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Jodie L. Babitt - One of the best experts on this subject based on the ideXlab platform.

  • coordination of Iron homeostasis by bone morphogenetic proteins current understanding and unanswered questions
    Developmental Dynamics, 2021
    Co-Authors: Allison L Fisher, Jodie L. Babitt
    Abstract:

    Iron homeostasis is tightly regulated to Balance the Iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from Iron excess. The liver hormone hepcidin is the master regulator of systemic Iron Balance by controlling the degradation and function of the sole known mammalian Iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less Iron, including plasma and tissue Iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)-SMAD pathway, which controls hepcidin transcription. Genetic disorders of Iron overload and Iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP-SMAD and hepcidin regulatory response to Iron. However, the precise molecular mechanisms by which serum and tissue Iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses Iron levels to regulate BMP-SMAD signaling and thereby hepcidin expression to control systemic Iron homeostasis. This article is protected by copyright. All rights reserved.

  • liver Iron sensing and body Iron homeostasis
    Blood, 2019
    Co-Authors: Chiayu Wang, Jodie L. Babitt
    Abstract:

    The liver orchestrates systemic Iron Balance by producing and secreting hepcidin. Known as the Iron hormone, hepcidin induces degradation of the Iron exporter ferroportin to control Iron entry into the bloodstream from dietary sources, Iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by Iron deficiency and erythropoietic drive to increase the Iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by Iron loading and inflammation to prevent the toxicity of Iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of Iron overload and deficiency, including hereditary hemochromatosis and Iron-refractory Iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to Iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to Iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue Iron levels, the Iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body Iron levels and coordinates this with other signals to regulate hepcidin production and systemic Iron homeostasis.

  • overview of Iron metabolism in health and disease
    Hemodialysis International, 2017
    Co-Authors: Som Dev, Jodie L. Babitt
    Abstract:

    Iron is an essential element for numerous fundamental biologic processes, but excess Iron is toxic. Abnormalities in systemic Iron Balance are common in patients with chronic kidney disease and Iron administration is a mainstay of anemia management in many patients. This review provides an overview of the essential role of Iron in biology, the regulation of systemic and cellular Iron homeostasis, how imBalances in Iron homeostasis contribute to disease, and the implications for chronic kidney disease patients.

  • endothelial cells produce bone morphogenetic protein 6 required for Iron homeostasis in mice
    Blood, 2017
    Co-Authors: Susanna Canali, Kimberly B Zumbrennenbullough, Amanda B Core, Chiayu Wang, Manfred Nairz, Richard Bouley, Filip K Swirski, Jodie L. Babitt
    Abstract:

    Bone morphogenetic protein 6 (BMP6) signaling in hepatocytes is a central transcriptional regulator of the Iron hormone hepcidin that controls systemic Iron Balance. How Iron levels are sensed to regulate hepcidin production is not known, but local induction of liver BMP6 expression by Iron is proposed to have a critical role. To identify the cellular source of BMP6 responsible for hepcidin and Iron homeostasis regulation, we generated mice with tissue-specific ablation of Bmp6 in different liver cell populations and evaluated their Iron phenotype. Efficiency and specificity of Cre-mediated recombination was assessed by using Cre-reporter mice, polymerase chain reaction of genomic DNA, and quantitation of Bmp6 messenger RNA expression from isolated liver cell populations. Localization of the BMP co-receptor hemojuvelin was visualized by immunofluorescence microscopy. Analysis of the Bmp6 conditional knockout mice revealed that liver endothelial cells (ECs) expressed Bmp6, whereas resident liver macrophages (Kupffer cells) and hepatocytes did not. Loss of Bmp6 in ECs recapitulated the hemochromatosis phenotype of global Bmp6 knockout mice, whereas hepatocyte and macrophage Bmp6 conditional knockout mice exhibited no Iron phenotype. Hemojuvelin was localized on the hepatocyte sinusoidal membrane immediately adjacent to Bmp6-producing sinusoidal ECs. Together, these data demonstrate that ECs are the predominant source of BMP6 in the liver and support a model in which EC BMP6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin transcription and maintain systemic Iron homeostasis.

