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Efficacy and safety of intravenous ferric carboxymaltose compared with oral iron for the treatment of iron deficiency anaemia in women after childbirth in Tanzania: a parallel-group, open-label, randomised controlled phase 3 trial.
Vanobberghen, F, Lweno, O, Kuemmerle, A, Mwebi, KD, Asilia, P, Issa, A, Simon, B, Mswata, S, Schmidlin, S, Glass, TR, et al
The Lancet. Global health. 2021;(2):e189-e198
Abstract
BACKGROUND Iron deficiency anaemia is of major concern in low-income settings, especially for women of childbearing age. Oral iron substitution efficacy is limited by poor compliance and iron depletion severity. We aimed to assess the efficacy and safety of intravenous ferric carboxymaltose versus oral iron substitution following childbirth in women with iron deficiency anaemia in Tanzania. METHODS This parallel-group, open-label, randomised controlled phase 3 trial was done at Bagamoyo District Hospital and Mwananyamala Hospital, Tanzania. Eligible participants were close to delivery and had iron deficiency anaemia defined as a haemoglobin concentration of less than 110 g/L and a ferritin concentration of less than 50 μg/L measured within 14 days before childbirth. Participants were randomly assigned 1:1 to receive intravenous ferric carboxymaltose or oral iron, stratified by haemoglobin concentration and site. Intravenous ferric carboxymaltose was administered at a dose determined by the haemoglobin concentration and bodyweight (bodyweight 35 kg to <70 kg and haemoglobin ≥100 g/L: 1000 mg in one dose; bodyweight 35 kg to <70 kg and haemoglobin <100 g/L, or bodyweight ≥70 kg and haemoglobin ≥100 g/L: 1500 mg in two doses at least 7 days apart; bodyweight ≥70 kg and haemoglobin <100 g/L: 2000 mg in two doses at least 7 days apart). Oral iron treatment consisted of three dried ferrous sulphate tablets of 200 mg containing 60 mg of elementary iron and 5 mg of folic acid every morning. Oral treatment was to be taken for 3 months after haemoglobin normalisation. The primary outcome was haemoglobin normalisation (>115 g/L) at 6 weeks. Follow-up visits were at 6 weeks, and 3, 6, and 12 months. Analyses were done in the modified intention-to-treat population of participants who had a 6-week haemoglobin concentration result, using logistic and linear regression models for binary and continuous outcomes, adjusted for baseline haemoglobin concentration and site. This trial is registered with ClinicalTrials.gov, NCT02541708. FINDINGS Between Oct 8, 2015, and March 14, 2017, 533 individuals were screened and 230 were enrolled and randomly assigned to a study group (114 to intravenous iron, 116 to oral iron). At 6 weeks, 94 (82%) participants in the intravenous iron group and 92 (79%) in the oral iron group were assessed for the primary outcome. 75 (80%) participants in the intravenous iron group and 47 (51%) in the oral iron group had normalised haemoglobin (odds ratio 4·65, 95% CI 2·33-9·27). There were two mild to moderate infusion-related adverse events; and five serious adverse events (three in the intravenous iron group, two in the oral iron group), unrelated to the study medication. INTERPRETATION Intravenous iron substitution with ferric carboxymaltose was safe and yielded a better haemoglobin response than oral iron. To our knowledge, this is the first study to provide evidence of the benefits and safety of intravenous iron substitution in a low-income setting. FUNDING Vifor Pharma, R Geigy-Stiftung, Freiwillige Akademische Gesellschaft, and Swiss Tropical and Public Health Institute.
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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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Abstract
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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Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron.
