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PubMed2006

Myocardial iron loading in patients with thalassemia major on deferoxamine chelation.

BACKGROUND: Heart failure secondary to myocardial iron loading remains the leading cause of death in thalassemia major (TM). We used cardiovascular magnetic resonance (CMR) to assess the prevalence of myocardial iron overload and ventricular dysfunction in a large cohort of TM patients maintained on conventional chelation treatment with deferoxamine. METHODS: A mobile CMR scanner was transported from London, UK, to Sardinia, Italy where 167 TM patients were assessed for myocardial iron loading, B-natriuretic peptide (BNP), and ferritin. In patients with myocardial iron loading CMR assessments of ventricular function were also made. RESULTS: Myocardial iron loading (T2* < 20 ms) was present in 108 (65%) patients, which was severe (T2* < 8 ms) in 22 (13%). Impaired (< 56%) left ventricular (LV) ejection fraction (EF) was present in 5%, 20% and 62% of patients with mild, moderate or severe iron loading. Increasing myocardial iron was related to impaired LVEF (Rs = 0.57, p < 0.001), weakly related to serum ferritin (Rs = -0.34, p < 0.001), and not related to liver iron (Rs = 0.11, p = 0.26). BNP was weakly related to myocardial iron (Rs = -0.35, p < 0.001) and was abnormal in only 5 patients. CONCLUSIONS: Myocardial siderosis was found in two-thirds of thalassemia major patients on maintenance deferoxamine treatment. This was combined with a high prevalence of impaired LV function, the severity of which tracked the severity of iron deposition. BNP was not useful to assess myocardial siderosis.

Cardiomyopathies↗
PubMed1989

Enhancement of in vitro activity against neuroblastoma by doxorubicin and deferoxamine.

A colorimetric assay was used to compare the in vitro effects on neuroblastoma cell viability of 3.75-60 microM deferoxamine or 0.125-2 microM doxorubicin alone with those of the two drugs in combination. For each of two human neuroblastoma cell lines (CHP 100 and CHP 126), exposure to each drug individually produced dose-related cytotoxic effects within 3 days. When these cells were simultaneously exposed to both drugs, even at concentrations achievable in vivo, cell death was greater than what could be accounted for by either drug alone. Cytotoxicity was further potentiated to a variable extent when the cells were sequentially exposed to deferoxamine and doxorubicin at 24-hour intervals. Thus, this combination of drugs warrants further study.

Cell Line↗
PubMed1984

Deferoxamine treatment of acute iron intoxication in pregnancy.

Acute iron intoxication in pregnancy presents a dilemma to the clinician. Toxic levels of iron are associated with severe complications and can be fatal, but the effective iron chelator, deferoxamine, has possible teratogenic potential. The present report discusses the clinical indications that can support the administration of deferoxamine for iron intoxication in pregnancy and discusses the benefits and risks of its usage.

Abortion, Induced↗
PubMed2003

Deferoxamine improves early postresuscitation reperfusion after prolonged cardiac arrest in rats.

The no-reflow phenomenon and delayed hypoperfusion after transient cardiac arrest (CA) impede postischemic recovery. Activation of lipid peroxidation (LPO) after ischemia and reperfusion is considered one of the mechanisms responsible for such abnormalities. The present study investigates the influence of iron-dependent LPO inhibitor deferoxamine (DFO) on the cerebral perfusion after prolonged CA and resuscitation. Fourteen male Sprague-Dawley rats were subjected to 17 minutes of CA, induced by esmolol (an ultrashort-acting beta-blocker) and apnea, followed by resuscitation by retrograde intraaortic infusion of oxygenated donor blood mixed with a resuscitation cocktail inside a vertical-bore 9.4-T magnetic resonance imaging (MRI) magnet. Animals were randomized double-blindly into two groups to receive DFO or saline, respectively. Cerebral perfusion was measured by MRI continuously using the arterial spin-labeling method before, during, and after CA. All animals were successfully resuscitated in 1.36 +/- 0.04 minutes with well-controlled arrest time (17.99 +/- 0.03 minutes) in both groups. Deferoxamine significantly increased cerebral perfusion in hippocampus, thalamus, hypothalamus, and amygdala, but not in cortex, during the first 20 minutes of reperfusion. In the DFO-treated group, the neurologic deficit score was significantly better (400 +/- 30 vs. 250 +/- 47, out of 500 as the best, P < 0.05) and weight loss was significantly less (33 +/- 6 vs. 71 +/- 19 g, P < 0.05) 5 d after arrest. The finding supports the notion that early reperfusion immediately after resuscitation is important for long-term outcome and that LPO may be involved in microvascular disorders during the reperfusion, particularly in the brain after prolonged cardiac arrest and resuscitation.

