Drug Safety

, Volume 26, Issue 8, pp 553–584 | Cite as

Benefits and Risks of Deferiprone in Iron Overload in Thalassaemia and Other Conditions

Comparison of Epidemiological and Therapeutic Aspects with Deferoxamine
  • George J. Kontoghiorghes
  • Katia Neocleous
  • Annita Kolnagou
Review Article


Deferiprone is the only orally active iron-chelating drug to be used therapeutically in conditions of transfusional iron overload. It is an orphan drug designed and developed primarily by academic initiatives for the treatment of iron overload in thalassaemia, which is endemic in the Mediterranean, Middle East and South East Asia and is considered an orphan disease in the European Union and North America. Deferiprone has been used in several other iron or other metal imbalance conditions and has prospects of wider clinical applications.

Deferiprone has high affinity for iron and interacts with almost all the iron pools at the molecular, cellular, tissue and organ levels. Doses of 50–120 mg/kg/day appear to be effective in bringing patients to negative iron balance. It increases urinary iron excretion, which mainly depends on the iron load of patients and the dose of the drug. It decreases serum ferritin levels and reduces the liver and heart iron content in the majority of chronically transfused iron loaded patients at doses >80 mg/kg/day. It is metabolised to a glucuronide conjugate and cleared through the urine in the metabolised and a non-metabolised form, usually of a 3 deferiprone: 1 iron complex, which gives the characteristic red colour urine. Peak serum levels of deferiprone are observed within 1 hour of its oral administration and clearance from blood is within 6 hours. There is variation among patients in iron excretion, the metabolism and pharmacokinetics of deferiprone.

Deferiprone has been used in more than 7500 patients aged from 2–85 years in >50 countries, in some cases daily for >14 years. All the adverse effects of deferiprone are considered reversible, controllable and manageable. These include agranulocytosis with frequency of about 0.6%, neutropenia 6%, musculoskeletal and joint pains 15%, gastrointestinal complains 6% and zinc deficiency 1%. Discontinuation of the drug is recommended for patients developing agranulocytosis.

Deferiprone is of similar therapeutic index to subcutaneous deferoxamine but is more effective in iron removal from the heart, which is the target organ of iron toxicity and mortality in iron-loaded thalassaemia patients. Deferiprone is much less expensive to produce than deferoxamine. Combination therapy of deferoxamine and deferiprone has been used in patients not complying with subcutaneous deferoxamine or experiencing toxicity or not excreting sufficient amounts of iron with use of either drug alone. New oral iron-chelating drugs are being developed, but even if successful these are likely to be more expensive than deferiprone and are not likely to become available in the next 5–8 years. About 25% of treated thalassaemia patients in Europe and more than 50% in India are using deferiprone. For most thalassaemia patients worldwide who are not at present receiving any form of chelation therapy the choice is between deferiprone and fatal iron toxicity.


  1. 1.
    Thomson AM, Rogers JT, Leedman PJ. Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int J Biochem Cell Biol 1999; 31: 1139–52PubMedCrossRefGoogle Scholar
  2. 2.
    Richardson DR, Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim Biophys Acta 1997; 1331: 1–40PubMedCrossRefGoogle Scholar
  3. 3.
    World Health Organisation. Community control of hereditary anaemias WHO Bull 1983; 61: 63–80Google Scholar
  4. 4.
    Modell B, Berdoukas V. The clinical approach to thalassaemia. London: Grune and Stratton, 1984Google Scholar
  5. 5.
    Weatherall DJ, Glegg JB. The Thalassaemia syndromes. 3rd ed. Oxford: Blackwell Scientific Publications, 1981Google Scholar
  6. 6.
    Agarwal MB. Living with thalassaemia. Bombay: Bhalani Book Depot, 1986: 240Google Scholar
  7. 7.
    Ringborn A. Chemical analysis. In: Elving PJ, Kolthoff IM, editors. Complexation in analytical chemistry. New York: Interscience Pub, 1963: 1–374Google Scholar
  8. 8.
    Anderson WF, Hiller MC, editors. Development of iron chelators for clinical use. Bethesda, USA: National Institute of Health, 1975: 1–277Google Scholar
  9. 9.
    Martell AE, Anderson WF, Badman DG, editors. Development of iron chelators for clinical use. Amsterdam: Elsevier, 1980: 1–311Google Scholar
  10. 10.
    Kontoghiorghes GJ, editor. Oral chelation in the treatment of thalassaemia and other diseases. Drugs Today (Barc) 1992; 28Suppl. A: 1–187Google Scholar
  11. 11.
    Kontoghiorghes GJ. Design, properties and effective use of the oral chelator L1 and other α-ketohydroxypyridines in the treatment of transfusional iron overload in thalassaemia. Ann N Y Acad Sci 1990; 612: 339–50PubMedCrossRefGoogle Scholar
  12. 12.
    Kontoghiorghes GJ. Comparative efficacy and toxicity of desferrioxamine, deferiprone and other iron and aluminium chelating drugs. Toxicol Lett 1995; 80: 1–18PubMedCrossRefGoogle Scholar
  13. 13.
    Barman Balfour JA, Foster RH. Deferiprone: a review of its clinical potential in iron overload in β-thalassaemia major and other transfusion dependent diseases. Drugs 1999; 58(3): 553–78PubMedCrossRefGoogle Scholar
  14. 14.
    Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, et al. Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1). Transfus Sci 2000; 23: 211–23PubMedCrossRefGoogle Scholar
  15. 15.
    Kontoghiorghes GJ. Clinical use, therapeutic aspects and future potential of deferiprone in thalassaemia and other conditions of iron and other metal toxicity. Drugs Today (Barc) 2001; 37: 23–35CrossRefGoogle Scholar
  16. 16.
    Addis A, Loebstein R, Koren G, et al. Meta-analytic review of the clinical effectiveness of oral deferiprone (L1). Eur J Clin Pharmacol 1999; 55: 1–6PubMedCrossRefGoogle Scholar
  17. 17.
    Porter JB. A risk benefit assessment of iron chelation therapy. Drug Saf 1997; 17(6): 407–21PubMedCrossRefGoogle Scholar
  18. 18.
    Brown EB. Thalassaemia. Prog Clin Biol Res 1983; 121: 33–42Google Scholar
  19. 19.
    Kontoghiorghes GJ. Present status and future prospects of oral iron chelation therapy in thalassaemia and other diseases. Indian J Paediatr 1993; 60: 485–507CrossRefGoogle Scholar
  20. 20.
    Zurlo MG, De Stefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassaemia major. Lancet 1989; II: 27–9CrossRefGoogle Scholar
  21. 21.
    Modell B, Khan M, Darlison M. Survival in beta thalassaemia major in the UK: data from the UK thalassaemia register. Lancet 2000; 355: 2051–2PubMedCrossRefGoogle Scholar
  22. 22.
    Kontoghiorghes GJ, Agarwal MB, Grady RW, et al. Deferiprone for thalassaemia. Lancet 2000; 356: 428–9PubMedCrossRefGoogle Scholar
  23. 23.
    Kontoghiorghes GJ. New concepts of iron and aluminium chelation therapy with oral L1 (deferiprone) and other chelators. Analyst 1995; 120: 845–51PubMedCrossRefGoogle Scholar
  24. 24.