  • Hemojuvelin and bone morphogenetic protein (BMP) signaling in Iron homeostasis.
    Frontiers in Pharmacology, 2014
    Co-Authors: Amanda B Core, Susanna Canali, Jodie L. Babitt
    Abstract:

    Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the Iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key Iron hormone hepcidin in the control of systemic Iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic Iron Balance.

Kostas Pantopoulos - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of mammalian Iron homeostasis
    Biochemistry, 2012
    Co-Authors: Kostas Pantopoulos, Suheel K Porwal, Alan M Tartakoff, Laxminarayana R Devireddy
    Abstract:

    Iron is vital for almost all organisms because of its ability to donate and accept electrons with relative ease. It serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism, as well as for several other essential processes. Mammalian cells utilize multiple mechanisms to acquire Iron. Disruption of Iron homeostasis is associated with various human diseases: Iron deficiency resulting from defects in the acquisition or distribution of the metal causes anemia, whereas Iron surfeit resulting from excessive Iron absorption or defective utilization causes abnormal tissue Iron deposition, leading to oxidative damage. Mammals utilize distinct mechanisms to regulate Iron homeostasis at the systemic and cellular levels. These involve the hormone hepcidin and Iron regulatory proteins, which collectively ensure Iron Balance. This review outlines recent advances in Iron regulatory pathways as well as in mechanisms underlying intracellular Iron trafficking, an important but less studied area of mammalian Iron homeostasis.

  • regulation of cellular Iron metabolism
    Biochemical Journal, 2011
    Co-Authors: Jian Wang, Kostas Pantopoulos
    Abstract:

    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.

John B. Porter - One of the best experts on this subject based on the ideXlab platform.

  • Iron overload in thalassemia and related conditions therapeutic goals and assessment of response to chelation therapies
    Hematology-oncology Clinics of North America, 2010
    Co-Authors: John B. Porter, Farrukh Shah
    Abstract:

    Transfusional Iron loading inevitably results in hepatic Iron accumulation, with variable extrahepatic distribution that is typically less pronounced in sickle cell disease than in thalassemia disorders. Iron chelation therapy has the goal of preventing Iron-mediated tissue damage through controlling tissue Iron levels, without incurring chelator-mediated toxicity. Historically, target levels for tissue Iron control have been limited by the increased frequency of deferoxamine-mediated toxicity and low levels of Iron loading. With newer chelation regimes, these limitations are less evident. The reporting of responses to chelation therapies has typically focused on average changes in serum ferritin in patient populations. This approach has three limitations. First, changes in serum ferritin may not reflect trends in Iron Balance equally in all patients or for all chelation regimens. Second, this provides no information about the proportion of patients likely respond. Third, this gives insufficient information about Iron trends in tissues such as the heart. Monitoring of Iron overload has advanced with the increasing use of MRI techniques to estimate Iron Balance (changes in liver Iron concentration) and extrahepatic Iron distribution (myocardial T2*). The term nonresponder has been increasingly used to describe individuals who fail to show a downward trend in one or more of these variables. Lack of a response of an individual may result from inadequate dosing, high transfusion requirement, poor treatment adherence, or unfavorable pharmacology of the chelation regime. This article scrutinizes evidence for response rates to deferoxamine, deferiprone (and combinations), and deferasirox.

  • effect of transfusional Iron intake on response to chelation therapy in beta thalassemia major
    Blood, 2008
    Co-Authors: Alan R. Cohen, Ekkehard Glimm, John B. Porter
    Abstract:

    The success of chelation therapy in controlling Iron overload in patients with thalassemia major is highly variable and may partly depend on the rate of transfusional Iron loading. Using data from the 1-year phase III study of deferasirox, including volumes of transfused red blood cells and changes in liver Iron concentration (LIC) in 541 patients, the effect of Iron loading on achieving neutral or negative Iron Balance was assessed in patients receiving different doses of deferasirox and the comparator deferoxamine. After dose adjustment, reductions in LIC after 1 year of deferasirox or deferoxamine therapy correlated with transfusional Iron intake. At a deferasirox dose of 20 mg/kg per day, neutral or negative Iron Balance was achieved in 46% and 75% of patients with the highest and lowest transfusional Iron intake, respectively; 30 mg/kg per day produced successful control of Iron stores in 96% of patients with a low rate of transfusional Iron intake. Splenectomized patients had lower transfusional Iron intake and greater reductions in Iron stores than patients with intact spleens. Transfusional Iron intake should be monitored on an ongoing basis in thalassemia major patients, and the rate of transfusional Iron loading should be considered when choosing the appropriate dose of an Iron-chelating agent. This study is registered at http://clinicaltrials.gov as NCT00061750.

