Haem iron versus ferrous iron salts to treat iron deficiency anaemia in Gambian children: protocol for randomised controlled trial {1}.

BACKGROUND: The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable, and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation. METHODS: This will be a two-arm, randomised controlled trial. Gambian children aged 6-12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0 mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team (see Bah et al. Additional file 4_Adverse event eCRF). Linear regression will be used to analyse continuous outcomes, with log transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor). DISCUSSION: This study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6-12 months. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR202210523178727.

A randomized double-blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia.

Restless legs syndrome (RLS) is a neurological disorder that can have a profound effect on sleep and quality of life. Idiopathic RLS is associated with brain iron insufficiency despite normal peripheral iron stores. There is, however, a five- to six-fold increase in prevalence of RLS in patients with iron deficiency anemia (IDA). Several open-label trials have demonstrated symptomatic improvement in RLS following treatment of IDA using oral or intravenous iron supplementation. To date, there have been no randomized double-blind controlled trials of intravenous iron compared with oral iron for the treatment of RLS patients with IDA. In the current study, oral ferrous sulfate and ferumoxytol were compared for efficacy and speed of response for treatment of RLS occurring in patients with IDA. The planned recruitment for this study was 70 patients with RLS and IDA, to be randomly assigned 1:1 to oral or intravenous iron, using double-blind, double-dummy procedures. At Week 6, the primary outcomes of Clinical Global Impression-Improvement score and change from baseline in the International Restless Legs Syndrome Study Group rating scale score were assessed. Due to challenges, performing the clinical trial during the COVID-19 pandemic, final-week data were found missing for 30 patients. As a result, in order to maintain the prespecified statistical analysis, an additional 30 patients were recruited. Both IV and oral iron were associated with a marked improvement in RLS symptoms, with no statistically significant difference between treatment groups. No serious adverse events were observed in either treatment group.

Tolerability of Oral Supplementation with Microencapsulated Ferric Saccharate Compared to Ferrous Sulphate in Healthy Premenopausal Woman: A Crossover, Randomized, Double-Blind Clinical Trial.

A single-center, crossover, randomized, double-blind, and controlled clinical study was conducted to assess the tolerability profile, especially with regard to gastrointestinal complaints, of oral supplementation with AB-Fortis®, a microencapsulated ferric saccharate (MFS), as compared with conventional ferrous sulphate (FS) in healthy premenopausal women. A dose of 60 mg/day of elemental iron was used. The test products were administered for 14 consecutive days with a washout period of two menstrual episodes and a minimum of one month between the two intervention periods. The subjects completed simple-to-answer questionnaires daily for 14 days during both the intervention and the washout periods, capturing the symptoms associated with oral iron supplementation and overall health aspects. Following product consumption, the incidences of symptoms, numbers of complaints/symptoms, overall intensity, and total days with symptoms were found to be significantly higher for FS consumption as compared to MFS. The better tolerability profile of MFS over FS was further substantiated when both products were compared to a real-life setting (i.e., the washout period). Overall, the administration of both study products was safe with no serious or significant adverse events reported. In summary, the current study shows the better tolerability of the MFS preparation when compared to that of the FS, presenting MFS as a well-tolerated and safe option for improving iron nutrition.

Lactoferrin for iron-deficiency anemia in children with inflammatory bowel disease: a clinical trial.