Ito, H, Nishio, Y, Hara, T, Sugihara, H, Tanaka, T, Li, XK
European journal of pharmacology. 2018;:25-33
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Heme oxygenase-1 (HO-1) is a major anti-inflammatory enzyme and a key regulator that induces immune tolerance through affecting the differentiation of dendritic cells. The aim of this study is to determine whether the combination of 5-aminolevulinic acid (ALA) and iron induces HO-1 expression in healthy human peripheral blood mononuclear cells (PBMC). The study was an open labeled, non-randomized, non-placebo-controlled trial using healthy male adults and consisted of three parts. Study A aimed to find the peak HO-1 expression at 0, 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after administration. Study B aimed to examine HO-1 dose dependency at 150, 300, and 600 mg of ALA and the need for iron supplementation. Study C aimed to investigate HO-1 changes during a three-day, repetitive administration of ALA and iron. The combination of ALA 600 mg and sodium ferrous citrate (SFC) 942 mg upregulated HO-1 in PBMC at 8 h after administration while sole administration of ALA or SFC was unable to induce HO-1. HO-1 in blood myeloid and plasmacytoid dendritic cells was also upregulated with ALA+SFC. Clear dose dependency of ALA+SFC was not detected, and a slight tendency towards a cumulative effect of HO-1 after three-day, repetitive administration was observed. ALA, which is already approved for use in several countries as a diagnosis agent for cancer, has the potential to become a novel therapeutic drug for diseases stemming from unwanted immune response such as autoimmune diseases and the rejection response following organ transplantation.
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Response of urinary biomarkers of systemic oxidation to oral iron supplementation in healthy men.
Orozco, MN, Solomons, NW, Schümann, K, Friel, JK
Food and nutrition bulletin. 2012;(1):53-62
Abstract
BACKGROUND Urinary biomarkers are used in assessment of severe, clinical oxidative stress. Little is known, however, about their diagnostic value within the normative range. OBJECTIVE To evaluate the response of urinary thiobarbituric acid reactive substances (TBARS) and 8-hydroxy-2-deoxyguanosine (8-OHdG) as indicators of systemic oxidation in response to short-term oral iron and antioxidant supplementation. METHODS Five healthy adult men participated in the pilot study phase and 12 in the definitive intervention trial. For 7 days each, separated by 12-day washouts, the subjects received different treatment regimens, consisting of 120 mg of iron, 120 mg of iron in refined palm oil, and 120 mg of iron in palm oil combined with one of the two doses of Carotino Tocotrienol Carotene Mixed Concentrate (CTCMC). Creatinine-normalized urinary TBARS and 8-OHdG concentrations were quantified in samples taken from subjects with and without active supplementation. Temporal and correlative associations between TBARS and 8-OHdG were explored. RESULTS Daily intake of supplemental iron failed to produce any increment in urinary excretion of TBARS or 8-OHdG. However, a significant within-individual correlation between the urinary biomarkers was observed (Spearman r = 0.697, p < .0001, n = 466). Both doses of CTCMC significantly lowered urinary excretion of both oxidation indicators. CONCLUSIONS Despite the lack of effect of oral iron on the biomarkers of systemic oxidation, they show a strong and significant mutual association within the nonpathological range of oxidative stress in healthy male adults.
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Mixture of ferric sodium ethylenediaminetetraacetate (NaFeEDTA) and ferrous sulfate: an effective iron fortificant for complementary foods for young Chinese children.
Chang, S, Huang, Z, Ma, Y, Piao, J, Yang, X, Zeder, C, Hurrell, RF, Egli, I
Food and nutrition bulletin. 2012;(2):111-6
Abstract
BACKGROUND Ferric sodium ethylenediaminetetraacetate (NaFeEDTA) enhances iron absorption in the presence of phytate. However, the amount of NaFeEDTA that would have to be added to a complementary food to provide the necessary intake of iron for an infant or young child if NaFeEDTA were the sole iron fortificant exceeds the Acceptable Daily Intake (ADI) of EDTA for this age group. EDTA increases iron absorption at a molar ratio EDTAiron of less than 1:1. OBJECTIVE To determine whether iron absorption is enhanced with a mixture offerrous sulfate (FeSO₄) and NaFeEDTA. METHODS Two studies with a crossover design were conducted in separate groups of 14 and 15 children aged 24 to 31 months. A complementary food consisting of millet porridge with cabbage, tofu, and pork-filled wheat flour dumplings was fortified with 2 mg iron as either FeSO₄ or NaFeEDTA (study 1) or 4 mg iron as FeSO₄ or a mixture of 2 mg each of FeSO₄ and NaFeEDTA (study 2). Iron absorption was determined based on erythrocyte incorporation of stable iron isotopes. RESULTS In study 1, the geometric mean (± SD) iron absorption was 8.0% (3.1, 20.8) and 9.2% (3.1, 27.0) from food fortified with FeSO₄ and NaFeEDTA, respectively. In study 2, iron absorption was significantly higher from food fortified with 4 mg iron as 1:1 mixture of FeSO₄/NaFeEDTA than from food fortified with FeSO₄; the geometric mean iron absorption was 6.4% (3.0, 13.5) and 4.1% (1.9, 8.9), respectively. CONCLUSIONS The enhancing effect of EDTA on iron absorption is less strong in composite meals containing enhancers; nevertheless, the equal mixture of FeSO₄ and NaFeEDTA significantly enhanced iron absorption and can be a strategy to ensure adequate iron absorption from phytate-containing complementary foods.
