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PubMed1993

A predictor for side effects in patients with Alzheimer's disease treated with deferoxamine mesylate.

In a previously reported clinical trial, patients with Alzheimer's disease were treated with deferoxamine mesylate, which resulted in a 50% reduction in the average rate of deterioration over 2 years. There were five deaths in the untreated group during the trial and no deaths in the treated group, although five of 25 treated patients reported anorexia. Deferoxamine metabolite analysis of urine for 24 hours after deferoxamine injection from sensitive and nonsensitive patients showed marked differences. Occurrence of side effects correlated with increased formation of a monoamine oxidase catalyzed (major) metabolite, MFO1. The metabolite ratio, MFO1/total metabolites, plus parent drug (TOT) showed a bimodal distribution with a mean +/- SD value of 0.68 +/- 0.06 for the nonsensitive and 0.79 +/- 0.04 for sensitive patients. The MFO1/TOT ratio discriminates between sensitive and nonsensitive patients, and we suggest that the half difference mark between the two mean values (0.735) can be used as a predictor of side effects. Patients with a MFO1/TOT ratio of greater than 0.70 would be considered at risk and observed for onset of side effects. Patients with a MFO1/TOT ratio greater than 0.80 would be considered for immediate adjunct treatment with isoniazid or other monoamine oxidase inhibitors.

Alzheimer Disease↗
PubMed2004

[Bull's-Eye Maculopathy with Deferoxamine Treatment].

BACKGROUND: A bull's-eye maculopathy can be provoked by drugs. CASE REPORT: A 67-year-old man observed transient green-yellow spots with both eyes. The visual acuity was 1.0 in the right eye and 0.9 in the left. Tiny pigmentary irregularities of the macula were observed by ophthalmoscopy. Fluorescein angiography revealed a cockade formation of the macula. The multifocal ERG showed normal latencies in the periphery, however, in the centre the amplitudes were reduced to approximately half of the normal values. An acute myeloid leukaemia was diagnosed in 1997 which arose from a myelodysplasia, after performance of a peripheral allogenic blood stem cell transplantation. Because of a serious anaemia, the patient received numerous multiple transfusions with packed blood red cells from April 1999 to April 2000 (a total of more than 90 transfusions). In consequence, a haemosiderosis occurred with a ferritin value of 4390 ng/ml (November 1999) which made treatment with deferoxamine necessary. Multiple injections of deferoxamine (one to two grams were given from August 2000 until February 2001, afterwards an intermittent application until November 2002 was carried out) which resulted in the maculopathy. CONCLUSION: Retinal changes, in particular, a maculopathy, should be considered even if visual acuity and visual fields are not remarkably changed. Dependent on the extent of the disease, deferoxamine treatment should be discontinued in case of distinct visual deterioration.

Aged↗
PubMed1986

[Continuous subcutaneous deferoxamine infusions in thalassemia major. Improvement in glucose tolerance].

Exocrine and endocrine pancreatic functions were studied in 30 patients with homozygotic beta-thalassaemia. All were treated with continuous subcutaneous deferoxamine infusions for a mean period of 30 months. Three patients (aged 18-22 years) had insulin-dependent diabetes, two before and one shortly after the onset of deferoxamine administration. There was no improvement during the treatment. An abnormal glucose tolerance test was demonstrated in 14 patients (47%) before and in seven (23%) during deferoxamine infusion. Enzyme activity of alpha-amylase and lipase as an expression of exocrine pancreatic function was normal in all during the observation period. Improvement in endocrine pancreatic function was apparently age-dependent: the younger the patient at the onset of treatment the more likely is normalization of the oral glucose tolerance test.

Adolescent↗
PubMed2000

Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin.

Replication of human immunodeficiency virus type 1 (HIV-1) can be influenced by iron. Hence, decreasing the availability of iron may inhibit HIV-1 replication. Deferoxamine and deferiprone, both forming catalytically inactive iron-chelator complexes, and bleomycin, by use of which iron catalyzes oxidative nucleic acid destruction, were investigated. Expression of p24 antigen in human monocyte-derived macrophages and peripheral blood lymphocytes (PBL) was reduced by all 3 iron chelators. In PBL, p24 reduction was mirrored by a decrease in proliferation after incubation with deferoxamine or deferiprone, suggesting that viral inhibition is closely linked to a decrease in cellular proliferation. In contrast, clinically relevant bleomycin concentrations reduced p24 levels by approximately 50% without affecting proliferation. When deferoxamine and the nucleoside analogue dideoxyinosine were used in combination, they acted synergistically in inhibiting HIV-1 replication. These observations suggest that iron chelators with different mechanisms of action could be of additional benefit in antiretroviral combination therapy.

