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Arzneimittelforschung 2011; 61(7): 399-410
DOI: 10.1055/s-0031-1296218
Therapeutics for States of Deficiency
Editio Cantor Verlag Aulendorf (Germany)

Assessment of the extent of oxidative stress induced by intravenous ferumoxytol, ferric carboxymaltose, iron sucrose and iron dextran in a nonclinical model

E Jorge Toblli
1   Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
,
Gabriel Cao
1   Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
,
Leda Oliveri
1   Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
,
Margarita Angerosa
1   Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
› Author Affiliations
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Publication History

Publication Date:
27 November 2011 (online)

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Abstract

Intravenous (i. v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i. v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malon-dialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.

Key words

Ferric carboxymaltose - Ferumoxytol - Inflammation - Intravenous iron - Iron sucrose - Oxidative stress
 

  • References

  • 1 Silverberg DS, Wexler D, Blum M, Iaina A. The cardio renal anemia syndrome: correcting anemia in patients with resistant congestive heart failure can improve both cardiac and renal function and reduce hospitalizations. Clin Nephrol 2003; 60 (1) S93-102
    PubMedGoogle Scholar
  • 2 Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med 2004; 116 (7A) 44S-49S
    PubMedGoogle Scholar
  • 3 Macdougall IC. The management of anaemia in chronic kidney disease – current and future issues. Eur Ren Geni-tourin Dis 2006; 1: 35-6
    PubMedGoogle Scholar
  • 4 Auerbach M, Silberstein PT, Webb RT, Averyanova S, Ciuleanu TE, Shao J et al. Darbepoetin alfa 300 or 500 μg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Am J Hematol 2010; 85: 655-63
    CrossrefPubMedGoogle Scholar
  • 5 Crichton R, Danielson B, Geisser P. Iron therapy with special emphasis on intravenous administration. 4th ed Bremen: UNI-MED Verlag AG; 2008: 1-128
    Google Scholar
  • 6 Alleyne M, Home MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med 2008; 121: 943-8
    CrossrefPubMedGoogle Scholar
  • 7 Johnson DW. Intravenous versus oral iron supplementation in peritoneal dialysis patients. Perit Dial Int 2007; 27 (2) S255-60
    PubMedGoogle Scholar
  • 8 Macdougall IC. Strategies for iron supplementation: oral versus intravenous. Kidney Int Suppl 1999; 69: S61-6
    PubMedGoogle Scholar
  • 09 Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialy-sis-dependent CKD. Kidney Int 2005; 68: 2846-56
    CrossrefPubMedGoogle Scholar
  • 10 Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant 2006; 21: 378-82
    CrossrefPubMedGoogle Scholar
  • 11 Nissenson AR, Charytan C. Controversies in iron management. Kidney Int Suppl 2003; S64-S71
    PubMedGoogle Scholar
  • 12 Geisser P, Baer M, Schaub E. Structure/histotoxicity relationship of parenteral iron preparations. Arzneimittelforschung 1992; 42: 1439-52
    PubMedGoogle Scholar
  • 13 Toblli JE, Cao G, Olivieri L, Angerosa M. Comparison of the renal, cardiovascular and hepatic toxicity data of original intravenous iron compounds. Nephrol Dial Transplant 2010; 25: 3631-40
    CrossrefPubMedGoogle Scholar
  • 14 Schellekens H, Klinger E, Mühlebach S, Brin JF, Storm G, Crommelin DJ. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol 2011; 59: 176-83
    CrossrefPubMedGoogle Scholar
