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Effect of Ferric Citrate versus Ferrous Sulfate on Iron and Phosphate Parameters in Patients with Iron Deficiency and CKD: A Randomized Trial.
Womack, R, Berru, F, Panwar, B, Gutiérrez, OM
Clinical journal of the American Society of Nephrology : CJASN. 2020;(9):1251-1258
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Abstract
BACKGROUND AND OBJECTIVES Ferric citrate is an oral medication approved for treatment of iron deficiency anemia in patients with CKD not requiring dialysis. The relative efficacy of ferric citrate versus ferrous sulfate in treating iron deficiency in patients with CKD is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We randomized 60 adults with moderate to severe CKD (eGFR 15-45 ml/min per 1.73 m2) and iron deficiency (transferrin saturation [TSAT] ≤30% and ferritin ≤300 ng/ml) to ferric citrate (2 g three times a day with meals, n=30) or ferrous sulfate (325 mg three times a day, n=30) for 12 weeks. Primary outcomes were change in TSAT and ferritin from baseline to 12 weeks. Secondary outcomes were change in hemoglobin, fibroblast growth factor 23 (FGF23), and hepcidin. RESULTS Baseline characteristics were well balanced between study arms. There was a greater increase in TSAT (between-group difference in mean change, 8%; 95% confidence interval [95% CI], 1 to 15; P=0.02) and ferritin (between-group difference in mean change, 37 ng/ml; 95% CI, 10 to 64; P=0.009) from baseline to 12 weeks in participants randomized to ferric citrate as compared with ferrous sulfate. Similarly, as compared with ferrous sulfate, treatment with ferric citrate resulted in a greater increase in hepcidin from baseline to 12 weeks (between-group difference, 69 pg/ml; 95% CI, 8 to 130). There were no between-group differences in mean change for hemoglobin (0.3 g/dl; 95% CI, -0.2 to 0.8), intact FGF23 (-29 pg/ml; 95% CI, -59 to 0.1), or C-terminal FGF23 (61 RU/ml; 95% CI, -181 to 58). The incidence of adverse events did not differ between treatment arms. CONCLUSIONS As compared with ferrous sulfate, treatment with ferric citrate for 12 weeks resulted in a greater mean increase in TSAT and ferritin concentrations in individuals with moderate to severe CKD and iron deficiency. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Impact of Ferric Citrate vs Ferrous Sulfate on Iron Parameters and Hemoglobin in Individuals With Moderate to Severe Chronic Kidney Disease (CKD) With Iron Deficiency, NCT02888171.
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Delayed iron improves iron status without altering malaria risk in severe malarial anemia.
Cusick, SE, Opoka, RO, Ssemata, AS, Georgieff, MK, John, CC
The American journal of clinical nutrition. 2020;(5):1059-1067
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BACKGROUND WHO guidelines recommend concurrent iron and antimalarial treatment in children with malaria and iron deficiency, but iron may not be well absorbed or utilized during a malaria episode. OBJECTIVES We aimed to determine whether starting iron 28 d after antimalarial treatment in children with severe malaria and iron deficiency would improve iron status and lower malaria risk. METHODS We conducted a randomized clinical trial on the effect of immediate compared with delayed iron treatment in Ugandan children 18 mo-5 y of age with 2 forms of severe malaria: cerebral malaria (CM; n = 79) or severe malarial anemia (SMA; n = 77). Asymptomatic community children (CC; n = 83) were enrolled as a comparison group. Children with iron deficiency, defined as zinc protoporphyrin (ZPP) ≥ 80 µmol/mol heme, were randomly assigned to receive a 3-mo course of daily oral ferrous sulfate (2 mg · kg-1 · d-1) either concurrently with antimalarial treatment (immediate arm) or 28 d after receiving antimalarial treatment (delayed arm). Children were followed for 12 mo. RESULTS All children with CM or SMA, and 35 (42.2%) CC, were iron-deficient and were randomly assigned to immediate or delayed iron treatment. Immediate compared with delayed iron had no effect in any of the 3 study groups on the primary study outcomes (hemoglobin concentration and prevalence of ZPP ≥ 80 µmol/mol heme at 6 mo, malaria incidence over 12 mo). However, after 12 mo, children with SMA in the delayed compared with the immediate arm had a lower prevalence of iron deficiency defined by ZPP (29.4% compared with 65.6%, P = 0.006), a lower mean concentration of soluble transferrin receptor (6.1 compared with 7.8 mg/L, P = 0.03), and showed a trend toward fewer episodes of severe malaria (incidence rate ratio: 0.39; 95% CI: 0.14, 1.12). CONCLUSIONS In children with SMA, delayed iron treatment did not increase hemoglobin concentration, but did improve long-term iron status over 12 mo without affecting malaria incidence.This trial was registered at clinicaltrials.gov as NCT01093989.