Animals↗
PubMedDate not supplied

Indolent zygomycosis associated with deferoxamine chelation therapy.

This paper describes a 71-year-old man with myelodysplasia who required multiple transfusions and subsequent deferoxamine chelation therapy and who then developed indolent cutaneous and probable pulmonary infection with Rhizopus species. The patient did not have rapidly progressive infection as has been described in almost all previously reported deferoxamine-treated patients with zygomycosis. Amphotericin B therapy was successful in curing the infection.

Aged↗
PubMed1990

Deferoxamine and eflornithine (DL-alpha-difluoromethylornithine) in a rat model of Pneumocystis carinii pneumonia.

The iron chelator deferoxamine and the polyamine biosynthesis inhibitor eflornithine (DL-alpha-difluoromethylornithine) were examined for anti-Pneumocystis carinii activity in the rat model of P. carinii pneumonia. The activity of deferoxamine at 250, 500, and 1,000 mg/kg given intraperitoneally provides evidence that iron chelation is a promising novel approach to P. carinii chemotherapy. Results with eflornithine at 2, 3, and 4% in drinking water confirm and extend previously reported activity in the rat model.

Animals↗
PubMed1996

Trophozoite elimination in a rat model of Pneumocystis carinii pneumonia by clinically achievable plasma deferoxamine concentrations.

In a rat model of Pneumocystis carinii pneumonia, a 3-week infusion of deferoxamine producing concentrations in plasma of > or = 1.5 micrograms m-1 eliminated the trophozoite life cycle stage. Since this concentration is well below that routinely achieved in patients treated for iron overload, deferoxamine has promise as a therapy for AIDS-associated P.carinii pneumonia.

Animals↗
PubMed1994

Inhibitory effect of deferoxamine or macrophage activation on transformation of Paracoccidioides brasiliensis conidia ingested by macrophages: reversal by holotransferrin.

Conidia of P. brasiliensis ingested by murine macrophages at 37 degrees C showed enhanced transformation to yeast cells and further intracellular growth compared with conidia in culture medium alone. Treatment of macrophages with the iron chelator deferoxamine inhibited the intracellular conidium-to-yeast transformation. Cytokine-activated macrophages could also exert this inhibitory effect. Holotransferrin reversed the inhibitory effect of either deferoxamine or activated macrophages on intracellular conidium-to-yeast transformation. These results indicate that iron restriction is one of the mechanisms by which activated macrophages control the intracellular transformation of ingested conidia and growth of yeast cells.

Animals↗
PubMed1993

Sulfhydryl-depleting agents, but not deferoxamine, modulate EDRF action in cultured pulmonary arterial cells.

The potential role of intracellular sulfhydryls and iron on the biological activity of endothelium-derived relaxing factor (EDRF) released basally from bovine pulmonary arterial endothelial (BPAE) cells was investigated in a cultured cell bioassay system, by measuring N omega-nitro-L-arginine-sensitive guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in rabbit pulmonary arterial smooth muscle (SM) cells. The role of sulfhydryls in the biosynthesis of EDRF was studied by selectively exposing the endothelial cells to thiol-depleting agents. Both N-ethylmaleimide (NEM) and maleic acid diethyl ester (DEM) inhibited EDRF-induced cGMP accumulation in a dose-dependent manner. To study the requirement of SM thiols in the metabolism of EDRF to a stimulator of cGMP formation, SM were selectively exposed to NEM and DEM before bioassay with control, untreated BPAE. DEM and NEM inhibited cGMP formation in response to EDRF by 30 and 68%, respectively. The requirement of SM sulfhydryls was further investigated in the stimulation of SM cGMP accumulation elicited by nitrosothiols [S-nitroso-L-cysteine, S-nitroso-mercaptoproprionic acid, and sodium nitroprusside (SNP)]. NEM pretreatment of SM cells abolished cGMP responses to all vasodilators; DEM did not affect the nitrosothiol responses but reduced by 30% the cGMP accumulation to SNP. The role of iron in the endothelial synthesis of EDRF was assessed by chelating endothelial low-molecular-weight iron compounds. Exposure of BPAE to deferoxamine mesylate had no effect on cGMP accumulation in SM, suggesting that deferoxamine-available iron is not necessary for the endothelial stimulation of SM cGMP formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Effect of deferoxamine and sympathectomy on vasospasm following subarachnoid hemorrhage.

