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PubMedDate not supplied

[Neurophysiologic and histopathologic correlates of the effect of deferoxamine on the formation of an epileptic focus during blood injection into the rat cerebral cortex].

Blood, 5 microliters, was injected into the brain cortex of 80 adult male Wistar rats weighing 200-250 g. The animals were randomly divided into 2 groups: (1) control and (2) experimental. The second group was used to investigate the effects of deferoxamine on the development of epileptic activity and histopathological changes. The drug was injected intramuscularly in a daily dose of 80 mg/kg during 30 days after subdural blood injection. Epileptic activity appeared on day 2 after operation. The number of epileptic discharges was increased and reached the maximum values on days 3-10. Significant changes were not observed in the following period. In the experimental animals, the frequency of epileptic discharges on day 2 was comparable with those seen in the control group. A significant decrease in epileptic discharges occurred on day 4 following the surgery. Spike-waves disappeared on day 10 of the drug injection and only single spikes were registered on day 30. The histopathological analysis revealed a massive accumulation of pigments in the necrotic zone in the animals on day 5 after operation in both groups. The above changes were shown to retain in control animals on day 30. A negative response to the pigments was obtained only after 60 days. In contrast, responses to the pigment appeared to be negative on day 15 after the operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The antibacterial activity of a siderophore. 3. The activity of deferoxamine in vitro and its influence on the effect of antibiotics against Escherichia coli, Proteus mirabilis and coagulase-negative staphylococci.

The in vitro activity of deferoxamine (DFO) both per se and in combination with the reductant ascorbic acid (AA) was determined against 10 E. coli strains, 5 P. mirabilis strains, and 10 coagulase-negative staphylococci. In terms of interaction, the influence of DFO on the activities of cephalothin and gentamicin was furthermore investigated against the same panel of strains employing a macrobroth dilution technique and killing-curve kinetics. The MICs of cephalothin and gentamicin were lowered for one half of the strains. Moreover, DFO prolonged the generation times of logarithmic growth phase considerably, especially when the reductant AA was present. The interactions between DFO or DFO+AA and subinhibitory concentrations of antibiotics were established by the application of growth constants, and resulted in synergy for 15 out of 25 strains with cephalothin and 9 out of 25 strains with gentamicin.

Anti-Bacterial Agents↗
PubMed1993

Iron chelation by deferoxamine in sickle cell patients with severe transfusion-induced hemosiderosis: a randomized, double-blind study of the dose-response relationship.

Transfusion-induced hemosiderosis is a serious and potentially life-threatening complication for some patients with sickle cell anemia. The use of high-dose intravenous deferoxamine (DFO) has become widespread in spite of a paucity of published data on safety and efficacy. We report a randomized double-blind study of the dose-response relationship of intravenous DFO in six subjects with sickle cell anemia and severe transfusion-induced hemosiderosis (serum ferritin 4100 to 14,176 ng/ml). Each subject received three different doses of intravenous DFO for 3 days each while consuming a constant diet. Total iron excretion (urine and fecal) was 91% greater at 180 mg/kg/day DFO than at 60 mg/kg/day DFO, and fecal iron excretion became a relatively larger proportion of total excretion at higher doses. Subsequent treatment for 3 months with 150 mg/kg/day DFO caused a 33% to 60% reduction in serum ferritin and demonstrable improvement in hepatic function in all patients. No toxicity was encountered, but DFO at 180 mg/kg/day was associated with a significant increase in fecal zinc excretion when compared with that observed at lower doses.

Adolescent↗
PubMed1993

Anthracycline toxicity is potentiated by iron and inhibited by deferoxamine: studies in rat heart cells in culture.

