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PubMed1990

Toxic effects associated with the administration of deferoxamine in the premature baboon with hyaline membrane disease.

We hypothesized that administration of the iron chelator deferoxamine would inhibit iron-catalyzed free radical generation and lessen the severity of oxygen-induced pulmonary injury. To evaluate its efficacy and safety in premature infants, we administered deferoxamine by intravenous infusion to five premature baboons with hyaline membrane disease supported with conventional ventilation and 100% oxygen for 6 days. Seven animals served as controls. Deferoxamine treatment was initiated at 10 mg/kg per hour but, after the precipitous death of the first animal, was progressively reduced to 1.25 mg/kg per hour in the other animals. Four of five deferoxamine-treated baboons developed cardiovascular collapse and all five died by 42 hours. Five of the seven control animals survived the 6-day experimental period. Since cardiovascular toxic effects have not previously been reported, these findings suggest unique vulnerability of the immature cardiovascular system to iron chelation.

Animals↗
PubMed1996

Assessment of microvascular integrity in the isolated perfused rat liver by contrast-enhanced MRI. Attenuation of reperfusion injury by conjugated deferoxamine.

Reperfusion of an ischemic organ can lead to microcirculatory impairment caused, in part, by the generation of reactive free radicals. The iron-catalyzed formation of these deleterious substances can be counteracted by strong metal chelators like deferoxamine. In this study, the protective effect of deferoxamine conjugate was evaluated by assessment of the hepatic microcirculation in the post-ischemic phase. Assessment of the microvasculature was performed by MRI on the isolated perfused rat liver. The restriction of sinusoids subsequent to reperfusion injury was demonstrated by the use of a particulate superparamagnetic contrast agent trapped in the microvasculature. The protective effect of conjugated deferoxamine was evaluated by both MRI and release of alanine aminotransferase. Contrast-enhanced MRI demonstrated a marked impairment of the microcirculation subsequent to the unprotected reperfusion of the ischemic tissue. This injury was attenuated by deferoxamine conjugated to hydroxyethyl-starch (HES-DFO).

Alanine Transaminase↗
PubMed1992

Deferoxamine inhibition of Cr(V)-mediated radical generation and deoxyguanine hydroxylation: ESR and HPLC evidence.

Electron spin resonance (ESR) and high-performance liquid chromatography (HPLC) techniques were utilized to investigate the effect of deferoxamine on free radical generation in the reaction of Cr(V) with H2O2 and organic hydroperoxides. ESR measurements demonstrated that deferoxamine can efficiently reduce the concentration of the Cr(V) intermediate as formed in the reduction of Cr(VI) by NAD(P)H or a flavoenzyme glutathione reductase/NADH. ESR spin trapping studies showed that deferoxamine also inhibits Cr(V)-mediated .OH radical generation from H2O2, as well as Cr(V)-mediated alkyl and alkoxy radical formation from t-butyl hydroperoxide and cumene hydroperoxide. HPLC measurements showed that .OH radicals generated by the Cr(VI)/flavoenzyme/NAD(P)H enzymatic system react with 2'-deoxyguanine to form 8-hydroxy-2'-deoxyguanine (8-OHdG), a DNA damage marker. Deferoxamine effectly inhibited the formation of 8-OHdG also.

Animals↗
PubMed1992

Deferoxamine inhibits methyl mercury-induced increases in reactive oxygen species formation in rat brain.

It has been suggested that methyl mercury may express its neurotoxicity by way of iron-mediated oxidative damage. Therefore, the effect of deferoxamine, a potent iron-chelator, on methyl mercury-induced increases in reactive oxygen species formation was studied in rat brain. The generation rate of reactive oxygen species was estimated in crude synaptosomal fractions using the probes 2',7'-dichlorofluorescin diacetate and dihydrorhodamine 123. The formation rate of the fluorescent oxidation products was used as the measure of reactive oxygen species generation. Seven days after a single injection of methyl mercury (5 mg/kg, ip), the formation rate of reactive oxygen species was significantly increased in the cerebellum. Pretreatment with deferoxamine (500 mg/kg, ip) completely prevented the methyl mercury-induced increase in cerebellar reactive oxygen species generation rates. The oxidative consequences of in vitro exposure to methyl mercury (20 microM) were also inhibited by deferoxamine (100 microM). The formation of the iron-saturated complex ferrioxamine was not affected by a 10-fold excess of methylmercuric chloride or mercuric chloride, suggesting that a deferoxamine-mercurial complex does not form. The findings in this study: (1) provide evidence that iron-catalyzed oxygen radical-producing reactions play a role in methyl mercury neurotoxicity, (2) demonstrate the potential of fluorescent probes as a measure of reactive oxygen species formation, and (3) provide support for iron-chelator therapy in protection against xenobiotic-induced oxidative damage.

