Mucormycosis Associated With Deferoxamine Therapy After allogeneic Bone Marrow Transplantation.
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Journal Article↗
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[Serum aluminum concentration and the deferoxamine test in a group of patients under chronic hemodialysis].
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Aluminum↗
[Inhibition of iron-catalyzed oxidative reactions restores mathcing between coronary blood flow and myocardial metabolic demand in type 2 diabetes].
In diabetes, endothelium-dependent dilation of large and small coronary arteries is impaired, which results in a mismatch between myocardial metabolic demand and coronary blood flow. It has been proved that deferoxamine, an iron chelator that inhibits Fenton and Haber-Weiss reactions, restores a normal response to cold pressor test and flow increase in angiographically normal epicardial coronary arteries of diabetic patients. This result suggests that nitric oxide could be inactivated by reactive oxygen species. The aim of this study was to assess the effects of deferoxamine on coronary microcirculation vasomotion when myocardial oxygen demand is increased by sympathetic stimulation elicited by cold pressor test in type 2 diabetic patients. In 17 patients with angiographically normal coronary arteries and without any other coronary risk factors, coronary blood flow has been measured using quantitative angiography and intracoronary Doppler at baseline and during a cold pressor test, before and after intravenous administration of 500 mg deferoxamine. Increase in rate-pressure product, an estimate of myocardial metabolic demand, was similar before and after deferoxamine (+21.1 +/- 8.7% vs +20.5 +/- 8.9%, respectively), but coronary blood flow increase was significantly higher after deferoxamine (+6.3 +/- 12.9% vs +31.8 +/- 16.7%, respectively, p < 0.001), and coronary resistance was increased before deferoxamine and decreased after (+14.8 +/- 21.9% vs -7.9 +/- 10.9%, respectively, p < 0.001). Moreover, before deferoxamine, the negative correlation between coronary blood flow and rate-pressure product changes before deferoxamine (R = 0.518, P < 0.05) was turned in a positive relationship after deferoxamine (r = 0.546, p < 0.05). In conclusion, in type 2 diabetic patients, endothelium-dependent dilation of the coronary microcirculation is restored when iron-catalysed oxidative reactions are inhibited by deferoxamine, which restores the normal matching between myocardial oxygen demand and coronary blood flow.
Adult↗
Age-Related differences on aluminium mobilization by chelating agents in aluminium-loaded uraemic rats.
The efficacy of deferoxamine, deferiprone, and a combination of these chelating agents in the mobilization and promotion of aluminium (Al) excretion was compared in two age groups of uraemic rats which had previously received Al nitrate nonahydrate intraperitoneally in a daily dose of 45 mg/kg for 5 weeks. At the end of the period of Al exposure, Al-loaded rats of each age (young and adult) group were given one of the following treatments for 5 days: 0.90 mmol/kg/ day of deferoxamine (subcutaneously), 0.90 mmol/kg/day of deferiprone (orally), and 0.45 mmol/kg/day of deferoxamine (subcutaneously) plus 0.45 mmol/kg/day of deferiprone (orally). Control rats were given 0.9% saline (subcutaneously) and deionized water (orally). Total urines were collected 24 hr after each chelator administration. Although young rats treated with deferoxamine, deferiprone, or deferoxamine plus deferiprone showed significant increases in the total amount of Al excreted into urine during 5 consecutive days, the effect of combined administration of deferoxamine and deferiprone was lower than that caused by deferoxamine or deferiprone only. On the other hand, after administration of deferoxamine and deferiprone, a significant reduction of Al was noted only in the liver of young rats, while no significant effects of the chelators were seen in any of the examined tissues of adult animals. The results of the current study show that a combined therapy with deferoxamine and deferiprone (at half-doses of each drug) can also be effective in mobilizing Al from the body of Al-loaded uraemic rats.
Administration, Oral↗
Iron-balance and dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease.
Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.
Administration, Oral↗
Evidence for a role of iron-catalyzed oxidants in functional and metabolic stunning in the canine heart.