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Fortification iron as ferrous sulfate plus ascorbic acid is more rapidly absorbed than as sodium iron EDTA but neither increases serum nontransferrin-bound iron in women.
Troesch, B, Egli, I, Zeder, C, Hurrell, RF, Zimmermann, MB
The Journal of nutrition. 2011;(5):822-7
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Abstract
The absorption profile of iron fortificants may be a determinant of their ability to generate nontransferrin-bound iron (NTBI) and, thus, their potential safety. Ferrous iron may be absorbed more rapidly than chelated ferric iron, but differences at the fortification level cannot be distinguished with nonisotopically labeled serum iron curves. Using stable isotope appearance curves (SIAC) in serum, we measured iron absorption profiles from FeSO(4) with ascorbic acid (AA) and from NaFeEDTA, as well as the serum hepcidin and NTBI response following the meals. Healthy women (n = 16) were given 6 mg oral iron as labeled FeSO(4) and NaFeEDTA with a maize porridge using a crossover design. SIAC, NTBI, and serum hepcidin were measured over 8 h after the meal. Iron from FeSO(4) plus AA was more rapidly absorbed, resulting in a 35% greater relative AUC during the first 2 h than for NaFeEDTA (P < 0.001). Median (95% CI) fractional iron absorption from the FeSO(4)- and NaFeEDTA-fortified meals was 15.2% (11.0-19.5) and 6.0% (5.0-9.2), respectively (P < 0.001). In response to the FeSO(4)-fortified meal, there was an ~60% increase in median serum hepcidin (P < 0.05) but no significant change in NTBI. There was no significant change in serum hepcidin or NTBI after the NaFeEDTA-fortified meal. SIAC are a useful new tool to compare iron absorption profiles from different iron compounds in fortified foods. Even with the use of a very well absorbed ferrous iron compound, iron fortification in this population does not increase NTBI, suggesting a low risk for adverse health consequences.
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Lactoferrin efficacy versus ferrous sulfate in curing iron disorders in pregnant and non-pregnant women.
Paesano, R, Berlutti, F, Pietropaoli, M, Goolsbee, W, Pacifici, E, Valenti, P
International journal of immunopathology and pharmacology. 2010;(2):577-87
Abstract
Iron homeostasis in pregnancy compensates for increased iron requirements and in women of child-bearing age for iron loss in menses. Oral administration of ferrous sulfate, prescribed to cure iron deficiency (ID) and ID anemia (IDA), often fails to increase hematological parameters and causes adverse effects. Recently, we demonstrated safety and efficacy of bovine lactoferrin (bLf) in pregnant women suffering from ID/IDA. Two clinical trials were conducted on pregnant and non-pregnant women of child-bearing age suffering from ID/IDA. In both trials, women received oral administration of bLf 100 mg/twice/day (Arm A), or ferrous sulfate 520 mg/day (Arm B). Hematological parameters, serum IL-6 and prohepcidin were assayed before and after therapy. Unlike ferrous sulfate, bLf increased hematological parameters (P less than 0.0001). In pregnant women, bLf decreased serum IL-6 (P less than 0.0001), and increased prohepcidin (P=0.0007). In non-pregnant women bLf did not change the low IL-6 levels while it increased prohepcidin (P less than 0.0001). Ferrous sulfate increased IL-6 (P less than 0.0001) and decreased prohepcidin (P=0.093). bLf established iron homeostasis by modulating serum IL-6 and prohepcidin synthesis, whereas ferrous sulfate increased IL-6 and failed to increase hematological parameters and prohepcidin. bLf is a more effective and safer alternative than ferrous sulfate for treating ID and IDA.
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The effect of iron supplementation on the level of haemoglobin after lower limb arthroplasty.