We examined the effects of subarachnoid hemorrhage (SAH) and treatment with deferoxamine (DFO) or sympathectomy on vascular smooth muscle function, as well as the underlying mechanisms involved, by recording the responses to nor-adrenaline and serotonin in isolated carotid arteries in vitro. All studies were performed before and 7 days after SAH. An experimental subarachnoid hemorrhage model was created in rabbits by injecting autologous arterial blood into the subarachnoid space of the rabbits via cisterna magna punction. During the chronic stage of vasospasm following SAH deferoxamine (DFO) was given to the animals and cervical and periarterial sympathectomy was performed in the other groups of animals. In isolated carotid arteries noradrenaline (10(-8) to 10(-4) mol/l) and serotonin (10(-8) to 10(-4) mol/l) produced concentration-dependent contractions. These contractile responses were significantly enhanced in animals 7 days after SAH compared to controls and did not return to control values in carotid arteries obtained from animals treated with DFO or sympathectomy for 7 days after SAH. These results show that SAH causes supersensitivity in the carotid as well as cerebral arteries during the first week after SAH and could contribute to the development of cerebral vasospasm. Both treatment with DFO and sympathectomy after SAH did not reduce the contractile responses to noradrenaline and serotonin in the carotid arteries. In conclusion, treatment with DFO or sympathectomy during the chronic stage of vasospasm after SAH did not affect the vascular responses of the extradural part of the carotid artery to vasoactive substances.

Animals↗
PubMed1990

Successful treatment of hemodialysis-related porphyria cutanea tarda with deferoxamine.

End-stage renal failure and long-term hemodialysis treatment promote the development of genetically conditioned porphyria cutanea tarda (PCT). The clinical manifestation is triggered off by unknown factors coexisting with renal insufficiency and hemodialysis. Iron overload is often associated with the disease and is thought to play a key role in its pathogenesis. Iron removal by deferoxamine infusions is regarded as the treatment of choice for patients who cannot undergo repeated phlebotomy procedures and has been successfully used in patients with normal renal function. We report a case of hemodialysis-related PCT and iron overload in whom repeated venesections were contraindicated on account of severe anemia and treatment with deferoxamine led to a striking improvement of symptoms.

Deferoxamine↗
PubMed1995

Modification of cisplatin-induced renal p-aminohippurate uptake alteration and lipid peroxidation by thiols, Ginkgo biloba extract, deferoxamine and torbafylline.

To determine whether inhibition of lipid peroxidation modifies cisplatin-induced changes of renal p-aminohippurate (PAH) uptake, we examined the effects of various radical scavengers and torbafylline on cisplatin-induced lipid peroxidation and PAH accumulation changes in rat renal cortical slices. Renal cortical slices were incubated with different cisplatin concentrations (0.3, 0.6, 1.0 mg/ml) in the presence of either glutathione, N-acetylcysteine, the iron chelator deferoxamine, Ginkgo biloba extract or the xanthine derivate torbafylline. Lipid peroxidation monitored as the production of malondialdehyde (MDA) was stimulated by increasing cisplatin concentrations in a dose-related manner. At a cisplatin concentration of 1.0 mg/ml, MDA production was twofold compared to controls (0.69 +/- 0.06 vs. 1.36 +/- 0.07 nmol/mg; p < 0.05). In turn, cisplatin decreased PAH uptake of kidney slices dose-dependently from 13.3 +/- 1.3 to 2.6 +/- 0.2 (p < 0.01). All agents tested inhibited cisplatin-induced lipid peroxidation; however, at a cisplatin concentration of 1.0 mg/ml, none of them prevented the decline of cisplatin-induced PAH uptake. Of the agents tested, deferoxamine proved to be the most effective antioxidant, completely inhibiting cisplatin-induced lipid peroxidation but in contrast preventing the decrease in PAH uptake only at a cisplatin concentration of 0.3 mg/ml. No strict association between lipid peroxidation and decline of PAH uptake was found, suggesting that lipid peroxidation may only in part participate in cisplatin-induced alterations of PAH uptake.