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The bioavailability of iron picolinate is comparable to iron sulfate when fortified into a complementary fruit yogurt: a stable iron isotope study in young women.
Sabatier, M, Grathwohl, D, Beaumont, M, Groulx, K, Guignard, LF, Kastenmayer, P, Dubascoux, S, Richoz, J, Habeych, E, Zeder, C, et al
European journal of nutrition. 2020;(4):1371-1378
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PURPOSE A technological gap exists for the iron (Fe) fortification of difficult-to-fortify products, such as wet and acid food products containing polyphenols, with stable and bioavailable Fe. Fe picolinate, a novel food ingredient, was found to be stable over time in this type of matrix. The objective of this study was to measure the Fe bioavailability of Fe picolinate in a complementary fruit yogurt. METHODS The bioavailability of Fe picolinate was determined using stable iron isotopes in a double blind, randomized cross-over design in non-anemic Swiss women (n = 19; 25.1 ± 4.6 years). Fractional Fe absorption was measured from Fe picolinate (2.5 mg 57Fe per serving in two servings given morning and afternoon) and from Fe sulfate (2.5 mg 54Fe per serving in two servings given morning and afternoon) in a fortified dairy complementary food (i.e. yogurt containing fruits). Fe absorption was determined based on erythrocyte incorporation of isotopic labels 14 days after consumption of the last test meal. RESULTS Geometric mean (95% CI) fractional iron absorption from Fe picolinate and Fe sulfate were not significantly different: 5.2% (3.8-7.2%) and 5.3% (3.8-7.3%) (N.S.), respectively. Relative bioavailability of Fe picolinate versus Fe sulfate was 0.99 (0.85-1.15). CONCLUSION Therefore, Fe picolinate is a promising compound for the fortification of difficult-to-fortify foods, to help meet Fe requirements of infants, young children and women of childbearing age.
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Iron Absorption is Greater from Apo-Lactoferrin and is Similar Between Holo-Lactoferrin and Ferrous Sulfate: Stable Iron Isotope Studies in Kenyan Infants.
Mikulic, N, Uyoga, MA, Mwasi, E, Stoffel, NU, Zeder, C, Karanja, S, Zimmermann, MB
The Journal of nutrition. 2020;(12):3200-3207
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BACKGROUND Whether lactoferrin (Lf) binds iron to facilitate its absorption or to sequester iron from potential enteropathogens remains uncertain. Bovine Lf is added to many infant formulas, but previous studies in infants reported that Lf had no effect on or inhibited iron absorption. The effects of the apo (iron-free) or the holo (iron-loaded) forms of Lf on iron absorption are unclear. OBJECTIVES Our objective was to compare iron absorption from a maize-based porridge containing: 1) labeled ferrous sulfate (FeSO4) alone; 2) labeled FeSO4 given with bovine apo-Lf; and 3) intrinsically labeled bovine holo-Lf. METHODS In a crossover study, we measured iron absorption in Kenyan infants (n = 25; mean ± SD age 4.2 ± 0.9 months; mean ± SD hemoglobin 109 ± 11 g/L) from maize-based test meals containing: 1) 1.5 mg of iron as 54Fe-labeled FeSO4; 2) 1.42 mg of iron as 58Fe-labeled FeSO4, given with 1.41 g apo-Lf (containing 0.08 mg iron); and 3) 1.41 g holo-Lf carrying 1.5 mg iron as 57Fe. The iron saturation levels of apo- and holo-Lf were 0.56% and 47.26%, respectively primary outcome was fractional iron absorption (FIA), assessed by erythrocyte incorporation of isotopic labels. RESULTS The FIA from the meal containing apo-Lf + FeSO4 (geometric mean, 9.8%; -SD and +SD, 5.4% and 17.5%) was higher than from the meals containing FeSO4 (geometric mean, 6.3%; -SD and +SD, 3.2% and 12.6%; P = 0.002) or holo-Lf (geometric mean, 5.0%; -SD and +SD, 2.8% and 8.9%; P <0.0001). There was no significant difference in FIA when comparing the meals containing holo-Lf versus FeSO4 alone (P = 0.24). CONCLUSIONS The amount of iron absorbed from holo-Lf was comparable to that of FeSO4, and the addition of apo-Lf to a test meal containing FeSO4 significantly increased (+56%) iron absorption. These findings suggest that Lf facilitates iron absorption in young infants. Because Lf binds iron with high affinity, it could be a safe way to provide iron to infants in low-income countries, where iron fortificants can adversely affect the gut microbiome and cause diarrhea. This study was registered at clinicaltrials.gov as NCT03617575.
