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Prior to the national shortage of iron dextran in early 2023, it was the most commonly administered intravenous iron infusion at our institution. After the shortage impacted the health system, alternatives such as iron sucrose and sodium ferric gluconate/sucrose were required that utilized lower doses given at more frequent patient visits. Coinciding with their more prevalent use, an increase in iron infusion reactions was observed. Our study analyzed 880 patients who received iron infusions in three Henry Ford Hospital clinics in metropolitan Detroit, Michigan, from July 2022-June 2023. The 74 reactions that occurred were most commonly associated with iron sucrose at the 500 mg dose (41/74, 55.41%, p < 0.0001). Most reactions observed across all iron formulations and doses were mild, with 83.7% being Grade 0 or 1 as defined by the United States Drug Allergy Registry (USDAR) grading scale for immediate reactions. Patients who experienced an infusion reaction were less likely to complete their infusion plans (OR 0.004 for iron dextran, OR 0.128 for iron sucrose, p < 0.0001), with infusions most commonly being completely discontinued thereafter, with a minority pursuing alternative options. More patients with lower number of doses scheduled for iron dextran completed their infusion schedules than those with more doses, but the opposite was seen for iron sucrose. We assessed the impact of the national shortage of iron dextran examining infusion reactions with various iron infusions and doses., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The objective of this study was to evaluate the potential of novel poloxamer thermosensitive hydrogels (PTHs) formulations for prolonged release of iron dextran particles (IDP) for intramuscular (IM) injection. The thermosensitive behaviour helps to avoid hepcidin overexpression and toxicity by releasing IDPs without iron accumulation in injection or deposit sites. We hypothesized that novel PTH formulation would prolong iron liberation compared to the commercial iron dextran formulation (FEDEX). PTHs loaded with IDPs were developed with increasing iron content (0.1, 0.2 and 0.4 g of iron/g of poloxamer) and characterized as a prolonged release IM iron supplement. The PTHs had a biocompatible pH for IM injection (6.4) and thermosensitive viscosity, increasing from ∼50 (4 °C) to ∼3000 mPa.s (37 °C). PTHs were successfully injected in the sol state (at 4 °C) into pork meat at 37 °C, transitioning to the gel state in situ (in ∼60-190 s). Structural characterization indicated that there were no PTH-IDP chemical interactions, suggesting that IDP entrapment in PTHs was physical upon gelation. In vitro release studies revealed that iron release from PTH (0.4 g of iron/g of poloxamer) reached 100 % by day 10, whereas 100 % release from FEDEX was complete in 4 h. This novel iron PTH formulation achieved a 60 times long iron release compared to the commercial product. In conclusion, the reported strategy shows adequate IDP entrapment/release properties for prolonged iron release following ex vivo IM injection using biocompatible materials. These results provide a strong basis for future preclinical evaluation to elucidate aspects such as drug release, local irritation, biocompatibility, and efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The most common and efficient iron supply to prevent neonatal anaemia in piglets is the injection of iron dextran or gleptoferron. This treatment is problematic in organic farms because organic specifications strictly limit the use of chemically synthesised allopathic drugs. Based on the observation that piglets raised outdoors rarely develop anaemia, we hypothesised that piglets satisfy their iron needs by ingesting soil from their environment. Therefore, we compared the efficacy of a 100-mg intramuscular iron dextran injection (Iron, 8 litters, n = 98 piglets) at 4 days (d) of age (d4), to a daily ad libitum supply of dried soil (Soil, 8 litters, n = 101) or dried peat-like river silt (Peat, 8 litters, n = 102) from d4 to weaning (at 49 days of age, d49). Pigs were raised according to organic farming rules. Blood was collected on three males and three females per litter on d4, 20, 41, 50 and 69. BW was similar in the three groups on d4, 20, 41, 50 and 69 (P > 0.1). During the experiment, piglets were affected by a severe digestive E. coli episode but litter mortality rate between d4 and d69 did not differ between groups (P > 0.1). Blood haemoglobin concentration (Hb) was similar in all groups on d4, 50 and 69. However, on d20, Hb was higher in Peat and Iron groups than in the Soil group (P < 0.001), and on d41 and d50, Hb was higher in the Peat group than in Iron and Soil groups (P < 0.001). Mean red blood cell volume (RBCV) remained stable over time in the Peat group. In comparison, RBCV dropped in the Soil group on d20 and d41 (P < 0.001), and in the Iron group on d41 (P < 0.001). Soil and Iron group RBCV returned values similar to the Peat group by d69 (P > 0.1). In conclusion, soil supply in the pen was not sufficient to ensure a satisfactory iron intake in piglets, unlike peat-like river silt, which enable to reach haemoglobin concentrations above 80 mg/mL for over 90% of the piglets from d20 and, over 100% of piglets at weaning. The daily supply of the silt proved more efficient than the 100-mg iron injection beyond 20 days., (Copyright © 2024. Published by Elsevier B.V.)

Background: Feeding milk substitutes with low iron content or whole milk without iron supplementation is considered a major factor in developing iron-deficiency anemia in neonatal dairy calves. Young calves are often supplemented with iron dextran injections on the first day of life to prevent anemia. However, the effects of preventive treatment and the presence of disease on serum iron (Fe) concentrations, serum ferritin levels, and hematological blood parameters during the early neonatal stages have not been examined in detail. Therefore, we examined and evaluated the effects of iron dextran injections and health status on the development of hematocrit (Ht), red blood cells (RBC), hemoglobin concentration (Hb), erythrocyte indices (mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration), Fe, and serum ferritin concentrations in dairy calves within the first 10 days of life. The suitability of serum ferritin as a reliable indicator of anemia in very young calves was evaluated by correlating ferritin concentrations with known laboratory diagnostic parameters of anemia., Results: Iron supplementation significantly increased Fe levels (P = 0.048) but did not affect serum ferritin levels in neonatal calves. Fe concentrations were significantly lower in diseased than healthy calves (P = 0.0417). Iron supplementation significantly affected the health status, as observed in Ht (P treat =0.0057; P health =0.0097), RBC (P treat =0.0342; P health =0.0243), and Hb (P treat =0.0170; P health =0.0168). Serum ferritin levels did not significantly correlate with Fe levels. Both groups showed marked differences in ferritin levels, with the highest levels measured on day 2. Fe concentrations showed weak negative correlations with Hb and Ht levels on day 3 (ρ=-0.45; P = 0.0034 and ρ=-0.045; P = 0.0032, respectively). RBC count showed strong positive correlations with Hb and Ht levels (ρ = 0.91 and ρ = 0.93; P < 0.001)., Conclusion: Iron dextran injections increased Fe concentrations but reduced Ht level, RBC count, and Hb level. The presence of diseases led to a reduction in Fe and higher values of Ht, RBC, and Hb in moderate disease than in severe disease. Due to physiological fluctuations during the first 3 days of life, serum ferritin level seems unuseful for evaluating iron storage before day 4 of life., (© 2024. The Author(s).)

Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

Background: Clinical studies have shown that diffuse chorioamniotic hemosiderosis (DCH) is a risk factor for bronchopulmonary dysplasia (BPD). However, the details of the underlying mechanism are unknown. We focused on iron, one of the blood components that diffuses within the amniotic cavity in DCH. Specifically, we conducted a histological evaluation of its effects on fetal lung development., Methods: Iron dextran 10 mg (Fe group) or physiological saline (control group) was injected into the individual amniotic cavities of pregnant Sprague Dawley rats on gestational day 19. The pups were born naturally, and the placentas and lungs collected on postnatal days 1, 14, and 60 were subjected to histological analysis., Results: The placenta and lungs of the Fe group on day 14 contained significantly larger numbers of iron-positive granules. Morphological analysis of the lungs showed that on day 60, the total number of alveoli was significantly lower in the Fe group (p = 0.015). Immunohistochemical staining of the lung tissue for 8-hydroxy-2'-deoxyguanosine showed that, on day 1, there were significantly more positive cells in the Fe group (p = 0.003). The number of ectodermal dysplasia 1 positive cells on day 14 was significantly increased in the Fe group (p = 0.001)., Conclusions: These results suggest that diffuse iron deposition in immature fetal lungs increases oxidative stress and decreases the number of postnatal alveoli associated with impaired lung development., (© 2024 Japan Pediatric Society.)

Iron supplementation is necessary for the treatment of anemia, one of the most frequent complications in inflammatory bowel disease (IBD). However, oral iron supplementation leads to an exacerbation of intestinal inflammation. Gut barrier plays a key role in the pathogenesis of IBD. The aim of this study was to characterize the interrelationship between systemic iron, intestinal barrier and the development of intestinal inflammation in a dextran sulfate sodium (DSS) induced experimental colitis mice model. We found that DSS-treated mice developed severe inflammation of colon, but became much healthy when intraperitoneal injection with iron. Iron supplementation alleviated colonic and systemic inflammation by lower histological scores, restorative morphology of colonic villi, and reduced expression of pro-inflammatory cytokines. Moreover, intraperitoneal supplementation of iron enhanced intestinal barrier function by upregulating the colonic expressions of tight junction proteins, restoring intestinal immune homeostasis by regulating immune cell infiltration and T lymphocyte subsets, and increasing mucous secretion of goblet cells in the colon. High-throughput sequencing of fecal 16 S rRNA showed that iron injection significantly increased the relative abundance of Bacteroidetes, which was suppressed in the gut microbiota of DSS-induced colitis mice. These results provided evidences supporting the protective effects of systemic iron repletion by intraperitoneal injection of iron on intestinal barrier functions. The finding highlights a novel approach for the treatment of IBD with iron injection therapy., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

There are multiple intravenous (IV) iron formulations available, of which several may be administered as single-dose infusions such as low-molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. However, administration of ferumoxytol as a single-dose infusion is off-label as it is approved as a two-dose series. Previous studies of ferumoxytol alone support the effectiveness and safety of the single-dose regimen, but there is a paucity of data directly comparing single-dose ferumoxytol to other single-dose IV iron formulations. This multicenter cohort study sought to affirm the safety and effectiveness of single-dose ferumoxytol compared to single-dose LMWID. Overall, 906 patients who received single-dose LMWID (n = 439) or ferumoxytol (n = 467) were identified, of whom 351 met criteria for the primary effectiveness endpoint defined as median change in hemoglobin (Hb), hematocrit (Hct), and ferritin 8 to 12 weeks from baseline. All 906 patients were included for the secondary analysis evaluating the incidence of adverse events (AE) and requirement of additional IV iron infusions. Median change in Hb (LMWID 0.5 g/dL; ferumoxytol 0.8 g/dL; P = .24), Hct (LMWID 1.1%; ferumoxytol 1.25%; P = .89), and ferritin (LMWID 87 ng/dL; ferumoxytol 71 ng/dL; P = .47) was not significantly different between groups. Both groups experienced similar rates of AEs (LMWID 2.3%; ferumoxytol 2.8%; P = .63). The LMWID patients more frequently required additional IV iron infusions (LMWID 28.5%; ferumoxtyol 16.1%; P < .001). These findings support that single-dose ferumoxytol is effective and safe, and that patients may require fewer additional infusions compared to patients who received LMWID., (© 2020 Wiley Periodicals LLC.)

A total of 336 newborn pigs (DNA 241 × 600, initially 1.75 ± 0.05 kg bodyweight [BW]) from 28 litters were used in a 63-d study evaluating the effects of increasing injectable Fe dose on suckling and subsequent nursery pig performance and blood Fe status. GleptoForte (Ceva Animal Health, LLC, Lenexa, KS) contains gleptoferron which is an Fe macromolecule complex that is commercially used as an injectable Fe source for suckling piglets. On the day of processing (day 3 after birth), all piglets were weighed and 6 barrows and 6 gilts per litter were allotted within sex to 1 of 6 treatments in a completely randomized design. Treatments consisted of a negative control receiving no Fe injection and increasing injectable Fe to achieve either 50, 100, 150, 200 mg, or 200 mg plus a 100 mg injection on day 11 after birth. Pigs were weaned (~21 d of age) and allotted to nursery pens based on BW and corresponding treatment in a completely randomized design. During lactation, increasing injectable Fe up to 100 mg improved (quadratic; P < 0.05) average daily gain (ADG) and day 21 BW with no further improvement thereafter. There was no evidence of differences (P > 0.10) observed between the 200 mg and 200 mg + 100 mg treatments for growth. For the nursery period, increasing Fe dosage increased (linear; P < 0.05) ADG, average daily feed intake, and day 42 BW. There was no evidence of differences (P > 0.10) between the 200 mg and 200 mg + 100 mg treatments for nursery growth. For blood criteria, significant treatment × day interactions (P = 0.001) were observed for hemoglobin (Hb) and hematocrit (Hct). The interactions occurred because pigs that had <150 mg of injectable Fe had decreased values to day 21 and then increased to day 63 while pigs with 150 or 200 mg of injectable Fe had increased values to day 21 then stayed relatively constant to day 63. In summary, piglet performance during lactation was maximized at 100 mg while nursery growth performance and blood Fe status were maximized with a 200 mg Fe injection at processing. Providing an additional 100 mg of Fe on day 11 of age increased Hb, and Hct values at weaning and 14 d into the nursery but did not provide a growth performance benefit in lactation or nursery. These results indicate that providing 200 mg of injectable Fe provided from GleptoForte is sufficient to optimize lactation and subsequent nursery growth performance and blood Fe status., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Heme is an efficient dietary iron supplement applied in humans and animals to prevent iron deficiency anemia (IDA). We have recently reported that the use of bovine hemoglobin as a dietary source of heme iron efficiently counteracts the development of IDA in young piglets, which is the common problem in pig industry. Here, we used maternal Polish Large White and terminal sire breed (L990) pigs differing in traits for meat production to evaluate the long-term effect of split supplementation with intramuscularly administered small amount of iron dextran and orally given hemoglobin on hematological indices, iron status, growth performance, slaughter traits, and meat quality at the end of fattening. Results of our study show that in pigs of both breeds split supplementation was effective in maintaining physiological values of RBC and blood plasma iron parameters as well as growth performance, carcass parameters, and meat quality traits. Our results prove the effectiveness of split iron supplementation of piglets in a far-reach perspective.

Patients with blood transfusion-dependent anemias develop transfusional iron overload (TIO), which may cause cardiosiderosis. In patients with an ineffective erythropoiesis, such as thalassemia major, common transfusion regimes aim at suppression of erythropoiesis and of enteral iron loading. Recent data suggest that maintaining residual, ineffective erythropoiesis may protect from cardiosiderosis. We investigated the common consequences of TIO, including cardiosiderosis, in a minipig model of iron overload with normal erythropoiesis. TIO was mimicked by long-term, weekly iron-dextran injections. Iron-dextran loading for around one year induced very high liver iron concentrations, but extrahepatic iron loading, and iron-induced toxicities were mild and did not include fibrosis. Iron deposits were primarily in reticuloendothelial cells, and parenchymal cardiac iron loading was mild. Compared to non-thalassemic patients with TIO, comparable cardiosiderosis in minipigs required about 4-fold greater body iron loads. It is suggested that this resistance against extrahepatic iron loading and toxicity in minipigs may at least in part be explained by a protective effect of the normal erythropoiesis, and additionally by a larger total iron storage capacity of RES than in patients with TIO. Parenteral iron-dextran loading of minipigs is a promising and feasible large-animal model of iron overload, that may mimic TIO in non-thalassemic patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests, and there are no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To assess the effects of protocolized recombinant human erythropoietin (r-HuEPO) therapy and standardized high dose iron supplementation on hematologic and iron status measures in a cohort of extremely low gestational age newborns (ELGANs)., Study Design: Charts of extremely low gestational age newborns admitted from 2006 to 2016 and who had received r-HuEPO per neonatal intensive care unit protocol were reviewed. The r-HuEPO was started at a dose of 900 IU/kg per week after 7 days of age and continued until 35 weeks postmenstrual age. Oral iron supplementation at 6-12 mg/kg per day was used to maintain a transferrin saturation of >20% during r-HuEPO treatment. Data on demographic features, hematologic and iron panel indices, red blood cell transfusions, and clinical outcomes were collected. Quartile groups were created based on serum ferritin levels at the conclusion of the r-HuEPO treatment and the quartiles were compared., Results: The cohort included 116 infants with mean gestational age 25.8 ± 1.5 weeks and birth weight 793 ± 174.1 g. The r-HuEPO promoted erythropoiesis as indicated by increasing hemoglobin, hematocrit, and reticulocyte count. Serum ferritin decreased over time and was ≤75 ng/mL in 60.2% of infants at the conclusion of r-HuEPO therapy; 87% received packed red blood cell transfusions. Transfusion volume, total iron intake, total iron binding capacity, and transferrin concentration differed among infants in the different serum ferritin quartiles (P < .05)., Conclusions: In extremely low gestational age newborns, r-HuEPO therapy promoted erythropoiesis. Despite a biomarker-based standardized high-dose iron supplementation, the majority of infants had evidence of iron deficiency to a degree that is associated with reduced brain function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The present study was to evaluate the consequences of iron status across oral and parenteral iron administrations in prevention of iron deficiency anemia. A total of 24 one-day-old male neonatal piglets were allocated into three groups given non-iron supplementation (NON), intramuscular iron dextran injection (FeDex), and oral administration of ferrous glycine chelate (FeGly), respectively. At day 8, no significant differences in final body weight, average weight gain, and tissue coefficients were observed among three groups (P > 0.05). Both oral FeGly and FeDex injection significantly increased serum iron, ferritin, hemoglobin, and tissue iron deposition (P < 0.05). However, FeDex-injected supplementation resulted in rapidly rising hepcidin levels and hepatic iron deposition (P < 0.05). In addition, compared to parenteral iron supplementation, greater serum IgA level, SOD, and GSH-Px activities, lower expressions of IL-1β and TNF-α in the liver, and lower expressions of IL-6 and TNF-α in the spleen were found in oral iron piglets (P < 0.05). According to our results, oral administration of ferrous glycine chelate improved iron homeostasis, and oxidative and immune status in anemic neonatal pigs.

Objectives : It is hypothesized that the risk of hypersensitivity reactions (HSRs) may be lower with ferric carboxymaltose than iron dextran because of its non-dextran carbohydrate moiety. This study compares the risk of HSRs between iron dextran and ferric carboxymaltose. Methods : This was a retrospective pharmacoepidemiological study with a case-population design covering 2008-2017. Global exposure data were estimated using IQVIA™ sales data. Spontaneously reported HSR data were retrieved from the World Health Organization database (VigiBase™) using different search criteria including: the Standardized MedDRA® Query (SMQ) 'Anaphylactic reaction'; type I-IV HSR terms; narrow terms for anaphylactic/anaphylactoid reactions; and cases with a fatal outcome. Results : Total exposure in 100 mg doses was 117.3 million for iron dextran and 84.2 million for ferric carboxymaltose. The relative risk (with 95% confidence interval) for ferric carboxymaltose versus iron dextran was 4.18 (3.88-4.50) for SMQ Anaphylactic reaction; 12.9 (9.90-16.7) for type I-IV HSRs; 1.72 (1.45-2.04) for anaphylactic/anaphylactoid reactions; and 1.92 (1.24-2.99) for death. Conclusion : The risk of spontaneously reported HSRs was consistently higher with ferric carboxy-maltose than with iron dextran over the period 2008-2017. Thus, this study does not support that dextran-free intravenous irons are associated with fewer HSRs than iron dextran.

Purpose: Iron supplementation therapy is used for iron-deficiency anemia but has been associated with macular degeneration in a 43-year-old patient. Iron entry into the neurosensory retina (NSR) can be toxic. It is important to determine conditions under which serum iron might cross the blood retinal barrier (BRB) into the NSR. Herein, an established mouse model of systemic iron overload using high-dose intraperitoneal iron dextran (IP FeDex) was studied. In addition, because the NSR expresses the iron regulatory hormone hepcidin, which could limit iron influx into the NSR, we gave retina-specific hepcidin knockout (RS-HepcKO) mice IP FeDex to test this possibility., Methods: Wild-type (WT) and RS-HepcKO mice were given IP FeDex. In vivo retina imaging was performed. Blood and tissues were analyzed for iron levels. Quantitative PCR was used to measure levels of mRNAs encoding iron regulatory and photoreceptor-specific genes. Ferritin and albumin were localized in the retina by immunofluorescence., Results: IP FeDex in both WT and RS-HepcKO mice induced high levels of iron in the liver, serum, retinal vascular endothelial cells (rVECs), and RPE, but not the NSR. The BRB remained intact. Retinal degeneration did not occur., Conclusions: Following injection of high-dose IP FeDex, iron accumulated in the BRB, but not the NSR. Thus, the BRB can shield the NSR from iron delivered in this manner. This ability is not dependent on NSR hepcidin production.

Aim: Iron overload is a life-threatening disorder that can increase the risks of cancer, cardiovascular disease, and liver cirrhosis. There is also a risk of iron overload in patients with chronic kidney disease. In patients with renal failure, iron storage is increased due to inadequate iron utilization associated with decreased erythropoiesis and also to the inflammatory status. To evade the risk of iron overload, an accurate and versatile indicator of body iron storage in patients with iron overload is needed. In this study, we aimed to find useful iron-related parameters that could accurately reflect body iron storage in mice in order to construct a murine model of iron overload., Methods: To select an appropriate indicator of body iron status, a variety of parameters involved in iron metabolism were evaluated. Noninvasively measured parameters were R1, R2, and R2 ∗ derived from magnetic resonance imaging (MRI). Invasively measured parameters included serum hepcidin levels, serum ferritin levels, and liver iron contents. Histopathological analysis was also conducted., Results/conclusion: Among the several parameters evaluated, the MRI T2 ∗ relaxation time was able to detect iron storage in the liver as sensitively as serum ferritin levels. Moreover, it is expected that using an MRI parameter will allow accurate evaluation of body iron storage in mice over time., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2019 Yukari Matsuo-Tezuka et al.)

Introduction: Iron deficiency anemia (IDA) is a global public health issue that affect more than 2 billion individuals worldwide. However evidence for optimal management of IDA is lacking., Methods: To assess the diagnostic criteria and therapeutic modalities for pediatric IDA employed by physicians in a major public healthcare facility in Riyadh, a validated questionnaire including demographic data and patient case-scenarios related to diagnosis and treatment of IDA was employed. Robust regression analysis was used to identify factors associated with overall score of participants., Results: Of the 166 physicians surveyed 147(88.6%) were included in the study. Wide variability was observed in IDA diagnosis and therapy practises. For nutritional IDA, only 15.6% recommended no other laboratory tests in addition to CBC. The majority preferred treatment with ferrous sulfate (77.6%) divided into two doses (57.1%), but the total daily elemental iron doses varied widely from 2 to 6 mg/kg. For intravenous iron, 42.9% recommended iron dextran, 32.7% iron sucrose, and 13.4% would continue oral iron. Of all assessed factors, median score was significantly highest in pediatric hematologists compared with pediatricians, family medicine specialists and GPs; p = 0.007, and those work in tertiary care compared with those in primary care; p = 0.043. However, in multivariate robust regression analysis, overall score was only significantly associated with professional qualification [pediatric hematologist β = 13.71,95%CI 2.48-24.95, p = 0.017; pediatrician β = 1.77,95%C (- 6.05-9.59, p = 0.66; family medicine β = 2.66,95%CI-4.30-9.58, p = 0.45 compared with general practitioner]., Conclusion: Wide variations exist among physicians in diagnosis and treatment of pediatric IDA. Intervention programs and national guidelines are urgently needed.

Background: Studies have reported conflicting findings on the infection risk posed by intravenous iron supplementation among hemodialysis (HD) patients. We used a novel study design to assess associations between intravenous iron and infectious diseases., Methods: Patients initiating HD between 1998 and 2008 were extracted from Taiwan's National Health Insurance Research Database. Their first infectious disease in the period between 1.5 years after dialysis initiation and 2010 was identified and defined as the index date. Through the case-crossover design, the odds of exposure to intravenous iron within the 1-month period immediately preceding the index date (i.e., the case period) were compared with iron exposure in three different matched control periods for the same enrollee, thus possibly reducing some unmeasured confounders., Results: A total of 1410 patients who met our enrollment criteria were extracted from incident HD patients. The odds of intravenous iron exposure during the case period versus total control periods exhibited no significant difference (odds ratio: 1.000, 95% confidence interval: 0.75-1.33). In subgroup analyses, this association remained nonsignificant across patients with diabetes mellitus, heart failure, chronic lung disease, venous catheter for HD, and higher iron load., Conclusions: We found that intravenous iron supplementation did not increase short-term infection risk among HD patients.

Background: Iron deficiency anemia (IDA) is one of the most common medical disorder disturbing pregnancies particularly in low resources countries, and contributes significantly to morbidities and mortalities. Thus, early diagnosis and prompt management of IDA is highly recommended., Aim: To Test the efficacy and safety of oral lactoferrin plus health education provided by a nurse versus total dose infusion (TDI) of low-molecular weight (LMW) iron dextran for treating IDA in the second and third trimester of pregnancy., Design: A prospective interventional, randomized, parallel-group, single-center longitudinal study., Setting: Woman's Health Assiut University Hospital, Assiut, Egypt, at the outpatient clinic and inpatient unit. It comprised 120 cases divided into two groups as pineapple flavored lactoferrin oral sachets 100 mg twice daily with health education (group A) and TDI of LMW iron dextran (group B)., Main Outcome Measures: The primary efficacy parameter was clinical improvement and the amount of increase in hemoglobin concentration by 4 weeks after therapy, secondary outcome measures included measurement of the rest of RBC, and iron indices, the adverse effects related to iron therapy and the patient compliance to the treatment., Results: There was insignificant difference between both groups regarding sociodemographic data, parity and mean gestational age. Both groups showed a significant clinical improvement of anemia 4 weeks post-therapy. There was no statistically significant difference in mean Hb level improvement in both groups after 1 month of therapy. However, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) improved significantly more in group B than A while iron indices (serum iron and serum ferritin) were significantly more in group A than group B., Conclusions: Pineapple flavored lactoferrin oral sachets plus health education can be widely used as an alternative to TDI iron dextran supplementation due to clinical as well as laboratory improvement of IDA during pregnancy after 1 month of treatment. Proper health education of the pregnant women with nurse recommendations of balanced diet containing good sources of iron would increase awareness of pregnant women and help eradicate IDA with its serious sequel during pregnancy.

Anemia is common in patients with mechanical circulatory support and is associated with increased morbidity. Repletion using parenteral iron infusions has been proven to be beneficial in patients with heart failure. In this report, we describe a case of increased power and flows of continuous-flow left ventricular assist device (LVAD) during an iron dextran infusion. We subsequently studied the effects of iron dextran infusion in an in vitro LVAD mock circulatory loop. The observed increase in flow and power was most likely due to drug-patient interaction rather than drug-LVAD interaction. Mock loops and in vivo animal models may be necessary for proactive evaluation of the safety of intravenous (IV) preparations in this patient population.

Background: Intravenous (IV) iron is frequently used to treat iron deficiency/anemia in patients who are unable to tolerate oral iron or the oral iron is not sufficient toreplete iron requirements. However, safety concerns regarding the potential increase in oxidative stress and other adverse effects persist and it remains unclear whether all iron preparations are equivalent. Indeed, the comparative risk of adverse events with IV iron preparations has not been extensively assessed. We hypothesize that IV iron leads to changes in oxidative stress, endothelial function, and potential renal damage depending on the iron formulation (related to the generation of "free" or catalytic labile iron) and this may result in more tubular and glomerular injury manifested as increased proteinuria and raised neutrophil gelatinase-associated lipocalin (NGAL) levels in patients with chronic kidney disease (CKD)., Methods: IRON-CKD is a prospective, open-label, explorative, randomized, single-center study designed to compare the safety and efficacy of three parenteral iron preparations: low-molecular-weight iron dextran-Cosmofer, iron sucrose-Venofer, and iron isomaltoside-Monofer. The study includes 40 adults who have established CKD stages 3-5 and serum ferritin (SF) of less than 200 μg/L or transferrin saturation (TS) of less than 20% (or both); they were randomly assigned in a 1:1:1:1 ratio to 200 mg iron dextran, 200 mg iron sucrose, 200 mg iron isomaltoside, or 1000 mg iron isomaltoside. After randomization, participants undergo baseline assessments and then an iron infusion. Each participant is followed up at 2 h, day 1, week 1, and months 1 and 3. At each follow-up visit, patients undergo clinical review, measurement of pulse wave velocity (PWV), blood tests for renal function, and collection of serum/plasma samples for oxidative stress and inflammatory markers. The primary outcomes are measures of oxidative stress, inflammatory markers, and markers of acute renal injury in comparison with baseline measures of each iron preparation and between each of the iron preparations. Secondary objectives include effects on hematinic profiles and hemoglobin concentrations, changes in arterial stiffness, incidence of significant side effects, and change in patients' quality of life., Results: Between October 2015 and April 2018, 521 individuals were identified as potential participants; 216 were contacted, 56 expressed an interest, 49 attended a screening visit, and 40 were confirmed to meet the eligibility criteria and were randomly assigned. The mean age was 58.8 (standard error of the mean 2.2) years, and 23 (58%) were male. All patients were white and English-speaking. The mean SF was 68.8 μg/L, TS was 21.4%, and haemoglobin was 122.6 g/L at randomization for the whole group. The mean estimated glomerular filtration rate was 28.2 mL/min/1.73 m2 the urinary protein/ creatinine ratio was 154.2 mg/mmol, and CRP was 7.5 mg/L., Discussion: IRON-CKD will provide important information on the short-term effects of three preparations of IV iron in CKD patients with biochemical functional or absolute iron deficiency on measures of oxidative stress, inflammation, endothelial function, and renal injury., Trial Registration: European Clinical Trials Database (EudraCT) number 2010-020452-64 .

Objective: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the benefits of intravenous (IV) iron in pregnancy., Study Design: Systematic review was registered with PROSPERO and performed using PRISMA guidelines. PubMed, MEDLINE, Web of Science, ClinicalTrials.gov, Cochrane Library, and Google Scholar were searched. Eleven RCTs, comparing IV to oral iron for treatment of iron-deficiency anemia in pregnancy, were included. Meta-analyses were performed with Stata software (College Station, TX), utilizing random effects model and method of DerSimonian and Laird. Outcomes were assessed by pooled odds ratios (OR) or pooled weighted mean difference (WMD). Sensitivity analyses were performed for heterogeneity., Results: We found that pregnant women receiving IV iron, compared with oral iron, had the following benefits: (1) Achieved target hemoglobin more often, pooled OR 2.66 (95% confidence interval [CI]: 1.71-4.15), p  < 0.001; (2) Increased hemoglobin level after 4 weeks, pooled WMD 0.84 g/dL (95% CI: 0.59-1.09), p  < 0.001; (3) Decreased adverse reactions, pooled OR 0.35 (95% CI: 0.18-0.67), p  = 0.001. Results were unchanged following sensitivity analyses., Conclusion: In this meta-analysis, IV iron is superior to oral iron for treatment of iron-deficiency anemia in pregnancy. Women receiving IV iron more often achieve desired hemoglobin targets, faster and with fewer side effects., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Safety of parenteral iron therapy is critical and has been demonstrated in several studies, but concerns persist on safety. We performed a retrospective single-center study investigating the safety and efficacy of parenteral iron administration using 2 iron preparations-Monofer and Cosmofer (Pharmacosmos A/S, Holbaek, Denmark)-in patients with chronic kidney disease (CKD), on peritoneal dialysis (PD) and non-dialysis. A database of CKD patients receiving intravenous (IV) iron was analyzed. Side effects were recorded during infusion, post-infusion, and after 48 hours. In a population of CKD patients (non-dialysis and PD), IV iron is safe with few major adverse effects for these 2 IV iron preparations studied with similar dosing schedules. These data provide reassurance on the relative short-term safety of IV iron preparations regarding acute infusion-related hypersensitivity reactions., (Copyright © 2019 International Society for Peritoneal Dialysis.)

