle for CP20, and was 1.1 and 1.6 for CP94, suggesting diffusion across the BBB. The extent of unbound distribution of CP40 was 0.2 for both the frontal cortex and lateral ventricle, suggesting the presence of a transporter moving it out of brain extracellular fluid. Introduction of cyanide into the brain did not affect the brain to blood CP40 ratio, suggesting that the transporter is not energy-dependent. Both CP94 and CP40 caused death due to respiratory failure, whereas CP20 did not. The ability of less toxic bidentate HP chelators, such as CP20, to enter the brain may enable their use in the treatment of metal-induced diseases and iron-facilitated oxidative injury involving the central nervous system.

Animals↗
PubMed2004

PCTH: a novel orally active chelator of the aroylhydrazone class that induces iron excretion from mice.

beta-Thalassaemia major is an inherited blood disorder which is complicated by repeated blood transfusion and excessive gastrointestinal iron (Fe) absorption, which leads to toxic Fe overload. Current treatment using the chelator, desferrioxamine (DFO), is expensive and cumbersome since the drug requires long subcutaneous infusions and it is not orally active. A novel chelator, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH), was recently designed and shown to have high Fe chelation efficacy in vitro. The aim of this investigation was to examine the Fe chelation efficacy of PCTH in vitro implementing primary cultures of cardiomyocytes and in vivo using mice. We showed that PCTH was significantly (P<0.005) more effective than DFO at mobilising (59)Fe from prelabelled cardiomyocytes. Moreover, PCTH prevented the incorporation of (59)Fe into ferritin during Fe uptake from (59)Fe-labelled transferrin. These effects were important to assess as cardiac complications caused by Fe deposition are a major cause of death in beta-thalassaemia major patients. Further studies showed that PCTH was orally active and well tolerated by mice at doses ranging from 50 to 200 mg/kg, twice daily (bd), for 2 days. A dose-dependent increase in faecal (59)Fe excretion was observed in the PCTH-treated group. This level of Fe excretion at 200 mg/kg was similar to the same dose of the orally effective chelators, pyridoxal isonicotinoyl hydrazone (PIH) and deferiprone (L1). Effective Fe chelation in the liver by PCTH was shown via its ability to reduce ferritin-(59)Fe accumulation. Mice treated for 3 weeks with PCTH at doses of 50 and 100 mg/kg/bd showed no overt signs of toxicity as determined by weight loss and a range of biochemical and haematological indices. In subchronic Fe excretion studies over 3 weeks, PIH and PCTH at 75 mg/kg/bd for 5 days/week increased faecal (59)Fe excretion to 140% and 145% of the vehicle control, respectively. This study showed that PCTH was well tolerated at 100 mg/kg/bd and induced considerable Fe excretion by the oral route, suggesting its potential as a candidate to replace DFO.

Administration, Oral↗
PubMed2004

Iron mobilization, cytoprotection, and inhibition of cell proliferation in normal and transformed rat hepatocyte cultures by the hydroxypyridinone CP411, compared to CP20: a biological and physicochemical study.

The present study analyzes the iron mobilization, the cytoprotective, and the antiproliferative effects of the lipophilic hydroxypyridinone CP411, in comparison with the hydrophilic chelator CP20 or deferiprone used in the treatment of iron overload. Primary rat hepatocyte cultures and the rat hepatoma cell line Fao were used. Chelator cell uptake was evaluated by mass spectrometry in the two models. This method was also used to investigate the stability of the chelators in an acellular system as well as their scavenging and chelating effects against the hydroxyl radical generated by the Fenton reaction. The iron mobilization and the cytoprotective effects of the chelators were evaluated in primary cultures by measuring respectively 55Fe and lactate dehydrogenase release in the culture medium. The antiproliferative effect of the chelators was studied using the Fao cell line and measuring DNA synthesis by thymidine incorporation and DNA content by flow cytometry. We observed that CP411 entered the hepatocytes and the Fao cells respectively 4 and 13 times more than CP20. CP411 was 2.5 times more effective than CP20 to mobilize iron from preloaded hepatocytes. Pretreatment of the hepatocytes with CP20 or CP411 decreased the toxic effect of iron and CP411 was 1.6 times more effective than CP20. A dose-dependent decrease of DNA synthesis, correlated to an accumulation of cells in S phase, was observed in the Fao cell line in the presence of CP411, while CP20 was without effect. CP411 effect was inhibited by addition of iron simultaneously with the chelator, the addition of Zn or Cu was without effect. The inhibitory effect of CP411 was reversible since, 24hr after removal of the chelator, DNA replication reached the control level. The results show that CP411 is more efficient to protect the hepatocyte from the toxic effect of iron load and to inhibit tumor cell proliferation. Its higher efficiency may result from its better cell uptake since equimolar solutions of the two chelators in an acellular system exhibit the same ability to inhibit the Fenton reaction.

Animals↗
PubMed2005

LPI-labile plasma iron in iron overload.

Labile plasma iron (LPI) represents a component of non-transferrin-bound iron (NTBI) that is both redox-active and chelatable, capable of permeating into organs and inducing tissue iron overload. It appears in various types of hemosiderosis (transfusional and non-transfusional) and in other iron-overload conditions. Sustained levels of LPI could over time compromise organ (e.g. heart) function and patient survival. With the advent of methods for measuring LPI in the clinical setting, it has become possible to assess the implications of LPI in the management of iron overload based on regimens of iron chelation. As LPI is detected primarily in patients with transfusional iron overload and other forms of hemosiderosis, we review here regimens of iron chelation with deferrioxamine and deferiprone (separately or combined) in terms of their efficacy in minimizing daily exposure to LPI in thalassemia major and thalassemia intermedia patients.

Deferiprone↗
PubMed2006

Evolution of OGTT in patients with beta-thalassaemia major in relation to chelation therapy.

Glucose metabolism disturbances are frequently reported among patients with beta-thalassaemia major on conventional treatment consisted of regular blood transfusions and adequate chelation treatment. Aim of this study was to evaluate the evolution of oral glucose tolerance test (OGTT) in thalassaemic patients in relation to their chelation treatment. Data from two OGTTs performed with an interval of 2 years were studied retrospectively. Patients considered eligible for this study were those who maintained unchanged chelation treatment and did not receive any anti-diabetic agent during the last 2 years. Thirty-one patients (16 M and 15 F) were enrolled with a mean age of 23.73+/-4.23 years at the end of the study. Patients were divided into three groups concerning chelation treatment. First group was receiving deferoxamine (DFO) by an 8-hourly subcutaneous infusion five-six times a week, second group was chelated with deferiprone (DFP) at a daily dose of 75 mg/kg orally and the third group was receiving combined therapy with DFO (3 days/week) and DFP (daily). At the time of the first OGTT, 26 patients (84%) were found to have normal OGTT; three of them showed an impaired glucose tolerance during second test (one was chelated with DFP and two were receiving combined therapy). None of the five patients with impaired glucose metabolism during the first test became diabetic. On contrary, one patient receiving combined therapy managed to normalize his second OGTT. In contrast with the overall trend of a deteriorating glucose tolerance in the whole patient series, the group receiving combined therapy managed to increased beta-cell function index and decreased insulin resistance index, although not statistically significant when compared to other groups. Further studies are needed to support these preliminary results.

Adolescent↗