  • a phase 3 study of deferasirox icl670 a once daily oral Iron chelator in patients with beta thalassemia
    Blood, 2006
    Co-Authors: Maria Domenica Cappellini, Alan R. Cohen, Antonio Piga, M Bejaoui, Silverio Perrotta, Leyla Agaoglu, Yesim Aydinok, Antonis Kattamis, Yurdanur Kilinc, John B. Porter
    Abstract:

    Deferasirox (ICL670) is a once-daily oral Iron chelator developed for the treatment of chronic Iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver Iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body Iron Balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body Iron Balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional Iron overload.

  • randomised prospective evaluation of Iron Balance chelation efficiency urine excretion and ntbi progression with deferiprone dfp or deferoxamine dfo monotherapy or with combined dfp plus dfo
    Blood, 2005
    Co-Authors: Yesim Aydinok, Patricia Evans, Aysen Terzi, Nurten Cetiner, John B. Porter
    Abstract:

    Rationale. The relative effects of monotherapy regimes with oral DFP or sc DFO or combinations of these drugs, on chelation efficiency, Iron Balance, plasma non-transferrin bound Iron (NTBI) and the proportion and speciation of urine Iron, have not been compared previously in prospective randomised trials. By examining these variables together in a single study, insights into the effectiveness and mechanisms of action of mono or combination regimens can be gained. Design. A total of 25 patients (pts) with thalassaemia major were randomised into one of the following 3 arms: DFP (LIPOMED AG, Switzerland) was given at a daily dose of 75 mg/kg either in combination with DFO (40–50 mg/kg twice weekly) or as single agent, and pts registered in the DFO control arm received 40–50 mg/kg sc DFO 5 days a week. All pts had been treated with DFO prior to the study. Methodology. Liver Iron concentration (LIC) was measured by biopsy at baseline and after 1 year. Total Iron excretion (IE)/day was calculated as (Iron transfused/year (mg) + (LIC at To - LIC at T1y) x 10.6 x body wt in Kg) /number of days treatment. Chelation efficiency (%) was calculated as [IE (in mg/kg/day)/chelator dose (in mg/kg/day)] x [molecular weight of the respective chelator(s)/56]x n x 100, where 56 is the molecular weight of Iron and n is 3 or 1 with DFP and DFO respectively. The average urinary Iron excretion (UIE) (weeks 1, 12, 26, 38 and 54) was calculated from atomic absorption measurements. In patients receiving combination, UIE was measured during both days of monotherapy and combination therapy. The % UIE was calculated from mean UIE divided by total IE. In patients receiving DFO with or without DFP, the concentration of feroxamine species were measured in urine, collected into aluminised containers. Plasma NTBI was measured by HPLC at baseline and at weeks 1, 12, 26 and 54 standardised to blood transfusion interval. Results. The results show that DFO sc 5 days a week was the regimen associated with the largest and most efficient IE and stabilised NTBI after 1 year. Single agent DFP showed the lowest IE and efficiency, and a significant increase in NTBI (* p=0.001). The addition of sc DFO two days a week to DFP resulted in significant increase in IE (^ p=0.03) and stabilised NTBI. The proportion of UIE was significantly lower with DFO than with DFP regimens. UIE on the days of combination (0.89± 0.14mg/kg/d) was significantly higher than on days of DFP monotherapy (0.41 ±0.09 mg/kg/d) (p=0.002). Speciation of urinary Iron showed that the proportion of DFO bound to Iron was higher on days of combination treatment than with DFO monotherapy, consistent with shuttling of Iron onto DFO by DFP. Conclusions. The addition of sc DFO twice weekly to DFP at 75mg/kg po is a regimen which appears as effective at producing Iron Balance as DFO given 5 days a week at standard doses. Both regimens are more effective at stabilising NTBI, and achieving Iron Balance than DFP at 75mg/kg/day. When DFP is combined with DFO, Iron excretion appears to be mainly by the urinary route as feroxamine.

