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Arzneimittelforschung 2011; 61(10): 553-565
DOI: 10.1055/s-0031-1300553
Therapeutics for States of Deficiency
Editio Cantor Verlag Aulendorf (Germany)

Evaluation of toxicity and oxidative stress induced by intravenous iron isomaltoside 1000 in a nonclinical model

Jorge E. 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:
01 February 2012 (online)

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Abstract

The physicochemical characteristics of intravenous iron complexes affect the extent of weakly-bound iron and thus the degree of oxidative stress. The new preparation iron isomaltoside 1000 (IIM) was compared to iron sucrose (IS) and a control group in terms of biochemistry, oxidative stress, inflammatory markers and iron deposition in the liver, heart and kidneys of healthy rats. Renal function was significantly impaired in the IIM group versus both IS and controls. Liver enzymes were also significantly higher in IIM-treated animals versus the other groups, indicative of hepatic injury. Systolic blood pressure was significantly lower following IIM administration compared to IS or control animals. Oxidative stress in the liver, heart and kidneys was greater in the IIM group, as indicated by significantly increased levels of malondialdehyde and antioxidant enzyme activity, accompanied by a significantly lower ratio of reduced to oxidized glutathione. Microscopy demonstrated more extensive positive staining for iron, and a smaller area of ferritin staining, in the liver, heart and kidneys of rats treated with IIM versus IS. Levels of the inflammatory markers TNF-α and IL6 were both significantly higher in the IIM group versus IS in all assessed tissues. These findings indicate that IIM has a less favorable safety profile than IS in healthy rats, adversely affecting iron deposition, oxidative stress and inflammatory responses, with impaired liver and renal function.

Key words

Intravenous iron - Iron dextran - Iron isomaltoside 1000 - Iron sucrose - Monofer - Oxidative stress
 

  • References

  • 1 Fishbane S, Pollack S, Feldman HI, Joffe MM. Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988–2004. Clin J Am Soc Nephrol. 2009; 4: 57-61
    CrossrefPubMedGoogle Scholar
  • 2 Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J. 2010; 31: 1872-80
    CrossrefPubMedGoogle Scholar
  • 3 Ludwig H, Van Belle S, Barrett-Lee P, Birgegârd G, Bokemeyer C, Gascon P et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer. 2004; 40: 2293-306
    CrossrefPubMedGoogle Scholar
  • 4 Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004; 53: 1190-7
    CrossrefPubMedGoogle Scholar
  • 5 Bodnar LM, Cogswell ME, Scanion KS. Low income postpartum women are at risk of iron deficiency. J Nutr. 2002; 132: 2298-302
    PubMedGoogle Scholar
  • 6 Beris P, Muñoz M, García-Erce JA, Thomas D, Maniatis A, Van der Linden P. Perioperative anaemia management: consensus statement on the role of intravenous iron. Br J Anaesth. 2008; 100: 599-604
    CrossrefPubMedGoogle Scholar
  • 7 Morrison J, Patel ST, Watson W, Zaidi QR, Mangione A, Goss TF. Assessment of the prevalence and impact of anemia on women hospitalized for gynecologic conditions associated with heavy uterine bleeding. J Reprod Med. 2008; 53: 323-30
    PubMedGoogle Scholar
  • 8 Arredondo M, Núñez MT. Iron and copper metabolism. Mol Aspects Med. 2005; 26: 313-27
    CrossrefPubMedGoogle Scholar
  • 9 Kalantar-Zadeh K, McAllister CJ, Lehn RS, Liu E, Kopple JD. A low serum iron level is a predictor of poor outcome in hemodialysis patients. Am J Kidney Dis. 2004; 43: 671-84
    CrossrefPubMedGoogle Scholar
  • 10 Kovesdy CP, Estrada W, Ahmadzadeh S, Kalantar-Zadeh K. Association of markers of iron stores with outcomes in patients with nondialysis-dependent chronic kidney disease. Clin J Am Soc Nephrol. 2009; 4: 435-41
    CrossrefPubMedGoogle Scholar
  • 11 Alleyne M, Home MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008; 121: 943-8
    CrossrefPubMedGoogle Scholar
  • 12 Macdougall IC. Strategies for iron supplementation: oral versus intravenous. Kidney Int Suppl. 1999; 69: S61-6
    PubMedGoogle Scholar
  • 13 Macdougall IC. Iron supplementation in the non-dialysis chronic kidney disease (ND-CKD) patient: oral or intravenous?. Curr Med Res Opin. 2010; 26: 473-82
    CrossrefPubMedGoogle Scholar
  • 14 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
  • 15 Locatelli F, Del Vecchio L. New erythropoiesis-stimulating agents and new iron formulations. Contrib Nephrol. 2011; 171: 255-60
    PubMedGoogle Scholar
  • 16 Jahn MR, Andreasen HM, Fütterer S, Nawroth T, Schünemann V, Kolb U et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer®), a new intravenous iron preparation and its clinical implications. Eur J Pharmaceut Biopharm. 2011; 78: 480-9
    PubMedGoogle Scholar
  • 17 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
  • 18 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; 23: 53-63
    PubMedGoogle Scholar
  • 19 Rottembourg J, Kadri A, Leonard E, Dansaert A, Lafuma A. Do two intravenous iron sucrose preparations have the same efficacy?. Nephrol Dial Transplant. 2011; Feb 25. [Epub ahead of print]
    PubMedGoogle Scholar
  • 20 Geisser P, Baer M, Schaub E. Structure/histotoxicity relationship of parenteral iron preparations. Arzneimittelforschung. 1992; 42: 1439-52
    PubMedGoogle Scholar
  • 21 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
  • 22 Pai AB, Boyd AV, McQuade CR, Harford A, Norenberg JP, Zager PG. Comparison of oxidative stress markers after intravenous administration of iron dextran, sodium ferric gluconate, and iron sucrose in patients undergoing hemodialysis. Pharmacotherapy. 2007; 27: 343-50
    CrossrefPubMedGoogle Scholar
  • 23 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
  • 24 Toblli JE, Cao G, Oliveri L, Angerosa M. Assessment of the extent of oxidative stress induced by intravenous. ferumoxytol, ferric carboxymaltose, iron sucrose and iron dextran in a nonclinical model. Arzneimittelforschung. 2011; 61: 399-410
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Meier T, Schropp P, Pater C, Leoni AL, Khov-Tran W, Elford P. Physicochemical and toxicological characterization of a new generic iron sucrose preparation. Arzneimittelforschung. 2011; 61: 112-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Landry R, Jacobs PM, Davis R, Shenouda M, Bolton WK. Pharmacokinetic study of ferumoxytol: a new iron replacement therapy in normal subjects and hemodialysis patients. Am J Nephrol. 2005; 25: 400-10
    CrossrefPubMedGoogle Scholar
  • 27 Public Assessment Report Scientific Discussion. Monofer 100 mg/ml solution for injection/infusion (iron(III) isomaltoside 1000. SE/H/734/01/DC. Available at http://www.lakemedelsverket.se/SPC_PIL/Pdf/par/Monofer%20solu-tion%20for%20infusion-injection.pdf
    PubMed
  • 28 Toblli JE, Stella I, de Cavanagh E, Angerosa M, Inserra F, Ferder L. Enalapril prevents tubulointerstitial lesions by hyperoxaluria. Hypertension. 1999; 33: 225-31
    CrossrefPubMedGoogle Scholar
  • 29 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
  • 30 Youn P, Kim S, Ahn JH, Kim Y, Park JD, Ryu DY. Regulation of iron metabolism-related genes in diethylnitrosamine-induced mouse liver tumors. Toxicol Lett. 2009; 184: 151-8
    CrossrefPubMedGoogle Scholar
  • 31 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
  • 32 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
  • 33 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
  • 34 Akerboom TP, Sies H. Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol. 1981; 77: 373-82
    PubMedGoogle Scholar
  • 35 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
  • 36 Niehaus Jr WG, Samuelsson B. Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem. 1968; 6: 126-30
    CrossrefPubMedGoogle Scholar
  • 37 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
  • 38 United States Pharmacopeial Convention: Iron Sucrose Injection, Official monograph in: The United States Pharmacopeia. 31st Revision. Rockville (MD, US): United States Pharmacopeial Convention; 2008. p. 2449–5118
    PubMed
  • 39 Ramaiah SK. A toxicologist guide to the diagnostic interpretation of hepatic biochemical parameters. Food Chem Toxicol. 2007; 45: 1551-7
    PubMedGoogle Scholar
  • 40 Diesen DL, Kuo PC. Nitric oxide and redox regulation in the liver: Part I. General considerations and redox biology in hepatitis. J Surg Res. 2010; 162: 95-109
    CrossrefPubMedGoogle Scholar
  • 41 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
  • 42 Zager RA. Parenteral iron compounds: potent oxidants but mainstays of anemia management in chronic renal disease. Clin J Am Soc Nephrol. 2006; 1 (Suppl 1) S24-31
    CrossrefPubMedGoogle Scholar
  • 43 Muñoz M, García-Erce JA, Remacha AF. Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis. J Clin Pathol. 2011; 64: 281-6
    CrossrefPubMedGoogle Scholar
  • 44 Fletcher LM, Roberts FD, Irving MG, Powell LW, Halliday JW. Effects of iron loading on free radical scavenging enzymes and lipid peroxidation in rat liver. Gastroenterology. 1989; 97: 1011-8
    PubMedGoogle Scholar
  • 45 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
  • 46 Danielson BG, Salmonson T, Derendorf H, Geisser P. Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers. Arzneimittelforschung. 1996; 46: 615-21
    PubMedGoogle Scholar
  • 47 Seligman PA, Dahl NV, Strobos J, Kimko HC, Schleicher RB, Jones M et al. Single-dose pharmacokinetics of sodium ferric gluconate complex in iron-deficient subjects. Pharmacotherapy. 2004; 24: 574-83
    CrossrefPubMedGoogle Scholar
  • 48 Nordfjeld K, Andreasen H, Thomsen LL Pharmacokinetic of iron isomaltoside 1000 (Monofer®) in inflammatory bowel disease. 6th Congress of the European Crohn’s and Colitis Organisation (ECCO), Dublin, 24–26 February 2011. Poster P212.
    PubMed
  • 49 Henderson PA, Hillman RS. Characteristics of iron dextran utilization in man. Blood. 1969; 34: 357-75
    PubMedGoogle Scholar
  • 50 Geisser P, Banké-Bochita J. Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia. Arzneimittelforschung. 2010; 60: 362-72
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 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
  • 52 Hausmann K, Wulfhekel U, Düllmann J, Kuse R. Iron storage in macrophages and endothelial cells. Histochemistry, ultrastructure, and clinical significance. Blut. 1976; 32: 289-95
    CrossrefPubMedGoogle Scholar
  • 53 Danielson J. Structure, chemistry, and pharmacokinetics of intravenous iron agents. Am Soc Nephrol. 2004; 15: S93-8
    PubMedGoogle Scholar