Dose Response of Deferoxamine, Deferiprone, and ICL670 Chelation Therapy in a Gerbil Model of Iron Overload.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3621-3621 ◽  
Author(s):  
John C. Wood ◽  
Maya Otto-Duessel ◽  
Michelle Aguilar ◽  
Hanspeter Nick ◽  
Thomas D. Coates ◽  
...  
Keyword(s):  
Dose Response ◽  
Iron Content ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Loss ◽  
Iron Dextran ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Iron Excretion ◽  
Iron Concentrations

Abstract Introduction: The Mongolian gerbil mimics many of the cardiac functional impairments observed in iron cardiomyopathy, however relatively few chelation studies have been performed in this model. The purpose of this study was to characterize the dose-response of deferoxamine, ICL670, and deferiprone (L1) with respect to liver and cardiac iron chelation in the gerbil Methods: Thirty three adult Mongolian gerbils underwent subcutaneous iron dextran loading with 1500 mg/kg iron dextran divided into three, weekly doses. Chelation began at 4 weeks and continued for 4 weeks. Animals were divided into 9 treatment groups of three animals each(DFO 50, 100, and 200 mg/kg/day (subQ BID), ICL670 25, 50, and 100 mg/kg/day(PO QD), and L1 125, 250, and 500 mg/kg/day(PO TID), 5 days per week). Three control animals were sacrificed at 4 weeks and 8 weeks to estimate sponatenous iron loss. Histology and quantitative iron were performed in all animals. Results: Iron loading yielded liver iron concentrations of 26.6±3.8 mg/g(dry wt) and cardiac iron concentrations of 3.7±0.5 mg/g(dry wt) at 4 weeks (normal < .5 mg/g for both organs). However, organ iron content fell 6.4% in liver and 8.9% in heart per week in animals without chelation therapy, reflecting high spontaneous iron excretion. All three chelators exhibited significant dose-responsiveness for liver iron elimination. However, only ICL670 chelation at 100 mg/kg reduced liver iron content greater than for controls. In fact, animals treated with low dose L1 and DFO had higher iron levels than controls, probably by interfering with spontaneous iron elimination. None of the agents chelated the heart effectively. In fact, 88% of the L1 group, 56% of the ICL670 group and 22% of the DFO group had cardiac iron levels outside the normal range predicted from the 8 wk control animals. Conclusion: Iron chelation in the gerbil model requires doses nearly 3.6 fold greater than in humans to produce discernable iron loss above background iron excretion in short-term studies. Subtherapeutic dosing may actually increase iron levels relative to control animals by decreasing spontaneous iron excretion. Groupwise Iron Concentration and Content HIC(mg/g dry) HIC(mg/g wet) Organ FE(mg) CIC(mg/g dry) CIC(mg/g wet) Organ FE(mg) Control(4wk) 26.6±3.8 7.0±1.4 27.5±2.6 3.74±0.5 0.74±0.1 0.32±0.05 Control(8wk) 23.1±1.1 5.9±0.5 20.5±2.2 2.64±0.19 0.52±0.03 0.20±0.01 DFO 50mg/kg 31.0±3.0 8.2±1.5 28.9±3.4 2.73±0.32 0.56±0.03 0.20±0.02 DFO100mg/kg 25.3±3.3 6.8±1.2 25.0±4.9 3.20±0.46 0.90±0.46 0.33±0.18 DFO200mg/kg 23.5±1.4 5.9±0.4 17.6±2.4 2.77±0.20 0.53±0.07 0.18±0.03 L1 125mg/kg 32.2±1.3 7.7±1.1 23.8±3.4 3.63±0.25 0.79±0.02 0.23±0.02 L1 250mg/kg 29.3±7.4 8.5±2.7 26.7±6.2 3.56±0.85 0.71±0.12 0.21±0.04 L1 500mg/kg 18.5±0.9 5.0±0.6 19.4±1.8 2.68±0.43 0.57±0.08 0.20±0.04 ICL 25mg/kg 24.3±6.3 6.2±1.3 21.5±5.6 3.47±0.09 0.74±0.02 0.25±.02 ICL 50mg/kg 27.6±1.7 6.7±1.1 19.7±4.3 3.22±0.05 0.64±0.14 0.23±0.04 ICL100mg/kg 18.5±3.7 4.1±1.1 13.8±1.8 2.96±0.38 0.59±0.09 0.23±0.04

