Vitamin E protective effects on genomic and cellular damage caused by paediatric preventive supplementation for anaemia: an experimental model.

Iron deficiency is the leading cause of anaemia. In Argentina, the prevalence of anaemia and iron deficiency is very high; for that reason, the Argentine Society of Pediatrics recommends daily ferrous sulphate supplementation as a preventive treatment strategy. Alternatively, weekly ferrous sulphate supplementation has also been shown to be effective for anaemia prevention. Excess iron could be related to oxidative stress, which may in turn cause cytomolecular damage. Both can be prevented with vitamin E supplementation. We evaluated the effect of both daily and weekly ferrous sulphate supplementation combined with two doses of vitamin E on cell viability, oxidative stress and cytomolecular damage in peripheral blood cultured in vitro. The experimental design included the following groups: untreated negative control, two vitamin E controls (8·3 and 16·6 µg/ml), weekly ferrous sulphate supplementation (0·55 mg/ml) with each vitamin E dose, daily ferrous sulphate supplementation (0·14 mg/ml) with each vitamin E dose and a positive control. Daily ferrous sulphate supplementation decreased cell viability and increased the levels of reactive oxygen species, lipid peroxidation and cytomolecular damage (P < 0·5) compared with the weekly supplementation, probably due to the excess iron observed in the former. Vitamin E seemed to reduce ferrous sulphate-induced oxidative stress and genomic damage.

Efficacy and Safety of Ferrous Bisglycinate and Folinic Acid in the Control of Iron Deficiency in Pregnant Women: A Randomized, Controlled Trial.

Iron deficiency in pregnancy is a major public health problem that causes maternal complications. The objective of this randomized, controlled trial was to examine the bioavailability, efficacy, and safety of oral ferrous bisglycinate plus folinic acid supplementation in pregnant women with iron deficiency. Subjects (12−16 weeks of gestation, n = 120) were randomly allocated to receive oral iron as ferrous bisglycinate (equiv. iron 24 mg) in supplement form with folinic acid and multivitamins (test group, n = 60) or as ferrous fumarate (equiv. iron 66 mg iron, control group, n = 60) after breakfast daily. Iron absorption was assessed by measuring fasted serum iron levels at 1 and 2 h immediately after supplementation. Hematological biomarkers and iron status were assessed before intervention, and at 3 and 6 months. Side effects were monitored throughout the intervention. A significant increase in serum iron was seen in both groups (p < 0.001) during the bioavailability assessment; however, the test group increases were comparatively higher than the control values at each timepoint (p < 0.001). Similarly, both test and control groups demonstrated a statistically significant increases in hemoglobin (Hb) (p < 0.001), erythrocytes (p < 0.001), reticulocytes (p < 0.001), mean corpuscular volume (MCV) (p < 0.001), mean corpuscular hemoglobin (MCH) (p < 0.001), mean corpuscular hemoglobin concentration (MCHC) (p < 0.001), % transferrin saturation (p < 0.001), and ferritin (p < 0.001) at 3 and 6 months after supplementation. However, in all cases, the test group increases were numerically larger than the control group increases at each timepoint. The test intervention was also associated with significantly fewer reports of nausea, abdominal pain, bloating, constipation, or metallic taste (p < 0.001). In conclusion, ferrous bisglycinate with folinic acid as a multivitamin nutraceutical format is comparable to standard ferrous fumarate for the clinical management of iron deficiency during pregnancy, with comparatively better absorption, tolerability, and efficacy and with a lower elemental iron dosage.

Applying reflective multicriteria decision analysis to understand the value of therapeutic alternatives in the management of gestational and peripartum anaemia in Spain.