    Donfrancesco A, Deb G, Domicini C, et al. Deferoxamine, cyclophosphamide, etoposide, carboplatin and thotepa (D-CECaT): a new cytoreductive chelation-chemotherapy regimen in patients with advanced neuroblastoma. Am J Clin Oncol 1992; 15: 319–22PubMedCrossRefGoogle Scholar
  25. 25.
    Georgiou NA, Van der Bruggen J, Oudshoorn M, et al. Combining iron chelators with the nucleoside analog didanosine in anti-HIV therapy. Transfus Sci 2000; 23: 249–50PubMedCrossRefGoogle Scholar
  26. 26.
    Blatt J, Taylor S, Kontoghiorghes GJ. Comparison of antineuroblastoma activity of desferrioxamine with that of oral iron chelators. Cancer Res 1989; 49: 2925–7PubMedGoogle Scholar
  27. 27.
    Kontoghiorghes GJ, Piga A, Hoffbrand AV. Cytotoxic and DNA inhibitory effects of iron chelators on human leukaemic cell lines. Haematol Oncol 1986; 4: 195–204CrossRefGoogle Scholar
  28. 28.
    Simonart T, Boelaert JR, Mosselmans R, et al. Antiproliferative and apoptotic effects of iron chelators on human cervical carcinoma cells. Gynecol Oncol 2002; 85: 95–102PubMedCrossRefGoogle Scholar
  29. 29.
    Hanauske-Abel HM, McCaffrey TA, Grady R. Protein hydroxylation inhibitors for fibroproliferative disorders. World Patent WO 9622021Google Scholar
  30. 30.
    Weinberg ED. Iron depletion: a defence against intracellular infection and neoplasm. Life Sci 1992; 50: 1289–97PubMedCrossRefGoogle Scholar
  31. 31.
    Kontoghiorghes GJ, Weinberg ED. Iron: mammalian defence systems, mechanisms of disease and chelation therapy approaches. Blood Rev 1995; 9: 33–46PubMedCrossRefGoogle Scholar
  32. 32.
    Douvas SG, May MH, Kolnagou A, et al. Effects on mycobacterium avium replication in normal human macrophages by deferiprone (L1) and other iron chelators. Possible implications on toxicity. Arzneimittel Forschung 2002; 52: 45–52PubMedGoogle Scholar
  33. 33.
    Brock JH, Liceaga J, Kontoghiotghes GJ. The effect of synthetic iron chelators on bacterial growth in human serum. FEMS Microbiol Immunol 1988; 47: 55–60CrossRefGoogle Scholar
  34. 34.
    Lesic B, Foulon J, Carniel E. Comparison of the effects of deferiprone versus deferoxamine on growth and virulence of Yersinia enterocolitica. Antimicrob Agents Chemother 2002; 46: 1741–5PubMedCrossRefGoogle Scholar
  35. 35.
    Heppner DG, Hallaway PE, Kontoghiorghes GJ, et al. Antimalarial properties of orally active iron chelators. Blood 1988; 72: 358–61PubMedGoogle Scholar
  36. 36.
    Mastrandrea S, Carvajal JL, Kaeda JS, et al. Growth inhibition of Plasmodium Falciparum by orally active iron chelators. Drugs Today (Barc) 1992; 28Suppl. A: 25–7Google Scholar
  37. 37.
    Gordeuk VR, Thuma PE, Brittenham GM, et al. Iron chelation with desferrioxamine B in adults with asymptomatic P. Falciparum parasitemia. Blood 1992; 79: 308–12PubMedGoogle Scholar
  38. 38.
    Mohanty D, Ghosh K, Pathare AV, et al. Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria. Indian J Med Res 2002; 115: 17–21PubMedGoogle Scholar
  39. 39.
    Kontoghiorghes GJ. Chelators affecting iron absorption in mice. Arzneimittel Forschung 1990; 40: 1332–5PubMedGoogle Scholar
  40. 40.
    Vreugdenhil G, Kontoghiorghes GJ, Van Eijk HG, et al. Impaired erythropoietin responsiveness to the anemia in rheumatoid arthritis: a possible inverse relationship with iron stores and effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Clin Exp Rheumatol 1991; 9: 35–40PubMedGoogle Scholar
  41. 41.
    Giordano N, Fioravanti A, Sancasciani S, et al. Increased storage of iron and anaemia in rheumatoid arthritis: usefulness of desferrioxamine. BMJ 1984; 289: 961–2PubMedCrossRefGoogle Scholar
  42. 42.
    Vreughtenhil G, Kontoghiorghes GJ, Van Eijk, et al. Efficacy and safety of the oral chelator L1 in anaemic rheumatoid arthritis patients. Lancet 1989; II: 1398–9CrossRefGoogle Scholar
  43. 43.
    Lodi R, Hart PE, Rajagopalana B, et al. Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich’s ataxia. Ann Neurol 2001; 49: 590–6PubMedCrossRefGoogle Scholar
  44. 44.
    Koeppen AH, Dickson AC. Iron in the Hallervorden-Spatz syndrome. Pediatr Neurol 2001; 25: 148–55PubMedCrossRefGoogle Scholar
  45. 45.
    Van der Kraaij AMM, Van Eijk HG, Koster JF. Prevention of postischemic cardiac injury by the orally active iron chelator 1,2-dimethyl-3—hydroxy-4-pyridone (L1) and the antioxidant (+)-cyanidanol-3. Circulation 1989; 80: 158–64PubMedCrossRefGoogle Scholar
  46. 46.
    Korkina LG, Afanas’ev IB, Deeva IB, et al. Free radical status of blood of patients with iron overload: the effect of chelating treatment. Drugs Today (Barc) 1992; 28Suppl. A: 137–41Google Scholar
  47. 47.
    Kontoghiorghes GJ, Bunce T, Bruckdorfer KR. Differentiation of the therapeutic and toxicological effects of iron and copper chelating drugs in relation to free radical toxicity. Toxicol Lett 1995; 78: 48–9Google Scholar
  48. 48.
    Korkina L, De Luca C, Deeva I, et al. L1 effects on reactive oxygen (ROS) and nitrogen species (RNS) release, haemoglobin oxidation, low molecular weight antioxidants, and antioxidant enzyme activities in red and white blood cells of thalassaemic patients. Transfus Sci 2000; 23: 253–4PubMedCrossRefGoogle Scholar
  49. 49.
    Moridani MY, O’Brien PJ. Iron complexes of deferiprone and dietary plant catechols as cytoprotective superoxide radical scavengers. Biochem Pharmacol 2001; 62: 1579–85PubMedCrossRefGoogle Scholar
  50. 50.
    Matthews AJ, Vercellotti GM, Menchaca HJ, et al. Iron and atherosclerosis: inhibition by the iron chelator deferiprone (L1). J Surg Res 1997; 73: 35–40PubMedCrossRefGoogle Scholar
  51. 51.
    Arthur AS, Fergus AH, Lanzino G, et al. Systemic administration of the iron chelator deferiprone attenuates subarachnoid hemorrhage-induced cerebral vasospasm in the rabbit. Neurosurgery 1997; 41: 1385–91PubMedCrossRefGoogle Scholar
  52. 52.
    Eybl V, Kotyzova D, Kolek M, et al. The influence of deferiprone (L1) and deferoxamine on iron and essential element tissue level and parameters of oxidative status in dietary iron-loaded mice. Toxicol Lett 2002; 128: 169–75PubMedCrossRefGoogle Scholar
  53. 53.
