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      Optimizing iron delivery in the management of anemia: patient considerations and the role of ferric carboxymaltose

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          Abstract

          With the challenge of optimizing iron delivery, new intravenous (iv) iron–carbohydrate complexes have been developed in the last few years. A good example of these new compounds is ferric carboxymaltose (FCM), which has recently been approved by the US Food and Drug Administration for the treatment of iron deficiency anemia in adult patients who are intolerant to oral iron or present an unsatisfactory response to oral iron, and in adult patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). FCM is a robust and stable complex similar to ferritin, which minimizes the release of labile iron during administration, allowing higher doses to be administered in a single application and with a favorable cost-effective rate. Cumulative information from randomized, controlled, multicenter trials on a diverse range of indications, including patients with chronic heart failure, postpartum anemia/abnormal uterine bleeding, inflammatory bowel disease, NDD-CKD, and those undergoing hemodialysis, supports the efficacy of FCM for iron replacement in patients with iron deficiency and iron-deficiency anemia. Furthermore, as FCM is a dextran-free iron–carbohydrate complex (which has a very low risk for hypersensitivity reactions) with a small proportion of the reported adverse effects in a large number of subjects who received FCM, it may be considered a safe drug. Therefore, FCM appears as an interesting option to apply high doses of iron as a single infusion in a few minutes in order to obtain the quick replacement of iron stores. The present review on FCM summarizes diverse aspects such as pharmacology characteristics and analyzes trials on the efficacy/safety of FCM versus oral iron and different iv iron compounds in multiple clinical scenarios. Additionally, the information on cost effectiveness and data on change in quality of life are also discussed.

          Most cited references79

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          Regulation of cellular iron metabolism

          Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron–sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance.
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            Identification of an intestinal heme transporter.

            Dietary heme iron is an important nutritional source of iron in carnivores and omnivores that is more readily absorbed than non-heme iron derived from vegetables and grain. Most heme is absorbed in the proximal intestine, with absorptive capacity decreasing distally. We utilized a subtractive hybridization approach to isolate a heme transporter from duodenum by taking advantage of the intestinal gradient for heme absorption. Here we show a membrane protein named HCP 1 (heme carrier protein 1), with homology to bacterial metal-tetracycline transporters, mediates heme uptake by cells in a temperature-dependent and saturable manner. HCP 1 mRNA was highly expressed in duodenum and regulated by hypoxia. HCP 1 protein was iron regulated and localized to the brush-border membrane of duodenal enterocytes in iron deficiency. Our data indicate that HCP 1 is the long-sought intestinal heme transporter.
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              The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress.

              Production of minute concentrations of superoxide (O2(*-)) and nitrogen monoxide (nitric oxide, NO*) plays important roles in several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur owing to redox imbalance-a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(*-), hydrogen peroxide (H2O2), and NO*. Iron is involved in both the formation and the scavenging of these species. Iron deficiency (anemia) (ID(A)) is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (iv) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation levels and, thus, formation of non-transferrin-bound iron, a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an iv iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for iv therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(*-), H2O2, NO*, and other more reactive compounds derived from these species, the potential of various iron therapies to induce oxidative and nitrosative stress is discussed and possible underlying mechanisms are proposed. Understanding the mechanisms, by which various iron formulations may induce oxidative and nitrosative stress, will help us develop better tolerated and more efficient therapies for various dysfunctions of iron metabolism. © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                11 December 2014
                : 8
                : 2475-2491
                Affiliations
                Nephrology Section, Department of Internal Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Argentina
                Author notes
                Correspondence: Jorge Eduardo Toblli, Laboratory of experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Av Pueyrredon, 1640, 1118 Buenos Aires, Argentina, Tel +54 11 4 827 7000 ext 2785, Fax +54 11 4805 6087, Email jorgetoblli@ 123456fibertel.com.ar
                Article
                dddt-8-2475
                10.2147/DDDT.S55499
                4266270
                25525337
                766f88a4-fe1e-4d50-a06a-8d3ebd5820ea
                © 2014 Toblli and Angerosa. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                intravenous iron,iron deficiency,anemia,ferric carboxymaltose

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