THERAPEUTIC ADVANCEMENTS IN MANAGEMENT OF IRON OVERLOAD–A REVIEW

Authors

  • Priyanka Tyagi Centre for Biomedical Engineering, Indian Institute of Technology, New Delhi, P. O. Box 110016, India
  • Yougesh Kumar Department of Zoology, DAV (PG) College, Muzaffarnagar, C. C. S. University, Meerut, U. P
  • Dikshi Gupta Centre for Biomedical Engineering, Indian Institute of Technology, New Delhi, P. O. Box 110016, India
  • Harpal Singh Centre for Biomedical Engineering, Indian Institute of Technology, New Delhi, P. O. Box 110016, India
  • Amit Kumar Institute of Nuclear Medicine and Allied Sciences, DRDO, New Delhi, P. O. Box 110054, India

Keywords:

Iron chelation, Iron overload, Phlebotomy, Siderophores, Deferasirox

Abstract

Removal of excess of free iron, produced under certain physiological conditions in human body, has always been of great concern for therapists worldwide. A number of naturally occurring and synthetic ligands are being explored for maximal iron decorporation, enhanced patient compliance and minimal side effects. Siderophores are the most important class of currently used chelators and few of them are approved for treating iron overload. This review focuses on the developments taking place in the field of iron overload treatment to find the most novel, efficient and safest iron decorporating agent. The importance of many natural and synthetic iron scavengers, having potential for clinical application in the treatment of iron overload and their associated side effects, are discussed along with the currently followed methods. Special emphasis is given to review the status of new ligands, combination therapy and methodologies adopted for overcoming limitations of existing therapeutic agents for treatment of different iron overload disorders.

 

Downloads

Download data is not yet available.

Author Biography

Amit Kumar, Institute of Nuclear Medicine and Allied Sciences, DRDO, New Delhi, P. O. Box 110054, India

SCIENTIST D, NUCLEAR MEDICINE

References

Gutteridge JMC, Richmond R, Halliwell B. Inhibition of the iron-catalyzed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine. Biochem J 1979;184:469-72.

Halliwell B. Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action? Free Radic Biol Med 1989;7:645-51.

Corbett JV. Accidental poisoning with iron supplements. MCN: Am J Maternal/Child Nursing 1995;20:234.

Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington DC, National Academy Press; 2001.

Rowley DA, Gutteridge JMC, Halliwell B. Superoxide dependent formation of hydroxyl radicals in the presence of iron salts. Biochem J 1981;199:263-5.

Rank BH, Carlsson J, Hebbel RP. Abnormal redox status of membrane protein thiols in sickle erythrocytes. J Clin Invest 1985;75:1531-7.

Golan DE, Corbett JD. Band 3 and glycophorin are progressively aggregated in density-fractionated sickle and normal red blood cells: Evidence from rotational and lateral mobility studies. J Clin Invest 1993;91:208-17.

Repka T, Hebbel RP. Hydroxyl radical formation by sickle erythrocyte membranes: role of pathologic iron deposits and cytoplasmic reducing agents. Blood 1991;78:2753–8.

Okada S. Iron-induced tissue damage and cancer: the role of reactive oxygen species-free radicals. Pathol Int 1996;46:311–32.

Horton AA, Fairhurst S. Lipid peroxidation and mechanisms of toxicity. Crit Rev Toxicol 1987;18:27-79.

Gilbert RS. Bloodletting over the centuries. N Y State J Med 1980;80:2022-8.

Antle EA. Who needs a therapeutic phlebotomy? Clin J Oncol Nurs 2010:14:694-6.

Barton JC, McDonnel SM, Adams PC, Brissot P, Powell LW, Edwards CQ, et al. Management of hemochromatosis. Hemochromatosis management working group. Ann Intern Med 1998;129:932–9.

Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. Clinical features of genetic hemochromatosis in women compared with men. Ann Intern Med 1997;127:105-10.

Alessandro B, Paola V, Filomena D, Paolo P, Enrico G, Sonia C, et al. Hepatic expression of hemochromatosis genes in two mouse strains after phlebotomy and iron overload. Haematologica 2005;90:1161-7.

Powars D, Wilson B, Imbus C, Pegelow C, Allen J. The natural history of stroke in sickle cell disease. Am J Med 1978;65:461–71.

Balkaran B, Char G, Morris JS, Serjeant BE, Serjeant GR. Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr 1992;120:360–6.

Emanuele A, Pietro M, Guido L, Marta R, Donatella B, Buket E, et al. Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Italian cooperative group for phlebotomy treatment of transplanted thalassemia patients. Blood 1997;90:994-8.

Russell WE, Zimmerman SA, Sylvestre PB, Mortier NA, Davis JS, Treem WR, et al. Prevention of secondary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy. J Pediatr 2004;145:346-52.

Li CK, Lai DH, Shing MM, Chik KW, Lee V, Yuen PM. Early iron reduction programme for thalassaemia patients after bone marrow transplantation. Bone Marrow Transplant 2000;25:653-6.

Lucarelli G, Galimberti M, Polchi P, Angelucci E, Baronciani D, Giardini C, et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med 1990;322:417-21.

