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PubMedDate not supplied

Suppression of HL-60 cell proliferation by deferoxamine: changes in c-myc expression.

Deferoxamine, an iron chelating agent, inhibits growth of HL-60 cells in a dose-dependent fashion. This inhibition of proliferation was completely blocked by simultaneous addition of equal molar FeCl3, and FeCl3 added after 24 hours of deferoxamine treatment was also effective. After 48 hrs, however, the delayed addition failed to reverse growth inhibition by deferoxamine. We showed that deferoxamine-treated HL-60 cells become arrested in S phase rather than at G1/0 phase. Changes in c-myc expression were examined in these deferoxamine-treated cells. A rapid decline of c-myc RNA expression was followed by increased expression (1.6-fold over untreated controls). Similar results were obtained when the expression of c-myc protein was evaluated. These changes in c-myc expression may be involved in the growth inhibition of HL-60 cells by deferoxamine. These results are contrasted with the effects of the differentiation inducer, 1 alpha,25(OH)2D3.

Cell Cycle↗
PubMed1989

Acute changes in renal function associated with deferoxamine therapy.

In three patients who received intravenous deferoxamine there was a twofold to eightfold increase in plasma creatinine level and a parallel decrease in creatinine clearance that resolved when treatment with the drug was discontinued. In two thalassemic patients, diuresis was evident by urine output exceeding fluid intake. The mechanism was studied in dogs that exhibited an acute and significant decrease in inulin and para-aminohippuric acid clearances induced by intravenous deferoxamine. Saline diuresis could prevent the decrease in the glomerular filtration rate but not the decrease in renal blood flow caused by deferoxamine. Deferoxamine induced an acute increase in the fractional excretion of sodium, potassium, chloride, phosphate, and urate, which may explain the relative diuresis observed in two of the patients. In a subsequent experiment, ferrioxamine induced an increase in the fractional excretion of sodium and chloride but did not affect the glomerular filtration rate and renal blood flow. Our studies suggest that adequate hydration may be needed to preserve renal hemodynamics during intravenous deferoxamine therapy. Repeated measurements of renal function should accompany treatment with this agent.

Adolescent↗
PubMed1991

Deferoxamine and aluminum clearance in pediatric hemodialysis patients.

Mobilization of aluminum by deferoxamine and the subsequent clearance from plasma by hemodialysis with or without charcoal hemofiltration was studied in four pediatric patients. Deferoxamine, 10-20 mg/kg, followed by dialysis with a Travenol CA50 dialyzer produced reductions in mean plasma aluminum levels from 2433 +/- 729 nmol/l (65.5 +/- 19.6 micrograms/l) to 1727 +/- 554 nmol/l (46.5 +/- 14.9 micrograms/l) during dialysis. The use of a charcoal cartridge in the circuit resulted in a reduction in mean plasma aluminum levels 2459 +/- 591 nmol/l (66.2 +/- 15.9 micrograms/ml) to 1380 +/- 106 nmol/l (35.8 +/- 2.9 micrograms/l). In one patient, high-flux dialysis produced a reduction from 2140 nmol/l (55.6 micrograms/l) to 1134 nmol/l (29.4 micrograms/l). No patients suffered direct adverse reactions to low-dose deferoxamine, although two patients had previously exhibited potential aluminum neurotoxicity after rapid increases in plasma aluminum levels with deferoxamine in higher doses. Aluminum levels must be monitored closely during deferoxamine therapy in uremic children to minimize the risk of exacerbating aluminum neurotoxicity.

Aluminum↗
PubMed1983

Synergy between the iron chelator deferoxamine and the antimicrobial agents gentamicin, chloramphenicol, cefalothin, cefotiam and cefsulodin.