The interrelation between iron, iron chelation, and anthracycline toxicity was investigated in a heart cell culture system. Two indicators of cellular damage have been used, lactate dehydrogenase (LDH) release and cell contractility. Both of these indicators have shown a marked increase in doxorubicin toxicity by prior iron loading. This was not a simple additive effect, because at the concentrations used, iron had only a minimal effect on LDH release and no effect at all on contractility, whereas doxorubicin had only a minor effect on contractility. Deferoxamine (DF) treatment of iron-loaded heart cells resulted in a marked decrease in anthracycline toxicity as judged both by LDH leakage and cell contractility. However, DF treatment of normal heart cells had no measurable protective effect against doxorubicin toxicity, whether DF was administered before or simultaneously with doxorubicin. Doxorubicin treatment did not alter cellular malondialdehyde (MDA) concentrations in either normal or iron-loaded cells. Conversely, the protective effect of DF in iron-loaded cells and its failure to prevent anthracycline toxicity in normal cells were both associated with a significant decrease in MDA measurements. Our data indicate that iron overload aggravates anthracycline toxicity and that this interaction may be prevented by effective iron chelating therapy. Because patients requiring anthracycline therapy often have increased tissue iron stores caused by multiple blood transfusions and bone marrow suppression, our observations may have important implications for the prevention of anthracycline toxicity.

Animals↗
PubMed1993

Effect of tracheal insufflation of deferoxamine on acute ozone toxicity in rats.

To test the hypothesis that deferoxamine (DFO) may protect the lung against the acute toxicity of ozone (O3), male Sprague-Dawley rats (250 to 300 gm) were tracheally insufflated before exposure to O3 (2 ppm for 4 hours) with DFO (25 mg/kg), ferric-DFO, or sterile water. Measurements of bronchoalveolar lavage fluid (BALF) protein, ascorbate, hydrogen peroxide, and lipid hydroperoxides were made immediately after O3 exposure and 12 and 24 hours later. DFO (25 mg/kg) decreased BALF protein concentration (p < 0.05) and was associated with higher BALF ascorbate concentrations (p < 0.01) in O3-exposed animals. Ferric-DFO did not show these protective effects. No peroxides were found in BALF from any control or O3-exposed animals (detection limit: H2O2, 1 pmol; lipid hydroperoxides, 0.3 pmol). Higher DFO doses (50 mg/kg and 100 mg/kg) did not decrease BALF protein concentration immediately after O3 exposure or 12 hours later. Indeed, the highest dose was toxic to O3-exposed animals. Although DFO is able to protect against O3-induced lung damage in rats, apparently by chelating iron, its effect dose range appears to be narrow.

Animals↗
PubMed1996

Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support.

In the present study, we tested whether apoptotic neuronal death caused by withdrawal of trophic support might be prevented by agents that block cell cycle progression. We used three complementary model systems that exhibit apoptotic death: dividing PC12 cells deprived of nerve growth factor (NGF); and primary cultures of postmitotic sympathetic neurons deprived of NGF. We show that cell death in each case can be suppressed by treatment with the G1/S blockers mimosine, ciclopirox, and deferoxamine at concentrations that correlate with their abilities to block PC12 cell proliferation. In contrast, agents that block cell cycle progression in the S-, G2-, or M-phase do not prevent cell death. These observations support the hypothesis that removal of trophic support from dividing or postmitotic neuronal cells provokes their apoptotic death by causing them either to proceed through or to attempt to re-enter an uncoordinated and consequently fatal cell cycle. Moreover, the data suggest that simply blocking the cycle at any point is not protective but, rather, that it is necessary to block at specific "safe" points. This study defines a safe point in the cell cycle before the G1/S transition that is demarcated by the action of these three agents.

Animals↗
PubMed1995

Protective effects of hydroxyethyl starch-deferoxamine in early sepsis.