BACKGROUND: Iron-deficiency anemia (IDA) is common in children with inflammatory bowel disease (IBD); however, oral iron supplements are commonly associated with poor compliance due to gastrointestinal side effects. We compared the effect of lactoferrin versus oral ferrous sulfate for the treatment of IDA in children with IBD. METHODS: Ninety-two IBD children with IDA were included but only 80 children completed the study and they were randomized into two groups: ferrous sulfate group (n = 40) who received ferrous sulfate 6 mg/kg/day for 3 months and lactoferrin group (n = 40) who received lactoferrin 100 mg/day for 3 months. Complete blood count, serum iron, total iron-binding capacity (TIBC), transferrin saturation (TS), serum ferritin, interleukin-6 (IL-6), and hepcidin 25 were measured before and after the treatment. RESULTS: Hemoglobin (Hb), mean corpuscular volume, serum iron, TS, and serum ferritin significantly increased, while TIBC decreased significantly after the administration of either ferrous sulfate or lactoferrin compared to their baseline data. In addition, lactoferrin significantly increased Hb, serum iron, TS, and serum ferritin compared to ferrous sulfate. Moreover, lactoferrin significantly decreased IL-6 and hepcidin levels. CONCLUSION: Lactoferrin is a promising effective treatment with fewer side effects than oral elemental iron in children with IBD and IDA. CLINICAL TRIAL REGISTRATION: The study was registered at www.pactr.org (PACTR202002763901803). IMPACT: Iron-deficiency anemia (IDA) in children with inflammatory bowel disease (IBD) is treated with oral iron therapy; however, oral iron supplements are commonly associated with poor compliance due to gastrointestinal side effects. To the best of our knowledge, our study was the first in pediatrics that compared the effect of lactoferrin versus oral ferrous sulfate as an iron supplement for the treatment of IDA in children with IBD. We found that lactoferrin is a promising effective treatment with fewer side effects than oral elemental iron in children with IBD and IDA.

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.

Iron pill-induced duodenitis: A distinct pattern of duodenal mucosal injury in a patient with a duodenal mass.

Ferrous sulfate is an oral iron supplement commonly used to treat iron deficiency anemia. Upper gastrointestinal (GI) tract mucosal damage with associated tissue iron accumulation can sometimes occur with therapeutic dosages of oral iron-containing medications. A distinct histologic pattern of iron deposition with associated inflammatory and reactive changes caused by mucosal injury from oral iron-containing medications has been most commonly described within gastric biopsies and has been referred to as "iron-pill gastritis". There have only been very rare reports of duodenal mucosa biopsies demonstrating predominantly extracellular crystalline iron deposits with surrounding tissue inflammation and injury analogous to the "iron-pill gastritis" pattern. Here we report a case of "iron pill-induced duodenitis", an uncommon histologic pattern of duodenal iron deposition and mucosal injury seen in a female in her 50 s with clinical findings of a duodenal mass.

Monitoring oral iron therapy in children with iron deficiency anemia: an observational, prospective, multicenter study of AIEOP patients (Associazione Italiana Emato-Oncologia Pediatrica).

Oral ferrous salts are standard treatment for children with iron deficiency anemia (IDA). The objective of our study was to monitor oral iron therapy in children, aged 3 months-12 years, with IDA. We prospectively collected clinical and hematological data of children with IDA, from 15 AIEOP (Associazione Italiana di Ematologia ed. Oncologia Pediatrica) centers. Response was measured by the increase of Hb from baseline. Of the 107 analyzed patients, 18 received ferrous gluconate/sulfate 2 mg/kg (ferrous 2), 7 ferrous gluconate/sulfate 4 mg/kg (ferrous 4), 7 ferric iron salts 2 mg/kg (ferric), 62 bis-glycinate iron 0.45 mg/kg (glycinate), and 13 liposomal iron 0.7-1.4 mg/kg (liposomal). Increase in reticulocytes was evident at 3 days, while Hb increase appeared at 2 weeks. Gain of Hb at 2 and 8 weeks revealed a higher median increase in both ferrous 2 and ferrous 4 groups. Gastro-intestinal side effects were reported in 16% (ferrous 2), 14% (ferrous 4), 6% (glycinate), and 0 (ferric and liposomal) patients. The reticulocyte counts significantly increased after 3 days from the start of oral iron supplementation. Bis-glycinate iron formulation had a good efficacy/safety profile and offers an acceptable alternative to ferrous iron preparations.

Nonclinical evaluation of IQG-607, an anti-tuberculosis candidate with potential use in combination drug therapy.