BACKGROUND: The objective of the FeminFER project was to assess the value of ferric carboxymaltose following a multicriteria decision analysis in obstetrics and gynaecology in Spain. METHODS: Ferric carboxymaltose (FCM) and ferrous sulphate were evaluated using the EVIDEM framework. Ten stakeholders participated to collect different perspectives. The framework was adapted considering evidence retrieved with a PICO-S search strategy and grey literature. Criteria/subcriteria were weighted by level of relevance and an evidence-based decision-making exercise was developed in each criterion; weights and scores were combined to obtain the value of intervention relative to each criterion/subcriterion, that were further combined into the Modulated Relative Benefit-Risk Balance (MRBRB). RESULTS: The most important criterion favouring FCM was Compared Efficacy/Effectiveness (0.183 ± 0.07), followed by Patient Preferences (0.059 ± 0.10). Only Direct medical costs criterion favoured FS (-0.003 ± 0.03). MRBRB favoured FCM; 0.45 ± 0.19; in a scale from -1 to + 1. CONCLUSIONS: In conclusion, considering the several criteria involved in the decision-making process, participants agreed with the use of FCM according to its MRBRB.

A Novel Ferritin-Core Analog Is a Safe and Effective Alternative to Oral Ferrous Iron for Treating Iron Deficiency during Pregnancy in Mice.

BACKGROUND: Many women enter pregnancy with iron stores that are insufficient to maintain maternal iron balance and support fetal development and consequently, often require iron supplements. However, the side effects associated with many currently available iron supplements can limit compliance. OBJECTIVE: This study aimed to test the safety and efficacy of a novel nanoparticulate iron supplement, a dietary ferritin analog termed iron hydroxide adipate tartrate (IHAT), in pregnant mice. METHODS: Female C57BL/6 mice were maintained on either an iron-deficient or a control diet for 2 wk prior to timed mating to develop iron-deficient or iron-sufficient pregnancy models, respectively. Mice from each model were then gavaged daily with 10 mg iron/kg body weight as either IHAT or ferrous sulfate, or with water only, beginning on embryonic day (E) 4.5. Mice were killed on E18.5 and maternal iron and hematological parameters were measured. The expression of genes encoding iron transporters and oxidative stress markers in the duodenum and placenta were determined, along with hepatic expression of the gene encoding the iron regulatory hormone hepcidin and fetal iron. RESULTS: Oral IHAT and ferrous sulfate were equally effective at increasing maternal hemoglobin (20.2% and 16.9%, respectively) and hepatic iron (30.2% and 29.3%, respectively), as well as total fetal iron (99.7% and 83.8%, respectively), in iron-deficient pregnant mice compared with those gavaged with water only, with no change in oxidative stress markers seen with either treatment. However, there was a significant increase in the placental expression of the oxidative stress marker heme oxygenase 1 in iron-replete pregnant mice treated with ferrous sulfate when compared with iron-replete pregnant mice gavaged with IHAT (96.9%, P <0.05). CONCLUSIONS: IHAT has proved a safe and effective alternative to oral ferrous sulfate in mice, and it has potential for treating iron deficiency in human pregnancy.

The Role of Iron and Zinc in the Treatment of ADHD among Children and Adolescents: A Systematic Review of Randomized Clinical Trials.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder common from childhood to adulthood, affecting 5% to 12% among the general population in developed countries. Potential etiological factors have been identified, including genetic causes, environmental elements and epigenetic components. Nutrition is currently considered an influencing factor, and several studies have explored the contribution of restriction and dietary supplements in ADHD treatments. Iron is an essential cofactor required for a number of functions, such as transport of oxygen, immune function, cellular respiration, neurotransmitter metabolism (dopamine production), and DNA synthesis. Zinc is also an essential trace element, required for cellular functions related to the metabolism of neurotransmitters, melatonin, and prostaglandins. Epidemiological studies have found that iron and zinc deficiencies are common nutritional deficits worldwide, with important roles on neurologic functions (poor memory, inattentiveness, and impulsiveness), finicky appetite, and mood changes (sadness and irritability). Altered levels of iron and zinc have been related with the aggravation and progression of ADHD. OBJECTIVE: This is a systematic review focused on the contribution of iron and zinc in the progression of ADHD among children and adolescents, and how therapies including these elements are tolerated along with its effectiveness (according to PRISMA guidelines). METHOD: The scientific literature was screened for randomized controlled trials published between January 2000 to July 2021. The databases consulted were Medline, PsycINFO, Web of Science, and Google Scholar. Two independent reviewers screened studies, extracted data, and assessed quality and risk of bias (CONSORT, NICE, and Cochrane checklists used). CONCLUSION: Nine studies met the eligibility criteria and were selected. Evidence was obtained regarding the contribution of iron-zinc supplementation in the treatment of ADHD among young individuals. The discussion was focused on how the deficits of these elements contribute to affectation on multiple ADHD correlates, and potential mechanisms explaining the mediational pathways. Evidence also suggested that treating ADHD with diet interventions might be particularly useful for specific subgroups of children and adolescents, but further investigations of the effects of these diet interventions are needed.