    Jeremy JY, Kontoghiorghes GJ, Hoffbrand AV, et al. The iron chelators desferrioxamine and 1-alkyl-methyl-3-hydroxypyrid-4-ones inhibit vascular prostacyclin synthesis in vitro. Biochem J 1988; 254: 239–44PubMedGoogle Scholar
  54. 54.
    Barradas MA, Jeremy J, Kontoghiorghes GJ, et al. Iron chelators inhibit human platelet aggregation, thromboxane A synthesis and lipoxygenase activity. FEBS Lett 1989; 245: 105–9PubMedCrossRefGoogle Scholar
  55. 55.
    Koning J, Palmer P, Franks GR, et al. Cardioxane-ICRF 187: towards anticancer drug specificity through selective toxicity reduction. Cancer Treat Rev 1991; 18: 1–19PubMedCrossRefGoogle Scholar
  56. 56.
    Speyer JL, Green MD, Kramer E, et al. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 1988; 319: 745–52PubMedCrossRefGoogle Scholar
  57. 57.
    Barnabe N, Zastre JA, Venkataram S, et al. Deferiprone protects against doxorubicin-induced myocyte cytotoxicity. Free Radic Biol Med 2002; 33: 266–75PubMedCrossRefGoogle Scholar
  58. 58.
    Halliwell B, Gutteridge JMC, Cross CE. Free radicals, antioxidants and human disease: where are we now? J Lab Clin Med 1992; 119: 598–620PubMedGoogle Scholar
  59. 59.
    Eybl V, Caisova D, Koutensky J, et al. Influence of iron chelators: 1,2-dialkyl-3-hydroxypyridin-4-ones on the lipid peroxidation and glutathione levels in the liver in mice. Arch Toxicol Suppl 1991; 14: 185–7PubMedCrossRefGoogle Scholar
  60. 60.
    McLachlan CDR, Dalton AJ, Kruch TPA, et al. Intramuscular desferioxamine in patients with Alzheimer’s disease. Lancet 1991; I: 1304–8CrossRefGoogle Scholar
  61. 61.
    Taylor DM, Kontoghiorghes GJ. Mobilisation of plutonium and iron from transferrin and ferritin by hydroxypyridone chelators. Inorg Chim Acta 1986; 125: L35–8CrossRefGoogle Scholar
  62. 62.
    Eybl V, Svihovcova P, Koutensky J, et al. Interaction of L1, L1NAll and deferoxamine with gallium in vivo. Drugs Today (Barc) 1992; 29Suppl. A: 173–5Google Scholar
  63. 63.
    Edwards DS, Christopher ER, Poirier MJ. Technetium-99m complexes with N-substituted 3-hydroxy-4-pridinones. World Patent WO 9310822Google Scholar
  64. 64.
    Niendorf HP, Alhassan A, Balzer TH, et al. Safety and risk of Gadolinium-DTPA: extended clinical experience after more than 5,000,000 applications. In: Felix R, Heshiki A, Hosten N, et al., editors. Gadopentetate dimeglumine (Gd-DTPA) Magnevist monograph. Oxford: Blackwell Science Pub, 1994: 21–31Google Scholar
  65. 65.
    Elorriaga R, Fernandez Martin JL, Menendez Fraga P, et al. Aluminium removal: short and long term preliminary results with L1 in rats. Drugs Today (Barc) 1992; 28Suppl. A: 177–82Google Scholar
  66. 66.
    Kontoghiorghes GJ, Barr J, Baillod RA. Studies of aluminium mobilisation in renal dialysis patients using the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Arzneimittel Forschung 1994; 44: 522–6PubMedGoogle Scholar
  67. 67.
    Pashalidis I, Kontoghiorghes GJ. Molecular factors affecting the complex formation between deferiprone (L1) ans Cu(II): possible implications on efficacy and toxicity. Arzneimittel Forschung 2001; 51: 998–1003PubMedGoogle Scholar
  68. 68.
    Volf V, Kontoghiorghes GJ. Retention of injected plutonium and americium in mice and rats after oral treatment with DTPA, desferrioxamine and alpha-ketohydroxypyridines. Drugs Today (Barc) 1992; 28Suppl. A: 169–72Google Scholar
  69. 69.
    Pashalidis I, Kontoghiorghes GJ. Effective complex formation in the interaction of I,2-dimethyl-3-hydroxypyrid-4-one (deferiprone or L1) with uranium (VI). J Radioanalyt Nucl Chem 1999; 242: 181–4CrossRefGoogle Scholar
  70. 70.
    Martell AE, Motekaitis RJ, Clarke ET, et al. Comparison of the drugs used for the treatment of iron overload with drugs that have the potential for the same purpose. Drugs Today (Barc) 1992; 28Suppl. A: 11–8Google Scholar
  71. 71.
    Llach F, Felsenfeld AJ, Coleman MK, et al. The natural course of dialysis osteomalaghia. Kidney Int 1986; 29: 74–9Google Scholar
  72. 72.
    Sedman AB, Klein LG, Merrit RJ, et al. Evidence of aluminium loading in infants receiving intravenous therapy. N Engl J Med 1985; 312: 1337–43PubMedCrossRefGoogle Scholar
  73. 73.
    Edwardson JA, Ferrier IN, McArthur FK, et al. Alzheimer’s disease and the aluminium hypothesis. In: Nicolini M, Zatta PF, Corain B, editors. Aluminium in chemistry, biology and medicine. New York: Raven Press, 1992: 85–96Google Scholar
  74. 74.
    Kurtzman NA, editor. Toxicity from aluminium and iron: recognition, treatment and prevention. Semin Nephrol 1986; 6Suppl. 1: 1–41Google Scholar
  75. 75.
    Van Cutsem J, Boelaert JR. Effects of deferoxamine, feroxamine and iron on experimental mucormycosis (zygomycosis). Kidney Int 1989; 36: 1061–8PubMedCrossRefGoogle Scholar
  76. 76.
    Mehta J, Singhal S, Revanker R, et al. Fatal systemic lupus erythematosus in patient taking oral iron chelator L1 [letter]. Lancet 1991; I: 298CrossRefGoogle Scholar
  77. 77.
    Berdoukas V. Antinuclear antibodies in patients taking L1 [letter]. Lancet 1991; I: 672CrossRefGoogle Scholar
  78. 78.
    Olivieri NF, Koren G, Freedman M, et al. Rarity of systemic lupus erythematosus after oral iron chelator L1. Lancet 1991; I: 924CrossRefGoogle Scholar
  79. 79.
    Berdoukas V, Bentley P, Frost H, et al. Toxicity of oral iron chelator L1 [letter]. Lancet 1993; 341: 1088PubMedCrossRefGoogle Scholar
  80. 80.
    Hershko C. Development of oral iron chelator L1. Lancet 1993; 343: 1088–9CrossRefGoogle Scholar
  81. 81.
    Kontoghiorghes GJ, Agarwal MB, Tondury P, et al. Future of oral iron chelator deferiprone (L1). Lancet 1993; I: 1479–80CrossRefGoogle Scholar
  82. 82.
    Kontoghiorghes GJ. Misinformation about deferiprone (L1) [letter]. Lancet 1993; II: 250CrossRefGoogle Scholar
  83. 83.
    Kontoghiorghes GJ, Nasseri-Sina P, Goddard JG, et al. Safety of iron chelator L1. Lancet 1989; II: 457–8CrossRefGoogle Scholar
  84. 84.
