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PubMed1988

Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity.

In ischemic acute renal failure oxygen free radicals may mediate injury. In addition, iron appears to play a critical role in hydroxyl radical formation and lipid peroxidation during reperfusion of ischemic kidneys. To determine whether iron may play a similar role in pigment (heme protein)-induced acute renal failure, we studied the effects of the iron chelator deferoxamine in two experimental models of pigment-induced acute renal failure, intramuscular glycerol injection and intravenous hemoglobin infusion without and with concurrent ischemia in the rat. Intramuscular injection of 50% glycerol (5 ml/kg) caused inulin clearance to fall to 0.13 +/- 0.03 (SE) ml/min (normal value, 1.0-1.2 ml/min). Continuous infusion of deferoxamine beginning at the time of glycerol injection significantly attenuated this renal dysfunction. Deferoxamine-treated animals had an inulin clearance of 0.37 +/- 0.06 ml/min (P less than 0.01). Glycerol injection was also associated with significant lipid peroxidation, measured as renal malondialdehyde content. Deferoxamine-treated glycerol-injected rats had renal malondialdehyde content not significantly different from control animals. In another model of heme pigment-induced renal injury, hemoglobin was infused to produce hemoglobinuria. Inulin clearance 1 h after hemoglobin infusion was significantly reduced to 0.84 +/- 0.5 ml/min (P less than 0.025). Infusion of deferoxamine after hemoglobin prevented the hemoglobin-induced decrease in inulin clearance. Thirty minutes of renal ischemia followed by infusion of hemoglobin resulted in more severe renal dysfunction with inulin clearance of 0.54 +/- 0.08 ml/min. Deferoxamine infused at the time of reperfusion attenuated the fall in glomerular filtration rate after ischemia and hemoglobin infusion:inulin clearance 1.04 +/- 0.07 (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed2001

Iron chelation improves endothelial function in patients with coronary artery disease.

BACKGROUND: Some epidemiological studies have shown that increased iron stores are associated with increased cardiovascular events. Redox-active iron may contribute to lipid peroxidation, endothelial cell activation, and generation of reactive oxygen species (especially hydroxyl radical, via Fenton chemistry). Increased oxidative stress is associated with impaired action of endothelium-derived nitric oxide in patients with atherosclerosis. METHODS AND RESULTS: To test the hypothesis that reducing vascular iron stores would reverse endothelial dysfunction, we examined the effects of the iron chelator deferoxamine (500 mg intra-arterially over 1 hour) on vasomotor function in forearm resistance vessels of patients with coronary artery disease by venous occlusion plethysmography. Patients with coronary artery disease had impaired endothelium-dependent vasodilation in response to methacholine compared with healthy control subjects (P<0.001). Deferoxamine infusion decreased serum iron levels (P<0.001). Deferoxamine improved the blood flow response to methacholine in patients with coronary artery disease (P<0.01 by 2-way repeated-measures ANOVA) but had no effect on the response to sodium nitroprusside. In normal volunteers, deferoxamine had no effect on the response to methacholine. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine abolished augmentation of the methacholine response associated with deferoxamine. The hydroxyl radical scavenger mannitol had no effect on the methacholine response. CONCLUSIONS: Deferoxamine improved nitric oxide-mediated, endothelium-dependent vasodilation in patients with coronary artery disease. These results suggest that iron availability contributes to impaired nitric oxide action in atherosclerosis.

Adult↗
PubMed1989

Acute iron poisoning. Rescue with macromolecular chelators.

Acute iron intoxication is a frequent, sometimes life-threatening, form of poisoning. Present therapy, in severe cases, includes oral and intravenous administration of the potent iron chelator, deferoxamine. Unfortunately, high dose intravenous deferoxamine causes acute hypotension additive with that engendered by the iron poisoning itself. To obviate this problem, we have covalently attached deferoxamine to high molecular weight carbohydrates such as dextran and hydroxyethyl starch. These macromolecular forms of deferoxamine do not cause detectable decreases in blood pressure of experimental animals, even when administered intravenously in very large doses, and persist in circulation much longer than the free drug. These novel iron-chelating substances, but not deferoxamine itself, will prevent mortality from otherwise lethal doses of iron administered to mice either orally or intraperitoneally. Further reflecting this enhanced therapeutic efficacy, the high molecular weight iron chelators also abrogate iron-mediated hepatotoxicity, suppressing the release of alanine aminotransferase. We conclude that high molecular weight derivatives of deferoxamine hold promise for the effective therapy of acute iron intoxication and may also be useful in other clinical circumstances in which control of free, reactive iron is therapeutically desirable.