Tomas JF, Pinilla I, Garc!ıa-Buey ML, García A, Figuera A, Gómez-García de Soria VGG, et al. Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplant 2000;26:649-55.

Rose C, Ernst O, Hecquet B, Patrice M, Pascale R, Marie PN, et al. Quantification by magnetic resonance imaging and liver consequences of post-transfusional iron overload alone in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Haematologica 2007;92:850-3.

Butt NM, Clark RE. Autografting as a risk factor for persistingiron overload in long-term survivors of acute myeloid leukaemia. Bone Marrow Transplant 2003;32:909-13.

Mateo-Gallego R, Calmarza P, Jarauta E, Elena B, Ana C, Fernando C. Serum ferritin is a major determinant of lipid phenotype in familial combined hyperlipidemia and familial hypertriglyceridemia. Metabolism 2010;59:154-8.

Solanas-Barca M, Mateo-Gallego R, Calmarza P, Jarauta E, Bea AM, Cenarro A, et al. Mutations in HFE causing hemochromatosis are associated with primary hypertriglyceridemia. J Clin Endocrinol Metab 2009;94:4391-7.

Paola CE, Nuria G, Eva A, Carmen G, Rocio MG, Pilar G, et al. Effect of phlebotomy on lipid metabolism in subjects with hereditary hemochromatosis. Metab Clin Exp 2011;60:830–4.

Bomford A, Williams R. Long term results for venesection therapy in idiopathic hemochromatosis. Q J Med 1976;45:611-23.

McAllen PM, Coghill NF, Lubran M. The treatment of hemochromatosis. Q1 Med 1957;26:251-76.

Skinner C, Kenmure ACF. Hemochromatosis presenting as congestive cardiomyopathy and responding to venesection. Br Heart J 1973;35:466-8.

Williams R, Smith PM, Spicer ElF, Barry M, Sherlock S. Venesection therapy in idiopathic hemochromatosis: an analysis of 40 treated and 18 untreated patients. Q1 Med 1969;38:1-16.

Mostert LJ, Cleton MI, Bruijn WC, Koster JF, Vaneijk HG. Studies on ferritin in rat liver and spleen during repeated phlebotomy. Int J Biochem 1989;21:39-47.

Farinato M, Di Pierro G, Amalfi G, Caravelli V, D'Angelo F, Morace M, et al. Iron overload in chronic liver diseases and clinical usefulness of therapeutic phlebotomy: our experience. Dig Liver Dis 2006;38:S185.

Hayashi H, Takikawa T, Nishimura N, Yano M, Isomura T, Sakamoto N. Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol 1994;89:986-8.

Limdi JK, Crampton JR. Review hereditary haemochromatosis. Q J Med 2013;97:315–24.

Adams PC, Barton C. How I treat hemochromatosis? Blood 2010;116:317-25.

Valenti L, Fracanzani AL, Dongiovanni P, Bugianesi E, Marchesini G, Manzini P, et al. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol 2007;102:1251-8.

Minamiyama Y, Takemura S, Kodai S, Shinkawa H, Tsukioka T, Ichikawa H, et al. Iron restriction improves type 2 diabetes mellitus in otsuka long-evans tokushima fatty rats. Am J Physiol: Endocrinol Metab 2010;298:1140-9.

Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-19.

Elizabeth MS, Roger AW, Margaret EB. Myocardial involvement in idiopathic hemochromatosis: Morphologic and clinical improvement following venesection. Am J Med 1981;70:1275–9.

Dabestani A, John SC, Eberhard H, Joseph KP, Hans S, William GF, et al. Primary hemochromatosis: Anatomic and physiologic characteristics of the cardiac ventricles and their response to phlebotomy. Am J Cardiol 1984;54;153–9.

Bacon BR, Adams PC, Kowdley KV, Lawrie WP, Anthony ST. Diagnosis and management of hemochromatosis: 2011 practice guideline by the american association for the study of liver diseases. Hepatology 2011;54:328-43.

Koliantzaki G, Sorras KD, Dimitrakopoulos SK, Kathopoulis NI, Bonas A, Saltamavros A, et al. Phlebotomy a longitudinal operating techniques. 9th European Congress on Menopause and Andropause/Maturitas; 2012;71:S1–S82.

McCaffery M, Beebe A. Pain: clinical manual for nursing practice. Baltimore: VV Mosby Company St. Louis; 1994.

Manea P, Loustaud-Ratti V, Mondary D, Arnold V, Ferley JP, Souris S, et al. Evaluation of at-home phlebotomy for iron overload: Feasibility and satisfaction of patients and healthcare workers. Gastroenterol Clin Biol 2008;32:172-9.

Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, Kolnagou A. Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1). Transfus Sci 2000;23:211–33.

Fabio G, Minonzio F, Delbini P, Bianchi A, Cappellini MD. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis. Blood 2007;109:362-4.

Cosgrove DJ. The determination of myo-inositol hexakisphosphate (phytate). J Sci Food Agric 1980 31;1253–6.

Hawkins PT, Poyner DR, Jackson TR, Letcher AJ, Lander DA, Irvine RF. Inhibition of iron-catalysed hydroxyl radical formation by inositol polyphosphates: a possible physiological function for myo-inositol hexakisphosphate. Biochem J 1993;294:929–34.

Mukhopadhyay S, Basak J, Kar M, Mandal S, Mukhopadhyay A. Wheatgrass as a natural iron chelator in myelodysplastic syndrome, the role of iron chelation activity of wheat grass juice in patients with myelodysplastic syndrome. J Clin Oncol 2009;27:7007-12.

Thephinlap C, Ounjaijean S, Khansuwan U, Fucharoen S, Porter JB. Epigallocatechin-3-gallate and epicatechin-3-gallate from green tea decrease plasma non-transferrin bound iron and erythrocyte oxidative stress. Med Chem 2007;3:289-96.

Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MB. Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol Nutr Food Res 2006;50:229-34.

Kessler M, Ubeau G, Jung L. Anti-and pro-oxidant activity of rutin and quercetin derivatives. J Pharm Pharmacol 2003;55:131-42.

Cook NC, Samman S. Flavonoids-chemistry, metabolism, cardioprotective effects, and dietary sources. Nutr Biochem 1996;7:66-76.

Shahidi F, Wanasundara PKJ. Phenolic antioxidants. Crit Rev Food Sci Nutr 1992;32:67-103.

Ali ME, Fereshteh P, Ahmad RB. Iron chelating activity, phenol and flavonoid content of some medicinal plants from Iran. Afr J Biotechnol 2008;7:3188-92.

Hutchinson C, Bomford A, Geissler CA. The iron-chelating potential of silybin in patients with hereditary haemochromatosis. Eur J Clin Nutr 2010;64:1239–41.

Gharagozloo M, Khoshdel Z, Amirghofran Z. The effect of an iron (III) chelator, silybin, on the proliferation and cell cycle of Jurkat cells: A comparison with desferrioxamine. Eur J Pharmacol 2008;589:1–7.

Borsari M, Gabbi C, Ghelfi F, Grandi R, Saladini M, Severi S. Silybin, a new iron-chelating agent. J Inorg Biochem 2001;85:123–9.

Borsari M, Ferrari E, Grandi R, Saladini M. Curcuminoids as potential new iron-chelating agents: spectroscopic, polarographic and potentiometric study on their Fe(III) complexing ability. Inorg Chim Acta 2002;328:61–8.

Benassi R, Ferrari E, Grandi R, Lazzari S, Saladini M. Synthesis and characterization of new b-diketo derivatives with iron chelating ability. J Inorg Biochem 2007;101:203–13.

Jurkevitch E, Hadar Y, Chen Y, Libman J, Shanzer A. Iron uptake and molecular recognition in Pseudomonas putida: receptor mapping with ferrichrome and its biomimetic analogs. J Bacterial 1992;174:78-83.

Reid RT, Live DH, Faulkner DJ, Butler A. A siderophore from a marine bacterium with an exceptional ferric ion affinity constant. Nature 1993;366:455-8.

Ito T, Neilands JB. Products of low iron fermentation with Bacillus subtilis: isolation, characterization and synthesis of 2,3-dihydroxybenzoylglycine. J Am Chem Soc 1958;80:4645-7.

Winkelmann G, Drechsel H. Microbial Siderophores. In: Rehm J, Reed G. editors. Biotechnology Set. 2nd ed. Germany: Wiley-VCH Verlag GmbH, Weinheim; 2008.

Sigel A, Sigel H. Metal ions in biological systems, Volume 35: Iron transport and storage microorganisms, plants, and animals. Met Based Drugs 1998;5:262.

Dionis JB, Jenny HB, Peter HH. Handbook of Microbial Iron Chelates. In: Winkelmann G Editor. CRC Press; 1991. p. 339-56.

Porter JB, Huehns ER, Hider RC. The development of iron chelating drugs. Baillieres Clin Haematol 1989;2:257-92.

Bulman RA. The chemistry of chelating agents in medical sciences. Struct Bonding 1987;67:91-141.

Zevin S, Link G, Grady RW, Hider RC, Peter HH, Hershko C. Origin and fate of iron mobilized by the 3-hydroxypyridin-4-one oral chelators: studies in hypertransfused rats by selective radioiron probes of reticuloendothelial and hepatocellular iron stores. Blood 1992;79:248-53.

Miller MJ. Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogues. Chem Rev 1989;89:1563–79.

Hider RC, Hall AD. Clinically useful chelators of tripositive elements. Prog Med Chem 1991;28:41–173.

Keberle H. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann New York Acad Sci 1964;119:758-68.

Summers JB, Gunn BP, Martin JG, Mazdiyasni H, Stewart AO, Young PR, et al. Orally active hydroxamic acid inhibitors of leukotriene biosynthesis. J Med Chem 1988;31:3–5.

Dhungana S, White PS, Crumbliss AL. Crystal structure of ferrioxamine b: a comparative analysis and implications for molecular recognition. J Biol Inorg Chem 2001;6:810.

Westlin WF. Deferoxamine as a chelating agent. Clin Toxicol 1971;4:597-02.

Robotham JL, Lietman PS. Acute iron poisoning. a review. Am J Dis Child 1980;34:875-9.

Cohen A, Schwartz E. Iron chelation therapy with deferoxamine in Cooley anemia. J Pediatr 1978;92:643-7.