    Olivieri NF, Brittenham GM, Mclaren C, et al. Long term safety and effectiveness of iron chelation therapy with deferiprone for thalassaemia major. N Engl J Med 1998; 339: 417–23PubMedCrossRefGoogle Scholar
  85. 85.
    Kowdly KV, Kaplan MM. Iron chelation therapy with oral deferiprone: toxicity or lack of efficacy. N Engl J Med 1998; 339: 468–9CrossRefGoogle Scholar
  86. 86.
    Pippard MJ, Weatherall DJ. Deferiprone for thalassaemia. Lancet 2001; 356: 1444–5CrossRefGoogle Scholar
  87. 87.
    Agarwal MB. Oral iron chelation: a review with special emphasis on Indian work on deferiprone (L1). Indian J. Pediatr 1993; 60: 509–16PubMedCrossRefGoogle Scholar
  88. 88.
    Cohen A, Galanello R, Piga A, et al. A multi-centre safety trial of the oral iron chelator deferiprone. Ann N Y Acad Sci 1998; 850: 466–8CrossRefGoogle Scholar
  89. 89.
    Cohen AR, Galanello R, Piga A, et al. Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 2000; 108: 305–12PubMedCrossRefGoogle Scholar
  90. 90.
    Kontoghiorghes GJ, Agarwal MB, Tondury P, et al. Deferiprone or fatal iron toxic effects? Lancet 2001; 357: 882–3PubMedCrossRefGoogle Scholar
  91. 91.
    Kontoghiorghes GJ. The design of orally active iron chelators for the treatment of thalassaemia [PhD thesis]. Colchester, UK: University of Essex, 1982: 1–243Google Scholar
  92. 92.
    Kontoghiorghes GJ. Method of synthesis of 1,2-dimethyl-3-hydroxypyrid-4-one. Greek patent 1003358. 2000Google Scholar
  93. 93.
    Sansville EA, Pelsach J, Horwitz SB. Effects of chelating agents and metal ions on the degradation of DNA by bleomycin. Biochemistry 1976; 17: 2740–6CrossRefGoogle Scholar
  94. 94.
    Hannekens CH, Buring JE, Peto PR. Antioxidant vitamins — benefits not yet proved. N Engl J Med 1994; 330: 1080–1CrossRefGoogle Scholar
  95. 95.
    Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, et al. Effective chelation of iron in β-thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. BMJ 1987; 295: 1509–12PubMedCrossRefGoogle Scholar
  96. 96.
    Pippard MJ, Jackson MJ, Hoffman K, et al. Iron chelation using subcutaneous infusion of diethylene triamine penta-acetic acid (DTPA). Scand J Haematol 1986; 36: 466–72PubMedCrossRefGoogle Scholar
  97. 97.
    Pippard MJ, Callender ST, Finch CA. Ferrioxamine excretion in iron loaded man. Blood 1982; 60: 288–94PubMedGoogle Scholar
  98. 98.
    Kontoghiorghes GJ, Bartlett AN, Hoffbrand AV, et al. Long term trial with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). (I) Iron chelation and metabolic studies. Br J Haematol 1990; 76: 295–300PubMedCrossRefGoogle Scholar
  99. 99.
    Olivieri NF, Koren G, Matsuii D, et al. Reduction of tissue iron stores and normalisation of serum ferritin during treatment with the oral iron chelator L1 in thalassaemia intermedia. Blood 1992; 79: 2741–8PubMedGoogle Scholar
  100. 100.
    Anderson LJ, Wonke B, Prescott E, et al. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in betathalassaemia. Lancet 2002; 360: 516–20PubMedCrossRefGoogle Scholar
  101. 101.
    Angellucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassaemia major. N Engl J Med 2000; 343: 327–31CrossRefGoogle Scholar
  102. 102.
    Nielsen P, Fischer R, Engelhardt R, et al. Liver iron stores in patients with secondary haemochromatosis under iron chelation therapy with deferoxamine or deferiprone. Br J Haematol 1995; 91: 827–33PubMedCrossRefGoogle Scholar
  103. 103.
    Mavrogeni SI, Gotsis ED, Markussis V, et al. T2 relaxation time study of iron overload in β-thalassaemia. MAGMA 1998; 6: 7–12PubMedGoogle Scholar
  104. 104.
    Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001; 22: 2171–9PubMedCrossRefGoogle Scholar
  105. 105.
    Breuer W, Hershko C, Cabantchik ZI. The importance of nontransferrin bound iron in disorders of iron metabolism. Transfus Sci 2000; 23: 185–92PubMedCrossRefGoogle Scholar
  106. 106.
    Kontoghiorghes GJ, Bartlett AN, Sheppard L, et al. Oral iron chelation therapy with deferiprone (L1): monitoring of biochemical, drug and iron excretion changes. Arzneimittel Forschung 1955; 45: 65–9Google Scholar
  107. 107.
    Kontoghiorghes GJ. Iron chelation in biochemistry and medicine. In: Rice-Evans C, editor. Free radicals, oxidant stress and drug action. London: Rechelieu Press, 1982: 277–303Google Scholar
  108. 108.
    Sheppard L, Kontoghiorghes GJ. Competition between deferiprone, desferrioxamine and other chelators for iron and the effect of other metals. Arzheimittel Forschung 1993; 43: 659–63Google Scholar
  109. 109.
    De Virgilis S, Cognia M, Turco MP, et al. Depletion of trace elements and acute occular toxicity induced by desferrioxamine in patients with thalassaemia. Arch Dis Child 1988; 63: 250–5CrossRefGoogle Scholar
  110. 110.
    Al-Refai FN, Wonke B, Wickens DG, et al. Zinc concentration in patients with iron overload receiving oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one or desferrioxamine. J Clin Pathol 1994; 47: 657–60CrossRefGoogle Scholar
  111. 111.
    Kontoghiorghes GJ, Sheppard L, Chambers S. New synthetic approach and iron chelation studies of 1-alkyl-2-methyl-3-hydroxypyrid-4-ones. Arzneimittel Forschung 1987; 37: 1099–102PubMedGoogle Scholar
  112. 112.
    Allain P, Chaleil D, Mauras Y, et al. Pharmacokinetics of desferrioxamine and its aluminium chelates in patients on haemodialysis. Clin Chim Acta 1987; 170: 331–8PubMedCrossRefGoogle Scholar
  113. 113.
    Kontoghiorghes GJ. Therapeutic, pharmacological and toxicological aspects of metals and new chelating drugs. Curr Top Mol Pharmacol 1993; 1: 189–211Google Scholar
  114. 114.
    Kontoghiorghes GJ. The study of iron mobilisation from transferrin using a-ketohydroxy heteroaromatic chelators. Biochim Biophys Acta 1986; 869: 141–6PubMedCrossRefGoogle Scholar
  115. 115.
    Kontoghiorghes GJ. Iron mobilisation from lactoferrin by chelators at physiological pH. Biochim Biophys Acta 1986; 882: 267–70PubMedCrossRefGoogle Scholar
  116. 116.
    Kontoghiorghes GJ, Chambers S, Hoffbrand AV. Comparative study of iron mobilisation from haemosiderin, ferritin and iron (III) precipitates by chelators. Biochem J 1987; 241: 87–92PubMedGoogle Scholar
  117. 117.
