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Recent studies have demonstrated that parenteral deferroxamine can prolong life in patients with iron overload. We have developed a non-human primate model of iron overload and have accurately determined negative iron balance in parenteral and oral studies of deferroxamine and a new chelator, desferrithiocin. Cebus monkeys were loaded with iron dextran (10 mg/kg twice weekly) until their serum contained a transferrin saturation greater than 75%, and (in two animals) liver biopsies showed iron loading. When complete iron balance studies were performed at this time, basal iron balance was -53 +/- 11 micrograms (N = 4), providing a low background for provocative studies. Iron balance was determined for intramuscular (N = 2) and oral (N = 3) deferroxamine, as well as intramuscular (N = 1) and oral (N = 4) desferrithiocin. The pattern of iron excretion after parenteral deferroxamine strongly resembled that of the iron-loaded, transfused human. Desferrithiocin was found to have significant activity as an oral chelator. This Cebus monkey model accurately determines negative iron balance and readily permits precise comparison of iron chelators given parenterally or orally. This model may offer an important step between rodent and human trials of promising new iron chelators.

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.

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.

This study was designed to determine the content of non-haem iron in the brain as iron deficiency develops in the rapidly growing rat. Rats were provided with either an iron-deficient diet or an identical control diet with added ferrous sulphate starting at 10 d of age and continuing after weaning at 21 d. At 28 d or 48 d of age the deficient animals received 5 mg of iron (iron dextran) i.m. and were placed on the control diet regimen. The deficient animals had a concentration of non-haem iron in the brain that was 27% below the control value at 28 d and 22% below at 48 d. After 14-45 d of iron treatment, the non-haem iron remained depressed, 19-29% below the control means (P less tha 0.05 to 0.001). Ferritin iron in brain also remained depressed, 33-42% below the control means (P less than 0.01). In contrast, haematocrit, liver non-haem iron, and liver ferritin iron, although they were more profoundly depressed in the iron-deficient animals, promptly returned to control values after treatment with iron. Thus, a brief period of severe iron deficiency in the young rat resulted in a deficit of brain iron that persisted in the adult animal despite an adequate intake of 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.

Summary. Previously published studies have documented a reduction in the rate at which iron stores laid down by iron dextran therapy can be utilized for haemoglobin synthesis after the acute demands of haemorrhage and phlebotomy. In order to determine if a defect in the mobilization of these stores exists in the face of a chronic stimulus to red cell production, 93 patients who had previously received a total dose infusion of iron dextran were examined for a recurrence of iron deficiency anaemia, and in those in whom anaemia had recurred, iron stores were assessed by marrow aspiration. Twenty of the 93 patients were found to have recurrent iron deficiency anaemia, and marrow aspiration in all failed to demonstrate stainable iron stores. Although the rate at which iron dextran can be mobilized from storage sites is reduced, the present study demonstrates that ultimately these stores are fully utilizable.

Summary. The effects of injected iron on the absorption of iron by iron deficient animals have been studied. When iron deficiency is partly or fully corrected by injection of iron dextran, prolonged and marked depression of iron absorption follows despite the persistence of iron deficiency. Although total absorption increases with decreasing size of parenteral replacement dose, the depression of absorption per unit of iron injected increases.

Summary. The rate and completeness of absorption of iron from the injection site were studied after intramuscular administration of 59Fe-labelled iron-dextran and the pattern of radio-iron distribution and utilization followed in normal subjects and patients with iron-deficiency anaemia. In both normal and anaemic subjects the major part of iron absorption took place within 72 hours of injection; absorption continued at a slower rate for 28 days but little further iron clearance occurred thereafter. Rate and completeness of absorption were not related to the presence or absence of iron deficiency or to the haemoglobin level. In both normal and anaemic subjects there was marked individual variation in iron clearance. Active exercise was not found to lead to increased iron absorption but both rate and completeness of iron clearance were shown to be influenced by the site of injection. A study was made of iron clearance after multiple injections of iron-dextran into the same site. Serial surface scintillation counting was carried out in both normal and anaemic subjects; in smaller numbers of subjects, serial estimations of serum-iron levels were made and percentage incorporation of radio-iron into haemoglobin measured. There was no evidence of significant excretion of radio-iron in urine and faeces, and no toxic manifestations were observed.

Summary A 59Fe labelled preparation has been used to follow the distribution and fate of intravenously administered iron-dextran (Imferon) in 10 patients with iron deficiency anaemia and three non-anaemic adult female subjects. In all anaemic patients a satisfactory reticulocyte response occurred with a peak between the 8th and 10th day, and was followed by a progressive and maintained rise in haemoglobin. The mean weekly haemoglobin increments for the first 3 weeks were 1.9, 1.6 and 0.7 g. and the haemoglobin had reached normal levels in all by the 9th week. Surface scintillation counting showed increasing radioactivity over liver, spleen and sacrum up to the end of the 1st week, followed by a gradual decrease during the next 2 weeks so that by the 21st day the radioactivity over these sites had fallen to below the initial values. The sternal counts dropped during the 1st week, then levelled off and thereafter showed a slow but maintained increase. The findings in the normal subjects did not differ significantly from those in the anaemic patients. There were no general systemic reactions during or after the infusions, nor was there evidence of disturbance of renal or hepatic function. Local venous thrombosis occurred in two patients. Iron-dextran is well tolerated when given intravenously. The stability of the compound is shown by the absence of untoward symptoms in the immediate post-infusion period when plasma iron levels are very high. The haematological response is rapid and complete, and the results compare favourably with those obtained by other methods of iron therapy.