Anti-HIV Agents↗
PubMedDate not supplied

Cunninghamella bertholletiae infection associated with deferoxamine therapy.

Cunninghamella bertholletiae, an uncommon cause of human infection, has been reported with increasing frequency in recent years. C. bertholletiae belongs to the order Mucorales and produces infections similar to those produced by the other agents of mucormycosis. Infections with this group of organisms have typically been seen either in patients with diabetes mellitus or in those receiving chemotherapy. Recent reports of mucormycosis in dialysis patients receiving deferoxamine for iron or aluminum overload have raised the possibility that deferoxamine therapy is a risk factor for mucormycosis. A case of C. bertholletiae infection in a patient receiving deferoxamine for iron overload unrelated to hemodialysis was investigated in detail, and possible explanations for this patient's infection were assessed.

Deferoxamine↗
PubMed1991

Effects of hydroxyethyl starch conjugated deferoxamine on myocardial functional recovery following coronary occlusion and reperfusion in dogs.

The effect of hydroxyethyl starch-conjugated deferoxamine (HES-DFO) on the recovery of regional myocardial function after 15 min of coronary artery occlusion followed by 3 h of reperfusion of the left anterior descending coronary artery (stunned myocardium) was investigated in anesthetized dogs. Regional myocardial blood flow was measured by radioactive microspheres and regional myocardial segment shortening (%SS) by sonomicrometry. HES-DFO (equivalent of 50 mg/kg DFO), iron saturated HES-DFO (HES-FO), deferoxamine (DFO, 50 mg/kg), or saline were administered by intravenous infusion starting 30 min before occlusion and throughout occlusion. Ischemic bed size and collateral blood flow were similar in all four groups. HES-DFO significantly improved %SS in the ischemic-reperfused region during reperfusion; however, HES-FO and DFO had no effect on %SS as compared to the saline-treated group. HES-DFO and HES-FO had no effect on hemodynamics; however, DFO produced a marked reduction in systemic blood pressure. Since HES-FO had no effect on the recovery of %SS, the beneficial effect of HES-DFO is thought to be due to its iron chelating characteristics. Plasma concentrations of HES-DFO not only reached a higher peak level but also had a longer half life (3 h) than that of regular DFO (20 min). Thus, high-molecular-weight HES-DFO is effective in enhancing the recovery of regional wall motion in stunned myocardium. The reason for the lack of efficacy of DFO compared to HES-DFO at this high dose may be related to the formation of a toxic deferoxamine free radical species.

Animals↗
PubMed1998

Deferoxamine arrests in vitro the proliferation of porcine hepatocyte in G1 phase of the cell cycle.

Iron is required for cell proliferation of all living species. Moreover, iron excess may be involved in the development of hepatocellular carcinoma. In this study we analyzed the effects of deferoxamine, an iron chelator, on normal porcine hepatocyte proliferation. We confirmed that hepatocytes isolated from young pigs proliferate in the presence of insulin and fetal calf serum as shown by [3H] methyl-thymidine incorporation, presence of mitotic figures and increase in cell number. This was paralleled by nuclear expression of p34cdc2 and its associated histone H1 kinase activity. In the presence of deferoxamine, [3H] methyl-thymidine incorporation, expression of nuclear proteins (p34cdc2 and PCNA) and H1 kinase activity were drastically reduced. In addition, in contrast with control cultures, cells in S-phase were not detected by flow cytometry. These data suggest that iron chelation by deferoxamine can arrest the progression of porcine hepatocytes in the G1 phase of the cell cycle.

Animals↗
PubMed1993

Deferoxamine prevents lipid peroxidation and attenuates reoxygenation injury in postischemic skeletal muscle.

