Search

Summary The changes in serum iron and total iron binding capacity were followed in pregnant women after total dose infusion of iron-dextran for iron deficiency anaemia. The mean halflife of the iron-dextran in serum over the first 60 hours was 42 hours. When the infusion was given during the second trimester the serum iron often fell after the infusion to the lower part of the normal range, and in some cases even below normal; in these the iron binding capacity, which also fell at first, later rose again in the manner seen towards the end of pregnancy in noninfused patients. These changes occurred even in patients who did not subsequently manifest iron deficiency after delivery. A low serum iron coupled with a high iron binding capacity may be difficult to interpret in late pregnancy, but can be useful post partum for assessing the adequacy of treatment.

The forebrains of various snakes were examined by electron microscopy. In the forebrain of Elaphe quadrivirgata, the banded structures were found within the perivascular basement membrane in the proximity of neural elements. These structures were composed of numerous fine filaments, 60-70A in diameter, running parallel to the blood vessel. Regularly repeated dense bands occur in crossing over the structures at interval of about 1, 700A. Sometimes a cluster of collagenous fibrils were located close to the banded structures, and some of the fibrils entered into them.Although the real chemical nature of these structures was not known, it was assumed that the structures are composed of collagenous components.The observation in the snake injected with iron dextran, demonstrated the existence of the blood-brain barrier in the snake, but did not suggest that the banded structures play any active role in lowering the blood-brain barrier of the snake. However, the fact that these banded structures were observed only in Ealphe quadrivirgata among snakes, shows differences in structure and therefore probably in function of the circulatory system in brain tissue in animals species.

The structure of the acid-hydrolysed and alkali-degraded dextran used in the production of an iron-dextran complex has been determined. The dextran has acidic end-groups and, after purification by fractionation on anion-exchange columns, was found to possess a low molecular weight (2500–6250) and no reducing properties, and to contain an average of one glucometasaccharinic acid residue per dextran chain. The evidence suggests that this acid group occurs at the former “reducing” end-group and protects the dextran against further attack by alkali. Approximately 12% of the original dextran was not degraded by the alkali and remains as an impurity in the acid dextran. In spite of the extensive acid hydrolysis and alkali degradation, the dextran still contained around 5% of α-(1 → 3)- d -glucosidic links.

The major portion of iron dextran iron becomes available to the erythroid marrow only after uptake and release of ionic iron by the reticuloendothelial system. With large intravenous infusions, (1000-2000 mg.), the rate of removal of the iron dextran complex from plasma is enough to supply the marrow with more than 200 mg. of iron/day. However, in the present studies the observed rate of iron delivery to the erythroid marrow was far below this level. Although iron supply immediately after infusion was sufficient to permit marrow production to rise to 4-6 times normal, this was maintained for less than two weeks. With time, reticuloendothelial iron dextran stores became less available, the serum iron level fell and marrow production was restricted to levels below twice normal. In fact, large infusion doses and prolonged storage may have made a portion of the iron dextran stores completely unavailable. Thus, an iron deficient type of erythropoiesis appeared in some patients while iron dextran stores were still readily visible on examination of marrow stroma.

Summary. A method is described for the separation of transferrin iron and iron-dextran in plasma samples. Estimation of plasma levels following the intravenous administration of labelled iron-dextran showed that the mean half clearance time was 5.9 hr. About 40% of the injected dose of iron in circulation was bound to transferrin 11 hr later and there was no difference between normal and iron deficient subjects in the rate of iron release by the reticuloendothelial system. The results indicate a need to re-evaluate present concepts of reticuloendothelial iron metabolism.

Induction of tumours in mice and rats with ferric sodium gluconate and iron dextran glycerol glycoside

Marrow iron stores were studied in 50 children with simple hypochromic or dimorphic anaemia, and 20 non-anaemic children. The stainable marrow iron was found to be deficient in 44 out of 50 anaemic subjects, while six patients showed adequate marrow iron despite a hypochromic red cell picture. In the group of 20 non-anaemic children the marrow iron stores were found to be deficient (grade 1–2) in 19 children. Iron dextran was administered to anaemic children by the intramuscular route in 21 patients and as an intravenous total dose infusion in 19 cases. Reassessment of marrow iron 4 to 11 weeks after therapy in 26 children showed that the iron stores were well replenished in 22 patients but were still inadequate in four patients (15%). The significance of the study of marrow iron in such cases is discussed.