Ohlsson WTL, Kullendorff GT, Ljungberg KL. Transfusion hemosiderosis; report of a case treated with BAL. Acta Med Scand 1953;145:410–8.

Seven MJ, Gottlieb H, Israel HL, Reinhold J0, Rubin M. N-hydroxyethyl-ethylenedianine triacetic acid, versenol, in the treatment of hemochromatosis. Am J Med Sci Direct 1954;228:646–51.

Bannerman RM, Callender ST, Williams DL. Effect of Desferrioxamine and DTPA in iron overload. Br Med J 1962;2:1573–7.

Bickel H, Bosshardt R, Gaumann E, Reusser P, Vischer E, Voser W. Stoffwechsel-produkte von actinomyceten, über die isolierung und charakterisierung der ferrioxamine A-F, neuer wuchsstoff der sideramin-gruppe. Helv Chim Acta 1960;43:2105-18.

Tufano TP, Pecoraro VL, Raymond KN. Ferric ion sequestering agents: kinetics of iron release from ferritin to catechoylamides. Biochim Biophys Acta 1981;668:420-8.

Kontoghiorghes GJ, Evans RW. Site specificity of iron removal from transferrin by ketohydroxypyridine chelators. FEBS Lett 1985;189:141–4.

Kretchmar SA, Raymond KN. Biphasic kinetics and temperature dependence of iron removal from transferrin by 3,4-LICAMS. J Am Chem Soc 1986;1086:6212-8.

Simeon P, Grace V, Fred L. Iron removal from transferrin: an experimental study. Biochim Biophys Acta 1977;497:481-7.

Sawas DC, Soulpi C. Alterations of the [59Fe] ferric citrate biodistribution in hyperferremic mice after the administration of pyrophosphate and desferrioxamine. J Pharmacol Exp Ther 1983;224:415-8.

Hershko C, Grady RW, Cerami A. Mechanism of iron chelation in the hypertransfused rat: definition of two alternative pathways of iron mobilization. J Lab Clin Med 1978;92:144-51.

Singh S, Mohammed N, Ackerman R, Porter JB, Hider RC. Quantificationof desferrioxamine and its iron chelating metabolites by high performance chromatography and simultaneous radioactive detection. Anal Biochem 1992;203:116-20.

Wapnick AA, Lynch SR, Charlton RW, Seftel HC, Bothwell TH. The effect of ascorbic acid deficiency on desferrioxamine induced urinary iron excretion. Br J Haematol 1969;17:563-8.

O’Brien RT. Ascorbic acid enhancement of desferrioxamine induced urinary iron excretion in thalassemia major. Ann NY Acad Sci 1974;232:221-5.

Pippard MJ, Callender ST, Finch CA. Ferrioxamine excretion in iron-loaded man. Blood 1982;60:288-94.

Rahko PS, Salerni R, Uretsky BF. Successful reversal by chelation therapy of congestive cardiomyopathy due to iron overload. J Am Coll Cardiol 1986;8:436-40.

Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term chelation therapy in thalassaemia major: effect on liver iron concentration, liver histology and clinical progress. Br Med J 1974;2:16-20.

Pignatti BC, Rugolotto S, Stefano PD, Zhao H, Cappellini MD, Vecchio GCD, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematol 2004;89:1187-93.

Zurlo MG, Stefano PD, Borgna-Pignatti C, Palma AD, Piga A, Melevendi C, et al. Survival and causes of death in thalassemia major. Lancet 1989;334:27-30.

Summers MR, Jacobs A, Tudway D, Perera P, Ricketts C. Studies in desferrioxamine and ferrioxamine metabolism in normal and iron-loaded subjects. Br J Haematol 1979;42:547–55.

Olivieri NF, Brittenham GM. Iron chelation therapy and the treatment of thalassemia. Blood 1997;89:739–61.

Wong B, Richardson DR. Beta-thalassemia: emergence of new and improved iron chelators for treatment. Int J Biochem Cell Biol 2003;35:1144–9.

Catsch A, Hartmuth-Hoene AE. Pharmacology and therapeutic applications of agents used in heavy metal poisoning. Pharmacol Ther 1976;1:1–118.

Polson RJ, Jawed A, Bomford A. Treatment of rheumatoid arthritis with desferrioxamine: relation between stores of iron before treatment and side effects. BMJ 1985;291:448.

Raymond KN, Muller G, Matzanke BF. Complexation of iron by siderophores. A review of their solution and structural chemistry and biological functions. Top Curr Chem 1984;123:49-102.

Carrano CJ, Raymond KN. Ferric ion sequestering agents. Kinetics and mechanism of iron removal from transferrin by enterobactin and synthetic tricatechols. J Am Chem Soc 1979;101:5401–4.

Guterman SK, Morris PM, Tannenberg WJK. Feasibility of enterochelin as an iron-chelating drug: Studies with human serum and a mouse model system. General Pharmacol Vascular System 1978;9:123–7.

Smithgall TE, Penning TM. Indomethacin-sensitive 3a-hydroxysteroid dehydrogenase in rat tissues. Biochem Pharmacol 1985;34:831-5.

