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PubMed1996

Benefits of parenteral deferoxamine for acute iron poisoning.

OBJECTIVE: To review the benefits of deferoxamine for the treatment of iron poisoning. METHODS: Both the basic science and clinical literature on deferoxamine were reviewed by comprehensive computer literature search. This was supplemented by references identified from bibliographies of pertinent articles and books. RESULTS: The basic science literature supports deferoxamine as an attractive antidote for iron poisoning. There were no dose response studies in the human or animal literature. There were no randomized controlled trials or case controlled studies of patients with toxicity (serum iron concentration > 500 micrograms/dL). All data were descriptive and anecdotal. Therefore fundamental parameters such as indications for administration, dose, route and duration of therapy are unclear and efficacy is unproven. CONCLUSION: Deferoxamine is attractive for the treatment of iron poisoning despite the lack of knowledge for its optimal use and remains the drug of choice for the treatment of significant iron poisoning.

Administration, Oral↗
PubMed2003

Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage.

OBJECT: In the authors' previous studies they found that brain iron accumulation and oxidative stress contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study they investigated whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury. METHODS: Male Sprague-Dawley rats received an infusion of 100 microl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days thereafter. Iron distribution was examined histochemically (enhanced Perl reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Apurinic/apyrimidinic endonuclease/redox effector factor-1 (APE/Ref-1), a repair mechanism for DNA oxidative damage, was quantitated by Western blot analysis. Iron accumulation was observed in the perihematoma zone beginning 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in APE/Ref-1. CONCLUSIONS: Deferoxamine and other iron chelators may be potential therapeutic agents for treating ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.

Animals↗
PubMed2004

Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage.

OBJECT: Previous studies undertaken by the authors have indicated that iron accumulation and oxidative stress in the brain contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study the authors investigate whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury. METHODS: Male Sprague-Dawley rats each received an infusion of 100 microl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days later. Iron distribution was examined histochemically (enhanced Perls reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Immunohistochemical analysis was performed to investigate 8-hydroxyl-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and Western blot analysis was performed to measure the amount of apurinic/apyrimidinic endonuclease/redox effector factor-1 (APE/Ref-1), a repair mechanism for DNA oxidative damage. Iron accumulation was observed in the perihematomal zone from 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in 8-OHdG and APE/Ref-1. CONCLUSIONS: Deferoxamine and other iron chelators may be potential therapeutic agents for ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.

Animals↗
PubMed1984

Use of the deferoxamine infusion test in the diagnosis of aluminum-related osteodystrophy.

The accumulation of aluminum in bone can cause disabling osteodystrophy in patients with renal failure. Because the chelating agent deferoxamine can mobilize aluminum from tissues, we evaluated the effect of a standard intravenous dose of deferoxamine on plasma aluminum concentrations in 54 patients on hemodialysis. Stainable bone aluminum, bone histologic findings, and bone aluminum content were studied. Baseline plasma aluminum concentrations of greater than 200 micrograms/L were associated with aluminum-related osteodystrophy (specificity, 93%), but concentrations of less than 200 micrograms/L did not exclude the diagnosis (sensitivity, 43%). After administration of deferoxamine, the increase in plasma aluminum concentration was 534 +/- 260 (SD) and 214 +/- 92 micrograms/L in patients with and without aluminum-related bone disease, respectively (p less than 0.001), and correlated with the bone aluminum content (r = 0.64). An increment in plasma aluminum concentration of greater than 200 micrograms/L identified 35 of the 37 patients with aluminum-related osteodystrophy; sensitivity was 94% and specificity, 50%. The deferoxamine infusion test is noninvasive, well tolerated, and of value particularly in excluding the diagnosis of aluminum-related osteodystrophy.

Aluminum↗
PubMed2000

Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia.

The optimal regimen of intravenous deferoxamine for iron overload in high-risk homozygous beta-thalassemia is unknown because only short-term follow-up has been described in small patient groups. We report the outcome over a 16-year period of a continuous 24-hour deferoxamine regimen, with dose adjustment for serum ferritin, delivered via 25 indwelling intravenous lines for 17 patients. Treatment indications were cardiac arrhythmias, left ventricular dysfunction, gross iron overload, and intolerability of subcutaneous deferoxamine. Cardiac arrhythmias were reversed in 6 of 6 patients, and the left ventricular ejection fraction improved in 7 of 9 patients from a mean (+/- SEM) of 36 +/- 2% to 49 +/- 3% (P =.002, n = 9). The serum ferritin fell in a biphasic manner from a pretherapy mean of 6281 +/- 562 microg/L to 3736 +/- 466 microg/L (P =.001), falling rapidly and proportionally to the pretreatment ferritin (r(2) = 0.99) for values >3000 microg/L but falling less rapidly below this value (at 133 +/- 22 microg/L/mo). The principal catheter-related complications were infection and thromboembolism (1. 15 and 0.48 per 1000 catheter days, respectively), rates similar to other patient groups. Only one case of reversible deferoxamine toxicity was observed (retinal) when the therapeutic index was briefly exceeded. An actuarial survival of 61% at 13 years with no treatment-related mortality provides evidence of the value of this protocol. (Blood. 2000;95:1229-1236)

Actuarial Analysis↗
PubMed2002

[Ocular toxicity of deferoxamine: description and analysis of three observations].

INTRODUCTION: Deferoxamine is a specific chelating agent of trivalent anions: iron ion and aluminum ion. The main prescriptions for this treatment are primary non-curable by blood letting hemochromatosis, secondary hemosiderosis, and aluminum intoxication associated with chronic kidney failure. Since the early 1980s, ocular toxicity has been documented in several publications. OBSERVATIONS: We recorded three clinical observations of patients presenting symptoms of an ocular toxicity caused by deferoxamine. The prescription of this treatment related to the presence of secondary hemosiderosis (a case of primitive myelofibrosis and a case of chronic myelomonocytic leukemia treated by blood transfusion) and an aluminum intoxication affecting a patient with chronic kidney failure. All three patients presented a gradual loss of visual acuity. The following were predominantly observed at the fundus examination which showed pigmentary anomalies near the macula such as mottling and dispersion affecting the electrophysiological studies. The termination of the treatment did not result in an improvement in the symptomatology. DISCUSSION: Considering the latest literature on the subject, the indications as well as the pharmaceutical properties of deferoxamine, the ophthalmological symptoms of this intoxication, the additional investigations and the anatomicopathological analyses are restated, together with the current pathogenical hypothesis. CONCLUSION: Deferoxamine can cause ocular toxicity resulting in severe and permanent lesions of the retinal pigment epithelium. The occurrence of disorders of the fundus and visual acuity requires, before and during the treatment, regular ophthalmological monitoring combined with electrophysiological explorations. This allows early treatment of the hematological or kidney disorder.

Aged↗
PubMed1992

Tempol and deferoxamine protect cultured rabbit lens epithelial cells from H2O2 insult: insight into the mechanism of H2O2-induced injury.

In order to investigate the mechanism by which H2O2 damages the epithelium, 8 x 10(5) rabbit lens epithelial cells were treated with TEMPOL or deferoxamine and exposed to a single sublethal dose of 0.5 mM H2O2. TEMPOL is a SOD mimic, has a characteristic EPR spectrum and is metal independent. EPR spectra indicated that TEMPOL was not destroyed by H2O2, catalyzed the destruction of the superoxide anion, and penetrated the cells. Cells treated with H2O2 showed membrane blebbing, growth inhibition, an increase in GSSG, a dose-dependent decrease in GSH, ATP, NAD+, and in the activity of G3PDH, and in lactate production. H2O2 stimulated the hexose mono-phosphate shunt and induced single strand breaks in DNA. Treatment with TEMPOL or deferoxamine prevented or curtailed H2O2-induced inhibition of growth, the decrease in NAD+, the induction of single strand breaks in DNA, and membrane blebbing, but not the other biochemical parameters investigated. Both TEMPOL and deferoxamine prevent Fe+2-mediated generation of the damaging hydroxyl radical. TEMPOL reacts with superoxide and thus prevents it from recycling Fe+3 to Fe+2. It also oxidizes DNA-Fe+2 to DNA-Fe+3. Deferoxamine chelates intracellular Fe+3 and prevents its reduction to Fe+2. These compounds which limit the availability of Fe+2 by different means indicate that transition metals (including those bound to DNA) mediate certain of the damaging effects of H2O2.

Adenosine Triphosphate↗
PubMed1991

Aluminum and deferoxamine kinetics in CAPD.

Reduced renal clearance of aluminum and regular intake of aluminum containing phosphate binders render dialysis patients at increased risk of aluminum accumulation and toxicity. Provided the inflow dialysate aluminum concentration is kept low (less than 10 micrograms/L) most CAPD patients have negative peritoneal mass transfer of aluminum in the effluent dialysate. Net removal of aluminum in the dialysate partially compensates for the loss of renal clearance of aluminum and helps prevent progressive tissue accumulation of aluminum. Rates of aluminum removal in the dialysate are too low, however, for effective treatment of patients with established aluminum accumulation or overt aluminum toxicity. Such patients usually require parenteral deferoxamine therapy to achieve increased aluminum removal rates. The optimum route, dosage and frequency of administration of deferoxamine in CAPD patients are not established. From the existing data, 2 g deferoxamine administration intraperitoneally three times per week in the overnight exchange appears to provide the maximum aluminum removal for minimum deferoxamine dosage.

Aluminum↗
PubMed2006

A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassemia.

We compared the safety and efficacy of alternating deferoxamine and deferiprone with that of deferoxamine monotherapy. Sixty transfusion-dependent thalassemia patients regularly treated with deferoxamine were randomized to continue deferoxamine alone or to receive an alternating therapy for one year. Both arms resulted in equivalent decreases of serum ferritin and liver iron concentration. There was no significant difference in the proportion of patients with adverse events in the two therapy groups although the nature of the adverse events differed according to the chelation regimen.

Adolescent↗
PubMed1990

Effect of deferoxamine pretreatment on acute pneumonic pasteurellosis and neutrophil oxidative metabolism in calves.

Iron plays a central role in bacterial infections, influencing both bacterial virulence and host cellular defense mechanisms. We investigated whether iron chelation might be of benefit in the treatment of pneumonic pasteurellosis of calves. Neutrophils obtained from calves previously treated with the iron chelator, deferoxamine, were studied for their responses to latex and opsonized zymosan by luminol-enhanced chemiluminescence and to phorbol myristate acetate and opsonized zymosan by superoxide generation. Treatment with deferoxamine in vivo failed to influence these in vitro measures of neutrophil oxidative metabolism. Furthermore, iron depletion with deferoxamine failed to modify the pathophysiological derangements that occurred in calves following experimental induction of pneumonia by intratracheal inoculation with Pasteurella haemolytica. These data indicate that iron chelation using deferoxamine cannot be recommended as an adjunct to conventional therapy in the treatment of pneumonic pasteurellosis of cattle.

Acute Disease↗
PubMed1988

Mechanism of antineuroblastoma activity of deferoxamine in vitro.

Deferoxamine previously has been shown to have potent activity in vitro against human neuroblastoma cells, activity that results from its ability to chelate iron. To further understand the mechanism of deferoxamine-induced cytotoxicity, we looked at its effects on cell cycling and on DNA, RNA, and protein synthesis by CHP 126, a cell line that is derived from tumor tissue of a patient with a neuroblastoma and that is known to be drug sensitive. After 24 hours of exposure to 60 mumol/L deferoxamine, there was a 35% increase in the percent of cells in the nonproliferating and prereplicative phases of the cell cycle and a corresponding decrease in the percent of cells in the DNA synthesis, postreplicative, and mitotic phases of the cell cycle, results that are consistent with a block of cell cycle progression at the early DNA synthesis phase. The inhibitory effects of deferoxamine on DNA synthesis were confirmed by demonstration of a 60% decrease in thymidine incorporation into DNA in short-term cultures of CHP 126. Effects on RNA and protein synthesis were minimal. Equivalent effects on growth were seen by using several chelators that interact with different iron pools, suggesting that both intracellular and extracellular iron are required for growth of neuroblastoma cells.

2,2'-Dipyridyl↗
PubMed1989

Oxygen-based free radical generation by ferrous ions and deferoxamine.

Deferoxamine accelerates the autooxidation of iron as measured by the rapid disappearance of Fe2+, the associated appearance of Fe3+, and the uptake of oxygen. Protons are released in the reaction. The formation of H2O2 was detected by the horseradish peroxidase-catalyzed oxidation of scopoletin, and the formation of hydroxyl radicals (OH.) was suggested by the formation of the OH. spin trap adduct (DMPO/OH). with the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and the generation of the methyl radical adduct on the further addition of dimethyl sulfoxide. (DMPO/OH). adduct formation was inhibited by catalase but not by superoxide dismutase. The oxidant formed converted iodide to a trichloroacetic acid-precipitable form (iodination) and was bactericidal to logarithmic phase Escherichia coli. Both iodination and bactericidal activity was inhibited by catalase and by OH. scavengers, but not by superoxide dismutase. Iodination was optimal in 5 x 10(-4) M acetate buffer, pH 5.0, and when the Fe2+ and deferoxamine concentrations were equimolar at 10(-4) M. Fe2+ could not be replaced by Fe3+, Co2+, Zn2+, Ca2+, Mg2+, or Mn2+, or deferoxamine by EDTA, diethylenetriaminepentaacetic acid, or bathophenanthroline. These findings indicate that Fe2+ and deferoxamine can act as an oxygen radical generating system, which may contribute to its biological effects in vitro and in vivo.

Catalase↗
PubMed1989

Comparison of activity of deferoxamine with that of oral iron chelators against human neuroblastoma cell lines.

The iron chelator, deferoxamine, has demonstrated cytotoxicity against neuroblastoma cells. In this study we examined the in vitro antineuroblastoma activity of several potentially less expensive oral chelating agents. On a mole for mole basis, 1-hydroxypyridine-2-thionine (omadine) had 100 times the cytotoxicity of deferoxamine. 1,2-Dimethyl-3-hydroxypyrid-4-one also caused demonstrable cell death but at considerably higher molar concentrations than those required for deferoxamine. 2,3-Dihydroxybenzoic acid had no effect on neuroblastoma cell viability over a range of concentrations. In contrast to the effect of both deferoxamine and 1,2-Dimethyl-3-hydroxypyrid-4-one, those due to omadine were permanent within 24 hours of incubation, were not significantly altered by the presence of ionic iron, and correlated with an increase in the percentage of cells in the S-G2-M phases of the cell cycle. On the basis of these in vitro studies, we believe that the use of omadine in particular and iron chelators in general, by themselves or as cell cycle-recruiting agents together with standard cell cycle specific drugs, is an approach to the treatment of cancer worth further investigation.

Administration, Oral↗
PubMed1987

A study of the ototoxicity of deferoxamine in chinchilla.

Deferoxamine is a chelating agent used for the treatment of chronic iron overload in patients requiring long-term blood transfusions. Audiological testing of patients with B-thalassemia major and steroid-unresponsive Diamond-Blackfan anemia who were on long-term deferoxamine treatment indicated a possible ototoxic side-effect. In the present study we have investigated this potential toxicity to the cochlea of experimental animals by monitoring electrophysiological responses to sound and also by histological evaluation of the cochlea. In animals having chronic deferoxamine treatment, there were no significant changes in cochlear function or morphology. Data from acutely treated animals indicated an elevation of cochlear response thresholds together with morphological changes at the inner hair-cell level. However, these changes were highly correlated with the respiratory depression caused by an acute general toxicity, rather than a direct ototoxic effect of deferoxamine.

Animals↗
PubMed1986

Encephalopathy in chronic renal failure responsive to deferoxamine therapy. Another manifestation of aluminum neurotoxicity.

We describe a patient undergoing chronic hemodialysis who developed a neurologic syndrome consisting of seizures, progressive myoclonus, and mild dementia and who responded to chelation therapy with deferoxamine mesylate. Neither her serum nor bone aluminum concentrations indicated aluminum toxicity. However, the presence of a positive deferoxamine-infusion test was suggestive of an elevated body burden of aluminum. Treatment with deferoxamine resulted in marked clinical improvement in her neurologic status within two months. The utility of using the deferoxamine-infusion test rather than serum aluminum levels in evaluating aluminum toxicity in chronic renal failure is suggested.

Aluminum↗
PubMed1984

Deferoxamine: a reversible S-phase inhibitor of human lymphocyte proliferation.

Deferoxamine is widely used therapeutically as a chelator of ferric ion in disorders of iron overload. This study demonstrates that this drug is a potent inhibitor of DNA synthesis by human B and T lymphocytes in vitro, but has relatively little effect on the synthesis of RNA and protein. The inhibitory effects of deferoxamine are completely reversible by washing or by adding stoichiometric amounts of Fe3+. Micromolar concentrations of deferoxamine decrease intracellular levels of deoxyribonucleoside triphosphates, which is similar to the effects of hydroxyurea. The binding of iron by deferoxamine likely causes an inhibition of ribonucleotide reductase activity, thereby preventing cells from completing the S phase of the cell proliferation cycle. As a reversible and nontoxic S-phase inhibitor, it may have important experimental and therapeutic applications.

Adolescent↗
PubMed1996

[Effect of deferoxamine on erythropoiesis in patients hemodialyzed for chronic renal insufficiency treated with erythropoietin].

The aim of the study was to evaluate the effect of deferoxamine therapy on erythropoiesis, aluminium concentration and iron metabolism in hemodialyzed patients with chronic renal insufficiency treated with human recombinant erythropoietin (Eprex, Cilag). 8 hemodialyzed patients (2 female and 6 male) in long-term programme with aluminium serum concentration over 160 micrograms/l were treated with deferoxamine (5 mg/kg b.m.) during the last hour of hemodialysis in slowly intravenous infusion since 1 months. During this treatment aluminium and iron serum concentrations, serum iron-binding capacity, transferrin and hematocrit were determined before and after 1 months of deferoxamine therapy. The significant decrease of aluminium serum concentration (p < 0.05) and increase of hematocrit (p < 0.01), iron (p < 0.05) and serum iron-binding capacity (p < 0.001) were determined. The results of performed analysis indicate that aluminium is able to inhibit erythropoiesis induced by erythropoietin. The improvement in erythropoiesis and iron metabolism after deferoxamine therapy was observed.

Adult↗
PubMedDate not supplied

The effect of deferoxamine on ciprofibrate-induced hepatocarcinogenesis in the rat.

BACKGROUND: Peroxisome proliferators (PP) are proven hepatocarcinogens in rats and mice. The carcinogenic effect of PP has been attributed to the oxidative stress that results from generation of high levels of hydrogen peroxide (H2O2). Since the hydroxyl radical is produced via metal mediated reaction from H2O2 and is DNA reactive, we have examined the effect of deferoxamine, the specific iron chelator, on ciprofibrate-induced hepatocarcinogenesis. MATERIALS AND METHODS: Male F-344 rats were fed a diet containing ciprofibrate (0.025%) alone or ciprofibrate plus deferoxamine (0.3% or 0.6%) for 60 to 61 weeks, and the livers were analyzed for the incidence, number and size of the tumors. RESULTS: One hundred percent of rats in all groups developed neoplastic nodules and hepatocellular carcinomas. However, in rats given a higher dose of deferoxamine there was a significant decrease in the number of tumors per liver and the number of tumors larger than 10mm. CONCLUSIONS: Although deferoxamine did not prevent tumor development, at the higher dose level it caused a decrease in the number of tumors. These findings indicate that the decreased tumor numbers maybe due to a reduction in the level of hydroxyl radicals.

Animals↗