In the presence of the transition metal iron, superoxide anion and H2O2 generated on reperfusion of postichemic tissue combine to form hydroxyl radical, which readily attacks membrane-associated polyunsaturated fatty acids in a free radical process, resulting in lipid peroxidation. To evaluate whether iron chelation with deferoxamine interrupts this process in postischemic skeletal muscle, high-grade partial hindlimb ischemia was created in Sprague-Dawley rats by clamping the infrarenal aorta for 90 min, after which period the clamp was removed and flow was reestablished for 60 min. Lipid peroxidation in skeletal muscle was assessed by determination of tissue thiobarbituric acid-reactive substances (TBARS); membrane dysfunction was assessed by measurement of resting membrane potential (Em). Ischemia was accompanied by an increase in muscle TBARS and depolarization of resting Em. On reperfusion, muscle TBARS continued to increase, whereas resting Em remained depolarized. Pretreatment with deferoxamine prevented lipid peroxidation during ischemia but had no effect on resting Em. On reperfusion in the deferoxamine-treated animals, there was still no increase in muscle TBARS, and partial repolarization of resting Em was noted. It is concluded that 1) high-grade partial ischemia in skeletal muscle is accompanied by iron-dependent lipid peroxidation via a mechanism that persists and accelerates on reoxygenation, 2) lipid peroxidation impacts on functional membrane integrity during the reperfusion phase only, and 3) membrane injury accompanying ischemia and reperfusion may occur through fundamentally different mechanisms, of which only the latter is iron dependent.

Animals↗
PubMed1991

The iron chelator deferoxamine prevents cisplatin-induced lipid peroxidation in rat kidney cortical slices.

We evaluated the effect of the iron chelator deferoxamine on lipid peroxidation produced by the nephrotoxic antineoplastic drug cisplatin in rat kidney cortical slices. The addition of deferoxamine to the incubation medium prevented such lipid peroxidation in the incubated slices. Treatment of rats with deferoxamine inhibited the increase in lipid peroxidation caused by cisplatin in the medium. These results suggest that iron may be a causal agent of cisplatin-induced lipid peroxidation.

Animals↗
PubMed2002

Effect of deferoxamine and L-arginine treatment on lipid peroxidation in an intestinal ischaemia-reperfusion model in rats.

This study investigated lipid peroxidation (LPO) changes during intestinal ischaemia-reperfusion with and without deferoxamine or L-arginine treatment. White Wistar rats were allotted into four groups as follows: sham-operated (Group SOP), ischaemia-reperfusion only (Group I/R), I/R with deferoxamine (Group D) or L-arginine (Group A) treatment. Concentration of thiobarbituric acid reactive substances (TBARS), overall concentration of malondialdehyde and 4-hydroxy-alkenals (LPO586), activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) of the jejunal homogenates were determined. The same analytes except LPO586 were assayed in RBC haemolysates. Measurements of ferric reducing ability (FRAP), total antioxidant status (TAS) and nitric oxide (NO) concentrations of plasma samples were also completed. The only significant change observed in the SOP group was an increased SOD activity after the ischaemic period. In the I/R group significant increase of intestinal LPO586 concentration was observed during hypoxia that was followed by similar changes in intestinal and RBC TBARS and plasma FRAP values upon reperfusion. In Group D the intestinal TBARS and LPO586 concentrations were significantly lower while FRAP and NO concentrations were significantly higher compared to the I/R group. At the same time RBC TBARS concentration and GPX activity significantly decreased within Group D. In Group A the intestinal LPO586 concentration was significantly lower than in the I/R group whilst RBC TBARS concentration showed a similar pattern. Plasma FRAP and NO concentration showed similar changes to those seen in Group D. It is concluded that I/R increased the LPO in the intestinal tissue and altered some parameters of plasma and RBCs, too. Deferoxamine treatment prevented these effects, while the usefulness of L-arginine remained doubtful.

Animals↗
PubMed1991

Deferoxamine-induced bone dysplasia in patients with thalassemia major.

Metaphyseal irregularity and abnormal vertebral bodies resembling a bone dysplasia were seen in two of five children with thalassemia major who were begun on a regimen of hypertransfusion and chelation with deferoxamine before the age of 3 years. Similar changes were not seen in 22 other children in whom chelation was started after the age of 3. Whether the dysplastic bone growth was related to drug dose or age of onset of chelation could not be determined, as deferoxamine dosages differed in the two groups. Findings on radiographs included flattening of the thoracic and lumbar vertebral bodies, circumferential metaphyseal osseous defects, sharp zones of provisional calcification, and widened growth plates. Healing was noted in one of the patients after the dose of deferoxamine was decreased. Zinc levels in both affected patients did not differ from those in the 25 other chelated patients.