  • 15 Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: Feru-moxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol 2010; 85: 315-9
    PubMedGoogle Scholar
  • 16 Macdougall IC. Intravenous administration of iron in epoe-tin-treated haemodialysis patients-which drugs, which regimen?. Nephrol Dial Transplant 2000; 15: 1743-5
    CrossrefPubMedGoogle Scholar
  • 17 Qunibi WY. The efficacy and safety of current intravenous iron preparations for the management of iron-deficiency anaemia: a review. Arzneimittelforschung 2010; 60: 399-412
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 United States Pharmacopeial Convention: IronSucrose Injection Official monographin: The United States Pharmacopeia. United States Pharmacopeial Convention, Rock-ville MD, US 2008 31. 2449-51
    PubMed
  • 19 Balakrishnan VS, Rao M, Kausz AT, Brenner L, Pereira BJ, Frigo TB et al. Physicochemical properties of ferumoxytol, a new intravenous iron preparation. Eur J Clin Invest 2009; 39: 489-6
    CrossrefPubMedGoogle Scholar
  • 20 FerahemeTM (ferumoxytol) Injection Prescribing Information, Lexington, MA, USA, AMAG Pharmaceuticals, Inc. 11–2010.
    PubMed
  • 21 Press release: AMAG Pharmaceuticals Announces Update to Feraheme® Label, Lexington, MA, USA, AMAG Pharmaceuticals, Inc. 29–11–2010.
    PubMed
  • 22 Ternes N, Scheiber-Mojdehkar B, Landgraf G, Goldenberg H, Sturm B. Iron availability and complex stability of iron hydroxyethyl starch and iron dextran a comparative in vitro study with liver cells and macrophages. Nephrol Dial Transplant 2007; 22: 2824-30
    CrossrefPubMedGoogle Scholar
  • 23 Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol 2007; 69: 69-85
    CrossrefPubMedGoogle Scholar
  • 24 Evans RW, Rafique R, Zarea A, Rapisarda C, Cammack R, Evans PJ et al. Nature of non-transferrin-bound iron: studies on iron citrate complexes and thalassemic sera. J Biol Inorg Chem 2008; 13: 57-74
    PubMedGoogle Scholar
  • 25 Zanen AL, Adriaansen HJ, van Bommel EF, Posthuma R, de Jong GMTh. ‘Oversaturation’ of transferrin after intravenous ferric gluconate (Ferrlecit®) in haemodialysis patients. Nephrol Dial Transplant 1996; 11: 820-4
    CrossrefPubMedGoogle Scholar
  • 26 Anirban G, Kohli HS, Jha V, Gupta KL, Sakhuja V. The comparative safety of various intravenous iron preparations in chronic kidney disease patients. Ren Fail 2008; 30: 629-38
    CrossrefPubMedGoogle Scholar
  • 27 Burns DL, Mascioli EA, Bistrian BR. Parenteral iron dextran therapy: a review. Nutrition 1995; 11: 163-8
    PubMedGoogle Scholar
  • 28 Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword?. Nephrol Dial Transplant 2003; 18 (Supple 8) viii24-8
    PubMedGoogle Scholar
  • 29 Michael B, Coyne DW, Fishbane S, Folkert V, Lynn R, Nissenson AR et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int 2002; 61: 1830-9
    CrossrefPubMedGoogle Scholar
  • 30 Charytan C, Schwenk MH, Al-Saloum MM, Spinowitz BS. Safety of iron sucrose in hemodialysis patients intolerant to other parenteral iron products. Nephron Clin Pract 2004; 96: c63-6
    CrossrefPubMedGoogle Scholar
  • 31 Funk F, Ryle P, Canclini C, Neiser S, Geisser P. The new generation of intravenous iron: chemistry, pharmacology and toxicology of ferric carboxymaltose. Arzneimittelforschung 2010; 60: 345-53
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Provenzano R, Schiller B, Rao M, Coyne D, Brenner L, Pereira BJ. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4: 386-93
    CrossrefPubMedGoogle Scholar
  • 33 Singh A, Patel T, Hertel J, Bernardo M, Kausz A, Brenner L. Safety of ferumoxytol in patients with anemia and CKD. Am J Kidney Dis 2008; 52: 907-15