Intramuscularly administered iron dextran in immature rabbits leads to iron deposition in the articular cartilage chondrocyte followed by lacunar enlargement, the appearance of transverse striations in the matrix, abnormal staining characteristics of the middle layer of cartilage, rounding of the surface chondrocytes, fibrillation and fraying of the cartilage matrix, and death and disappearance of the chondrocytes. Iron deposition also occurs in the synovium and leads to mild thickening with no inflammatory cell reaction. In mature rabbits, iron is deposited in the synovium only, and none of the above cartilage changes occur.

SummaryErythropietic iron uptake and erythropoietic plasma iron clearance were a linear decreasing function of hematocrit, both in hemolytic (phenylhydrazine) and hemorrhagic anemia. The gain of the system that is the slope of the line relating erythropoietic iron clearance to hematocrit was greater in hemolytic than in hemorrhagic anemia. Injection of iron dextran in bled rats, increased the gain of the system, without raising plasma iron concentration. Erythropoietic plasma iron clearance of bled rats treated with iron dextran was same as that of rats with hemolytic anemia.

Images Figs. 7-8 Figs. 1-2 Figs. 3-4 Figs. 5-6

Summary An index of reticuloendothelial cell release of iron for erythropoiesis can be derived from simultaneous measurements of iron—dextran and transferrin-bound iron utilization. Reticuloendothelial iron release was found to be reduced in patients with Hodgkins disease, chronic renal failure and some cases of rheumatoid arthritis. It was increased in patients with iron deficiency.

The systemic carcinogenicity of iron-dextran has been investigated after single and repeated injections of Imferon in mice and rats. Systemic iron deposits induced by irondextran resulted in a stepwise development of reticulosarcomas. Such a histologic reaction, however, was not seen in relation to iron deposits following iron-carbohydrate complex (Intrafer) administration. Distant tumours arising in the lymphoreticular structures showed a uniform latency in test and control mice, while tumours of other origin showed a prolonged latency as compared to such tumours in control animals. It is suggested, therefore, that iron-dextran may act as a co-carcinogenic factor in the case of lymphoreticular neoplasia, increasing host susceptibility to the oncogenic virus presumably present in both control and test animals. The non-lymphoreticular distant and local tumours may stem from a different and direct carcinogenic action of iron since these tumours showed a prolonged latency and were seen after the administration of either iron-dextran or iron-carbohydrate complex. The results indicate an inconclusive dose-response relationship, though no significant difference was found between tumour yield in the larger groups receiving 500 and 25 mg Fe…/kg body weight, the latter dose being within the therapeutic level on a comparative weight basis. INDUCTION DE TUMEURS A DISTANCE PAR LE FER-DEXTRANE CHEZ LA SOURIS On a etudie la carcinogenicite d'action generale du fer-dextrane apres des injections uniques ou repetees d'Imferon a des souris et des rats. Les depǒts de fer dans l'organisme, provoques par le fer-dextrane, ont entraǐne par degres la formation de reticulosarcomes. En revanche, cette reaction tissulaire n'a pas ete observee avec des depǒts de fer consecutifs a l'administration d'un complexe fer-glucide (Intrafer). Les tumeurs apparaissant a distance dans les structures lymphoreticulaires ont presente une latence uniforme chez les souris d'epreuve et les temoins, tandis que les tumeurs d'une autre origine presentaient une latence prolongee par rapport aux měmes tumeurs chez les animaux temoins. Il y a donc lieu de penser que le fer-dextrane pourrait avoir un rǒle co-carcinogene dans les cas des tumeurs lymphoreticulaires, augmentant la receptivite de l'hǒte au virus oncogene que l'on suppose present tant chez les animaux temoins que chez les animaux d'epreuve. Il est possible que les tumeurs a distance ou locales non lymphoreticulaires proviennent d'une action carcinogene differente et directe du fer, puisque ces tumeurs ont presente une latence prolongee et ont ete observees apres administration soit de fer-dextrane soit du complexe fer-glucide. Les resultats indiquent une relation dose-reponse non concluante, mais on n'a pas trouve de difference significative de rendement tumoral entre les groupes nombreux qui ont recu respectivement 500 et 25 mg de Fe+++ par kg de poids corporel, cette derniere dose se situant a l'interieur des limites therapeutiques, compte tenu des poids relatifs.

Early development of injection-site sarcomas in rats: a study of tumours induced by iron-dextran.

Two Articles in this issue of Pediatrics report on the use of an iron-dextran complex (Imferon), a preparation which, on April 25, 1960, was withdrawn from the American market. This action was taken by the distributor, Lakeside Laboratories, upon recommendation of the Food and Drug Administration and followed publication of experiments which demonstrated the induction of sarcomas in mice and rats at the sites of repeated injections of the drug. In view of the extensive clinical use of Imferon in recent years it seems appropriate to review critically the evidence for the possible carcinogenicity of the preparation and the justification for its removal from the market.

A study designed to compare the effectiveness of parenteral iron dextran with oral ferrous sulfate in the treatment of anemia of pregnancy has been carried out on 246 patients. The results indicate that the iron dextran can be expected to give a more rapid response but if treatment can be continued for as long as 4 to 6 weeks the ferrous sulfate will give an over-all improvement similar to that with the parenteral preparation.

Images Figs. 1-4

Summary Seventy-two children with nutritionaliron-deficiency anemia were given iron-dextran complex intramuscularly. The average gain in hemoglobin in the first and second weeks after intramuscular therapy was 2.1 and 2.2 Gm. per cent in the 28 uncomplicated cases, 1.8 and 1.7 Gm. per cent in 19 cases complicated by infection, and 0.7 and 1.3 Gm. per cent in 9 cases complicated by lead poisoning. In 12 patients, with uncomplicated iron-deficiency anemia, receiving weekly injections, the gain for the first week was 1.4 Gm. per cent and 2.3 Gm. per cent for the second week. In the oral-iron group, this gain was about 1.0 Gm. per cent each week. Only one patient had staining of the skin at the site of injection. One patient developed urticaria after an iron-dextran injection. From these observations, it wouldappear that in situations where a rapid elevation of hemoglobin is important, injection of iron intramuscularly is desirable. Intramuscular iron also provides for a faster and surer way of replenishing depleted iron stores. Another indication for intramuscular iron is that of a careless mother who might not give the oral medication.

An account is given of the autopsy findings in 78 piglets which died from iron poisoning. They belonged to an experimental series which included a further 6 piglets that also died but will not be accounted for here. The experiment was designed to study why iron treatment causes occasional deaths among piglets. The results will be reported in full elsewhere (Tollerz, in press). In 63 piglets, the sows had been fed special experimental diets, and in 8 piglets from a field case where deaths occurred after conventional iron treatment to prevent anaemia, the predominant autopsy finding was waxy degeneration of the skeletal muscles, which appeared irrespective of whether iron dextran or iron dextrin was injected intramuscularly, or whether ferrofumarate or ferous sulphate was given orally. Only one piglet had slight heart-muscle degeneration, and hydropericardium was not present. The remaining 7 piglets received ferrous sulphate orally, which resulted in catarrhal to necrotizing gastroenteritis. Three of these piglets had waxy degeneration of the skeletal muscles, but in the other 4 the musculature was intact, which indicates another mechanism of toxicity than that in the cases of muscle degeneration.

Iron-dextran was given intramuscularly to 84 small prematurely born babies during their stay in the nursery; 97 similar babies were not so treated and served as controls. By 8 to 10 weeks of age, values for hemoglobin in the babies who received iron-dextran were significantly higher than in the controls and remained high throughout the first year. Virtually all of the control babies became anemic and hemoglobin levels below 5 gm/100 ml were observed in four infants. There was no difference in the rate of growth or in the incidence of common infections in the two groups. It is concluded that intramuscular injections of iron given prophylactically in the nursery will effectively prevent iron-deficiency anemia in premature infants and that this practice has definite clinical applicability. (See Addendum.) Prevention of iron deficiency anemia does not reduce the high incidence of common infections experienced by prematurely born infants.

