Abstract
Abstract 1040
Background:
Iron(III) polymaltose complex (IPC) shows similar efficacy to ferrous sulfate for the treatment of iron deficiency anemia but with superior tolerability. The stable structure of IPC prevents unregulated uptake of iron from the gut, avoiding an increase in non-transferrin bound iron with associated oxidative stress. IPC similars have been developed which vary in structure from the originator IPC preparation (Maltofer®, IPCM). A direct comparison between the originator and IPC similars in their potential to induce oxidative stress has not been performed. In this study, we compared acute and early toxicity in the gastrointestinal (GI) tract and liver in healthy rats randomized to IPCM, an IPC similar (Vitalix, IPCV) or a control arm.
Methods:
LD50 values were determined by administering single increasing doses of IPCM or IPCV (each n=12) and counting deaths at 24 hours. Three groups of rats (each n=12) then received doses equivalent to 10% of LD50 for IPCM (280 mg iron/kg/day) or IPCV (280 mg iron/kg/day), or tap water (controls) for 28 days. Iron-induced lesions in the GI tract were scored: 1, superficial 1–5 hemorrhagic points; 2, superficial 6–10, hemorrhagic points; 3, sub-mucosal hemorrhagic lesions with small erosions; 4, severe hemorrhagic lesions and some invasive lesions. Iron deposits (Prussian blue) and tissue ferritin in the liver and small intestine were assessed by immunohistochemistry. Ferritin immunostaining in the small intestine was scored: 1, none; 2, mild; 3, moderate; 4, very intense.
Results:
LD50 was the same for IPCM and IPCV (>2800 mg iron/kg). Animals treated with IPCV had lower food consumption and body weight vs those treated with IPCM and controls. IPCV was associated with increased serum iron and transferrin saturation vs the IPCM group, suggesting bypass of the regulated iron uptake system. Microscopically, the villi/crypt ratio and the number of Goblet cells per villi in the small intestine were significantly lower with IPCV vs IPCM or controls, and the number of eosinophils per villi was increased in IPCV-treated animals. Gross anatomy and microscopy findings showed that IPCV- treated animals experienced variable degrees of inflammation in the GI tract while the IPCM and control groups showed no lesions. Ferritin immunostaining of liver tissue indicated that iron was appropriately stored in IPCM-treated within Kupffer's cells (Prussian blue). Ferritin deposits in the small intestine were also higher with IPCM. Differences were statistically inferior for IPCV versus IPCM for clinical and iron parameters, gross anatomy, microscopic findings and ferritin immunostaining (Table).
Conclusions:
IPCV showed the same LD50 as IPCM, but considerably greater early GI tract toxicity. Increased numbers of eosinophils in the IPCV group suggest an allergic component of the small intestine injury in these groups. Markers of iron transport and distribution indicated less well controlled uptake and storage following ingestion of IPCV compared to IPCM. The increased levels of ferritin deposits in the small intestine of IPCM-treated animals suggests that excess iron is stored in the gut wall instead of saturating the iron transport mechanism and increasing non-transferrin bound iron levels.
Disclosures:
Toblli: Vifor (International) Ltd: Consultancy, Research Funding.
Ozone Inhalation Impairs Coronary Artery Dilation via Intracellular Oxidative Stress: Evidence for Serum-Borne Factors as Drivers of Systemic Toxicity