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PubMed2006

Comparative study of the protective effect between deferoxamine and deferiprone on chronic iron overload induced cardiotoxicity in rats.

Patients with iron overload frequently suffer from hemochromatosis of major organs, such as the heart and liver. Heart affection is the most common cause of death in patients with iron overload. Although the beneficial effects of deferoxamine (DFO) on iron-associated mortality are well documented, the role of deferiprone in the management of transfusional iron overload is controversial. The aim of this study was to compare the protective effect of iron chelators (DFO and deferiprone) individually and in combination with the anti-oxidant (vitamin C) in the prevention of myocardial damage. Sixty albino rats were divided into six groups: two control groups (noniron-loaded and iron-loaded) and four iron-loaded groups classified as follows: DFO group, DFO combined with vitamin C group, deferiprone group and deferiprone combined with vitamin C group. Heart tissue and blood samples were taken for histopathological examination of the heart, determination of total iron-binding capacity, 8-OH-deoxyguanosine (8-OH-dG), myocardial lipid peroxidation and glutathione (GSH) content. Less histopathological cardiac changes and a significant decrease in all biochemical parameters, except myocardial GSH, were observed in the deferiprone group. The addition of vitamin C improves the biochemical and histopathological changes in comparison to those rats administered DFO or deferiprone individually.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Recent insights into interactions of deferoxamine with cellular and plasma iron pools: Implications for clinical use.

Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred-fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4-8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non-transferrin-bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high-dose DFO are less desirable than continuous infusions at low doses, particularly in high-risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*-visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.

Animals↗
PubMed2005

Combined therapy with deferoxamine and deferiprone.

Therapy with either deferiprone (DFP) or deferoxamine (DFO) is inadequate in achieving negative iron balance in many patients with thalassemia. There are mounting theoretical, experimental, and clinical evidences of increased efficacy when therapy includes both chelating agents. DFP and DFO chelate excess iron in different ways without affecting each other's metabolism. When both chelators are administered simultaneously, they interact either in an additive or synergistic manner, probably through "shuttling" iron from DFP to DFO. Iron-balance studies have shown that the use of both agents on the same day can induce negative iron balance in all patients. Long-term combined therapy with DFO with DFP results in considerable reduction of both ferritin levels and liver iron concentration as well as significant improvement in cardiac siderosis and function. This therapeutic regimen is well tolerated and safe, even though it may be related to a small increase in the incidence of agranulocytosis compared with DFP monotherapy. Apart from using both agents simultaneously, sequential administration of DFP and DFO has also shown promising results. Combining the available iron chelators offers many therapeutic options that can be tailored to each patient individually. It is an exciting advance in treating hemosiderosis in thalassemic patients.

Agranulocytosis↗
PubMed2005

A simple model to assess and improve adherence to iron chelation therapy with deferoxamine in patients with thalassemia.

Adherence to deferoxamine (DFO) is vital for the long-term survival of patients with thalassemia; however, currently no measure exists to quantify adherence directly. In this study, 90 patients with thalassemia major underwent liver iron concentration (LIC) assessment by SQUID biosusceptometer, were asked to rate their adherence to DFO using a Numerical Likert Scale (NLS), and were educated about complications of iron overload. Of 38% (n = 28) of patients who rated themselves as very compliant, 19 had elevated LIC related to inadequate dosing of DFO and nine reported nonadherence in the past. Adherence improved after counseling and LIC decreased by 25% (7-60%) in eight previously noncompliant patients who returned for subsequent LIC over 15 months. In conclusion, the NLS seems to be a simple but reliable tool to assess patients' adherence to DFO. Education and frequent noninvasive LIC assessments can improve adherence and iron burden. Elevated LIC does not necessarily reflect concurrent noncompliance; however, it can be an indication of nonadherence in the past.

Adolescent↗
PubMed2000

Effects of deferoxamine, a chelator of free iron, on NA(+), K(+)-ATPase activity of cortical brain cell membrane during early reperfusion after hypoxia-ischemia in newborn lambs.