    CrossrefPubMedGoogle Scholar
  • 34 Santosh S, Podaralla P, Miller B. Anaphylaxis with elevated serum tryptase after administration of intravenous ferumoxytol. NDT Plus 2010; 3: 341-2
    CrossrefPubMedGoogle Scholar
  • 35 Toblli JE, Cao G, Oliveri L, Angerosa M. Differences between the original iron sucrose complex Venofer® and the iron sucrose similar Generis®, and potential implications. Port J Nephrol Hypert 2009; 1: 53-63
    PubMedGoogle Scholar
  • 36 Toblli JE, Cao G, Oliveri L, Angerosa M. Differences between original intravenous iron sucrose and iron sucrose similar preparations. Arzneimittelforschung 2009; 59: 176-90
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Toblli JE, Stella I, de CE, Angerosa M, Inserra F, Ferder L. Enalapril prevents tubulointerstitial lesions by hyperoxaluria. Hypertension 1999; 33: 225-31
    CrossrefPubMedGoogle Scholar
  • 38 Toblli JE, Ferrini MG, Cao G, Vernet D, Angerosa M, Gonzalez-Cadavid NF. Antifibrotic effects of pioglitazone on the kidney in a rat model of type 2 diabetes mellitus. Nephrol Dial Transplant 2009; 24: 2384-91
    CrossrefPubMedGoogle Scholar
  • 39 Toblli J, Cao G, Rivas C, Munoz M, Giani J, Dominici F et al. Cardiovascular protective effects of nebivolol in Zucker diabetic fatty rats. J Hypertens 2010; 28: 1007-19
    CrossrefPubMedGoogle Scholar
  • 40 Fergelot P, Ropert-Bouchet M, Abgueguen E, Orhant M, Radosavljevic M, Grimber G et al. Iron overload in mice expressing HFE exclusively in the intestinal villi provides evidence that HFE regulates a functional cross-talk between crypt and villi enterocytes. Blood Cells Mol Dis 2002; 28: 348-60
    CrossrefPubMedGoogle Scholar
  • 41 Youn P, Kim S, Ahn JH, Kim Y, Park JD, Ryu DY. Regulation of iron metabolism-related genes in diethylnitrosamine-in-ducedmouseliver tumors. Toxicol Lett 2009; 184: 151-8
    CrossrefPubMedGoogle Scholar
  • 42 Rossi R, Cardaioli E, Scaloni A, Amiconi G, Di Simplicio P. Thiol groups in proteins as endogenous reductants to determine glutathione-protein mixed disulphides in biological systems. Biochim Biophys Acta 1995; 1243: 230-8
    CrossrefPubMedGoogle Scholar
  • 43 Akerboom TP, Sies H. Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol 1981; 77: 373-82
    PubMedGoogle Scholar
  • 44 de Cavanagh EM, Inserra F, Toblli J, Stella I, Fraga CG, Ferder L. Enalapril attenuates oxidative stress in diabetic rats. Hypertension 2001; 38: 1130-6
    CrossrefPubMedGoogle Scholar
  • 45 Niehaus Jr WG, Samuelsson B. Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem 1968; 6: 126-30
    CrossrefPubMedGoogle Scholar
  • 46 Toblli JE, Cao G, Olivieri L, Angerosa M. Comparative study of gastrointestinal tract and liver toxicity of ferrous sulfate, iron amino chelate and iron polymaltose complex in normal rats. Pharmacology 2008; 82: 127-37
    CrossrefPubMedGoogle Scholar
  • 47 Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis 2001; 38: 988-91
    CrossrefPubMedGoogle Scholar
  • 48 Bastani B, Jain A, Pandurangan G. Incidence of side-effects associated with high-dose ferric gluconate in patients with severe chronic renal failure. Nephrology (Carlton) 2003; 8: 8-10
    CrossrefPubMedGoogle Scholar
  • 49 Groman EV, Paul KG, Frigo TB, Bengele H, Lewis JM. Heat stable colloidal iron oxides coated with reduced carbohydrates and carbohydrate derivatives. (US Patent 6,599,498). 29–7–2007. United States.
    PubMedGoogle Scholar
