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PubMed1987

A free radical scavenger reduces hematoma-induced flap necrosis in Fischer rats.

Free radicals have been shown to play an important role in hematoma-induced flap necrosis. The present study investigated the effect of deferoxamine, a free radical scavenger and iron chelator, on flap necrosis. A 4 X 2 cm dorsal flap was raised in Fischer inbred rats, and 3 cc of blood from inbred donors was instilled beneath the flap. Saline-treated control animals (Group 1) were compared with two experimental groups. In Group 2, deferoxamine 150 mg/kg was administered 15 minutes before surgery and every 8 hours for 5 days. In Group 3, deferoxamine was given every 8 hours for 3 days before surgery and every 8 hours for 5 days postoperatively. Flap necrosis was assessed on postoperative day 5. Group 2 had significantly less necrosis, 18.6%, than the control group, 64.0% (p less than 0.001). Group 3, with 36.0% necrosis, also showed improvement (p less than 0.05). Group 2 and Group 3 were not significantly different. Deferoxamine, a safe and well-tolerated free radical scavenger, greatly enhanced flap survival, presumably by the neutralization of damaging free radical species and by chelation of iron.

Animals↗
PubMed2001

Bone aluminum uptake in uremic rats receiving intraperitoneal iron.

To assess the effect of concomitant iron and aluminum loads on bone aluminum accumulation and on the response to the deferoxamine test in rats with the same aluminum surcharge, Wistar rats with chronic renal failure were divided into three groups: iron-overloaded rats (N = 6) (intraperitoneal iron); iron-depleted rats (N = 6) (blood withdrawal two to three times per week); control rats (N = 4) (no manipulation). All groups received intraperitoneal aluminum simultaneously. After 6 wk, a deferoxamine challenge test was performed. Thereafter, bone aluminum and iron were measured. The iron-overloaded rats showed higher bone iron content (iron overloaded: 147.7+/-55.4 microg/g; iron depleted: 7.9+/-1.0, and controls 13.3+/-9.9 microg/g, p < 0.010) and lower bone aluminum content (iron overloaded: 14.2+/-4.0 microg/g; iron depleted: 70.9+/-35.1 microg/g; controls: 72.7+/-28.3 microg/g p < 0.005). No differences were found between the iron-depleted and control rats. After the deferoxamine infusion, the iron-depleted rats tended to have higher serum aluminum increments (p = NS) and higher urinary aluminum excretion (p < 0.012, p < 0.020) than control rats despite similar amounts of aluminum in bone of the two groups. Aluminum bone accumulation was minor if iron and aluminum loads were given concomitantly. The iron depletion influenced the results of the deferoxamine challenge test in rats with similar bone aluminum burden.

Aluminum↗
PubMed1991

Pituitary function in thalassemic patients and the effect of chelation therapy.

This study examined anterior pituitary function and the effect of chelation therapy in 31 patients with beta-thalassemia/HbE disease. Patients were divided into those receiving chelation therapy by deferoxamine and those receiving no such therapy (control group). Pituitary function studies were repeated in both groups 18 months later. The results showed decreased pituitary responses following stimulation in 22 patients. Among these, gonadotropin and PRL responses were most affected. After 18 months, serum ferritin levels had significantly decreased in the deferoxamine group. PRL and GH responses were improved in 3 patients receiving chelation therapy without changes in other hormone responses. In contrast, no changes in pituitary responses were shown in the control group at the end of follow-up. There were 6 drop-outs (4 in the control and 2 in the deferoxamine group) and 3 deaths (2 in the control and 1 in the deferoxamine group) during 18 months. In conclusion, gonadotropin and PRL deficiencies occur most frequently in thalassemic patients. Chelation therapy for 18 months markedly reduced serum ferritin level and might preserve or improve PRL and GH secretions, but seems to have no beneficial effects on other pituitary hormone reserves.

Adult↗
PubMed1997

A risk-benefit assessment of iron-chelation therapy.