New effective compounds to treat tuberculosis are urgently needed. IQG-607 is an orally active anti-tuberculosis drug candidate, with promising preliminary safety profile and anti-mycobacterial activity in both in vitro and in vivo models of tuberculosis infection. Here, we evaluated the mutagenic and genotoxic effects of IQG-607, and its interactions with CYP450 isoforms. Moreover, we describe for the first time a combination study of IQG-607 in Mycobacterium tuberculosis-infected mice. Importantly, IQG-607 had additive effects when combined with the first-line anti-tuberculosis drugs rifampin and pyrazinamide in mice. IQG-607 presented weak to moderate inhibitory potential against CYP450 isoforms 3A4, 1A2, 2C9, 2C19, 2D6, and 2E1. The Salmonella mutagenicity test revealed that IQG-607 induced base pair substitution mutations in the strains TA100 and TA1535. However, in the presence of human metabolic S9 fraction, no mutagenic effect was detected in any strain. Additionally, IQG-607 did not increase micronucleus frequencies in mice, at any dose tested, 25, 100, or 250 mg/kg. The favorable activity in combination with first-line drugs and mild to moderate toxic events described in this study suggest that IQG-607 represents a candidate for clinical development.

Comparative liver function assessment of natural and available drug (Ferrous sulfate) for iron-deficiency anemia in rat model.

To assess the comparative effect of anti-anaemic drug (ferrous sulfate) with naturally occurring anti-anaemic compound (Illicium verum commonly called star anise) on liver in rat model. Model and both test groups were made anaemic. Ferrous sulfate was given to T1 group of rats as 30mg/kg body weight (b.w) and Illicium verum to T2 group of rats with dose of 80mg/kg b.w for six weeks. Illicium verum treated group (T2 rats) produced depression, decreased anxiety and enhanced short-term memory, whereas ferrous sulfate treated group (T1 rats) enhanced long term memory. The liver function test of T2 rats showed that the total bilirubin was in normal range, but direct bilirubin, SGPT, ALP and GGT were significantly decreased in T2 rats in comparison with T1 and also from model group of rats. It was concluded in this study that by comparing the effect of ferrous sulfate with naturally occurring Illicium verum on iron-defficiency anaemia, illicium verum produces same effects and can be used to treat iron-defficiency anaemia without affecting liver function.

Single versus Split Dose of Iron Optimizes Hemoglobin Mass Gains at 2106 m Altitude.

PURPOSE: To determine if a single versus a split equivalent daily dose of elemental iron was superior for hemoglobin mass (Hbmass) gains at altitude while minimizing gastrointestinal (GI) discomfort. METHODS: Twenty-four elite runners attended a 3.1 ± 0.3 wk training camp (Flagstaff, AZ; 2106 m). A two-group design, randomized and stratified to baseline Hbmass, sex, and ferritin (>30 µ·L), was implemented daily as: 1) single dose of 1 × 200 mg (PM only, SINGLE) versus 2) split dose of 2 × 100 mg (AM and PM; SPLIT) elemental iron (ferrous fumarate). The Hbmass and venipuncture assessments were completed upon arrival and departure (±2 d) from camp for ferritin, hepcidin, and erythroferrone (ERFE) concentrations. Validated food frequency, GI distress, menstrual blood loss (MBL) and training questionnaires were implemented throughout. Univariate analysis was used to compare Hbmass, with baseline ferritin, dietary iron intake, MBL, and training volume used as covariates. RESULTS: Both conditions increased Hbmass from baseline (P < 0.05), with SINGLE (867.3 ± 47.9 g) significantly higher than SPLIT (828.9 ± 48.9 g) (P = 0.048). The GI scores were worse in SINGLE for weeks 1 and 2 combined (SINGLE, 18.0 ± 6.7 points; SPLIT, 11.3 ± 6.9 points; P = 0.025); however, GI scores improved by week 3, resulting in no between-group differences (P = 0.335). Hepcidin significantly decreased over time (P = 0.043) in SINGLE, with a nonsignificant decrease evident in SPLIT (~22%). ERFE significantly decreased in both groups (~28.5%; P < 0.05). No between-group differences existed for ERFE, hepcidin, food frequency, MBL, or daily training outcomes (P > 0.05). CONCLUSIONS: A single nightly 200-mg dose of elemental iron was superior to a split dose for optimizing Hbmass changes at altitude in runners over an approximately 3-wk training camp.