The Effect of Supplemental Ascorbate on Defersirox Iron Chelation In the Iron-Loaded Gerbil

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2059-2059
Author(s):  
Maya Otto-Duessel ◽  
Casey Brewer ◽  
Aleya Hyderi ◽  
Jens Lykkesfeldt ◽  
Ignacio Gonzalez-Gomez ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Dextran ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Wet Weight

Abstract Abstract 2059 Introduction: Iron dextran injections are often used to induce iron overload in rodents, for the purposes of assessing iron chelation therapy. In gerbils, we have previously described that deferasirox therapy preferentially clears hepatocellular iron when compared with reticuloendothelial stores. Ascorbate deficiency, which is common in humans with iron overload, produces similar profound disparities between reticuloendothelial and parenchymal iron stores. We postulated that iron-induced ascorbate deficiency might be exaggerating reticuloendothelial iron retention in gerbils receiving deferasirox therapy. This study examined the effect of supplemental ascorbate on spontaneous iron loss and deferasirox chelation efficiency in the iron-dextran loaded gerbil. Methods: 48 female gerbils underwent iron dextran loading at 200 mg/kg/week for 10 weeks. Sixteen animals were sacrificed at 11 weeks to characterize iron loading; eight were on standard rodent chow and eight had chow supplemented with 2250 ppm of ascorbate. 32 additional animals that were not ascorbate supplemented during iron loading transitioned into the chelation phase. Half were subsequently placed on ascorbate supplemented chow and both groups were assigned to receive either deferasirox 100 mg/kg/day five days per week or sham chelation. Animals received iron chelation for twelve weeks. Liver histology was assessed using H & E and Prussian blue stains. Iron loading was ranked and graded on a five-point scale by an experienced pathologist screened to the treatment arm. Iron quantitation in liver and heart was performed by atomic absorption. Results: Table 1 one summarizes the findings. During iron dextran loading, ascorbate supplementation lowered wet weight liver iron concentration but not liver iron content suggesting primarily changes in tissue water content. Spontaneous iron losses were insignificant, regardless of ascorbate therapy. Deferasirox lowered liver iron content 56% (4.7% per week) in animals without ascorbate supplementation and 48.3% (4.0% per week) with ascorbate supplementation (p=NS). Cardiac iron loading, unloading and redistribution were completely unaffected by ascorbate supplementation. Spontaneous iron redistribution was large (1.9% – 2.3% per week). Deferasirox chelation did not lower cardiac iron to a greater degree than spontaneous cardiac iron redistribution. Histologic grading paralleled tissue wet weight iron concentrations. Ascorbate treatment lowered the rank and absolute iron score in liver during iron loading (p=0.003) and there was a trend toward lower iron scoring in sham treated animals (p=0.13). Ascorbate had no effect on histological score or relative compartment distributions of iron in deferasirox chelated animals (p=0.5). Ascorbate supplementation was sufficient to increase total plasma ascorbate levels from 25 ± 12.2 uM to 38.4 ± 11 uM at 10 weeks (p=0.03). In the liver, ascorbate increased from 1203 ± 212 nmol/g of tissue to 1515 ± 194 nmol/g of tissue (p=0.01) with supplementation. No significant change in total ascorbate was observed in the heart. Discussion: We hypothesized that ascorbate supplementation might improve reticuloendothelial iron accessibility to deferasirox by facilitating redox cycling. Although gerbils synthesize their own ascorbate, supplementation was able to raise both serum and hepatic total ascorbate levels. However, increasing ascorbate did not change either the amount or distribution of tissue iron in deferasirox-treated animals. Disclosures: Nick: Novartis: Employment. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4632-4639 ◽  
Author(s):  
Peter D. Jensen ◽  
Finn T. Jensen ◽  
Thorkil Christensen ◽  
Hans Eiskjær ◽  
Ulrik Baandrup ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Myocardial Iron ◽  
Resonance Imaging ◽  
Liver Iron ◽  
Iron Pool ◽  
Iron Excretion