Acetylcysteine↗
PubMed1985

Red cell ghost-entrapped deferoxamine as a model clinical targeted delivery system for iron chelators and other compounds.

In iron overload resulting from repeated blood transfusion, phagocytic reticuloendothelial cells are the primary and major sites of iron accumulation. Removal of this iron by the iron chelator deferoxamine can be enhanced by targeted delivery of this agent to reticuloendothelial cells. We have used resealed erythrocyte ghosts as a model system for delivery of deferoxamine to reticuloendothelial cells and have demonstrated a several-fold enhancement of urine iron excretion in children and adults with congenital or acquired iron-loading anemias. Although presently not cost-effective, this approach provides a useful, practical and safe model for [1] iron chelator targeting to reticuloendothelial cells, and [2] the clinical use of resealed erythrocyte ghosts for targeting pharmacologic agents to reticuloendothelial cells.

Deferoxamine↗
PubMed1988

Iron-load increases the susceptibility of rat hearts to oxygen reperfusion damage. Protection by the antioxidant (+)-cyanidanol-3 and deferoxamine.

To investigate whether iron is involved in the reperfusion syndrome by aggravating free radical injury, the hearts from iron-loaded and control rats were perfused under normoxic, anoxic, and reperfusion conditions. Normoxic perfusion revealed no change in coronary flow, contractility, or lactate dehydrogenase (LDH) release between these two groups. Under anoxic and reperfusion conditions, however, we found a significant increase of ventricle fibrillation (56% vs. 0%, p less than 0.01, n = 9), a significantly lower recovery of contractility (21 +/- 7.4% vs. 81 +/- 6.6%, mean +/- SEM; p less than 0.001), and a significant increase of LDH release (667 +/- 142 vs. 268 +/- 37 mU LDH/min/g wet wt, mean +/- SEM; p less than 0.05). Administration of either 20 microM of the antioxidant (+)-cyanidanol-3 or 50 microM of the iron-chelator deferoxamine totally prevented the generation of ventricle fibrillation and normalized contractility to control levels in the iron-loaded group. Moreover, 20 microM (+)-cyanidanol-3 significantly lowered LDH release in this period (312 +/- 67 mU), whereas deferoxamine had no protective effect on this LDH release (1,494 +/- 288 mU). Normal hearts appeared to be protected by 20 microM (+)-cyanidanol-3 as well. In this group (n = 6), a significantly higher recovery of contractility (97.1 +/- 3.2% vs. 81 +/- 6.6%, p less than 0.05) and a significantly lower release of LDH (110 +/- 27 vs. 268 +/- 37 mU, p less than 0.05) was found compared with the control group (n = 9). No difference in superoxide dismutase or glutathione peroxidase activity was found between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Postischemic free radical production in the venous blood of the regionally ischemic swine heart. Effect of deferoxamine.

BACKGROUND: We tested the hypothesis that secondarily produced free radicals can be detected in venous coronary effluent without the need for direct exposure of postischemic tissue to the spin trapping agent alpha-phenyl-tert-butylnitrone (PBN). METHODS AND RESULTS: The left anterior descending coronary artery (LAD) of pigs was ligated for 15, 30, 40, or 60 minutes, and the tissue was subsequently reperfused for 60 minutes. Venous effluent (6.5 ml) from the risk area was withdrawn sequentially at 1.5-minute intervals during reperfusion. The effluent blood was immediately infused (4.5 ml/min) with an isotonic saline solution containing 120 mM PBN: Preischemic control effluent samples were collected in an identical fashion. Plasma from each sample was extracted in organic solvent and subsequently analyzed by electron spin resonance (ESR) spectroscopy. Another group of pigs received an infusion of the metal chelator deferoxamine mesylate (25 mg/kg/hr) into the right atrium starting 1 hour before the 40-minute ligation and continuing throughout ligation and reperfusion. We were able to demonstrate the postischemic production of ESR signals for PBN adduct(s) from untreated hearts having spectral characteristics similar to an alkoxyl adduct (PBN-RO.; hyperfine splitting constants for beta-hydrogen [alpha H] = 2.0-2.25 G; nitrogen [alpha N] = 13.5-13.75 G). The reperfusion time course of PBN adduct production had a unique pattern: 1) multiple low-level bursts during the initial 15 minutes of reperfusion, and 2) a prominent PBN adduct signal during a relatively late time (20-25 minutes) of reperfusion. Total postischemic PBN adduct production rose with increasing duration (15-60 minutes) of ischemia and was associated with a progressive elevation of total lactate dehydrogenase in the effluent. Infusion of deferoxamine markedly diminished PBN adduct production as well as total release of lactate dehydrogenase. CONCLUSIONS: These data suggest the potential feasibility of using an ex vivo ESR spin trapping technique in blood-perfused models of cardiovascular injury and that chelatable free iron contributes to the production of alkoxyl radicals.

