Abstract

Introduction: The Mongolian gerbil mimics many of the cardiac functional impairments observed in iron cardiomyopathy, however relatively few chelation studies have been performed in this model. The purpose of this study was to characterize the dose-response of deferoxamine, ICL670, and deferiprone (L1) with respect to liver and cardiac iron chelation in the gerbil

Methods: Thirty three adult Mongolian gerbils underwent subcutaneous iron dextran loading with 1500 mg/kg iron dextran divided into three, weekly doses. Chelation began at 4 weeks and continued for 4 weeks. Animals were divided into 9 treatment groups of three animals each(DFO 50, 100, and 200 mg/kg/day (subQ BID), ICL670 25, 50, and 100 mg/kg/day(PO QD), and L1 125, 250, and 500 mg/kg/day(PO TID), 5 days per week). Three control animals were sacrificed at 4 weeks and 8 weeks to estimate sponatenous iron loss. Histology and quantitative iron were performed in all animals.

Results: Iron loading yielded liver iron concentrations of 26.6±3.8 mg/g(dry wt) and cardiac iron concentrations of 3.7±0.5 mg/g(dry wt) at 4 weeks (normal < .5 mg/g for both organs). However, organ iron content fell 6.4% in liver and 8.9% in heart per week in animals without chelation therapy, reflecting high spontaneous iron excretion. All three chelators exhibited significant dose-responsiveness for liver iron elimination. However, only ICL670 chelation at 100 mg/kg reduced liver iron content greater than for controls. In fact, animals treated with low dose L1 and DFO had higher iron levels than controls, probably by interfering with spontaneous iron elimination. None of the agents chelated the heart effectively. In fact, 88% of the L1 group, 56% of the ICL670 group and 22% of the DFO group had cardiac iron levels outside the normal range predicted from the 8 wk control animals.

Conclusion: Iron chelation in the gerbil model requires doses nearly 3.6 fold greater than in humans to produce discernable iron loss above background iron excretion in short-term studies. Subtherapeutic dosing may actually increase iron levels relative to control animals by decreasing spontaneous iron excretion.

Groupwise Iron Concentration and Content

 HIC(mg/g dry) HIC(mg/g wet) Organ FE(mg) CIC(mg/g dry) CIC(mg/g wet) Organ FE(mg) 
Control(4wk) 26.6±3.8 7.0±1.4 27.5±2.6 3.74±0.5 0.74±0.1 0.32±0.05 
Control(8wk) 23.1±1.1 5.9±0.5 20.5±2.2 2.64±0.19 0.52±0.03 0.20±0.01 
DFO 50mg/kg 31.0±3.0 8.2±1.5 28.9±3.4 2.73±0.32 0.56±0.03 0.20±0.02 
DFO100mg/kg 25.3±3.3 6.8±1.2 25.0±4.9 3.20±0.46 0.90±0.46 0.33±0.18 
DFO200mg/kg 23.5±1.4 5.9±0.4 17.6±2.4 2.77±0.20 0.53±0.07 0.18±0.03 
L1 125mg/kg 32.2±1.3 7.7±1.1 23.8±3.4 3.63±0.25 0.79±0.02 0.23±0.02 
L1 250mg/kg 29.3±7.4 8.5±2.7 26.7±6.2 3.56±0.85 0.71±0.12 0.21±0.04 
L1 500mg/kg 18.5±0.9 5.0±0.6 19.4±1.8 2.68±0.43 0.57±0.08 0.20±0.04 
ICL 25mg/kg 24.3±6.3 6.2±1.3 21.5±5.6 3.47±0.09 0.74±0.02 0.25±.02 
ICL 50mg/kg 27.6±1.7 6.7±1.1 19.7±4.3 3.22±0.05 0.64±0.14 0.23±0.04 
ICL100mg/kg 18.5±3.7 4.1±1.1 13.8±1.8 2.96±0.38 0.59±0.09 0.23±0.04 
 HIC(mg/g dry) HIC(mg/g wet) Organ FE(mg) CIC(mg/g dry) CIC(mg/g wet) Organ FE(mg) 
Control(4wk) 26.6±3.8 7.0±1.4 27.5±2.6 3.74±0.5 0.74±0.1 0.32±0.05 
Control(8wk) 23.1±1.1 5.9±0.5 20.5±2.2 2.64±0.19 0.52±0.03 0.20±0.01 
DFO 50mg/kg 31.0±3.0 8.2±1.5 28.9±3.4 2.73±0.32 0.56±0.03 0.20±0.02 
DFO100mg/kg 25.3±3.3 6.8±1.2 25.0±4.9 3.20±0.46 0.90±0.46 0.33±0.18 
DFO200mg/kg 23.5±1.4 5.9±0.4 17.6±2.4 2.77±0.20 0.53±0.07 0.18±0.03 
L1 125mg/kg 32.2±1.3 7.7±1.1 23.8±3.4 3.63±0.25 0.79±0.02 0.23±0.02 
L1 250mg/kg 29.3±7.4 8.5±2.7 26.7±6.2 3.56±0.85 0.71±0.12 0.21±0.04 
L1 500mg/kg 18.5±0.9 5.0±0.6 19.4±1.8 2.68±0.43 0.57±0.08 0.20±0.04 
ICL 25mg/kg 24.3±6.3 6.2±1.3 21.5±5.6 3.47±0.09 0.74±0.02 0.25±.02 
ICL 50mg/kg 27.6±1.7 6.7±1.1 19.7±4.3 3.22±0.05 0.64±0.14 0.23±0.04 
ICL100mg/kg 18.5±3.7 4.1±1.1 13.8±1.8 2.96±0.38 0.59±0.09 0.23±0.04 

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