Laser-triggered combination therapy by iron sulfide-doxorubicin@functionalized nanozymes for breast cancer therapy.

BACKGROUND: The use of magnetic nanozymes (NZs) with the ability to synchronize gas therapy through photodynamic and chemotherapy in the treatment of breast cancer has received much attention. RESULTS: Hence, in this study, we designed a bovine lactoferrin-coated iron sulfide NZs containing doxorubicin (abbreviated as: FeS-Dox@bLf NZs) by wet-chemical synthesis method. Then, the physicochemical characteristics of synthesized NZs were explored by several methods. Also, the level of Fe2+, H2S and Dox releases from FeS-Dox@Lf NZs. Also, the cytotoxic effects of FeS-Dox@Lf NZs were investigated by cellular assays. After intravenous injections of NZs and laser irradiation, significant effects of FeS-Dox@Lf NZs on mice weight and tumor status were observed. Afterwards, not only the distribution of Dox in the body was examined by fluorescent, but also the time of Fe clearance and the amount of Dox and Fe retention in vital tissues were determined. The findings confirm that FeS-Dox@Lf NZs, in addition to targeted drug distribution in tumor tissue, resulted in superior therapeutic performance compared to free Dox due to reduced Dox side effects in vital tissues, and increased level of free radicals in 4T1 cells. CONCLUSION: Overall, FeS-Dox@Lf NZs with the ability to synchronize chemotherapy and gas therapy raised hopes for more effective treatment of breast cancer.

Comparative Evaluation of Sucrosomial Iron and Iron Oxide Nanoparticles as Oral Supplements in Iron Deficiency Anemia in Piglets.

Iron deficiency is the most common mammalian nutritional disorder. However, among mammalian species iron deficiency anemia (IDA), occurs regularly only in pigs. To cure IDA, piglets are routinely injected with high amounts of iron dextran (FeDex), which can lead to perturbations in iron homeostasis. Here, we evaluate the therapeutic efficacy of non-invasive supplementation with Sucrosomial iron (SI), a highly bioavailable iron supplement preventing IDA in humans and mice and various iron oxide nanoparticles (IONPs). Analysis of red blood cell indices and plasma iron parameters shows that not all iron preparations used in the study efficiently counteracted IDA comparable to FeDex-based supplementation. We found no signs of iron toxicity of any tested iron compounds, as evaluated based on the measurement of several toxicological markers that could indicate the occurrence of oxidative stress or inflammation. Neither SI nor IONPs increased hepcidin expression with alterations in ferroportin (FPN) protein level. Finally, the analysis of the piglet gut microbiota indicates the individual pattern of bacterial diversity across taxonomic levels, independent of the type of supplementation. In light of our results, SI but not IONPs used in the experiment emerges as a promising nutritional iron supplement, with a high potential to correct IDA in piglets.

Does the Combined Effect of Resistance Training with EPO and Iron Sulfate Improve Iron Metabolism in Older Individuals with End-Stage Renal Disease?

