Consequences of parenteral iron-dextran loading investigated in minipigs. A new model of transfusional iron overload.

Patients with blood transfusion-dependent anemias develop transfusional iron overload (TIO), which may cause cardiosiderosis. In patients with an ineffective erythropoiesis, such as thalassemia major, common transfusion regimes aim at suppression of erythropoiesis and of enteral iron loading. Recent data suggest that maintaining residual, ineffective erythropoiesis may protect from cardiosiderosis. We investigated the common consequences of TIO, including cardiosiderosis, in a minipig model of iron overload with normal erythropoiesis. TIO was mimicked by long-term, weekly iron-dextran injections. Iron-dextran loading for around one year induced very high liver iron concentrations, but extrahepatic iron loading, and iron-induced toxicities were mild and did not include fibrosis. Iron deposits were primarily in reticuloendothelial cells, and parenchymal cardiac iron loading was mild. Compared to non-thalassemic patients with TIO, comparable cardiosiderosis in minipigs required about 4-fold greater body iron loads. It is suggested that this resistance against extrahepatic iron loading and toxicity in minipigs may at least in part be explained by a protective effect of the normal erythropoiesis, and additionally by a larger total iron storage capacity of RES than in patients with TIO. Parenteral iron-dextran loading of minipigs is a promising and feasible large-animal model of iron overload, that may mimic TIO in non-thalassemic patients.

Electrochemical sensing of iron (III) by using rhodamine dimer as an electroactive material.

The voltammetric and potentiometric sensors based on a novel electroactive rhodamine dimer (RD) have been developed for the determination of Fe (III) ions. The RD exhibits two anodic peaks at 0.5 V and 0.7 V vs. Ag/Ag(+) within the potential range of 0.2-1.2V, which on addition of Fe (III) ions get converted to single anodic peak with a shift toward more positive potential of 0.9 V vs. Ag/Ag(+) due to the formation of Fe (III)-RD complex. The voltammetric sensor has been found to work well in the concentration range of 1.5 × 10(-5)-3.5 × 10(-4)M with the detection limit of 3.3 × 10(-6)M. Further, the potentiometric response of proposed PVC based solid contact coated graphite electrode (CGE-1) was linear for Fe (III) ions in the concentration range of 1.0 × 10(-1)-1.0 × 10(-7)M. The electrode showed a slope of 18.8 mV/decade with a detection limit of 4.68 × 10(-8)M for Fe (III) ions. Both of the sensors revealed good selectivity towards Fe (III) ions in comparison to various diverse metal ions. The analytical utility of the proposed sensors has been confirmed by the estimation of the Fe (III) content in different sample matrices.

Comparative study of the iron cores in human liver ferritin, its pharmaceutical models and ferritin in chicken liver and spleen tissues using Mössbauer spectroscopy with a high velocity resolution.

Application of Mössbauer spectroscopy with a high velocity resolution (4096 channels) for comparative analysis of iron cores in a human liver ferritin and its pharmaceutically important models Imferon, Maltofer(®) and Ferrum Lek as well as in iron storage proteins in chicken liver and spleen tissues allowed to reveal small variations in the (57)Fe hyperfine parameters related to differences in the iron core structure. Moreover, it was shown that the best fit of Mössbauer spectra of these samples required different number of components. The latter may indicate that the real iron core structure is more complex than that following from a simple core-shell model. The effect of different living conditions and age on the iron core in chicken liver was also considered.

Use of iron sucrose in dialysis patients sensitive to iron dextran.

This study aimed to assess the safety and efficacy of iron sucrose in hemodialysis (HD) patients with documented hypersensitivity reactions to iron dextran. Of 205 HD patients who received low molecular weight iron dextran, 15 (7.3%) patients developed documented hypersensitivity reactions. The patients were treated with iron sucrose (100 mg administered as an intravenous push over 5-10 minutes once a week) for 8 weeks. Complete blood count, serum iron, serum ferritin, and parathyroid hormone were measured at the beginning and at the end of the study (except parathyroid hormone). All patients received subcutaneous erythropoietin at a constant dose of 5000 IU twice weekly unless a change was required. All the patients completed the study period and none of them developed hypersensitivity reactions to iron sucrose. The mean hematocrit increased from 23.8% to 32.27% (p < 0.0001), the mean serum ferritin from 185 ng/mL to 599 ng/mL (p < 0.0001), and the mean serum iron from 29.3 ng/dL to 76.8 ng/dL (p = 0.01). We conclude that iron sucrose is safe and effective in HD patients with documented hypersensitivity reactions to low molecular weight iron dextran.