Free iron chelation after hypoxia-ischemia can reduce free radical-induced damage to brain cell membranes and preserve electrical brain activity. We investigated whether chelation of free iron with deferoxamine (DFO) preserved cortical cell membrane activity of Na(+),K(+)-ATPase and electrocortical brain activity (ECBA) of newborn lambs during early reperfusion after severe hypoxia-ischemia. Hypoxia was induced in 16 lambs by decreasing the fraction of inspired oxygen to 0.07 for 30 min, followed by a 5-min period of hypotension (mean arterial blood pressure <35 mm Hg). ECBA (in microvolts) was measured using a cerebral function monitor. Immediately after hypoxia and additional ischemia, eight lambs received DFO (2.5 mg/kg, i.v.), and seven lambs received a placebo (PLAC). Two lambs underwent sham operation. One hundred eighty minutes after completion of hypoxia and ischemia, the brains were obtained and frozen. Na(+),K(+)-ATPase activity was measured in the P(2) fraction of cortical tissue. Na(+),K(+)-ATPase activity was 35.1 +/- 7.4, 42.0 +/- 7.6, and 40.7 +/- 1.4 micromol inorganic phosphate/mg protein per hour in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p < 0.05: DFO versus PLAC). ECBA was 11.2 +/- 6.1, 14.8 +/- 4.8, and 17.5+/-.0.5 microV in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p = 0.06: DFO versus PLAC). Na(+),K(+)-ATPase activity correlated with ECBA at 180 min of reperfusion (r = 0.85, p < 0.001). We conclude that Na(+),K(+)-ATPase activity of cortical brain tissue was higher in DFO-treated lambs compared with PLAC-treated animals during the early reperfusion phase after severe hypoxia-ischemia, suggesting a reduction of free radical formation by DFO. Furthermore, a positive relationship was found between Na(+),K(+)-ATPase activity and ECBA.

Animals↗
PubMed1997

Effects of storage on venous and capillary blood samples: the influence of deferoxamine and butylated hydroxytoluene on the fatty acid alterations in red blood cell phospholipids.

Fatty acid concentrations in plasma and red blood cell phospholipids isolated from paired venous and capillary blood samples were compared and the effect of storage at -20 degrees C was evaluated as well. Plasma fatty acid profiles from venous and capillary blood were found to be comparable and not affected by up to four weeks of storage, while fatty acid profiles of venous and capillary red blood cells were no longer comparable after four weeks. Substantial losses of long-chain polyunsaturated fatty acids were observed in capillary red blood cells. To investigate whether the observed long-chain polyunsaturated fatty acids loss could be prevented, capillary red blood samples were stored for up to one year at -50 degrees C in the presence of the iron-binding agent deferoxamine or the free radical scavenger butylated hydroxytoluene. Both compounds protected the long-chain polyunsaturated fatty acids. Similarly, storage of red blood cell lipid extracts at -50 degrees C for up to one year was not associated with reduced levels of long-chain polyunsaturated fatty acids. In conclusion, the lipid loss from capillary red blood cells can be reduced for at least one year during storage at -50 degrees C with prior addition of either a metal chelating compound or a free radical scavenger, or by preparing lipid extracts of the samples within one week of blood collection.

Blood Preservation↗
PubMed2002

Urinary iron excretion induced by intravenous infusion of deferoxamine in beta-thalassemia homozygous patients.

The purpose of the present study was to identify noninvasive methods to evaluate the severity of iron overload in transfusion-dependent beta-thalassemia and the efficiency of intensive intravenous therapy as an additional tool for the treatment of iron-overloaded patients. Iron overload was evaluated for 26 beta-thalassemia homozygous patients, and 14 of them were submitted to intensive chelation therapy with high doses of intravenous deferoxamine (DF). Patients were classified into six groups of increasing clinical severity and were divided into compliant and non-compliant patients depending on their adherence to chronic chelation treatment. Several methods were used as indicators of iron overload. Total gain of transfusion iron, plasma ferritin, and urinary iron excretion in response to 20 to 60 mg/day subcutaneous DF for 8 to 12 h daily are useful to identify iron overload; however, urinary iron excretion in response to 9 g intravenous DF over 24 h and the increase of urinary iron excretion induced by high doses of the chelator are more reliable to identify different degrees of iron overload because of their correlation with the clinical grades of secondary hemochromatosis and the significant differences observed between the groups of compliant and non-compliant patients. Finally, the use of 3-9 g intravenous DF for 6-12 days led to a urinary iron excretion corresponding to 4.1 to 22.4% of the annual transfusion iron gain. Therefore, continuous intravenous DF at high doses may be an additional treatment for these patients, as a complement to the regular subcutaneous infusion at home, but requires individual planning and close monitoring of adverse reactions.