Effectiveness of a Program Intervention with Reduced-Iron Multiple Micronutrient Powders on Iron Status, Morbidity and Growth in Young Children in Ethiopia.

Despite the potential for improving iron status and child growth in low- and middle-income settings, concerns on the safety of high iron dosages of Micronutrient Powders (MNP currently limit their applicability in programs. We examined the effectiveness and risks of an integrated complementary feeding program with low iron dose (6 mg/serving) MNP among 6⁻23-month-old Ethiopian children using a quasi-experimental study design comparing children from five intervention districts (n = 1172) to those from four matched non-intervention districts (n = 1137). Haemoglobin concentrations increased in intervention and decreased in non-intervention children (group-difference +3.17 g/L), but without improvement in iron stores. Intervention children were 2.31 times more likely to have diarrhoea and 2.08 times more likely to have common cold and flu, but these differences decreased towards the end of the intervention. At end line, intervention children had higher mean Height-for-Age Zscore (HAZ) and a 51% reduced odds of being stunted compared to non-intervention children. MNP with low iron dose, when provided combined with other Infant and Young Child Feeding (IYCF) interventions, marginally improved haemoglobin status and resulted in a remarkable improvement in linear growth in 6⁻23-month-old children. These benefits likely outweigh the relatively small increase in the risk of diarrhoea.

Dual action of vitamin C in iron supplement therapeutics for iron deficiency anemia: prevention of liver damage induced by iron overload.

Vitamin C, an excellent reducing agent, aids in increasing absorbable ferrous iron in iron deficiency anemia. As an efficient antioxidant, it is still unknown whether vitamin C exerts protective effects against liver damage caused by iron excess and whether mitochondria are the target effectors of the above effects. In this study, 48 mice were randomly divided into a control group, iron-overload group, TAU-treated + iron-overload group and vitamin C-treated + iron-overload group with 12 mice per group. The mice were fed 4 months on pellet diets supplemented with iron in the form of ferrocene. The iron ratio in the diet was maintained at 0.2% (w/w) for 90 days and then 0.4% (w/w) for the remaining 30 days. Furthermore, 2 g kg-1 vitamin C and 20 mg kg-1 TAU were administered daily by oral gavage prior to iron-overload administration at 6 weeks and throughout the course of the experiments. We investigated the protective effects of vitamin C against liver damage by assessing the liver weight to body weight ratio (LW/BW), serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and histological changes. In addition, enzymatic and non-enzymatic antioxidants, reactive oxygen species (ROS) generation, mitochondrial swelling, and mitochondrial membrane potential (MMP) were evaluated to clarify the antioxidant effects of vitamin C. We found that vitamin C significantly attenuated impaired liver function in mice induced by iron overload via antioxidation, whereas no significant effect on iron uptake was observed. Vitamin C targeted the mitochondria, preventing mitochondrial swelling, MMP dissipation, and ROS burst, thus inhibiting hepatic apoptosis. Collectively, our results suggest that vitamin C acts as a "double agent" in iron supplementation therapy for iron deficiency anemia, boosting iron absorption for preventing iron deficiency and preventing liver damage due to excessive iron intake during treatment.

Sucrosomial® Iron Supplementation in Mice: Effects on Blood Parameters, Hepcidin, and Inflammation.

Sucrosomial® Iron is a recently developed formulation to treat iron deficiency based on ferric pyrophosphate covered by a matrix of phospholipids plus sucrose esters of fatty acids. Previous data indicated that Sucrosomial® Iron is efficiently absorbed by iron-deficient subjects, even at low dosage, and without side effects. Its structural properties may suggest that it is absorbed by an intestinal pathway which is different to the one used by ionic iron. Although, studies in vitro showed that Sucrosomial® Iron is readily absorbed, no animal models have been established to study this important aspect. To this aim, we induced iron deficient anemia in mice by feeding them with a low-iron diet, and then we treated them with either Sucrosomial® Iron or sulfate iron by gavage for up to two weeks. Both iron formulations corrected anemia and restored iron stores in a two-week period, but with different kinetics. Ferrous Sulfate was more efficient during the first week and Sucrosomial® Iron in the second week. Of note, when given at the same concentrations, Ferrous Sulfate induced the expression of hepcidin and four different inflammatory markers (Socs3, Saa1, IL6 and CRP), while Sucrosomial® Iron did not. We conclude that anemic mice are interesting models to study the absorption of oral iron, and that Sucrosomial® Iron is to be preferred over Ferrous Sulfate because of similar absorption but without inducing an inflammatory response.