Acute Disease↗
PubMed1995

Antioxidant and iron-chelating agents in cerebral vasospasm.

Prior work in our laboratory showed that the perivascular application of deferoxamine (an antioxidant and iron-chelating agent) inhibited delayed arterial narrowing after chronic blood exposure in a rat femoral artery model of vasospasm. To determine which of these mechanisms was operant in vasospasm, we compared deferoxamine with two agents (ascorbic acid and U74389F) that have antioxidant but not iron-chelating capacity. For the systemic application of drugs in 23 rats, whole blood encased in a silastic cuff was applied to the right femoral artery of each rat; whole-blood serum (lacking erythrocytes) was similarly applied to the left femoral artery. Deferoxamine (30 mg/kg/d), ascorbic acid (1000 mg/kg/d), U74389F (30 mg/kg/d), or pH-matched control vehicle was administered three times daily by intraperitoneal injection for 7 days. After exposure to whole blood, arteries treated with intraperitoneal vehicle showed an 85% reduction in the lumen, compared with vessels exposed to erythrocyte-free serum (P < 0.001). Intraperitoneal ascorbic acid and U74389F produced moderate amelioration in arterial narrowing (53 and 61% decrease, respectively, in the lumen versus controls; P < 0.05 versus vehicle); deferoxamine had no significant effect when administered intraperitoneally. To test the efficacy of these agents by the perivascular application of drugs, whole blood was applied to both femoral arteries in each of 25 rats. Solutions of deferoxamine (10 mg/ml), ascorbic acid (50 or 100 mg/ml), or U74389F (15 or 30 mg/ml) were directly applied to the perivascular thrombus surrounding the femoral arteries, compared with vehicle applied to contralateral vessels. The perivascular application of 50 mg of ascorbic acid (36% reduction, P < 0.05), 100 mg of ascorbic acid (31% reduction, P < 0.01), or 10 mg of deferoxamine (41% reduction, P < 0.05) significantly inhibited arterial narrowing, compared with vehicle. The application of U74389F at a dose of 15 or 30 mg directly into the perivascular thrombus produced nonsignificant reduction in arterial narrowing. These data suggest that mechanisms other than direct iron toxicity, such as generation of cytotoxic free radicals, may play an important role in cerebral vasospasm. In addition, the route of administration and concentration of drugs in the perivascular region adjacent to the thrombus may be critical to their efficacy.

Animals↗
PubMed1991

Role of lipid peroxidation in renal proximal tubule cell death induced by haloalkene cysteine conjugates.

The role of lipid peroxidation in the cell death produced by the haloalkene cysteine conjugates S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBC), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC) was investigated using a well-defined suspension of rabbit renal proximal tubules. PCBC, DCVC, TFEC, and CTFC at a concentration of 25 microM caused renal proximal tubular death (measured by lactate dehydrogenase release) in a time-dependent (2-6 hr) manner and increased tubular malondialdehyde (MDA) formation prior to and during cell death (1-6 hr). The antioxidants butylated hydroxytoluene (BHT) (25 microM) and N,N'-diphenyl-1,4-phenylenediamine (DPPD) (50 microM) and the iron chelator deferoxamine (1 mM) blocked the increase in MDA formation produced by these four compounds. BHT and deferoxamine delayed PCBC-, DCVC-, and CTFC-induced cell death but had no effect on the overall extent of cell death. BHT and deferoxamine had no effect on TFEC-induced cell death. DPPD had effects similar to those of deferoxamine on DCVC- and CTFC-induced cell death, but, unlike deferoxamine, DPPD significantly reduced PCBC- and TFEC-induced cell death. This difference in the effect of DPPD may not be related to its effects as an antioxidant. The antioxidant, putative cellular phospholipase inhibitor and calmodulin antagonist, chlorpromazine (100 microM), blocked the increase in MDA formation and after 6 hr decreased by 50% the degree of cell death produced by PCBC, DCVC, TFEC, and CTFC. Furthermore, chlorpromazine could be added 1 or 2 hr after DCVC or PCBC and still provide the same degree of protection. The enhanced protection with chlorpromazine, in relation to deferoxamine and BHT, may be related to its actions as a phospholipase inhibitor and/or calmodulin antagonist. These results show that iron-dependent lipid peroxidation plays a role in PCBC-, DCVC-, and CTFC-induced rabbit renal proximal tubule cell death. In contrast, iron-dependent lipid peroxidation plays no role in TFEC-induced proximal tubule cell death. These observations suggest that mechanisms other than peroxidative damage may predominate in the cell death produced by these four compounds.