Indirect determination of Fe(III) in synthetic samples and iron dextran tablets by capillary electrophoresis with ultraviolet detection.

A capillary electrophoresis method based on the oxidation of ascorbic acid is proposed for the indirect determination of Fe(III). Fe(III) concentration corresponds to the decrease in ascorbic acid peak area. The calibration graph was linear in the range of 1.68-112 mg/L for Fe(III), which was easily detected at a concentration of 1.12 mg/L at 3 times the standard deviation of the blank divided by the slope of the calibration graph. The lack of interferences from Fe(II) in synthetic samples and 3 excipients (starch, magnesium strearate, and microcrystalline cellulose) in dextran tablets in the determination of Fe(III) confirmed the high selectivity of the proposed method. Its application to the determination of Fe(III) in several synthetic samples and iron dextran tablets produced excellent results.

The molecular formula and proposed structure of the iron-dextran complex, imferon.

The first iron-dextran complex was discovered in 1953, when we attempted to synthesize an analog of ferritin, by substituting polysaccharide for its protein shell. This new complex soon became the most widely used parental therapy for hypochromic anemia in humans. No molecular formula has been proposed, but Cox has attributed an outline structure to it. The present article proposes a structure greatly different from the Cox model, by having a polynuclear beta-ferric oxyhydroxide core, closely similar or identical to Akaganeite, chelated firmly by an encircling framework of dextran gluconic acid chains and surrounded by a removable outer sheath of colloidal dextran gluconic acid. The molecular weight of the iron-dextran core molecule, including its chelated framework, has been determined by gel filtration and analysis and its molecular formula (1.3) calculated. Also, these new data and existing electron photomicrographic, X-ray diffraction and crystallographic studies, have enabled a molecular weight, formula, and model structure to be proposed for its complex (2), which includes the outer sheath. The 480 iron atoms in both the core molecule and its sheathed complex are close to the number calculated from the core's unit cell dimensions and volume.

Paralysis of the preterm rabbit fetus inhibits the pulmonary uptake of intraamniotic iron dextran.

OBJECTIVE: Whether fetal breathing movements or gasping result in the movement of amniotic fluid substances into the distal airways remains controversial. We evaluated the effect of paralysis of the preterm rabbit fetus on the pulmonary distribution of iron dextran. STUDY DESIGN: Laparotomy was performed on 10 New Zealand White rabbits of 25 days' gestation (term 31 days) under general anesthesia. Fetuses in one uterine horn were given an intramuscular injection of pancuronium (1.5 mg/kg) and fetuses in the other horn were given an equal volume of normal saline solution as controls. A 1 ml volume of iron dextran (100 mg/ml) was injected into the amniotic sac of all fetuses. The laparotomy was closed, and 20 to 24 hours later the fetuses were removed by hysterotomy and assessed for paralysis. Necropsy was performed. Lungs were stained with prussian blue and evaluated histologically for the presence of iron. RESULTS: A total of 92 pups were delivered (49 given pancuronium, 43 given normal saline solution), of which 64 were born alive. There were no differences between groups for live births (31 pancuronium, 33 normal saline solution), pup body weight, or lung weight. Pups given normal saline solution demonstrated more breathing motions, spontaneous movement, and brown (color of iron dextran) stomach contents than did the pups given pancuronium (p < 0.001). At necropsy a greater number of control pups (31/33) had brown lungs grossly compared with pups given pancuronium (2/31, p < 0.001). Lung histologic examination showed that more control pups (29/29) had iron in the trachea and main bronchi compared with pancuronium pups (0/27, p < 0.001), and more control pups (29/29) had iron in the distal lung airways compared with pancuronium pups (0/27, p < 0.001). With use of the Optimas Image Analysis System, iron in the lungs of control pups was found to be equally distributed between right versus left lungs, upper half versus lower half lungs, and anterior versus posterior lung sections. More iron was identified in the central airways than in the periphery (p < 0.001). CONCLUSION: We conclude that paralysis prevents the uptake of iron dextran into the main and distal airways of the rabbit fetus. Although lung fluid production results in a net efflux of fluid, we speculate that fetal breathing movements can result in the movement of fluid into distal airways and potentially provide fetal therapy.