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Single-arm, open-label pilot intervention study to investigate an effect of oral 5-aminolevulinic acid plus sodium ferrous citrate on glucocorticoid reduction in patients with adult-onset Still disease: Study protocol for clinical trial (SPIRIT compliant).
Sumiyoshi, R, Koga, T, Shimizu, T, Sato, S, Tashiro, S, Hosogaya, N, Yamamoto, H, Kawakami, A
Medicine. 2020;(50):e22708
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BACKGROUND Glucocorticoids are an important class of medication for patients with adult-onset Still disease (AOSD), however, relapse following glucocorticoid reduction and adverse events due to long-term effects of glucocorticoid are still problematic. It is of course essential to minimize the risk of treatment. Immunosuppressive therapies such as methotrexate and biologics including tocilizumab are used in glucocorticoid-dependent patients with AOSD, but no second-line treatments for patients with glucocorticoid dependence have been established yet. Given that these drugs also have the potential to cause adverse events, alternative treatments are sought. Recently, elevated heme oxygenase-1 (HO-1) has been reported in the serum of patients with AOSD, suggesting that HO-1 activity contributes to AOSD pathogenesis and may represent a new therapeutic target for the treatment of AOSD. The amino acid 5-aminolevulinic acid (5-ALA) is a non-proteinogenic δ amino acid in human body. An addition of ferrous iron to 5-ALA enhances heme biosynthesis. The increase in heme in vivo induces HO-1 production, a heme-degrading enzyme. Elevated HO-1 has been suggested to contribute to the pathogenesis of AOSD, and administration of 5-ALA and ferrous iron may be a potential treatment for AOSD. METHODS/DESIGN This study is a single-arm, open-label pilot intervention study using clinical endpoints to investigate the effects of oral 5-ALA with sodium ferrous citrate on glucocorticoid reduction in patients with AOSD receiving glucocorticoid therapy. DISCUSSION This pilot intervention study will provide evidence regarding the effectiveness and safety of 5-ALA/sodium ferrous citrate as a potential new therapeutic agent for glucocorticoid-dependent patients with AOSD. TRIAL REGISTRATION This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on January 14, 2020 as jRCTs071190042.
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Anemia management in non-menopausal women in a primary care setting: a prospective evaluation of clinical practice.
