ferric-carboxymaltose and Disease-Models--Animal

β-Thalassemia is a genetic anemia caused by partial or complete loss of β-globin synthesis, leading to ineffective erythropoiesis and RBCs with a short life span. Currently, there is no efficacious oral medication modifying anemia for patients with β-thalassemia. The inappropriately low levels of the iron regulatory hormone hepcidin enable excessive iron absorption by ferroportin, the unique cellular iron exporter in mammals, leading to organ iron overload and associated morbidities. Correction of unbalanced iron absorption and recycling by induction of hepcidin synthesis or treatment with hepcidin mimetics ameliorates β-thalassemia. However, hepcidin modulation or replacement strategies currently in clinical development all require parenteral drug administration. We identified oral ferroportin inhibitors by screening a library of small molecular weight compounds for modulators of ferroportin internalization. Restricting iron availability by VIT-2763, the first clinical stage oral ferroportin inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia intermedia. VIT-2763 not only improved erythropoiesis but also corrected the proportions of myeloid precursors in spleens of Hbbth3/+ mice. VIT-2763 is currently being developed as an oral drug targeting ferroportin for the treatment of β-thalassemia.

Topics: Administration, Oral; Animals; beta-Globins; beta-Thalassemia; Cation Transport Proteins; Cell Line; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Erythropoiesis; Female; Ferric Compounds; Hepcidins; Humans; Iron; Madin Darby Canine Kidney Cells; Male; Maltose; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Proteolysis; Rats, Sprague-Dawley; Ubiquitination

Iron deficiency is present in ~50% of heart failure (HF) patients. Large multicenter trials have shown that treatment of iron deficiency with i.v. iron benefits HF patients, but the underlying mechanisms are not known. To investigate the actions of iron deficiency on the heart, mice were fed an iron-depleted diet, and some received i.v. ferric carboxymaltose (FCM), an iron supplementation used clinically. Iron-deficient animals became anemic and had reduced ventricular ejection fraction measured by magnetic resonance imaging. Ca2+ signaling, a pathway linked to the contractile deficit in failing hearts, was also significantly affected. Ventricular myocytes isolated from iron-deficient animals produced smaller Ca2+ transients from an elevated diastolic baseline but had unchanged sarcoplasmic reticulum (SR) Ca2+ load, trigger L-type Ca2+ current, or cytoplasmic Ca2+ buffering. Reduced fractional release from the SR was due to downregulated RyR2 channels, detected at protein and message levels. The constancy of diastolic SR Ca2+ load is explained by reduced RyR2 permeability in combination with right-shifted SERCA activity due to dephosphorylation of its regulator phospholamban. Supplementing iron levels with FCM restored normal Ca2+ signaling and ejection fraction. Thus, 2 Ca2+-handling proteins previously implicated in HF become functionally impaired in iron-deficiency anemia, but their activity is rescued by i.v. iron supplementation.

Topics: Administration, Intravenous; Anemia, Iron-Deficiency; Animals; Calcium; Calcium-Binding Proteins; Cells, Cultured; Disease Models, Animal; Down-Regulation; Ferric Compounds; Heart Failure; Humans; Iron; Magnetic Resonance Imaging; Male; Maltose; Mice; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Primary Cell Culture; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stroke Volume

