ferric-oxide--saccharated and Iron-Overload

Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated because of the long incubation period for MM.

Topics: Adsorption; Animals; Asbestos; Asbestosis; Benzoates; Carcinogens, Environmental; Carcinoma, Renal Cell; Cell Transformation, Neoplastic; Comparative Genomic Hybridization; Deferasirox; Ferric Compounds; Ferric Oxide, Saccharated; Genes, p16; Glucaric Acid; Humans; Iron Chelating Agents; Iron Overload; Japan; Kidney Neoplasms; Male; Mesothelioma; Mineral Fibers; Peritoneal Neoplasms; Phlebotomy; Pleural Neoplasms; Rats; Triazoles

Absolute and functional iron deficiency is the most common cause of epoetin (recombinant human erythropoietin) hyporesponsiveness in renal failure patients. Diagnostic procedures for determining iron deficiency include measurement of serum iron levels, serum ferritin levels, saturation of transferrin and percentage of hypochromic red blood cells. Patients with iron deficiency should receive supplemental iron, either orally or intravenously. Adequate intravenous iron supplementation allows reduction of epoetin dosage by approximately 40%. Intravenous iron supplementation is recommended for all patients undergoing haemodialysis and for pre-dialysis and peritoneal dialysis patients with severe iron deficiency. During the maintenance phase (period of epoetin therapy after correction of iron deficiency), the use of low-dose intravenous iron supplementation (10 to 20 mg per haemodialysis treatment or 100 mg every second week) avoids iron overtreatment and minimises potential adverse effects. Depending on the degree of pre-existing iron deficiency, markedly higher iron doses are necessary during the correction phase (period of epoetin therapy after correction of iron deficiency) [e.g. intravenous iron 40 to 100 mg per haemodialysis session up to a total dose of 1000 mg]. The iron status should be monitored monthly during the correction phase and every 3 months during the maintenance phase to avoid overtreatment with intravenous iron.

Topics: Anemia, Iron-Deficiency; Citric Acid; Drug Combinations; Drug Monitoring; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Ferrous Compounds; Glucaric Acid; Humans; Infusions, Intravenous; Injections, Intravenous; Iron Compounds; Iron Overload; Iron-Dextran Complex; Kidney Failure, Chronic; Sorbitol

Sodium glucose co-transporter (SGLT) 2 inhibitors are oral anti-diabetic drugs with proven kidney protective effects. Renal protective effects in non-diabetic individuals have also been shown in recent studies. The aim of this study was to determine the renal protective effects of dapagliflozin by evaluating the oxidative stress markers in the kidney tissue and demonstrating it in renal histological sections in an iron-overloaded rat model.. A total of 24 Wistar Albino rats were separated into 3 groups of 8 rats. Iron sucrose (60 ​mg/kg/day) was administered intraperitoneally to the first group (Group Fe) (n ​= ​8), iron sucrose and dapagliflozin (0.1 ​mg/kg/day) to the second group (Group Fe ​+ ​D) (n ​= ​8) and intraperitoneal saline as placebo to the control group (Group C) (n ​= ​8) for 4 weeks. The glomerular changes were semi-quantitatively scored with Oxford Classification. Oxidative stress was analyzed from the tissue fluorescent oxidation product (FLOP), malondialdehyde (MDA) and total sulfhydryl (T-SH) levels.. Dapagliflozin prevented glomerular and mesangial damage of iron overload in the non-diabetic rat model. MDA levels were significantly higher in Group Fe compared to the Group C, and there was no significant difference between the Fe ​+ ​D group and Group C. T-SH levels were preserved in the Fe ​+ ​D group and were significantly higher than in the Fe group.. The results of this study showed that dapagliflozin helped preserve the glomerular and mesangial structure histologically and reduced oxidative stress markers in a non-diabetic iron overload rat model.

Topics: Animals; Ferric Oxide, Saccharated; Glucose; Iron; Iron Overload; Kidney Diseases; Malondialdehyde; Oxidative Stress; Rats; Rats, Wistar; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Symporters

The iron-based phosphate binders, sucroferric oxyhydroxide (SFOH) and ferric citrate (FC), effectively lower serum phosphorus in clinical studies, but gastrointestinal iron absorption from these agents appears to differ. We compared iron uptake and tissue accumulation during treatment with SFOH or FC using experimental rat models.. Iron uptake was evaluated during an 8-h period following oral administration of SFOH, FC, ferrous sulphate (oral iron supplement) or control (methylcellulose vehicle) in rat models of anaemia, iron overload and inflammation. A 13-week study evaluated the effects of SFOH and FC on iron accumulation in different organs.. In the pharmacokinetic experiments, there was a minimal increase in serum iron with SFOH versus control during the 8-h post-treatment period in the iron overload and inflammation rat models, whereas a moderate increase was observed in the anaemia model. Significantly greater increases (P < 0.05) in serum iron were observed with FC versus SFOH in the rat models of anaemia and inflammation. In the 13-week iron accumulation study, total liver iron content was significantly higher in rats receiving FC versus SFOH (P < 0.01), whereas liver iron content did not differ between rats in the SFOH and control groups.. Iron uptake was higher from FC versus SFOH following a single dose in anaemia, iron overload and inflammation rat models and 13 weeks of treatment in normal rats. These observations likely relate to different physicochemical properties of SFOH and FC and suggest distinct mechanisms of iron absorption from these two phosphate binders.