Animals↗
PubMed1996

Vanadium(IV)-mediated free radical generation and related 2'-deoxyguanosine hydroxylation and DNA damage.

Free radical generation, 2'-deoxyguanosine (dG) hydroxylation and DNA damage by vanadium(IV) reactions were investigated. Vanadium(IV) caused molecular oxygen dependent dG hydroxylation to form 8-hydroxyl-2'-deoxyguanosine (8-OHdG). During a 15 min incubation of 1.0 mM dG and 1.0 mM VOSO4 in phosphate buffer solution (pH 7.4) at room temperature under ambient air, dG was converted to 8-OHdG with a yield of about 0.31%. Catalase and formate inhibited the 8-OHdG formation while superoxide dismutase enhanced it. Metal ion chelators, DTPA and deferoxamine, blocked the 8-OHdG formation. Incubation of vanadium(IV) with dG in argon did not generate any significant amount of 8-OHdG, indicating the role of molecular oxygen in the mechanism of vanadium(IV)-induced dG hydroxylation. Vanadium(IV) also caused molecular oxygen-dependent DNA strand breaks in a pattern similar to that observed for dG hydroxylation. ESR spin trapping measurements demonstrated that the reaction of vanadium(IV) with H2O2 generated OH radicals, which were inhibited by DTPA and deferoxamine. Incubation of vanadium(IV) with dG or with DNA in the presence of H2O2 resulted in an enhanced 8-OHdG formation and substantial DNA double strand breaks. Sodium formate inhibited 8-OHdG formation while DTPA had no significant effect. Deferoxamine enhanced the 8-OHdG generation by 2.5-fold. ESR and UV measurements provided evidence for the complex formation between vanadium(IV) and deferoxamine. UV-visible measurements indicate that dG, vanadium(IV) and deferoxamine are able to form a complex, thereby, facilitating site-specific 8-OHdG formation. Reaction of vanadium(IV) with t-butyl hydroperoxide generated hydroperoxide-derived free radicals, which caused 8-OHdG formation from dG and DNA strand breaks. DTPA and deferoxamine attenuated vanadium(IV)/t-butyl-OOH-induced DNA strand breaks.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Upregulation of hypoxia inducible factor is associated with attenuation of neuronal injury in neonatal piglets undergoing deep hypothermic circulatory arrest.

BACKGROUND: Prolonged deep hypothermic circulatory arrest is known to cause neurological injury. Hypoxia inducible factor, a transcription factor that mediates adaptive changes during hypoxia, is neuroprotective in models of ischemic brain injury, in part by upregulating erythropoietin. This study tested the hypothesis that upregulation of hypoxia inducible factor and erythropoietin by preconditioning with hypoxia or the hypoxia-mimetic agents deferoxamine and cobalt chloride would be neuroprotective in a piglet model of deep hypothermic circulatory arrest. METHODS: Anesthetized neonatal piglets were randomized to 4 preconditioning groups (15 per group): hypoxia, deferoxamine, cobalt chloride, or control (NaCl vehicle). Brain hypoxia inducible factor and erythropoietin contents were assessed by means of Western blotting at 3, 8, and 24 hours after treatment (n = 3 per time point). Twenty-four hours after treatment, 6 to 7 animals per group underwent cardiopulmonary bypass and 110 minutes of deep hypothermic circulatory arrest. After recovery, serial neurobehavioral examinations were conducted for 6 days, after which histopathologic brain injury and neuronal apoptosis (cleaved caspase 3) were assessed. RESULTS: Erythropoietin expression was not significantly increased by any of the pretreatment strategies. In contrast, there was a significant upregulation of hypoxia inducible factor by pretreatment with deferoxamine and cobalt chloride (P = .002). Neurobehavioral measures revealed no significant differences in time to recovery or extent of injury. Examination of histopathologic brain injury in the hippocampus revealed that pretreatment with deferoxamine (0.4 +/- 0.3) and cobalt chloride (0.5 +/- 0.3) were associated with significantly less neuronal loss than pretreatment with hypoxia or control (2.8 +/- 0.5, P = .004). Finally, cleaved caspase 3 (a marker of apoptotic cell death) was also shown to be diminished in the cobalt and deferoxamine groups, but the difference was not significantly different from the value in the control group. CONCLUSIONS: In contrast to hypoxia, deferoxamine and cobalt chloride preconditioning upregulated hypoxia inducible factor and were associated with histopathologic neuroprotection after exposure to cardiopulmonary bypass and prolonged deep hypothermic circulatory arrest.