We sought to investigate the effects of resistance training (RT) combined with erythropoietin (EPO) and iron sulfate on the hemoglobin, hepcidin, ferritin, iron status, and inflammatory profile in older individuals with end-stage renal disease (ESRD). ESRD patients (n: 157; age: 66.8 ± 3.6; body mass: 73 ± 15; body mass index: 27 ± 3), were assigned to control (CTL; n: 76) and exercise groups (RT; n: 81). The CTL group was divided according to the iron treatment received: without iron treatment (CTL-none; n = 19), treated only with iron sulfate or EPO (CTL-EPO or IRON; n = 19), and treated with both iron sulfate and EPO (CTL-EPO + IRON; n = 76). The RT group followed the same pattern: (RT-none; n = 20), (RT-EPO or IRON; n = 18), and (RT-EPO + IRON; n = 86). RT consisted of 24 weeks/3 days per week at moderate intensity of full-body resistance exercises prior to the hemodialysis section. The RT group, regardless of the iron treatment, improved iron metabolism in older individuals with ESRD. These results provide some clues on the effects of RT and its combination with EPO and iron sulfate in this population, highlighting RT as an important coadjutant in ESRD-iron deficiency.

Síndrome de Plummer-Vinson / Plummer-Vinson syndrome

Introducción: El síndrome de Plummer-Vinson es una entidad rara caracterizada por la tríada anemia ferropénica, disfagia y membrana esofágica. Descrito en la segunda década del siglo pasado, en la actualidad la mayoría de los datos que se obtienen provienen de presentaciones de casos o pequeñas series de estudios prospectivos. Objetivo: Hacer la revisión de la bibliografía disponible a propósito de un caso portador de síndrome de Plummer-Vinson. Caso clínico: Paciente femenina de 35 años de edad con anemia desde la adolescencia remitida por presentar disfagia de 8 años de evolución. Se realizaron complementarios de laboratorio donde se constata anemia ferropénica y estudio contrastado del tracto digestivo superior que reveló imagen sugestiva de membrana en esófago cervical. Conclusiones: A pesar de su baja frecuencia en la actualidad debemos mantenernos alertas ante la aparición de síntomas sugestivos del síndrome de Plummer-Vinson fundamentalmente en mujeres con cuadros de anemia(AU)

Introduction: Plummer-Vinson syndrome is a rare entity characterized by the triad of iron deficiency anemia, dysphagia and esophageal membrane. Described in the second decade of the last century, today most of the data obtained comes from case presentations or small series of prospective studies. Objective: To review the available bibliography regarding a case with Plummer-Vinson syndrome. Clinical case: 35-year-old female patient with anemia since adolescence, referred to surgery clinic for presenting dysphagia of 8 years of evolution. Additional laboratory tests were carried out where iron deficiency anemia was found. A contrasted study of the upper digestive tract revealed a suggestive image of a membrane in the cervical esophagus. Conclusions: Despite its low frequency we must be alert to the appearance of symptoms suggestive of Plummer-Vinson syndrome, mainly in women with anemia. Its association with esophageal cancer indicates this(AU)

Iron distribution in different tissues of homozygous Mask (msk/msk) mice and the effects of oral iron treatments.

Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive disorder caused by genetic mutations on TMPRSS6 gene which encodes Matriptase2 (MT2). An altered MT2 cannot appropriately suppress hepatic BMP6/SMAD signaling in case of low iron, hence hepcidin excess blocks dietary iron absorption, leading to a form of anemia resistant to oral iron supplementation. In this study, using the IRIDA mouse model Mask, we characterized homozygous (msk/msk) compared to asymptomatic heterozygous (msk/wt) mice, assessing the major parameters of iron status in different organs, at different ages in both sexes. The effect of carbonyl iron diet was analyzed as control iron supplementation being used for many studies in mice. It resulted effective in both anemic control and msk/msk mice, as expected, even if there is no information about its mechanism of absorption. Then, we mainly compared two forms of oral iron supplement, largely used for humans: ferrous sulfate and Sucrosomial iron. In anemic control mice, the two oral formulations corrected hemoglobin levels from 11.40 ± 0.60 to 15.38 ± 1.71 g/dl in 2-4 weeks. Interestingly, in msk/msk mice, ferrous sulfate did not increase hemoglobin likely due to ferroportin/hepcidin-dependent absorption, whereas Sucrosomial iron increased it from 11.50 ± 0.60 to 13.53 ± 0.64 g/dl mainly in the first week followed by a minor increase at 4 weeks with a stable level of 13.30 ± 0.80 g/dl, probably because of alternative absorption. Thus, Sucrosomial iron, already used in other conditions of iron deficiency, may represent a promising option for oral iron supplementation in IRIDA patients.

Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia.

Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.

Iron preparations for women of reproductive age with iron deficiency anaemia in pregnancy (FRIDA): a systematic review and network meta-analysis.

BACKGROUND: Numerous iron preparations are available for the treatment of iron deficiency anaemia in pregnancy. We aimed to provide a summary of the effectiveness and safety of iron preparations used in this setting. METHODS: We did a systematic review and network meta-analysis of randomised trials. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, trial registers, and grey literature for trials published in any language from Jan 1, 2011, to Feb 28, 2021. We included trials including pregnant women with iron deficiency anaemia and evaluating iron preparations, irrespective of administration route, with at least 60 mg of elemental iron, in comparison with another iron or non-iron preparation. Three authors independently selected studies, extracted data, and did a risk of bias assessment using the Cochrane tool (version 1.0). The primary outcome was the effectiveness of iron preparations, evaluated by changes in haemoglobin concentration at 4 weeks from baseline. The secondary outcomes were change in serum ferritin concentration at 4 weeks from baseline and treatment-related severe and non-severe adverse events. We did random-effects pairwise and network meta-analyses. Side-effects were reported descriptively for each trial. This study is registered with PROSPERO, CRD42018100822. FINDINGS: Among 3037 records screened, 128 full-text articles were further assessed for eligibility. Of the 53 eligible trials (reporting on 9145 women), 30 (15 interventions; 3243 women) contributed data to the network meta-analysis for haemoglobin and 15 (nine interventions; 1396 women) for serum ferritin. The risk of bias varied across the trials contributing to network meta-analysis, with 22 of 30 trials in the network meta-analysis for haemoglobin judged to have a high or medium global risk of bias. Compared with oral ferrous sulfate, intravenous iron sucrose improved both haemoglobin (mean difference 7·17 g/L, 95% CI 2·62-11·73; seven trials) and serum ferritin (mean difference 49·66 µg/L, 13·63-85·69; four trials), and intravenous ferric carboxymaltose improved haemoglobin (mean difference 8·52 g/L, 0·51-16·53; one trial). The evidence for other interventions compared with ferrous sulfate was insufficient. The most common side-effects with oral iron preparations were gastrointestinal effects (nausea, vomiting, and altered bowel movements). Side-effects were less common with parenteral iron preparations, although these included local pain, skin irratation, and, on rare occasions, allergic reactions. INTERPRETATION: Iron preparations for treatment of iron deficiency anaemia in pregnancy vary in effectiveness, with good evidence of benefit for intravenous iron sucrose and some evidence for intravenous ferric carboxymaltose. Clinicians and policy makers should consider the effectiveness of individual preparations before administration, to ensure effective treatment. FUNDING: None.

Addition of oral iron bisglycinate to intravenous iron sucrose for the treatment of postpartum anemia-randomized controlled trial.