  • Iron chelation efficiency of deferasirox exjade icl670 in patients with transfusional hemosiderosis
    Blood, 2005
    Co-Authors: John B. Porter, C Borgnapignatti, M Baccarani, A Saviano, Sharon Abish, R Malizia, Hanspeter Nick, Herbert Opitz, B Rabault, Insa Gathmann
    Abstract:

    Iron excretion can be calculated according to Angelucci et al (NEJM 2000). As applied to the novel oral Iron chelator deferasirox (DSX), chelation efficiency can then be determined as the % Iron excretion vs theoretical Iron binding capacity of chelator dose: % efficiency = [Iron excretion (mg/kg/day)/chelator dose (mg/kg/day)] x [374/56] x 2 x 100 (374 and 56 represent the molecular weights of DSX and Iron; factor 2 accounts for the tridentate ligand). In a total of 325 patients with β-thalassemia (n=285) or rare anemias, such as MDS (n=13), DBA (n=14) or other anemias (n=13), included in the DSX Phase II and III Studies 0108 and 0107, liver Iron concentration (LIC) was evaluated by liver biopsy at baseline and study end. All patients were treated with once-daily oral DSX 5, 10, 20 or 30 mg/kg according to baseline LIC (2–3, >3–7, >7–14 and >14 mg Fe/g dw, respectively). In these patients, the average dose during study was 22.8 ± 7.6 mg/kg. The average Iron intake was 0.37 mg/kg/day and was similar between dose cohorts. There were no differences in the chelation efficiency of DSX between the overall initial dose groups, and thus between different LIC categories at baseline, or between age and disease groups. Using the estimated efficiency of 27%, and the formula above, the approximate dose (mg) needed to achieve Iron Balance corresponds to an Iron intake in mg Fe/kg/day divided by 0.02. For a patient receiving 0.2, 0.4 or 0.6 mg/kg Fe/day the doses of 10, 20 or 30 mg/kg, respectively, are estimated to achieve Iron Balance (eg for a 44 kg person receiving 4 units of blood/month a dose of 30 mg/kg would be required to achieve Iron Balance). Further analysis reveals that chelation efficiency does appear to increase somewhat with Iron intake: in patients with 0.5 mg/kg/day Fe (average 0.55). Applying different chelation efficiency estimates for low and high Iron intake, 14 and 22 mg/kg/day DSX, respectively, would be required to chelate the transfused Iron. In Study 0107, 230 patients were treated with deferoxamine (DFO) at an average daily dose of 45 mg/kg (5 days/week). Using the molecular weight of DFO (656) and a factor of 1 for a hexadentate ligand in the calculation, the overall chelation efficiency for DFO is 13% (10–17% in the lowest and highest Iron intake categories, respectively). These calculations, based on the formula of Angelucci et al, correspond well to the overall observation in the DSX clinical studies, that Iron Balance or net negative Iron Balance is achieved by daily doses of 20–30 mg/kg in regularly transfused patients. The results also confirm that the estimated chelation efficiency of DSX is around twice that of DFO.

Robert W Grady - One of the best experts on this subject based on the ideXlab platform.

  • toward optimizing the use of deferasirox potential benefits of combined use with deferoxamine
    Haematologica, 2013
    Co-Authors: Robert W Grady, Renzo Galanello, Carlo Dessi, Rachel Randolph, Dorothy A Kleinert, Patricia J Giardina
    Abstract:

    Patients with β-thalassemia require Iron chelation therapy to protect against progressive Iron overload and non-transferrin-bound Iron. Some patients fail to respond adequately to deferoxamine and deferasirox monotherapy while others have side effects which limit their use of these drugs. Since combining deferiprone and deferoxamine has an additive effect, placing all patients into net negative Iron Balance, we investigated the possibility that combining deferasirox and deferoxamine would lead to similar results. We conducted 34-day metabolic Iron Balance studies in six patients in whom the relative effectiveness of deferasirox (30 mg/kg/day) and deferoxamine (40 mg/kg/day) was compared, alone and in combination. Patients consumed fixed low-Iron diets; daily urinary and stool Iron excretion were determined by atomic absorption. Red blood cell transfusions were given prior to each drug treatment to minimize the effects of ineffective erythropoiesis. Serial safety measures, hematologic parameters, serum chemistries, ferritin levels and urinalyses were determined. All patients were in negative Iron Balance when treated with deferoxamine alone while four of six patients remained in positive Balance when deferasirox monotherapy was evaluated. Daily use of both drugs had a synergistic effect in two patients and an additive effect in three others. Five of six patients would be in negative Iron Balance if they used the combination of drugs just 3 days a week. No significant or drug-related changes were observed in the blood work-ups or urinalyses performed. We conclude that supplementing the daily use of deferasirox with 2 – 3 days of deferoxamine therapy would place all patients into net negative Iron Balance thereby providing a convenient way to tailor chelation therapy to the individual needs of each patient.

  • Combined Iron chelation therapy
    Annals of the New York Academy of Sciences, 2010
    Co-Authors: Renzo Galanello, Patricia J Giardina, Annalisa Agus, Simona Campus, Fabrice Danjou, Robert W Grady
    Abstract:

    Patients with thalassemia major accumulate body Iron over time as a consequence of continuous red blood cell transfusions which cause hepatic, endocrine, and cardiac complications. Despite the availability of three Iron chelators, some patients fail to respond adequately to monotherapy with any of them. Combination therapy, consisting in the use of two chelators on the same day, has been introduced to increase the efficacy and to induce negative Iron Balance in patients with severe Iron overload. Extensive long-term experience has shown that combined chelation with deferiprone and deferoxamine (DFO) rapidly reduces liver Iron, serum ferritin, and myocardial siderosis, improves cardiac function, reverses and prevents endocrine complications, reduces cardiac mortality, and improves survival. Side effects, though significant, are manageable if properly monitored. Preliminary promising results have been obtained using combined chelation with deferasirox and DFO. As more drug combination regimes are evaluated, it should be possible to better tailor Iron chelation to the needs of the patients, minimizing toxicity and maximizing efficacy throughout life.

  • efficacy of the novel oral Iron chelator deferitrin in metabolic Iron Balance studies
    Blood, 2007
    Co-Authors: Robert W Grady, Patricia J Giardina, Renzo Galanello, Farrukh Shah, Maria Sitarou, Hannah Tamary, Eliana Lai, Aurelio Maggio, Joanne M Donovan
    Abstract:

    Abstract Deferiprone (L1, Ferriprox) and deferasirox (ICL670, Exjade), two orally effective Iron-chelating agents, have revolutionized the management of Iron overload. Nonetheless, neither drug is effective in all patients, deferoxamine (DFO) still being the only drug capable of placing all affected individuals in net negative Iron Balance. Deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, GT56-252), is a tridentate ligand with a demonstrated efficacy and an acceptable toxicity profile in preclinical evaluations in primates. In Phase 1 studies, it was well absorbed and no safety issues were identified. Thus, given the need for additional oral chelation options, we explored the efficacy of deferitrin in Iron-overloaded patients with β-thalassemia major. Total Iron Balance studies were carried out wherein the effectiveness of single daily ascending doses of deferitrin (4.5, 6.75, 11 and 17 mg/kg/day) was compared with that of a standard DFO regimen (40 mg/kg infused subcutaneously over 8 hours). Twenty patients were admitted to our clinical research center for 28 days and placed on fixed individualized low-Iron diets. On days 5 – 10 they were infused nightly with DFO and on days 15 – 24 given a dose of deferitrin with breakfast. Groups of 4 patients were studied at the three lowest doses of deferitrin, only 2 patients being given 17 mg/kg. Drug-free days allowed for washout of stool Iron due to previous treatments, a stool marker being given at the beginning and end of each period of drug evaluation. Safety was assessed by hematology (CBC and coagulation parameters), chemistry (electrolytes, BUN, creatinine, liver function tests), urinalysis, and urinary β-2-microglobulin as well as by EKG, physical examination and monitoring of adverse events. Iron Balance due to DFO ranged from 52% – 325% (mean 157%) with 40% – 77% (mean 61%) of total Iron excretion appearing in the stool. Only 4 patients failed to achieve net negative Iron Balance. The response to deferitrin was highly variable at each dose studied, there being patients who responded poorly and others in whom there was a good response. Overall, Iron Balance ranged from 7% – 42%, nearly all of the Iron excreted (0.04 – 0.14 mg/kg/day) appearing in the stool. Of note, total Iron excretion appeared to reach a plateau at a deferitrin dose of 11 mg/kg/day. As animal studies suggested that more Iron might be excreted upon giving the drug in divided doses, we interrupted our evaluation of 17 mg/kg/day and studied an additional 6 patients at 25 mg/kg/day, the drug being divided t.i.d. with breakfast, dinner and a bedtime snack. Iron Balance in these patients ranged from 28% – 62% (mean 43%), stool Iron excretion (0.14 – 0.29 mg/kg/day) accounting for 99% of the total. Their DFO-induced Iron Balance was similar to that of the patients previously studied, ranging from 123% – 233% (mean 173%). At all doses, no significant changes were noted in the EKGs or any hematological, biochemical or urinary parameters. There were no serious adverse events. These results suggest that deferitrin was orally effective and, while less effective than DFO, it was of sufficient efficacy to warrant further evaluation in a longer-term study as an alternative to DFO.