    Kontoghiorghes GJ. Decreased solubilisation of ferritin iron and fresh iron (III) precipitate following repeated chelator treatments. Inorg Chim Acta 1987; 138: 36–40CrossRefGoogle Scholar
  118. 118.
    Keberle H. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann N Y Acad Sci 1964; 119: 758–68PubMedCrossRefGoogle Scholar
  119. 119.
    Lee P, Mohammed N, Marshall RD, et al. Intravenous infusion pharmacokinetics of desferrioxamine in thalassaemia patients. Drug Metab Dispos 1993; 21: 640–4PubMedGoogle Scholar
  120. 120.
    Evans RW, Sharma M, Ogwang W, et al. The effect of alphaketohydroxypyridine chelators on transferrin saturation in vitro and in vivo. Drugs Today (Barc) 1992; 28Suppl. A: 19–23Google Scholar
  121. 121.
    Mostert LJ, Van Dorst JA, Koster JF, et al. Free radical and cytotoxic effects of chelators and their iron complexes in the hepatocyte. Free Radic Res Commun 1987; 3: 379–88PubMedCrossRefGoogle Scholar
  122. 122.
    Brock JH, Liceaga J, Arthur HML, et al. The effect of novel 1-alkyl-3-hydroxy-2-methylpyrid-4-one chelators on uptake and release of iron from macrophages. Am J Haematol 1990; 34: 21–5CrossRefGoogle Scholar
  123. 123.
    Weinberg ED. Cellular iron metabolism in health and disease. Drug Metab Rev 1990; 22: 531–79PubMedCrossRefGoogle Scholar
  124. 124.
    Proper RD, Shurin SB, Nathan DG. Reassessment of the use of desferrioxamine B in iron overload. N Engl J Med 1976; 294: 1421–3CrossRefGoogle Scholar
  125. 125.
    Cases A, Velly J, Sabater J, et al. Acute visual and auditory neurotoxicity in patients with end-stage renal disease receiving desferoxamine. Clin Nephrol 1988; 29: 176–8PubMedGoogle Scholar
  126. 126.
    Tenenbein M, Kowalski S, Sienko A, et al. Pulmonary toxic effects of continous desferrioxamine administration in acute iron poisoning. Lancet 1992; I: 699–701CrossRefGoogle Scholar
  127. 127.
    Sofroniadou K, Drossou M, Foundoulaki M, et al. Acute bone marrow aplasia associated with intravenous administration of deferoxamine (desferrioxamine). Drug Saf 1990; 5(2): 152–4PubMedCrossRefGoogle Scholar
  128. 128.
    Sharnetzky M, Konig R, Lamomek M, et al. Prophylaxis of systemic yersiniasis in Thalassaemia major [letter]. Lancet 1984; II: 791CrossRefGoogle Scholar
  129. 129.
    De Sanctis V, Pinamonti A, Di Palma A, et al. Growth and development in thalassaemia major patients with severe bone lesions due to desferrioxamine. Eur J Paediatr 1996; 155: 368–72CrossRefGoogle Scholar
  130. 130.
    Hoffbrand AV, Bartlett A, Veys PA, et al. Agranulocytosis and thrombocytopenia in a patient with Blackfan-Diamond anaemia during oral chelator trial [letter]. Lancet 1989; II: 457CrossRefGoogle Scholar
  131. 131.
    Kontoghiorghes GJ, Bartlett AH, Hoffbrand AV. Prospects for effective oral iron chelation therapy in man with 1,2-dimethyl-3-hydroxypyrid-4-one and other alphaketohydroxypyridines. Prog Clin Biol Res 1989; 309: 107–14PubMedGoogle Scholar
  132. 132.
    Loebstein R, Diav-Citrin O, Atanackovic G, et al. Deferiproneinduced agranulocytosis: a critical review of five rechallenged cases. Clin Drug Invest 1997; 13: 345–9CrossRefGoogle Scholar
  133. 133.
    Castriota-Scanderbeg A, Sacco M. Agranulocytosis, arthritis and systemic vasculitis in a patient receiving the oral iron chelator L1 (deferiprone). Br J Haematol 1997; 96: 254–5PubMedCrossRefGoogle Scholar
  134. 134.
    Ceci A, Baiardi P, Felisi M, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol 2002; 118: 330–6PubMedCrossRefGoogle Scholar
  135. 135.
    Kersten MJ, Lange R, Smeets MEP, et al. Long term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicentre trial. Ann Haematol 1996; 73: 247–52CrossRefGoogle Scholar
  136. 136.
    Bartlett AN, Hoffbrand AV, Kontoghiorghes GJ. Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Br J Haematol 1990; 76: 301–9PubMedCrossRefGoogle Scholar
  137. 137.
    Davies SC, Marcus RE, Hungerford JL, et al. Ocular toxicity of high dose intravenous desferrioxamine. Lancet 1983; II: 181–4CrossRefGoogle Scholar
  138. 138.
    Rahi AHS, Hungerford JL, Ahmed AI. Ocular toxicity of desferrioxamine: light microscopic histochemical and ultrastructural findings. Br J Ophthal 1986; 70: 373–81CrossRefGoogle Scholar
  139. 139.
    Rubinstein M, Dupont P, Doppel JP, et al. Ocular toxicity of desferrioxamine. Lancet 1985; I: 817–8CrossRefGoogle Scholar
  140. 140.
    Borgna-Pignatti C, De Stefano P, Broglia AM. Visual loss in patient on high dose subcutaneous desferrioxamine. Lancet 1984; I: 68Google Scholar
  141. 141.
    Agarwal MB, Gupta SS, Viswanathan C, et al. Long term assessment of efficacy and toxicity of L1 (1, 2-dimethyl-3-hydroxypyrid-4-one) in transfusion dependent thalassaemia: Indian trial. Drugs Today (Barc) 1992; 28Suppl. A: 107–14Google Scholar
  142. 142.
    Berkovitch M, Laxer RM, Inman R, et al. Arthropathy in thalassaemia patients receiving deferiprone. Lancet 1994; 343: 1471–2PubMedCrossRefGoogle Scholar
  143. 143.
    Guerin A, London G, Marchais S, et al. M. Acute deafness and desferrioxamine. Lancet 1985; II: 39–40CrossRefGoogle Scholar
  144. 144.
    Roger SD, Stewart JH, Harris DCU. Desferrioxamine enhances the haemopoietic response to erythropoietin but adverse events are common. Nephron 1991; 58: 33–6PubMedCrossRefGoogle Scholar
  145. 145.
    Polson RJ, Jawed A, Bomford A, et al. Treatment of rheumatoid arthritis with desferrioxamine: relation between stores of iron before treatment and side effects. Br Med J (Clin Res Ed) 1985; 291: 448CrossRefGoogle Scholar
  146. 146.
    Bentur Y, Koren G, Tegoro A, et al. Comparison of deferoxamine pharmacokinetics between asymptomatic thalassemic children and those exhibiting severe neurotoxicity. Clin Pharmacol Ther 1990; 47: 478–82PubMedCrossRefGoogle Scholar
  147. 147.
    Blake DR, Winyard P, Lunec J, et al. Cerebral and ocular toxicity induced by desferrioxamine. Q J Med 1985; 56: 345–55PubMedGoogle Scholar
  148. 148.
    Freedman MH, Grisaru D, Olivieri N, et al. Pulmonary syndrome in patients with thalassaemia major receiving intravenous deferoxamine infusions. Am J Dis Child 1990; 144: 565–9PubMedGoogle Scholar
  149. 149.