Animals↗
PubMed1986

The effect of carbon dioxide, lidoflazine and deferoxamine upon long term survival following cardiorespiratory arrest in rats.

This study examined the effect of carbon dioxide, lidoflazine and deferoxamine therapy upon the 10-day survival incidence and subsequent neurologic function of rats subjected to 7 min of cardiorespiratory arrest with resuscitation. Cardiac arrest (asystole) was induced at time zero by injection of cold, 1% KCl into the left ventricle of ketamine-anesthetized rats pretreated with succinylcholine. Positive pressure ventilation was discontinued at time zero. Cardiopulmonary resuscitation (CPR) was begun at 7 min, and animals with return of spontaneous circulation were entered into the study. Twenty treated rats were ventilated for 1 h with 7% carbon dioxide-93% oxygen and given lidoflazine (2.0 mg/kg, i.v.) and deferoxamine (50 mg/kg, i.v.) 5 min after CPR. Twenty control rats were ventilated for 1 h with 100% oxygen and given lidoflazine vehicle and deferoxamine vehicle. Lidoflazine treatment (1.0 mg/kg) for the treated group, or lidoflazine vehicle for the control group, was repeated at 8 h postresuscitation. At 2 days postresuscitation, 75% of treated rats vs. 25% of control rats were alive (CHI2 = 10.0, d.f. = 1, P less than 0.01), and at 10 days, 60% of treated rats vs. 25% of control rats were alive (CHI2 = 5.01, d.f. = 1, P less than 0.05). There was no detectable neurologic deficit among survivors in either group at 15 days. The combination of carbon dioxide, lidoflazine and deferoxamine, administered after return of spontaneous circulation, is a simple and easily administered treatment regimen that improves the survival incidence without neurologic deficits in this animal model of cardiorespiratory arrest and CPR.

Animals↗
PubMed2006

Treatment with deferoxamine increases neurons from neural stem/progenitor cells.

Neural transplantation is a promising approach for treating neurodegenerative disease. Neural stem/progenitor cells (NPCs) are self-renewing and multipotent and thus are good candidates for donor cells when they have been clearly defined to differentiate into neurons. As neuronal differentiation follows cell cycle exit, we investigated whether neuron production from NPCs is increased by treatment with cell cycle blockers. NPCs from E12.5 rat ventral mesencephalon were cultured as neurospheres in DMEM/F12 medium containing N2 supplements and bFGF. Treatment of NPCs with deferoxamine, a G1/S phase blocker, increased the number of beta-tubulin III-positive cells after differentiation, concomitant with increases of MAP2 mRNA and protein, and a decrease of GFAP protein. Further, an increase in beta-tubulin III/BrdU double-positive cells and a decrease in GFAP/BrdU double-positive cells were confirmed. In real-time PCR, the expressions of p21(cip1), p27(kip1) and p57(kip2) mRNAs remained unaltered for 8 h after treatment with deferoxamine but were significantly elevated after 1 day. Deferoxamine specifically enhanced the elevation of p27(kip1) mRNA at 1-2 days and the accumulation of p27(kip1) protein at 3 days, along with the activation of neuroD promoter and the elevation of neuroD mRNA. Transfection of p27(kip1) into NPCs induced activation of neuroD promoter and increase of number of beta-tubulin III-positive cells. These data suggest that pretreatment with deferoxamine increases the number of neurons from NPCs related to prolonged p27(kip1) elevation and activation of the neuroD signaling pathway. In this way, regulation of the cell cycle should be a useful first step in engineering NPCs for neural transplantation.

Animals↗
PubMed1996

Long-term intraperitoneal deferoxamine for hemochromatosis.

Intraperitoneal deferoxamine is a well established treatment for aluminum accumulation syndrome in patients with end-stage renal disease receiving peritoneal dialysis, but the use of intraperitoneal deferoxamine has not been described outside of the setting of chronic renal failure. We present here a case of secondary hemochromatosis, complicated by cirrhosis and cardiomyopathy, in which a chronic peritoneal dialysis catheter was used both to treat ascites and to deliver parenteral deferoxamine for iron overload. Daily urinary iron excretion was similar to that achieved when using standard routes of deferoxamine administration. Over a 2-year period, reversal of both the biochemical indicators and the clinical manifestations of iron overload was accomplished.

Adult↗
PubMed2003

Deferoxamine, allopurinol and oxypurinol are not neuroprotective after oxygen/glucose deprivation in an organotypic hippocampal model, lacking functional endothelial cells.

Reactive oxygen species-induced reperfusion injury of the brain is an important cause of neonatal morbidity and mortality following perinatal hypoxia-ischemia. Deferoxamine, allopurinol and oxypurinol have previously been shown to be neuroprotective in vivo during or directly after hypoxia-ischemia. To further characterize and more precisely elucidate whether the neuroprotective properties of these agents are mediated via neuronal and glial cells, or whether endothelial cells contribute to this effect, we tested their ability to protect CA1 neurons in organotypic hippocampal slices. Hippocampal slices obtained from 8-day-old rats were cultured for 7 days and exposed to oxygen/glucose deprivation for 50 min, or used as control slices. Cell damage was assessed at 48 h after oxygen/glucose deprivation using propidium iodide staining. At different time points following oxygen/glucose deprivation we administered dizocilpine, 6-cyano-7-nitroquinoxaline-2,3-dione, and alpha-phenyl-N-tert-butyl nitrone for validation purposes. Deferoxamine, allopurinol or oxypurinol were used as test substances. As expected, 89% and 98% protection was demonstrated with dizocilpine present during or during/after oxygen/glucose deprivation resp. alpha-Phenyl-N-tert-butyl nitrone administered during/after oxygen/glucose deprivation provided 44% protection. However, iron chelation with deferoxamine and inhibition of xanthine oxidase by allopurinol or oxypurinol did not confer neuroprotection. The neuroprotective effect of deferoxamine, allopurinol or oxypurinol, as seen in vivo, may be obtained via inhibition of the production of damaging factors by blood born substances or endothelial cells.

Allopurinol↗
PubMed1984

High-performance liquid chromatography of deferoxamine and ferrioxamine: interference by iron present in the chromatographic system.

The assay of the complexed (ferrioxamine) and uncomplexed forms of deferoxamine, a strong iron(III) chelating agent, by reversed-phase high-performance liquid chromatography was investigated. Complex formation with trace amounts of iron in the chromatographic system hinders the assay of deferoxamine by causing appearance of unexpected peaks, reaction zones and variations in retention time. By purging the column with deferoxamine and using EDTA in the mobile phase, these adverse effects in the determination of deferoxamine were eliminated. No interference by iron contamination of the chromatographic system was found in the assay of ferrioxamine, which is facilitated by the strong absorption of the analyte at 430 nm.

Chromatography, High Pressure Liquid↗
PubMed1990

Vision and hearing during deferoxamine therapy.

To determine the frequency of eye and auditory complications and their relationship to drug dosage and iron stores in patients receiving deferoxamine, we studied 52 regularly transfused patients who received deferoxamine by subcutaneous or intravenous infusion in doses from 26 to 136 mg/kg/day, and whose serum ferritin levels of 185 to 17,775 micrograms/L reflected a wide range of iron stores. Forty-nine patients (94%) had no evidence of drug-induced visual or auditory abnormalities. Symptomatic loss of vision and hearing developed in one patient; both problems improved when chelation therapy was stopped. Of the 51 symptom-free patients, one had a mild degree of macular stippling and one had a mild, bilateral, high-frequency sensorineural hearing loss. Eye and ear abnormalities in the symptom-free patients did not progress despite continuation or resumption of chelation therapy at the same dosage. Patients with ophthalmologic and audiologic abnormalities did not receive higher doses of deferoxamine and did not have lower serum ferritin levels than patients without such abnormalities. These findings demonstrate that eye and ear abnormalities during chelation therapy with deferoxamine may not occur uniformly at as high a frequency as previously reported, even in patients who receive large doses of the chelating agent or who have only modest amounts of excessive iron.

Adolescent↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. IV. Role of the iron-catalyzed pathway: deferoxamine.

This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.

Alkadienes↗
PubMed2001

Improving adherence with deferoxamine regimens for patients receiving chronic transfusion therapy.

We designed a study to obtain follow-up on behavioral aspects of compliance with home deferoxamine administration, explore social factors that might influence compliance, and evaluate the effectiveness of a pilot intervention program for patients with thalassemia or sickle cell disease who were receiving chronic transfusion therapy. Thirty-one patients between the ages of 6 and 21 years and their primary caregivers were administered a 24-hour recall Interview about home care. Fifteen went on to participate in a Desferal Day Camp, which combined educational strategies with peer support. Behavioral measures of treatment adherence were similar for most patients with sickle cell disease and thalassemia. Patient compliance with days of deferoxamine administration at follow-up was associated with initial compliance, perceived support, and patient and caregiver knowledge. Increased sharing of responsibilities for home care by patients and caregivers and caregiver knowledge were associated with lower ferritin and liver iron levels. A subsample of 3 patients who were extremely noncompliant with days of deferoxamine administration was examined separately; these patients were found to be moderately compliant with the number of hours and amount of deferoxamine administered and to share fewer home care tasks with primary caregivers. Participation in Desferal Day Camp did not result in increases in knowledge or peer support, suggesting that future interventions should focus on family support and on improving self-regulatory skills. The crucial role of collaboration among patients, families, and health care providers in developing interventions to enhance adherence was emphasized.

Adolescent↗
PubMed1996

Fluid resuscitation with deferoxamine hetastarch complex attenuates the lung and systemic response to smoke inhalation.

BACKGROUND: We determined the effect of infusing the iron chelator deferoxamine complexed to hetastarch on the degree of lung dysfunction and systemic abnormalities produced by a severe smoke exposure. METHODS: Adult sheep were given a smoke exposure under anesthesia that produced a peak carboxyhemoglobin between 40% and 45%. Twenty-eight sheep were studied; eight were given smoke alone and resuscitated with sufficient lactated Ringer's solution to maintain baseline hemodynamics. Seven sheep were given a bolus plus 1 ml/kg/hr of a 10% deferoxamine-hetastarch solution for resuscitation; five were given hetastarch alone. The response was compared with eight controls during a period of 24 hours. RESULTS: Smoke alone and smoke with hetastarch resulted in a shunt fraction of greater than 25% and a 50% decrease in compliance, severe airway inflammation, mucosal slough, atelectasis, and some alveolar edema. Increased lipid peroxides measured as malondialdehyde were present in airway fluid. In addition, oxygen consumption increased by 100% early after injury, net 24-hour positive fluid balance was almost 3 L, and a significant increase occurred in liver lipid peroxidation. The group given deferoxamine had a significantly attenuated lung response, with only modest airway damage lung dysfunction, and minimal systemic changes including a net positive fluid balance of just over 1L and no liver lipid peroxidation. CONCLUSIONS: An iron chelator deferoxamine complexed to hetastarch, given after a severe smoke exposure, significantly attenuates the airway and the systemic inflammatory (oxidant) injury, indicating free iron release and subsequent increased oxidant activity to be a major etiologic factor.

Animals↗
PubMed1992

Serum bactericidal activity for Yersinia enterocolitica in hemodialysis patients: effects of iron overload and deferoxamine.

Human serum has been shown to be bactericidal for most strains of Yersinia enterocolitica. Systemic Y enterocolitica infections have been reported in iron-overloaded hemodialysis patients treated with deferoxamine. Both iron and deferoxamine are known to enhance the growth of Y enterocolitica. We inoculated sera from 12 hemodialysis patients whose serum ferritin levels ranged from 26 to 6,855 micrograms/mL (ng/mL), as well as three controls, with Yersinia organisms. After latencies of 0 to 24 hours, inoculated sera were then plated on blood agar. Bactericidal activity was demonstrated in all sera and the degree of activity did not correlate with ferritin levels. Bactericidal activity was also demonstrated in sera from three deferoxamine treated patients. We conclude that in vitro, sera of end-stage renal failure patients, with and without iron overload, are as bactericidal as control sera for Y enterocolitica and that deferoxamine therapy does not interfere with that bactericidal activity.

Adult↗
PubMed1997

Morphological evidence of ototoxicity of the iron chelator deferoxamine.

Recent reports of the role of iron-catalyzed free radical formation in gentamicin ototoxicity and the successful attenuation of gentamicin ototoxicity by iron chelators led us to re-examine experimental material from a previously unpublished study of deferoxamine. Deferoxamine was injected i.m. into adult Japanese quail at either 300 or 750 mg/kg body weight for 30 days. Examination of sections from the basilar papilla at the light microscope level indicated that supporting cells were damaged after the lower drug dose, and that both supporting cells and hair cells were damaged after the higher drug dose. High, prolonged exposure to deferoxamine produced pathological changes similar to those seen in the basilar papilla after much lower, shorter doses of gentamicin. These results demonstrate that deferoxamine damages the quail inner ear and are consistent with the idea that the ototoxic actions of gentamicin may be mediated by iron chelation.

Animals↗
PubMed1987

Bone histologic response to deferoxamine in aluminum-related bone disease.

We have examined the changes in bone histology in 28 uremic patients after long-term treatment with the aluminum chelator, deferoxamine. Marked declines in stainable bone-surface aluminum were associated with increases in bone formation rate and osteoblastic osteoid following deferoxamine. The increased bone formation resulted from increases in bone apposition and length of double-tetracycline labels, the latter being highly correlated with the increase in osteoblastic osteoid (r = 0.85). While bone surface aluminum was highly correlated with bone formation rate (r = .69, p less than .001), bone aluminum content did not correlate with bone formation (r = 0.13) and was often elevated after treatment despite an improvement in bone histology. Patients who had undergone prior parathyroidectomy were less likely to have improved bone histology than those with intact parathyroid glands. We conclude that aluminum chelation therapy with deferoxamine is effective in ameliorating the bone histology of patients with chronic renal failure and bone aluminum accumulation, and that the change in stainable bone-surface aluminum is a more sensitive indicator than the change in bone aluminum content in assessing adequacy of chelation therapy. Patients who need deferoxamine treatment but have undergone a prior parathyroidectomy will probably require a more intensive treatment schedule than those who have intact parathyroid glands.

Aluminum↗
PubMed1989

Intraperitoneal deferoxamine therapy for iron overload in children undergoing CAPD.

We treated three children with renal failure and chronic iron overload with intraperitoneal deferoxamine therapy. Each child had an elevated serum ferritin level, a dense liver as measured by computerized tomography (Hounsfield Units) and one had dialysis related porphyria cutanea tarda. Deferoxamine therapy (10 to 17.5 mg/kg) was given in the overnight exchange for three to six months. Prior to therapy, iron was not detected in the dialysate; during the course of therapy, daily dialysate iron removal averaged 5652 micrograms, 2241 micrograms and 4028 micrograms in the three children. The serum ferritin level fell during the course of therapy in two children who were estimated to be in negative iron balance, and was unchanged in the third who was estimated to be in positive iron balance due to frequent transfusions. In 10 children with chronic renal failure, there was a linear correlation (r = 0.855; P less than 0.01) between the serum ferritin and the liver density, suggesting that an increased serum ferritin correlates with hepatic iron content. Interestingly, in each of the three children who received deferoxamine therapy, the liver density increased during therapy regardless of the estimated iron balance and the change in the serum ferritin level. We conclude that intraperitoneal deferoxamine therapy results in substantial iron losses in peritoneal dialysate, can result in negative iron balance but, in this study, did not result in lower liver iron content as measured by density on computerized tomography scan.

Adolescent↗
PubMed2003

Preventative effect of deferoxamine on degenerative changes in the optic nerve in experimental retrobulbar haematoma.

PURPOSE: Changes in the optic nerve due to the breakdown of blood elements and the effect of deferoxamine on these changes were evaluated. METHODS: The study group consisted of 12 rabbits. Three rabbits were used as control. In Group I, three rabbits had bilateral retrobulbar haematoma induced. In Group II, three rabbits had bilateral retrobulbar haematoma induced and were given systemic deferoxamine. In Group III, three rabbits were only given deferoxamine. At day 21, all the rabbits underwent bilateral enucleation and specimens from the orbital fat tissue were removed for light microscopic examination. The optic nerves were examined by light and electron microscopy. RESULTS: Light microscopic examination of the optic nerves did not reveal significant differences among the groups. Electron microscopy revealed ultrastructural changes in Group I. There were no significant pathological findings observed in Groups II or III. There was abundant iron pigment in the orbital fat tissue of Group I, but only a small amount in Group II. CONCLUSION: Systemic deferoxamine treatment is effective in preventing degenerative changes in retrobulbar haema-toma.

Animals↗