Adolescent↗
PubMed1989

Deferoxamine therapy in high-ferritin diabetes.

Serum ferritin and diabetes control were evaluated in 18 White patients with poorly controlled type II (non-insulin-dependent) diabetes who had no known causes of iron-storage disorder. Serum ferritin levels were found to be elevated with normal serum iron and total iron-binding capacity in 9 of the 18 patients studied. Because excess iron, typified by hemochromatosis, is associated with diabetes, and diabetes has been shown to improve after lowering total-body iron load through repeat venesection, I investigated whether regulating elevated ferritin levels could facilitate diabetes control. Deferoxamine (DFO), a known specific chelator of iron, was used because of its capacity to correct excess iron stores. All 9 patients in the high-ferritin diabetic group and 7 of 9 diabetic control subjects with normal serum ferritin levels were given DFO (10 mg/kg i.v.) twice weekly. Diabetic control, fasting glucose, triglyceride, cholesterol, HbA1c, and serum ferritin levels were monitored. Data show that lowering elevated ferritin levels correlated well with diabetes control and improved fasting glucose, triglyceride, and HbA1c in 8 of 9 patients with high ferritin levels. Lowering normal ferritin levels had no effect on diabetes control or on any of the other parameters in the 7 control subjects. This study shows there is a need to study iron metabolism in poorly controlled diabetes and demonstrates the value of DFO in controlling high-ferritin diabetes.

Aged↗
PubMedDate not supplied

The effects of deferoxamine mesylate and hypoxia on the cochlea.

Deferoxamine mesylate (DF) is a chelating agent used for the treatment of iron overload. Recently audiological testing of patients on long-term treatment with this drug indicated the possibility of an ototoxic side effect (1). We administered DF to chinchillas with both acute and chronic regimes. Functional and histological damage to the cochlea was detected only in the acute experiment. This was assumed to come not from the direct effect of DF on the cochlea but from the hypoxia as a result of respiratory suppression due to DF toxicity. To confirm this, animals were exposed to hypoxia during the same time course as for the DF experiment. Histological and physiological consequences of this hypoxia alone revealed very similar results to that observed in the acute DF experiment. This implies that DF has little direct toxic effect on the cochlea and, more importantly that considerable attention to hypoxia should be paid when assessing the cochlear pathology of animals which have been subjected to general anesthesia for long periods.

Animals↗
PubMed1995

Protection against acetaminophen-induced liver injury in vivo by an iron chelator, deferoxamine.

BACKGROUND: Recent data indicate that iron ions play a major role in lipid peroxidation, a hepatotoxic effect of acetaminophen (APAP). METHODS: We investigated whether an iron chelator, deferoxamine (DFO), can protect against APAP-induced liver injury in vivo in rats. RESULTS: DFO diminished the increase in serum alanine aminotransferase (ALAT) in a dose-dependent manner after APAP administration and also reduced mortality. Administration of 750 mg/kg APAP resulted in an increased ALAT (11,666 +/- 4633) after 8 h, and the mortality at 24 h was 88%. Pretreatment with 200 mg/kg DFO for 1 h significantly reduced ALAT (to 3406 +/- 894) and mortality (38%). DFO also attenuated histopathologic changes. Treatment with DFO depressed malondialdehyde formation by APAP without inhibiting glutathione depletion in the liver or reducing covalent binding of [3H]APAP to liver proteins. CONCLUSIONS: These results indicate that the protective effect of DFO against APAP-induced liver injury may be attributable not to changes in APAP metabolism but to the chelation of iron, which can catalyze the generation of active oxygen species, in hepatocytes.

Acetaminophen↗
PubMed1980

Iron and deferoxamine in lymphocyte blastogenesis.

Murine lymphocytes in tissue culture accumulate 59Fe during the blastogenic process. The accumulation of iron is related to the time of maximal activity of DNA synthesis. A chelator of iron, deferoxamine, inhibits blastogenesis with 50% inhibitory concentration of 5 microM. These results suggest that iron is necessary for the blastogenic response and may partially explain the immune deficiency associated with iron deficiency anemia.

Animals↗
PubMedDate not supplied

Effects of hydroxyethyl starch-deferoxamine on arachidonic acid metabolism and small bowel wall perfusion in early sepsis.

The effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, were investigated on eicosanoid release and bowel wall perfusion following cecal ligation puncture (CLP) in rats. Animals were randomly given an intravenous dose of 3.0 ml of HES-DFO or either vehicle (HES) or 9.0 ml saline immediately following completion of the CLP procedure. At 30, 60, 120, and 240 min after sepsis induction, blood pressure and bowel perfusion were measured. The animals were sacrificed and blood was collected for subsequent analysis of thromboxane, prostacyclin, and prostaglandin F2 alpha. The tissue content of energy-rich phosphates was determined in small-bowel samples at each time point. The antioxidative HES-DFO therapy did not diminish the eicosanoid release after CLP when compared with either HES-treated or saline-infused rats. However, treatment with the polymeric iron chelator resulted in an impaired bowel wall perfusion that was not reflected in alterations in total adenine nucleotide content or in energy charge. Considering hemodynamic and biochemical endpoints, these results are contradictory to the hypothesis that iron-driven oxygen radicals are major determinants of the eicosanoid release that is elevated following CLP-induced sepsis.

Animals↗
PubMed1989

Protective effect of the iron chelator deferoxamine on cold-induced brain edema.

Oxygen free radicals such as superoxide radical and iron-catalyzed hydroxyl radical generated by the superoxide system have been implicated in the genesis of brain edema. Therefore, deferoxamine (DFO), an iron chelator, could potentially be used to treat brain edema. To examine this hypothesis, vasogenic brain edema was produced in 48 cats by a cortical freezing lesion. The animals were separated into three groups: Group 1 comprised 14 cats that received no DFO and were sacrificed at 6 or 24 hours; Group 2 consisted of 12 cats that were treated with DFO (50 mg/kg/ml, intravenously) at 15 minutes before the lesion was made and 60 minutes later and were sacrificed at 6 or 24 hours; and Group 3 included 12 cats that were treated with DFO (50 mg/kg/ml, intravenously) at 15 minutes after the lesion was produced and 60 minutes later and were sacrificed at 6 or 24 hours. The effect of DFO on arterial blood pressure was also studied in the remaining 10 cats. Brain water content in eight sampling areas was measured by the specific gravity method. Blood-brain barrier disruption was assessed by spread of Evans blue dye with planimetry. Specific gravity values at 6 and 24 hours were significantly higher in Group 2 than in Group 1 animals. Areas of Evans blue dye extravasation at 6 and 24 hours were significantly reduced in Group 2 relative to Group 1. Group 3 cats showed improvement in specific gravity values and Evans blue extravasation at 6 hours, but not at 24 hours. The iron chelator DFO prevented early development of brain edema; thus, this oxygen free radical scavenger may provide a foundation for a new therapy for brain edema.

Animals↗
PubMed1999

Therapeutic values of different routes of administration of vitamin A with ferrous sulfate in treating deferoxamin-induced iron-deficiency anemia.

About half the pregnant women in developing countries suffer from iron-deficiency anemia. The treatment of choice for these patients includes iron compounds such as ferrous sulfate. It was recently shown that a concomitant administration of vitamin A with ferrous sulfate increases iron-induced hematopoietic effect. In the current study, the efficacy of various routes of administration of vitamin A with ferrous sulfate in deferoxamin-treated anemic rats were compared. The work reveals no difference among various routes of administration, including several alternates of oral and intramuscular injection of vitamin A and ferrous sulfate for 28 d. It was therefore concluded that the therapeutic effect of vitamin A in iron-deficiency anemia is probably not via its influence on iron absorption from the gastrointestinal tract.

Administration, Oral↗
PubMed1988

Effect of aluminum and deferoxamine on biliary iron elimination in the rat.

Iron (Fe) and aluminum (Al) eliminations in bile were studied in rats after intravenous administration of Fe, Al, deferoxamine mesylate (Desferal, Ciba) (DFA), feroxamine (FeA), and aluminoxamine (AlA) at the dose of 50 mumole/kg body weight. Bile was obtained from the bile duct of anesthetized rats, and the concentrations of Fe and Al in bile were measured by an inductively coupled plasma optical emission spectrometer. The results showed an increase of Fe elimination in bile, from 10 to more than 20 mumole/liter after Fe and also after Al administration; an increase to about 350 mumole/liter after DFA administration; to 250 mumole/liter after FeA administration; and to 100 mumole/liter after AlA administration. Aluminum elimination in bile was increased only after Al and particularly after AlA administration but not after Fe and FeA administration. In conclusion, Al and AlA were able to increase Fe elimination in bile. Thus Al overload observed in hemodialyzed patients may induce an excessive iron loss in bile and partly explain microcytic anemia.