Brief (15-minute) coronary occlusion and subsequent reperfusion lead to prolonged functional and metabolic abnormalities (stunned myocardium). Previous work suggests that one factor responsible for this phenomenon is oxygen-derived free radicals. The formation of the highly reactive hydroxyl radical requires the presence of metal ions, most importantly iron. In the present study, the effect of the iron-chelator deferoxamine on the recovery of segment shortening (%SS) in the stunned myocardium was compared with a control group in barbital anesthetized dogs. Deferoxamine (500 mg intra-atrially) was administered 15 minutes prior to and throughout 15 minutes of coronary occlusion. %SS, regional myocardial blood flow, hemodynamics, and myocardial high-energy phosphates were measured. Areas at risk, collateral blood flow, and all hemodynamic parameters were similar between control and deferoxamine-treated animals. While deferoxamine did not prevent the loss of systolic wall function that occurred during ischemia, deferoxamine significantly improved the recovery of %SS at all times throughout reperfusion (3-hour %SS of pretreatment: control, 12 +/- 11; deferoxamine, 65 +/- 12), normalized endocardial ATP (percent of nonischemic area: control, 79 +/- 3%, deferoxamine, 93 +/- 6%), attenuated the reperfusion-induced rebound increase in phosphocreatine and prevented the increase in tissue edema at 3 hours after reperfusion. Thus, deferoxamine exhibited a cardioprotective action both metabolically and functionally in the stunned myocardium presumably by decreasing the redox cycling, and hence, the availability of catalytic iron for use in hydroxyl radical formation and for the initiation of lipid peroxidation. These data suggest a possible role for the hydroxyl radical as a mediator of postischemic abnormalities in reversibly injured tissue.
Animals↗
Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria.
Some patients with acute hereditary porphyrias have seizures and require anticonvulsant therapy, but many anticonvulsants induce exacerbations of the hepatic porphyrias. Recently, several new anticonvulsants have become available. Among these are gabapentin, vigabatrin, felbamate, lamotrigine, and tiagabine. Little is known about their potential for induction of porphyric attacks. We used a cell culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of these new anticonvulsants on porphyrin accumulation. Treatment of the cells with deferoxamine (250 microM) led to a partial block in heme synthesis, simulating the conditions encountered in human beings with porphyria. Concomitant exposure of these cells to phenobarbital (2 mM) strongly induced accumulation of porphyrins, serving as a positive control in this model. Cells were treated for 20 hours with increasing doses (3.2 to 1,000 microM) of the newer anticonvulsants, with or without deferoxamine. For most of these anticonvulsants 5 to 100 microM is representative of the concentrations achieved in humans with therapeutic doses. Porphyrins were measured spectrofluorometrically as uro-, copro-, and protoporphyrins. Results were confirmed by high-pressure liquid chromatography. Neither vigabatrin nor gabapentin treatment, with or without deferoxamine, led to any increase in porphyrin accumulation. Similar doses of felbamate (with deferoxamine) led to a marked increase in (mainly proto-) porphyrin levels, qualitatively and quantitatively almost identical to the accumulation produced by phenobarbital. Lamotrigine or tiagabine (with deferoxamine) caused similar porphyrin accumulation. Tiagabine treatment up to 100 microM (with deferoxamine) also resulted in very high levels of predominantly proto-porphyrin. In contrast to the other anticonvulsants tested, tiagabine without deferoxamine led to mild porphyrin accumulation. In the presence of deferoxamine, phenobarbital, felbamate, lamotrigine, or tiagabine, but not gabapentin or vigabatrin, increased levels of the mRNA of ALA synthase, the first and rate-controlling enzyme of porphyrin synthesis. Such enzyme induction is a sine qua non for acute porphyric attacks. We conclude that neither vigabatrin nor gabapentin is porphyrogenic, whereas felbamate, lamotrigine, and, especially, tiagabine lead to much accumulation of porphyrins. The latter three anticonvulsants, therefore, may precipitate or exacerbate acute porphyric attacks in humans. We recommend use of vigabatrin or gabapentin, but not felbamate, lamotrigine, or tiagabine, in patients with acute porphyria and seizures.