Alcohols↗
PubMed1989

Continuous intravenous infusion of deferoxamine reduces mortality by paraquat in vitamin E-deficient rats.

Paraquat, an oxygen radical-generating agent, is a widely used agrochemical that is also toxic for humans, in whom it may cause respiratory failure. In the present study, we investigated the effect of deferoxamine (DF), an iron chelator with antioxidant capacity, on paraquat toxicity in vitamin E-deficient rats. After the administration of paraquat at a dose of 20 mg/kg the animals were treated with a continuous intravenous infusion of DF for 14 days. In a dose-response study, four of six animals receiving 100 mg DF/kg/24 h survived the study period of 14 days compared with none in the saline-treated control group (n = 6), and three and two animals in the groups receiving 50 (n = 6) and 200 mg DF/kg/24 h (n = 6), respectively. In another series of experiments, animals were monitored for a total period of 35 days, at which time any survivors were killed, and lung histologic examination was carried out. Deferoxamine treatment was started simultaneously (n = 21), 6 h (n = 18), and 16 h (n = 18) after paraquat poisoning. Percent survival in the various time-point groups was 47.7 (p less than 0.01), 38.9 (p less than 0.02), and 22.2 (not significant), respectively, compared with 7.1 (n = 14) in the control group. The presence of lung damage was seen only in those of the surviving rats where DF was started at the 16 h time point after paraquat administration. In ancillary in vitro studies, where Escherichia coli was used as a source of enzymic activity for the redox-cycling of paraquat, DF completely inhibited the formation of hydroxyl radical (.OH).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Acute encephalopathy due to aluminum toxicity successfully treated by combined intravenous deferoxamine and hemodialysis.

Acute aluminum intoxication is uncommon in clinical practice but can be fatal. This limited experience is reflected in the paucity of data assessing a viable approach to the treatment of these patients. In this report, the authors describe the clinical course and successful, pharmacokinetic-based deferoxamine-hemodialysis treatment regimen of a patient with severe aluminum encephalopathy following alum bladder irrigation. The combined use of deferoxamine and appropriately timed hemodialysis appears to be a very reasonable means of treating patients with severe acute aluminum intoxication.

Acute Disease↗
PubMed2005

Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major.

Deferoxamine (DFO) therapy has been associated with improved survival of thalassemia patients. However, cardiac disease remains the main cause of death in those patients. In 1995, the oral chelator deferiprone became available for clinical use. We compared the occurrence of cardiac disease in patients treated only with DFO and in those whose therapy was switched to deferiprone during the period of observation, from January 31, 1995, to December 31, 2003. All patients with thalassemia major treated in 7 Italian centers who were born between 1970 and 1993 and who had not experienced a cardiac event prior to January 1995 were included. DFO only was given to 359 patients, and 157 patients received deferiprone for part of the time. A total of 3,610 patient-years were observed on DFO and 750 on deferiprone. At baseline, the 2 groups were comparable for age and sex, while ferritin levels were significantly higher in patients switched to deferiprone. Fifty-two cardiac events, including 10 cardiac deaths, occurred during therapy with DFO. No cardiac events occurred during deferiprone therapy or within at least 18 months after the end of it. In the setting of a natural history study, deferiprone therapy was associated with significantly greater cardiac protection than deferoxamine in patients with thalassemia major.

Adolescent↗