Synergy between the iron chelator deferoxamine in the presence or absence of ascorbic acid and gentamicin, chloramphenicol, cephalothin, cefotiam or cefsulodin, used against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, proteus mirabilis and species of Salmonella, Enterobacter, Pseudomonas and Providencia, was determined by measuring the effect of the drugs and combination of drugs on growth of the bacteria in an automated turbidimeter. The combination of drugs was considered to be synergistic when the growth inhibiting effect of the combination was greater than that of the combined action of each of the drugs separately. Deferoxamine plus ascorbic acid together with either gentamicin or cefsulodin showed synergy in 10 out of 10, and 5 out of 6 cultures respectively, whereas deferoxamine plus ascorbic acid with chloramphenicol, cephalothin or cefotiam was synergistic in 6 out of 14, 5 out of 11, and 3 out of 6 cultures. This synergistic effect was much lower when microorganisms were incubated with deferoxamine combined with the various antibiotics but without ascorbic acid. Ascorbic acid alone had no synergistic effect. When deferoxamine was saturated with iron, its antibacterial effect was completely abolished.

Alcaligenes↗
PubMed1995

Deferoxamine cardioplegia reduces superoxide radical production in human myocardium.

Recent studies have demonstrated enhanced myocardial protection during ischemia using the oxygen free radical scavenger, deferoxamine. This effect of deferoxamine may be related either to its iron-chelating property or to intervention in an iron-independent mechanism. We tested the latter by determining the rate of superoxide anion production and the degree of lipid peroxidation in human myocardial tissue after including deferoxamine in cardioplegic solution. Fourteen patients who underwent aortic, mitral, or double valve replacement were included in the study. The mean value for superoxide radical production was 59.8 +/- 17.0 nmol.min-1.g-1 for the control group (group C; n = 7) and 21.3 +/- 8.1 (p < 0.001) for the deferoxamine-treated group (group D; n = 7). The mean value for thiobarbituric reactive substances was 80.00 +/- 23.4 in group C and 38.7 +/- 23.8 nmol.min-1.g-1 in group D (p < 0.01). In conclusion, deferoxamine appears to have a moderating effect on the biochemical markers of ischemia reperfusion injury. Its scavenging effect on superoxide anion could play a role in the cellular defense against oxygen radicals during cardiac operations.

Aged↗
PubMed1992

Deferoxamine, an iron chelator, reduces myocardial injury and free radical generation in isolated neonatal rabbit hearts subjected to global ischaemia-reperfusion.

The protective action of deferoxamine, an iron chelator, against functional and metabolic deteriorations of ventricular muscle, induced by ischaemia-reperfusion, was investigated in Langendorff-perfused hearts of neonatal rabbits in comparison with superoxide dismutase (SOD) plus catalase. The perfused hearts were subjected to normothermic (37 degrees C) global ischaemia for 45 min following cardiac arrest with St Thomas cardioplegic solution and then reperfused with oxygenated Krebs-Henseleit solution. In control hearts, the recovery of the left ventricular developed pressure (LVDP) after 30 min reperfusion was 50.7 +/- 3.1% (mean +/- SE, n = 5) of the pre-ischaemic value. The LVDP recovery was significantly improved in the hearts treated with deferoxamine at 10-100 microM (89.4 +/- 1.4% at 30 microM, P < 0.01 vs. control). The improvement in LVDP was less prominent when treated with 30 x 10(4) U/l SOD plus 30 x 10(4) U/l catalase (67.9 +/- 2.0%, P < 0.01 vs. deferoxamine at 30 microM). CPK leakage into the coronary effluent during the initial 5 min of reperfusion was reduced to around half of the control value with 30 microM deferoxamine (P < 0.05 vs. control), while unaffected by the addition of SOD plus catalase. Free radicals in the coronary effluent were measured with electron spin resonance spectroscopy in separate experiments by using a spin-trapping agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). A burst of DMPO-OH signal was detected during the initial minutes of reperfusion. The intensity of DMPO-OH signal was significantly reduced by 30 microM deferoxamine to about one-third of control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of deferoxamine and a diet deficient in vitamin E on isoelectric electroencephalographic responses associated with ischemia by the four vessel occlusion method.

This study reports the effects of subchronic administration of the iron chelator deferoxamine (4.2 mg/day by osmotic minipump for 6 days) and a diet deficient in Vitamin E (15% RDA for 60 days) on the isoelectric electroencephalographic responses associated with 15 minutes of global transient cerebral ischemia in rats. Brain levels of thiobarbiturate-reacting substance (TBARS), a measure of lipid peroxidation, were lower in deferoxamine-treated animals and higher in Vitamin E deficit animals suggesting the treatments altered free radical activity at the time of ischemia. During ischemia, all test animals were observed to lose the righting reflex and enter a quiescent state. Fifty percent of the animals in two control groups (N = 15 per group) demonstrated an isoelectric electroencephalographic pattern (defined as 10% or less of pre-ischemia total EEG power) with a mean onset of 5.44 minutes. One third of the animals treated with deferoxamine (N = 15) experienced an isoelectric encephalogram with a mean onset of 8.6 minutes and 73% of the Vitamin E-deficient group (N = 15) experienced an isoelectric EEG with a mean onset of 3.43 minutes. Following reperfusion, EEG patterns returned to power levels within 20% of pre-ischemia levels in all animals. Control animals obtained this EEG power level within 1.34 minutes, deferoxamine-treated animals within 1.25 minutes and animals provided a diet deficient in Vitamin E within 5.03 minutes. Compared to mean total EEG power prior to the onset of ischemia, mean total EEG power five days after reperfusion was reduced 14% in the control groups and 59% in the Vitamin E-deficient group and increased 123% in the deferoxamine group. Results are discussed in relation to the possible involvement of free radicals in the ischemic and postischemic process.

Animals↗
PubMed1988

Modulation of the development of bleomycin-induced fibrosis by deferoxamine.

Bleomycin is an antineoplastic compound which produces a time- and dose-dependent pulmonary fibrosis. The mechanisms which cause this fibrosis are not known. The ability of bleomycin to produce oxygen radicals in the presence of iron and molecular oxygen appears to be related to the fibrosis. Previous studies, which have examined single time points utilizing the ferric ion chelator deferoxamine and iron-deficient diets, suggest that iron plays a central role in bleomycin-induced pulmonary fibrosis. Therefore, the present study was designed to determine the effects of deferoxamine on the development of bleomycin-induced pulmonary fibrosis. Deferoxamine pretreatment and daily injections resulted in a significant reduction in lung collagen content and lung lipid peroxidation 21 days after intratracheal bleomycin compared with bleomycin treatment alone. In addition deferoxamine treatment significantly inhibited lung DNA increases at 4, 7, and 14 days after bleomycin treatment compared with bleomycin treatment alone. These data indicate that deferoxamine treatment reduces the development of bleomycin-induced pulmonary fibrosis in the later phase. The mechanism might be by the prevention of iron-catalyzed, free-radical formation and modulation of some cellular functions.

Animals↗
PubMed1991

Coronary venous retroinfusion of deferoxamine reduces infarct size in pigs.

The efficacy of coronary venous retroinfusion of the iron chelator deferoxamine was studied in 24 pentobarbital-anesthetized open chest pigs with a 60 min occlusion of the left anterior descending coronary artery followed by 3 h of reperfusion. Eight retrogradely treated pigs were given 10 mg/kg body weight of deferoxamine by way of the anterior interventricular vein and eight systemically treated pigs received the same doses of deferoxamine intravenously. Drug infusions lasted for 5 min, beginning 15 min before reperfusion. Eight control pigs received systemic intravenous saline solution. Myocardial area at risk and necrotic area were assessed by the monastral blue dye and the triphenyltetrazolium chloride staining method, respectively. There were no significant differences in hemodynamics or regional myocardial function (sonomicrometry) among the groups. Infarct size expressed as percent of risk area was 73.9 +/- 13.5% in the control group, 70.6 +/- 16.4% in the systemically treated group and 48.5 +/- 21.4% (p less than 0.05) in the retrogradely treated group. In conclusion, deferoxamine significantly reduced infarct size after coronary occlusion only when given regionally by way of the coronary vein. Because there was no significant hemodynamic effect caused by deferoxamine infusion, it is suggested that this drug prevents postischemic reperfusion injury by a direct cardioprotective effect.

Animals↗
PubMed2003

Deferoxamine enhances neovascularization and recovery of ischemic skeletal muscle in an experimental sheep model.

BACKGROUND: Iron chelators have been reported to interfere with inflammatory cells and possibly enhance vascular growth factor expression. The objective of this study was to investigate the efficacy of the iron chelator deferoxamine mesylate in preventing skeletal muscle ischemia. METHODS: The latissimus dorsi muscle (LDM) was mobilized in 20 adult sheep. Two separate pockets were created in each sheep. Autologous fibrin sealant with or without 100 mg/mL of deferoxamine mesylate (10 pockets) was added to the pockets. Deferoxamine mesylate alone was also applied to another 10 pockets, whereas the 10 other pockets served as controls. RESULTS: Conventional, indirect immunofluorescent enface staining showed that in nonmobilized, nonischemic LDM the capillary density was 196 +/- 14 capillaries/mm2 in the distal and 207 +/- 19 capillaries/mm2 in the middle part. After severe ischemic shock (subtotal mobilization), the muscle did not recover completely even after 2 months (149 +/- 15 capillaries/mm2 in the distal part and 177 +/- 16 capillaries/mm2 in the middle part of the LDM). Fibrin application only increased muscle neovascularization. The number of capillaries per mm2 of muscle increased to 250 +/- 25 in the distal part and to 271 +/- 24 in the middle part of the LDM. However, when fibrin was applied with added deferoxamine mesylate, the capillary density increased to 361 +/- 25 capillaries/mm2 in the distal part (p < 0.05 vs fibrin only; controls) and to 401 +/- 20 capillaries/mm2 in the middle part of the LDM (p < 0.05 vs fibrin only and p < 0.001 vs controls). The data are concordant with the blood flow estimation before and after mobilization (severe ischemic shock) in the different parts of the LDM. CONCLUSIONS: Local application of deferoxamine mesylate enhances neovascularization and recovery of surgically induced skeletal muscle ischemia in a sheep model.

Animals↗
PubMed2002

Growth inhibition of bloodstream forms of Trypanosoma brucei by the iron chelator deferoxamine.

Treatment of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine inhibits the proliferation of the parasites. Compared with mammalian cells, bloodstream forms of Trypanosoma brucei are 10 times more sensitive to iron depletion. The primary target of the chelator is obviously the intracellular iron as the toxicity of deferoxamine is abolished by addition of holotransferrin, the exogenous source of iron for the parasite. To identify probable target sites, the effect of deferoxamine on ribonucleotide reductase, alternative oxidase and superoxide dismutase, three iron-dependent enzymes in bloodstream-form trypanosomes, was studied. Incubation of the parasites with the chelator leads to inhibition of DNA synthesis and lowers oxygen consumption indicating that deferoxamine may affect ribonucleotide reductase and alternative oxidase. The compound does not inhibit the holoenzymes directly but probably acts by chelating cellular iron thus preventing its incorporation into the newly synthesised apoproteins. Treatment of the parasites with deferoxamine for 24 h has no effect on the activity of superoxide dismutase. The results have implications for antitrypanosomal drug development based on specific intervention with the parasite's iron metabolism.

Animals↗
PubMed1997

Induction of embryonal carcinoma cell differentiation by deferoxamine, a potent therapeutic iron chelator.

We investigated the effects of deferoxamine on the differentiation of embryonal carcinoma F9 cells. Deferoxamine, a widely used therapeutic agent for thalassemia and iron overload, was found to induce F9 cell differentiation and to have some unique characteristics compared with other chelators, hinokitiol and dithizone, which were previously reported to induce differentiation of these cells. This hydrophilic agent induced reversible differentiation as did sodium butyrate, whereas other chelators did not. However, morphological features of the cells after deferoxamine-induced differentiation were similar to those of cells incubated with the other chelators. The differentiation-inducing activity of deferoxamine was abolished by preincubation with Fe3+ ions, similarly to the other chelators examined. Moreover, cell proliferation was inhibited by treatment with this agent, and the numbers of cells in the colonies were reduced by apoptosis. Based on these results, we conclude that deferoxamine induces differentiation and apoptosis of F9 cells via chelation of extracellular and/or intracellular Fe3+ ions.

Apoptosis↗
PubMed1990

Cerebrospinal fluid aluminum levels following deferoxamine.

Deferoxamine is widely used in the diagnosis and treatment of aluminum toxicity and has a characteristic combination of side effects, including a poorly defined worsening of existing neurologic symptoms. However, to date, no measurement of cerebrospinal fluid (CSF) aluminum concentrations after deferoxamine exist. We report the case of a patient who developed acute neurological deterioration in conjunction with sepsis and elevated serum aluminum levels shortly after renal transplantation. Simultaneous values for blood and CSF aluminum were measured in response to deferoxamine and hemodialysis. The increase in CSF aluminum levels appears to parallel that seen in serum after deferoxamine. We hypothesize that this elevation in CSF aluminum may account for the observed neurologic deterioration after deferoxamine and postulate various pathophysiologic mechanisms that might be involved.

Adult↗
PubMed1987

Deferoxamine-induced bone changes in haemodialysis patients: a histomorphometric study.

1. The histological effects of deferoxamine therapy were assessed on transiliac bone biopsies taken after double tetracycline labelling from 16 uraemic patients undergoing chronic haemodialysis, all having aluminium deposits in bone. Eight patients had osteomalacia, five had an "aplastic" bone lesion and three a high bone turnover with a marked increase in osteoid volume. 2. Deferoxamine was administered intravenously once a week at doses ranging from 1 to 6 g for a mean duration of 7.6 +/- 3.3 (SD) months. 3. Deferoxamine therapy was associated with significant reductions in stainable aluminium deposits, osteoid volume, osteoid surfaces and thickness index of osteoid seams. The osteoblastic osteoid surfaces as well as the bone formation rates also increased significantly. 4. A rise in resorption parameters and in serum parathyroid hormone levels was observed in patients with osteomalacia. The percentage reductions in stainable aluminium and in osteoid volume were correlated with the degree of hyperparathyroidism. 5. These data show that deferoxamine therapy reduces stainable bone aluminium and improves bone mineralization in low turnover osteomalacia and that the presence of hyperparathyroidism is associated with an increased response to deferoxamine therapy.

Adult↗
PubMed1989

Intranasal administration of deferoxamine to iron overloaded patients.

We examined the effect of intranasal administration of deferoxamine on iron excretion in seven patients with iron overload secondary to chronic transfusion therapy. Deferoxamine was administered in doses of 0.75 to 3.0 gm given over 12 hours in a variety of dosing schedules. There was a probable, though not significant, dose response relationship between the amount of iron excreted and the dose administered. The amount of iron excreted was 10%-15% of that obtained using the same dosage of deferoxamine given by the subcutaneous route over the same time period. Hourly administration was more effective than less frequent administration. Addition of taurodeoxycholate to deferoxamine did not increase its absorption as measured by the levels of iron excretion. Side effects were few and consisted mainly of mild nasal irritation and a bad taste in the mouth. Nasal administration of deferoxamine may be a useful adjunct to iron chelation in patients receiving chronic transfusion therapy, particularly in those who are noncompliant with parenteral means of administration.

