Pharmaco/ferrokinetic-related pro-oxidant activity of deferiprone in<i>β</i>-thalassemia

Jirasomprasert, Totsapol; Morales, Noppawan Phumala; Limenta, Lie Michael George; Sirijaroonwong, Srisuporn; Yamanont, Paveena; Wilairat, Prapin; Fucharoen, Suthat; Chantharaksri, Udom

doi:10.1080/10715760902870611

Cited by 12 publications

(6 citation statements)

References 34 publications

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“…These confirm Fig S1A but also allow examination of higher DFP concentrations. Peak clinical DFP concentrations of 100 μmol/l have been reported (Jirasomprasert et al , ; Morales et al , ; Limenta et al , ) and under these concentrations and at trough concentrations of DFX, about 60% of iron(III) is predicted to be bound to DFP. This analysis suggests a ‘push–pull’ effect for iron binding over the range of clinically achieved concentrations, providing conditions for both shuttle and sink effects to occur.…”

Section: Resultsmentioning

confidence: 99%

Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization

2015

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SummaryIron chelators are increasingly combined clinically but the optimal conditions for cellular iron mobilization and mechanisms of interaction are unclear. Speciation plots for iron(III) binding of paired combinations of the licensed iron chelators desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) suggest conditions under which chelators can combine as 'shuttle' and 'sink' molecules but this approach does not consider their relative access and interaction with cellular iron pools. To address this issue, a sensitive ferrozine-based detection system for intracellular iron removal from the human hepatocyte cell line (HuH-7) was developed. Antagonism, synergism or additivity with paired chelator combinations was distinguished using mathematical isobologram analysis over clinically relevant chelator concentrations. All combinations showed synergistic iron mobilization at 8 h with clinically achievable concentrations of sink and shuttle chelators. Greatest synergism was achieved by combining DFP with DFX, where about 60% of mobilized iron was attributable to synergistic interaction. These findings predict that the DFX dose required for a halfmaximum effect can be reduced by 3Á8-fold when only 1 lmol/l DFP is added. Mechanisms for the synergy are suggested by consideration of the iron-chelate speciation plots together with the size, charge and lipid solubilities for each chelator. Hydroxypyridinones with low lipid solubilities but otherwise similar properties to DFP were used to interrogate the mechanistic interactions of chelator pairs. These studies confirm that synergistic cellular iron mobilization requires one chelator to have the physicochemical properties to enter cells, chelate intracellular iron and subsequently donate iron to a second 'sink' chelator.

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Section: Resultsmentioning

confidence: 99%

Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization

2015

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“…Electron paramagnetic resonance (EPR) 'radical probe' was used to determine the total oxidative status in patients affected by thalassemia, and to evaluate new strategies of chelation, new chelators, or the efficacy of antioxidant formulas [166,167]. Raman spectroscopic technique has been developed for the monitoring of Raman hemoglobin bands to evaluate oxygenation capability, oxidative stress and deformities of thalassemic erythrocytes and to assess the responses to drug therapies [168].…”

Section: Evaluation Of Oxidative Stress and Antioxidant Status In Thamentioning

confidence: 99%

Antioxidants as Complementary Medication in Thalassemia

Srichairatanakool¹,

Fucharoen²

2014

Pharmacology and Nutritional Intervention in the Treatment of Disease

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Inhibitors of iron absorption (tea, Ca) Foods (phytate and oxalate) Antioxidative compounds (vitamin C, E, NAC) Antioxidative phytochemicals (flavonoids, curcuminoids) Oxidative stress Hemosiderosis Cardiomyopathy Liver inflammation and cirrhosis Thalassemias with iron overload (From Nature Genetics Review, 2004) Endocrinopathy Ineffective erythropoiesis Hormone supplement Hb F modifiers (hydroxyurea, hydroxycarbamide, decitabin and phenylbutyrate) Hb stimulating agents (erythropoietin, folic acid) Bone marrow transplantation Gene therapy HSC therapy (www.nctrallawblog.com) Blood transfusion (420 ml/unit  200 mg Fe) (http://saschina.org) Duodenal iron absorption (3-9 mg Fe/day in thalassemia intermedia) Bone deformity Hypercoagulability Vitamin D Osteoclast supplement Hydroxyurea Aspirin Coumadin Antioxidants as Complementary Medication in Thalassemia

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“…Recently the pro-oxidant effect of non-transferrin bound iron complexes has been reviewed. 36 In this context the SOD-like activity of the iron(III) complexes of HPO, could be important in the reduction of side effects due to iron overload in addition to the chelation activity. The SOD activity of iron(III) complexes of HPO and β-CD conjugates were determined by competition kinetics using NBT target as reported elsewhere.…”

Section: Sod-like Activitymentioning

confidence: 99%

Synthesis, physicochemical properties and antioxidant activity of deferiprone-cyclodextrin conjugates and their iron(iii) complexes

et al. 2012

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3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (deferiprone) is a successful iron chelator, which has been widely investigated for its activity in mitigating iron overload and in protecting against oxidative stress due to Reactive Oxygen Species (ROS). Herein, we present the synthesis, characterisation, physicochemical properties and antioxidant activity of two novel bioconjugates of β-cyclodextrin bearing the deferiprone moiety either on the upper rim (1) or on the lower rim (2) of the cyclodextrin and their iron(III) complexes. Protonation and iron stability constants were measured by spectrophotometric titration for the two systems and antioxidant activity studied for both the ligands and the iron(III) complexes.

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Pharmaco/ferrokinetic-related pro-oxidant activity of deferiprone inβ-thalassemia

Cited by 12 publications

References 34 publications

Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization

Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization

Antioxidants as Complementary Medication in Thalassemia

Synthesis, physicochemical properties and antioxidant activity of deferiprone-cyclodextrin conjugates and their iron(iii) complexes

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