BACKGROUND: Studies that have compared the effectiveness of oral with intravenous iron supplements to treat postpartum anemia have shown mixed results. The superiority of one mode of treatment vs the other has yet to be demonstrated. Therefore, despite guidelines and standards of care, treatment approaches vary across practices. A single 500 mg dose of iron sucrose, which is higher than what is usually administered, has not been evaluated to treat postpartum moderate to severe anemia. OBJECTIVE: This study aimed to compare the efficacy of intravenous iron sucrose alone with intravenous iron sucrose in combination with oral iron bisglycinate supplementation in treating moderate to severe postpartum anemia. STUDY DESIGN: A randomized controlled trial was conducted between February 2015 and June 2020. Women with postpartum hemoglobin level of ≤9.5 g/dL were treated with 500 mg intravenous iron sucrose after an anemia workup, which ruled out other causes for anemia. In addition to receiving intravenous iron, women were randomly allocated to receive either 60 mg of oral iron bisglycinate for 45 days or no further iron supplementation. The primary outcome was hemoglobin level at 6 weeks after delivery. Secondary outcomes were iron storage parameters and quality of life. RESULTS: Of 158 patients who participated, 63 women receiving intravenous and oral iron, and 44 women receiving intravenous iron-only, completed the study and were included in the analysis. Baseline and obstetrical characteristics were similar between the study cohorts. Although statistically significant, postpartum hemoglobin levels were only 0.4 g/dL higher in the intravenous and oral iron than intravenous iron-only cohort (12.4 g/dL vs 12.0 g/dL, respectively; P=.03), with a respective increase from baseline of 4.2 g/dL vs 3.7 g/dL (P=.03). There was no difference in the rate of women with hemoglobin level of <12.0 or 11.0 g/dL. Iron storage and health quality were not different between the cohorts. Oral iron treatment was associated with 29% rate of adverse effects. Compliance and satisfaction from treatment protocol were high in both cohorts. CONCLUSION: Intravenous 500 mg iron sucrose treatment alone is sufficient to treat postpartum anemia without the necessity of adding oral iron treatment.

Supramolecular Polymerization-Induced Nanoassemblies for Self-Augmented Cascade Chemotherapy and Chemodynamic Therapy of Tumor.

The clinical application of chemodynamic therapy is impeded by the insufficient intracellular H2 O2 level in tumor tissues. Herein, we developed a supramolecular nanoparticle via a simple one-step supramolecular polymerization-induced self-assembly process using platinum (IV) complex-modified ß-cyclodextrin-ferrocene conjugates as supramolecular monomers. The supramolecular nanoparticles could dissociate rapidly upon exposure to endogenous H2 O2 in the tumor and release hydroxyl radicals as well as platinum (IV) prodrugs in situ, which is reduced into cisplatin to significantly promote the generation of H2 O2 in the tumor tissue. Thus, the supramolecular nanomedicine overcomes the limitation of conventional chemodynamic therapy via the self-augmented cascade radical generation and drug release. In addition, dissociated supramolecular nanoparticles could be readily excreted from the body via renal clearance to effectively avoid systemic toxicity and ensure long term biocompatibility of the nanomedicine. This work may provide new insights on the design and development of novel supramolecular nanoassemblies for cascade chemo/chemodynamic therapy.

Iron Protein Succinylate in the Management of Iron Deficiency Anemia: A Comparative Study with Ferrous Sulphate at Low and High Therapeutic Doses.

Oral iron supplementation constitutes the first line treatment for iron deficiency anemia (IDA), with daily doses between 80 mg and 200 mg of elemental iron. Ferrous salts, such as ferrous sulphate (FeSO4), while efficacious, frequently give rise to gastrointestinal side effects. In the present paper we attempted to directly compare the efficacy of an alternative to the FeSO4 formulation, which presents a better tolerability profile, iron protein succinylate (Ferplex®). In a diet-induced anemia model, rats were treated by oral gavage with vehicle, FeSO4, or Ferplex® at a human-dose equivalent of 80 mg and 200 mg of elemental iron. We evaluated the change in anemia-related hematological and biochemical parameters, conducting a histological examination of the intestine at sacrifice. Results indicate that both types of iron supplementation are equally effective in the treatment of IDA, restoring hemoglobin, hematocrit, erythrocytes, free iron and transferrin levels in 15 days, with no statistical differences between treated groups and control. The impact of anemia on body weight was also attenuated following treatment with both iron supplements. Thrombocyte and reticulocyte levels, altered by the anemic condition, returned to homeostasis after 15 days of either FeSO4 or Ferplex® treatment. Importantly, the lower and higher doses of iron were equally effective, thus supporting the current school of thought which states that lower therapeutic doses are sufficient for management of IDA. In addition, the study shows for the first time that oral treatment with Ferplex® does not increase serum hepcidin. Finally, Ferplex® induced minimal iron depositions in the intestinal tissue compared to FeSO4.