  • phase ib clinical trial of starch conjugated deferoxamine 40sd02 a novel long acting Iron chelator
    British Journal of Haematology, 2007
    Co-Authors: Paul Harmatz, Elliott Vichinsky, Robert W Grady, Paul R Dragsten, Patricia J Giardina, Jacqueline Madden, Michael Jeng, Becky Miller, Gregory J Hanson, Bo E Hedlund
    Abstract:

    The most widely used drug for Iron chelation is deferoxamine (DFO) mesylate. While effective in promoting Iron excretion, it requires prolonged daily infusions, often resulting in poor compliance. A clinical trial was conducted using starch-conjugated DFO (S-DFO; 40SD02), a high-molecular-weight Iron chelator possessing prolonged vascular retention. Single doses of S-DFO were infused intravenously into groups of four transfusion-dependent patients with beta-thalassaemia at doses of 150, 300, 600 and 900 mg/kg. Urinary Iron excretion and various pharmacologic parameters were evaluated for 1 week and safety for 3 weeks. No drug-related effects were observed on clinical chemistries, haematological and coagulation parameters, urinalyses, vital signs or electrocardiograms. Drug-related adverse events were limited to four urticarial reactions, none requiring termination of the infusion. The drug stimulated clinically significant urinary Iron excretion, with the highest dose (900 mg/kg) inducing excretion of 1.31 mg of Iron/kg (range 0.79-1.90 mg/kg) over 1 week, with residual Iron-binding capacity present in the plasma for over 6 d. In summary, treatment with S-DFO, administered weekly, has the potential to achieve Iron Balance in the poorly compliant patient.

James D Cook - One of the best experts on this subject based on the ideXlab platform.

  • effect of ascorbic acid intake on nonheme Iron absorption from a complete diet
    The American Journal of Clinical Nutrition, 2001
    Co-Authors: James D Cook, Manju B Reddy
    Abstract:

    Background: Ascorbic acid has a pronounced enhancing effect on the absorption of dietary nonheme Iron when assessed by feeding single meals to fasting subjects. This contrasts with the negligible effect on Iron Balance of long-term supplementation with vitamin C. Objective: Our goal was to examine the effect of vitamin C on nonheme-Iron absorption from a complete diet rather than from single meals. Design: Iron absorption from a complete diet was measured during 3 separate dietary periods in 12 subjects by having the subjects ingest a labeled wheat roll with every meal for 5 d. The diet was freely chosen for the first dietary period and was then altered to maximally decrease or increase the dietary intake of vitamin C during the second and third periods. Results: There was no significant difference in mean Iron absorption among the 3 dietary periods despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d. When absorption values were adjusted for differences in Iron status and the 3 absorption periods were pooled, multiple regression analysis indicated that Iron absorption correlated negatively with dietary phosphate (P = 0.0005) and positively with ascorbic acid (P = 0.0069) and animal tissue (P = 0.0285). Conclusions: The facilitating effect of vitamin C on Iron absorption from a complete diet is far less pronounced than that from single meals. These findings may explain why several prior studies did not show a significant effect on Iron status of prolonged supplementation with vitamin C.

