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Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Ferric Carboxymaltose in Chinese Patients with Iron-deficiency Anemia.
Ding, Y, Zhu, X, Li, X, Zhang, H, Wu, M, Liu, J, Palmen, M, Roubert, B, Li, C
Clinical therapeutics. 2020;(2):276-285
Abstract
PURPOSE Iron deficiency (ID) is one of the most commonly known nutritional deficiencies and is considered the primary cause of anemia (iron-deficiency anemia). Ferric carboxymaltose (FCM), an intravenous iron preparation, has been widely used for >10 years for iron-deficiency anemia treatment worldwide because of its many advantages. METHODS This single-center, open-label, single dose escalation study in Chinese subjects was designed to assess the pharmacokinetic/pharmacodynamic parameters and safety of FCM in this population. The first 12 subjects received a 500-mg dose; after assessing safety data from the first 6 subjects in this cohort, another 12 subjects were assigned to the 1000-mg dose cohort. FINDINGS After an infusion of FCM over 15 min, a rapid dose-dependent increase in total serum iron levels was observed with a median Tmax of 30 min following the start of the infusion for both cohorts. The Cmax and AUC for the 1000-mg dose were ~1.8-fold (p = 0.2929) and 2.3-fold (p = 0.0318) those associated with the 500-mg dose, respectively. Mean terminal t1/2 values were 12.3 and 10.5 h for the 2 cohorts. The renal elimination of FCM was negligible (<0.1%). Increase in mean serum iron levels and ferritin concentrations showed dose dependency. Iron-binding capacity was transiently well utilized after dosing, as indicated by transferrin saturation >88% with 500-mg FCM and >90% with 1000-mg FCM. Hemoglobin levels did not show significant changes during the 7-day observation period, whereas mean reticulocyte counts significantly increased in both cohorts, suggesting activation of the hematopoietic system. FCM was well tolerated in these Chinese subjects. No new or unexpected treatment-emergent adverse events were attributable to FCM. IMPLICATIONS The pharmacokinetic/pharmacodynamic and safety profiles in Chinese subjects seemed comparable to those in white and Japanese populations. ChinaDrugTrials.org.cn identifier: CTR20160863.
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High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23.
Dahlerup, JF, Jacobsen, BA, van der Woude, J, Bark, LÅ, Thomsen, LL, Lindgren, S
Scandinavian journal of gastroenterology. 2016;(11):1332-8
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OBJECTIVE Iron isomaltoside (Monofer(®)) is a high-dose intravenous iron preparation with good tolerability and efficacy in inflammatory bowel disease (IBD) patients with iron deficiency anaemia (IDA). This trial evaluates the safety and efficacy, including effect on intact fibroblast growth factor 23 (iFGF23) of a high single dose and cumulative doses of iron isomaltoside in IBD patients with IDA. MATERIALS AND METHODS The trial was a prospective, open-label, multi-centre trial conducted in IBD patients with IDA. Based upon haemoglobin (Hb) levels at baseline and weight, the patients received 1500, 2000, 2500 or 3000 mg of iron isomaltoside infused in single doses up to 2000 mg. The outcome measurements included adverse drug reactions (ADRs) and changes in haematology and biochemistry parameters. RESULTS Twenty-one IBD patients with IDA were enrolled, receiving 1500 (seven patients), 2000 (eight patients), 2500 mg (four patients) or 3000 (two patients) mg of iron. No serious ADRs were observed. Four patients experienced nine mild to moderate ADRs (hypersensitivity, pyrexia, vomiting, constipation, abdominal pain, dyspepsia (two events) and eye allergy (two events)). In total, 15 (75%) patients had an increase in Hb of ≥2.0 g/dL during the trial, with normalisation of ferritin. No changes in iFGF23 or clinically significant hypophosphataemia were found. CONCLUSION Rapid infusions of high-dose iron isomaltoside, administered as single doses up to 2000 mg and cumulative doses up to 3000 mg, were without safety concerns and were efficacious in increasing Hb levels in IBD patients. Iron isomaltoside did not induce profound phosphate wasting via increased iFGF23 levels.