Abstract Evaluation of myocardial iron during iron chelation therapy is not feasible by repeated endomyocardial biopsies owing to the heterogeneity of iron distribution and the risk of complications. Recently, we described a noninvasive method based on magnetic resonance imaging. Here, the method was used for repeated estimation of the myocardial iron content during iron chelation with deferrioxamine in 14 adult nonthalassemic patients with transfusional iron overload. We investigated the repeatability of the method and the relationship between the myocardial iron estimates and iron status. The repeatability coefficient (2sD) was 2.8 μmol/g in the controls (day-to-day) and 4.0 μmol/g in the patients (within-day). Myocardial iron estimates were elevated in 10 of all 14 patients at first examination, but normalized in 6 patients after 6 to 18 months of treatment. If liver iron declined below 350 μmol/g all but one of the myocardial iron estimates were normal or nearly normal. At start (R2 = 0.69, P = .0014) and still after 6 months of iron chelation (R2 = 0.76, P = .001), the estimates were significantly and more closely related to the urinary iron excretion than to liver iron or serum ferritin levels. In conclusion, our preliminary data, which may only pertain to patients with acquired anemias, suggest the existence of a critical liver iron concentration, above which elevated myocardial iron is present, but its extent seems related to the size of the chelatable iron pool, as reflected by the urinary iron excretion. This further supports the concept of the labile iron pool as the compartment directly involved in transfusional iron toxicity.

Magnetic Ressonance Imaging (MRI) in the Evaluation of Iron Overload in Patients with Beta Thalassaemia. The Brazilian National Program Preliminary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3825-3825
Author(s):  
Nelson Hamerschlak ◽  
Laercio Rosemberg ◽  
Alexandre Parma ◽  
Fernanda F. Assir ◽  
Frederico R. Moreira ◽  
...  
Keyword(s):  
Iron Overload ◽  
Ventricular Function ◽  
Iron Content ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Inverse Correlation ◽  
Liver Iron ◽  
Liver Iron Content ◽  
Cooperative Program

Abstract Magnetic Ressonance Imaging (MRI) using T2 star (T2*) tecnique appears to be a very useful method for monitoring iron overload and iron chelation therapy in thalassaemia. In Brazil, we have around 400 thalassaemic major patients all over the country. They were treated with hipertransfusion protocols and desferroxamine and/or deferiprone chelation. We developed a cooperative program with the Brazilian Thalassaemic Patients Association (ABRASTA) in order to developT2* tecnique in Brazil to submit brazilian patients to an annual iron overload monitoring process with MRI.. We performed the magnetic ressonance T2* using GE equipment (GE, Milwaukee USA), with validation to chemical estimation of iron in patients undergoing liver biopsy. Until now, 60 patients were scanned, median age=23,2 (12–54); gender: 18 male (30%) and 42 female (70%). The median ferritin levels were 2030 ng/ml (Q1=1466; Q3=3296). As other authors described before, there was a curvilinear inverse correlation between iron concentration by biopsy, liver T2*(r=0,92) and also there were a correlation with ferritin levels. We also correlated myocardial iron measured by T2* with ventricular function.. As miocardial iron increased, there was a progressive decline in ejection fraction and no significant correlation was found between miocardial T2* and the ferritin levels. Liver iron content can be predicted by ferritin levels. On the other hand, cardiac disfunction is the most important cause of mortality among thalassaemic patients. Since Miocardio iron content cannot be predicted from serum ferritin or liver iron, and ventricular function can only detect those with advance disease, intensification and combination of chelation therapy, guided by T2* MRI tecnique should reduce mortality from the reversible cardiomyopathy among thalassaemic patients.

ICL670 Removes Cardiac Iron in a Gerbil Model of Iron Overload.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2695-2695 ◽  
Author(s):  
John C. Wood ◽  
Maya Otto-Duessel ◽  
Ignacio Gonzales ◽  
Michelle Aguilar ◽  
Hanspeter Nick ◽  
...  
Keyword(s):  
Iron Content ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Loading ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Myocyte Hypertrophy ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Wet Weight