O'Brien IG, Cox GB, Gibson F. Enterochelin hydrolysis and iron metabolism in Escherichia coli. Biochim Biophys Acta 1971;237:537-49.

Wei Y, Guo M. Hydrogen peroxide triggered prochelator activation, subsequent metal chelation and attenuation of the Fenton reaction. Angew Chem Int Ed 2007;46:4722–5.

Sun J, Chu Y, Wu X, Liu RH. Antioxidant and antiproliferative activities of common fruits. J Agric Food Chem 2002;50:7449–54.

Guo M, Perez C, Wei Y, Rapoza E, Su G, Bou-Abdallah F, Chasteen ND. Iron-binding properties of plant phenolics and cranberry’s bio-effects. Dalton Trans 2007;43:4951–61.

Bergeron RJ, Wiegand J, Brittenham GM. HBED: a potential alternative to deferoxamine for iron-chelating therapy. Blood 1998;91:1446–52.

Neufeld EJ, Galanello R, Viprakasit V, Aydinok Y, Piga A, Harmatz P, et al. A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload. Blood 2012;119:3263-8.

Grünblatt E, Mandel S, Berkuzki T, Youdim MB. Apomorphine protects against MPTP-induced neurotoxicity in mice. Mov Disord 1999;14:612–8.

Drechsel H, Jung G, Winkelmann. Stereochemical characterization of rhizoferrin and identification of its dehydration products. G Biol Met 1992;5:141-8.

Galey JB, Destree O, Dumats J, Pichaud P, March J, Genard S, et al. Protection of U937 cells against oxidative injury by a novel series of iron chelators. Free Radical Biol Med 1998;25:881–90.

Cox CD, Adams P. Siderophore activity of pyoverdin for Pseudomonas aeruginosa. Infect Immun 1985;48:130-8.

Jego P, Lescoat G, Hubert N, Pasdeloup N, Brissot P, Ocaktan AZ, et al. Inhibition of iron overload toxicity by pyoverdins in adult rat hepatocyte cultures. J Inorg Biochem 1991;43:639.

Chenoufi N, Hubert N, Loréal O, Morel I, Pasdeloup N, Cillard J, et al. Inhibition of iron toxicity in rat and human hepatocyte cultures by the hydroxypyridin-4-ones CP20 and CP94. J Hepatol 1995;23:166-73.

Somporn S, Susan A, Malulee T, Sumonrat M. Comparison between Pseudomonas aeruginosa siderophores and desferrioxamine for iron acquisition from ferritin. Asian Biomed 2010;4:631-35.

Morel I, Cillard J, Lescoat G, Sergent O, Pasdeloup N, Ocaktan AZ, et al. Antioxidant and free radical scavenging activities of the iron chelators pyoverdin and hydroxypyrid-4-ones in iron-loaded hepatocyte cultures: comparison of their mechanism of protection with that of desferrioxamine. Free Radic Biol Med 1992;13:499-08.

Richardson DR. Iron chelators as therapeutic agents for the treatment of cancer. Crit Rev Oncol Hematol 2002;42:267-81.

Liu ZD, Hider RC. Design of iron chelators with therapeutic application. Coord Chem Rev 2002;232:151-71.

Dean RT, Nicholson P. The action of nine chelators on iron-dependent radical damage. Free Radic Res 1994;20:83–101.

Singh S, Khodr H, Taylor MI, Hider RC. Therapeutic iron chelators and their potential side-effects. Biochem Soc Symp 1995;61:127–37.

Baret P, Claude B, Gaude D, Gellon G, Mourral C, Pierre JL, et al. Tripodal ligands possessing six convergent hydroxyl groups a novel family of iron sequestering agents based on o, o’-dihydroxybiphenyl subunits tetrahedron. 1994;50:2077-94.

Fredenburg AM, Wedlund PJ, Skinner TL, Damani LA, Hider RC, Yokel RA. Pharmacokinetics of representative 3-hydroxypyridin-4-ones in rabbits: CP20 and CP94. Drug Metab Dispos 1993;21:255-8.

Toso L, Crisponi G, Nurchi VM, Crespo-Alonso M, Lachowicz JI, Santos MA, et al. A family of hydroxypyrone ligands designed and synthesized as iron chelator. J Inorg Biochem 2013;127:220–31.

Hartley A, Rice-Evans C. The chelation of nonheme iron within sickle erythrocytes by the hydroxypyridinone chelator CP094. Arch Biochem Biophys 1992;297:377-82.

Ponka P, Borova J, Neuwirt J, Fuchs O. Mobilization of iron from reticulocytes. Identification of pyridoxal isonicotinoyl hydrazone as a new iron chelating agent. FEBS Lett 1979;97:317–21.

Hoy T, Humphreys J, Jacobs A, Williams A, Ponka P. Effective iron chelation following oral administration of an isoniazid pyridoxalhydrazone. Br J Haematol 1979;43:443–9.

Brittenham GM. Pyridoxal isonicotinoyl hydrazone: an effective chelator after oral administration. Semin Hematol 1990;27:112–6.

Wong CSM, Kwok JC, Richardson DR. PCTH: a novel orally active chelator of the aroylhydrazone class that induces iron excretion from mice. Biochim Biophys Acta 2004;1739:70–80.