Animals↗
Role of iron in oxidative stress in skeletal muscle atrophied by immobilization.
To clarify the role of iron in oxidative stress in skeletal muscle atrophied by immobilization, we investigated the effect of deferoxamine--an iron-chelating agent. Deferoxamine, iron-saturated deferoxamine and double-distilled water (control) were administered subcutaneously from the 4th day after immobilization via osmotic pumps to male Wistar rats (14 weeks old), one ankle joint of which was immobilized in the extended position. After 12 days' immobilization, soleus--typical slow red muscles were collected from both hind limbs and their levels of thiobarbituric acid-reactive substance (TBARS) and glutathione were measured. Deferoxamine suppressed the increase of TBARS and glutathione disulfide in atrophied muscle while iron-saturated deferoxamine did not, which strongly suggests that the iron-chelating action of deferoxamine suppressed the increased oxidative stress. This means that iron plays a very important role in increasing oxidative stress in atrophied muscle. In addition, deferoxamine decreased the degree of atrophy, an effect thought to be mediated by the suppression of oxidative stress.
Animals↗
Iron chelation in myocardial preservation after ischemia-reperfusion injury: the importance of pretreatment and toxicity.
Oxygen-derived free radicals have been implicated in myocardial ischemia-reperfusion injury. It has been proposed that deferoxamine, an iron chelator, improves myocardial preservation by reducing the iron-catalyzed production of the hydroxyl radical. The objectives of this study were to define the appropriate timing of iron chelation therapy and the dose-response properties of deferoxamine. Isolated working rat hearts were subjected to 25 minutes of normothermic global ischemia. Deferoxamine was given as pretreatment (n = 39; doses of 10 or 30 mg/kg), added to cardioplegic solution (n = 43; doses 0.46 to 1.90 mmol/L), or administered upon reperfusion (n = 52; doses 0.15 to 0.76 mmol/L) and compared with saline controls (n = 25). Deferoxamine pretreatment improved survival at each dose from a control value of 44% to 71% and 72% (p less than 0.05), respectively. A cardioplegia dose of 0.46 mmol/L improved survival from 48% to 75%. Higher doses reduced survival and implied a toxic effect. Reperfusion therapy did not alter survival. Regardless of time of administration, deferoxamine did not improve ventricular function or adenosine triphosphate levels. Deferoxamine given as pretreatment 1 hour before ischemia at doses of 30 mg/kg, and perhaps as low as 10 mg/kg, significantly improved survival. The addition of deferoxamine to cardioplegic solution was safe and may be protective at approximately 0.50 mmol/L; however, toxicity should be considered at concentrations greater than 0.76 mmol/L. These data support the postulate that iron catalysis is involved in the production of oxygen-derived free radicals during ischemia-reperfusion injury. We conclude that pretreatment before ischemia is an important component of iron chelation therapy in myocardial preservation.
Adenosine Triphosphate↗
Cellular injury induced by oxidative stress is mediated through lysosomal damage.
