The controversial role of deferiprone in the treatment of thalassemia

doi:10.1067/mlc.2001.114105

Journal of Laboratory and Clinical Medicine

Volume 137, Issue 5, May 2001, Pages 324-329

https://doi.org/10.1067/mlc.2001.114105 Get rights and content

Abstract

The role of the orally active iron (Fe) chelator deferiprone in the treatment of β-thalassemia remains a controversial subject. Despite initial studies showing high Fe chelation efficacy in vitro and also in animals and human subjects, several latter studies have not been so successful. In fact, it has been reported in several clinical trials that deferiprone after long-term treatment had either little effect or actually increased hepatic Fe loading. In addition, an increase in liver fibrosis was noted in one study. However, more recently, results by other investigators have suggested that the drug may be used under some circumstances without marked toxicity. In particular, it has been demonstrated that the combination of deferoxamine (DFO) and deferiprone results in more Fe excretion than when either chelator is used alone. Moreover, a combination of both drugs led to a decrease in deferiprone-mediated toxicity. Other studies performed in patients for up to 10 years showed no progressive fibrosis after deferiprone therapy, while a possible trend toward increasing fibrosis was noted in another investigation. Additional studies using larger numbers of deferiprone-treated patients are essential to determine the efficacy and safety of this drug, particularly in relation to the development of fibrosis. The present review discusses the possible role of deferiprone in the treatment of Fe overload. (J Lab Clin Med 2001:137:324-9)

Section snippets

Deferiprone: Its properties and ability to effectively induce iron excretion in iron-loaded β-thalassemia patients

Deferiprone belongs to a group of bidentate chelators known as the α-ketohydroxypyridones. The high activity of these compounds is probably related to their ability to quickly diffuse across cell membranes and chelate intracellular Fe pools.9, 10 This property is probably related to their low molecular weight and relatively high lipophilicity in comparison with DFO.¹¹ Interestingly, deferiprone is capable of effectively removing Fe from the high-affinity Fe-binding sites of serum transferrin.12

Other orally effective iron chelators in development

To increase the efficacy of the bidentate ligands,38, 39, 40 tetradentate and hexadentate chelators have been synthesized based on HOPO.³⁸ The bidentate ligand methyl-3,2-hydroxypyridone-propylamide and its hexadentate analog TREN-(Me-3,2-HOPO) have been compared in terms of their ability to increase urinary and fecal Fe excretion in Fe-loaded rats.³⁸ The bidentate ligand Pr-(Me-3,2-HOPO) only slightly increased urinary and biliary Fe excretion, whereas its hexadentate analog TREN-(Me-3,2-HOPO)

Conclusions

Although progress has been agonizingly slow, the prospects for an effective oral chelator are improving. Individually tailored dosing regimens and the use of drug combinations rather than single agents may improve the efficiency of Fe depletion while decreasing toxicity. To date, these strategies have been used only in rather small studies, so “the jury is still out.” The long-term goal, of course, is to develop a single orally effective agent that reliably produces a negative Fe balance while

Acknowledgements

I thank Professor Roger Dean and Mr David Lovejoy for their useful suggestions on the manuscript before submission. I also thank Professor Dale Hammerschmidt for careful editorial assistance in preparing the article for publication.

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In the majority of patients with thalassemia major or other transfusion-dependent refractory anemias, treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body is the only therapeutic option available. Current choices (Fig. 1) include Desferal, the mesylate salt27 of desferrioxamine B (DFO), 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone, L1),28,29 and 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox, ICL670A).30,31 Each presents with palpable shortcomings32 and in some cases, serious toxicity issues.
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^☆: Supported by grants 970360 and 980826 from the National Health and Medical Research Council of Australia, by an Australian Research Council Large Grant, and by The Heart Research Institute.

^☆☆: Reprint requests: Des R. Richardson, PhD, The Iron Metabolism and Chelation Group, The Heart Research Institute, 145 Missenden Rd, Camperdown, New South Wales, Australia 2050.

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Review ArticleThe controversial role of deferiprone in the treatment of thalassemia☆,☆☆

Abstract

Section snippets

Deferiprone: Its properties and ability to effectively induce iron excretion in iron-loaded β-thalassemia patients

Other orally effective iron chelators in development

Conclusions

Acknowledgements

Blood

Blood

Blood

Blood

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Blood

J Biol Chem

Lancet

Blood

J Lab Clin Med

J Lab Clin Med

J Lab Clin Med

J Pharm Sci

Blood

FEBS Lett

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Biochem Pharmacol

Biochim Biophys Acta

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Inorg Chim Acta

Biochim Biophys Acta

Blood

Blood

Blood

J Lab Clin Med

Inorg Chim Acta

The future of new iron chelating drugs

The development of iron chelators to treat iron overload disease and their use as experimental tools to probe intracellular iron metabolism

Am J Hematol

Therapeutic potential of iron chelators

Exp Opin Invest Drugs

Iron chelation therapy with oral deferiprone in patients with thalassemia major

N Engl J Med

Review Article
The controversial role of deferiprone in the treatment of thalassemia☆,☆☆