Abstract Introduction: Deferasirox (ICL670) is a novel tridentate oral iron chelator currently being evaluated for the treatment of transfusional iron overload. Phase III clinical trials have demonstrated that once-daily ICL670 (20 mg/kg) is equally effective at controlling liver iron concentration as standard deferoxamine therapy (40 mg/kg/day, 5 days per week). While ICL670’s long serum half-life should offer good protection against cardiac iron accumulation, little is known regarding its ability to remove stored cardiac iron. Therefore, we compared the relative efficacy of ICL670, deferiprone (L1), and deferoxamine (DFO) in removing cardiac iron from iron-loaded gerbils. Methods: 37 8–10 week old female gerbils underwent ten weekly iron dextran injections of 200 mg/kg/D, followed by a 13 day equilibration period. Five animals were then sacrificed to determine pre-chelation iron burdens. Chelation was initiated in 3 groups of 8 animals (ICL670 100 mg/kg/D po QD, L1 375 mg/kg/D po divided TID, DFO 200 mg/kg/D sub Q divided BID) five days per week and maintained for 12 weeks. The remaining 8 animals received sham chelation. All animals underwent ECG and treadmill assessment at baseline, following iron loading, and after completing chelation therapy. Animals were sacrificed for liver and heart iron measurement (Mayo Medical Laboratory) and semiquantitative histology. Hearts were evaluated for iron loading/distribution, tissue fibrosis, and myocyte hypertrophy, while livers were scored for iron loading/distribution and fibrosis. Results: Chelator-independent iron excretion and redistribution was evident, unlike in humans. Cardiac and liver iron contents fell 30.4% and 23.2%, respectively, with sham chelation; all subsequent chelator comparisons are reported with respect to the sham-chelated animals. ICL670 reduced cardiac iron content 20.5%. There were no changes in cardiac weight, myocyte hypertrophy, fibrosis, or wet-to-dry weight ratio. ICL670 treatment reduced liver iron content 51%. Iron elimination was greatest in hepatocytes with no detectable Kupfer-cell iron clearance. L1 produced comparable reductions in cardiac iron content (18.6%). Wet weight cardiac iron concentration fell nearly 30% but this was offset by greater cardiac mass (16.5% increase). Histologic analysis demonstrated decreased iron staining but increased myocyte hypertrophy. L1 decreased liver iron content 24.9%. Wet weight liver iron concentration fell 43.8% but was offset by a 30% increase in liver weight and water content. Iron elimination was balanced between Kupfer cells and hepatocytes. DFO did not reduce biochemically-assayed cardiac or liver iron content, although it improved histologic iron scores in both organs. Hearts from DFO treated animals were enlarged and had greater fibrosis. Cardiac and liver iron contents were closely correlated (r = 0.66), but ICL670 animals had lower hepatic iron contents for any given cardiac iron content. Iron loading broadened QRS duration by 10.6%; this effect was antagonized by both L1 and ICL670 therapy. PR, QRS, and QTc interval were weakly correlated with cardiac and liver iron contents. Treadmill exercise time was independent of chelation therapy. Conclusion: ICL670 and L1 were equally effective in removing stored cardiac iron in a gerbil animal model but ICL670 removed more hepatic iron for a given cardiac iron burden.

Twice-Daily Deferasirox Improves Cardiac Iron Chelation in the Gerbil Model of Iron Cardiomyopathy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1777-1777
Author(s):  
Maya Otto-Duessel ◽  
Michelle I. Aguilar ◽  
Hanspeter Nick ◽  
Rex Moats ◽  
John C. Wood
Keyword(s):  
Iron Content ◽  
Group Versus ◽  
Iron Chelation ◽  
Hepatic Iron ◽  
Mongolian Gerbils ◽  
Liver Iron ◽  
Once Daily ◽  
Treatment Groups ◽  
Cardiac Iron ◽  
Labile Iron