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The strategies to reduce iron deficiency in blood donors randomized trial: design, enrolment and early retention.
Bialkowski, W, Bryant, BJ, Schlumpf, KS, Wright, DJ, Birch, R, Kiss, JE, D'Andrea, P, Cable, RG, Spencer, BR, Vij, V, et al
Vox sanguinis. 2015;(2):178-85
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BACKGROUND AND OBJECTIVES Repeated blood donation produces iron deficiency. Changes in dietary iron intake do not prevent donation-induced iron deficiency. Prolonging the interdonation interval or using oral iron supplements can mitigate donation-induced iron deficiency. The most effective operational methods for reducing iron deficiency in donors are unknown. MATERIALS AND METHODS 'Strategies To Reduce Iron Deficiency' (STRIDE) was a two-year, randomized, placebo-controlled study in blood donors. 692 donors were randomized into one of two educational groups or one of three interventional groups. Donors randomized to educational groups either received letters thanking them for donating, or, suggesting iron supplements or delayed donation if they had low ferritin. Donors randomized to interventional groups either received placebo, 19-mg or 38-mg iron pills. RESULTS Iron deficient erythropoiesis was present in 52·7% of males and 74·6% of females at enrolment. Adverse events within 60 days of enrolment were primarily mild gastrointestinal symptoms (64%). The incidence of de-enrolment within 60 days was more common in the interventional groups than in the educational groups (P = 0·002), but not more common in those receiving iron than placebo (P = 0·68). CONCLUSION The prevalence of iron deficient erythropoiesis in donors enrolled in the STRIDE study is comparable to previously described cohorts of regular blood donors. De-enrolment within 60 days was higher for donors receiving tablets, although no more common in donors receiving iron than placebo.
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Safety and tolerability of intravenous ferric carboxymaltose in patients with iron deficiency anemia.
Bailie, GR, Mason, NA, Valaoras, TG
Hemodialysis international. International Symposium on Home Hemodialysis. 2010;(1):47-54
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There is limited safety information about ferric carboxymaltose (FCM), a new intravenous iron preparation. This randomized, crossover study compared the safety and tolerability of double-blinded intravenous doses of FCM or placebo in patients with iron deficiency anemia. Subjects (559) with iron deficiency anemia received a dose of either FCM (15 mg/kg, maximum 1000 mg) over 15 minutes or placebo on day 0. On day 7, subjects received the other agent. Safety evaluations were performed on days 7 and 14. The primary endpoint was the incidence of treatment-emergent adverse events during each 7-day study period. During the first 24 hours and during the 7-day treatment period, at least one treatment-emergent adverse event was experienced by 15.0% and 29.3% of subjects after FCM and 11.4% and 19.7% after placebo, respectively. Most were classified as Grade 1 or 2. Six subjects had Grade 3 treatment-emergent adverse events after FCM and 9 subjects after placebo. One subject had a Grade 4, and 1 subject had a Grade 5 treatment-emergent adverse event, but neither was considered study drug-related. During the first 24 hours of the treatment period, drug-related adverse events were reported in 9.3% of subjects receiving FCM and 4.8% receiving placebo. Of drug-related Grade 3 events, 4 subjects received FCM and 5 subjects received placebo. Administration of FCM (15 mg/kg, maximum of 1000 mg) over 15 minutes was well tolerated and associated with minimal risk of adverse reactions in patients with iron deficiency anemia.
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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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Regulation of growth differentiation factor 15 expression by intracellular iron.