Study Objective: To test safety, efficacy, and cost-effectiveness of total dose infusion (TDI) of low molecular weight (LMW) iron dextran for treatment of iron deficiency anemia (IDA) during pregnancy in comparison to oral ferrous fumarate., Design: Prospective interventional randomized controlled trial (RCT). Design classification. Canadian Task Force II3., Setting: Antenatal clinic and causality unit of a tertiary care referral facility and University Hospital., Patients: A total 66 anemic pregnant women (hemoglobin level between 7-10 g/dl)., Intervention: Administration of a LMW iron dextran as a TDI (group A) or Oral iron ferrous fumarate 60 mg elemental iron three times daily (group B) followed by remeasurement of hemoglobin after 4 weeks., Measures and Main Results: The main outcome measure was clinical and laboratory improvement of anemia after 4 weeks of starting the therapy. Both groups showed a significant clinical improvement of anemia 4 weeks post-therapy. However, the first improvement of symptoms was significantly faster in group A. Complete blood count (CBC) as well as all iron indices were improved in both groups after 4 weeks of therapy, but were significantly better in group A than B. Side effects in group B were mainly gastrointestinal (GIT) while one case of mild hypersensitivity to TDI and another one case of local reaction at the site of injection were reported in group A., Conclusions: It is concluded that despite being equally effective in improving both clinical and laboratory evidence of IDA, TDI allows iron restoration with a single dose faster than oral iron therapy with a reasonable safety profile. It is a good example of office one-stop therapy. Nevertheless, noninvasive selfusage at home is a clear advantage of the cheaper oral iron therapy which makes it the first choice for treating IDA in the second and third trimesters of pregnancy in tolerable cases.

Early nutrition is key to promoting gut growth and education of the immune system. Although iron deficiency anemia has long been recognized as a serious iron disorder, the effects of iron supplementation on gut development are less clear. Therefore, using suckling piglets as the model for iron deficiency, we assessed the impacts of iron supplementation on hematological status, gut development, and immunity improvement. Piglets were parenterally supplied with iron dextran (FeDex, 60 mg Fe/kg) by intramuscular administration on the third day after birth and slaughtered at the age of two days, five days, 10 days, and 20 days. It was expected that iron supplementation with FeDex improved the iron status with higher levels of serum iron, ferritin, transferrin, and iron loading in the liver by regulating the interaction of hepcidin and ferroportin (FPN). FeDex supplementation increased villus length and crypt depth, attenuated the pathological status of the duodenum, and was beneficial to intestinal mucosa. FeDex also influenced the intestinal immune development by stimulating the cytokines' production of the intestine and enhancing the phagocytotic capacity of monocytes. Overall, the present study suggested that iron supplementation helped promote the development of the intestine by improving its morphology, which maintains its mucosal integrity and enhances the expression of immuno-associated factors.

Although parenteral iron products have been established to medicinal use decades before, their structure and pharmacokinetic properties are not fully characterized yet. With its' second reflection paper on intravenous iron-based nano-colloidal products (EMA/CHMP/SWP/620008/2012) the European Medicine Agency provided an extensive catalogue of methods for quality, non-clinical and pharmacokinetic studies for the comparison of nano-sized iron products to an originator (EMA, 2015). For iron distribution studies, the reflection paper assumed the use of rodents. In our tests, we used a turkey fetus model to investigate time dependent tissue concentrations in pharmacological and toxicological relevant tissues liver, heart and kidney. We found turkey embryos to be a suitable alternative to rodents with high discriminatory sensitivity. Clear differences were found between equimolar doses of iron products with hydroxyethyl amylopectin, sucrose, dextrane and carboxymaltose shell. A linear dose dependency for the tissue accumulation was also demonstrated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cystoisospora suis causes diarrhoeal disease and reduced weight gain in suckling piglets, and a toltrazuril-based oral suspension is available for treatment. Recently a combinatorial product with toltrazuril plus iron has been developed for parenteral application. In this study we compared the efficacy of the injectable product with the oral suspension against experimentally induced piglet cystoisosporosis., Methods: In a randomised controlled study, three groups of piglets (n = 10-13) were treated either with a fixed dose of 45 mg toltrazuril + 200 mg gleptoferron i.m. per piglet (Forceris®) on the second day of life (study day 2; SD 2) or with 20 mg toltrazuril/kg body weight as an oral suspension (Baycox® 5%) on SD 4 or left untreated (Control group). The Baycox® and the Control group received 200 mg of iron dextran/piglet on SD 2. All piglets were infected with 1000 sporulated C. suis oocysts on SD 3. Faecal samples were taken daily from SD 7 to SD 20 to determine faecal consistency, oocyst shedding and other diarrhoeal pathogens. Body weight was recorded on SD 1 and then weekly until SD 29. Animals were observed daily for general health and after treatment for possible adverse events., Results: In the Control group all animals shed oocysts for 3.1 days on average and all animals showed diarrhoea for an average of five days. Excretion peaked on SD 9 (max. 48,618 oocysts per gram of faeces). Treatment with Forceris® completely suppressed oocyst excretion. In the Baycox® group, low levels of excretion could be detected. Diarrhoea was reduced to single piglets in the treated groups. Body weight development was reduced in the Control group compared to the treated groups. Enteropathogenic bacteria (Escherichia coli, Clostridium perfringens) could be detected. All parameters related to oocyst excretion, faecal consistency and weight gain were significantly improved in the treated groups compared to the Control group without significant differences between the treated groups. Both products were safe to use., Conclusions: Treatment with both the injectable (Forceris®) and the oral (Baycox®) formulation of toltrazuril in the prepatent period were safe and highly effective against experimental infection with C. suis in newborn piglets.

Studies suggest iron overload may cause bone lesion. The mechanisms are not well understood at present. Therefore, this study was designed to observe the effect of iron overload on bone metabolism in young male rats and explore its possible mechanism. Eighteen SD rats were randomly assigned to iron-loading and control groups. Fe-dextran (250 mg/kg of body weight) was injected intraperitoneally into the rats from iron-loading group, every other day for 5 weeks. The bone mineral density (BMD) of femur, length and diameter of tibia, and histological microstructure of femur and vertebra was determined. The concentrations of serum superoxide dismutase (SOD) and malondialdehyde (MDA) were assayed by ELISA. The mRNA expression of cytokines was detected by real-time PCR. The results showed an obvious bone abnormality after iron intervention, such as significantly decreased content of Ca in bone tissue, shorter length of tibia, lower BMD of femur, and obvious lesion of bone microarchitecture. At the same time, with iron intervention, the concentrations of serum SOD decreased but MDA increased; the mRNA expression of osteocalcin and osteoprotegerin (OPG) decreased, whereas that of receptor activator of nuclear factor kappa B ligand (RANKL) and IL-6 increased significantly. In summary, iron overload indeed give rise to the abnormal changes of bone metabolism independently. Increased bone resorption, and probably decreased bone formation are involved in the process of bone lesion caused by iron overload. Oxidative stress and RANKL participate in the pathological process, and IL-6 may play a supporting role., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Iron deficiency is the leading cause of anemia in patients with inflammatory bowel disease (IBD). Intravenous iron is the first-line treatment for clinically active IBD or previous oral iron intolerance. The aim of the present study was to develop a comparative model of iron deficiency and delivery for iron isomaltoside (IIM), ferric carboxymaltose (FCM), low molecular weight iron dextran (LMWID), and iron sucrose (IS) in the treatment of iron deficiency anemia associated with IBD. Areas covered: A model was developed to evaluate iron delivery characteristics, resource use and costs associated with IIM, FCM, LMWID and IS. Iron deficiency was modeled using dosing tables and retreatments were modeled based on a pooled retrospective analysis. The analyses were conducted over 5 years in patients with IBD with mean bodyweight of 75.4 kg and hemoglobin levels of 10.77 g/dL based on observational data. Expert opinion: The modeling analysis showed that using IIM required 1.2 infusions (per treatment) to correct the mean iron deficit, compared with 1.6, 1.2, and 7.1 with FCM, LMWID and IS, respectively. Costs were estimated to be 2,518 pounds sterling (GBP) per patient with IIM or LMWID, relative to GBP 3,309 with FCM or GBP 14,382 with IS.