5-aminolevulinic acid combined with sodium ferrous citrate ameliorated lupus nephritis in a mouse chronic graft-versus-host disease model.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the abnormal activation of immune cells and hypersecretion of autoantibodies and causes irreversible chronic damage, such as lupus nephritis. Chronic graft-versus-host-disease (cGvHD) in mice induced by the injection of parental mouse lymphocytes into F1 hybrids leads to a disease similar to SLE. 5-aminolevulinic acid (5-ALA) is a key progenitor of heme, and its combination with sodium ferrous citrate (SFC) can up-regulate the heme oxygenase (HO-1) expression, resulting in an anti-inflammatory effect. While HO-1 had been reported to be involved in T cell activation and can limit immune-based tissue damage through Treg suppression, which promotes effector response. Thus, we hypothesized that treatment with 5-ALA/SFC could ameliorate lupus nephritis in a mouse cGvHD model. Our results showed that 5-ALA/SFC-treatment significantly decreased the anti-double-stranded DNA (ds-DNA) autoantibodies, blood urea nitrogen (BUN) and creatinine (Cre) levels, reduced kidney inflammatory dendritic cells (DCs) and B cell activation, and increased the regulatory T cells (Tregs) at nine weeks. Furthermore, 5-ALA/SFC suppressed mRNA expression of TNF-α, IL-1ß, IFN-γ and markers on DCs. In addition, we also found that 5-ALA/SFC treatment increased the HO-1 expression on donor-derived DCs and Tregs concurrently, increased the number of Tregs, and reduced the population of activated DCs, B cells and CD8+ T cells at three weeks (early stage of the disease). We thus identified a novel role of 5-ALA/SFC for therapeutically improving the symptoms of lupus nephritis in a mouse cGvHD model and expanded the current understanding of how this immunoregulatory agent can be used to generate beneficial immune responses and treat autoimmune disease.

Intravenous iron infusion and newer non-dextran formulations.

There are several newer intravenous iron formulations to treat iron deficiency and its anaemia. Its use in the primary care setting has been infrequent compared to tertiary centres, due to historical concerns such as anaphylaxis. There is a lack of overall comparison among the intravenous formulations of iron. Compared to oral iron therapy, the newer intravenous formulations, which allow a complete or near-complete replacement in a single sitting of 15-30 minutes, have an improved safety profile with better tolerability, efficacy and effectiveness. They are suited for administration in the primary care setting. The four non-dextran formulations (ferric carboxymaltose, iron sucrose, iron isomaltoside and ferumoxytol) share an equal or near equal efficacy and safety profile. This article also outlines how to provide iron infusion safely and effectively in the community.

Ferric carboxymaltose vs. ferrous sulfate for the treatment of anemia in advanced chronic kidney disease: an observational retrospective study and cost analysis.