Abstract Introduction: Iron cardiomyopathy remains the leading cause of death in thalassemia major patients because effective chelation of cardiac iron is difficult. Cardiac iron stores respond more slowly to chelation therapy and appear to require a sustained gradient of labile iron species between myocytes and serum. We have previously demonstrated the efficacy of once-daily deferasirox in removing stored cardiac iron in the gerbil but changes in cardiac iron were relatively modest compared with hepatic iron. We postulated that twice daily dosing (BID), by sustaining a longer labile iron gradient from myocytes to serum, would produce better cardiac iron chelation than a comparable once daily dose (QD). Methods: Twenty four eight-to-ten week old female Mongolian gerbils underwent iron dextran loading for 10 weeks, followed by a 1 week iron equilibration period. Animals were divided into 3 treatment groups of 8 animals apiece and treated with deferasirox 100 mg/kg/day as a single dose (n=8), deferasirox 100 mg/kg/day divided BID (n=8), or sham chelation (n=8) for a total of 12 weeks. Following euthanasia, organs were harvested for quantitative iron determination and tissue histology. Results: All of the animals tolerated the 10-week loading and 12-week chelation with no adverse events. After the 22-week period, hepatic iron content was 17.7 ± 4.8 mg and 21.1 ± 5.3 mg in the QD and BID groups, compared with 43.1 ± 5.3 mg in the sham-chelated animals (p < 0.0001 sham versus treatment, p=0.2 between groups). Corresponding cardiac iron content was 0.19 ± 0.04 mg, 0.16 ± 0.04 mg and 0.23 ± 0.04 mg respectively. These changes were significant in the BID group (p< 0.006 versus sham). While BID versus QD cardiac iron contents were not statistically different, treatment groups were clearly distinct when viewed as a scattergram of heart and liver iron content (Figure 1). The BID treated animals exhibited lower cardiac iron for any given hepatic iron content. This is best observed by comparing the ratio of cardiac to hepatic iron content (Figure 2, which was 0.78% in the BID group versus 1.11% in the QD treated animals (p=0.0007). Discussion: In Mongolian gerbils, deferasirox effectively removed liver and cardiac iron with either BID or QD dosing. BID dosing changed the relative cardiac and liver iron chelation profile compared with QD dosing, trading improvements in cardiac iron elimination for a modest decrease in hepatic chelation. Caution should be exercised in extrapolating these results to humans, however clinical studies of BID administration should be considered for patients requiring high chelator dosing or who have high cardiac iron burden. Figure 1 Figure 1. Figure 2 Figure 2.

Impact of Iron Assessment by MRI

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 443-450 ◽  
Author(s):  
John C. Wood
Keyword(s):  
Chelation Therapy ◽  
Hypogonadotropic Hypogonadism ◽  
Iron Concentration ◽  
Elevated Serum ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
The Body ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Kinetics Of Uptake

Abstract The use of magnetic resonance imaging (MRI) to estimate tissue iron was conceived in the 1980s, but has only become a practical reality in the last decade. The technique is most often used to estimate hepatic and cardiac iron in patients with transfusional siderosis and has largely replaced liver biopsy for liver iron quantification. However, the ability of MRI to quantify extrahepatic iron has had a greater impact on patient care and on our understanding of iron overload pathophysiology. Iron cardiomyopathy used to be the leading cause of death in thalassemia major, but is now relatively rare in centers with regular MRI screening of cardiac iron, through earlier recognition of cardiac iron loading. Longitudinal MRI studies have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration (LIC) increase the risk of cardiac and endocrine toxicities, some patients unequivocally develop extrahepatic iron deposition and toxicity despite having low total body iron stores. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. Future frontiers in MRI monitoring include improved prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes.

Efficacy and Safety of Deferasirox (Exjade®) in Preventing Cardiac Iron Overload in β-Thalassemia Patients with Normal Baseline Cardiac Iron: Results from the Cardiac Substudy of the EPIC Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3874-3874 ◽  
Author(s):  
Dudley Pennell ◽  
Pranee Sutcharitchan ◽  
Amal El-Beshlawy ◽  
Yesim Aydinok ◽  
Ali Taher ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Chelation Therapy ◽  
Geometric Mean ◽  
Iron Chelation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Iron Chelation Therapy ◽  
Myocardial Iron ◽  
Liver Iron ◽  
Cardiac Iron