The protective effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, on the initial pathophysiological cascade in septic shock were evaluated following cecal ligation puncture (CLP) in rats. Animals were given an intravenous dose of 3.0 mL of either vehicle (HES) or HES-DFO immediately following completion of the CLP procedure. Animals were sacrificed 30, 60, 120, and 240 min following CLP, and samples of lung, kidney, bowel, and liver were collected for subsequent analysis of glutathione, myeloperoxidase, and evidence for lipid peroxidation based on measurement of thiobarbituric acid reactive substances and conjugated dienes. In addition, the endotoxin levels were determined in the plasma and histomorphological examination was conducted on tissue samples collected at each time point. At almost all time points, a reduction in lipid peroxidation was noted in the HES-DFO-treated rats (p < .05). Glutathione and myoloperoxidase levels were less affected. Lung tissue from animals receiving HEs demonstrated marked microatelectases, septal destruction, and splicing of basal membranes, which were greatly attenuated in animals having received HES-DFO. Similarly, tubulotoxic and mitochondrial damages observed in kidney samples from HES-treated animals were noticeably reduced in the animals having received the chelator. Liver and gut samples demonstrated unspecific inflammatory injury in both groups of animals. In summary, oxygen radical-mediated tissue damage occurs rapidly following CLP-induced sepsis. Based on histological and biochemical endpoints, treatment with the polymeric iron chelator, HES-DFO, significantly attenuates systemic oxidant injury, the degree of protection being most impressive in the lung and kidney.

Animals↗
PubMed1996

Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy.

The rapidity and duration of the response of non-transferrin-bound iron (NTBPI) to chelation therapy are largely unknown and have important implications for the design of optimal chelation regimens. Methodology was developed to measure simultaneously NTBPI, deferoxamine (DFO), and its major metabolite. NTBPI was present in all but 2 of 28 thalassaemia major (TM) patients who had received conventional subcutaneous DFO the previous night, suggesting a short duration of NTBPI clearance by DFO. The detailed kinetics of NTBPI were therefore studied in response to intravenous DFO at 50 mg/kg/27 h for 48 hours and compared in 17 regularly transfused TM and 8 untransfused thalassaemia intermedia (TI) patients to determine the influence of hypertransfusion and iron overload on NTBPI response. Before DFO infusion, NTBPI was present in all patients and was significantly higher in TI (4.52 +/- 0.53 mumol/L) than TM (2.92 +/- 0.03 mumol/L; P = .03). NTBPI values in TM correlated with transferrin saturation (r = .6, P = .03) but not with serum ferritin. Removal of NTBPI by intravenous DFO is in a biphasic manner. The initial rapid rate constant (alpha) was similar in TI (1.5 hour-1) and TM (1.6 hour-1), but the subsequent beta phase was slower (0.04 hour-1) in TI when compared with TM (0.4 hour-1, P = .002). Detectable NTBPI persisted during the beta phase, particularly in TI, despite an excess of plasma DFO also being present (steady state 8 mumol/L). On cessation of DFO infusion, NTBPI reappearance was rapid; the kinetics also being biphasic. The rapid initial rate constant (alpha = 2.5 hour-1) lasted less than 30 minutes and was approximately equal to the summation of the initial rate constant for removal of DFO (1.8 hour-1) and its major metabolite (0.6 hour-1). This was followed by a slower return to pretreatment levels, usually between 6 and 12 hours, which was faster in TI than in TM. This marked NTBPI lability supports the use of continuous rather than intermittent DFO in high risk patients.

Adolescent↗
PubMed1996

Effects of pentastarch-deferoxamine conjugate on lung injury after cardiopulmonary bypass.

BACKGROUND: Oxygen-derived free radicals have been implicated in the pathogenesis of lung injury and endothelial dysfunction after cardiopulmonary bypass (CPB). We examined the effects of priming the CPB pump with a low-molecular-weight hydroxyethyl starch pentastarch (PS) solution, PS conjugated to the iron chelator deferoxamine (DFO), or lactated Ringer's solution alone (LR) on lung injury parameters and skeletal microvessel relaxation responses. METHODS AND RESULTS: Sheep were placed on hypothermic CPB with a prime of PS (n = 8), PS-DFO (n = 8), or LR (n = 8). A 60-minute period of cardioplegia-ischemia was followed by rewarming, separation from CPB, and 2 hours of post-CPB monitoring. Hemodynamics, oxygenation, pulmonary lymph flow, lymph protein clearance, and total body weight were measured. Right and left atrial blood samples were obtained simultaneously for white blood cell and platelet counts. No statistically significant hemodynamic or oxygenation differences were found between groups. Lymph flow was increased after CPB but significantly more in the LR group (264.6 +/- 45%, P < .05) compared with PS-DFO (126.6 +/- 22%) or PS (120.9 +/- 25%). Increases in lymph protein clearance and weight gain were significantly less with PS and PS-DFO compared with LR (P < .05). CONCLUSIONS: The oncotic agent PS ameliorates lung derangements seen after CPB compared with that seen with an LR prime, and no significant additional pulmonary benefit was demonstrated with PS conjugated to the oxygen-derived free radical scavenger DFO.