Free radical scavenging activity of Telfairia occidentalis extracts and their effects on iron-sulphate induced lipid per oxidation.

Non-enzymic natural antioxidants of plant origin are known to play a key role in inflammation linked with free radicals and oxidative stress. This study investigates the free radical scavenging activity of various Telfairia occidentalis leaves extracts in relation to their inhibitory effects on lipid peroxidation. The extracts markedly exhibited antioxidants activity especially the ethyl acetate (EE) and chloroform (CE) extract which scavenged 1,1-diphenyl-2-picryhydraxyl (DPPH) radicals significantly (p<0.05) by 76.34 and 76.62% respectively at 600µ/ml with minimum effects (53.34%) obtained with the methanol (ME) extract. Similarly the extracts scavenged iron/EDTA/H2O2 induced hydroxyl radical formation in a dose-dependent manner as the ME, EE and CE extracts scavenged the radicals at 300µg/ml by 40.55, 24.23 and 19.64% respectively. Interestingly, ME, EE and CE extracts inhibited iron-induced lipid per oxidation significantly (P<0.05) by 93.56, 76.24 and 70.54% respectively at 300µg/ml. Phytochemical analysis showed the presence of phenols and flavonoids at 2.58, 1.98, 3.24 and 0.840, 0.300, 0.400mg/g garlic acid and quercetin equivalence at 300 µg/ml concentrations respectively. Bioactive constituents of the leaves extracts shows antioxidants potentials, radical scavenging and inhibitory effects on lipid per oxidation which were highly expressed in methanol extract and may be a template for drug discovery.

Iron Supplementation in Twin Pregnancy - The Benefit of Doubling the Iron Dose in Iron Deficient Pregnant Women: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy of doubling the daily dose of iron supplement in iron-deficient women with twin pregnancies. STUDY DESIGN: Using a prospective randomized controlled trial, iron-deficient women with twin gestations were randomized to receive a single or a double dose of daily iron from 16 weeks of gestation until 6 weeks postpartum. The primary outcome was hemoglobin at 32 weeks. Secondary outcomes included ferritin at 32 weeks, hemoglobin during pregnancy and postpartum, birth weights, preterm birth rate, gastrointestinal side effects, intravenous iron administration, and compliance with treatment. RESULTS: Eighty-five and 87 women were randomized to receive one capsule (group A) or two capsules (group B) of 34 mg of ferrous sulfate, respectively. Mean hemoglobin (9.6 g/dL and 9.7 g/dL) and ferritin (8.6 ng/ml and 8.5 ng/ml) were similar in both groups A and B, respectively, at allocation. Hemoglobin in group B was significantly higher from 32 weeks onward, until 6 weeks postpartum. There were no significant differences in any of the secondary outcomes examined. CONCLUSIONS: In twin pregnancies complicated by iron deficiency anemia, doubling the dose of iron increases hemoglobin and ferritin without worsening gastrointestinal side effects.

High Consumption of Iron Exacerbates Hyperlipidemia, Atherosclerosis, and Female Sterility in Zebrafish via Acceleration of Glycation and Degradation of Serum Lipoproteins.