Becker E, Richardson DR. Development of novel aroylhydrazone ligands for iron chelation therapy: 2-pyridylcarboxaldehydeisonicotinoyl hydrazine analogs. J Lab Clin Med 1999;134:510–21.

Zanninelli G, Choudury R, Loreal O, Guyader D, Lescoat G, Arnaud J, et al. Novel orally active iron chelators (3-hydroxypyridin-l-ones) enhance the biliary excretion of plasma non-transferrin-bound iron in rats. J Hepat 1991;27:116-84.

Grazina R, Gano L, Sebestialk J, Santos MA. New tripodal hydroxypyridinone based chelating agents for Fe(III), Al(III)and Ga(III): Synthesis, physicochemical properties and bioevaluation. J Inorg Biochem 2009;103:262–73.

Santos MA, Gama S, Gano L, Cantinho G, Farkas E. A new bis(3-hydroxy-4-pyridinone)-IDA derivative as a potential therapeutic chelating agent. Synthesis, metal-complexation and biological assays. Dalton Trans 2004;7:3772-81.

Liu ZD, Hider RC. Design of clinically useful iron (III)-selective chelators. Med Res Rev 2002;22:26-64.

Santos MA. Review: Recent developments on 3-hydroxy-4-pyridinones with respect to their clinical applications-Mono and combined ligand approaches. Coord Chem Rev 2008;252:1213–24.

Hershko C, Grady RW, Link G. Phenolic ethylenediamine derivatives: a study of orally effective iron chelators. J Lab Clin Med 1984;103:337–46.

Grady RW, Salbe AD, Hilgartner MW, Giardina PJ. Results from a phase I clinical trial of HBED. Adv Exp Med Biol 1994;356:351–9.

Samuni AM, Afeworki M, Stein W, Yordanov AT, DeGraff W, Krishna MC, et al. Multifunctional antioxidant activity of HBED iron chelator. Free Radical Biol Med 2001;30:170–7.

Galey JB, Dumats J, Beck I, Fernandez B, Hocquaux M. N, N-9-Bis dibenzyl ethylenediaminediacetic acid (DBED): a site-specific hydroxyl radical scavenger acting as an oxidative stress activatable iron chelator in vitro. Free Radic Res 1995;22:67–86.

Maxton DG, Bjarnason I, Reynolds AP, Catt SD, Peters TJ, Menzies IS. Lactulose [15]Cr-labelled ethylenediaminetetra-acetate, L-rhamnose and polyethyleneglycol 500 as probe marker for assessment in vivo of human intestinal permeability. Clin Sci 1986;71:71-80.

Bailly T, Burgada R, Prange T, Lecouvey M. Synthesis of tetradentate mixed bisphosphonates-new hydroxypyridinonate ligands for metal chelation therapy. Tetrahedron Lett 2003;44:189–92.

Wodzinska J. Proof of concept of treatment with novel hydroxypyridinone iron chelators in a non-clinical model of parkinson's disease. Therapeutics Development Initiative. The Micheal J. Fox Foundation; 2011.

Hider RC, Liu ZD, Piyamongkol S. The design and properties of 3-hydroxypyridin-4-one iron chelators with high pFe3 values. Transfus Sci 2000;23:201-9.

Hider RC, Singh S, Porter JB, Huehns ER. The development of hydroxypyridin-4-ones as orally active iron chelators. Ann N Y Acad Sci 1990;612:327–8.

Scarrow RC, Riley PE, Abu-Dari K, White DL, Raymond KN. Ferric ion sequestering agents. Synthesis, structures, and thermodynamics of complexation of cobalt(III) and iron(III) tris complexes of several chelating hydroxypyridinones. Inorg Chem 1985;24:954–67.

Matsui D, Klein J, Hermann C, Grunau V, McClelland R, Chung D, 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 thalassemia. Clin Pharmacol Ther 1991;50:294–8.

Richardson R. Deferiprone: greater efficacy at depleting myocardial than hepatic iron? Lancet 2002;360:501-2.

Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM, Pennell DJ. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricularfunction in beta-thalassaemia. Lancet 2002;360:516–20.

Piga A, Gagliotic C, Fogliacco E, Tricta F. Comparative effects of deferioprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica 2003;88:489–96.

Peng CT, Tsai CH, Wu KH, Hsu CC, Sheng YT. Improvement of cardiac function in thalassemia patients using deferiprone-Review article. Tzu Chi Med J 2007;19:192–9.

Filosa A, Vitrano A, Rigano P, Calvaruso G, Barone R, Capra M, et al. Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major. Blood Cells Mol Dis 2013;51:85–8.

Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, et al. Improving survival with deferiprone treatment in patients with thalassemia major: A prospective multicenter randomised clinical trial under the auspices of the italian society for thalassemia and Hemoglobinopathies. Blood Cells Mol Dis 2009;42:247–51.

Aqodad N, Loréal O, Erdtman L, Brissot P, Guyader D. Fatal congestive heart failure with deferiprone. Gastroenterol Clin Biol 2008;32:656-9.

Ladis V, Chouliaras G, Berdoukas V. Fatal congestive heart failure with deferiprone. Gastroenterol Clin Biol 2009;33:593-4.