Animals↗
PubMed1990

Increased prooxidant action of hepatic cytosolic low-molecular-weight iron in experimental iron overload.

In the iron-loaded liver there may be an increase in the putative intracellular transit pool of iron, components of which could be catalytically active in stimulating lipid peroxidation. To study the levels of low-molecular-weight, catalytically active iron in the liver, cytosolic ultrafiltrates were tested in an assay containing rat liver microsomes and NADPH. Malondialdehyde production was used as an index of lipid peroxidation. This assay system was sensitive enough to detect 0.25 mumol/L ferrous iron; progressive but non-linear increases in malondialdehyde were produced as the iron concentration was increased to 5 mumol/L. Ultrafiltrates from hepatic cytosol of iron-loaded rats had greater prooxidant action than did those from controls. When added to the assay, deferoxamine, an iron chelator, completely suppressed the prooxidant action of hepatic ultrafiltrates, showing that this activity is iron-dependent. Deferoxamine administered intraperitoneally to control animals at a dose of 1 gm/kg completely inhibited the prooxidant effect of hepatic ultrafiltrates prepared from rats killed after 1, 2 and 3 hr. Partial inhibition was observed at 4 hr; by 6 hr the inhibitory effect of deferoxamine was completely lost. Administration of deferoxamine (1 gm/kg intraperitoneally, 1 hr before killing) completely inhibited the prooxidant action of hepatic ultrafiltrates in moderately iron-loaded rats and controls but had no protective effect in heavily iron-loaded rats. These results support the concept that iron overload results in an increase in a hepatic cytosolic pool of low-molecular-weight iron that is catalytically active in stimulating lipid peroxidation. This pool can be chelated transiently in vivo by deferoxamine in moderate, but not heavy, iron overload.

Animals↗
PubMed1999

Screening of transcriptionally regulated genes following iron chelation in human astrocytoma cells.

Deferoxamine is an effective iron chelator and a potential therapeutic agent for use in minimizing free radical-mediated injury following trauma. Iron chelation may also be an effective means of limiting tumor growth by decreasing bioavailable iron. Deferoxamine can modulate gene expression through manipulation of intracellular iron levels; specifically at the posttranscription level by changing the activity of iron regulatory proteins (IRPs). The effect of iron chelation on the transcription of genes is still unclear, but iron-binding sites on DNA have been reported. Here we investigate the influence of deferoxamine on gene transcription. Two-directional (forward and backward) suppression subtraction hybridization (SSH) was performed on human astrocytoma cells (SW1088) cultured in either standard media or treated for 48 hours with deferoxamine. To restrict the number of false-positive clones, reverse Northern blotting was used to further verify the differentially expressed cDNA clones. Positive clones were sequenced and the mRNAs were re-examined on Northern blots for changes in expression over time of deferoxamine exposure. The results of these analyses have identified both novel and known genes whose expression is influenced by iron chelation. The known genes include a group related to energy production and a group related to protease function. These results provide examples of genes not previously known to be directly influenced by iron availability, and as such may be potential targets for iron chelation therapy.

Astrocytoma↗
PubMed2000

Activation of NF-kappaB by PM(10) occurs via an iron-mediated mechanism in the absence of IkappaB degradation.