Iron deficiency without anemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival.. We hypothesized that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy.. Rats were fed an iron-deficient diet (IDD, 7 mg/kg) and investigated for 4 weeks. Iron deficiency was evident from depleted iron stores (decreased liver, serum iron, and ferritin), reduced erythropoiesis, and significantly decreased transferrin saturation and lung iron stores after 2 weeks IDD. IDD rats exhibited profound pulmonary vascular remodeling with prominent muscularization, medial hypertrophy, and perivascular inflammatory cell infiltration, associated with raised pulmonary artery pressure and right ventricular hypertrophy. IDD rat lungs demonstrated increased expression of hypoxia-induced factor-1α and hypoxia-induced factor-2α, nuclear factor of activated T cells and survivin, and signal transducers and activators of transcription-3 activation, which promote vascular cell proliferation and resistance to apoptosis. Biochemical examination showed reduced mitochondrial complex I activity and mitochondrial membrane hyperpolarization in mitochondria from IDD rat pulmonary arteries. Along with upregulation of the glucose transporter, glucose transporter 1, and glycolytic genes, hk1 and pdk1, lung fluorine-18-labeled 2-fluoro-2-deoxyglucose ligand uptake was significantly increased in IDD rats. The hemodynamic and pulmonary vascular remodeling were reversed by iron replacement (ferric carboxymaltose, 75 mg/kg) and attenuated in the presence of iron deficiency by dichloroacetate and imatinib, 2 putative treatments explored for pulmonary arterial hypertension that target aerobic glycolysis and proliferation, respectively.. These data suggest a major role for iron in pulmonary vascular homeostasis and support the clinical evaluation of iron replacement in patients with pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Benzamides; Cell Proliferation; Deficiency Diseases; Dichloroacetic Acid; Disease Models, Animal; Erythropoiesis; Ferric Compounds; Ferritins; Glycolysis; Hematinics; Homeostasis; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Imatinib Mesylate; Iron; Iron Deficiencies; Liver; Male; Maltose; Piperazines; Pulmonary Artery; Pyrimidines; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Transferrin; Vascular Remodeling

Iron restriction has been proposed as a cause of erythropoietic suppression in malarial anemia; however, the role of iron in malaria remains controversial, because it may increase parasitemia. To investigate the role of iron-restricted erythropoiesis, A/J mice were infected with Plasmodium chabaudi AS, treated with intravenous ferric carboxymaltose at different times, and compared with untreated controls. Iron treatment significantly increased weight and hemoglobin nadirs and provided enhanced reticulocytosis and faster recovery, compared with controls. Our findings challenge the restrictive use of iron therapy in malaria and show the need for trials of intravenous ferric carboxymaltose as an adjunctive treatment for severe malarial anemia.

Topics: Anemia, Iron-Deficiency; Animals; Disease Models, Animal; Erythropoiesis; Ferric Compounds; Growth Substances; Malaria; Male; Maltose; Mice; Mice, Inbred A; Plasmodium chabaudi; Treatment Outcome

Anemia is common in critically ill patients, due to inflammation and blood loss. Anemia can be associated with iron deficiency and low serum hepcidin levels. However, iron administration in this setting remains controversial because of its potential toxicity, including oxidative stress induction and sepsis facilitation. The objective of this work was to determine the efficacy and toxicity of iron administration using a mouse model mimicking critical care anemia as well as a model of acute septicemia.. Prospective, randomized, open label controlled animal study.. University-based research laboratory.. C57BL/6 and OF1 mice.. Intraperitoneal injection of zymosan inducing generalized inflammation in C57BL/6 mice, followed in our full model by repeated phlebotomies. A dose equivalent to 15 mg/kg of ferric carboxymaltose was injected intravenously on day 5. To assess the toxicity of iron in a septicemia model, OF1 mice were simultaneously injected with iron and different Escherichia coli strains.. To investigate the effect of iron on oxidative stress, we measured reactive oxygen species production in the blood using luminol-amplified chemiluminescence and superoxide dismutase 2 messenger RNA levels in the liver. These markers of oxidative stress were increased after iron administration in control mice but not in zymosan-treated mice. Liver catalase messenger RNA levels decreased in iron-treated control mice. Iron administration was not associated with increased mortality in the septicemia model or in the generalized inflammation model. Iron increased hemoglobin levels in mice fed with a low iron diet and subjected to phlebotomies and zymosan 2 wks after treatment administration.. Adverse effects of intravenous iron supplementation by ferric carboxymaltose seem to be minimal in our animal models. Furthermore, iron appears to be effective in correcting anemia, despite inflammation. Studies of efficacy and safety of iron in critically ill patients are warranted.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Catalase; Diet; Disease Models, Animal; Ferric Compounds; Hematinics; Hemoglobins; Hepcidins; Inflammation; Injections, Intravenous; Iron; Liver; Luminescence; Maltose; Mice; Mice, Inbred C57BL; Phlebotomy; Random Allocation; Reactive Oxygen Species; RNA, Messenger; Sepsis; Spleen; Superoxide Dismutase; Trace Elements; Zymosan