title: Evaluation of toxicity and oxidative stress induced by intravenous iron isomaltoside 1000 in a nonclinical model.
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, accompaniedby 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-alpha 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.
authors.affiliation: Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina. jorgetoblli@fibertel.com.ar
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Toblli
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cao
authors.forename: Leda
authors.initials: L
authors.lastname: Oliveri
authors.forename: Margarita
authors.initials: M
authors.lastname: Angerosa
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004187:Disaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005290:Ferric Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000077605:Ferric Oxide, Saccharated; D005293:Ferritins / Q000097:blood; D005937:Glucaric Acid; D006454:Hemoglobins / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000097:blood / Q000139:chemically induced; D007275:Injections, Intravenous; D007501:Iron / Q000097:blood; D007505:Iron-Dextran Complex / Q000633:toxicity; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008970:Molecular Weight; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D004187:Disaccharides; D005290:Ferric Compounds; D006454:Hemoglobins; C557707:iron isomaltoside 1000; D007505:Iron-Dextran Complex; D005293:Ferritins; D003404:Creatinine; D007501:Iron; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid