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PubMed1998

Subcutaneous bolus injection of deferoxamine in adult patients affected by onco-hematologic diseases and iron overload.

BACKGROUND AND OBJECTIVE: Chelation therapy is often necessary for patients who undergo chronic transfusion therapy for myelodysplastic syndromes. In these patients, deferoxamine, the most widely used chelating agent, has been reported to be effective in reducing the iron burden and the transfusion requirement. Unfortunately, compliance with the drug, that is usually administered by slow subcutaneous infusion via a battery operated pump, is often poor, especially in elderly patients. DESIGN AND METHODS: To verify efficacy and tolerability of deferoxamine by subcutaneous bolus injection as compared to the conventional pump-driven slow infusion, eleven patients affected by oncohematologic diseases were given 2 g of deferoxamine diluted in 10 mL of distilled water over twelve hours by continuous infusion, or by bolus injection in two divided doses. RESULTS: Mean urinary excretion was comparable with the two methods, being 9,183 +/- 4,349 micrograms/48 h after two daily subcutaneous bolus injections and 8,291 +/- 3,970 micrograms/48 h with the slow infusion. The bolus injection was preferred by all eleven patients, who chose to continue chelation therapy by this method. INTERPRETATION AND CONCLUSIONS: The iron excretion induced by bolus injection is not statistically different from that induced by subcutaneous infusion. The side effects are acceptable. Subcutaneous bolus injection of deferoxamine is an acceptable alternative to slow, pump-driven infusion.

Adult↗

PubMed1998

Modulation of ras p21 oncoprotein levels and DNA strand breakage in human cells with chemotherapeutic agents and/or deferoxamine.

Oncogenes are involved with the regulation of cellular proliferation. Ras oncogenes can be activated by chemical treatment and any increased activity could be modulated by further chemical treatment. In the present study, therefore, ras p21 protein expression was examined in in vitro cultures of human lymphocytes treated with mitomycin C and in the human colon adenocarcinoma Caco-2 cell line treated with doxorubicin with and without deferoxamine. Both chemotherapeutic agents act partially through oxygen radical mechanisms. Increases in p21 protein levels were seen with mitomycin C but no clear response was seen with doxorubicin. However, deferoxamine, with and without doxorubicin, altered p21 expression. Deferoxamine is an iron chelator so these results support the hypothesis that oxygen radicals were responsible for the altered p21 protein levels. Modulating responses were confirmed by measuring DNA strand-breakage in the Comet assay after treatment with doxorubicin and deferoxamine. Alterations of ras p21 protein expression in vitro might prove a suitable system for examining modulating effects on chemical carcinogens.

Antineoplastic Agents↗

PubMed2000

Synthesis and solution properties of deferoxamine amides.

The poor membrane permeability and oral bioavailability of the iron chelating agent deferoxamine (DFO) mesylate result from the low octanol/water partition coefficient and high aqueous solubility. With the ultimate aim to improve biomembrane permeability while retaining the iron-binding ability of DFO, a series of more lipophilic amides were prepared by reacting the terminal primary amino group with fatty and aromatic acid chlorides or anhydrides. Octanol/water partition coefficients and equilibrium solubilities of these analogs in solvents, chosen to delineate physicochemical interactions, were determined as a function of temperature. Solid-state properties were evaluated by calorimetry. All DFO amide derivatives had higher melting points, indicating that derivatives formed strong intermolecular interactions in the solid phase. Formamidation of the primary amine of deferoxamine resulted in a 200-fold increase in the octanol/water partition coefficient and reduced aqueous solubility at least 2000-fold compared with the parent molecule. The partition coefficient increased and aqueous solubility decreased 2-fold with the addition of each methylene group in the homologous series of aliphatic amides. Solubilities of the derivatives in water-saturated octanol and hexane showed irregular profiles as a function of increasing aliphatic chain length that were attributed to intermolecular packing in the solid state. The temperature dependence of the partition coefficients was interpreted to indicate that interfacial transfer of the deferoxamine amides was, in part, affected by an apparent diminished ability to form energetically favorable interactions in the water-saturated organic phase.

Amides↗

PubMed2006

Tandem mass spectrometry of coprogen and deferoxamine hydroxamic siderophores.

Mechanisms of fragmentation of hydroxamic siderophores are proposed comparing deuterated and nondeuterated samples. Standard siderophores (e.g. deferoxamine and coprogen) were directly injected into both ion trap and linear quadrupole mass spectrometers with electrospray ionization (ESI). Four and two fragmentation steps were carried out for deferoxamine and coprogen (analyzed by positive and negative ESI, respectively). Deferoxamine cleavages occurred in both peptide and hydroxamic bonds while the coprogen fragmentation pattern is more elaborate, since it contains Fe(III) in its structure.

Chromatography, Liquid↗

PubMed1993

Deferoxamine reduces the reperfusion injury in isolated neonatal rabbit hearts after hypothermic preservation.

The protective action of deferoxamine, an iron chelator, against reperfusion injury following hypothermic preservation was investigated in the Langendorff-perfused hearts of neonatal rabbits. Left ventricular function and radical generation were used as parameters to evaluate functional and metabolic changes. The free radicals in coronary effluents were measured with an electron spin resonance spectroscope using a spin trapping agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). The hearts were preserved in cold St. Thomas solution at 4 degrees C for 6 h following cardiac arrest, then reperfused with oxygenated Krebs-Henseleit solution in a control. Deferoxamine (100 microM) was added to the perfusate just prior to reperfusion in group I, and 3 min after the start of reperfusion in group II. In the control group, the left ventricular developed pressure (LVDP) after 30-min reperfusion recovered up to 43.5 +/- 3.1% (mean +/- SD, n = 5) the preischemic value. Group I showed a significant improvement in LVDP recovery after 30-min reperfusion at 57.1 +/- 3.1% (P < 0.01 vs control), but group II did not (47.5 +/- 2.3%). When a burst of DMPO-OH signals was detected during the initial 5 min of reperfusion, the signal intensity in group I was significantly reduced to about 35-40% of the control value. Group II showed a similar intensity to the control group. Thus, we conclude that deferoxamine may exert a protective action against the dysfunction of neonatal mammalian hearts induced by preservation-reperfusion through an inhibition of iron-catalyzed radical formation.

Animals↗

PubMed1997

[Deferoxamine-conjugated hydroxyethyl starch reduces reperfusion injury to the liver following hemorrhagic shock].

UNLABELLED: Deferoxamine is known to reduce the iron-dependent generation of toxic oxygen-derived radicals during reperfusion of ischaemic tissue. The present study investigates the antioxidative properties of a deferoxamine-conjugated hydroxyethyl starch solution and its effects on the hepatic microcirculation in a haemorrhagic-shock rat model. METHODS: Anaesthetized Sprague-Dawley rats were tracheotomized, prepared for invasive haemodynamic monitoring, and subject to haemorrhagic shock (MAP = 40 mmHg during 60 min). The animals were resuscitated blood-free with lactated Ringer's (RILA, n = 10), gelatin (GELA, n = 10), hydroxyethyl starch (HES, n = 10), or deferoxamine-conjugated HES (DFO, n = 8) solution (MAP > or = 70 mmHg). After 1 h of resuscitation the hepatic microcirculation was investigated by intravital microscopy, the glutathione concentration was measured in liver homogenate, and the thiobarbituric acid reactive substances (TBARS) were determined as markers of lipid peroxidation. RESULTS: Resuscitation resulted in restoration of MAP to > or = 70 mmHg within a short time. The volume required to stabilise the arterial pressure during 1 h of resuscitation was significantly less in the DFO group compared with HES, GELA, and RILA. Significantly higher glutathione levels in liver homogenate as well as decreased TBARS levels were observed in the DFO group. The shock-induced increase of leukocyte adhesion in liver sinusoids was significantly attenuated by DFO. CONCLUSION: DFO significantly attenuates shock-induced oxidative stress, thereby reducing the early inflammatory reaction and improving the hepatic microcirculation.

Animals↗

PubMed1997

Pulmonary embolism developing in patients with sickle cell disease on hypertransfusion and IV deferoxamine chelation therapy.

Pulmonary disease, including thromboembolic problems, accounts for a large portion of the morbidity of sickle cell disease. Chronic transfusion therapy is now a part of long-term treatment of sickle cell patients with stroke and chest syndrome. The resultant iron overload must be treated with chelation therapy using deferoxamine. Poor compliance with subcutaneous chelation therapy has necessitated intravenous deferoxamine treatment. We describe two patients with sickle cell disease on such a regimen, who became hypoxic as a result of pulmonary thromboembolism, secondary to venous thrombophlebitis. The thrombophlebitis and subsequent pulmonary embolism probably reflect the hypercoagulable state seen in sickle cell and are not due to the deferoxamine therapy.

Adolescent↗

PubMed2003

Acute renal failure following deferoxamine overdose.

A 17-year-old patient with sickle cell-beta thalassemia undergoing treatment with home iron chelation therapy inadvertently received ten times the recommended dose of intravenous deferoxamine. Acute renal failure (ARF) developed within hours. Immediate treatment with high-efficiency hemodialysis resulted in the prompt return of renal function after only one hemodialysis session. No long-term nephrotoxic effects of the deferoxamine overdose developed after more than 1 year of follow-up. Children with sickle cell disease who are on intravenous deferoxamine and their parents should be cautioned about the possibility of ARF with overdose due to malfunction of the pump and/or inadequate monitoring during treatment. ARF, should it occur in such children, appears to respond well to treatment with high-efficiency hemodialysis.

Acute Kidney Injury↗

PubMed1996

Deferoxamine improves spatial memory performance following experimental brain injury in rats.

Traumatic brain injury (TBI) causes impairments of both motor and spatial memory performances. Research is only beginning to reveal the biochemical mechanism(s) underlying these deficits. It has been postulated that reactive oxygen species such as the superoxide and hydroxyl radicals, as well as the peroxynitrite anion, are generated by injury and may play a critical role in the observed memory deficits. The highly reactive hydroxyl radical, which is thought to contribute to neuronal toxicity, can be generated by an iron-catalyzed reaction. The source of this iron (or iron-bound proteins) could be a compromise of the blood-brain barrier, which can occur following TBI. In this report, we investigate the ability of deferoxamine, a scavenger of free iron, the hydroxyl radical and the peroxynitrite anion, to facilitate behavioral recovery following a controlled cortical impact of rats. Intraperitoneal administration of this drug prior to the injury did not affect the rate of recovery from motor deficits in comparison to vehicle (saline)-injected animals. However, deferoxamine-treated animals showed significant improvement in spatial memory performance in a Morris water maze task. Volumetric analysis of cortical tissue loss showed no significant differences between vehicle- and drug-injected animals. Similarly, histological examination of the hippocampus did not reveal any gross differences between the two groups. These results indicate that deferoxamine improves spatial memory performance, possibly through protection from neuronal dysfunction.

Animals↗

PubMed1989

The effect of deferoxamine on tolerance to secondary ischaemia caused by venous obstruction.

The current study investigated the efficacy of deferoxamine for treating secondary ischaemia due to venous obstruction in a rodent epigastric pedicle flap model. Rats receiving one dose of the free radical scavenger and iron chelator deferoxamine (150 mg/kg) intravenously prior to reperfusion had a mild improvement in flap survival: 46% in controls, 77% in deferoxamine-treated. This was statistically significant at p less than 0.05 (chi 2 = 5.2). This suggests that free radicals are partly involved in the mechanism of ischaemia/reperfusion injury in secondary ischaemia, as has been previously demonstrated for primary ischaemia (Angel et al., 1986b). Supporting biochemical evidence will be necessary to understand better the mechanisms involved in secondary ischaemia.

Animals↗

PubMed1994

The effect of deferoxamine on brain lipid peroxide levels and Na-K ATPase activity following experimental subarachnoid hemorrhage.

1. In the present study we have studied the effects of deferoxamine treatment on lipid peroxidation and Na-K ATPase activity after experimental induction of subarachnoid haemorrhage (SAH) in guinea pigs. 2. We assessed the extent of lipid peroxidation by measuring the level of malondialdehyde and Na-K ATPase activity in 3 different groups (sham-operated, SAH, SAH + deferoxamine). 3. There was no significant difference in lipid peroxide content between sham-operated and haemorrhagic animals, but Na-K ATPase activity decreased after SAH. 4. Deferoxamine treatment reduced the malondialdehyde content and induced the recovery of Na-K ATPase activity, exerting a brain protective role against the detrimental effects of the haemorrhage.

Animals↗

PubMed1998

Deferoxamine blocks interactions of fluoride and carbachol in isolated mammalian cardiac preparations.

In papillary muscles, carbachol reduced the positive inotropic effects of isoprenaline (10 nmol/l). The negative inotropic effects of carbachol in isoprenaline-stimulated guinea pig papillary muscles were attenuated by additionally applied sodium fluoride (3 mmol/l). These effects of sodium fluoride were blocked by deferoxamine (200 micromol/l). In guinea pig left atria, sodium fluoride alone greatly reduced force of contraction. These effects in atria were blocked by 200 micromol/l deferoxamine, and positive inotropic effects of sodium fluoride were observed. It is suggested that the cardiac effects of muscarinic M2 receptor agonists in the ventricle involve, at least in part, the activation of phosphatases which are blocked by fluoride and reactivated by deferoxamine.

Adrenergic beta-Agonists↗

PubMed1978

Excretion of iron in response to deferoxamine in sickle cell anemia.

Iron chelation with deferoxamine was studied in ten patients with sickle cell anemia who had received 2 to 37 liters of red blood cells. Urinary excretion of iron in response to 1.5 gm of deferoxamine administered intravenously ranged from 5.9 to 28.7 mg/24 hours and was closely related to the amount of iron acquired from transfusions. Administration of ascorbic acid did not improve deferoxamine-induced excretion of iron. Urinary excretion of iron in response to 0.75 gm of DFO intramuscularly was 4.7 to 6.9 mg/24 hours in three patients who had received 15 to 37 liters of red cells. The data indicate that measurement of DFO-induced excretion of iron is of value in detecting increased iron stores in children with sickle cell anemia who have received repeated transfusions and that chelation therapy will retard the accumulation of iron.

Adolescent↗

PubMed1986

Effect of deferoxamine on late deaths following CPR in rats.

The iron-chelating agent deferoxamine was studied in an animal model as postresuscitation therapy to prevent late deaths and brain damage following total circulatory arrest and resuscitation. Cardiorespiratory arrest was induced by injection of cold, 1% KCl into the left ventricles of ketamine-anesthetized rats pretreated with succinylcholine, and by discontinuation of positive pressure ventilation. CPR was begun after six minutes, and animals with return of spontaneous circulation were entered into the study. Within five minutes after return of spontaneous circulation, treated animals received deferoxamine (50 mg/kg, IV). At ten days, 16 of 25 (64%) of treated animals had survived without neurologic deficit, compared to nine of 25 (36%) of controls (chi square = 3.92, P less than .05). Chelation of intracellular iron by deferoxamine may have prevented free-radical-mediated reactions that led to late deaths in control animals.

Animals↗

PubMed1991

Deferoxamine therapy and mucormycosis in dialysis patients: report of an international registry.

Fifty-nine cases of mucormycosis in dialysis patients have been reported to the registry (25 new cases and 34 previously reported cases). The presenting forms of mucormycosis included disseminated in 44%, rhinocerebral in 31%, and other forms in 25%. The diagnosis was made during life in only 39%, while the diagnosis was discovered at autopsy in 61% of the cases. The fungus, cultured in only 36%, was always Rhizopus. The infection was fatal in 86% of cases. No known risk factors for fungal infections, eg, diabetes mellitus, liver disease, splenectomy, neutropenia, steroid therapy, or other immunosuppressive therapy, were present in 70% of patients, but 78% of patients were being treated with deferoxamine. The role played by this drug and more particularly by its iron chelate, feroxamine, in the pathogenesis of mucormycosis in these patients is underscored. Because of this risk, deferoxamine therapy in dialysis patients should be limited to severe aluminum toxicity, the deferoxamine should be given at the lowest possible dose, and dialytic methods to augment the removal of feroxamine should be studied.

Adolescent↗

PubMed2000

The neuroprotective effect of deferoxamine in the hypoxic-ischemic immature mouse brain.

The iron chelator deferoxamine is efficacious in ameliorating hypoxic-ischemic brain injury in some models, perhaps by decreasing oxidative stress. Transgenic copper/zinc superoxide dismutase-1 (SOD1) overexpression in neonatal mice increases brain injury after hypoxia-ischemia compared to non-transgenic wildtype littermates because of increased oxidative stress. A neonatal mouse model of hypoxia-ischemia was used to examine histopathological damage, iron histochemistry and free iron concentration in the brains of SOD1 transgenic and non-transgenic littermates. Deferoxamine significantly decreased injury in non-transgenics compared to controls with a trend toward neuroprotection in the transgenics. There was no difference in free iron concentrations in the brains of SOD1 overexpressors or non-transgenics. Deferoxamine may protect the neonatal brain by a number of anti-oxidant mechanisms including iron chelation, enhancement of stress gene expression, or induction of other factors responsible for neuroprotection.

Animals↗

PubMed2000

Chromate-induced human erythrocytes haemoglobin oxidation and peroxidation: influence of vitamin E, vitamin C, salicylate, deferoxamine, and N-ethylmaleimide.

In order to attenuate or to prevent chromate-induced human erythrocytes injury, the influence of vitamin E, vitamin C, salicylate, deferoxamine, and N-ethylmaleimide on chromate-induced human erythrocytes haemoglobin oxidation and peroxidation were investigated. It was observed that pretreatment of human erythrocytes with vitamin E (20 microM), vitamin C (1 mM), salicylate (3 mM), and deferoxamine (4 mM) significantly increased (P=0.0001) chromate-induced human erythrocytes haemoglobin oxidation in a time dependent manner, while it was significantly decreased (P=0.0001) by pretreatment with N-ethylmaleimide (1 mM). In contrast, pretreatment of human erythrocytes with deferoxamine (4 mM) immediately inhibited (P=0.0001) chromate-induced human erythrocytes peroxidation, while it was significantly increased (P=0.0001) by pretreatment with N-ethylmaleimide (1 mM) during the first 4 h of cells exposition to chromate. For time periods superior to 6 h pretreatment with N-ethylmaleimide (1 mM) significantly decreased (P=0.0001) chromate-induced human erythrocytes peroxidation. It was concluded that care must be taken as these drugs are used to prevent against toxicity induced by chromium(VI) compounds.

Ascorbic Acid↗

PubMed2001

Long-term administration of high-dose deferoxamine 2 days per week in thalassemic patients.

OBJECTIVE: Compliance with parenteral administration of deferoxamine is often poor in thalassemic patients with iron overload. We tested the efficacy and tolerance of the drug at high dosage 2 d per week for 24 months in two adult thalassemic patients with permanently high serum ferritin using a portable pump and an implanted chamber. METHODS: Deferoxamine was administered using a pressure-operated portable pump through an implanted chamber. The patients were infused over 48 h every week with 198 mg/kg/d (patient 1) and 170 mg/kg/d (patient 2). Serum ferritin levels were measured at regular intervals. RESULTS: Serum ferritin decreased progressively from 2967 to 457 microg/L in patient 1 and from 6476 to 1951 microg/L in patient 2. Compliance and tolerance to treatment were excellent in the two patients. CONCLUSION: Intravenous administration of high-dose deferoxamine over 48 h per week using a portable pump and implanted chamber improved compliance in two thalassemic adult patients, resulting in a significant decrease in iron overload. We suggest that high-dose chelation therapy should be assessed in selected groups of iron-overload thalassemic patients receiving regular blood transfusions.

Adult↗