Abstract Background: Myocardial siderosis is a leading cause of cardiac morbidity in patients (pts) with β-thalassemia undergoing regular blood transfusion therapy. Myocardial and liver siderosis do not correlate in cross-sectional studies, hence the importance of monitoring both cardiac and liver iron in heavily transfused β-thalassemia pts. Iron chelation therapy has an important role in preventing the accumulation of cardiac iron. Deferasirox (Exjade®) is a once-daily, oral iron chelator with efficacy in removing cardiac iron in preclinical and small clinical studies. This subgroup analysis from the cardiac substudy of the EPIC trial, the largest prospective, multicenter clinical trial evaluating the effects of iron chelation therapy, assesses the longitudinal effect of deferasirox over 1 year in preventing myocardial siderosis (maintaining T2* values >20 ms) in non-cardiac iron overloaded pts with β-thalassemia and normal cardiac function. Methods: Pts with β-thalassemia (≥10 years) and with normal myocardial iron levels (magnetic resonance [MR] myocardial T2* of ≥20ms) were included in the prevention arm of the cardiac substudy. Other inclusion criteria were: serum ferritin (SF) >2500 ng/mL; MR (R2) liver iron concentration (LIC) >10 mg Fe/g dry weight (dw); left ventricular ejection fraction (LVEF) ≥56%; and a lifetime minimum of 50 previous packed red blood cell transfusions. Deferasirox was initiated at 30 mg/kg/day with subsequent dose adjustments of 5–10 mg/kg/day based on changes in SF, month-6 myocardial T2*, and safety parameters. Change from baseline in myocardial iron at 1 year was the primary endpoint. Changes in cardiac function, SF and LIC were also evaluated. Results: We enrolled 78 pts into the cardiac prevention arm (35 male and 43 female; mean age, 20.2±7.5 years). The geometric mean (± coefficient of variation) myocardial T2* was 32.0 ms ±25.6%. Mean baseline (±SD) LVEF was 67.7±4.7%, LIC 28.8±10.2 mg Fe/g dw, and median SF 4712 ng/mL. Transfusion requirements were 133.7 mL/kg in the year prior to enrollment. Previous chelation therapy had been received by 76 pts (deferoxamine [DFO], 69.2%; combination DFO/deferiprone, 28.2%). Mean deferasirox dose over 1 year was 27.6±6.0 mg/kg/day. After 12 months of therapy, the geometric mean myocardial T2* was 32.5 ms ±25.1% (ratio of geometric mean = 1.02; P=ns) and LVEF increased to 69.6% (P<0.0001). None of the pts from this cohort with cardiac T2* >20 ms at baseline had a value below 20 ms at 12 mths. Median SF was significantly reduced from baseline at 12 months by 1048 ng/mL (P<0.0001), representing a 20% relative reduction. LIC was also significantly reduced from baseline by 7.2 mg Fe/g dw (P<0.0001; 30% reduction). One year of treatment was completed by 75 pts (96.2%); three pts (3.8%) discontinued because of AEs (n=2) or for other reasons (n=1). The most common investigator-assessed drug-related AEs were mild (78%) in severity and included diarrhea (n=8, 10%), rash (n=7, 9%), nausea (n=4, 5%) and urticaria (n=4, 5%). One pt (1.3%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. No pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits. No pts died and no drug-related serious AEs were reported in this cohort. Conclusions: In β-thalassemia pts with normal myocardial iron levels at baseline, deferasirox treatment over 1 year maintained myocardial iron levels whilst significantly reducing body iron burden measured by SF and LIC. LVEF increased significantly. Deferasirox was well tolerated with a clinically manageable safety profile.

Comparison of Two Animal Models for Evaluation of Defersirox Iron Chelation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4244-4244
Author(s):  
Maya Otto-Duessel ◽  
Casey Brewer ◽  
Aleya Hyderi ◽  
Jens Lykkesfeldt ◽  
Peter Nielson ◽  
...  
Keyword(s):  
Carbonyl Iron ◽  
Iron Chelation ◽  
Oral Iron ◽  
Fluid Replacement ◽  
Iron Loss ◽  
Iron Dextran ◽  
Iron Loading ◽  
Liver Iron ◽  
Iron Losses ◽  
Parenteral Iron