    Tondury P, Zimmerman A, Nielsen P, et al. Liver iron fibrosis during long-term treatment with deferiprone in Swiss thalassaemic patients. Br J Haematol 1998; 101: 413–5PubMedCrossRefGoogle Scholar
  150. 150.
    Wanless IR, Sweeney G, Dhillon AP, et al. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood 2002; 100: 1566–9PubMedCrossRefGoogle Scholar
  151. 151.
    De Virgidis S, Cognie M, Frau F, et al. Deferoxamine-induced growth retardation in patients with thalassaemia major. J Pediatr 1988; 113: 661–9CrossRefGoogle Scholar
  152. 152.
    De Sanctis V, Atti C, Banim P, et al. Growth in thalassaemia major. Acta Med Auxal 1991; 23: 29–36Google Scholar
  153. 153.
    Robins-Browne RM, Pipic JK. Desferrioxamine and systemic yersiniosis [letter]. Lancet 1983; II: 1372CrossRefGoogle Scholar
  154. 154.
    Scharnetzky M, Konig R, Lakomek M, et al. Prophylaxis of systemic yersiniosis in thalassaemia major [letter]. Lancet 1984; I: 791CrossRefGoogle Scholar
  155. 155.
    Gordts B, Rummens E, De Meirleir L, et al. Yersinia pseudotuberculosis septicaemia in thalassaemia major. Lancet 1984; I: 41–2CrossRefGoogle Scholar
  156. 156.
    Kelly D, Price E, Wright V, et al. Yersinia and iron overload. BMJ 1986; 292: 413PubMedCrossRefGoogle Scholar
  157. 157.
    Del Vecchio GC, Schettini F, Placente L, et al. Effects of deferiprone on immune status and cytokine pattern in thalassaemia major. Acta Haematol 2002; 108: 144–9PubMedCrossRefGoogle Scholar
  158. 158.
    Aydinok Y, Nisli G, Kavakli K, et al. Sequential use of L1 and desferrioxamine in primary school children with thalassaemia major in Turkey. Acta Haematol 1999; 102: 17–21PubMedCrossRefGoogle Scholar
  159. 159.
    Van Cutsem J, Boelaert JR. Effects of deferoxamine, feroxamine and iron on experimental mucormycosis (zygomycosis). Kidney Int 1989; 36: 1061–8PubMedCrossRefGoogle Scholar
  160. 160.
    Walker JA, Sherman RA, Eisinger RP. Thrombocytopenia associated with intravenous desferrioxamine. Am J Kidney Dis 1985; 6: 254–6PubMedGoogle Scholar
  161. 161.
    Nebeker HG, Milliner DS, Ott SA, et al. Aluminium-related osteomalagia: clinical response to desferrioxamine [abstract]. Kidney Int 1984; 25: 173Google Scholar
  162. 162.
    Romeo MA, Di Gregorio F, Schiliro G. Allergy to desferrioxamine. J Inherit. Metab Dis 1984; 7: 121Google Scholar
  163. 163.
    Athanasiou A, Shepp MA, Necheles TF. Anaphylactic reaction to desferrioxamine [letter]. Lancet 1977; II: 616CrossRefGoogle Scholar
  164. 164.
    Bousquet J, Navarpo M, Robert G, et al. Rapid desensitisation for desferrioxamine anaphylactic reactions. Lancet 1983; II: 859–60CrossRefGoogle Scholar
  165. 165.
    Miller KB, Rosenwasser LJ, Bessette JA, et al. Rapid desensitisation for desferrioxamine anaphylactic reaction [letter]. Lancet 1987; I: 1059Google Scholar
  166. 166.
    Batey R, Scott J, Jain S, et al. Acute renal insufficiency occurring during intravenous desferrioxamine therapy. Scand J Haematol 1979; 22: 277–9PubMedCrossRefGoogle Scholar
  167. 167.
    Wayne AS, Rosenblum ND, Sallan D, et al. Renal abnormalities in patients with β-thalassaemia major treated with chronic subcutaneous deferoxamine [abstract]. Blood 1993; 82Suppl. 1: 476aGoogle Scholar
  168. 168.
    Kontoghiorghes GJ. Orally active α-ketohydroxypyridine iron chelators: effects on iron and other metal mobilisations. Acta Haematol 1987; 78: 212–6PubMedCrossRefGoogle Scholar
  169. 169.
    Klebanoff SJ, Waltersdorph AM, Michel BR, et al. Oxygenbased free radical generation by ferrous ions and desferioxamine. J Biol Chem 1989; 254: 19765–71Google Scholar
  170. 170.
    Ganeshaguru K, Lally KM, Piga A, et al. Cytotoxic mechanisms of iron chelators. Drugs Today (Barc) 1992; 28Suppl. A: 29–34Google Scholar
  171. 171.
    Lederman HM, Cohen A, Lee JWW, et al. Deferrioxamine: a reversible S-phase inhibitor of human lymphocyte proliferation. Blood 1984; 64: 748–53PubMedGoogle Scholar
  172. 172.
    Summers MR, Jacobs A, Tudway D, et al. Studies in desferrioxamine and ferrioxamine iron metabolism in normal and iron loaded subjects. Br J Haematol 1979; 42: 547–55PubMedCrossRefGoogle Scholar
  173. 173.
    Marcus RE, Davies SG, Bantock HM, et al. Desferrioxamine to improve cardiac function in iron-overloaded patients with thalassaemia major. Lancet 1984; I: 392–3CrossRefGoogle Scholar
  174. 174.
    Cohen A, Martin M, Schwartz E. Depletion of excessive liver iron stores with desferrioxamine. Br J Haematol 1984; 58: 369–73PubMedCrossRefGoogle Scholar
  175. 175.
    Kontoghiorghes GJ, Marcus RE, Huehns ER. Desferrioxamine suppositories [letter]. Lancet 1983; II: 454CrossRefGoogle Scholar
  176. 176.
    Callender ST, Weatherall DJ. Iron chelation with oral desferrioxamine [letter]. Lancet 1980; II: 689CrossRefGoogle Scholar
  177. 177.
    Kontoghiorghes GJ. L1 (1,2-dimethyl-3-hydroxypyrid-4-one). Drugs Future 1988; 13: 413–5Google Scholar
  178. 178.
    Kontoghiorghes GJ, Piga A, Hoffbrand A. Cytotoxic effects of the lipophilic iron chelator omadine. FEBS Lett 1986; 204: 208–12PubMedCrossRefGoogle Scholar
  179. 179.
    Kontoghiorghes GJ, Goddard JG, Bartlett AN, et al. Pharmacokinetic studies in humans with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Clin Pharmacol Ther 1990; 48: 255–61PubMedCrossRefGoogle Scholar
  180. 180.
    Sheppard L, Kontoghiorghes GJ. Synthesis and metabolism of L1 and other novel alpha-ketohydroxypyridine iron chelators and their metal complexes. Drugs Today (Barc) 1992; 28Suppl. A: 3–10Google Scholar
  181. 181.
    Matsui D, Klein J, Hermann C, et al. Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one in patients with thalassaemia. Clin Pharmacol Ther 1991; 50: 294–8PubMedCrossRefGoogle Scholar
  182. 182.
