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PubMed2000

Use of ultrafiltration and chromatography to assess aluminum speciation in serum after deferoxamine administration.

Deferoxamine effectively chelates aluminum by forming aluminoxamine, a low-molecular-weight compound removable by dialysis. However, aluminum-bound species other than aluminoxamine might be present in serum after the administration of deferoxamine. To study aluminum speciation after the administration of deferoxamine, high-performance liquid chromatography (HPLC) and ultrafiltration techniques were used. Samples of serum were obtained from six dialysis patients 44 hours after the administration of a single dose of deferoxamine. HPLC and ultrafiltration studies were performed. In the HPLC studies, samples underwent ultrafiltration, the filtrate was injected into the chromatographic system, and detection was performed by UV light and atomic absorption spectrometry. Unknown species of aluminum other than aluminoxamine were found in the early elution fractions. In the ultrafiltration studies, the same samples of serum from the six patients underwent ultrafiltration using membranes with different molecular-weight cutoff values from 1 to 30 kd. The percentages of aluminum found by ultrafiltration using membranes with cutoff values of 5, 10, and 30 kd were greater (64.4% +/- 2.5%, 63.5% +/- 3.7%, and 65.6% +/- 4.3%, respectively) than the percentages obtained with membranes with a 1-kd cutoff value (38.7%), suggesting that the unknown species of aluminum have a molecular weight between 1 and 5 kd. The unknown species of aluminum cannot be aluminoxamine because they behaved in a different way with HPLC.

Aluminum↗
PubMed1989

[Chronic aluminum poisoning in continuous ambulatory peritoneal dialysis: treatment with deferoxamine].

After six years of home haemodialysis and two years of continuous ambulatory peritoneal dialysis a 59-year-old woman developed an aluminium-induced osteopathy, myopathy and normochromic anaemia. She was at first treated with intravenous, then peritoneal, deferoxamine, 1 g every other day. Before treatment, 15.8 micrograms aluminium (Al) had been eliminated daily, with a peritoneal clearance of 0.3 ml/min; after intravenous deferoxamine a mean of 774.3 +/- 102.3 micrograms Al was eliminated per day, after peritoneal deferoxamine 646.7 +/- 89.6 micrograms of Al per day, with a peritoneal clearance of 2.2 +/- 0.9 (intravenous) and 1.9 +/- 0.7 ml/min (intraperitoneal). After four months of deferoxamine administration, mostly intraperitoneally as an out-patient, the osteomalacia clearly improved, as did the myopathy and anaemia.

Aluminum↗
PubMed1984

The use of deferoxamine in the management of aluminum accumulation in bone in patients with renal failure.

Aluminum frequently accumulates in patients with end-stage renal failure. We investigated the value of long-term, intermittent infusions of deferoxamine for the removal of aluminium from bone in seven patients undergoing long-term maintenance dialysis. Transient rises in serum aluminum levels occurred initially after treatment. Three patients who were studied by bone biopsy had absent or reduced levels of bone aluminum. Histologic studies of bone before and after therapy showed differences similar to those observed between patients with uremia who had an accumulation of aluminum in bone and those who did not. The diagnostic value of rises in the serum aluminum level after a single infusion of deferoxamine was studied in 12 patients with and 10 patients without aluminum accumulation in bone. All patients with bone aluminum had rises in serum aluminum levels, but rises were also observed in some patients without bone aluminum. Thus, the test cannot be used to diagnose aluminum accumulation in bone. Urinary aluminum levels increased significantly after a single infusion of deferoxamine in three patients with kidney transplants and accumulation of aluminum in bone. These findings indicate that deferoxamine is beneficial for the therapy of aluminum accumulation in the bone of patients with renal failure.

Adult↗
PubMed1987

Protection from reperfusion injury in the isolated rat heart by postischaemic deferoxamine and oxypurinol administration.

A Langendorff isolated rat heart preparation was used to determine the effect of oxypurinol, a xanthine oxidase inhibitor, and deferoxamine, an iron binding agent, on the extent of myocardial reperfusion injury after 60 minutes of ischaemia. Thirty rats were divided into three groups of 10, and an isolated heart preparation made from each rat. The isolated hearts were perfused for 15 minutes with a modified Krebs-Henseleit perfusate solution to permit stabilisation of the preparation. Each heart was then subjected to 60 minutes of total ischaemia at 37 degrees C followed by 60 minutes of reperfusion with either saline treated perfusate, oxypurinol treated perfusate (1.3 mmol.litre-1), or deferoxamine treated perfusate (0.61 mmol.litre-1). Reperfusion injury was assessed by the total amount of creatine phosphokinase released into the perfusate, by changes in myocardial vascular resistance, and by morphological examination. The saline treated group released significantly more creatine phosphokinase into the perfusate than either the oxypurinol treated group (p less than 0.05) or the deferoxamine treated group (p less than 0.05). The mean vascular resistance increased for all groups during the 60 minutes of reperfusion compared with that just before ischaemia but was significantly greater in the saline treated group than in the drug treated groups (p less than 0.01). Ultrastructural examination of a randomly selected heart from each group after 60 minutes of reperfusion showed pronounced attenuation of mitochondrial and endoplasmic reticulum swelling, increased maintenance of membrane integrity, and diminished separation of myofilaments in the oxypurinol treated and deferoxamine treated hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Deferoxamine and hespan complex as a resuscitative adjuvant in hemorrhagic shock rat model.

The optimal type and amount of fluid for resuscitation of injured patients in hemorrhagic hypovolemic shock remains controversial. Use of deferoxamine, an iron chelator and oxygen-free radical scavenger, and hespan (hydroxyethyl starch), a colloid plasma expander, was evaluated in a rat hemorrhagic shock model. Eighty Sprague-Dawley male rats were utilized in four experiments. In these rats, bi-femoral cutdowns were performed for blood withdrawal, resuscitation, blood sampling, and continuous blood pressure monitoring. All rats, except control (with bilateral cutdown only), were bled and maintained at 40 mmHg for 90 min. The shed blood was returned and animals were resuscitated. One hour later, 2 mg/kg lidocaine was injected and blood samples were taken at 10, 15, 30, and 60 min for evaluation of lidocaine derivative monoethylglycinexylidide (MEGX) by fluorescent polarization immunoassay. In experiment 1 (n = 31), resuscitation with different volumes of Ringer's lactate (7.5 mL, 15.0 mL, and 30.0 mL/kg) was compared and 7.5 mL/kg LR was most beneficial. In experiment 2 (n = 22), resuscitation with three doses of Hespan (3.75 mL, 7.5 mL, and 15 mL/kg) was compared. A dose of 15 mL/kg significantly improved the liver function. In experiment 3 (n = 15), resuscitations with two doses of deferoxamine (30 mg and 100 mg/kg) were compared. A dose of 100 mg/kg significantly improved the liver function. In experiment 4 (n = 12), a combination of deferoxamine (100 mg/kg) and Hespan (3.75 and 7.5 mL) was used. Deferoxamine (100 mg/kg) complexed with 7.5 mL of Hespan was found the most beneficial resuscitation. This conjugate could be a choice as a resuscitative adjuvant in hypovolemic shock without any side effects.

Animals↗
PubMed2006

Weekend very high-dose intravenous deferoxamine in children with transfusional iron overload.

Iron overload can be a major complication in children requiring chronic red cell transfusions. Compliance with subcutaneous deferoxamine is often poor. We report the use of very high-dose deferoxamine in 14 children. Patients received intravenous deferoxamine at 15 mg/kg/h over 48 hours every 2 or 4 weeks. The mean duration of treatment was 18 months. Therapy was well tolerated and our regimen was successful in removing excess iron. Intermittent very high-dose intravenous deferoxamine is practical, safe, and effective in managing iron overload in children. Treatment can be given as an outpatient without a central venous catheter.

Adolescent↗
PubMed1992

Protective action of iron-chelating agents (catechol, mimosine, deferoxamine, and kojic acid) against ischemia-reperfusion injury of isolated neonatal rabbit hearts.