  • 50 Simon GH, von Vopelius-Feldt J, Fu Y, Schlegel J, Pinotek G, Wendland MF et al. Ultrasmall supraparamagnetic iron oxide-enhanced magnetic resonance imaging of antigen-induced arthritis: a comparative study between SHU 555 C, ferumoxtran-10, and ferumoxytol. Invest Radiol 2006; 41: 45-51
    CrossrefPubMedGoogle Scholar
  • 51 Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant 2004; 19: 1571-5
    CrossrefPubMedGoogle Scholar
  • 52 Chertow GM, Winkelmayer WC. On the relative safety of intravenous iron formulations: new answers, new questions. Am J Hematol 2010; 85: 643-4
    CrossrefPubMedGoogle Scholar
  • 53 Olsson S, Lundvall O, Weinfeld A. Availability of iron stores built up by iron dextrin as studied with desferrioxamine and phlebotomy. Acta Med Scand 1972; 191: 49-56
    PubMedGoogle Scholar
  • 54 Meier T, Schropp P, Pater C, Leoni AL, Khov-Tran VV, Elford P. Physicochemical and toxicological characterization of a new generic iron sucrose preparation. Arzneimittelforschung 2011; 61: 112-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Caperna TJ, Failla ML, Steele NC, Richards MP. Accumulation and metabolism of iron-dextran by hepatocytes, Kupf-fer cells and endothelial cells in the neonatal pig liver. J Nutr 1987; 117: 312-20
    PubMedGoogle Scholar
  • 56 Beshara S, Lundqvist H, Sundin J, Lubberink M, Tolmachev V, Valind S et al. Pharmacokinetics and red cell utilization of iron(III) hydroxide-sucrose complex in anaemic patients: a study using positron emission tomography. Br J Haematol 1999; 104: 296-302
    CrossrefPubMedGoogle Scholar
  • 57 Beshara S, Sorensen J, Lubberink M, Tolmachev V, Langstrom B, Antoni G et al. Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography. Br J Haematol 2003; 120: 853-9
    CrossrefPubMedGoogle Scholar
  • 58 Henderson PA, Hillman RS. Characteristics of iron dextran utilization in man. Blood 1969; 34: 357-75
    PubMedGoogle Scholar
  • 59 Hausmann K, Wulfhekel U, Dullmann J, Kuse R. Iron storage in macrophages and endothelial cells. Histochemistry, ultrastructure, and clinical significance. Blut 1976; 32: 289-95
    CrossrefPubMedGoogle Scholar
  • 60 Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol 2004; 15 (2) S93-8
    PubMedGoogle Scholar
  • 61 IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis 2001; 37: S182-238
    CrossrefPubMedGoogle Scholar
  • 62 Van Wyck DB, Anderson J, Johnson K. Labile iron in parenteral iron formulations: a quantitative and comparative study. Nephrol Dial Transplant 2004; 19: 561-5
    CrossrefPubMedGoogle Scholar
  • 63 Ramaiah SK. A toxicologist guide to the diagnostic interpretation of hepatic biochemical parameters. Food Chem Toxicol 2007; 45: 1551-7
    PubMedGoogle Scholar
  • 64 Lim PS, Wei YH, Yu YL, Kho B. Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy. Nephrol Dial Transplant 1999; 14: 2680-7
    CrossrefPubMedGoogle Scholar
  • 65 Ishiyama A, Atarashi K, Minami M, Takagi M, Kimura K, Goto A et al. Role of free radicals in the pathogenesis of lipid-induced glomerulosclerosis in rats. Kidney Int 1999; 55: 1348-58
    CrossrefPubMedGoogle Scholar
  • 66 Fishbane S. Safety in iron management. Am J Kidney Dis 2003; 41: 18-26
    CrossrefPubMedGoogle Scholar
  • 67 Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell 2010; 142: 24-38
    CrossrefPubMedGoogle Scholar
  • 68 Ramey G, Deschemin JC, Durel B, Canonne-Hergaux F, Nicolas G, Vaulont S. Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica 2010; 95: 501-4
    CrossrefPubMedGoogle Scholar
  • 69 Fontecave M, Pierre JL. Iron: metabolism, toxicity and therapy. Biochimie 1993; 75: 767-73
    CrossrefPubMedGoogle Scholar