Removal of iron dextran by hemodialysis: an in vitro study.

Intravenous iron dextran is frequently prescribed for iron-deficient hemodialysis patients, a practice that has increased during the erythropoietin era. Whether iron dextran is removed by hemodialysis has been a concern, especially for high permeability membranes. The purpose of this in vitro study was to measure iron dextran clearance by nine different hemodialyzers (Fresenius F3, F8, and F80B; Baxter CF25, CA150, CA210, and CT190; Toray BK2.1P; and Hospal Filtral 16) representing six types of membranes (polysulfone, cuprophane, cellulose acetate, cellulose triacetate, polymethylmethacrylate, and polyacrylonitrile) and including membranes considered high efficiency and high flux. Clearances were assessed using a closed-loop, fixed-volume reservoir model. Absolute drug removal also was determined over the 30-minute experiments. Iron dextran clearance did not exceed 25 mL/min, and clearances also were minimal after a single automated reuse with glutaraldehyde sterilant. A maximum of 8% of iron dextran was removed during the experiment. We conclude that iron dextran clearance by the nine hemodialyzers studied was small or too low to be detected in this sensitive in vitro dialysis system and that adjusting dosing schedules is not needed.

Vascular to alveolar leak of iron dextran (120 kD) in the immature ventilated rabbit lung.

Rabbit fetuses were delivered by hysterotomy on day 27 or 28 of gestation. Immediately after birth, the animals were tracheotomized and received by intravenous injection 0.2 mu Ci radiolabeled albumin and 11 mg iron dextran in 0.2 ml saline. The newborn rabbits then were ventilated artificially with a tidal vol of 12 ml/kg for 5-20 min. One group of nonventilated animals served as controls. At the end of the experiment, one lung was lavaged via the airways and the other was fixed for histologic examination. The recovery of labeled albumin and iron dextran in the lavage fluid was quantified. Iron dextran complexes were easily identified in the lung sections by staining with Prussian blue. Iron dextran accumulated in the airspaces of animals delivered on day 27 (about 4% of the injected dose during 10-20 min of ventilation). The albumin leakage was slightly higher than that of the dextran, a result consistent with different mol wt of the markers. The vol density of leaking alveoli in histologic sections increased with time, from 0 at birth to a mean value of 0.36 after 20 min of ventilation. The leakage starts as a focal event, gradually involving more and more terminal airspaces. In the histologic sections, there was no indication of a significant leakage at the bronchiolar level, although the epithelium of terminal and preterminal airways was clearly injured in all ventilated animals.

Compatibility considerations in parenteral nutrient solutions.

Information on compatibility of nutrients and drugs with parenteral nutrient (PN) solutions is reviewed and evaluated. Precipitation of calcium phosphate when calcium and phosphate salts are added can be affected by pH, amino acid concentration, amino acid product, temperature, sequence of additives, specific salt used, and time since admixture; precipitate formation can occur gradually over 24 hours. Insulin is chemically stable in PN solutions, but adsorption to the infusion system can cause decreased availability. Poor delivery of vitamin A via PN solutions has been reported. The sodium bisulfite content of amino acid injections may cause degradation of thiamine, but studies simulating clinical use are needed. Folic acid stability in PN solutions has been demonstrated, and phytonadione appears to be stable. Drug administration via PN solutions may be advantageous when fluid intake is restricted or peripheral vein access is limited and in home PN therapy. Summarized are results of studies involving heparin, cimetidine hydrochloride, aminophylline, amphotericin B, iron dextran, hydrochloric acid, corticosteroids, narcotics, metoclopramide, digoxin, and fluorouracil. Many antibiotics are probably stable, especially when administered by co-infusion rather than by direct mixture in the PN solution container. When lipids are mixed in the same container with amino acid-dextrose solutions, compatibility and stability of electrolytes, vitamins, and trace elements must be reassessed. Practical research is needed, and availability of additives should be studied in specific patient populations and for specific PN formulations. Valid conclusions are dependent on careful study design.