Elevated serum iron level is linked with an increased risk of diabetes and atherosclerosis. However, the pathological mechanism by which iron affects serum lipoprotein levels is unknown. To elucidate the mechanism, a high dose of ferrous ion was applied (final 60 µM, 120 µM) to human serum lipoproteins, macrophages, and human dermal fibroblast (HDF) cells. Iron-treated lipoproteins showed loss of antioxidant ability along with protein degradation and multimerization, especially co-treatment with fructose (final 10 mM). In the presence of fructose, HDF cells showed 3.5-fold more severe cellular senescence, as compared to the control, dependent on the dosage of fructose. In macrophages, phagocytosis of acetylated low-density lipoprotein (acLDL) was more accelerated by ferrous ion, occurring at a rate that was up to 1.8-fold higher, than acLDL alone. After 24 weeks supplementation with 0.05% and 0.1% ferrous ion in the diet (wt/wt), serum total cholesterol (TC) level was elevated 3.7- and 2.1-fold, respectively, under normal diet (ND). Serum triglyceride (TG) was elevated 1.4- and 1.7-fold, respectively, under ND upon 0.05% and 0.1% ferrous ion supplementation. Serum glucose level was elevated 2.4- and 1.2-fold under ND and high cholesterol diet (HCD), respectively. However, body weight was decreased by the Fe2+ consumption. Iron consumption caused severe reduction of embryo laying and reproduction ability, especially in female zebrafish via impairment of follicular development. In conclusion, ferrous ion treatment caused more pro-atherogenic, and pro-senescence processes in human macrophages and dermal cells. High consumption of iron exacerbated hyperlipidemia and hyperglycemia as well as induced fatty liver changes and sterility along with reduction of female fertility.

The Safety and Tolerability of 5-Aminolevulinic Acid Phosphate with Sodium Ferrous Citrate in Patients with Type 2 Diabetes Mellitus in Bahrain.

Type 2 diabetes mellitus is prevalent especially in Gulf countries and poses serious long-term risks to patients. A multifaceted treatment approach can include nutritional supplements with antioxidant properties such as 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC). This prospective, randomized, single-blind, placebo-controlled, dose escalating pilot clinical trial assessed the safety of 5-ALA with SFC at doses up to 200 mg 5-ALA/229.42 mg SFC per day in patients living in Bahrain with type 2 diabetes mellitus that was uncontrolled despite the use of one or more antidiabetic drugs. Fifty-three patients (n = 53) from 3 sites at one center were enrolled by Dr. Feryal (Site #01), Dr. Hesham (Site #02), and Dr. Waleed (Site #03) (n = 35, 5-ALA-SFC; n = 18, placebo). There was no significant difference in incidence of adverse events reported, and the most frequent events reported were gastrointestinal in nature, consistent with the known safety profile of 5-ALA in patients with diabetes. No significant changes in laboratory values and no difference in hypoglycemia between patients receiving 5-ALA and placebo were noted. Overall, the current results support that use of 5-ALA-SFC up to 200 mg per day taken as 2 divided doses is safe in patients taking concomitant oral antidiabetic medications and may offer benefits in the diabetic population. This trial is registered with ClinicalTrials.gov NCT02481141.

High-dose intravenously administered iron versus orally administered iron in blood donors with iron deficiency: study protocol for a randomised, controlled trial.

BACKGROUND: About 2-3 % of the population participates in blood donation programmes. Each whole blood donation or ten apheresis donations cause a loss of 200-250 mg of iron. As a result, one of the most common risks of regular blood donors is iron deficiency. Although this has been known for decades, in most countries, iron status is currently not assessed or treated in this population. Premenopausal women are particularly affected, as they have lower iron reserves and higher daily requirements. Besides anaemia, iron deficiency may lead to fatigue and impaired cognitive and physical performance. Current iron preparations for intravenous administration are well tolerated and allow for application of large doses up to 1 g in one visit. Our hypothesis is that in blood donors with iron deficiency, intravenously administered iron is more efficient and as safe as oral iron supplementation. Since anaemia is one of the most frequent reasons for permanent or intermittent donor deferral, maintaining an iron-replete donor pool may help to prevent shortages in blood supply and to avoid iron deficiency-related comorbidities. METHODS/DESIGN: In this randomised clinical trial we include male and female blood donors aged ≥18 and ≤65 years with a ferritin value of ≤30 ng/ml. Stratified by gender, participants are randomized with a web-based randomisation tool in a 1:1 ratio to either 1 g of intravenously administered ferric carboxymaltose or 10 g of iron fumarate supplements at one to two daily doses of 100 mg each. Eight to 12 weeks after the first visit, iron status, blood count and symptoms are assessed in both groups. The primary endpoint is the difference in transferrin saturation (%) following the intervention between both groups. Secondary endpoints include other parameters of iron metabolism and red blood cell count, the number of patients with drug-related adverse events, and subjective symptoms including those of the restless legs syndrome, quality of life, and fatigue. DISCUSSION: Iron supplementation administered intravenously in non-anaemic but iron-deficient blood donors could represent an effective strategy to protect blood donors from comorbidities related with iron deficiency and therefore improve blood donor wellbeing. Furthermore, iron supplementation will help to maintain an iron-replete blood donor pool. TRIAL REGISTRATION: EudraCT: 2013-000327-14, Clinical Trials Identifier: NCT01787526 . Registered on 6 February 2013.

