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.

Protein-bound molybdenum cofactor is bioavailable and rescues molybdenum cofactor-deficient C. elegans.

The molybdenum cofactor (Moco) is a 520-Da prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco as a prosthetic group. Moco is essential in animals; humans with mutations in genes that encode Moco biosynthetic enzymes display lethal neurological and developmental defects. Moco supplementation seems a logical therapy; however, the instability of Moco has precluded biochemical and cell biological studies of Moco transport and bioavailability. The nematode Caenorhabditis elegans can take up Moco from its bacterial diet and transport it to cells and tissues that express Moco-requiring enzymes, suggesting a system for Moco uptake and distribution. Here we show that protein-bound Moco is the stable, bioavailable species of Moco taken up by C. elegans from its diet and is an effective dietary supplement, rescuing a Celegans model of Moco deficiency. We demonstrate that diverse Moco:protein complexes are stable and bioavailable, suggesting a new strategy for the production and delivery of therapeutically active Moco to treat human Moco deficiency.

Effect of Iron Supplementation on the Modulation of Iron Metabolism, Muscle Damage Biomarkers and Cortisol in Professional Cyclists.

BACKGROUND: The intense efforts made during 3-week stage races may reduce iron metabolism and hematological parameters. These efforts may increase the levels of circulating muscle damage markers and some hormones. All of these physiological changes may have negative consequences not only for the performance of athletes but also for their health. The main aim of this study was to evaluate the effects of supplementation with 80 mg/day of iron on haematological parameters, serum cortisol and biochemical muscle indicators on elite male cyclists during the 3-week stage race the Vuelta a España. Our secondary aim was to examine whether the hematological profile is associated with muscular damage parameters and cortisol. METHODS: Eighteen elite male cyclists from two teams were randomly assigned to one of two groups: (1) control group (CG, n = 9; age: 26.1 ± 4.6 years; maximum oxygen uptake per kg: 78.0 ± 5.4 mL/kg/min) or (2) group treated with 80 mg/day iron (800 mg of iron protein succinylate, ITG, n = 9; age: 25.7 ± 6.4 years; maximum oxygen uptake per kg: 77.6 ± 6.5 mL/kg/min). The cyclists were subjected to blood tests one week before the start of the race (T1) and after 4 weeks of treatment, coinciding with the end of the competition (T2). Iron metabolism parameters, muscle damage indicators and serum cortisol were assessed. Repeated-measures ANOVA with group as a factor (GC and ITG) were used to examine the differences between groups throughout the study (time × group) after iron supplementation treatment. RESULTS: Significant differences were observed between groups throughout the study in the group-by-time interaction and changes in serum iron (GC: -8.93 ± 10.35% vs. ITG: 0.60 ± 8.64%; p = 0.018), ferritin (GC: -13.88 ± 23.53% vs. ITG: 91.08 ± 118.30%; p = 0.004), haemoglobin (GC: 10.00 ± 3.32% vs. ITG: 13.04 ± 5.64%; p < 0.001), haematocrit (GC: -1.17 ± 3.78% vs. ITG: 7.32 ± 3.92%; p < 0.001) and cortisol (GC: 24.74 ± 25.84% vs. ITG: ⁻13.54 ± 13.61%; p = 0.005). However, no significant group-by-time interaction was observed for the circulating muscle biomarkers. Additionally, significant negative correlations of serum iron, haemoglobin and haematocrit with muscle circulating biomarkers and cortisol (p < 0.05) were observed. CONCLUSIONS: Oral iron supplementation with 80 mg/day iron (800 mg of iron protein succinylate) effectively prevented a decline in haematological parameters (serum iron, ferritin, haemoglobin and haematocrit) and maintained optimal levels of recovery in elite cyclists during the Vuelta a España. Moreover, the hematological values were shown to have relationship with muscular recovery parameters.

Subcutaneous administration of bovine superoxide dismutase protects lungs from radiation-induced lung injury.

BACKGROUND: The objective of the present study was to determine whether single administration of the antioxidant enzyme bovine superoxide dismutase (bSOD) after radiation therapy (RT) mitigates development of pulmonary toxicity in rats. METHODS: Female F344 rats (n = 60) were divided among six experimental groups: (1) RT, single dose of 21 Gy to the right hemithorax; (2) RT + 5 mg/kg bSOD; (3) RT + 15 mg/kg bSOD; (4) No RT; (5) sham RT + 5 mg/kg bSOD; and (6) sham RT + 15 mg/kg bSOD. A single subcutaneous injection of bSOD (5 or 15 mg/kg) was administered 24 h post-radiation. The effects of bSOD on radiation-induced lung injury were assessed by measurement of body weight, breathing frequency, and histopathological changes. Immunohistochemistry was used to evaluate oxidative stress (8-OHdG(+), NOX4(+), nitrotyrosine(+), and 4HNE(+) cells), macrophage activation (ED1(+)), and expression of profibrotic transforming growth factor-ß or TGF-ß in irradiated tissue. RESULTS: Radiation led to an increase in all the evaluated parameters. Treatment with 15 mg/kg bSOD significantly decreased levels of all the evaluated parameters including tissue damage and breathing frequency starting 6 weeks post-radiation. Animals treated with 5 mg/kg bSOD trended toward a suppression of radiation-induced lung damage but did not reach statistical significance. CONCLUSIONS: The single application of bSOD (15 mg/kg) ameliorates radiation-induced lung injury through suppression of reactive oxygen species/reactive nitrogen species or ROS/RNS-dependent tissue damage.

From amino acids to proteins as targets for metal-based drugs.

Metallomics and metalloproteomics are emerging fields addressing the role, uptake, transport and storage of trace metals ions both toxic and essential for an organism. Research areas related to the understanding of the mechanisms of life processes associated to metals are covered. Similarly to the genome and proteome terms, metallome was introduced to refer to metalloproteins, metalloenzymes and other metal-containing biomolecules in a biological system. This review aims to give an overview of metal ions behaviour in organisms. The interactions of metals with biomolecules such as amino acids, peptides and protein are the main focus. Special attention is paid to the application of nanotechnology-based techniques using these interactions for medical purposes such as diagnostics, imaging and therapy.

Role of sucrose in the fitness of Streptococcus mutans.

INTRODUCTION: Dental caries has been closely linked to fermentable carbohydrates as key environmental factors. Sucrose has been identified as the most cariogenic carbohydrate. Streptococcus mutans, considered to be the primary pathogen causing dental caries, is able to utilize sucrose as a nutrient source, partially for the production of intracellular storage components and for the production of extracellular glucans via the glucosyltransferases GtfB, GtfC, and GtfD. The following study explores the competitiveness and fitness of S. mutans when grown with different concentrations of sucrose. METHODS: Growth competition with oral streptococci and antimicrobial susceptibility in static biofilm models grown without sucrose or with 0.1% or 0.5% sucrose were investigated using confocal laser scanning microscopy. The numbers of surviving S. mutans of both wild-type and an isogenic Gtf-negative mutant after antimicrobial treatment were determined as colony-forming units. RESULTS: S. mutans was able to establish microcolonies with increasing sucrose concentration in the presence of other streptococcal competitors during biofilm development. The antimicrobial susceptibility decreased when sucrose was available as substrate and was dependent on the presence of the Gtfs. CONCLUSION: The increased resistance against antimicrobial treatment was associated with the availability of sucrose, but was not influenced much by the concentration used during this study. The resistance was strongly associated with the Gtf activity, excluding any intracellular metabolic effect of sucrose in the resistance mechanism.

The efficacy and tolerability of iron protein succinylate in the treatment of iron-deficiency anemia in pregnancy.

The aim of this study was to evaluate the efficacy and tolerability of iron protein succinylate in the treatment of iron-deficiency anemia in pregnancy. One hundred and thirty anemic pregnant women were studied. Inclusion criteria were iron-deficiency type of anemia, and hemoglobin levels below of 11.5, 10.9 and 10.3 g/dl for the three trimesters of pregnancy, respectively. Twenty-five women who presented pregnancy-related complications were excluded during treatment. The remaining 105 were treated with 1600-mg iron protein succinylate per os daily for a period of four months. A group of anemia-related clinical signs and symptoms, and hematological parameters were recorded at the beginning of treatment, as well as two and four months later. They included epidermis and mucosal paleness, skin and nail lesions, glossitis, heart pulse, sickness, anorexia, apathy, ataxia, polypnea, insomnia, nervousness, paresthesias and other neurological symptoms; the hematological parameters included Hgb, hct, RBCs, WBCs, MCV, MCH, MCHC, PLTs, serum Fe and ferritin. Possible side or adverse effects were considered during treatment. The majority of symptoms and signs of anemia were gradually improved. There was a statistically significant increase in the means of Hgb, hct, WBCs, MCV, MCH, PLTs and serum ferritin (p < 0.05). Anemia was effectively treated in 100/105 (95.2%) women, but not in five patients (4.8%) who displayed poor compliance to the therapeutic protocol. There were transient and mild side-effects in seven (6.6%) treated women, namely diarrhea, epigastralgia, vomiting, and nausea, which however, did not necessitate discontinuation of the therapeutic protocol. Iron protein succinylate is an effective and well tolerated treatment of iron-deficiency anemia in pregnancy.

A comparative study on the gastroduodenal tolerance of different antianaemic preparations.

The most significant adverse effect of repeated oral administration of iron-containing antianaemic preparations is the gastroduodenal toxicity, attributable to a direct toxic effect of iron on the glandular epithelium. To assess gastroduodenal mucosal damage and the potential protective effect of different antianaemic preparations, a study was carried out to compare the gastroduodenal toxicity caused by three different types of antianaemic drugs in normal and anaemic rats administered at repeated therapeutic doses. Histological damage to the gastroduodenal mucosa was evaluated using light and electron microscopy. In both normal and anaemic rats, pathological changes were less marked in animals treated with ferrimannitol-ovoalbumin (TM/FMOA) than in those treated with iron protein succinylate or ferrous sulphate. Electron microscopic studies of duodenal mucosa in normal rats treated with iron protein succinylate and ferrous sulphate confirmed a severe ultrastructural alteration, whereas no changes were detected in animals treated with TM/FMOA. In anaemic rats, slight duodenal ultrastructural changes were noted with all three types of treatment. The effectiveness of the preparations in resolving the anaemia was similar in the three groups. It was concluded that TM/FMOA exerts a protective effect against the toxicity normally observed of the iron in other formulations in normal and anaemic rats, which was attributed to the fact that administration of iron bound to a protein core allows for gradual release of iron.

Iron plus folate is more effective than iron alone in the treatment of iron deficiency anaemia in pregnancy: a randomised, double blind clinical trial.

OBJECTIVE: To evaluate whether folate supplementation to iron is able to accelerate solving of iron deficiency anaemia in pregnancy. DESIGN: Multicentre, double blind, randomised clinical trial. SETTING: Nine hospital gynaecologic units located in Mexico. POPULATION: Three hundred seventy-one women with iron deficiency anaemia between 14 and 27 weeks of pregnancy. METHODS: Random allocation of the study population to receive 80 mg iron proteinsuccinylate, with or without 0.370 mg folinic acid daily for 60 days. MAIN OUTCOME MEASURE: Haemoglobin concentration increase. RESULTS: Combined iron and folate therapy showed a better therapeutic response: the increase in haemoglobin levels from baseline was 1.42 (0.14) g/dL for women treated with both compounds vs 0.80 (0.125) g/dL for those given iron only (P < 0.001). A multivariable regression analysis showed that this effect was independent of basal levels of blood iron, ferritine and serum folate and was more evident in women with more severe anaemia. In the 64 women belonging to the subgroup defined by the per-protocol (PP) population and the lowest quartile of baseline haemoglobin values (mean 8.96, range 5.9-9.8 g/dL), the increase at day 60 was estimated 2.3 (0.53) g/dL for the combined therapy vs 0.5 (0.5) g/dL for iron only (P = 0.07). No significant differences in tolerability were observed between the two groups. CONCLUSION: Folate supplementation is recommendedin pregnant women with iron deficiency anaemia irrespective of the serum levels of folate.

Aerosol orgotein (Ontosein) for the prevention of radiotherapy-induced adverse effects in head and neck cancer patients: a feasibility study.

Orgotein is an anti-inflammatory superoxide dismutase agent successfully used in treating several inflammatory diseases. It is also used in treating radiation-induced adverse effects in difference malignancies, notably breast, lung, bladder, prostate, cervix, and head and neck cancers. It is administered either topically or parenterally. To our knowledge, it has never been used before for prophylaxis of radiation-induced adverse effects or in aerosol form. Here we report on the results from a feasibility study on aerosol orgotein (Ontosein) for prevention of acute and deferred radiation-induced adverse effects in patients treated for head and neck malignancies. Our results show that aerosol orgotein administered before each radiation therapy session may impart some benefits in both incidence and severity of acute and deferred radiation-induced adverse effects in head and neck cancer patients, when compared with historical controls. In addition, aerosol orgotein administration is easy and convenient for both the patient and the radiotherapist.

Transdermal electromotive multi-drug administration for Peyronie's disease: preliminary results.

The purpose of this study was to clarify the actual therapeutic potential of a new transdermal drug delivery system (electromotive drug administration; EMDA) for selected patients with Peyronie's disease. Forty patients with Peyronie's disease were treated by electromotive administration of the 3-drug association orgotein-dexamethasone-lidocaine in a double-blind, placebo-controlled, partial crossover study (study 1). Another 25 patients were treated by EMDA with a combination of verapamil-dexamethasone in an uncontrolled study (study 2). Treatment sessions lasted 20 minutes each and took place 3 times a week for 3 weeks with a current of 3 mA. Patients were assessed before treatment and at 1- and 3-month follow-up examinations. Assessments were based on sexual history, physical examination, and dynamic color Doppler ultrasonographic results. Adverse effects of EMDA were not reported. In study 1, the clinical results observed after treatment proved to be significantly better than those of the placebo. Penile pain disappeared in all patients in both studies. Penile lesion (nodule or plaque) either disappeared or significantly improved in 79% and 90% of patients treated by the 3- and 2-drug association, respectively. The improvement of penile deformity also was notable although it did not match the effect observed on penile nodules or plaque (62% and 88%, in studies 1 and 2, respectively). In both studies, more than 80% of patients reported a definite amelioration of penile rigidity, which paralleled the improvement of penile dynamic color Doppler ultrasonographic parameters. Overall, the combination of verapamil-dexamethasone achieved better clinical results than the 3-drug combination. Electromotive drug administration is a novel technique capable of safely achieving satisfactory results in selected patients with Peyronie's disease not only in terms of improvement of patient's symptoms but also due to the reduced need for penile surgery.

Transfer of heterologous immunoglobulin into the uterine lumen of pigs.

Transfer of circulating heterologous immunoglobulin G (IgG) into the uterine lumen of pigs has not been reported. The present study determined if ovine IgG (oIgG) could be transferred into the uterine lumen of pigs. Six gilts (nonparous female pigs) were injected i.v. with either immune sheep serum (25 or 50 ml) to porcine uteroferrin (Uf) or non-immune sheep serum (50 ml) on days 9, 11 and 13 of the estrous cycle. Serum was collected daily from days 9 to 15 and uterine flushings were collected at hysterectomy on day 15. An ELISA detecting oIgG was used to determine levels of oIgG in pig sera and uterine flushings. High oIgG levels in serum (ranging from 87 +/- 11 to 141 +/- 14 micrograms/ml) were maintained by injecting the gilts at 48 h intervals with ovine antiserum to porcine Uf. Serum concentrations of oIgG did not differ (P > 0.05) regardless of whether immune or non-immune sera or different doses of immune serum were injected. oIgG in uterine flushings (2 +/- 1 micrograms/uterine flushing) was detectable when the samples were concentrated 40-fold, but were lower (P < 0.01) than serum levels of oIgG (107 +/- 10 micrograms/ml). Results indicate that small amounts of circulating heterologous IgG can be transferred into the uterine lumen of pigs. However, passive immunization may not result in titers high enough to examine in vivo functions of proteins secreted into the uterine lumen of pigs.

Fate of cadmium bound to phytochelatin in rats.

The fate cadmium(Cd) bound to phytochelatin [PC, (gamma-Glu-Cys)n-Gly)] was studied in rats using synthesized 109Cd-PC. Less Cd was absorbed through the digestive tracts than CdCl2, but the ratio of renal Cd to hepatic Cd was higher. After parenteral administration of Cd-PC, Cd was distributed mainly in the liver, kidney, small intestine and pancreas. More Cd was found in the kidney than the liver after Cd-PC (n = 5) administration. Most of the Cd was bound to the high molecular weight fraction in the hepatic cytosol 0.5 hr after administration and moved to the metallothionein fraction at 6 hr. The tissue distribution of Cd was not affected even when free PC (n = 5) was administered 3 hr after or before Cd injection. The distribution in the kidney increased only in the case of the simultaneous administration of Cd with PC. These findings show that the absorbance of Cd bound to PC from the alimentary tract is lower than that of CdCl2 although absorbed Cd is distributed to the kidney more than CdCl2, and Cd is liberated from PC soon after uptake by the cells.

Systemic anaphylaxis following parenteral orgotein administration.

We present a patient displaying a systemic anaphylactic reaction after local infiltration of orgotein. An IgE-mediated mechanism was demonstrated with skin tests and specific IgE measurement. It is concluded that orgotein can rarely cause IgE-mediated anaphylaxis.

A French controlled multicenter study of intraarticular orgotein versus intraarticular corticosteroids in the treatment of knee osteoarthritis: a one-year followup.

The efficacy of injection of orgotein was compared with that of betamethasone over a one-year period in 419 patients with osteoarthritis of the knee. The criteria for efficacy were the number of recurrences, the rate of persistence in the trial and, secondarily, Lequesne index and the visual analogue scale. Though betamethasone was quicker-acting, the efficacy of orgotein at low doses (4 or 8 mg) was comparable with that of the corticosteroid from Week 4 and up to a year after the beginning of the study, at the cost of a greater number of injections and more numerous local side effects.

Evaluation of the siderohaemic curve after loading administration of iron--protein--succinylate to gastrectomized subjects: a controlled study.

The absorption of iron after oral administration of 80 mg iron--protein--succinylate complex was evaluated by determining serum iron concentrations in 10 patients who had undergone total gastrectomy more than 1 year before and were suffering from hypochromic anaemia. Serum iron concentrations in these patients were no different from those obtained in 10 'normal' hypochromic anaemic patients.

[The effect of parenteral gold preparations on heart function in rheumatoid arthritis patients (based on echocardiographic data)]. / Vliianie parenteral'nykh preparatov zolota na funktsional'noe sostoianie serdtsa u bol'nykh revmatoidnym artritom (po dannym ékhokardiografii).

A total of 30 patients were treated by chrisanolum and myocrisin. The course of treatment lasted more than 2 years. The authors observed clear positive effect of parenteral preparations of gold on the contractile and pumping function of the heart in RA patients; clinical and laboratory manifestations of the disease were decreased.

Intra-articular orgotein in osteoarthritis of the knee: a placebo-controlled efficacy, safety, and dosage comparison.

PURPOSE: Superoxide dismutase (orgotein for injection) has been used in managing osteoarthritis for more than seven years in Europe; however, well-controlled studies to establish an optimum dosage regimen have not been conducted. In this study, three orgotein dose/regimens were compared with placebo in terms of efficacy, safety, and duration of effect in patients with active osteoarthritis of the knee. PATIENTS AND METHODS: A total of 139 patients with osteoarthritis of the knee were enrolled in the study. Nonsteroidal anti-inflammatory agents were withdrawn to induce a flare of disease activity. Patients were then randomly assigned to receive one intra-articular injection of either placebo or orgotein (8 mg to 32 mg) each week for three weeks. Both investigators and patients evaluated disease activity and adverse experiences at a series of follow-up visits for three months. RESULTS: Orgotein was effective in reducing symptoms of osteoarthritis for up to three months after treatment; 16 mg given twice was the most effective and most best-tolerated regimen. Discomfort at the injection site was drug related, although this effect also occurred occasionally after injection of placebo. CONCLUSION: The long-lasting effects of intra-articular superoxide dismutase contribute to a favorable risk-benefit ratio and support the importance of the free-radical anion, superoxide (O2-), in the biochemical pathology of osteoarthritis.