Mallat NS, Beydoun A, Musallam KM, Koussa S. Deferiprone-induced seizures in a patient withβ-thalassemia major. Blood Cells Mol Dis 2013;51:94–5.

Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis LM, Cameron RG, et al. Iron chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med 1995;332:918-22.

Tondury P, Kontoghiorghes GJ, Rdolfi-Luthy A, Hirt A, Hoffbrand AV, Lottenbach AM, et al. L1(1,2-dimethyl-3-hydroxypyrid-4-one) for oral iron chelation in patients with beta-thalassemia major. Br J Haematol 1990;76:550-3.

Farmaki K, Tzoumari I, Pappa C. Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications. Blood Cells Mol Dis 2011;47:33–40.

Hoffbrand V. Deferiprone therapy for transfusional iron overload. Best Pract Res Clin Haematol 2005;18:299–317.

Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003;102:1583–7.

Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol 2002;118:330-6.

Agarwal MB, Gupta SS, Viswanathan C, Vasandani D, Ramanathan J, Desai N, et al. Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion dependent thalassemia: Indian trial. Br J Haematol 1992;82:460–6.

Pennell DJ, Porter JB, Piga A, Lai Y, El-Beshlawy A, Belhoul KM, et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major. Blood 2014;123:1447-54.

Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007;136:501-8.

Kim J, Kim Y. A time-cost augmented economic evaluation of oral deferasirox versus infusional deferoxamine for patients with iron overload in South Korea. Value Health 2009;12:78-81.

Cappellini MD, Bejaoui M, Agaoglu L, Canatan D, Capra M, Cohen A, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years follow-up. Blood 2011;118:884–93.

Waldmeier F, Bruin GJ, Glaenzel U, Hazell K, Sechaud R, Warrington S, et al. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos 2010;38:808-16.

Taher AT, Porter J, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, et al. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double blind, placebo-controlled study. Blood 2012;120:970-7.

Ho WL, Chung KP, Yang SS, Lu MY, Jou ST, Chang HH, et al. A pharmaco-economic evaluation of deferasirox for treating patients with iron overload caused by transfusion-dependent thalassemia in Taiwan. J Formosan Med Assoc 2013;112:221-9.

Fenauxd P, Gansere A, Guerci-Breslerf A, Schmidg M, Taylorh K, Vassilieff D, et al. Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes. Leukemia Res 2010;34:1143–50.

Chang HH, Lu MY, Liao YM, Lin PC, Yang YL, Lin DT, et al. Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion dependent beta-thalassemia. Pediatr Blood Cancer 2011;56:420–4.

Chirnomas D, Smith AL, Braunstein J, Finkelstein Y, Pereira L, Bergmann AK, et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood 2009;114:4009–13.

Chen J. The youth team. Nature 2001;411:13–4.

Kuhnigk O, Bothern AM, Reimer J, Schäfer I, Biegler A, Jueptner M, et al. Benefits and pitfalls of scientific research during undergraduate medical education. GMS Z Med Ausbild 2010;27:72.

Pongtanakul B, Viprakasit V. Letter to the Editor. Blood Cells Mol Dis 2013;51:96–7.

Meerpohl JJ, Antes G, Rücker G, Fleeman N, Motschall E, Niemeyer CM, et al. Deferasirox for managing iron overload in people with thalassemia. Cochrane Database Syst Rev 2012;2:CD007476. doi: 10.1002/14651858.CD007476. [Article in Press]

Neufeld EJ. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 2006;107:3436-41.

European Medicines Agency (EMA), Committee for Medicinal Products for Human Use plenary meeting monthly report. London, EMEA/CHMP/674356/2009; 2009.

Stein J. Deferasirox beneficial in patients with transfusion-dependent myelodysplastic syndrome and iron overload; 2013. Available from: URL: http://www.docguide.com/deferasirox-beneficial-patients-transfusion-dependent-myelodysplastic-syndrome-and-iron-overload?tsid=6. [Last accessed on 20 Apr 2015]

Guarigliaa R, Martorellia MC, Villani O, Pietrantuonoa G, Mansuetoa G, Auriaa FD, et al. Positive effects on hematopoiesis in patients with myelodysplastic syndrome receiving deferasirox as oral iron chelation therapy: A brief review. Leukemia Res 2011;35:566–70.

Breccia M, Finsinger P, Latagliata R, Cannella L, Loglisci G, Federico V, et al. Deferasirox treatment in myelodysplastic syndromes: real-life efficacy and safety in a single institution patient population. Leukemia Res 2011;35:S27–S142.

Cappellini MD, Bejaoui M, Agaoglu L, Canatan D, Capra M, Cohen A, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years follow-up. Blood 2011;118:884–93.

Lindsey WT, Olin BR. Deferasirox for transfusion-related iron overload: a clinical review. Clin Ther 2007;29:2154-66.

Phatak P, Brissot P, Wurster M, Adams PC, Bonkovsky HL, Gross J, et al. A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology 2010;52:1671-779.

Adlette I. Recent advances in improving the management of sickle cell disease. Blood Rev 2009;23:S9–S13.

Thuret I. Post-transfusional iron overload in the haemoglobinopathies. CR Biologies 2013;336:164–72.