Animals↗
PubMedDate not supplied

Superoxide release by human polymorphonuclear leukocytes in the presence of deferoxamine.

BACKGROUND AND OBJECTIVE: Anecdotal reports in patients with acute and chronic iron overload have recently indicated that the efficacy and safety of an alternative chelation program including intravenous and/or continuous delivery of deferoxamine (DFO) may be in contrast with the risk of developing lung injury. Production of oxygen radicals has been postulated to be an important mechanism by which polymorphonuclear leukocytes (PMNs) could cause tissue injury in patients undergoing this alternative treatment method. METHODS: PMNs obtained from healthy donors were incubated at 37 degrees C for 30 min with DFO (across the drug concentration 0.125 to 10 mg/mL). Superoxide (O2) production was measured by superoxide inhibitable cytochrome c reduction as well as by an NBT densitometric kinetic test. In the same run the effect of lipid peroxidation was demonstrated by means of a malonyl-dialdehyde (MDA) assay. RESULTS: Preincubation of PMNs with any study concentration of DFO significantly enhanced O2 release as well as MDA production upon PMA stimulation. Maximal intracellular and extracellular O2-release as well as MDA production occurred at certain drug concentrations. INTERPRETATION AND CONCLUSIONS: Our in vitro findings suggest that O2-release may be an additional detrimental contribution to tissue injury in some patients who develop pulmonary toxic effects while on intravenous and/or continuous DFO administration.

Antidotes↗
PubMed1998

HBED: A potential alternative to deferoxamine for iron-chelating therapy.

To examine the potential clinical usefulness of the hexadentate phenolic aminocarboxylate iron chelator N, N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) for the chronic treatment of transfusional iron overload, we compared the iron excretion induced by subcutaneous (SC) injection of HBED and deferoxamine (DFO), the reference chelator, in rodents and primates. In the non-iron-overloaded, bile-duct-cannulated rat, a single SC injection of HBED, 150 micromol/kg, resulted in a net iron excretion that was more than threefold greater than that after the same dose of DFO. In the iron-loaded Cebus apella monkey, a single SC injection of HBED, 150 micromol/kg, produced a net iron excretion that was more than twice that observed after the same dose of SC DFO. In patients with transfusional iron overload, SC injections of HBED may provide a much needed alternative to the use of prolonged parenteral infusions of DFO.

Animals↗
PubMed1999

HBED: the continuing development of a potential alternative to deferoxamine for iron-chelating therapy.