Exposure to particulate air pollution (PM(10)) is associated with exacerbations of respiratory diseases and increased cardiopulmonary mortality. PM(10) induces lung inflammation in rats, which has been attributed to many factors, including the ultrafine components of PM(10), endotoxins, and transition metals. In this study, we investigated in alveolar epithelial (A549) cells whether PM(10) could activate nuclear factor-kappa B (NF-kappaB), a transcription factor stimulated in response to many proinflammatory agents. Our results show that PM(10) samples from various sites within the United Kingdom cause nuclear translocation, DNA-binding, and transcriptional activation of NF-kappaB in A549 cells. Furthermore, increased NF-kappaB activity was observed in the absence of IkappaB degradation. To evaluate the role of iron, A549 cells were exposed to PM(10) previously treated with phosphate-buffered saline (PBS), deferoxamine mesylate, or deferoxamine plus ferrozine. PBS-treated and, to a lesser extent, deferoxamine-treated PM(10) were able to activate NF-kappaB, whereas this response was completely abrogated in cells exposed to PM(10) treated with both deferoxamine and ferrozine. Moreover, we studied the effects of soluble components of PM(10) on NF-kappaB activation by exposing alveolar epithelial cells to soluble fractions from PM(10) treated with PBS or the metal chelators. We found that, compared with fractions from PBS-treated PM(10) which activated NF-kappaB, fractions from PM(10) treated with deferoxamine and ferrozine did not stimulate NF-kappaB activity above background levels. Coincubation of polymixin B, an endotoxin-binding compound, and PM(10) did not inhibit NF-kappaB. In summary, PM(10) activates NF-kappaB in A549 cells by an iron-mediated mechanism in the absence of IkappaB degradation.

Adenocarcinoma↗
PubMed1998

DNA damage induces p21 protein expression by inhibiting ubiquitination in ML-1 cells.

We previously reported that deferoxamine, an iron chelating agent, induced p53 and cell accumulation in the G1 phase of ML-1 cells in the same way as the DNA damaging agent, etoposide. Etoposide treatment increased expression of the p21 gene, a cyclin kinase inhibitor, at both the mRNA and protein levels. However, deferoxamine treatment only increased the p21 mRNA level without the appearance of a detectable protein product. A substrate for cyclin kinase, pRB, was unphosphorylated by etoposide treatment, but remained unaffected by deferoxamine, indicating that p21 was functional after etoposide, but not after deferoxamine treatment. Therefore, in the present study, we investigated the involvement of the ubiquitin proteasome pathway in post-transcriptional regulation of p21. By the addition of lactacystin, a proteasome inhibitor, to deferoxamine treatment, the level of unubiquitinated p21 protein product was similar to that induced by etoposide treatment, and the ubiquitinated p21 bands became apparent. After etoposide treatment, the level of ubiquitinated p21 was diminished and a high level of unubiquitinated p21 expression was observed. We concluded that (1) efficient expression of p21 protein requires inhibition of the ubiquitin-proteasome pathway, and (2) DNA damage inhibits the ubiquitination of p21.

Acetylcysteine↗
PubMed1999

Performance characteristics of three serum iron and total iron-binding capacity methods in acute iron overdose.

Accurate serum iron and total iron binding capacity (TIBC) measurements may be useful in acute iron overdoses. Two alumina column TIBC methods were found to measure increased TIBC when free iron was present. A homogeneous TIBC method gave consistent results until iron concentrations exceeded 500 micrograms/dL (90 mumol/L), when it began to underestimate the TIBC. Serious iron overdoses require chelation therapy with deferoxamine. Iron recovery was reduced by up to 50% for all 3 methods with clinically achievable concentrations of deferoxamine 8,400 micrograms/dL (150 mumol/L). TIBC measurements by both alumina column methods were reduced by deferoxamine in the presence of free iron and unaffected when the iron concentration was less than the TIBC. The homogeneous TIBC method yielded falsely elevated results in the presence of free deferoxamine. Procedures that measure TIBC by addition of excess ferric iron followed by alumina adsorption are not suitable for monitoring TIBC in acute iron overdose. The homogeneous TIBC assay can be used in acute iron overdose but underestimates TIBC when iron concentrations exceed 500 micrograms/dL (90 mumol/L). None of the methods examined are useful for measuring iron or TIBC in the presence of deferoxamine.

Acute Disease↗
PubMed1989

Continuous arteriovenous hemofiltration in experimental iron intoxication.

This study evaluated continuous arteriovenous hemofiltration (CAVH) as a method for removing the iron-deferoxamine complex in experimental iron intoxication. Five anesthetized dogs were instrumented for hemodynamic monitoring and then given 600 mg/kg of elemental iron as ferrous sulfate. After a 3-h absorption period, CAVH was begun from the femoral artery to femoral vein. Deferoxamine was infused into the arterial lines of the CAVH cartridge at increasing doses. We found a dose-dependent increase in the ultrafiltrate excretion of iron. However, most of the deferoxamine was excreted unbound. The efficiency of complex formation was greater at lower BP and ultrafiltrate formation rate, suggesting that inadequate mixing of deferoxamine with blood may occur when arterial administration is used. Iron excretion in the urine over the same time period was not significantly greater than that removed by CAVH. We conclude that CAVH can remove iron using deferoxamine as a chelating agent.

Animals↗
PubMed2000

Desmethyl tirilazad improves neurologic function after hypoxic ischemic brain injury in piglets.

OBJECTIVE: Desmethyl tirilazad is a lipid-soluble free radical quencher. Deferoxamine reduces free radicals by chelating iron and reducing hydroxyl formation. Free radical inhibitors have shown promise in several hypoxic ischemic brain injury models, and we wished to see if this work could be extended to our newborn piglet model. DESIGN: Randomized controlled trial. SUBJECTS: Piglets (0 to 3 days old). INTERVENTION: Carotid snares and arterial and venous catheters were placed under 1.5% isoflurane anesthesia. In Experiment 1, piglets were randomly assigned to receive either 3 mg/kg desmethyl tirilazad or vehicle at -15 and 90 mins. In Experiment 2, piglets were randomly assigned to receive either 20 mg/kg desmethyl tirilazad at -15 mins followed by 8 mg/kg/hr for 90 mins or 100 mg/kg deferoxamine at -15 mins or vehicle. At time 0, both carotid arteries were clamped and blood was withdrawn to reduce the blood pressure to two-thirds normal. At 15 mins, inspired oxygen was reduced to 6%. At 30 mins, the carotid snares were released, the withdrawn blood was reinfused, and the oxygen was switched to 100%. On the third day after the hypoxic ischemic injury, the animals were killed by perfusing their brains with 10% formalin. We tested the timing of lipid peroxidation and inhibition of lipid peroxidation by these agents by freezing the brains of a subset of pigs in liquid nitrogen. MEASUREMENTS: Neurologic examination and brain pathology were scored by blinded observers. Thiobarbituric acid-reactive substance and oxidized and reduced glutathione were measured on frozen brains. MAIN RESULTS: Desmethyl tirilazad (20 mg/kg) and 100 mg/kg deferoxamine inhibit lipid peroxidation. Desmethyl tirilazad (20 mg/kg) improves neurologic exam, but 3 mg/kg Desmethyl tirilazad or 100 mg/kg deferoxamine does not. Neither desmethyl tirilazad nor deferoxamine improves pathologic results. CONCLUSIONS: High-dose desmethyl tirilazad improves neurologic function after hypoxic ischemic brain injury in the newborn piglet.

Animals↗
PubMed1998

Attenuation of neomycin ototoxicity by iron chelation.

Increasing evidence suggests that aminoglycoside ototoxicity is mediated by the formation of an aminoglycoside-iron complex and that the creation of this complex is a preliminary step in generation of free radical species and subsequent hair cell death. In this study we have assessed the ability of the iron chelator deferoxamine to attenuate the hearing loss induced by an ototoxic dose of the aminoglycoside neomycin (100 mg/kg per day for 14 days). Experiments were carried out on pigmented guinea pigs weighing 250 to 300 g. Changes in auditory sensitivity were characterized by monitoring shifts in compound action potential (CAP) thresholds, recorded through indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results show that animals receiving neomycin alone suffered a mean threshold shift exceeding 35 dB at all test frequencies (2.0, 4.0, and 8.0 kHz) 30 days after initiation of treatment. In comparison, all animals receiving cotherapy of neomycin and deferoxamine (150 mg/kg twice daily for 14 days) maintained their CAP threshold, suggesting significant protection from neomycin ototoxicity. A statistical comparison of treatment groups showed that in the animals receiving cotherapy with neomycin and deferoxamine, deferoxamine produced a significant protective effect against neomycin-induced ototoxicity (P < 0.001). These results provide further evidence of the intrinsic role of iron in aminoglycoside ototoxicity and suggest that deferoxamine may have a therapeutic role in attenuating the cytotoxic action of aminoglycoside antibiotics.