Topics: Administration, Oral; Anemia; Animals; Drug Combinations; Female; Ferric Compounds; Inflammation; Iron; Iron Overload; Kinetics; Male; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sucrose; Tissue Distribution

Excessive iron can generate reactive oxygen species (ROS), leading to oxidative stress that is closely associated with cardiovascular dysfunction. Iron overload was induced in male ICR mice by injection of iron sucrose (10mg/kg/day) for eight weeks. Iron overload was evidenced by increased serum iron indices. The mice developed increased blood pressure, impaired vascular function and blunted response of the autonomic nervous system. These effects were accompanied by increased malondialdehyde levels in various tissues, increased nitric oxide metabolites in plasma and urine, and decreased blood glutathione. Tetrahydrocurcumin (THU, 50mg/kg/day), deferiprone (or L1, 50mg/kg/day) or both was orally administered throughout the period of iron sucrose injection. The treatments significantly alleviated the deleterious cardiovascular effects of iron overload, and were associated with modulation of nitric oxide levels. An imbalance between endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) expression in response to iron overload was normalized by THU, L1 or the combination treatment. Moreover, the treatment decreased the upregulated expression levels of gp91

Topics: Administration, Oral; Animals; Baroreflex; Curcumin; Deferiprone; Disease Models, Animal; Drug Therapy, Combination; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hypertension; Iron Chelating Agents; Iron Overload; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Pyridones

Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2'-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers, Tumor; Calbindin 2; Cell Cycle Proteins; Cell Line, Tumor; Chromosome Deletion; Deoxyguanosine; Down-Regulation; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Iron; Iron Overload; Lung Neoplasms; Male; Membrane Glycoproteins; Mesothelioma; Mesothelioma, Malignant; Neoplasms, Experimental; Nuclear Proteins; Rats; Rats, Wistar; RNA Splicing Factors; Thromboxane-A Synthase

Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.

Topics: Animals; Antisickling Agents; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hydroxyurea; Iron Chelating Agents; Iron Overload; Liver; Male; Mice; Mice, Inbred BALB C; Myocardium; Time Factors

Iron constitutes a critical nutrient source for bacterial growth, so iron overload is a risk factor for bacterial infections. This study aimed at investigating the role of iron overload in modulating bacterial endotoxin-induced lung inflammation. Weaning male Wistar rats were intraperitoneally injected with saline or iron sucrose [15 mg kg(-1) body weight (bw), 3 times per week, 4 weeks]. They were then intratracheally injected with Pseudomonas aeruginosa lipopolysaccharide (LPS) (5 μg kg(-1) bw) or saline. Inflammatory indices were evaluated 4 or 18 h post-LPS/saline injection. At 4 h, LPS-treated groups revealed significant increases in the majority of inflammatory parameters (LPS-binding protein (LBP), immune cell recruitment, inflammatory cytokine synthesis, myeloperoxidase activity, and alteration of alveolar-capillary permeability), as compared with control groups. At 18 h, these parameters reduced strongly with the exception for LBP content and interleukin (IL)-10. In parallel, iron acted as a modulator of immune cell recruitment; LBP, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant 3, and IL-10 synthesis; and alveolar-capillary permeability. Therefore, P. aeruginosa LPS may only act as an acute lung inflammatory molecule, and iron overload may modulate lung inflammation by enhancing different inflammatory parameters. Thus, therapy for iron overload may be a novel and efficacious approach for the prevention and treatment of bacterial lung inflammations.

Topics: Analysis of Variance; Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Cytokines; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Iron; Iron Overload; Lipopolysaccharides; Lung; Male; Peroxidase; Pneumonia; Pseudomonas aeruginosa; Rats; Rats, Wistar; Weaning

The majority of murine models of iron sucrose-induced iron overload were carried out in adult subjects. This cannot reflect the high risk of iron overload in children who have an increased need for iron. In this study, we developed four experimental iron overload models in young rats using iron sucrose and evaluated different markers of iron overload, tissue oxidative stress and inflammation as its consequences. Iron overload was observed in all iron-treated rats, as evidenced by significant increases in serum iron indices, expression of liver hepcidin gene and total tissue iron content compared with control rats. We also showed that total tissue iron content was mainly associated with the dose of iron whereas serum iron indices depended essentially on the duration of iron administration. However, no differences in tissue inflammatory and antioxidant parameters from controls were observed. Furthermore, only rats exposed to daily iron injection at a dose of 75 mg/kg body weight for one week revealed a significant increase in lipid peroxidation in iron-treated rats compared with their controls. The present results suggest a correlation between iron overload levels and the dose of iron, as well as the duration and frequency of iron injection and confirm that iron sucrose may not play a crucial role in inflammation and oxidative stress. This study provides important information about iron sucrose-induced iron overload in rats and may be useful for iron sucrose therapy for iron deficiency anemia as well as for the prevention and diagnosis of iron sucrose-induced iron overload in pediatric patients.

Topics: Animals; Antimicrobial Cationic Peptides; Biomarkers; Disease Models, Animal; Dose-Response Relationship, Drug; Ferric Compounds; Ferric Oxide, Saccharated; Gene Expression; Glucaric Acid; Hepcidins; Humans; Inflammation; Iron; Iron Overload; Lipid Peroxidation; Liver; Oxidative Stress; Rats; Serum; Time Factors

Topics: Anemia, Iron-Deficiency; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hemoglobins; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis