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PubMed1990

Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro.

Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

Animals↗
PubMed1990

Effect of supplementing cardioplegic solution with deferoxamine on reperfused human myocardium.

Fourteen randomized patients undergoing myocardial revascularization were divided into group A standard hypothermic cardioplegic solution) and group B (the same cardioplegic solution supplemented with deferoxamine 1000 mg/L). In all patients myocardial biopsy specimens were obtained before ischemia and during reperfusion and were assessed for chemiluminescence (to indirectly determine oxygen-free radical activity) and for electron microscopic studies. Chemiluminescence in group A showed a photoemission of 36.5 +/- 1.5 cpm/mg protein X10(-3) for the preischemia samples and 72 +/- 5.7 cpm/mg protein X10(-3) for the reperfusion samples (p less than 0.01). In the patients who received deferoxime (group B), values for chemiluminescence for preischemia and reperfusion samples were not significantly different. Electron microscopic studies showed a significant increase in grade 4 (severely damaged) mitochondria in reperfusion biopsy specimens from both groups as compared with preischemia samples. However, reperfusion samples from group B showed a better preservation of myocardial cells with marked reduction of grade 4 (severely damaged) mitochondria. These results support the hypothesis that oxygen-free radicals are responsible in part for the production of reperfusion injury in the human heart. They suggest that this mechanism may be at least partially controlled by adding an iron chelating agent such as deferoxime.

Cardioplegic Solutions↗
PubMed1985

Deferoxamine injection does not affect bleomycin-induced lung fibrosis in rats.

Bleomycin is an antineoplastic agent that causes a dose-related lung fibrosis that limits its therapeutic effectiveness. It has been proposed that the cellular toxicity and antitumor effects of bleomycin occur by formation of O2-Fe(II)-bleomycin complexes that degrade DNA and release O2- and OH radicals that attack other cellular components. Twice daily injections of the iron chelator deferoxamine were utilized in an attempt to ameliorate bleomycin-induced lung fibrosis. They failed to diminish bleomycin-induced lung inflammation and fibrosis in rats.

Animals↗
PubMed1989

The inhibitory effect of deferoxamine on DNA synthesis in human lymphocytes.

As an iron-chelating agent, deferoxamine (DFO) is widely used in treating iron poisoning and disorders of iron overload. This study demonstrates that DFO is a potent S-phase inhibitor of DNA synthesis in human lymphocytes in vitro, and this inhibitory effect of DFO is reversible by adding appropriate amounts of ferric ion. As a nontoxic and selective-S-phase inhibitor, it may play a role in immunosuppression in experimental and therapeutic situations. It may even become an auxiliary therapy for leukemia or other malignant tumors.

Cell Division↗
PubMed1989

A high-performance liquid chromatographic method for the measurement of deferoxamine in body fluids.

A high-performance liquid chromatography method for the analysis of deferoxamine (DFO) in 100 microliters of serum or plasma is described. The procedure involves the addition of the internal standard ciprofloxacin to the sample, followed by ultrafiltration to remove protein. The ultrafiltrate is then directly injected into the chromatography system. Separation is achieved using a reverse-phase mu Bondapak C18 column and a ternary solvent system (sodium phosphate:acetonitrile:methanol) running at 2.0 ml/min. Assay time is 10 min, and chromatograms show no interference from coadministered drugs during this period of time. Coefficients of variation were found to be less than 5%, and analytical recovery of DFO was 85%. Validation experiments in an experimental dog model and in patients with iron overload demonstrate that the method is appropriate for studying the pharmacokinetics of DFO in thalassemic patients receiving drug for the treatment of chronic iron overload.

Adolescent↗
PubMed1989

[A case report of rhinocerebral mucormycosis in hemodialysis patient receiving deferoxamine].

Deferoxamine (DFO) has been widely used in the treatment of aluminum toxicity in patients on chronic dialysis. Mucormycosis is an opportunistic infection caused by fungi of the Mucorales order and some reports suggested a role for DFO in the precipitation of this infection. A 50-year-old man had been on hemodialysis for 16 years. 6 weeks before admission, he was begun on DFO because of aluminum toxicity. 2 weeks before admission, general fatigue and fever developed and followed by headache and loss of vision. He was admitted to this hospital with disturbed consciousness. His clinical course and a CT scan of the head suggested cerebral infarction. Within 24 hours he required ventilatory support and died 5 days after the admission. On autopsy, rhino-cerebral mucormycosis was demonstrated with a mycotic thrombus involving the left middle cerebral artery. Dialysis-related mucormycosis has recently appeared in the literature. We feel that hemodialysis patients on DFO may be at risk for potentially fatal mucormycosis infections. With a possible relationship between DFO treatment and this fatal opportunistic infection, caution should be given before using this drug and the indications should be definitive.

Brain Diseases↗
PubMed1989

Antileukemic effects of deferoxamine on human myeloid leukemia cell lines.

Deferoxamine (DFO) possesses antiproliferative activity against mitogen-stimulated lymphocytes, several tumor cell lines, and human leukemia and neuroblastoma cells. We have investigated its effects on the human myeloid leukemia lines HL-60, HEL, and U-937. In suspension culture, DFO causes a dose-dependent inhibition of proliferation of each cell line, with maximal inhibition observed at concentrations greater than 20 microM. These effects were prevented by cotreatment with iron salts and were at least partially reversible by removal of DFO from the culture system or addition of iron before 48 h of DFO exposure. Similar results were obtained in methylcellulose cultures of leukemic cells, with complete abolition of cell aggregates at day 7 in concentrations of 20 microM DFO or higher. DFO treatment caused a dose- and time-related decrease in DNA synthesis as measured by [3H]thymidine uptake, which was also reversed by treatment with iron salts. DFO caused slight reduction in RNA synthesis and did not affect protein synthesis. DFO caused significant antiproliferative effects on three myeloid leukemia cell lines, associated with inhibition of DNA synthesis, with in vitro effects observed at concentrations attainable in vivo. Evaluation of the antileukemic properties of DFO should continue.

Antineoplastic Agents↗
PubMed1988

Deferoxamine inhibition of human neuroblastoma viability and proliferation.

Patients with widespread neuroblastoma (NB) frequently have elevated serum ferritin levels, and recently anti-NB effects of the iron chelator deferoxamine (DFO) have been reported. We have investigated the effect of DFO on human bone marrow NB cells from two untreated children with Evans Stage IV disease. DFO treatment caused dose- and time-dependent cytotoxicity of NB cells, with maximal killing at exposure to 50 micron DFO for 72 h. Cytotoxicity was prevented by cotreatment with stoichiometric amounts of iron salts and reversible by removal of DFO or addition of iron salts within 48 h of treatment. Additionally, DFO inhibited clonal growth of human bone marrow NB cells in methylcellulose in a time- and dose-dependent manner. These effects were also prevented by cotreatment with iron salts. Thus, DFO has potent antitumor effects on human NB cells which appear to be related to iron deprivation. DFO should be considered for further preclinical evaluation as an anti-NB agent.

Bone Marrow↗
PubMed1987

Antimicrobial alternatives for calf diarrhea: sera trace element responses to Escherichia coli-, deferoxamine-, or gallium-induced diarrhea.

Aseptic and septic inflammatory diseases often are associated with marked changes in tissue and sera trace element kinetics. Iron and zinc sequestration by the host may serve as a protective effect against microbial proliferation, but may deprive host tissues of these necessary elements as well. Conversely, systemic iron administration has been shown to increase susceptibility to, and severity of, infectious diseases, although deficient iron stores may be repleted. Escherichia coli enteritis in calves provides a model wherein the effects of enteric iron antagonism and parenteral iron supplementation may be studied simultaneously. Male calves (n = 12) were given (IM injection) 300 mg of iron-dextran after base-line blood samples were obtained, then the calves were allotted to 4 groups (each of 3 calves): group 1 (control)--orally given nonpathogenic E coli; group 2--orally given enterotoxigenic B44 E coli; group 3--orally given deferoxamine (50 mg/kg, twice a day); group 4--orally given gallium (4 mg/kg; twice a day). Calves were studied for 8 days; blood samples were obtained each day (day 1 through day 8) for hematologic and serum biochemical analyses. There were significant increases in serum iron concentration and % saturation in all calves within 24 hours of iron-dextran administration, which returned to base-line values in all but group 4 (given gallium) within 3 days. In the exceptional group (4), total iron-binding capacity decreased with time, as in the other groups, but serum iron concentration remained significantly increased, implying gallium interference with systemic iron assimilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Diagnosis of aluminum-related bone disease and treatment of aluminum toxicity with deferoxamine.

Bone disease related to aluminum toxicity (aluminum-related bone disease) presents with variable clinical and biochemical findings in patients with renal failure. Bone pain and muscle weakness are common, although afflicted patients can be asymptomatic. Bone pain can be generalized or localized to the hips, back, feet, or ankles; proximal muscle weakness is common. Most cases in the United States arise from the ingestion of aluminum-containing gels by patients on long-term dialysis treatment. Patients at increased risk for developing aluminum-related bone disease include those with earlier parathyroidectomy, failed renal transplant, previous bilateral nephrectomy, and diabetes mellitus. Biochemical features that are common with aluminum-related bone disease include plasma aluminum levels greater than 100 to 150 micrograms/L, serum parathyroid hormone (PTH) levels equal to or lower than those in dialysis patients without bone disease, and normal or slightly elevated serum calcium levels. Plasma alkaline phosphatase levels are often elevated. In our experience, microcytic anemia has been uncommon. An increase in plasma aluminum levels greater than 200 micrograms/L 24 to 48 hours after the infusion of the chelating agent deferoxamine (DFO) correlates with an increased bone aluminum content, and an increment greater than 400 micrograms/L suggests marked aluminum accumulation. Radiographs are usually nonspecific. When results from indirect diagnostic procedures are equivocal, a bone biopsy is necessary. After a diagnosis of aluminum-related bone disease is established, therapy with DFO may be useful. DFO increases both the total plasma aluminum level and its ultrafilterable fraction. After an infusion of DFO, the removal of aluminum increases from 50 to 300 micrograms to 4 to 8 mg per dialysis session. Aluminum removal is similar during continuous ambulatory peritoneal dialysis after either intravenous (IV) or intraperitoneal (IP) administration of DFO. Usually, 2 to 4 g of DFO is administered once weekly, but the optimal dose and duration of therapy have not been determined. Symptoms usually improve after 4 to 12 weeks, and bone biopsies show improvement after treatment for 6 to 12 months. Further experience with DFO is needed, both to identify the optimal dosage and to clarify the risks of long-term therapy in patients with renal failure.

Aluminum↗
PubMed1986

Iliac crest bone biopsy for diagnosis of aluminum toxicity and a guide to the use of deferoxamine.

Diagnosis of aluminum-related bone disease in patients with renal failure often requires a bone biopsy. Percutaneous biopsy of the iliac crest has been safely carried out as an outpatient procedure in over 300 patients. No instances of significant bleeding or infection have occurred. The procedure was well accepted in 85% to 90% of patients recently surveyed. Before biopsy, each patient received two short courses of oral tetracycline, separated by a ten- to 14-day interval. Double tetracycline labeling permits the evaluation of dynamic characteristics of bone for the diagnosis of aplastic disease due to aluminum toxicity. When a diagnosis of aluminum toxicity is established, treatment with the chelating agent deferoxamine (DFO) administered during dialysis is effective for aluminum removal. Initially, a standardized infusion of DFO, 40 mg/kg, is administered over two hours immediately following dialysis treatment. The increase in plasma aluminum 24 to 48 hours following such an infusion provides an index of tissue aluminum stores and provides a guide to the appropriate therapeutic dose of DFO. DFO (2 to 4 g) is administered once weekly during the last two hours of dialysis; in rare cases higher dosages have been used. Reported side effects of DFO therapy include hypotension, hypoferremia, and allergic reactions; other investigators have reported ocular abnormalities and unusual infections. Patients are reevaluated after 6 to 12 months of therapy with a DFO infusion test and/or bone biopsy. However, the duration of therapy needed for the successful treatment of aluminum-related bone disease is uncertain.

Aluminum↗
PubMed1988

Cell cycle specific effects of deferoxamine on human and murine hematopoietic progenitor cells.

The effect of the iron chelator deferoxamine (DSF) on the proliferation of normal erythroid and granulocyte-macrophage progenitor cells from human and murine bone marrow was examined. The addition of DSF at a concentration equivalent to the concentration of iron present in the culture system resulted in dose dependent inhibition of colony formation by human and murine granulocyte-macrophage progenitor cells and human normal erythroid progenitor cells. The addition of FeCl3 at culture initiation completely reversed the effects of DSF. Furthermore, significant numbers of progenitor cells could be rescued from the effects of DSF by iron added back as late as 24-48 h after exposure to DSF. The cell cycle specificity of DSF was also examined using bone marrow cells treated with high specific activity tritiated thymidine. Kinetic experiments demonstrated that in the presence of DSF the number of erythroid or granulocyte-macrophage colonies that could be rescued was dependent on the length of exposure to DSF. Comparisons between control and tritiated thymidine treated cells indicated that the proliferation of progenitor cells in S phase of the cell cycle was inhibited if iron was withheld until 6 and 24 h after exposure to DSF for murine and human cells, respectively, with little to no effect observed on progenitor cells not in S phase during this time period. These results confirm the importance of iron for hematopoietic progenitor cell proliferation and represent a new method by which the proliferation of cycling cells may be investigated in situ in semisolid culture systems.

Animals↗
PubMed1988

Deferoxamine mesylate inhibits bacterial growth in vivo.

Iron is one of the essential element for bacterial growth. To study the effect of chelation of iron on bacterial growth, 17 different strains of bacteria were cultured in chocolate-agar medium in the presence or absence of deferoxamine methylate (DM), a potent chelating agent for iron. A fairly low concentration of DM (10 mg/ml) in the culture medium markedly inhibited the growth rates of the three bacterial strains, B. catarrhalis, N. meningiditis and N. gonorrhoeae. In vivo effect of DM was also tested in mice that were intraperitoneally inoculated with a lethal number of N. meningiditis (2 x 10(8)/animal). After 40 h of inoculation, more than 90% of the control animals died for acute peritonitis. In contrast, animals which were intraperitoneally administered with DM showed a marked resistance to the inoculated bacteria without showing toxic effects of the agent: less than 30% of animals died of acute peritonitis caused by infection within 40 h. The results suggest that, in addition to the currently used antibiotics. DM might also be an useful therapeutic agent for treatment of bacterial infection.

Animals↗
PubMed1987

In vitro and in vivo effects of deferoxamine in neonatal acute leukemia.

A six week old infant with acute leukemia failed to attain remission with chemotherapy. Because we previously demonstrated that the iron chelator deferoxamine (DFO) has antiproliferative properties and modulatory effects on cell differentiation, a protocol was designed for in vitro study and for clinical use in the patient. At diagnosis, blast cells were morphologically undifferentiated, had nondiagnostic cytochemistry, showed an abnormal karyotype (t[4;11]), expressed markers of B cell lineage, and demonstrated C mu gene rearrangement. Tissue culture of marrow or blood cells yielded colonies of leukemic blasts. Increasing concentrations of DFO produced a dose-dependent suppression of patient's blast colony growth in vitro, and blasts within colonies showed a marked change in surface antigen expression from lymphoid to myelomonocytic markers, became monocytic in appearance, and developed intense staining for nonspecific esterase. When DFO was given intravenously to the patient as a single agent for 48 hours, blasts no longer expressed lymphoid antigens and became strongly positive for myelomonocytic markers, identical to the in vitro findings. Intravenous DFO halted rising peripheral blood blast cell numbers and allowed a several-fold increase in normal hematopoietic progenitor colony growth. When combined with low-dose cytosine arabinoside in the treatment protocol, DFO caused striking leukemic cytoreduction. Our findings indicate that DFO has antileukemic properties by virtue of its effects on proliferation and differentiation, and they prompt further experimental and clinical studies with this agent.

Antigens, Neoplasm↗
PubMedDate not supplied

Neonatal hemochromatosis: failure of deferoxamine therapy.

We describe a premature neonate with severe hepatic dysfunction from birth which progressed to fatal hepatic failure at 3 months of age. The diagnosis of a familial disorder, neonatal hemochromatosis, was made, and therapy was attempted with deferoxamine. Features of iron metabolism are presented, and this infant's illness is contrasted with other liver diseases of infancy associated with hepatic iron overload.

Deferoxamine↗
PubMed1985

Storage iron exchange in the rat as affected by deferoxamine.

The initial tissue localization and redistribution of radioactive iron injected intravenously into the rat as ferritin, chondroitin sulfate, and nonviable red cells was determined. Ferritin iron, initially localized in the hepatocyte, showed minimal redistribution over 24 hours in the normal animal. This may be compared with the active release of iron from the reticuloendothelial cell after the intravenous injection of nonviable red cells and chondroitin sulfate iron. All forms of iron were actively mobilized in iron-deficient animals. The effect of chelation of iron by deferoxamine (DFO) on the redistribution pattern over 4 to 6 hours was determined in iron-deficient, normal, iron-loaded, and phenylhydrazine-treated rats to evaluate the effect of iron stores and erythropoiesis. Use of DFO resulted in extensive chelation of radioactive iron within the hepatocyte and greatly reduced the amount of hepatocyte iron available for erythropoiesis. Very little chelation of reticuloendothelial cell-processed iron occurred, and there was little decrease in its utilization for red cell production. Total urinary chelate iron was independent of erythropoiesis but varied in parallel with the iron load of the animal. These studies suggest that DFO does not act on the reticuloendothelial cell but does have at least two sites of action, both of which relate to total storage iron. One involves hepatocyte stores with excretion into the intestinal tract. The other, possibly located at the hepatocyte membrane, results in urinary iron excretion.

Anemia, Hemolytic↗
PubMed1985

Ultrafiltration studies in vitro of serum aluminum in dialysis patients after deferoxamine chelation therapy.

Using gel filtration chromatography, we evaluated aluminum bound to albumin, transferrin, and other plasma proteins in the serum of patients on maintenance hemodialysis. The proportion of dialyzable aluminum, as determined by selective membrane ultrafiltration and flameless atomic absorption spectrometry, increased by more than fourfold on treatment with the metal chelator, deferoxamine. This ultrafiltration technique may prove useful for monitoring the proportion of aluminum mobilized during such therapy.

Aluminum↗