Iron overload caused by lifelong transfusion-dependent anaemias, such as beta-thalassaemia major, usually results in lethal cardiac toxicity in the second decade of life if not treated by iron chelation. There is no physiological mechanism for excreting the excess iron accumulated from blood transfusions and, unlike hereditary haemochromatosis, venesection is not an option. Therefore, chelation therapy is the only way to remove excess iron. This must be removed while not depriving cells of the essential iron needed for normal metabolism. Additionally, the iron chelator must prevent iron from participating in the generation of harmful free radicals. Parenteral chelation therapy with deferoxamine (desferrioxamine) is well established as promoting negative iron balance, reversing cardiac toxicity, and prolonging life expectancy well into the fourth decade of life and, most likely, beyond. Unfortunately, poor compliance with the rigours of parenteral treatment in a minority of patients limits its regular use, resulting in reduced life expectancy in these patients. Use of deferoxamine in excessive dosages may result in growth retardation, sensorineural ototoxicity and ocular toxicity, as well as bone deformities. These effects can be largely avoided if the dosage is adjusted to take account of the degree of iron overload (using the therapeutic index) and if the mean daily dose does not exceed 40 mg/kg. Nevertheless, it is recommended that patients be regularly monitored for such adverse effects. Deferiprone (L1; CP20) is an orally absorbed bidentate hydroxypyridinone iron chelator that can induce urinary iron excretion, promote negative iron balance and reduce hepatic iron levels in some transfusion-dependent patients, particularly in those who are markedly iron overloaded and have not received regular deferoxamine therapy. The long term efficacy and toxicity of deferiprone are the subjects of some controversy, and the published results of randomised controlled trials are awaited. Preliminary results suggest that when currently recommended dosages of deferiprone (75 mg/kg/day) are used, hepatic iron settles at levels that still put most patients at an increased risk from iron overload. A number of adverse effects may occur, and require cessation of therapy in up to 30% of patients. These effects include arthritis, nausea and (most seriously) agranulocytosis in 0.6 to 4% of patients. The risk of the latter complication means that frequent white blood cell counts are mandatory for patients taking this drug. There remains an urgent need to identify an orally active chelator regimen that is as effective as deferoxamine and has an acceptable degree of tolerability.

Administration, Oral↗
PubMedDate not supplied

Liver hyperthermia and oxidative stress: role of iron and aldehyde production.

Hyperthermia has been used to treat cancer in the liver. However, significant hepatotoxicity occurs at a therapeutic temperature of 42-43 degrees C. We have proposed that heat toxicity is the result of oxidative stress from superoxide generation with resultant lipid peroxidation. Further, iron release from liver iron stores (ferritin) appears to play a central role in hyperthermic toxicity. In this study, rat livers were perfused in situ at 37 or 42.5 degrees C with and without deferoxamine for 1 h with an asanguinous perfusate. Oxidative stress was assessed by the efflux of glutathione (GSH) into the perfusage. Prior studies by Skibba et al. (1989a, 1991) showed that perfusage equivalents of GSH were primarily present as oxidized glutathione (GSSG). Lipid peroxidation was assessed by the measurement of aldehydes appearing in the perfusate and formation of hydrocarbon gases (ethane and pentane) in the perfusion chamber head space. Liver injury was assessed by the leakage of cytosolic enzymes, AST and LDH, into the perfusate. Livers perfused at 42.5 degrees C showed significant rises (p < 0.05) in AST and LDH after 60 min of perfusion but perfusion at 42.5 degrees C with deferoxamine added, was not significantly different from perfusion at 37 degrees C. Perfusion at 42.5 degrees C caused an increase in GSH into the perfusate at a level significantly (p < 0.05) greater than at 37 degrees C. GSH levels in the liver after 60 min of perfusion decreased from 4.82 +/- 0.76 microM/gm at 37 degrees C to 1.48 +/- 0.54 microM/gm at 42.5 degrees C (p < 0.05) but only fell to 3.42 +/- 1.23 microM/gm at 42.5 degrees C with deferoxamine added. Efflux of iron into the perfusate increase significantly with time and temperature. Low molecular weight chelated iron within the liver after perfusion increased from 5.88 +/- 1.46 nM/gm at 37 degrees C to 25.8 nM/gm at 42.5 degrees C (p < 0.05). Perfusate total aldehyde levels increased from 0.085 +/- 0.056 to 0.32 +/- 0.09 microM/ml after 60 min at 37 degrees C and 0.87 +/- 0.45 to 2.01 +/- 0.90 microM/ml at 42.5 degrees C (n = 8). There was a significant decrease in total aldehyde levels at 42.5 degrees C with the addition of deferoxamine to the perfusate, 0.36 +/- 0.14 to 0.86 +/- 0.27 microM/ml, when compared to 42.5 degrees C levels (p < 0.05). Levels of ethane and pentane in the perfusion chamber head space showed no significant changes with time or temperature of perfusion. The data suggest that lipid peroxidation may play a causal role in hyperthermia induced liver toxicity and that iron plays a major role in this injury. Failure of hydrocarbon analysis to support this conclusion appears related to the use of membrane oxygenators.