1. 1. This is a study of 75 women with iron deficiency anemia who were treated by totaldose intravenous infusion of iron-dextran complex; 50 women were obstetric patients and 25 women were from the gynecologic wards. 2. 2. The average hemoglobin rise after infusion was at the rate of 1 Gm. per cent per week. 3. 3. Three patients had severe reactions which could have been avoided. Ten patients had mild reactions. 4. 4. The use of iron-dextran complex by total-dose infusion technique does reduce the period of hospitalization, and avoids the local complications of intramuscular injections. 5. 5. The total-dose infusion technique is still not safe enough to be advocated for general use. It should be given only in a hospital after proper selection of patients.

Summary: Late severe reactions to intravenous iron dextran are uncommon but particularly dangerous. Four such cases are reported and appear to have been due to the administration of a new form of iron dextran.

A case of severe iron-deficiency anaemia as a result of intractable menorrhagia is described. Following treatment with an iron dextran infusion, an impaired haematological response occurred; this was shown to be the result of vitamin B12deficiency despite the presence of abundant free hydrochloric acid in the gastric juice. The severe anaemia (3.5 g. %) was corrected within 5 weeks by one iron dextran infusion and vitamin B12therapy prior to hysterectomy.

A rapid technique for the determination of iron in serum, after the intravenous injection of iron-dextran, is presented. Dithionite is used for the reduction of ferric to ferrous iron. The use of a detergent solution enables protein precipitation to be omitted. The iron reagent, 4: 7-diphenyl-1: 10-phenanthroline, and its ferrous complex are both soluble in the dilute detergent solution. Lipaemic serum can be used without affecting the results. The recovery of added ferric iron, as iron-dextran, is quantitative.

The use of promethazine and chloroquine sulphate to reduce reaction to total dose infusion of iron dextran (Imferon) is described. The patients chosen for the investigation were anaemic pregnant African women living in the coastal region of East Africa where malaria due to Plasmodium falciparum is holoendemic. The results show that promethazine has little value in the reduction of reactions whereas chloroquine appears to be effective.

SummaryTwo dogs with anemia induced by bleeding were injected intramuscularly with iron dextran to replace the iron lost through the bleedings. They were given intraperitoneally 1.5 ml/kg/day of a hemolysate containing 15 g/100 ml of 59Fe-labeled hemoglobin. Seventeen and 24.7% of the injected heme-59Fe was reincorporated in the RBC, which accounted for only 13.9 and 11.9% of the iron present in the hemoglobin gained following injections of hemolysate. These results indicate that the 60.7% increase in hemoglobin production after hemolysate administration observed in previous similar experiments (1), cannot be ascribed to availability of large amounts of heme iron.

Summary. The absorption, distribution and utilization of I-I'diethyl α-α′-thiabis-cyclopentadienyl-iron (EX10–478), in which iron is present in a non-ionized form, was studied in normal mice and mice with sex-linked anaemia, an X-linked recessive trait characterized by a defect in the intestinal absorption of ionic iron. Treatment of anaemic mice with intragastric EX10–478 and intraperitoneal iron dextran resulted in a complete cure, whereas intragastric treatment with an equivalent amount of ionic iron had no beneficial effect. Investigations using 59Fe labelled EX 10–478 demonstrated relatively high intestinal iron absorption in both anaemic and normal animals, greater utilization of EX10–478 iron for erythropoiesis in anaemic animals compatible with their known iron deficiency and higher deposition of EX10–478 iron in the livers of normal animals. These results indicate that (a) EX10–478 is well absorbed from the intestine, (b) there is no defect in the absorption of non-ionized iron in sex-linked anaemia, (c) EX10–478 iron is readily available for haemoglobin synthesis, (d) the liver is probably the principle iron storage site in the mouse, and (e) EX10–478 is a promising new haematinic and a potentially useful experimental tool for the study of iron metabolism.