Cultured primary hepatocytes pretreated (protected) with the iron chelator deferoxamine or the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD) were resistant to the toxicity of 5 microM naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) during a 180-min exposure. Hepatocytes exposed to naphthazarin without any protection were abruptly depleted of intracellular reduced glutathione, and the level of cytosolic Ca2+ was rapidly increased. This was followed by lipid peroxidation, measured as accumulation of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNA) intra- and extracellularly; decrease in ATP levels; destabilization of lysosomes; and finally cell death. The stability of the lysosomal membranes was evaluated by determining retention of the lysosomotropic weak base acridine orange (AO). Naphthazarin exposure caused leakage of protons from the acidic compartment, as indicated by relocalization of AO to the cytosol. Protection of the cell cultures with deferoxamine or DPPD prevented destabilization of lysosomes and cell killing. It also reduced the loss of ATP but did not prevent the depletion of glutathione or the increase in Ca2+. In cells subjected to naphthazarin exposure, DPPD protection also completely inhibited lipid peroxidation, whereas deferoxamine pretreatment only slightly reduced the intracellular accumulation of MDA and 4-HNA but completely prevented cell rupture and the leakage of these lipid peroxidation products to the medium that took place in large amounts from unprotected cells exposed to naphthazarin. Deferoxamine is taken up by endocytosis and is thus transported to the acidic vacuolar apparatus, whereas the lipophilic DPPD is rapidly distributed throughout the cells. Inhibiting endocytosis during deferoxamine pretreatment, by incubating at +4 degrees C or by preexposure to a mixture of the endocytosis-inhibitors cytochalasin B and monensin, abolished the protective effect of deferoxamine. The findings suggest that naphthazarin-induced cell killing is not caused directly by either thiol oxidation or an increase in cytosolic free Ca2+, but rather is preceded by lysosomal destabilization, which may be prevented either by inhibition of cellular peroxidation in general or by prevention of iron-catalyzed oxidative reactions, and involves peroxidation of cellular membranes, energy depletion, and leakage of lysosomal content. DPPD would protect against cell killing by preventing lipid peroxidation of cellular membranes in general, whereas deferoxamine seems to allow a limited general cellular peroxidation but specifically prevents peroxidation and fragmentation of lysosomal membranes by chelating intralysosomal iron and, consequently, leakage of destructive lysosomal contents with ensuing cell rupture and death. Thus, a certain degree of cellular peroxidation does not appear to be lethal as long as lysosomal membranes are protected, placing lysosomes into a category of cellular loci minora resistentia.
Adenosine Triphosphate↗
Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria.
To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose.
Antidotes↗
An ovine model of maternal iron poisoning in pregnancy.
An ovine model of maternal iron poisoning in pregnancy was used to examine the placental transport of deferoxamine and ferrioxamine and to follow maternal and fetal serum iron concentrations when maternal serum iron levels exceeded total iron-binding capacity. Ewes in the third stage of gestation underwent hysterotomy and delivery of the fetal head through an abdominal incision while under ketamine and halothane anesthesia. The fetal external jugular vein was catheterized for sampling of venous blood while the fetus remained in utero. Administration of deferoxamine mesylate or ferrioxamine mesylate IV to ewes was not accompanied by measurable deferoxamine or ferrioxamine in fetal blood. In a final experiment, four gravid ewes in a control group received 2 mg/kg maternal body wt iron IV over 60 minutes. An experimental group comprising another four ewes received similar doses of iron but then received 50 mg/kg deferoxamine mesylate IV over 15 minutes. Control and deferoxamine ewes reached similar peak maternal serum iron concentrations (2,479 +/- 266 and 2,121 +/- 343 micrograms/dL, respectively). The markedly elevated maternal serum iron concentrations were not accompanied by meaningful elevations in fetal serum iron levels over baseline values. Maternal deferoxamine infusion resulted in a more rapid fall in maternal serum iron concentrations but had no effect on fetal serum iron levels. The ovine fetus appears to be protected from elevated maternal serum iron concentrations in the last trimester of pregnancy. It could not be demonstrated that meaningful quantities of deferoxamine or ferrioxamine cross the placenta in the last trimester.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria.
BACKGROUND: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy. METHODS: To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. RESULTS: The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52). CONCLUSIONS: Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.
Child, Preschool↗
Deferiprone: a review of its clinical potential in iron overload in beta-thalassaemia major and other transfusion-dependent diseases.