Aldehydes↗
PubMedDate not supplied

Comparison of new iron chelating agents in the prevention of ischemia/reperfusion injury: a swine model of heart-lung transplantation.

The preservation of the heart and lung for transplantation remains a major concern in extended ischemic intervals. This experimental endeavor evaluates and compares the efficacy of iron chelating agents such as high molecular weight deferoxamine and 21-aminosteroid (U74006F) in a swine model of heart-lung transplantation. Heat-lung blocks were exposed to 4 h and 45 min of ischemia and 2 h of reperfusion. Animals were divided into three groups. Group A was a control without pharmacological intervention. In groups B and C, 21-aminosteroid (U74006F), 10 mg/kg, and high molecular weight deferoxamine, 50 mg/kg, were used, respectively. The results of functional parameters (cardiac index, stroke index, lung water, PO2, PCO2, alveolar-arterial gradient, and alveolar-arterial ratio) demonstrated superior heart and lung function for group C, where high molecular weight deferoxamine was used. Alterations of heart and lung function were significantly more (p less than .001) for control animals and for group B where U74006F was used. This study suggests that formation of hydroxyl radicals was affected by chelation of iron with high molecular weight deferoxamine, which reflects better heart and lung function and consequently less damage to this group of animals. The compound 21-aminosteroid U74006F failed to protect the heart and lung from ischemic-reperfusion injury in this model of heart-lung transplantation.

Animals↗
PubMed1990

Autophagic degradation of protein generates a pool of ferric iron required for the killing of cultured hepatocytes by an oxidative stress.

Pretreatment of cultured hepatocytes with the ferric iron chelator deferoxamine prevents the killing of the cells by tert-butyl hydroperoxide (TBHP). Incubation of the deferoxamine-pretreated hepatocytes in a serum-free medium containing only 0.25 nM iron restored the sensitivity of the cells to TBHP within 4 to 6 hr. An amino acid-free medium accelerated the restoration of sensitivity in parallel with an enhanced rate of degradation of 14C-prelabeled protein. By contrast, inhibitors of the autophagic degradation of protein, including chymostatin, 3-methyladenine, benzyl alcohol, colchicine, oligomycin, and methylamine, inhibited the restoration of sensitivity of deferoxamine-treated hepatocytes to TBHP in parallel with their inhibition of protein degradation. With chymostatin, 3-methyladenine, benzyl alcohol, and colchicine, there was a parallel dose dependency of both the inhibition of protein turnover and the inhibition of the restoration of sensitivity to TBHP. Ascorbic acid, known to specifically retard the autophagic degradation of ferritin, inhibited the restoration of sensitivity to TBHP without effect on the general rate of protein turnover. None of the agents studied had any protective effect on the toxicity of TBHP for hepatocytes that were not pretreated with deferoxamine. These data indicate that the autophagic degradation of protein generates a pool of ferric iron required for the killing of cultured hepatocytes by TBHP.

Adenine↗
PubMed1988

67Ga-labeled antibodies for immunoscintigraphy and evaluation of tumor targeting of drug-antibody conjugates in mice.

To assess the in vivo behavior of cytotoxic agents linked to antibodies, deferoxamine, known to form stable chelates with 67Ga, was conjugated with monoclonal antibodies using three different methods. One method used a homocoupling reagent, glutaraldehyde, whereas two other methods used heterocoupling reagents, N-succinimidyl-3-(2-pyridyldithio)propionate and succinimidyl-6-maleimidohexanoate, linking deferoxamine to antibodies through alkylamine, disulfide, and thioether bonds, respectively. Antibodies were efficiently labeled with 67Ga through chelation with deferoxamine without losing antigen-binding capability. 67Ga-labeled antibodies clearly visualized transplanted tumors in nude mice. However, the biodistribution of radioactivity was markedly different with the coupling methods used for the conjugation of deferoxamine and antibodies. High nonspecific uptake in the liver and spleen was observed with 67Ga-labeled antibodies prepared by the glutaraldehyde method. 67Ga-labeled antibodies linked by thioether bonds demonstrated in vivo stability and the highest tumor:liver ratio, whereas 67Ga-labeled antibodies conjugated with disulfide bonds were rapidly cleared from the circulation. These results indicate that antibody conjugates linked by thioether bonds are a better choice for drug targeting and that 67Ga-labeled antitumor monoclonal antibodies are useful not only for the immunoscintigraphy but also for the quantitative assessment and visualization of the biodistribution of drug-antibody conjugates.