Lakhal, S, Talbot, NP, Crosby, A, Stoepker, C, Townsend, AR, Robbins, PA, Pugh, CW, Ratcliffe, PJ, Mole, DR
Blood. 2009;(7):1555-63
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Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-beta superfamily and has been identified in different contexts as a hypoxia-inducible gene product and as a molecule involved in hepcidin regulation. The biology of iron and oxygen is closely related, and known regulatory pathways involving hypoxia-inducible factor (HIF) and iron-regulatory proteins (IRPs) are responsive to both these stimuli. We therefore sought to characterize the regulation of GDF15 by iron and oxygen and to define the involvement or otherwise of HIF and IRP pathways. Here we show that GDF15 is strongly up-regulated by stimuli that deplete cells of iron and that this response is specifically antagonized by the reprovision of iron. GDF15 exhibits greater sensitivity to iron depletion than hypoxia, and responses to hypoxia and iron depletion are independent of HIF and IRP activation, suggesting a novel mechanism of regulation. We also report significant induction of serum GDF15 in iron-deficient subjects and after administration of an iron chelator to normal subjects. These findings indicate that GDF15 can be induced by pathophysiologic changes in iron availability, raising important questions about the mechanism of regulation and its role in iron homeostasis.
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Effects of vitamin A, vitamin A plus iron and multiple micronutrient-fortified seasoning powder on preschool children in a suburb of Chongqing, China.
Chen, K, Li, TY, Chen, L, Qu, P, Liu, YX
Journal of nutritional science and vitaminology. 2008;(6):440-7
Abstract
Preschool children in developing countries are likely to have multiple, concurrent micronutrient deficiencies. This study was designed to evaluate the effectiveness of different combinations of nutritional fortified diet to improve the blood levels of iron, vitamin A and other essential micronutrients in the preschool population of Banan District of Chongqing, China. From December 2005 to June 2006, a total of 226 2-6 y old preschool children were recruited from three nurseries in the area, and they were randomly assigned to three different fortified diet groups for 6 mo. Group I was fortified with vitamin A; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron, thiamine, riboflavin, folic acid, niacinamide, zinc and calcium, respectively. Subjects' weight and height were measured for assessing the children's growth and development. Blood samples were taken at the beginning and the end of the 6-mo study period for measuring serum levels of micronutrients. Group III with the multiple micronutrient fortified diet was the most effective to improve the serum level of retinol from [media (P25, P75): 1.06 (0.89, 1.32)] micromol/L to 1.29 (1.04, 1.39) micromol/L (p<0.05) and retinol binding protein from 17.0 (12.6, 25.6) mg/L to 31.6 (24.4, 44.0) mg/L (p<0.05) and to mobilize the stored iron in the liver (p<0.05). In addition, the three groups' hemoglobin levels were elevated from 117.0 (109.0, 124.1) g/L, 114.0 (109.2, 119.7) g/L and 115.0 (109.5, 122.7) g/L to 125.7 (119.2, 133.1) g/L, 126.5 (122.2, 135.9) g/L and 125.1 (119.8, 131.6) g/L over the 6 mo of intervention period, but there were no difference among the three groups (p>0.05). Nevertheless, unexpected results were obtained when comparing the effects on growth status among the different supplement groups. Our study has demonstrated that a multiple micronutrient fortified diet for 6 mo is more effective to improve the levels of hemoglobin, serum retinol, and RBP as well as to facilitate the mobilization of iron storage in preschool children.
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Maternal iron deficiency anemia affects postpartum emotions and cognition.