Mundy, GM, Birtwistle, SJ, Power, RA
The Journal of bone and joint surgery. British volume. 2005;(2):213-7
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We randomised 120 patients who were undergoing either primary total hip or knee arthroplasty to receive either ferrous sulphate or a placebo for three weeks after surgery. The level of haemoglobin and absolute reticulocyte count were measured at one and five days, and three and six weeks after operation. Ninety-nine patients (ferrous sulphate 50, placebo 49) completed the study. The two groups differed only in the treatment administered. Recovery of level of haemoglobin was similar at five days and three weeks and returned to 85% of the pre-operative level, irrespective of the treatment group. A small, albeit greater recovery in the level of haemoglobin was identified at six weeks in the ferrous sulphate group in both men (ferrous sulphate 5%, placebo 1.5%) and women (ferrous sulphate 6%, placebo 3%). The clinical significance of this is questionable and may be outweighed by the high incidence of reported side effects of oral iron and the cost of the medication. Administration of iron supplements after elective total hip or total knee arthroplasty does not appear to be worthwhile.
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Comparative assessment of the bioavailability, efficacy and safety of a modified-release (MR) carbonyl iron tablet and oral conventional iron preparation in adult Indian patients with nutritional iron deficiency anaemia.
Adsul, BB, Desai, A, Gawde, A, Baliga, V
Journal of the Indian Medical Association. 2005;(6):338-42
Abstract
The objective of the study is to evaluate the bioavailability, efficacy and safety of a new modified-release (MR) formulation of carbonyl iron (45 mg) relative to a commercially available conventional formulation of ferrous fumarate (300 mg) in adult Indian patients with clinical and laboratory diagnosis of nutritional iron deficiency anaemia. This prospective, comparative, randomised, double-blind study was carried out among 60 patients received a single daily dose of either MR carbonyl iron or ferrous fumarate for 12 weeks. The effect of therapy on haematological parameters and iron status and estimation of bioavailability were the main efficacy outcomes. There was a significant (p<0.05) increase in mean haemoglobin levels, reticulocyte counts, haematocrit and mean corpuscular volume in MR carbonyl iron group compared to ferrous fumarate group. There was also an increase in mean serum iron and ferritin levels and a corresponding decrease in total iron binding capacity in MR carbonyl iron group compared to ferrous fumarate group at the end of 12 weeks therapy. The estimated overall bioavailability of MR carbonyl iron was about 147% that of ferrous fumarate. Both the formulations were equally well-tolerated and adverse events were mainly gastrointestinal in nature. The prevalence of adverse events was slightly more in the ferrous fumarate group. It can be concluded that the MR formulation of carbonyl iron was more efficacious than ferrous fumarate in correcting haematologic abnormalities and improving iron status in patients with nutritional iron deficiency anaemia. In conditions where efficacy is an important consideration, the higher bioavailability of MR carbonyl iron may make it the treatment of choice for nutritional iron deficiency anaemia.
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Once-weekly and 5-days a week iron supplementation differentially affect cognitive function but not school performance in Thai children.
Sungthong, R, Mo-suwan, L, Chongsuvivatwong, V, Geater, AF
The Journal of nutrition. 2004;(9):2349-54
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Many studies have reported comparable hemoglobin response in subjects given intermittent and daily iron supplements. However, the effect of intermittent iron supplementation on impaired cognitive function, one of the serious consequences of iron deficiency among children, has not been studied. We investigated the effects of 1 d/wk (weekly) and 5 d/wk (daily) iron supplementation on changes in results of intelligence quotient (IQ), Thai language, and mathematics tests among Thai primary schoolchildren. A double-blind, randomized, placebo-controlled trial was conducted. Primary schoolchildren (n = 397) were randomly assigned to receive iron supplements daily or weekly or placebo. Ferrous sulfate (300 mg) or placebo tablets were given under direct observation by the researcher for 16 wk. Changes in IQ, and Thai language and mathematics scores were then compared. The increases in hemoglobin concentration were comparable in the weekly and daily iron supplementation groups but serum ferritin increased more in the children supplemented daily. Children receiving daily iron supplements, however, had a significantly lower increase in IQ (3 +/- 12 points) than those receiving the supplement weekly (6 +/- 12 points) or placebo (6 +/- 12 points), whereas the last-mentioned two groups did not differ. Z-scores of Thai language and mathematics test results did not differ among the groups. We conclude that weekly iron supplementation is the regimen of choice in this study community.