To further examine the potential clinical usefulness of the hexadentate phenolic aminocarboxylate iron chelator N, N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) for the chronic treatment of transfusional iron overload, we performed a subchronic toxicity study of the HBED monosodium salt in rodents and have evaluated the iron excretion in primates induced by HBED. The HBED-induced iron excretion was determined for the monohydrochloride dihydrate that was first dissolved in a 0.1-mmol/L sodium phosphate buffer at pH 7.6 and administered to the primates either orally (PO) at a dose of 324 micromol/kg (149.3 mg/kg, n = 5), subcutaneously (sc) at a dose of 81 micromol/kg (37.3 mg/kg, n = 5), sc at 324 micromol/kg (n = 5), and sc at 162 micromol/kg (74.7 mg/kg) for 2 consecutive days for a total dose of 324 micromol/kg (n = 3). In addition, the monosodium salt of HBED in saline was administered to the monkeys sc at a single dose of 150 micromol/kg (64.9 mg/kg, n = 5) or at a dose of 75 micromol/kg every other day for three doses, for a total dose of 225 micromol/kg (n = 4). For comparative purposes, we have also administered deferoxamine (DFO) PO and sc in aqueous solution at a dose of 300 micromol/kg (200 mg/kg). In the iron-loaded Cebus apella monkey, whereas the PO administration of DFO or HBED even at a dose of 300 to 324 micromol/kg was ineffective, the sc injection of HBED in buffer or its monosodium salt, 75 to 324 micromol/kg, produced a net iron excretion that was nearly three times that observed after similar doses of sc DFO. In patients with transfusional iron overload, sc injections of HBED may provide a much needed alternative to the use of prolonged parenteral infusions of DFO. Note: After the publication of our previous paper (Blood, 91:1446, 1998) and the completion of the studies described here, it was discovered that the HBED obtained from Strem Chemical Co (Newburyport, MA) that was labeled and sold as a dihydrochloride dihydrate was in fact the monohydrochloride dihydrate. Therefore, the actual administered doses were 81, 162, or 324 micromol/kg; not 75, 150, or 300 micromol/kg as was previously reported. The new data have been recalculated accordingly, and the data from our earlier study, corrected where applicable, are shown in parentheses.

Administration, Oral↗
PubMed1997

[The effects of deferoxamine on bovine pulmonary endothelial cell injury induced by hydrogen peroxide].

The effect of deferoxamine (DFX), the ferric iron chelator, on bovine pulmonary endothelial cell (BPAEC) injury induced by hydrogen peroxide (H2O2) was examined in vitro. It was found that, when compared with unpretreated cells, H2O2-induced the release of lactate dehydrogenase and the production of thiobarbituric acid reactive substances were decreased, at the meantime the cellular activites of catalase and superoxide dismutase were maintained in DFX (2 mmol.L-1) pretreated BPAECs challenged by 1 mmol.L-1 H2O2. These data indicate that DFX provided almost complete protection against H2O2-mediated cytotoxicity. This suggests that intracellular iron may play an essential role in the endothelial cell injury mediated by H2O2.

Animals↗
PubMed2002

Prevention of apoptosis by deferoxamine during 4 hours of cold cardioplegia and reperfusion: in vitro study of isolated working rat heart model.

INTRODUCTION: Heart transplantation is often accompanied by multiple functional alterations, especially in reperfusion period. These are probably related to the reactive oxygen species (ROS) formation catalyzed by transition metals such as iron and copper, and thus the preservation time of the donor hearts is limited. Metabolic protection of the heart grafts is a permanent objective of numerous experiments. Recently, an iron chelator deferoxamine (DFX) was proposed as antioxidant agent for storage solutions in heart grafts. Oxidative stress is also known to mediate the apoptotic cell death in different tissues during ischemia-reperfusion. METHODS: The aim of this study was to evaluate a possible role of DFX in prevention of apoptosis using in vitro model of isolated working rat heart and cold cardioplegia. Two groups of rats were evaluated: (a) group 'DFX 50 &mgr;M' (n=8) and (b) group 'controls' (n=8). Isolated rat hearts were perfused by Krebs-Henseleit buffer (KHB) for 30 min, arrested by cardioplegic solution and stored for 4 h in B21 solution at 4 degrees C. Then, the hearts were reperfused by KHB for 45 min. DFX was added to the cardioplegic and storage solutions and in KHB in reperfusion. Basic functional parameters were evaluated: coronary, aortic, cardiac outputs and heart rate. At the end of reperfusion period a tissue samples were taken from left ventricle and in situ detection of apoptotic cells was performed using an ApopTag kit. RESULTS: DFX significantly reduced the occurrence of apoptotic cells in myocardium (*P<0.05). Hearts treated by 50 &mgr;M of DFX showed also a better recovery of the cardiac output (***P<0.001). The presence of DFX in KHB, cardioplegic and storage solution reduced also the incidence of postischemic arrhythmias and fibrillation's but without statistical significance. CONCLUSIONS: Our results give evidence of the protective potential of DFX during cold ischemia and reperfusion, presumably due to its antioxidant properties. The significant decrease of apoptosis in hearts treated by DFX could be considered as an existence of close link between oxidative stress and apoptotic death promotion in ischemia-reperfusion injury.