Administration, Intranasal↗
PubMed1996

Effects of deferoxamine on ischemia/reperfusion injury after peripheral nerve compression.

We have demonstrated previously that acute nerve compression produces ischemia/reperfusion injury in rat sciatic nerve. In this study, we evaluated the effects of deferoxamine, an antioxidant, on recovery from ischemia/reperfusion injury after nerve compression. The sciatic nerves of male Sprague-Dawley rats, 370 to 430 g, were subjected to 24 hours of compression with Silastic tubing. The control group received intravenous saline solution at the time of decompression. The therapeutic group received intravenous deferoxamine (50 mg per kilogram) at the time of removal of the Silastic tubing. Nerve tissues within and distal to the compression site were assayed for malondialdehyde (MDA) levels and for growth-associated protein 43 (GAP-43) expression, as markers of ischemia/reperfusion injury and nerve regeneration, respectively. In the control group (injury alone), the MDA levels were three times higher than normal during the initial 10 days and returned to normal by 14 days. In contrast, the deferoxamine treatment group had MDA levels that were not significantly different from precompression levels. In the control group, enhanced GAP-43 expression persisted until late in the recovery period. In the deferoxamine treatment group, the increased GAP-43 expression subsided early. The results suggest that the treatment of compressed peripheral nerve with deferoxamine at the time of surgical decompression reduces ischemia/reperfusion injury.

Animals↗
PubMed2001

Effects of deferoxamine on tissue superoxide dismutase and glutathione peroxidase levels in experimental head trauma.

BACKGROUND: This study aims to evaluate the effects of deferoxamine on tissue superoxide dismutase (SOD) and glutathione peroxidase (GPx) brain levels after head trauma. METHODS: Thirty rabbits were divided equally into three groups: group 1 was the sham-operated group, group 2 suffered head trauma (no treatment was given), and group 3 received deferoxamine 50 mg/kg after the trauma. Head trauma was applied unilaterally. One hour after trauma, brain cortices were resected and SOD and GPx levels were determined. One-way analysis of variance and Tukey-HSD tests were used for analysis. Significance was defined as p < 0.05. RESULTS: Baseline SOD levels are preserved in the traumatized side of the deferoxamine-treated group. Although GPx level of the traumatized side of the deferoxamine-treated group decreased significantly, the decrease was significantly less than the nontreated group. CONCLUSION: Trauma leads to a decrease in brain tissue SOD and GPx levels. Deferoxamine suppresses this decrease completely in SOD level and partially in GPx level when given after trauma.

Animals↗
PubMed2000

The role of allopurinol and deferoxamine in preventing pressure ulcers in pigs.

Ischemia and reperfusion may be important in the pathogenesis of pressure ulcers. On the basis of this hypothesis, the effects of intermittent pressure and the anti-free radical agents allopurinol and deferoxamine were studied in a pig model in which a pressure of 150 mmHg was applied intermittently to the scapulae. Cutaneous blood flow, transcutaneous oxygen tension, skin and muscle damage, and muscle levels of adenosine triphosphate were quantified. A control group of pigs (n = 6) was untreated, the allopurinol group (n = 6) received oral allopurinol beginning 2 days before the experiment, and the deferoxamine group (n = 6) received an intramuscular injection of deferoxamine 2 hours before the experiment. Pressure (150 mmHg) was applied to the scapulae for 210 minutes, and it was relieved for 30 minutes. This 4-hour cycle was repeated continuously for 48 hours, and it resulted in pressure injuries in all animals. Allopurinol and deferoxamine improved cutaneous blood flow and tissue oxygenation, but only deferoxamine could significantly reduce cutaneous and skeletal muscle necrosis (p < 0.001). This study suggests a future role for anti-free radical agents in the reduction of pressure-induced injury.

Adenosine Triphosphate↗