Aluminum↗
PubMed1994

The effect of deferoxamine on the preneoplastic lesions in the chemically induced hepatocarcinogenesis.

Iron is essential for the growth of all living cells. One of the most important intracellular roles of iron is the activation of ribonucleotide reductase, which is indispensible to the production of deoxyribonucleotide necessary for DNA synthesis. Deferoxamine (DFO) is an iron chelating agent and has been known to have an antiproliferative effect in various malignant cells including hepatocellular carcinoma and the effect seems to be related to depletion of iron. This study was undertaken to investigate the effect of DFO on preneoplastic lesions in chemically induced hepatocarcinogenesis. The resistant hepatocyte model was used and Sprague Dawley rats were divided into the following groups; I: normal control, II: carcinogen administered group, III: carcinogen and DFO administered group. Rats were sacrificed at 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks and 8 weeks after partial hepatectomy (PH). DFO (50 mg/kg/day, I.P.) was daily injected from 3 weeks before administration of carcinogen to the time when rats were sacrificed. Hepatic iron content was higher in group II than in group III, especially at 3 days and 1 week after PH. Hyperplastic lesions of resistant hepatocytes were less well developed in group III than in group II. Bromodeoxyuridine labelling indices of oval cells and hyperplastic lesions of resistant hepatocytes were higher in group II than in group III except for rats examined at 3 days after PH. The results suggest that DFO has an antiproliferative effect on preneoplastic lesions in hepatocarcinogenesis and it might be related to reduction of the hepatic iron.

Animals↗
PubMed1998

[An experimental study of ototoxicity induced by deferoxamine mesilate].

We investigated the possibility of ototoxicity induced by deferoxamine mesilate (DFO). DFO was administered to guinea pigs intraperitoneally at 200 or 400 mg/kg body weight/day, 6 days/week for 5 weeks, or 600 mg/kg body weight/day, 6 days/week for 4 weeks. Physiological saline instead of DFO was given to animals as a control. After the course of administration was completed, we measured the threshold of the compound action potential (CAP) and the endocochlear potential (EP). We also examined the cochlear histology by scanning electron microscopy. The CAP threshold of animals treated with 200 or 400 mg of DFO per kg was not elevated. In the animals treated with 600 mg/kg , however, the CAP threshold was clearly elevated when compared with that of control animals. The EP values of animals treated with 200 or 400 mg of DFO per kg were comparable to those of control animals. In some animals treated with 600 mg of DFO per kg, however, the EP values were decreased. Histological examination revealed that the outer hair cells of the cochlea were missing. DFO presumably acts on hair cells, resulting in elevation of the CAP threshold. We concluded that hair cell damage is one of the contributing factors to CAP threshold elevation.

Action Potentials↗
PubMed2000

Lipid peroxidation and glutathione levels after cortical injection of ferric chloride in rats: effect of trimetazidine and deferoxamine.

Intracortical injection of iron salts causes seizures. Oxidation of lipids in neural membranes by reactive oxygen species is involved in the mechanism responsible for iron-induced seizures as a model of posttraumatic epilepsy. In this study, we examined the effect of trimetazidine (TMZ) and deferoxamine (DFO) on lipid peroxidation after cortical injection of 5 microliters of an aqueous solution containing 100 mM of ferric chloride (FeCl3) in rats. Animals were divided into four groups (n = 7 each) and treated as follows: group 1, saline injection into the cortex (control group); group 2, iron injection into the cortex (injury group); group 3, iron injection into the cortex plus TMZ; group 4, iron injection into the cortex plus DFO. The animals were killed 3 h after injections, and the levels of malondialdehyde (MDA), a lipid peroxidation product, and reduced glutathione (GSH) were measured. A significant elevation of MDA was observed in group 2 (P < 0.05). MDA levels were found to be lower in both the TMZ-treated (P < 0.05) and DFO-treated (P < 0.05) groups than in the injury group. Tissue GSH levels were significantly decreased in group 2 (P < 0.05). GSH levels were increased in the TMZ-treated (P < 0.05) and DFO-treated (P < 0.05) groups compared to the injury group. The results of our study suggest that lipid peroxidation is a critical event in iron-induced epilepsy and that treatment with TMZ and DFO is effective in preventing the formation of free radicals and reducing lipoperoxides in brain tissue.

Analysis of Variance↗