In non-dialysis-dependent chronic kidney disease (NDD-CKD), erythropoiesis-stimulating agents (ESAs) and iron supplementation are essential for anemia management. Ferric carboxymaltose (FCM) is a relatively novel intravenous iron formulation used in different clinical settings, although scarce data exist in NDD-CKD patients. Primary objective of this study was to retrospectively evaluate the efficacy of FCM compared with oral ferrous sulfate for the treatment of iron-deficiency anemia in a cohort of NDD-CKD patients, considering also the treatment costs. This was a monocentric, retrospective observational study reviewing 349 NDD-CKD patients attending an outpatient clinic between June 2013 and December 2016. Patients were treated by either FCM intravenous infusion or oral ferrous sulfate. We collected serum values of hemoglobin, ferritin and transferrin saturation (TSAT) and ESAs doses at 12 and 18 months. The costs related to both treatments were also analysed. 239 patients were treated with FCM intravenous infusion and 110 patients with oral ferrous sulfate. The two groups were not statistically different for age, BMI and eGFR values. At 18 months, hemoglobin, serum ferritin and TSAT values increased significantly from baseline in the FCM group, compared with the ferrous sulfate group. ESAs dose and rate of infusion decreased only in the FCM group. At 18 months, the treatment costs, analysed per week, was higher in the ferrous sulfate group, compared with the FCM group, and this was mostly due to a reduction in ESAs prescription in the FCM group. Routine intravenous FCM treatment in an outpatient clinic of NDD-CKD patients results in better correction of iron-deficiency anemia when compared to ferrous sulfate. In addition to this, treating NDD-CKD patients with FCM leads to a significant reduction of the treatment costs by reducing ESAs use.

Efficacy and safety of ferric citrate hydrate compared with sodium ferrous citrate in Japanese patients with iron deficiency anemia: a randomized, double-blind, phase 3 non-inferiority study.

Oral iron preparations are used as first-line treatment for iron deficiency anemia (IDA), but their gastrointestinal side effects prevent patients from appropriate adherence. We recently conducted a randomized, double-blind, phase 3 non-inferiority study to evaluate the efficacy and safety of two dosages of ferric citrate hydrate (FC) compared with sodium ferrous citrate (SF) in patients with IDA. FC at both 500 and 1000 mg/day was non-inferior to SF at 100 mg/day in terms of the change in the hemoglobin concentration at Week 7 from baseline. Logistic regression analysis suggested that the cumulative proportion of patients who achieved the target hemoglobin concentration (≥ 13.0 g/dL in male patients and ≥ 12.0 g/dL in female patients) at Week 7 was highest among those treated with FC at 1000 mg/day, followed by SF at 100 mg/day and FC at 500 mg/day. Both dosages of FC were well tolerated in patients with IDA. The incidences of nausea and vomiting were significantly lower in the FC treatment groups than in the SF group. In conclusion, FC has potential to be an oral iron preparation with sufficient efficacy for the treatment of IDA and a lower risk of nausea and vomiting.

Impact of iron fortification on anaemia and iron deficiency among pre-school children living in Rural Ghana.

Anaemia in young sub-Saharan African children may be due to the double burden of malaria and iron deficiency. Primary analysis of a double-blind, cluster randomized trial of iron containing micronutrient powder supplementation in Ghanaian children aged 6 to 35 months found no difference in malaria risk between intervention and placebo groups. Here, we performed a secondary analysis of the trial data to assess the impact of long-term prophylactic iron fortificant on the risk of iron deficiency and anaemia in trial subjects. This population-based randomized-cluster trial involved 1958 children aged between 6 to 35 months, identified at home and able to eat semi-solid foods. The intervention group (n = 967) received a daily dose containing 12.5 mg elemental iron (as ferrous fumarate), vitamin A (400 µg), ascorbic acid (30 mg) and zinc (5 mg). The placebo group (n = 991) received a similar micronutrient powder but without iron. Micronutrient powder was provided daily to both groups for 5 months. At baseline and endline, health assessment questionnaires were administered and blood samples collected for analysis. The two groups had similar baseline anthropometry, anaemia, iron status, demographic characteristics, and dietary intakes (p > 0.05). Of the 1904 (97.2%) children who remained at the end of the intervention, the intervention group had significantly higher haemoglobin (p = 0.0001) and serum ferritin (p = 0.0002) levels than the placebo group. Soluble transferrin receptor levels were more saturated among children from the iron group compared to non-iron group (p = 0.012). Anaemia status in the iron group improved compared to the placebo group (p = 0.03). Continued long-term routine use of micronutrient powder containing prophylactic iron reduced anaemia, iron deficiency and iron deficiency anaemia among pre-school children living in rural Ghana's malaria endemic area.