The hypothesis of this study is that the cerebral cortex, hippocampus, and striatum of the rat brain are differentially affected in terms of oxidative stress and antioxidant capacity by acute Fe overload because Fe is distributed in a heterogeneous fashion among different regions and cells of the brain. The effects on the lipophilic and hydrophilic cellular environment were compared between regions and with the whole brain. A single dose of Fe-dextran increased Fe deposits, reaching a maximum after 6 hr. Both in whole brain and in cortex region, the ascorbyl/ascorbate content ratio was increased after 6 hr of Fe administration, while in striatum and hippocampus, there was no significant changes after Fe overload. Total thiol content decreased in whole brain and cortex, while there were no significant changes in striatum and hippocampus after Fe overload. The content of α-tocopherol (α-T), whether measured in the whole brain or in the isolated regions, did not change following Fe treatment. Lipid radical (LR•) generation rate after Fe-dextran overload only increased in the cortex region. The LR•/α-T content ratio was increased by Fe treatment in cortex but not in the whole brain, striatum, or hippocampus, in agreement with the study tested hypothesis.

Background: Perioperative and critically ill patients are often exposed to iron (in the form of parenteral-iron administration or blood transfusion) and inflammatory stimuli, but the effects of iron loading on the inflammatory response are unclear. Recent data suggest that mitochondrial reactive oxygen species have an important role in the innate immune response and that increased mitochondrial reactive oxygen species production is a result of dysfunctional mitochondria. We tested the hypothesis that increased intracellular iron potentiates lipopolysaccharide-induced inflammation by increasing mitochondrial reactive oxygen species levels., Methods: Murine macrophage cells were incubated with iron and then stimulated with lipopolysaccharide. C57BL/6 wild-type mice were intraperitoneally injected with iron and then with lipopolysaccharide. Markers of inflammation and mitochondrial superoxide production were examined. Mitochondrial homeostasis (the balance between mitochondrial biogenesis and destruction) was assessed, as were mitochondrial mass and the proportion of nonfunctional to total mitochondria., Results: Iron loading of mice and cells potentiated the inflammatory response to lipopolysaccharide. Iron loading increased mitochondrial superoxide production. Treatment with MitoTEMPO, a mitochondria-specific antioxidant, blunted the proinflammatory effects of iron loading. Iron loading increased mitochondrial mass in cells treated with lipopolysaccharide and increased the proportion of nonfunctional mitochondria. Iron loading also altered mitochondrial homeostasis to favor increased production of mitochondria., Conclusions: Acute iron loading potentiates the inflammatory response to lipopolysaccharide, at least in part by disrupting mitochondrial homeostasis and increasing the production of mitochondrial superoxide. Improved understanding of iron homeostasis in the context of acute inflammation may yield innovative therapeutic approaches in perioperative and critically ill patients.

Introduction: Erythropoietin (EPO) is a commonly used option in the treatment of chemotherapy-induced anaemia (CIA). However, ∼30-50% of patients fail to achieve an adequate response after initial treatment. Prior studies have demonstrated that intravenous iron might synergistically improve therapeutic response to EPO treatment in this patient population., Methods and Analysis: We will perform this multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study to compare the two combination therapies of EPO plus intravenous iron regimen versus doubling the dose of EPO in patients with CIA who have an inadequate response to initial EPO treatment at a routine dose. A total of 603 patients with an increase in haemoglobin (Hb) <1 g/dL will be enrolled and randomised to one of the three study treatment groups at a 1:1:1 ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose without preplanned iron supplementation. The primary outcome measure to compare is the Hb response rate at week 15 and the secondary end points involve therapeutic blood transfusions. Time-to-progression, adverse events and quality of life will also be evaluated., Ethics and Dissemination: All participants will provide informed consent; the study protocol has been approved by the independent ethics committee of Shanghai East Hospital. This study would clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China., Trial Registration Number: NCT02731378., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Iron deficiency is common in heart failure (HF), and intravenous (IV) iron therapy has been associated with improved clinical status in ambulatory patients with HF. There are limited data to support the safety and efficacy of IV iron administration in patients with acute HF. This was a retrospective cohort study of patients admitted to the University of Michigan Health System for HF with low iron studies during admission. Patients were grouped based on the receipt of IV iron therapy. Study outcomes included change in hemoglobin, 30-day readmission, and adverse events. Forty-four patients who received IV iron and 128 control patients were identified. The mean dose of IV iron received was 1,057 (±336) mg. IV iron resulted in a significantly greater increase in hemoglobin over time (p = 0.0001). The mean change in hemoglobin in the iron and control groups was 0.74 g/dl and 0.01 g/dl at day 7 and 2.61 g/dl and 0.23 g/dl at day 28, respectively. Thirty-day readmission rates were 30% and 22% for patients in the iron and control groups, respectively (p = 0.2787). In conclusion, total dose infusion IV iron is well tolerated and associated with significant improvement in hemoglobin in acute HF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Maternal iron deficiency anemia (IDA) is associated with risk of adverse perinatal outcomes. Oral iron is recommended to reverse anemia, but has gastrointestinal toxicity and frequent non-adherence. Intravenous (IV) iron is reserved for intolerance of, or unresponsiveness to, oral therapy, malabsorption, and severe anemia (1% with hemoglobin [Hgb] levels <7 g/dL). With rare (<100 per one million) adverse events (AEs) ability to infuse a sufficient dose of low molecular weight iron dextran (LMWID) over 60 min, LMWID is an attractive option. This study demonstrated safety and efficacy of rapid IV infusion of 1,000 mg LMWID to gravidas with moderate to severe IDA. An observational treatment study of 1,000 mg LMWID administered over 1 hr for IDA in 189 consecutive, unselected second and third trimester gravidas after oral iron failure was conducted. All received a test dose of 25 mg LMWID and were monitored for AEs during the 60-min infusion. No premedication was administered unless more than one drug allergy or asthma was present in which case IV methylprednisolone was administered. All were followed through pregnancy and delivery. Monitored parameters included Hgb, mean corpuscular volume, serum ferritin, and percent transferrin saturation. About 189 subjects received 1,000 mg LMWID. No serious AEs occurred. About 2% experienced transient infusion reactions. Hgb improved by 1-1.9 g/dL in 82% and ≥2 g/dL in 24%. Second trimester treatment was not associated with greater Hgb improvement than third trimester treatment. Anemia resolved in 95%. Administration of a single large dose of IV LMWID was effective, safe, and convenient. Am. J. Hematol. 91:590-593, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The observed biological differences in safety and efficacy of intravenous (IV) iron formulations are attributable to physicochemical differences. In addition to differences in carbohydrate shell, polarographic signatures due to ferric iron [Fe(III)] and ferrous iron [Fe(II)] differ among IV iron formulations. Intravenous iron contains Fe(II) and releases labile iron in the circulation. Fe(II) generates toxic free radicals and reactive oxygen species and binds to bacterial siderophores and other in vivo sequestering agents. To evaluate whether differences in Fe(II) content may account for some observed biological differences between IV iron formulations, samples from multiple lots of various IV iron formulations were dissolved in 12 M concentrated HCl to dissociate and release all iron and then diluted with water to achieve 0.1 M HCl concentration. Fe(II) was then directly measured using ferrozine reagent and ultraviolet spectroscopy at 562 nm. Total iron content was measured by adding an excess of ascorbic acid to reduce Fe(III) to Fe(II), and Fe(II) was then measured by ferrozine assay. The Fe(II) concentration as a proportion of total iron content [Fe(III) + Fe(II)] in different lots of IV iron formulations was as follows: iron gluconate, 1.4 and 1.8 %; ferumoxytol, 0.26 %; ferric carboxymaltose, 1.4 %; iron dextran, 0.8 %; and iron sucrose, 10.2, 15.5, and 11.0 % (average, 12.2 %). The average Fe(II) content in iron sucrose was, therefore, ≥7.5-fold higher than in the other IV iron formulations. Further studies are needed to investigate the relationship between Fe(II) content and increased risk of oxidative stress and infections with iron sucrose.

Background: Intravenous (IV) iron is commonly used for correcting iron deficiency anaemia in patients with chronic kidney disease (CKD). There remains a concern for its use in patients with asthma as it may trigger an acute exacerbation. Pre-treatment with a single dose of parenteral hydrocortisone may obviate this risk., Method: We carried out a prospective study of known asthmatic patients with CKD requiring single-dose iron repletion therapy. We analysed the efficacy and safety of IV CosmoFer (low molecular weight iron dextran). Twenty non-dialysis CKD patients with iron deficiency anaemia and a history of asthma were enrolled. Severity of asthma and level of control were recorded as per British Thoracic Society Guidelines and Royal Collage of Physician questionnaire, respectively. All patients received IV hydrocortisone 30 min before the test dose of CosmoFer followed by the remaining total dose. Patients were monitored for adverse reactions. Haemoglobin, serum ferritin levels and estimated glomerular filtration rate were measured pre and 6-weeks post-infusion. All patients were followed up until 6 weeks to assess the control of their asthma., Results: All 20 patients completed the study. No patient experienced acute hypersensitivity or infusion reactions. At 6 weeks follow-up, no patient reported worsening of their asthma. There was an increase in mean haemoglobin from 10.1 to 11.1 g/dl and mean ferritin from 93.5 to 302.6 ng/ml., Conclusions: This study demonstrates that IV CosmoFer may be administered safely in asthmatics by administering a single 50 mg dose of hydrocortisone pre-infusion., (© The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Abnormal placentation can be associated with significant blood loss and massive blood transfusions. Caring for parturients with abnormal placentation who refuse blood transfusion is very challenging. We present a 35-year-old, gravida 3, para 1, Jehovah's Witness at 35 weeks of gestation with placenta percreta, who underwent cesarean delivery and delayed hysterectomy. A multidisciplinary team developed a plan, including the use of perioperative erythropoietin and IV iron dextran, intraoperative acute normovolemic hemodilution, cell salvage, tranexamic acid, and uterine artery embolization. This strategy was successful in avoiding the need for allogeneic transfusion and ensuring an uneventful recovery after both surgical procedures.

This work was aimed to test the hypothesis that sub-chronic administration of iron-dextran (Fe-dextran) (six doses of 50 mg Fe-dextran/kg) to rats triggers a transient oxidative stress in brain and mechanisms of cellular antioxidant defence. After 2 h of administration of the 6th dose, a significant increase of total Fe, the labile Fe pool (LIP), the lipid radical (LR(•))/α-tocopherol (α-T) content ratio were observed, as compared to values in control brain homogenates. The ascorbyl radical (A(•))/ascorbate (AH(-)) content ratio and the oxidation rate of 2',7'-dichlorodihidrofluorescein (DCFH-DA) were significantly higher in Fe-dextran treated rats, as compared to values in brain from control rats after 4 h treatment. An increase in both catalase (CAT) and superoxide dismutase (SOD) activity was observed at 8 and 1-2 h, respectively. No significant changes were detected in the nuclear factor-κB (NF-κB) levels in nuclear extracts from rat brains after 1-8 h of Fe-dextran administration. After 2 h of Fe administration Fe concentration in cortex, striatum and hippocampus was significantly increased as compared to the same areas from control animals. Both, CAT and SOD activities were significantly increased in cortex after Fe administration over control values, without changes in striatum and hippocampus. Taken as a whole, sub-chronic Fe administration enhances the steady state concentration of Fe in the brain LIP that favors the settlement of an initial oxidative stress condition, both at hydrophilic and lipophilic compartments, resulting in cellular protection evidenced by antioxidant enzyme upregulation.

It is estimated that one-third of the world's population is anemic, the majority being due to iron deficiency (ID). In adults, ID is associated with fatigue in the absence of anemia, restless legs syndrome, pica and, in neonates, delayed growth and development. In adolescents, ID is associated with decrements in learning and behavioral abnormalities. In the absence of a clear cause, search for a source of bleeding is indicated. No single test is diagnostic of ID unless the serum ferritin is low or the percent transferrin saturation is low with an elevated total iron binding capacity. Oral iron is considered front line therapy except for conditions such as gastric bypass, heavy uterine bleeding, inflammatory bowel disease, and hereditary hemorrhagic telangiectasia. Oral iron has many unpleasant side effects, resulting in low patient adherence. For patients intolerant of, or unresponsive to, oral iron, intravenous (IV) administration is the preferred route. While early formulations were associated with a high incidence of serious adverse events (SAEs), newer formulations are much safer with SAEs occurring very infrequently. Full replacement doses can be administered in a matter of minutes to a few hours. Nevertheless, there remains a reluctance to use IV iron due to a misunderstanding of the safety of the available formulations. IV iron is safe and effective in all clinical circumstances including pregnancy. The preponderance of published evidence suggests IV iron therapy is underutilized and we believe that IV iron should be moved forward in the treatment of ID and iron deficiency anemia (IDA)., (© 2015 Wiley Periodicals, Inc.)

Importance: All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established., Objective: To compare the risk of anaphylaxis among marketed IV iron products., Design, Setting, and Participants: Retrospective new user cohort study of IV iron recipients (n = 688,183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013., Exposures: Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data., Main Outcomes and Measures: Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups., Results: A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8-78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100,000 persons, 95% CI, 15.3- 26.4)., Conclusions and Relevance: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

This study was conducted to compare effects of dietary administration of iron dextran and bacterial-iron on growth performance, fecal microbial flora, and blood profiles in sows and their litters. A total of 20 multiparous sows (Landrace × Yorkshire) were randomly allotted into two treatments: (i) ID (basal diet, piglets were injected with iron dextran); (ii) BR (basal diet + bacterial-iron; bacterial-iron was given to sows, piglets were not injected with iron dextran). There were five replicates per treatment with two sows per replicate. No differences were observed on sow and piglet growth performance, fecal microbial flora as well as sow blood profiles between ID and BR treatments. In piglets, blood iron, red blood cell and hemoglobin concentrations in ID treatment were higher (P < 0.05) on days 12 and 24. Furthermore, concentration of white blood cells in BR treatment was lower (P < 0.05) on day 12. However, the percentage of lymphocytes on day 12 was increased (P < 0.05) in BR treatment. In conclusion, effect of iron dextran and bacterial-iron has no difference on growth performance in lactating sows and piglets, but iron dextran injection has higher blood iron, white blood cell, red blood cell and hemoglobin concentrations in piglets., (© 2015 Japanese Society of Animal Science.)

Iron deficiency is common throughout the world and has been linked to immunity impairments. Using piglets to model human infants, we assessed the impact of systemic iron homeostasis on proinflammatory status. Artificially reared piglets were parenterally supplied with iron dextran by intramuscular administration at the age of 3 days. Relative to no iron supplementation (control), iron dextran-treated (FeDex) piglets increased hematological parameters as well as iron levels in serum and tissues from days 21 to 49. High expression of hepcidin was observed in FeDex-treated piglets, which correlated with suppressed expression of ferroportin in duodenum. Lower levels of proinflammatory cytokine (IL-6, TNF-α, IFN-γ, and IL-1β) transcripts were detected in ileum of FeDex-treated piglets, which indicated that iron supplementation could attenuate the increase of inflammatory cytokines caused by iron deficiency. Histopathological analysis of liver and duodenum proved the less inflammatory responses after iron supplementation. Hepcidin was highly stimulated by FeDex supplementation and attenuated the inflammation of anemia, which implied that hepcidin might had antiinflammatory function and is a candidate regulator of the cross-talk between iron regulation and inflammation.