Journal Article↗
PubMed1999

Erythropoiesis: Comparison of Cytotoxic Aldehyde Generation in Beta-Thalassemia Patients Chelated with Deferoxamine or Deferiprone (L1) Versus NO Chelation.

The mechanism of iron-induced organ failure in iron overload disorders is not known, but it is conjectured that excess iron-catalyzed free radical generation contributes to organ damage. We hypothesized that free radical generation, quantified by the presence of 20 separate cytotoxic aldehydes in plasma, would be significantly increased in non-chelated beta-thalassemia major patients, in comparison to those chelated with either deferiprone (L1) or deferoxamine (desferal). We also report on red cell glutathione peroxidase activity in these patient groups, an enzyme involved in averting the damaging effects of free radicals. Ten patients were chelated with nightly subcutaneous infusions of desferal and 10 received the experimental oral chelator L1. Body iron burden was assessed by serum ferritin and hepatic iron concentrations. In comparison to non-chelated controls, significant decreases of 62% and 64% in total cytotoxic aldehyde concentrations were observed in patients chelated with desferal and L1, respectively (p < 0.001). Significantly lower red cell glutathione peroxidase activity was also observed in non-chelated controls, in comparison to those chelated with either desferal or L1 (p < 0.001). This is the first report on the concentrations of cytotoxic aldehydes in non-chelated beta-thalassemia major patients, and the first to report on the effects of L1 against cytotoxic aldehyde formation in plasma of patients with iron-overload.

Journal Article↗
PubMed1981

Detection of abscesses and lymphosarcoma with 111In-deferoxamine mesylate.

Indium-111 deferoxamine was used to delineate induced abscesses or different ages in a baboon, and lymph nodes in a case of canine spontaneous lymphosarcoma, by means of gamma-scintigraphy. Positive results were obtained already 1 hr after administration of the scanning agent, and the lesion-to-background ratio improved progressively with time. The tissue distribution of the radiopharmaceutical was determined in rats, and showed a relatively high isotope retention in the kidneys.

Abscess↗
PubMed1993

Amino-dextran-deferoxamine: a potential polymeric heterobifunctional agent for high-level 111In-labeling of anti-melanoma monoclonal antibody TP41.2.

Amino-dextran-10 (ADX-10) was partially oxidized to polyaldehyde-ADX which was then reacted with deferoxamine (DFO) to form a Schiff's base and converted into a secondary amine, ADX-DFO (I) with ten moles of DFO per mole of ADX. ADX-DFO was chelated with Indium or 111In to yield ten moles of In or 111In per mole of ADX-DFO. A selective maleimide derivatization of (I) with sulfosuccinimidyl-4-(p-maleimidophenyl) butyrate yielded (II), which contained 3 moles of maleimide groups per mole of (II). The sulfhydryl-amidinium derivatization of the monoclonal antibody (MoAb) TP41.2 with 2-IT produced (III). Compounds (II) and (III) were combined to form the thioether space-arm linkage of (IV), which was subsequently radiolabeled with 111In to yield (V). MoAb-DFO-111In, (VI), was also prepared for a control study. Direct cell binding revealed the immunoreactivity of (V) to be 79.7% and that of (VI) to be 60.3%. The in vitro stability of (V) at 4, 24, and 48 hours resulted in 1.7%, 7.0% and 16.0% hydrolysis respectively, as compared with 2.1%, 8.7% and 18.5% hydrolysis of the control (VI), at the same time intervals. In a biodistribution study in non-tumor rats at 4, 24, and 48 hours post-injection, the liver concentration at 48 hours was 2.97% (ID/g) for (V) and 4.84% (ID/g) for (VI). This novel technique for radiolabeling antibodies allows for a high level of radiometallic labeling, preservation of immunoreactivity, and reduction of uptake by the liver.

Humans↗