Animals↗
PubMed1986

Calcium-dependent and calcium-independent mechanisms of irreversible cell injury in cultured hepatocytes.

It has been proposed that alterations in intracellular calcium homeostasis mediate the genesis of lethal cell injury with an acute oxidative stress. It is shown here, however, that such changes can be dissociated by two different means from the cell death occurring with the exposure of cultured hepatocytes to hydrogen peroxide generated either in the medium by glucose oxidase or intracellularly by the mechanism of menadione. The chelation of intracellular ferric iron with deferoxamine inhibits the formation of hydroxyl radicals from hydrogen peroxide and prevents cell killing. Deferoxamine did not prevent, however, an elevation of the cytosolic Ca2+ ion concentration detected as an activation of phosphorylase alpha. Sulfhydryl reagents inhibited the rise in phosphorylase alpha activity in deferoxamine-pretreated hepatocytes. Conversely, cultured hepatocytes were depleted of Ca2+ ions by treatment with EGTA in a calcium-free medium. Calcium-depleted cells were not resistant to the toxicity of hydrogen peroxide despite the virtual elimination of the activation of phosphorylase alpha. In contrast, it was possible to kill cultured hepatocytes by a mechanism dependent upon a disordered intracellular calcium homeostasis using hepatocytes pretreated in calcium-free medium with the ionophore A23187. These cells were killed in a dose-dependent manner by the addition of calcium ions to the culture medium in concentrations ranging from 0.1 to 2.0 mM. There was a similar dose-dependent activation of phosphorylase alpha, but phosphorylase alpha activities were higher than with H2O2 at comparable cell killing. Deferoxamine pretreatment and sulfhydryl reagents had no effect on the loss of viability with this calcium-dependent cell killing.

Acetylcysteine↗
PubMed1995

Iron-chelation therapy with oral deferiprone in patients with thalassemia major.

BACKGROUND: To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. RESULTS: The patients received deferiprone therapy for a mean (+/-SE) of 3.1 +/- 0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 mumol per gram of liver, wet weight -- values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3 +/- 11.5 to 60.3 +/- 9.6 mumol per gram (P < 0.005), with values that were less than 80 mumol per gram in 8 of the 10 patients (P < 0.005). In all 11 patients in whom deferoxamine therapy had previously been effective, deferiprone maintained hepatic iron concentrations below 80 mumol of iron per gram. CONCLUSIONS: Oral deferiprone induces sustained decreases in body iron to concentrations compatible with the avoidance of complications from iron overload. The risk of agranulocytosis associated with deferiprone may restrict its administration to patients who are unable or unwilling to use deferoxamine.

Administration, Oral↗
PubMed1996

Perfusing isolated rat hearts with hydrogen peroxide: an experimental model of cardiac dysfunction caused by reactive oxygen species.

A model of cardiac dysfunction induced by reactive oxygen species (ROS) was established by adding hydrogen peroxide (H2O2) to the perfusate of isolated, Langendorff-perfused rat hearts, and the mechanism of functional injury was investigated. The following groups were included: 1 (n = 7), control perfusion; 2 (n = 11), perfusion with H2O2 (180 mumol 1(-1) for 10 min followed by recovery for 50 min; 3 (n = 4), control perfusion with N-acetylcysteine (NAC, 100 mumol 1(-1); 4 (n = 7), perfusion with H2O2 and NAC; 5 (n = 4), control perfusion with thiourea (15 mmol 1(-1), 6 (n = 7), H2O2 and thiourea together; 7 (n = 4), control perfusion with catalase (150 U ml-1); 8 (n = 7), catalase and H2O2, 9 (n = 4), control perfusion with deferoxamine (5 mmol 1(-1); and 10 (n = 7), deferoxamine and H2O2. coronary flow (CF), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and heart rate (HR) were measured. All values are mean +/- SEM. When given alone, catalase, thiourea, NAC and deferoxamine did not influence left ventricular pressures, but NAC, catalase and thiourea increased CF. H2O2 increased CF (maximum 146 +/- 6% of baseline value after 5 min, p < 0.001 compared to group 1), decreased LVDP (minimum 14 +/- 5% of baseline value after 10 min, p < 0.0004), and increased LVEDP (from 0 mmHg to a maximum of 54 +/- 7 mmHg after 5 min recovery, p < 0.0003). All these changes gradually reversed during recovery. Catalase and thiourea both inhibited the H2O2-induced effects, but catalase inhibition was more complete. Neither NAC nor deferoxamine had any effect on H2O2-induced cardiac dysfunction. In conclusion, H2O2 perfusion is a convenient and reversible model of ROS-induced functional injury to isolated rat hearts. H2O2, rather than the hydroxyl radical, seems to be the main injurious ROS in this model.

Animals↗
PubMed2000

Effects of iron salts and haemosiderin from a thalassaemia patient on oxygen radical damage as measured in the comet assay.

Thalassaemia is a group of genetic diseases where haemoglobin synthesis is impaired. This chronic anaemia leads to increased dietary iron absorption, which develops into iron overload pathology. Treatment through regular transfusions increases oxygen capacity but also provides iron through the red cells' haemoglobin. An essential treatment, in parallel with transfusions, is the use of chelating agents to remove the excess iron deposited in tissues. These deposits are found in the liver, spleen, heart, and pancreas and are associated with cardiac failure and diabetes. The deposits in these tissues of patients have been isolated as haemosiderin. Thalassaemia patients are particularly at risk of free radical induced damage. Thus, the present study has investigated, as a model system, human cells in vitro in the Comet assay in the presence of free radicals. This assay measures DNA damage, particularly DNA strand breakage. The effects of iron overload on cells oxidatively stressed with hydrogen peroxide (H(2)O(2)) have been determined as well as the effect of the chelating agent, deferoxamine. Iron overload was simulated with ferric (FeCl(3)) and ferrous chloride (FeCl(2)), ferrous sulphate (FeSO(4)) and haemosiderins. Both human lymphocytes from a male and a female donor and human adenocarcinoma colonic cells showed an increase in DNA damage in the Comet assay after treatment with H(2)O(2). Ferric chloride produced an increase in DNA damage in human colonic cells, but little or no damage in human lymphocytes. Ferrous chloride also produced weak DNA damage in human lymphocytes, but ferrous sulphate produced a dose-related response. Deferoxamine produced no DNA damage. When H(2)O(2) was combined with FeCl(3), FeCl(2), or FeSO(4), the DNA damage produced was as least as great as or slightly greater than with H(2)O(2) alone. When deferoxamine was combined with H(2)O(2) and FeSO(4) there was a consistent decrease in response. There was little or no decrease in response when deferoxamine was combined with H(2)O(2) and FeCl(3) or FeCl(2), but at high (100-300microm) doses there were changes in the appearance of cellular DNA from Comet tails to dense centres surrounded by a diffuse area. This was probably as a consequence of chelation processes. Haemosiderin produced no damage. The three fractions of haemosiderin examined were of three different densities and from a Thai patient where the oxyhydroxide phase is the ferrihydrite. The colour change was similar to that for FeCl(3), but the level of the ferric ion in the haemosiderin was possibly too low in the sample to produce a response. The next stage is to examine peripheral lymphocytes from thalassaemic patients, with and without chelation therapy, whose cells may be more sensitive to simulated iron overload and to lower levels of haemosiderin. Teratogenesis Carcinog. Mutagen. 20:11-26, 2000.

Caco-2 Cells↗
PubMed1989

Antimalarial effect of HBED and other phenolic and catecholic iron chelators.

Previous studies showed that deferoxamine inhibits malaria by interacting with a labile iron pool within parasitized erythrocytes. Consequently, we studied the antimalarial properties of other iron-chelating drugs such as 2,3-dihydroxybenzoic acid (2,3-DHB) and its methyl ester as well as two polyanionic amines, N.N'-bis (o-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) and N,N'-ethylenebis(o-hydroxyphenylglycine) (EHPG) in rats infected with Plasmodium berghei. All drugs were delivered by subcutaneous injection at 8-hour intervals, 40 mg per animal per day. All animals receiving N,N'-ethylenebis(o-hydroxyphenylglycine) died of drug toxicity between days 6 and 11. Peak parasitemia on day 11 of infection was 32.8% in control animals; 25.3% with methyl 2,3-DHB, 15.5% with 2,3-DHB, 8.0% with deferoxamine, and 0.9% with HBED. Subsequent studies of HBED and deferoxamine in P falciparum cultures in human erythrocytes showed a marked suppression of parasite counts by both drugs at concentrations of greater than 5 mumol/L. At all concentrations tested, HBED was four to five times more effective than deferoxamine in suppressing parasite counts. The superior antimalarial activity of HBED is attributed to its increased lipophilicity and higher affinity to ferric iron. These findings indicate that selective iron deprivation by interaction with an intracellular chelator may represent a novel approach to antimalarial drug development, and that systematic screening of available iron-chelating drugs may result in identification of potentially useful antimalarial compounds.

