RESUMEN
BACKGROUND AND AIMS: Iron deficiency is common in inflammatory bowel disease, yet oral iron therapy may worsen the disease symptoms and increase systemic and local oxidative stress. The aim of this study was to compare the effects of oral ferrous sulfate and iron polymaltose complex on inflammatory and oxidative stress markers in colitic rats. METHODS: Animals were divided into four groups with ten animals each. Rats of three groups received dextran sodium sulfate to induce colitis and animals of two of these groups received 5 mg iron/kg of body weight a day, as ferrous sulfate or iron polymaltose complex, for 7 days. Gross colon anatomy, histology of colon and liver, stainings of L-ferritin, Prussian blue, hepcidin, tumor necrosis factor-α, and interleukin-6, as well serum levels of liver enzymes, inflammatory markers, and iron markers, were assessed. RESULTS: Body weight, gross anatomy, crypt injury and inflammation scores, inflammatory parameters in liver and colon, as well as serum and liver hepcidin levels were not significantly different between colitic animals without iron treatment and colitic animals treated with iron polymaltose complex. In contrast, ferrous sulfate treatment caused significant worsening of these parameters. As opposed to ferrous sulfate, iron polymaltose complex caused less or no additional oxidative stress in the colon and liver compared to colitic animals without iron treatment. CONCLUSION: Iron polymaltose complex had negligible effects on colonic tissue erosion, local or systemic oxidative stress, and local or systemic inflammation, even at high therapeutic doses, and may thus represent a valuable oral treatment of iron deficiency in inflammatory bowel disease.
Asunto(s)
Colitis/inducido químicamente , Compuestos Férricos/toxicidad , Compuestos Ferrosos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Administración Oral , Animales , Colitis/patología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Femenino , Compuestos Férricos/administración & dosificación , Compuestos Ferrosos/administración & dosificación , Hematínicos/administración & dosificación , Hematínicos/toxicidad , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: The originator iron polymaltose complex (Maltofer®, IPC, Vifor International, St. Gallen, Switzerland) has been used for over 30 years to treat iron deficiency anemia. Its physico-chemical properties allow for a controlled release of iron, a property which translates into low toxicity and good gastrointestinal (GI) tolerability of the drug compared to the commonly used ferrous salts. A variety of different iron polymaltose complex similars are commercially available with varying structures and, thus, different efficacy and toxicity compared to IPC. In this study, the median lethal dose, the GI tract and liver toxicity of an IPC similar (Vitalix®, IPCSVITA, Laboratorios Roemmers, Buenos Aires, Argentina) were compared with those of IPC in healthy rats. METHODS: The median lethal dose of IPCSVITA was determined as the dose required to kill 6 out of 12 rats after 24 h from dosing. To compare the GI and liver toxicities, rats received IPCSVITA or IPC (both 280 mg iron/kg body weight) for 28 days. GI toxicity was assessed macroscopically by scoring lesion severities and microscopically by analyzing the villi/crypt ratio, number of eosinophils/villi and number of Goblet cells/villi. Ferritin was assessed in the small intestine villi and in the liver by immunostaining. Iron deposits in the liver were assessed by Prussian blue staining. RESULTS: Serum iron concentration and transferrin saturation (TSAT) were significantly higher in the IPCSVITA group vs. the IPC and the control groups. Food consumption, body weight, and bowel movement at Day 29 were significantly lower within the IPCSVITA group vs. the IPC or the control groups. The lesion scores in the stomach and in the lower GI tract of the IPCSVITA group were significantly higher than those of the IPC and control groups. The villi/crypt ratio and the number of Goblet cells/villi in the small intestine were significantly lower in IPCSVITA-treated animals than in IPC-treated or control animals. The number of eosinophils per villi was significantly increased in the IPCSVITA group vs. IPC and control group. In the lower GI tract, microscopic lesions were observed only in the IPCSVITA group. The amount of ferritin in the small intestine and in the liver was higher in IPC-treated animals vs. IPCSVITA- treated or control animals. CONCLUSIONS: Higher serum iron and TSAT levels, lesions in the stomach and lower GI tract suggest the presence of weakly bound iron on the surface of the IPCSVITA complex, which has different physico-chemical properties than IPC. The lower levels of iron deposits in the liver suggest that the iron from IPCSVITA is taken up in a less controlled way than from IPC, thus, potentially accumulating in the wrong cellular compartment.
Asunto(s)
Compuestos Férricos/toxicidad , Tracto Gastrointestinal/efectos de los fármacos , Hematínicos/toxicidad , Hígado/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Química Farmacéutica , Defecación/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Ferritinas/metabolismo , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/patología , Hierro/sangre , Dosificación Letal Mediana , Hígado/metabolismo , Hígado/patología , Masculino , Ratas , Ratas Sprague-Dawley , Transferrina/metabolismoRESUMEN
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 malondialdehyde, 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.
Asunto(s)
Compuestos Férricos/toxicidad , Hematínicos/toxicidad , Complejo Hierro-Dextran/toxicidad , Nanopartículas de Magnetita/toxicidad , Maltosa/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/análisis , Presión Sanguínea/efectos de los fármacos , Creatinina/metabolismo , Femenino , Compuestos Férricos/administración & dosificación , Sacarato de Óxido Férrico , Óxido Ferrosoférrico , Ácido Glucárico , Corazón/efectos de los fármacos , Hematínicos/administración & dosificación , Inmunohistoquímica , Inflamación/inducido químicamente , Inyecciones Intravenosas , Complejo Hierro-Dextran/administración & dosificación , Riñón/efectos de los fármacos , Riñón/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Nanopartículas de Magnetita/administración & dosificación , Masculino , Maltosa/administración & dosificación , Maltosa/toxicidad , Peso Molecular , Proteinuria/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Iron chloride injections into the rat SNc can cause chronic decreases in striatal dopamine (DA) levels. However, changes in striatal DA content after iron-dextran injection into rat SNc have not been completely elucidated. The aim of this work was to measure striatal DA concentrations after iron-dextran injection into the SNc. We divided 40 male Wistar rats into five groups, including control, saline injected then sacrificed 7 days or 30 days later, and iron-dextran injected then sacrificed 7 days or 30 days later. Striatal DA content was measured in control animals and in all animals sacrificed 7 days or 30 days after injection, and motor performance was assessed in iron-dextran and saline injected groups 30 days after injection. The striatal DA levels were determined using HPLC. There were significant (P < 0.05) decreases in DA concentrations in the striatum ipsilateral to the injection site in the iron-dextran treated rats compared to control and saline-injected rats. There were no significant differences in DA concentration between the sham-operated (i.e., saline-injected) and control rats. We also observed motor deficits in the iron-dextran injected rats. The striatal DA reduction observed after iron-dextran injection may be attributable to iron-induced oxidative injury in the SNc. Motor deficits, in turn, may be explained by subsequent disturbances in striatal and cortical dopaminergic neuromodulation.