UNLABELLED: Patients with beta-thalassaemia and other transfusion-dependent diseases develop iron overload from chronic blood transfusions and require regular iron chelation to prevent potentially fatal iron-related complications. The only iron chelator currently widely available is deferoxamine, which is expensive and requires prolonged subcutaneous infusion 3 to 7 times per week or daily intramuscular injections. Moreover, some patients are unable to tolerate deferoxamine and compliance with the drug is poor in many patients. Deferiprone is the most extensively studied oral iron chelator to date. Non-comparative clinical studies mostly in patients with beta-thalassaemia have demonstrated that deferiprone 75 to 100 mg/kg/day can reduce iron burden in regularly transfused iron-overloaded patients. Serum ferritin levels are generally reduced in patients with very high pretreatment levels and are frequently maintained within an acceptable range in those who are already adequately chelated. Deferiprone is not effective in all patients (some of whom show increases in serum ferritin and/or liver iron content, particularly during long term therapy). This may reflect factors such as suboptimal dosage and/or severe degree of iron overload at baseline in some instances. Although few long term comparative data are available, deferiprone at the recommended dosage of 75 mg/kg/day appears to be less effective than deferoxamine; however, compliance is superior with deferiprone, which may partly compensate for this. Deferiprone has additive, or possibly synergistic, effects on iron excretion when combined with deferoxamine. The optimum dosage and long term efficacy of deferiprone, and its effects on survival and progression of iron-related organ damage, remain to be established. The most important adverse effects in deferiprone-treated patients are arthropathy and neutropenia/agranulocytosis. Other adverse events include gastrointestinal disturbances, ALT elevation, development of antinuclear antibodies and zinc deficiency. With deferiprone, adverse effects occur mostly in heavily iron-loaded patients, whereas with deferoxamine adverse effects occur predominantly when body iron burden is lower. CONCLUSION: Deferiprone is the most promising oral iron chelator under development at present. Further studies are required to determine the best way to use this new drug. Although it appears to be less effective than deferoxamine at the recommended dosage and there are concerns regarding its tolerability, it may nevertheless offer a therapeutic alternative in the management of patients unable or unwilling to receive the latter drug. Deferipone also shows promise as an adjunct to deferoxamine therapy in patients with insufficient response and may prove useful as a maintenance treatment to interpose between treatments.
Clinical Trials as Topic↗
Management of acute iron overdose.
Treatment of severe iron overdose in two children is described, and the pathophysiology of iron toxicity and management of acute iron poisonings are reviewed. An 11-month-old boy was comatose and in shock several hours after ingesting approximately 50 ferrous sulfate tablets (elemental iron 390 mg/kg). He had hyperglycemia and leukocytosis. Lavage was performed with a solution containing deferoxamine and sodium bicarbonate, and deferoxamine was given by continuous i.v. infusion for 48 hours. The initial serum iron (SI) concentration of 14,250 micrograms/dL decreased to 657 micrograms/dL nine hours after i.v. deferoxamine therapy was initiated. A roentgenogram showed tablets in the stomach and small bowel. Packed red blood cells were administered to treat apparent necrotizing gastroenteritis. SI concentration returned to normal by day three [corrected], and the child recovered. A 2.5-year-old boy was examined 1.25 hr after ingesting an estimated 55 tablets of ferrous gluconate 325 mg (elemental iron 130 mg/kg). Initial SI concentration was 134 micrograms/dL, and total iron-binding capacity (TIBC) was 219 micrograms/dL. A roentgenogram indicated iron concretion in the stomach and iron tablets in the small bowel. He underwent lavage with solution containing sodium bicarbonate. An i.m. dose of deferoxamine was administered, followed by i.v. deferoxamine therapy. SI concentration eight hours after the ingestion was 290 micrograms/dL, and whole-bowel irrigation was begun with polyethylene glycol-electrolyte solution. The irrigation and deferoxamine therapy were discontinued 20 hours after the ingestion, when SI concentration was 73 micrograms/dL, and the child recovered. Acute iron ingestions of more than 60 mg/kg are potentially serious. Patient 1 had severe iron intoxication, while aggressive treatment prevented severe toxicity in patient 2. Acute iron toxicity includes effects on the GI tract and the cardiovascular, metabolic, hepatic, and central nervous systems. Guidelines for assessing the severity of an overdose and selecting the most appropriate therapy are provided. The indications for chelation therapy with deferoxamine, gastric decontamination procedures including use of lavage solutions and whole-bowel irrigation, and adjunctive measures are described. Management of acute iron overdose includes supportive care, GI decontamination, and chelation therapy.