Animals↗
PubMed1987

Modification of iron uptake and lipid peroxidation by hypoxia, ascorbic acid, and alpha-tocopherol in iron-loaded rat myocardial cell cultures.

The ability of ascorbic acid, alpha-tocopherol, and hypoxia to modify iron uptake, chelation, and toxicity as manifested by the generation of malonyldialdehyde (MDA) was studied in myocardial cell cultures obtained from newborn rats. Exposure to 20 micrograms/ml iron provided as 59Fe-ferric ammonium citrate in serum-free Ham F-10 culture medium resulted in the accumulation of 39% of the iron within 24 hours and a 10- to 12-fold increase in cellular MDA. Hypoxia (1% oxygen) resulted in a more than twofold increase in iron uptake but only minor changes in cellular MDA concentrations. Ascorbic acid and alpha-tocopherol (1 mg/ml) had opposing effects on iron uptake and MDA production. Ascorbic acid reduced 24-hour iron uptake by 73% (P less than 0.001) whereas alpha-tocopherol increased iron uptake by 19% (P less than 0.025). In contrast, cellular MDA after iron loading increased by 86% with the addition of ascorbate, and was reduced by 75% with alpha-tocopherol (P less than 0.001). The ratio of increase in cellular MDA relative to percent iron uptake (lipid peroxidation ratio) was 7.29 with iron loading plus ascorbate vs. 0.13 with iron loading plus alpha-tocopherol, a 56-fold difference between the two extremes. In vitro deferoxamine treatment for 3 hours resulted in a 53% reduction in the radioactive iron content of iron-loaded heart cells and a 40% reduction in MDA. Simultaneous deferoxamine and ascorbate or alpha-tocopherol treatment did not affect iron mobilization, but had a profound effect on MDA concentrations. Ascorbic acid prevented entirely the beneficial effect of deferoxamine on MDA concentrations in iron-loaded cells, whereas alpha-tocopherol potentiated the effect of deferoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Hematoma-induced flap necrosis and free radical scavengers.

Skin flap necrosis due to underlying hematoma can be devastating in reconstructive surgery. The production of free radicals in ischemic tissue and cellular damage caused by them have been well established. Deferoxamine, which is both an iron chelator and a free radical scavenger may have a dual benefit in the pharmacologic manipulation of necrosis in a flap jeopardized by hematoma. Past studies showing the importance of free radical scavengers in improving flap survival in hematoma-induced flap necrosis have used the rat model. The porcine model was used for this study because it is the animal model that most closely resembles human skin. A statistically significant benefit of deferoxamine in reducing necrosis of a skin flap induced by hematoma formation was found. Deferoxamine appears to be promising but requires further investigation before it can be optimally used in human applications.

Animals↗
PubMed2000

Effect of iron salts, haemosiderins, and chelating agents on the lymphocytes of a thalassaemia patient without chelation therapy as measured in the comet assay.