    Nielsen P, Frtjes M, Drescow B, et al. The iron-decorporating effect of L1 in normal and TMH-ferrocene iron loaded rats and in one patient with post-transfusional siderosis as judged by 59Fe-labelling technique. Drugs Today (Barc) 1992; 28 Suppl. A: 45–53Google Scholar
  183. 183.
    Diav-Citrin O, Atanackovic G, Koren G. An investigation into variability in the therapeutic response to deferiprone in patients with thalassaemia major. Ther Drug Monit 1999; 21: 74–81PubMedCrossRefGoogle Scholar
  184. 184.
    Kontoghiorghes GJ, Aldouri MA, Sheppard LN, et al. 1, 2-Dimethyl-3-hydroxypyrid-4-one, on orally active chelator for the treatment of transfusional iron overload. Lancet 1987; I: 1294–5CrossRefGoogle Scholar
  185. 185.
    Olivieri NF, Koren G, Hermann C, et al. Comparison of oral iron chelator L1 and desferrioxamine in iron loaded patients. Lancet 1990; II: 1275–9CrossRefGoogle Scholar
  186. 186.
    Agarwal MB, Gupta SS, Viswanathan C, et al. Long term assessment of efficacy and safety of L1, an oral iron chelator in transfusion dependent thalassaemia: Indian trial. Br J Haematol 1992; 82: 460–6PubMedCrossRefGoogle Scholar
  187. 187.
    Tondury P, Kontoghiorghes GJ, Ridolfi-Luthy R, et al. L1 (1,2-dimethyl-3-hydroxypyrid-4-one) for oral iron chelation in patients with B -thalassaemia major. Br J Haematol. 1990; 76: 550–3PubMedCrossRefGoogle Scholar
  188. 188.
    Goudsmit R, Kersten MJ. Long term treatment of transfusion hemosiderosis with the oral iron chelator L1. Drugs Today (Barc) 1992; 28Suppl. A: 133–5Google Scholar
  189. 189.
    Jaeger M, Aul C, Sohngen D, et al. Iron overload in polytransfused patients with MDS: use of L1 for oral iron chelation. Drugs Today (Barc) 1992; 28Suppl. A: 143–7Google Scholar
  190. 190.
    Carnelli V, Spadaro C, Stefano V, et al. L1 efficacy and toxicity in poorly compliant and for refractory to desferrioxamine thalassaemia patients: interim report. Drugs Today (Barc) 1992; 28Suppl. A: 119–21Google Scholar
  191. 191.
    Collins AF, Fassos FF, Stobie S, et al. Iron balance and dose response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron loaded patients with sickle cell disease. Blood 1994; 83: 2329–3PubMedGoogle Scholar
  192. 192.
    Rombos Y, Tzanetea R, Konstantopoulos K, et al. Chelation therapy in patients with thalassaemia using the orally active iron chelator deferiprone (L1). Haematologica 2000; 85: 115–7PubMedGoogle Scholar
  193. 193.
    Diav-Citrin O, Koren G. Oral iron chelation with deferiprone. Pediatr Clin North Am 1997; 44: 235–47PubMedCrossRefGoogle Scholar
  194. 194.
    Mazza P, Amurri B, Lazzari G, et al. Oral iron chelating therapy: a single centre interim report on deferiprone (L1) in thalassemia. Haematologica 1998; 83: 496–501PubMedGoogle Scholar
  195. 195.
    Berdoukas V, Bohane T, Eagle C, et al. The Sydney children’s hospital experience with the oral iron chelator deferiprone (L1). Transfus Sci 2000; 23: 239–40PubMedCrossRefGoogle Scholar
  196. 196.
    Dresow B, Fischer R, Nielsen P, et al. Effect of oral iron chelator L1 in iron absorption in man. Ann N Y Acad Sci 1998; 850: 466–8PubMedCrossRefGoogle Scholar
  197. 197.
    Kontoghiorghes GJ. New orally active iron chelators. Lancet 1985; II: 817CrossRefGoogle Scholar
  198. 198.
    Kontoghiorghes GJ, Bartlett AN, Hoffbrand AV, et al. Intensive chelation and iron balance studies using oral 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in man [abstract]. Br J Haematol 1990; 74Suppl. 1: 10Google Scholar
  199. 199.
    Ciba Report on Desferal. Adverse Drug Reaction Centre. Information No.2. 1965 Oct: 1–38Google Scholar
  200. 200.
    Pope E, Berkovitch M, Klein J, et al. Salivary measurement of deferiprone concentrations and correlation with serum levels. Ther Drug Monit 1997; 19: 95–7PubMedCrossRefGoogle Scholar
  201. 201.
    Taher A, Chamoun FM, Koussa S, et al. Efficacy and side effects of deferiprone (L1) in thalassaemia patients not compliant with desferrioxamine. Acta Haematol 1999; 101: 173–7PubMedCrossRefGoogle Scholar
  202. 202.
    Zahet L, Murad FH, Alameddine R, et al. Effect of iron chelation therapy with deferiprone (L1) on the psychosocial status of thalassaemia patients. Haematologia 2002; 31: 333–9CrossRefGoogle Scholar
  203. 203.
    Al-Refai FN, Wonke B, Hoffbrand AV, et al. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassaemia major. Blood 1992; 80: 593–9Google Scholar
  204. 204.
    Cermak J, Brabec V. Treatment of iron overload states with oral administration of the chelator L1. Vnitr Lek 1994; 40: 586–90PubMedGoogle Scholar
  205. 205.
    Adhikari D, Roy TB, Biswas A, et al. Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassaemia and hemoglobin E-beta thalassemia. Indian Pediatr 1995; 32: 855–61PubMedGoogle Scholar
  206. 206.
    Lucas GN, Perera BJ, Foneka EA, et al. A trial of deferiprone in transfusion-dependent iron overloaded children. Ceylon Med J 2000; 45: 71–4PubMedGoogle Scholar
  207. 207.
    Uetrecht JP. Drug metabolism by leukocytes and its role in drug-induced Lupus and other idiosyncratic drug reactions. Toxicology 1990; 20: 213–35Google Scholar
  208. 208.
    Fugata S, Murakami Y, Kuma K, et al. G-CSF levels during spontaneous recovery from drug-induced agranulocytosis [letter]. Lancet 1993; 342; 1495: 242Google Scholar
  209. 209.
    Al-Refai FN, Wonke B, Hoffbrand AV. Deferiprone-associated myelotoxicity. Eur J Haematol 1994; 53: 298–301CrossRefGoogle Scholar
  210. 210.
    Kontoghiorghes GJ. Advances in oral iron chelation in man. Int J Haematol 1992; 55: 27–38Google Scholar
  211. 211.
    Kontoghiorghes GJ. Dose response studies using desferrioxamine and orally active chelators in a mouse model. Scand J Haematol 1986; 37: 63–70PubMedCrossRefGoogle Scholar
  212. 212.
    Kontoghiorghes GJ, Hoffbrand AV. Orally active aketohydroxy pyridine iron chelators intended for clinical use: in vivo studies in rabbits. Br J Haematol 1986; 62: 607–13PubMedCrossRefGoogle Scholar
  213. 213.
    Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and deferoxamine. Br J Haematol 1998; 103: 361–4PubMedCrossRefGoogle Scholar
  214. 214.
    Kontoghiorghes GJ, Kolnagou A. Deferiprone versus desferoxamine in thalassaemia, and T2* validation and utility. Lancet 2003; 361: 184PubMedCrossRefGoogle Scholar
  215. 215.