Navneet SM, Lazarus HM, Burns LJ. A prospective study of iron overload management in allogeneic hematopoietic cell transplantation survivors. Biol Blood Marrow Transplant 2010;16:832-37.

Bae SJ, Kang C, Sung KW, Chueh HW, Son MH, Lee SH. Iron overload during follow-up after tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk neuroblastoma. J Korean Med Sci 2012;27:363–9.

Kennedy GA, Morris KL, Subramonpillai E, Curley C, Butler J, Durrant S. A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia. Br J Haematol 2013;161:794-801.

McDevitt P. A viable alternative to deferoxamine. Community Oncol 2007;4:722-3.

Kontoghiorghes G J. Turning a blind eye to deferasirox's toxicity? Lancet 2013;381:1183–4.

Pierre JL, Baret P, Serratrice G. Hydroxyquinolines as iron chelators. Curr Med Chem 2003;10:1077–84.

Zheng H, Weiner LM, Epsztejn OS, Cabantchik ZI, Warshawsky A, Youdim MB, et al. Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorg Med Chem 2005;13:773–83.

Kidani Y, Naga S, Koike H. Mass spectrometry of 5-chloro-7-iodo-8-quinol metal chelates. JPN Analyst 1974;23:1375–8.

Mounsey RB, Teismann P. Chelators in the treatment of iron accumulation in Parkinson's disease. Int J Cell Biol 2012;1-12. doi.org/10.1155/2012/983245. [Article in Press]

Aydinok Y, Ulger Z, Nart D, Terzi A, Cetiner N, Ellis G, et al. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. Haematol 2007;92:1599-606.

Porcu M, Landis N, Salis S, Corda M, Orrùa P, Serraa E, et al. Effects of combined deferiprone and desferrioxamine iron chelating therapy in {beta}-thalassemia major end-stage heart failure. Eur J Heart Failure 2009;9:320-2.

Telfer PT, Warburton F, Christou S, Hadjigavriel M, Sitarou M, Kolnagou A. Improved survival in thalassemia major patients on switching from desferrioxamine to combined chelation therapy with desferrioxamine and deferiprone. Haematol 2009;94:1777-8.

Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and desferrioxamine. Br J Haematol 1998;103:361–4.

Balveer K, Pyar K, Wonke B. Combined oral and parenteral iron chelation in beta thalassaemia major. Med J Malaysia 2000;55:493–7.

Mourad FH, Hoffbrand AV, Sheikh-Taha M, Koussa S, Khoriaty AI, Taher A. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Br J Haematol 2003;121:187–9.

Origa R, Bina P, Agus A, Crobu G, Defraia E, Dessì C, et al. Combined therapy with deferiprone and desferrioxamine in thalassemia major. Haematologica 2005;90:1309-14.

Zareifar S, Jabbari A, Cohan N, Haghpanah S. Efficacy of combined desferrioxamine and deferiprone versus single desferrioxamine therapy in patients with major thalassemia. Arch Iran Med 2009;12:488-91.

Winston A. Iron complexing bioactive polymers. Handbook of bioactive polymeric systems. In: Gebelein CG, Carraher CE. editors. Chemistry/Food Science, general. Springer US; 1985. p. 621-49.

Meshchanov AY, Kol'tsova GN, Minina LT. Biodegradable polymeric hydroxamic acids for the elimination of iron from the body. Pharm Chem J 1994;28:173-6.

Onsoyen E, Skaugrud OJ. Metal recovery using chitosan. Chem Technol Biotechnol 1990;49:395–404.

Burke A, Yilmaz E, Hasirci N. Evaluation of chitosan as a potential medical iron (III) ion adsorbent. Turk J Med Sci 2000;30:341-8.

Phillips SF, Fernandez R. Pectin and cellulose binding of iron in vitro. Am Soc Clin Nutr 1981;34:2322–3.

Brzonova I, Steiner W, Zankel A, Nyanhongo GS, Guebitz GM. Enzymatic synthesis of catechol and hydroxyl-carboxylic acid functionalized chitosan microspheres for iron overload therapy. Eur J Pharm Biopharm 2011;79:294–303.

Berkland C, Mohammadi Z. Polyamine-dihydroxybenzoic acid conjugate hydrogels as iron chelators. Patent publication number EP2542248A1; 2011.

Hallaway PE, Eaton JW, Panter SS, Hedlund BE. Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers. Proc Natl Acad Sci 1989;86:10108-12.

Harmatz P, Grady RW, Dragsten P, Vichinsky E, Giardina P, Madden J, et al. Phase Ib clinical trial of starch-conjugated deferoxamine (40SD02): a novel long-acting iron chelator. Br J Haematol 2007;138:374-8.

Published

01-08-2015

How to Cite

Tyagi, P., Y. Kumar, D. Gupta, H. Singh, and A. Kumar. “THERAPEUTIC ADVANCEMENTS IN MANAGEMENT OF IRON OVERLOAD–A REVIEW”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 8, no. 8, Aug. 2015, pp. 35-44, https://journals.innovareacademics.in/index.php/ijpps/article/view/6149.

Issue

Section

Review Article(s)

Most read articles by the same author(s)