Bayen, S, Le Grand, C, Bayen, M, Richard, F, Messaadi, N
BMC family practice. 2020;(1):13
Abstract
BACKGROUND The study aimed to analyze anemia management in non-pregnant, and non-menopausal women aged from 18 to 50 years old, in a French primary care setting. METHODS An observational descriptive prospective study was conducted between November 2018 and February 2019. Inclusion criteria were as followed: anemia diagnosed in women aged from 18 to 50, not pregnant and not menopausal. Quantitative and qualitative data were anonymized and collected through an electronic survey. Investigating general practitioners completed the questionnaire for each newly diagnosed woman. Mean values and medians were calculated for the quantitative data. Answers to the open questions were encoded manually and proportions of the different modalities have been calculated. RESULTS Altogether, 43 women with anemia were ascertained. Moderate microcytic anemia, due to an iron deficiency in a context of menorrhagia, was the most observed anemia profile. The mean value of hemoglobin was 10.5 ± 1 g/dl. Among these women: 32 (74%) presented an iron deficiency, 17 (53%) had inappropriate intakes, and 9 (28%) reported menorrhagia. For 17 (40%) women, unnecessary or inappropriate exams were prescribed. The investigations did not allow to establish a differential diagnosis for 12 women (28%). Even for similar clinical situations, anemia management was variable. Among the women who presented iron deficiency, 15 (47%) were informed about an iron-rich diet and received a daily iron supplementation of ferrous sulfate between 80 mg and 160 mg. CONCLUSIONS Our study highlights that, in the absence of specific national guidelines for anemia management in non-pregnant, non-menopausal women in primary care settings, French GPs undergo various clinical management strategies leading to a heterogeneous, sometimes inappropriate follow-up. Women with iron deficiency were prescribed higher daily iron supplementation than recommended, according to new evidence, suggesting a maximal daily dose of 50 mg of elementary iron in a context of Hepcidin up-regulation in the case of an iron overload. Additional longitudinal studies with a bigger sample size and randomized controlled trials are needed to confirm our results and to elaborate national guidelines.
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N-Alkylaminoferrocene-Based Prodrugs Targeting Mitochondria of Cancer Cells.
Reshetnikov, V, Özkan, HG, Daum, S, Janko, C, Alexiou, C, Sauer, C, Heinrich, MR, Mokhir, A
Molecules (Basel, Switzerland). 2020;(11)
Abstract
Intracellular concentration of reactive oxygen species (e.g., H2O2) in cancer cells is elevated over 10-fold as compared to normal cells. This feature has been used by us and several other research groups to design cancer specific prodrugs, for example, N-alkylaminoferrocene (NAAF)-based prodrugs. Further improvement of the efficacy of these prodrugs can be achieved by their targeting to intracellular organelles containing elevated reactive oxygen species (ROS) amounts. For example, we have previously demonstrated that lysosome-targeted NAAF-prodrugs exhibit higher anticancer activity in cell cultures, in primary cells and in vivo (Angew. Chem. Int. Ed. 2017, 56, 15545). Mitochondrion is an organelle, where electrons can leak from the respiratory chain. These electrons can combine with O2, generating O2-• that is followed by dismutation with the formation of H2O2. Thus, ROS can be generated in excess in mitochondria and targeting of ROS-sensitive prodrugs to these organelles could be a sensible possibility for enhancing their efficacy. We have previously reported on NAAF-prodrugs, which after their activation in cells, are accumulated in mitochondria (Angew. Chem. Int. Ed. 2018, 57, 11943). Now we prepared two hybrid NAAF-prodrugs directly accumulated in mitochondria and activated in these organelles. We studied their anticancer activity and mode of action. Based on these data, we concluded that ROS produced by mitochondria is not available in sufficient quantities for activation of the ROS-responsive prodrugs. The reason for this can be efficient scavenging of ROS by antioxidants. Our data are important for the understanding of the mechanism of action of ROS-activatable prodrugs and will facilitate their further development.
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Oral iron supplementation with Feralgine® in inflammatory bowel disease: a retrospective observational study.
Vernero, M, Boano, V, Ribaldone, DG, Pellicano, R, Astegiano, M
Minerva gastroenterologica e dietologica. 2019;(3):200-203
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a relapsing chronic disease of the gastrointestinal (GI) tract. Among IBD patients, anemia is more frequent than in general population. Recent studies demonstrated a good iron absorption using Feralgine®, a compound of ferrous bysglicinate chelate and alginic acid, oral supplementation with both good compliance rate and efficacy in treating iron deficiency anemia especially due to its high oral bioavailability. In this study we evaluated hemoglobin (Hb) improvement after Feralgine® supplementation in patients with IBD and anemia. METHODS This is a retrospective observational study. All data were derived from the patients' registry of the Inflammatory Bowel Disease Center, San Giovanni Antica Sede-Molinette Hospital, Turin, Italy. All IBD patients suffering from anemia and treated with Feralgine® (Tecnofer Plus), 1 capsule daily, were selected. RESULTS Mean Hb value increased from 11 g/dL (95% confidence interval [CI]: 10.72-11.47) to 12.2 g/dL (95% CI: 11.6-12.52, P=0.0001), after three months of Feralgine® supplementation. While 90% of the patients did not report adverse events, 10% experienced dyspepsia and worsening of diarrhea. Only 6% of patients suspended oral iron supplementation due to GI intolerance (adherence rate 94%). CONCLUSIONS Oral supplementation with Feralgine® induced a significant improvement in Hb levels, suggesting that in IBD patients with mild or moderate anemia, oral iron supplementation could be considered the first line therapy. We suggest further studies on larger cohorts to assess iron, ferritin and transferrin saturation improvement after this treatment.