Iron is suggested to play an important role in free radical generation during ischemia reperfusion. In the present study, the protective action of 4 iron-chelating agents, with different iron affinities, against reperfusion injury was examined in Langendorff-perfused hearts of neonatal rabbits. The chelators and their iron-binding constants (log Km) were as follows: catechol (43), mimosine (36), deferoxamine (31) and kojic acid (27). Following cardiac arrest, the hearts were subjected to global ischemia for 45 min at 37 degrees C, and then reperfused with modified Krebs-Henseleit solution for 30 min. In control, the left ventricular developed pressures (LVDP) after 30 min reperfusion recovered to 50.5 %/- 3.0% (mean +/- SEM; n = 5) of the preischemic level. In the hearts treated with catechol (30 microM), mimosine (30 microM) or deferoxamine (30 microM), the LVDP recovery was significantly improved up to 84.9 +/- 1.3, 88.2 +/- 2.9 or 87.4 +/- 1.5%, respectively (p < 0.01 vs. control). Creatine phosphokinase (CPK) leakage during the initial 5 min of reperfusion was significantly decreased to about half of control in the hearts treated with catechol, mimosine, or deferoxamine. However, the treatment with kojic acid (30 microM) showed no improvement in the LVDP recovery and CPK leakage. Free radical generation was measured with an electron spin resonance using a spin-trapping agent, 5,5-dimethyl-pyrroline-N-oxide (DMPO). The treatment with catechol, mimosine, or deferoxamine reduced the maximum intensity of DMPO-OH signal to about one third of control. However, the maximum intensity in the hearts treated with kojic acid showed a similar level to control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Coronary artery responses to physiological stimuli are improved by deferoxamine but not by L-arginine in non-insulin-dependent diabetic patients with angiographically normal coronary arteries and no other risk factors.

BACKGROUND: Acetylcholine produces coronary artery (CA) constriction in diabetic patients, suggesting an impairment of endothelium-dependent dilation. In diabetes, multiple metabolic abnormalities may inactivate nitric oxide through oxygen free radical production. METHODS AND RESULTS: To examine the mechanism of this abnormal response, two physiological tests (ie, a cold pressor test [CPT] and coronary flow increase induced by an injection of 10 mg papaverine [PAP] in the distal left anterior descending CA) were performed before and after either intravenous L-arginine (625 mg/min x 10 minutes) or intravenous deferoxamine (50 mg/min x 10 minutes) in 22 normotensive nonsmoking diabetic patients with angiographically normal CAs and normal cholesterol. Coronary surface areas were measured with quantitative angiography. Before the administration of L-arginine or deferoxamine, CPT induced CA constriction in both groups (-14 +/- 10% and -15 +/- 11%, respectively; each P<.001), and PAP injection in distal LAD did not modify significantly proximal LAD dimensions. In the 10 diabetic patients receiving L-arginine, responses to CPT and PAP were not modified. Conversely, in the 12 patients receiving deferoxamine, CA dilated in response to the two tests (+10 +/- 9% after CPT and +22 +/- 7% after PAP, each P<.001). Intracoronary isosorbide dinitrate, an endothelium-independent dilator, produced similar dilation in the two groups (+47 +/- 19% and +41 +/- 15%, respectively; each P<.001). CONCLUSIONS: This study shows that (1) responses of angiographically normal CAs to CPT and to flow increase are impaired in diabetic patients; (2) abnormal responses are not improved by L-arginine, suggesting that a deficit in substrate for nitric oxide synthesis is not involved; and (3) deferoxamine restores a vasodilator response to the two tests, suggesting that inactivation of NO by oxygen species might be partly responsible for the impairment of CA dilation in diabetic patients.

Adult↗
PubMedDate not supplied

Failure of deferoxamine, an iron chelator, to improve neurologic outcome following complete cerebral ischemia in dogs.

Eleven minutes of complete cerebral ischemia was produced in 17 dogs by temporary ligation of the venae cavae and aorta. Immediately prior to the ischemic episode, 7 dogs received deferoxamine, an iron chelator, 50 mg/kg i.v., and 10 dogs received an equivalent volume of saline placebo i.v. Five dogs failed to meet preestablished protocol criteria and were excluded from data analysis. Neurologic recovery was evaluated by an observer blind to the treatment groups in the remaining 12 dogs at 48 hours postischemia. The neurologic effects of complete cerebral ischemia were compared between dogs treated with deferoxamine and those receiving placebo treatment. One of 6 deferoxamine-treated dogs was normal and 5 were moderately to severely damaged. Similarly, 1 of 6 placebo-treated dogs was normal and 5 were moderately to severely damaged. The authors conclude that deferoxamine does not provide cerebral protection in this model of complete cerebral ischemia.

Animals↗
PubMed1989

Deferoxamine decreases necrosis in dorsally based pig skin flaps.

Deferoxamine, a free radical scavenger and iron chelator, has been shown to improve skin flap survival in ischemic flap surgery in rats. The present study investigates the value of deferoxamine in ischemic flap surgery in the porcine model. Four 4 x 12 cm flaps, 3 cm apart and 3 cm from the dorsal midline, were elevated on each of six female pigs, weighing 50 to 60 pounds each. The animals were divided into two test groups. Group 1 received six 1 gm doses of deferoxamine in 4 ml of sterile water intramuscularly every 6 hours preoperatively for five doses, followed by the administration of 1 g every 6 hours for the first 6 days postoperatively. Group 2 received 4 ml of normal saline administered intramuscularly as above. The percentage of flap necrosis was assessed on postoperative day 7 by the weighing paper technique. Group 1 had 17.1% necrosis and group 2 had 33% necrosis (p less than 0.005). Deferoxamine has decreased flap necrosis in the porcine model and may be of use in augmenting the surviving length of flaps in human beings.

Animals↗
PubMed1998

Characterization of Fe(III)-deferoxamine and Mn(II)-pectin as magnetic resonance imaging contrast agents.

To find new contrast agents for magnetic resonance imaging (MRI), the spin-lattice relaxation time (T1)-reducing activities of metal complexes of EDTA, N-hydroxyethyethylenediamine-N,N',N'-triacetic acid (HEDTA), diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA), deferoxamine, mugineic acid, and pectin with Fe(III) or Mn(II) were investigated. Strong activity was found in Fe(III)-deferoxamine, Fe(III)-mugineic acid, or Mn(II)-pectin. In the actual MRI tomogram, Fe(III)-deferoxamine exhibited a contrast-enhancing effect comparable with that of Gd(III)-DTPA, and a much stronger effect was observed for Mn(II)-pectin. Fe(III)-deferoxamine and the Mn(II)-pectin appear to be candidates, respectively, as a new intravenous contrast agent and an oral gastrointestinal one.

Chelating Agents↗
PubMed2003

Effects of deferoxamine on tissue lactate and malondialdehyde levels in cerebral ischemia.

In the present study, the effects of deferoxamine on tissue lactate and malondialdehyde (MDA) levels after cerebral ischemia in rabbits was studied. Rabbits were divided equally into three groups: group 1: sham-operated group; group 2: cerebral ischemia produced by clamping bilateral common carotid arteries for 60 min; and group 3: deferoxamine 100 mg/kg i.v. administered within 5 min after opening the clamps. EEG recordings were obtained in all groups before clamping and in group 2 and 3 60 min after clamping and 60 min after opening the clamps. One hour after opening the clamps and taking EEG recordings, brain cortices were resected and the concentrations of lactate and MDA were determined using the spectrophotometric enzymatic and thiobarbituric acid methods, respectively. There were significant differences between group 1 and the other groups in MDA and lactate levels (p < 0.05). There were no significant differences in lactate levels between groups 2 and 3. Preischemic EEG grades were the same in all groups. Preischemic and postischemic EEG values were significantly different (p < 0.05), but there were no significant differences between postischemic EEG grades in groups 2 and 3. There was also a correlation between postischemic EEG grades and lactate levels, but no correlation between postischemic EEG grades and MDA levels. These results demonstrate that cerebral ischemia leads to an increase in brain tissue lactate and MDA levels and deferoxamine suppresses the increase of MDA, but not lactate. Deferoxamine treatment caused no significant EEG changes. EEG grades correlated well with lactate levels.