Abstract Abstract 4244 Introduction: Long-term storage iron (hemosiderin) is insoluble and not directly accessible to iron chelation. Ascorbate is a potent facilitator of redox cycling and facilitates the mobilization of cellular iron stores in patients chelated with deferoxamine. Ascorbate deficiency is quite common in thalassemia major and may create a phenotype of relative chelator refractoriness. However, the synergistic role of ascorbate supplementation has never been demonstrated for other chelators, including the oral chelator deferasirox. Ascorbate can be freely synthesized in many animals, making them unsuitable models to address this question. The osteodystrophic syndrome (ODS) rat is a spontaneous mutant lacking L-gulono-gamma-lactone oxidase, the initial enzyme in ascorbate synthesis. Iron loading and chelation have never been performed in ODS rats, so we report a pilot study aimed at optimizing organ iron loading and clearance. Methods: Twenty-six 8-week old male ODS rats were maintained vitamin C replete by supplying ascorbate in the chow or drinking water. Fourteen animals were iron loaded using a combination of 0.4% TMH ferrocene and 3% carbonyl iron in standard rodent chow. Twelve animals were loaded with iron dextran (200 mg/kg/week) by subcutaneous injection. To characterize loading kinetics, two animals were analyzed at five, ten, and twelve weeks of oral iron loading as well as five and ten weeks of iron dextran injections. Sixteen animals were iron loaded for ten weeks (half enterally, half parenterally) and transitioned into the chelation arm. Iron chelation was performed with oral deferasirox at 75 mg/kg/dose, once daily five times per week. Chelation was administered for six and twelve weeks in six animals, divided equally between parenteral and enteral iron loading; sham chelation was given to the remaining four animals. Following euthanasia, H&E and iron staining were performed and tissue iron was quantified by atomic absorption. Results: Parenteral iron loading was well tolerated and yielded liver iron concentration (LIC) values of approximately 3 and 4.5 mg/g wet weight (∼11-16.8 mg/g dry weight) at five and ten weeks, respectively. Iron loading was predominantly reticuloendothelial, with little parenchymal redistribution. Spontaneous iron loss after 12 weeks of iron chelation was modest at 1.3% per week. In contrast, oral iron loading with the combination of TMH-ferrocene and carbonyl iron was poorly tolerated. Animals developed severe diarrhea and required fluid replacement and frequent dose reductions. These GI disturbances gradually lessened over a period of four weeks and animals received approximately 80% of the targeted iron dose. LIC values were lower at five weeks (2.2 mg/g ww) but nearly equivalent by 10 weeks (4.2 mg/g ww). Iron was entirely parenchymal, with little reticuloendothelial deposition. Spontaneous iron losses after 12 weeks of iron chelation were strikingly higher than for parenteral iron loading, measuring 4.7% per week. Iron chelation with deferasirox was well tolerated in both groups. Iron chelation was less efficient in iron dextran loaded animals. LIC was 3.1 ± 0.7 mg/g ww compared with 3.8 ± 0.2 mg/g ww in sham chelated animals, p=0.25. In contrast, deferasirox treatment nearly completely cleared liver iron in TMH treated animals 0.4 ± 0.1 mg/g ww vs 1.5 ± 0.04 mg/g ww, p = 0.001, with most of the residual iron located primarily in reticuloendothelial store on histologic analysis. Discussion: Iron loading in the ODS rat can be performed with either iron dextran or TMH-ferrocene but the characteristics of iron staining, spontaneous iron loss, and chelator accessibility are completely different. Iron dextran loads the reticuloendothelial system. Iron redistribution to parenchymal tissues is sluggish, based upon the low spontaneous iron elimination rate and modest response to deferasirox therapy (1.5% per week). In contrast, TMH produced exclusively parenchymal loading, high spontaneous iron losses (4.7% per week) and more vigorous response to chelation (6.3% per week). Subsequent studies will determine whether the degree of ascorbate sufficiency modulates deferasirox efficacy in animals with primarily reticuloendothelial iron loading. Disclosures: Nick: Novartis: Employment. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

scholarly journals MRI evaluation of hepatic and cardiac iron burden in pediatric thalassemia major patients: spectrum of findings by T2*

2019 ◽  
Vol 50 (1) ◽  
Author(s):  
Samar M. Shehata ◽  
Mohamed I. Amin ◽  
El Sayed H. Zidan
Keyword(s):  
Chelation Therapy ◽  
Statistical Significance ◽  
Iron Chelation ◽  
Good Method ◽  
Thalassemia Major ◽  
Local Magnetic Field ◽  
Cardiac Complications ◽  
Liver Iron ◽  
Cross Sectional ◽  
Signal Decay

Abstract Background Iron deposition distorts the local magnetic field exerting T2* signal decay. Biopsy, serum ferritin, echocardiography are not reliable to adjust iron chelation therapy. Quantified MRI signal decay can replace biopsy to diagnose iron burden, guide treatment, and follow up. The objective of this study is to evaluate the role of T2* in quantification of the liver and heart iron burden in thalassemia major patients. This cross-sectional study included 44 thalassemia patients who were referred to MRI unit, underwent T2* MRI. Results Twenty-one male (47.7%) and 23 female (52.3%) were included (age range 6–15 years, mean age 10.9 ± 2.9 years). Patients with excess hepatic iron show the following: 11/40 (27.5%) mild, (13/40) 32.5% moderate, and (14/40) 35% severe liver iron overload. High statistical significance regarding association between LIC and liver T2* (p = 0.000) encountered. Cardiac T2* values showed no relationship with age (p = 0.6). Conclusion T2* is a good method to quantify, monitor hepatic and myocardial iron burden, guiding chelation therapy and prevent iron-induced cardiac complications.

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