    Maggio A, D’Amico G, Morabito A, et al. Deferiprone versus deferoxamine in patients with thalassaemia major: a randomised clinical trial. Blood Cells Mol Dis 2002; 28: 196–208PubMedCrossRefGoogle Scholar
  216. 216.
    Panayi GS, Huston G, Shah RR. Deficient sulphoxidation status in D-penicillamine toxicity. Lancet 1983; I: 414CrossRefGoogle Scholar
  217. 217.
    Stobie S, Tyberg J, Matsui D, et al. Comparison of the pharmacokinetics of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in healty volunteers, with and without co-administration of ferrous sulfate, to thalassaemia patients. Int J Clin Pharmacol Ther Toxicol 1993; 31: 602–5PubMedGoogle Scholar
  218. 218.
    Kontoghiorghes GJ, Barr J, Baillod RA. Aluminium mobilisation in renal dialysis patients using the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Drugs Today (Barc) 1992; 28Suppl. A: 183–7Google Scholar
  219. 219.
    Thuma PE, Olivieri NF, Mabeza GF, et al. Assessment of the effect of the oral iron chelator deferiprone on asymptomatic Plasmodium falciparum parasitaemia in humans. Am J Trop Med Hyg 1998; 58: 358–64PubMedGoogle Scholar
  220. 220.
    Kontoghiorghes GK, Jackson MI, Lunec J. In vitro screening of iron chelators using models of free radical damage. Free Radic Res Commun 1986; 2: 115–24PubMedCrossRefGoogle Scholar
  221. 221.
    Ling G, Tirosh R, Pinson A, et al. Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as major site of iron-anthracycline interactions. J Lab Clin Med 1996; 127: 272–8CrossRefGoogle Scholar
  222. 222.
    Forsbeck K, Nillson K, Kontoghiorghes GJ. Variation in iron accumulation, transferrin membrane binding and DNA synthesis in the K562 and U937 cell lines induced by chelators and their iron complexes. Eur J Haematol 1987; 39: 318–25PubMedCrossRefGoogle Scholar
  223. 223.
    Voest EE, Vreugdenhil G, Marx JJM. Iron-chelating agents in non-iron overload conditions. Ann Intern Med 1994; 120: 490–9PubMedGoogle Scholar
  224. 224.
    Sadrzadeh SMH, Nanji AA, Price PL. The oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one reduces hepatic-free iron, lipid peroxidation and fat accumulation in chronically ethanolfed rats. J Pharmacol Exp Ther 1994; 269: 632–6PubMedGoogle Scholar
  225. 225.
    Fredenburg AM, Sethi RK, Allen DD, et al. The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2-dimethyl, 1,2-diethyl, and 1-[ethan-1’ol]-2-methyl-3-hydroxypyrid-4-one in the rat. Toxicology 1996; 108(3): 191–9PubMedCrossRefGoogle Scholar
  226. 226.
    Kontoghiorghes GJ, May A. Uptake and intracellular distribution of iron from transferrin and chelators in erythroid cells. Biol Met 1990; 3: 183–7PubMedCrossRefGoogle Scholar
  227. 227.
    Motekaitis R. J, Martell AE. Stabilities of the iron (III) chelates of 1,2-dimethyl-3-hydroxy-4-pyridinone and related ligands. Inorg Chim Acta 1991; 183: 71–80CrossRefGoogle Scholar
  228. 228.
    Borgna-Pignatti C, Cohen A. Evaluation of a new method of administration of the iron chelating agent deferoxamine. J Pediatr 1997; 130: 86–8PubMedCrossRefGoogle Scholar
  229. 229.
    Hirase N, Abe Y, Salamura S, et al. Anemia and neutropenia in a case of copper deficiency: role of copper in normal hematopoiesis. Acta Haematol 1992; 87: 195–7PubMedCrossRefGoogle Scholar
  230. 230.
    Higuchi S, Higashi A, Nahamura T, et al. Anti-neutrophil antibodies in patients with nutritional copper deficiency. Eur J Paediatr 1991; 150: 327–30CrossRefGoogle Scholar
  231. 231.
    Young GAR, Vincent PC. Drug induced agranulocytosis. Clin Haematol 1980; 9: 483–504PubMedGoogle Scholar
  232. 232.
    Uetrecht JP. Idiosyncratic drug reaction: possible role of reactive metabolites generated by leukocytes. Pharm Res 1989; 6: 265–73PubMedCrossRefGoogle Scholar
  233. 233.
    Kontoghiorghes GJ. L1NAll. -Allyl-2-methyl-3-hydroxypyrid-4-one. Drugs Future 1990; 15: 230–2Google Scholar
  234. 234.
    Nortey P, Barr J, Matsakis M, et al. Effect on iron excretion and animal toxicology of L1 and other alpha-ketohydroxypyridine chelators. Drugs Today (Barc) 1992; 28Suppl. A: 81–8Google Scholar
  235. 235.
    Goddard JG, Kontoghiorghes GJ. Development of an HPLC analytical method for orally administered 1-substituted-2-alkyl-3-hydroxypyrid-4-one iron chelators in biological fluids. Clin Chem 1990; 36: 5–8PubMedGoogle Scholar
  236. 236.
    Spino M, Yang J. Pharmacokinetics and whole body distribution of CP 502: a hydroxypyridinone second generation oral iron chelator [abstract book]. 12th International Conference on Oral Chelation (ICOC); 2002 Jul 4-7: Santorini Hellas 2002, 83–4Google Scholar
  237. 237.
    Alberti A. ICL 670: update on the clinical development of this new oral iron chelator [abstract book]. 12th International Conference on Oral Chelation (ICOC); 2002 Jul 4-7: Santorini, Hellas 2002, 85–6Google Scholar
  238. 238.
    Galanello R, Cappellini MD, Piga A, et al. Update on the effects of ICL 670, a novel tridentate oral iron chelator, on liver iron concentration in patients with transfusion dependent iron overload [abstract book]. 12th International Conference on Oral Chelation (ICOC); 2002 Jul 4-7: Santorini, Hellas 2002, 90–1Google Scholar
  239. 239.
    Marquis JK, Bree M, Appelqvist T. Bioavailability and pharmacokinetic properties of GT56-252, a novel orally available iron chelator [abstract book]. 12th International Conference on Oral Chelation (ICOC); 2002 Jul 4-7: Santorini, Hellas. 2002: 113(P1)Google Scholar
  240. 240.
    Marquis JK, Aoude-Dagher R, Guillaumat PO. Pharmaology and toxicology of GT56-252, a novel orally available iron chelator [abstract book]. 12th International Conference on Oral Chelation (ICOC); 2002 Jul 4-7: Santorini, Hellas 2002, 113(P2)Google Scholar
  241. 241.
    Kontoghiorghes GJ, Sheppard L. Simple synthesis of the potent iron chelators 1-alkyl-3-hydroxy-2-methylpyrid-4-ones. Inorg Chim Acta 1987; 136: L11–2CrossRefGoogle Scholar
  242. 242.
    Kontoghiorghes GJ. Oral iron chelation is here. BMJ 1991; 303: 1279–80PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • George J. Kontoghiorghes
    • 1
  • Katia Neocleous
    • 1
  • Annita Kolnagou
    • 1
  1. 1.Postgraduate Research Institute of ScienceTechnology, Environment and MedicineCyprusUnited Kingdom

Personalised recommendations