Animals↗
PubMed1989

Role of iron in postischemic microvascular injury.

Iron-catalyzed formation of hydroxyl radicals has been postulated to occur during reperfusion of ischemic tissues. To assess the role of iron-catalyzed oxidant production in ischemia/reperfusion (I/R) injury to skeletal muscle, we examined the effects of deferoxamine (an iron chelator) and apotransferrin (an iron-binding protein) on the increased vascular permeability produced by I/R in isolated, pump-perfused rat hindquarters. Solvent drag reflection coefficients (sigma) were measured in hindquarters subjected to 2 h of ischemia and 30 min of reperfusion with either no pretreatment, pretreatment with 50 mg/kg deferoxamine, 200 mg/kg apotransferrin, or iron-loaded deferoxamine (50 mg/kg). I/R alone was associated with an increase in vascular permeability as indicated by the significantly lower estimates of sigma obtained after I/R (0.68 +/- 0.03) compared with those obtained in nonischemic preparations (0.82 +/- 0.02). Pretreatment with deferoxamine or apotransferrin attenuated this permeability increase (sigma = 0.83 +/- 0.03 and 0.86 +/- 0.02, respectively), whereas pretreatment with iron-loaded deferoxamine afforded no protection (sigma = 0.71 +/- 0.02). These findings are consistent with the hypothesis that iron-catalyzed oxidant production is important in the genesis of microvascular injury following I/R. Since the enzyme xanthine oxidase has been implicated as a major source of oxidants generated during reperfusion, we also measured tissue levels of xanthine oxidase and xanthine dehydrogenase in muscle samples obtained from the same hindquarters in which we measured permeability changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions.

For nearly 30 years, patients with transfusional iron overload have depended on nightly deferoxamine infusions for iron chelation. Despite dramatic gains in life expectancy in the deferoxamine era for patients with transfusion-dependent anemias, the leading cause of death for young adults with thalassemia major and related disorders has been cardiac disease from myocardial iron deposition. Strategies to reduce cardiac disease by improving chelation regimens have been of the highest priority. These strategies have included development of novel oral iron chelators to improve compliance, improved assessment of cardiac iron status, and careful epidemiologic assessment of European outcomes with deferiprone, an oral alternative chelator available for about a decade. Each of these strategies is now bearing fruit. The novel oral chelator deferasirox was recently approved by the Food and Drug Administration (FDA); a randomized clinical trial demonstrates that deferasirox at 20 to 30 mg/kg/d can maintain or improve hepatic iron in thalassemia as well as deferoxamine. A randomized trial based on cardiac T2* magnetic resonance imaging (MRI) suggests that deferiprone can unload myocardial iron faster than deferoxamine. Retrospective epidemiologic data suggest dramatic reductions in cardiac events and mortality in Italian subjects exposed to deferiprone compared with deferoxamine. These developments herald a new era for iron chelation, but many unanswered questions remain.

Administration, Oral↗
PubMed2003

Pharmacotherapy of iron overload in thalassaemic patients.

The recommended treatment for thalassaemia major is regular blood transfusions, although these lead to the harmful accumulation of iron in the body. If untreated, iron overload is responsible for heart, liver and endocrine diseases. The only two iron chelating agents available for the treatment of iron overload are deferoxamine and deferiprone. The standard iron chelation therapy is based on the use of deferoxamine. Although this drug was introduced in the 1970s, it still remains the treatment of choice. Recently, another iron chelator, deferiprone, became available for clinical use in the European Community. Deferiprone is indicated as second-line treatment in patients with thalassaemia major, for whom deferoxamine therapy is contraindicated or in patients who present with serious toxicity to deferoxamine therapy. This paper examines this chelating agent and compares it with deferoxamine in order to ascertain the current and potential contribution of deferiprone to the treatment of thalassaemic patients.

Clinical Trials as Topic↗