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Enhancing Antioxidant Effect against Peroxyl Radical-Induced Oxidation of DNA: Linking with Ferrocene Moiety!
Liu, ZQ
Chemical record (New York, N.Y.). 2019;(12):2385-2397
Abstract
As a major member in the family of reactive oxygen species, peroxyl radical is able to abstract hydrogen atom from 4-position of ribose, leading to the collapse of DNA strand. Thus, inhibiting oxidative stress with exogenous antioxidants acts as a promising strategy to protect the integrity of DNA structure and is thereby suggested to be a pathway against developments of related diseases. Ferrocene as an organometallic scaffold is widely applied in the design of organometallic drugs, and redox of Fe(II)/Fe(III) in ferrocene offers advantage for providing electron to radicals. Presented herein are our ongoing studies on ferrocene-appended antioxidants, including McMurry reaction applied to construct ferrocifen; Aldol condensation used to prepare ferrocenyl curcumin; Povarov reaction employed to prepare ferrocenyl quinoline; Biginelli reaction used to construct ferrocenyl dihydropyrimidine; Groebke reaction used to synthesize ferrocenyl imidazo[1,2-a]pyridine; and Passerini three-component reaction as well as Ugi four-component reaction applied to synthesize α-acyloxycarboxamide and bisamide, respectively. It is found that ferrocene moiety is able to enhance antioxidative effect of the aforementioned scaffolds even without the aid of phenolic hydroxyl group. The role of ferrocene in enhancing antioxidative effect can be attributable to trapping radicals, decreasing oxidative potential, and increasing the affinity toward DNA strand. Therefore, ferrocene is worthy to be taken into consideration in the design of drugs in relation to DNA oxidation.
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Minimizing experimental artefacts in synchrotron-based X-ray analyses of Fe speciation in tissues of rice plants.
Wang, P, McKenna, BA, Menzies, NW, Li, C, Glover, CJ, Zhao, FJ, Kopittke, PM
Journal of synchrotron radiation. 2019;(Pt 4):1272-1279
Abstract
Iron (Fe) plays an important role within environmental systems. Synchrotron-based X-ray approaches, including X-ray absorption spectroscopy (XAS), provide powerful tools for in situ analyses of Fe speciation, but beam damage during analysis may alter Fe speciation during its measurement. XAS was used to examine whether experimental conditions affect the analysis of Fe speciation in plant tissues. Even when analyzed in a cryostat at 12 K, it was found that FeIII can rapidly (within 0.5-1 min) photoreduce to FeII, although the magnitude of photoreduction varied depending upon the hydration of the sample, the coordination chemistry of the Fe, as well as other properties. For example, photoreduction of FeIII was considerably higher for aqueous standard compounds than for hydrated plant-root tissues. The use of freeze-dried samples in the cryostat (12 K) markedly reduced the magnitude of this FeIII photoreduction, and there was no evidence that the freeze-drying process itself resulted in experimental artefacts under the current experimental conditions, such as through the oxidation of FeII, although some comparatively small differences were observed when comparing spectra of hydrated and freeze-dried FeII compounds. The results of this study have demonstrated that FeIII photoreduction can occur during X-ray analysis, and provides suitable conditions to preserve Fe speciation to minimize the extent of beam damage when analyzing environmental samples. All studies utilizing XAS are encouraged to include a preliminary experiment to determine if beam damage is occurring, and, where appropriate, to take the necessary steps (such as freeze drying) to overcome these issues.