Acute Disease↗
PubMedDate not supplied

Deferoxamine (desferrioxamine). New toxicities for an old drug.

Iron is an essential element for body homoeostasis, but there is no effective mechanism for elimination of an excess of this mineral. Deferoxamine (desferrioxamine) is currently the treatment of choice for iron overload states from both acute iron intoxication and transfusion-dependent anaemias. The pharmacokinetics of deferoxamine are confounded both by its ability to chelate endogenous and exogenous iron and by the laboratory techniques used for its determination. Its iron-complex (ferrioxamine) has different pharmacokinetic properties. Because of its effectiveness, the use of deferoxamine is becoming more common, involving long term and high dose regimens. As a result of this, more and more toxicities that were not known in the past have been described and characterised. The most serious of these include hypotension, renal insufficiency, neurotoxicity, growth retardation and opportunistic infections: some of these side effects may be attributed to or aggravated by ferrioxamine. The pharmacological and toxicological literature on deferoxamine, and possible mechanisms for its toxicity, are reviewed and discussed.

Animals↗
PubMed2003

Benefits and risks of deferiprone in iron overload in Thalassaemia and other conditions: comparison of epidemiological and therapeutic aspects with deferoxamine.

Deferiprone is the only orally active iron-chelating drug to be used therapeutically in conditions of transfusional iron overload. It is an orphan drug designed and developed primarily by academic initiatives for the treatment of iron overload in thalassaemia, which is endemic in the Mediterranean, Middle East and South East Asia and is considered an orphan disease in the European Union and North America. Deferiprone has been used in several other iron or other metal imbalance conditions and has prospects of wider clinical applications. Deferiprone has high affinity for iron and interacts with almost all the iron pools at the molecular, cellular, tissue and organ levels. Doses of 50-120 mg/kg/day appear to be effective in bringing patients to negative iron balance. It increases urinary iron excretion, which mainly depends on the iron load of patients and the dose of the drug. It decreases serum ferritin levels and reduces the liver and heart iron content in the majority of chronically transfused iron loaded patients at doses >80 mg/kg/day. It is metabolised to a glucuronide conjugate and cleared through the urine in the metabolised and a non-metabolised form, usually of a 3 deferiprone: 1 iron complex, which gives the characteristic red colour urine. Peak serum levels of deferiprone are observed within 1 hour of its oral administration and clearance from blood is within 6 hours. There is variation among patients in iron excretion, the metabolism and pharmacokinetics of deferiprone. Deferiprone has been used in more than 7500 patients aged from 2-85 years in >50 countries, in some cases daily for >14 years. All the adverse effects of deferiprone are considered reversible, controllable and manageable. These include agranulocytosis with frequency of about 0.6%, neutropenia 6%, musculoskeletal and joint pains 15%, gastrointestinal complains 6% and zinc deficiency 1%. Discontinuation of the drug is recommended for patients developing agranulocytosis. Deferiprone is of similar therapeutic index to subcutaneous deferoxamine but is more effective in iron removal from the heart, which is the target organ of iron toxicity and mortality in iron-loaded thalassaemia patients. Deferiprone is much less expensive to produce than deferoxamine. Combination therapy of deferoxamine and deferiprone has been used in patients not complying with subcutaneous deferoxamine or experiencing toxicity or not excreting sufficient amounts of iron with use of either drug alone. New oral iron-chelating drugs are being developed, but even if successful these are likely to be more expensive than deferiprone and are not likely to become available in the next 5-8 years. About 25% of treated thalassaemia patients in Europe and more than 50% in India are using deferiprone. For most thalassaemia patients worldwide who are not at present receiving any form of chelation therapy the choice is between deferiprone and fatal iron toxicity.

Deferoxamine↗
PubMed2005

Advances in iron overload therapies. prospects for effective use of deferiprone (L1), deferoxamine, the new experimental chelators ICL670, GT56-252, L1NA11 and their combinations.