Adolescent↗
PubMed1997

A phase II trial of deferoxamine in patients with hormone-refractory metastatic prostate cancer.

The management of hormone-refractory metastatic prostate cancer remains a therapeutic dilemma. We report the results of a phase II trial with deferoxamine administrated at a dose of 50 mg/kg (maximum dose 5 g) administered intravenously over 8 hr daily, repeated for 5 days at 4-week intervals for 2 courses. Fourteen patients with advanced hormone-refractory prostate cancer were treated and 28 courses were delivered. Essentially no toxicity was observed. Using combined clinical and prostate-specific antigen (PSA) criteria. 13 of 14 patients had disease progression. However, 9 of 14 patients had stable measurable or evaluable disease and progressed solely based on PSA criteria. Deferoxamine in this dose and schedule has no activity in hormone-refractory prostate cancer. Further investigation of the effect of deferoxamine on PSA production/expression is warranted.

Adenocarcinoma↗
PubMedDate not supplied

The effect of deferoxamine on ischemic changes in rat skeletal muscle: a preliminary study.

The purpose of this study was to evaluate the effectiveness of deferoxamine in preventing detrimental microvascular changes in ischemically damaged skeletal muscle during the initial reperfusion stage. Sprague-Dawley rats were given saline or deferoxamine (25 or 50 mg/kg) intravenously just prior to release of an air tourniquet placed around one hindlimb for 4 h. The limb was allowed to reperfuse for 2 h. Vascular leakage of plasma protein was assayed by determining the amount of 131I-labeled serum albumin that was given intravenously 30 min prior to release of the tourniquet. The wet and dry weights of the gastrocnemius and tibialis anterior muscles and the 131I activity were evaluated in both ischemic and nonischemic limbs. Although vascular permeability and edema increased markedly in both muscles in the ischemic limbs, there were no significant differences between the saline or either treatment groups. The lack of effect of deferoxamine in this initial report suggests that skeletal muscle may differ from other tissues in the early reperfusion stage.

Animals↗
PubMed1995

Survival after a severe iron poisoning treated with intermittent infusions of deferoxamine.

Iron poisoning is the most common cause of overdose mortality in children under six years of age and there are no reports of survival with iron levels > 2687 mumol/L (> 15,000 micrograms/dL). A 22-month-old male was brought to the emergency department by his parents after ingesting an estimated 50 ferrous sulfate tablets (60 mg elemental iron/tablet) several hours earlier. Despite spontaneous emesis and gastric lavage his condition deteriorated and he was found to have a serum iron of 2992 mumol/L (16,706 micrograms/dL). During the first four days in the intensive care unit, he developed coma, metabolic acidosis, hypovolemic and cardiogenic shock, liver failure, coagulopathy and adult respiratory distress syndrome. He was treated with a unique deferoxamine dosage schedule (25 mg/kg/h for 12 h/d x 3 d), mechanical ventilation, Swan-Ganz catheter monitoring, dopamine/nitroprusside therapy, blood product, bicarbonate, electrolyte and volume replacement. After a prolonged hospital course complicated primarily by gastric outlet obstruction he was dismissed on full oral feedings, gaining weight, and neurologically intact. Swan-Ganz catheter monitoring guided the management of this patient's shock, iron-induced cardiac failure, and deferoxamine mesylate induced adult respiratory distress syndrome. Further experience and research is required to determine the most appropriate deferoxamine mesylate dosing schedule and our experience expands the range for possible survival after massive iron overdose.

Deferoxamine↗
PubMed2001

Deferoxamine-induced dysplasia of the knee: sonographic features and diagnostic performance compared with magnetic resonance imaging.

OBJECTIVE: To evaluate the features and diagnostic performance of sonography in the assessment of deferoxamine-induced dysplasia of the knee. METHODS: The left knees of 32 patients with thalassemia who were receiving regular blood transfusions and chelation therapy were studied with sonography for signs of deferoxamine-induced bone dysplasia. Abnormal physeal and metaphyseal changes detected on sonography included notching at the metaphyseal corner, a blurred or irregular peripheral juxtaphyseal metaphyseal contour, and widening of the peripheral juxtaphyseal metaphyseal echogenic interface. The accuracy of sonography in diagnosing dysplasia was evaluated by using magnetic resonance imaging as the standard of reference. RESULTS: There were 14 true-positive findings, 10 true-negative findings, 7 false-negative findings, and 1 false-positive sonographic diagnosis of dysplasia, giving 67% sensitivity, 91% specificity, a 93% positive predictive value, and a 59% negative predictive value. CONCLUSION: Sonography was specific but only moderately sensitive in the diagnosis of deferoxamine-induced dysplasia at the knee when compared with magnetic resonance imaging.