Impairment of haemoglobin synthesis occurs in the genetic diseases known as thalassaemia. The consequent chronic anaemia leads to increased dietary iron absorption which results in iron overload. Treatment through regular blood transfusions increases oxygen capacity, but also adds iron from haemoglobin. An essential treatment, in parallel with transfusions, is the use of chelating agents to remove the excess iron. Thalassaemia patients are particularly at risk of free radical damage. Human lymphocytes from normal individuals can be investigated in vitro as a model system in the presence of free radicals in the Comet assay. This assay measures DNA damage, particularly DNA strand breakage. We examined cells from an Australian thalassaemic patient (sickle/beta thal double heterozygote-sickle phenotype) who had not yet received chelation therapy to determine if the cells were more sensitive to simulated iron overload and to haemosiderins. Lymphocytes from the patient were received as frozen samples after 28 h on dry ice and then placed in liquid nitrogen. Normal lymphocytes frozen under the same conditions and normal nonfrozen lymphocytes were compared. The lymphocytes from a normal female did not respond in vitro to ferric chloride (FeCl(3)) or haemosiderin but did to ferrous chloride (FeCl(2)) and ferrous sulphate (FeSO(4)). Deferoxamine appeared to reduce the response to FeCl(2) and FeSO(4) but deferiprone did not. When the lymphocytes from the nonchelated patient were treated with FeSO(4) and hydrogen peroxide, deferoxamine and deferiprone both reduced the response. Over the same dose range of iron salt (FeSO(4)), the lymphocytes from the thalassaemic patient were more sensitive, with much higher background levels of damage and induced damage. When deferiprone and deferoxamine were compared over a nontoxic range, deferiprone appeared to produce a greater reduction of damage in lymphocytes of the thalassaemia patient. Ferritin iron appears to be more available than haemosiderin iron in reactions leading to DNA damage. Haemosiderin containing higher amounts of the goethite-like (alpha-FeOOH) iron oxide phase leads to lower levels of DNA damage.

Australia↗
PubMed1995

Use of a eutectic mixture of local anesthetics for prolonged subcutaneous drug administration.

The efficacy of a eutectic mixture of local anesthetics (EMLA) in alleviating the pain associated with subcutaneous needle insertion for infusion of the iron-chelating agent, deferoxamine, was examined in 12 patients with homozygous beta-thalassemia. As reported by the patient using a 100-mm visual analogue scale, the pain of insertion was rated as significantly less after application of EMLA (mean +/- SD, 1.5 +/- 2.2 mm) than the pain associated with needle insertion without EMLA (34.8 +/- 33.5 mm, P = .005). Subsequently, in a double-blind randomized trial of 10 beta-thalassemia patients, EMLA was significantly better (5.7 +/- 8.2 mm) than placebo (27.0 +/- 22.8 mm, P = .01) in reducing the pain of needle insertion for deferoxamine infusion. No adverse effects were reported with the use of EMLA cream. These results suggest that EMLA may be effective in reducing the pain associated with needle insertion for subcutaneous deferoxamine infusion in beta-thalassemia patients, which may lead to improved compliance with this irritating, prolonged therapy. The safety of EMLA use in these patients, and others receiving regular parenteral therapy, should now be examined.

Anesthetics, Local↗
PubMed1994

Reactive oxygen metabolite-induced toxicity to cultured bovine endothelial cells: status of cellular iron in mediating injury.

We aimed to determine the status of iron in mediating oxidant-induced damage to cultured bovine aortic endothelial cells. Chromium-51-labeled cells were exposed to reaction mixtures of xanthine oxidase/hypoxanthine and glucose oxidase/glucose; these produce superoxide and hydrogen peroxide, or hydrogen peroxide, respectively. Xanthine oxidase caused a dose dependent increase of 51Cr release. Damage was prevented by allopurinol, oxypurinol, and extracellular catalase, but not by superoxide dismutase. Prevention of xanthine oxidase-induced damage by catalase was blocked by an inhibitor of catalase, aminotriazole. Glucose oxidase also caused a dose-dependent increase of 51Ci release. Glucose oxidase-induced injury, which was catalase-inhibitable, was not prevented by extracellular superoxide dismutase. Both addition of and pretreatment with deferoxamine (a chelator of Fe3+) prevented glucose oxidase-induced injury. The presence of phenanthroline (a chelator of divalent Fe2+) prevented glucose oxidase-induced 51Cr release, whereas pretreatment with the agent did not. Apotransferrin (a membrane impermeable iron binding protein) failed to influence damage. Neither deferoxamine nor phenanthroline influenced cellular antioxidant defenses, or inhibited lysis by non-oxidant toxic agents. Treatment with allopurinol and oxypurinol, which inhibited cellular xanthine oxidase, failed to prevent glucose oxidase injury. We conclude that (1) among the oxygen species extracellularly generated by xanthine oxidase/hypoxanthine, hydrogen peroxide induces damage via a reaction on cellular iron; (2) deferoxamine and phenanthroline protect cells by chelating Fe3+ and Fe2+, respectively; and (3) reduction of cellular stored iron (Fe3+) to Fe2+ may be prerequisite for mediation of oxidant-induced injury, but this occurs independently of extracellular superoxide or cellular xanthine oxidase-derived superoxide.

Allopurinol↗