Effective new therapies and mechanisms have been developed for the targeting and prevention of iron overload and toxicity in thalassaemia and idiopathic haemochromatosis patients. A new era in the development of chelating drugs began with the introduction of deferiprone or L1, which as a monotherapy or in combination with deferoxamine can be used universally for effective chelation treatments, rapid iron removal, maintenance of low iron stores and prevention of heart and other organ damage caused by iron overload. Several experimental iron chelators such as deferasirox (4-[3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid) or ICL670, deferitrin (4,5-dihydro-2- (2,4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one or L1NAll and starch deferoxamine polymers have reached different stages of clinical development. The lipophilic ICL670, which can only be administered once daily is generally ineffective in causing negative iron balance but is effective in reducing liver iron. It is suspected that it may increase iron absorption and the redistribution of iron from the liver to the heart and other organs. The experimental iron chelators do not appear to have significant advantages in efficacy and toxicity by comparison to deferiprone, deferoxamine or their combination. However, the prospect of combination therapies using deferiprone, deferoxamine and new chelators will provide new mechanisms of chelator interactions, which may lead to higher efficacy and lower toxicity by comparison to monotherapies. A major disadvantage of the experimental chelators is that even if they are approved for clinical use, they are unlikely to be as inexpensive as deferiprone and become available to the vast majority of thalassaemia patients, who live in developing countries.

Benzoates↗
PubMed1988

Deferoxamine (Desferal)-induced ocular toxicity.

A 4-year-old girl with juvenile chronic myeloid leukemia relapsed after an allogeneic bone marrow transplantation (BMT) and became refractory to conventional chemotherapy. Treatment with two courses of high-dose deferoxamine, an iron chelator (130-180 mg/kg/day), along with low-dose ARA-c (5 mg/kg/day) caused a remarkable decrease of the WBC and fetal Hb. Three days following the last dose of deferoxamine, the patient experienced an acute visual loss, confirmed by electroretinogram (ERG) and visual evoked response (VER). Slight improvement occurred a few days later, but the patient developed severe pancytopenia and died of Klebsiella septic shock. The ocular manifestations were attributed to deferoxamine toxicity in light of the rapid onset after first exposure, the electrophysiological pattern of metabolic damage in the ERG and VER, and the long interval between the last chemotherapy and BMT. The pathogenesis of deferoxamine toxicity is discussed.

Blindness↗
PubMed1982

Use of high doses of deferoxamine (Desferal) in an adult patient with acute iron overdosage.

Deferoxamine, a specific chelator of ferric iron, has recognized efficacy in the treatment of acute iron overdosage. Toxicological references, however, vary in the preferred route of administration and recommended maximum dosage. A 19-year-old female patient ingested an estimated 50-60 ferrous sulfate tablets, representing approximately 9.8-11.7 g of elemental iron. At the time of admission, she had a serum iron level of 915 micrograms/dL and a total iron binding capacity of 515 micrograms/dL. She was treated with intravenous deferoxamine at 15 mg/kg/h via continuous infusion for a total dose of 37.1 g over a 52-h period until her urine exhibited no evidence of deferoxamine-iron chelation products for 24 consecutive hours. This paper supports the safety and efficacy of a slow IV infusion of deferoxamine in an adult patient, using a regimen recommended for pediatric patients.

Adult↗
PubMed1995

The effect of oral deferoxamine on iron absorption in humans.

Acute iron overdose is a serious cause of morbidity and mortality, however, optimal gastric decontamination procedures in iron overdose are unclear. In order to determine the effectiveness of oral deferoxamine mesylate solution in humans to prevent the absorption of iron in acute exposures, the following prospective case control crossover study was designed. Seven informed adult human volunteers were given an oral dose of 5 mg/kg elemental iron alone in a control phase and again in an experimental phase followed by a single equimolar dose of oral buffered deferoxamine solution. Plasma iron concentrations were determined spectrophotometrically for eight hours following administration of iron alone and following doses of iron with deferoxamine. There was no significant difference in peak iron concentration, time to peak iron concentration or area-under-the-curve between the two groups. Based on our results, equimolar doses of oral deferoxamine do not appear to decrease the absorption of low doses of oral iron in humans.

Administration, Oral↗