Beard, JL, Hendricks, MK, Perez, EM, Murray-Kolb, LE, Berg, A, Vernon-Feagans, L, Irlam, J, Isaacs, W, Sive, A, Tomlinson, M
The Journal of nutrition. 2005;(2):267-72
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The aim of this study was to determine whether iron deficiency anemia (IDA) in mothers alters their maternal cognitive and behavioral performance, the mother-infant interaction, and the infant's development. This article focuses on the relation between IDA and cognition as well as behavioral affect in the young mothers. This prospective, randomized, controlled, intervention trial was conducted in South Africa among 3 groups of mothers: nonanemic controls and anemic mothers receiving either placebo (10 microg folate and 25 mg vitamin C) or daily iron (125 mg FeS0(4), 10 microg folate, 25 mg vitamin C). Mothers of full-term normal birth weight babies were followed from 10 wk to 9 mo postpartum (n = 81). Maternal hematologic and iron status, socioeconomic, cognitive, and emotional status, mother-infant interaction, and the development of the infants were assessed at 10 wk and 9 mo postpartum. Behavioral and cognitive variables at baseline did not differ between iron-deficient anemic mothers and nonanemic mothers. However, iron treatment resulted in a 25% improvement (P < 0.05) in previously iron-deficient mothers' depression and stress scales as well as in the Raven's Progressive Matrices test. Anemic mothers administered placebo did not improve in behavioral measures. Multivariate analysis showed a strong association between iron status variables (hemoglobin, mean corpuscular volume, and transferrin saturation) and cognitive variables (Digit Symbol) as well as behavioral variables (anxiety, stress, depression). This study demonstrates that there is a strong relation between iron status and depression, stress, and cognitive functioning in poor African mothers during the postpartum period. There are likely ramifications of this poorer "functioning" on mother-child interactions and infant development, but the constraints around this relation will have to be defined in larger studies.
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Weekly iron supplements given by teachers sustain the haemoglobin concentration of schoolchildren in the Philippines.
Roschnik, N, Parawan, A, Baylon, MA, Chua, T, Hall, A
Tropical medicine & international health : TM & IH. 2004;(8):904-9
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OBJECTIVES To examine the effectiveness of weekly iron supplements given for 10 weeks by teachers to children in rural schools in the Philippines. METHODS Forty-nine rural primary schools took part in the study and were randomly assigned to two groups: children in 25 schools received a weekly tablet providing 108 mg iron while children in 24 schools acted as controls. All children were dewormed before the start of the iron supplementation. The haemoglobin concentration of a systematic sample of one in three children in two classes in each school was estimated before and 5-17 weeks after the end of the iron supplementation. RESULTS A total of 1510 children aged 7-12 years were studied at both surveys. The mean haemoglobin concentration of children in the intervention group did not change significantly; in the untreated group it fell by 3.8 g/l and the prevalence of anaemia rose from 14.3% to 25.6%. The difference between study groups was significantly larger amongst the younger children (7-8 years), and was observed in both anaemic and non-anaemic children. CONCLUSION Even where anaemia is only a mild public health problem, weekly iron supplements given by teachers may prevent a fall in the haemoglobin concentration, and can benefit both anaemic and non-anaemic children.
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The effect on haemoglobin of the use of iron cooking pots in rural Malawian households in an area with high malaria prevalence: a randomized trial.
Geerligs, PP, Brabin, B, Mkumbwa, A, Broadhead, R, Cuevas, LE
Tropical medicine & international health : TM & IH. 2003;(4):310-5
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BACKGROUND Innovative low-cost sustainable strategies are required to reduce the high prevalence of iron-deficiency anaemia in developing countries. METHODS We undertook a community-based randomized controlled intervention trial to assess the effects of cooking in iron or aluminium cooking pots in Malawian households in an area with high malaria prevalence. Analysis was by intention to treat and consistency of use. The primary outcomes were change in haemoglobin and iron status. FINDINGS The study population comprised 164 participants eating from aluminium cooking pots and 158 from iron cooking pots. The mean haemoglobin change was significantly increased after 6 weeks in adults who consistently ate from an iron cooking pot (+3.6 g/l compared to -3.2 g/l, mean difference between groups 6.8 g/l, 95% CI +0.86, +12.74). In children, no significant haemoglobin change was observed in consistent pot users, although they showed a significant reduction in iron deficiency (iron 8.6 ZP/g and aluminium 10.8 ZP/g, mean difference 2.2 ZP/g, 95% CI +1.08, +3.32). INTERPRETATION Rural Malawian adults in a high malaria transmission area who consistently consume food prepared in iron cooking pots show a significant rise in haemoglobin after 6 weeks use. Children showed a reduction in iron deficiency, but no significant improvement in haemoglobin, possibly because of their high malaria parasite prevalence. Using iron cooking pots in developing countries could provide an innovative way to prevent iron deficiency and anaemia in malarious areas where regular iron supplementation is problematic.