Background: Cutaneous siderosis is accumulation of iron in the dermis and the subcutaneous tissue secondary to extravasation of an intramuscular or intravascular iron injection. It presents as varying shades of brown macules with no distinct contours. The hyperpigmentation is permanent without treatment., Objective: Q-switched lasers have been used effectively to treat lentigines and tattoos however, there is little data on the treatment of cutaneous siderosis with lasers. Our objective was to effectively treat cutaneous siderosis with a Q-switched alexandrite laser., Results: A 50-year-old female had received nine injections of intramuscular iron dextran, one injection every 2 weeks alternating right buttock and left buttock over the course of 5 months. A couple of weeks after her 9th injection which was on the left, she noted brown hyperpigmentation in the injection area with the left worse than the right. She waited 3 months for the hyperpigmentation to self-resolve before presenting in our clinic. We utilized the Q-switched alexandrite laser to treat the patient with a test spot. One week later, there was nice partial clearance from the test spot so we commenced full treatment of the hyperpigmentation. There was significant improvement after the first treatment and she has been treated 4 times with continued improvement over the past 2 months., Conclusion: The Q-switched alexandrite laser is a useful tool in the treatment of cutaneous siderosis secondary to iron injection., (© 2015 Wiley Periodicals, Inc.)

Objective: For patients with chronic heart failure (CHF), exertional fatigue is one of the most common and debilitating symptoms. However, the poor relationship between heart dysfunction and exercise capacity has been ascribed to peripheral abnormalities. Several previous studies confirmed that iron supplementation could significantly improve the exercise capacity of patients with CHF, although they did not analyze effects in the musculoskeletal system. The aim of this study was to investigate the effect of iron treatment on gastrocnemius muscles of CHF rats with anemia., Methods: Male Sprague-Dawley rats were subjected to coronary ligation to induce heart failure. At the same time, blood (1-1.5 mL) was withdrawn from the retro-orbital plexus once every week to induce anemia. After 6 wk of this process, iron dextran was administered to the CHF rats with anemia (CHFa rats) at the dose of 8, 16, 32, or 64 mg/kg every 2 d for 2 wk., Results: Iron dextran (8 mg/kg every 2 d) effectively improved hemodynamic parameters (P < 0.05) compared with CHFa rats. Similarly, this dose of iron dextran significantly reduced the ratio of heart weight to body weight (P < 0.01), whereas it significantly increased the distance run (m) to exhaustion (P < 0.01). Iron dextran effectively inhibited sarcoplasmic vacuolation and muscle atrophy of gastrocnemius muscles in CHFa rats, as evaluated by pathologic examinations. Other iron treatments, however, were found to be ineffective on the same parameters, so particular focus was placed on the iron dextran (8 mg/kg every 2 d) group in subsequent analyses. Consistently, phospho-p38 in gastrocnemius muscles of CHFa rats was markedly suppressed by iron dextran. Additionally, iron dextran significantly decreased c-fos and c-jun and up-regulated cellular FLICE-inhibitory protein expression levels., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Iron is involved in the formation as well as in the scavenging of reactive oxygen and nitrogen species. Thus, iron can induce as well as inhibit both oxidative and nitrosative stress. It also has a key role in reactive oxygen and nitrogen species-mediated apoptosis. We assessed the differences in tyrosine nitration and caspase 3 expression in the liver, heart, and kidneys of rats treated weekly with intravenous ferumoxytol, iron isomaltoside 1000, iron dextran, iron sucrose and ferric carboxymaltose (40 mg iron/kg body weight) for 5 weeks. Nitrotyrosine was quantified in tissue homogenates by Western blotting and the distribution of nitrotyrosine and caspase 3 was assessed in tissue sections by immunohistochemistry. Ferric carboxymaltose and iron sucrose administration did not result in detectable levels of nitrotyrosine or significant levels of caspase 3 vs. control in any of the tissue studied. Nitrotyrosine and caspase 3 levels were significantly (p<0.01) increased in all assessed organs of animals treated with iron dextran and iron isomaltoside 1000, as well as in the liver and kidneys of ferumoxytol-treated animals compared to isotonic saline solution (control). Nitrotyrosine and caspase 3 levels were shown to correlate positively with the amount of Prussian blue-detectable iron(III) deposits in iron dextran- and iron isomaltoside 1000-treated rats but not in ferumoxytol-treated rats, suggesting that iron dextran, iron isomaltoside 1000 and ferumoxytol induce nitrosative (and oxidative) stress as well as apoptosis via different mechanism(s)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Rates of postpartum hemorrhage have been increasing in Canada over the last 10 years, with postpartum iron deficiency anemia as the most common consequence. Postpartum anemia is treated with oral iron supplementation and/or blood transfusion. Recent studies have evaluated the use of parenteral iron as a better tolerated treatment modality. Compared with oral iron supplements, parenteral iron is associated with a more rapid rise in serum ferritin and hemoglobin and improved maternal fatigue scores in the postpartum period. It may also decrease rates of blood transfusion. Parenteral iron may be considered in select clinical situations for the treatment of postpartum anemia.

Iron overload cardiomyopathy results from iron accumulation in the myocardium that is closely linked to iron-mediated myocardial fibrosis. Salvia miltiorrhiza (SM, also known as Danshen), a traditional Chinese medicinal herb, has been widely used for hundreds of years to treat cardiovascular diseases. Here, we investigated the effect and potential mechanism of SM on myocardial fibrosis induced by chronic iron overload (CIO) in mice. Kunming male mice (8 weeks old) were randomized to six groups of 10 animals each: control (CONT), CIO, low-dose SM (L-SM), high-dose SM (H-SM), verapamil (VRP) and deferoxamine (DFO) groups. Normal saline was injected in the CONT group. Mice in the other five groups were treated with iron dextran at 50 mg/kg per day intraperitoneally for 7 weeks, and those in the latter four groups also received corresponding daily treatments, including 3 g/kg or 6 g/kg of SM, 100 mg/kg of VRP, or 100 mg/kg of DFO. The iron deposition was estimated histologically using Prussian blue staining. Myocardial fibrosis was determined by Masson's trichrome staining and hydroxyproline (Hyp) quantitative assay. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and protein expression levels of type I collagen (COL I), type I collagen (COL III), transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase-9 (MMP-9) were analyzed to investigate the mechanisms underlying the effects of SM against iron-overloaded fibrosis. Treatment of chronic iron-overloaded mice with SM dose-dependently reduced iron deposition levels, fibrotic area percentage, Hyp content, expression levels of COL I and COL III, as well as upregulated the expression of TGF- β1 and MMP-9 proteins in the heart. Moreover, SM treatment decreased MDA content and increased SOD activity. In conclusion, SM exerted activities against cardiac fibrosis induced by CIO, which may be attributed to its inhibition of iron deposition, as well as collagen metabolism and oxidative stress.

Objective: To compare the efficacy and safety profile of total dose infusion of low molecular weight iron dextran with divided doses of intravenous iron sucrose for the treatment of iron deficiency anemia during pregnancy., Study Design: Randomized controlled trial., Place and Duration of Study: Shifa International Hospital, Islamabad, over a period of two years from January 2008 to December 2009., Methodology: Pregnant women at gestational age more than 12 weeks with the confirmed diagnosis of Iron Deficiency Anemia (IDA) were divided into two groups. In the group-A, intravenous iron sucrose was given in divided doses while in the group-B, total daily intake of Low Molecular Weight (LMW) of iron dextran was given. Post-infusion Hemoglobin (Hb) was checked at 4 weeks and at the time of delivery for both groups. Paired sample t-test is applied and comparison (in terms of rise in hemoglobin from pre to post) of both groups was not found to be significant., Results: In the group-A (iron sucrose group), mean pre-infusion Hb levels was 9.09 ± 0.83 gm/dl. Mean increase in Hemoglobin (Hb) was 10.75 ± 1.097 gm/dl after 4 weeks of infusion and 11.06 ± 0.866 gm/dl at delivery (p < 0.001). In group-B (iron dextran group) pre-infusion haemoglobin was 8.735 ± 0.956 gm/dl and the mean increase in hemoglobin was 10.613 ± 1.22 gm/dl at 4-week while mean increase of 10.859 ± 1.11 gm/dl at the time of delivery (p < 0.001)., Conclusion: Both LMW iron dextran, as well as iron sucrose are equally effective in treatment of IDA during pregnancy, however, LMW iron dextran has the advantage of single visit treatment.