Adolescent↗
PubMed2003

[Successful treatment of haemodialysis-related porphyria cutanea tarda with deferoxamine].

BACKGROUND: End-stage renal failure and long-term hemodialysis treatment promote porphyria cutanea tarda. Iron overload is often associated with this disease and is thought to play a role in its pathogenesis. We report a case of hemodialysis related-porphyria cutanea tarda improved by deferoxamine. CASE REPORT: A 45-year-old man, with end-stage renal failure and who had received hemodialysis treatment since 1993, presented a several months-history of blisters of the face and the dorsum of the hands. Laboratory analysis showed: hemoglobin 10 g/dl; a moderate hepatic cytolysis; ferritin 195 ng/l. HIV, HBV, HCV serologies were negative. Porphyries analyses showed a porphyria cutanea tarda pattern. The cutaneous histology was non specific; direct immunofluorescence was negative. The patient received deferoxamine (40 mg/kg intravenously every week for 6 weeks) which led to dramatic improvement of the symptoms. DISCUSSION: Several treatments are proposed in the management of dialysis-related porphyria cutanea tarda. This case confirms that deferoxamine can induce rapid and prolonged remission.

Deferoxamine↗
PubMedDate not supplied

Deferoxamine and human neuroblastoma and primitive neuroectodermal tumor cell lines.

Deferoxamine at concentrations of 3.28 microM to 32.8 microM for five days causes in vitro growth inhibitory and cytolytic activities in human neuroblastoma and neuroectodermal cell lines. These effects are most likely due to intracellular iron depletion and vary with each cell line tested. A 3.28 microM threshold for cytolytic effects was observed in the most sensitive cell lines SK-N-DZ and SK-PN-LI, while proportionate responses ranging from lysis to relative growth inhibition was observed in the more refractory VA-N-BR, SK-N-LO and SK-N-AS cell lines. Cytolytic effects may represent an artifact of the in vitro setting where maximum exposure of cells to the drug can be achieved. Different sensitivities to deferoxamine in controlled in vitro conditions suggest variable anti-tumor effects can be expected in the clinical setting. Deferoxamine in patients may require a maximum tolerated dosage as a constant infusion for greater than 72 hours.

Cell Division↗
PubMed1992

Inhibition of hematopoietic tumor growth by combined treatment with deferoxamine and an IgG monoclonal antibody against the transferrin receptor: evidence for a threshold model of iron deprivation toxicity.

Recent studies have suggested that iron deprivation may represent a useful new approach in cancer therapy, and several strategies for producing such deprivation are now under investigation. Thus, for example, we recently provided evidence that combined treatment with the iron chelator deferoxamine and an IgG monoclonal antibody against the transferrin receptor (ATRA) produces synergistic inhibition of hematopoietic tumor cell growth in vitro (J. D. Kemp, K. M. Smith, L. J. Kanner, F. Gomez, J. A. Thorson, and P. W. Naumann, Blood, 76: 991-995, 1990). The current study is an attempt to analyze the mechanisms responsible for the synergistic interaction. The data show that a single IgG ATRA can produce up to 75% inhibition of iron uptake while having little effect on DNA synthesis; this suggests that tumor cells either take up or have stored amounts of iron well in excess of that required to support immediate metabolic needs. When deferoxamine and the IgG ATRA are used together, the effects on iron acquisition and receptor down-modulation are either additive or subadditive but are clearly not synergistic. Overall, the findings suggest that the IgG ATRA produces an injury to iron uptake that is just below a critical threshold and that the additional effect provided by the iron chelator is sufficient to exceed that threshold and produce a rapid depletion of iron pools that are vital for short-term DNA synthesis. IgG ATRAS thus seem to be of even greater interest as therapeutic reagents, and further study of their properties and of how they interact with deferoxamine appears to be warranted.

Animals↗