  • ferritin excretion and Iron Balance in humans
    British Journal of Haematology, 1995
    Co-Authors: Barry S Skikne, Paul Whittaker, Allen Cooke, James D Cook
    Abstract:

    Under normal circumstances, most of the lumenal Iron taken into the intestinal mucosal cell is stored within the cell as ferritin and subsequently is lost in the faeces when the cell exfoliates at the end of its lifespan. To evaluate whether faecal Iron proteins reflect mucosal cell Iron as well as whole body Iron and to examine further the kinetics of gastrointestinal Iron transport, faecal H-rich and L-rich ferritin were measured in normal subjects and patients with Iron deficiency and genetic haemochromatosis. In normal and Iron-deficient subjects, the concentration of L-rich but not H-rich faecal ferritin correlated closely with body Iron status. In genetic haemochromatosis, the faecal L-rich and H-rich ferritin concentrations were lower than expected for their body Iron status. The administration of oral Iron to normal subjects led to a rise in L-rich ferritin. Administration of oral or parenteral Iron to patients with Iron deficiency led to a prompt rise in both forms of faecal ferritin, although the relative increase of L-rich ferritin was greater than that of H-rich ferritin with oral Iron administration. Faecal ferritin correlated closely with Iron stores in normals and patients with Iron deficiency but faecal ferritin levels were lower than expected in genetic haemochromatosis, similar to that previously noted in the duodenal mucosal cells of these patients.

  • serum transferrin receptor
    Annual Review of Medicine, 1993
    Co-Authors: James D Cook, Barry S Skikne, Roy D Baynes
    Abstract:

    Transferrin receptors (TfRs) are the conventional pathway by which cells acquire Iron for physiological requirements. Under Iron-deficient conditions there is an increased concentration of surface TfR, especially on bone marrow erythroid precursors, as a mechanism to sequester needed Iron. TfRs are also present in the circulation, and the circulating serum TfR (sTfR) level reflects total body TfR concentration. Under normal conditions erythroid precursors are the main source of sTfR. Disorders of the bone marrow with reduced erythroid precursors are associated with low sTfR levels. The sTfR concentration begins to rise early in Iron deficiency with the onset of Iron-deficient erythropoiesis, and continues to rise as Iron-deficient erythropoiesis progressively worsens, prior to the development of anemia. The sTfR level does not increase in anemia of chronic inflammation, but is increased when anemia of chronic inflammation is combined with Iron deficiency. The sTfR level is also increased in patients with expanded erythropoiesis, including hemolytic anemias, myelodysplastic syndromes, and use of erythropoietic stimulating agents. The ratio of sTfR/ferritin can be used to quantify the entire spectrum of Iron status from positive Iron stores through negative Iron Balance, and is particularly useful in evaluating Iron status in population studies. The sTfR/log ferritin ratio is valuable for distinguishing anemia of chronic inflammation from Iron deficiency anemia, whether the latter occurs alone or in combination with anemia of chronic inflammation.

  • assessment of the role of nonheme Iron availability in Iron Balance
    The American Journal of Clinical Nutrition, 1991
    Co-Authors: James D Cook, S A Dassenko, Sean R Lynch
    Abstract:

    To assess the nutritional relevance of absorption studies that use extrinsically labeled single meals, we developed a method for measuring nonheme-Iron absorption from the diet and compared the results with absorption from single meals. When subjects consumed their usual diet, there was good agreement between dietary absorption (6.4%) and representative single meals fed in the laboratory (6.1%). Nonheme-Iron availability, as estimated by a model that incorporated the effect of both enhancers and inhibitors, correlated significantly with absorption from single meals but not with dietary absorption. When the diet was modified to promote Iron absorption maximally, dietary absorption increased only slightly (8.0%) and remained significantly lower than it was from single meals (13.5%). With an inhibitory diet, the decrease in absorption from single meals was similarly exaggerated. These results indicate that in the context of a varied Western diet, nonheme-Iron bioavailability is less important than absorption studies with single meals would suggest.