Efficacy and safety of adjuvant recombinant human erythropoietin and ferrous sulfate as treatment for iron deficiency anemia during the third trimester of pregnancy.

PURPOSE: Gestational anemia increases the incidence of maternal and fetal complications. Adjuvant recombinant human erythropoietin (rHuEPO) has been used in patients who refuse blood transfusions, have a low response to treatment with iron sulfate, have limited time before birth, or have other illnesses that complicate the anemia. We demonstrated that the use of adjuvant rHuEPO with iron sulfate reduces the anemia time period and is innocuous to the fetus. METHOD: An experimental longitudinal prospective study; 100 pregnant women in their third trimester were included. Group 1 (n=50) was set as control for prevalence of anemia and establish hematological maternal and fetal parameters at delivery for our population; 50 women diagnosed with iron deficiency anemia were randomly assigned to treatment groups. Group 2 (n=25) third trimester women with a hemoglobin of <11g/dL were treated with iron sulfate, 600mg administered orally daily for 4 weeks, evaluating the hematologic response for the mother weekly and for both mother and fetus at birth; Group 3 (n=25) women similar to group 2, treated in addition with adjuvant rHuEPO, 4000 units subcutaneously, three times a week, for 4 weeks evaluating the same parameters. RESULTS: Group 2 and 3 showed a corrected anemia before delivery (mean 11.1 vs 11.4g/dL), but Group 3 showed a statistically broader and more rapid increase in hemoglobin (1.22 vs 1.92g/dL, p value 0.013) with an rHuEPO dose of 4000 units, three times a week for 1 month. No clinical or hematologic difference or changes in growth were observed in the fetus. CONCLUSIONS: Erythropoietin is safe and effective for both mother and fetus, although an ideal pregnancy dose has not yet been established.

Iron Supplements and Magnesium Peroxide: An Example of a Hazardous Combination in Self-Medication.

The use of self-medication, which includes dietary supplements and over-the-counter drugs, is still on the rise, while safety issues are not well addressed yet. This especially holds for combinations. For example, iron supplements and magnesium peroxide both produce adverse effects via the formation of reactive oxygen species (ROS). This prompted us to investigate the effect of the combination of three different iron supplements with magnesium peroxide on ROS formation. Hydroxyl radical formation by the three iron supplements either combined with magnesium peroxide or alone was determined by performing a deoxyribose assay. Free iron content of iron supplements was determined using ferrozine assay. To determine hydrogen peroxide formation by magnesium peroxide, a ferrous thiocyanate assay was performed. Finally, electron spin resonance spectroscopy (ESR) was performed to confirm the formation of hydroxyl radicals. Our results show that magnesium peroxide induces the formation of hydrogen peroxide. All three iron supplements induced the formation of the extremely reactive hydroxyl radical, although the amount of radicals formed by the different supplements differed. It was shown that combining iron supplements with magnesium peroxide increases radical formation. The formation of hydroxyl radicals after the combination was confirmed with ESR. All three iron supplements contained labile iron and induced the formation of hydroxyl radicals. Additionally, magnesium peroxide in water yields hydrogen peroxide, which is converted into hydroxyl radicals by iron. Hence, iron supplements and magnesium peroxide is a hazardous combination and exemplifies that more attention should be given to combinations of products used in self-medication.