Chelating Agents↗
Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia. A hemodynamic and electrophysiological perspective.
The purpose of this study was to investigate whether combined inhibition of neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine improved cerebral oxygenation, electrocortical brain activity, and brain energy status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet. Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both carotid arteries and phosphorous magnetic resonance spectroscopy ((31)P-MRS)-guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion, piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared spectrophotometry (NIRS), electrocortical brain activity was assessed with amplitude-integrated EEG (aEEG), and cerebral energy status with (31)P-MRS. The oxygenated hemoglobin (HbO(2)) and total hemoglobin (tHb) were significantly increased in vehicle-treated piglets compared with 2-iminobiotin-treated and deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated over time. The aEEG was significantly preserved in 2-iminobiotin- and deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol treatment was not as effective as 2-iminobiotin treatment after HI. Phosphocreatine/inorganic phosphate ratios (PCr/P(i)) were significantly decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin, allopurinol, and deferoxamine prevented the development of secondary energy failure. We speculate that the beneficial effects, especially of 2-iminobiotin, but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.
Allopurinol↗
Prevention of postasphyxia electroretinal dysfunction with a pyridoxal hydrazone.
The newborn retina is particularly sensitive and frequently subjected to peroxidative stresses that result in visual sequelae. We compared two iron chelators, deferoxamine and a newer compound, pyridoxal isonicotinoyl hydrazone (PIH), in protecting the retina of newborn pigs (1-3 d old) from asphyxia-reoxygenation insults. Animals were treated IV with either saline, deferoxamine 15.2 mumol/kg (10 mg/kg) or PIH 34.8 mumol/kg (10 mg/kg); n = 10 in each treatment group. Scotopic and photopic electroretinograms (ERG) were recorded before and 40 min after drug treatment as well as 45 min following a 5-min period of asphyxia by interrupting ventilation. In separate animals the indices of peroxidation, malondialdehyde (MDA: TBARS) and hydroperoxides, were measured in retina at the same times. In saline-treated animals, there was a marked increase in MDA and hydroperoxide concentrations in the retina following the asphyxia-reoxygenation period. This was associated with a decrease in the a- (photoreceptor generated) and b-wave (generated by Müller and bipolar cells) amplitudes measured under photopic (cone-mediated response) and scotopic (rod-mediated response) conditions, and an increase in their implicit times. PIH and deferoxamine prevented the postasphyxial increase in MDA and hydroperoxides. However, only PIH prevented the postasphyxial changes in a- and b-wave amplitudes and implicit times, whereas deferoxamine markedly altered the preasphyxial ERG and provided only partial postasphyxial protection simply to the retinal outer segment. Our findings indicate that the iron chelator PIH effectively inhibits peroxidation and retinal electrophysiological alterations secondary to asphyxia-reoxygenation-induced oxidative stresses to newborn animals, whereas deferoxamine adversely affects retinal function; hence, PIH may be a preferred alternative to deferoxamine.
Animals↗
Role of iron in postischemic renal injury in the rat.
To determine whether iron participates in free radical-mediated postischemic renal injury and lipid peroxidation, we examined the effects of removal of endogenous iron or provision of exogenous iron following renal ischemia, as well as the effects of renal ischemia and reperfusion on renal venous and urinary "free" iron. Rats underwent 60 minutes of renal ischemia and were studied after either 24 hours (inulin clearance) or 15 minutes (renal malondialdehyde content) of reperfusion. Infusion of the iron chelator deferoxamine (200 mg/kg/hr) during the first 60 minutes of reperfusion resulted in a marked improvement in renal function (inulin clearance: 879 +/- 154 vs. 314 +/- 74 microliter/min; P less than 0.025) and a reduction in lipid peroxidation (renal malondialdehyde: 0.449 +/- 0.06 vs. 0.698 +/- 0.08 mmol/mg prot; P less than 0.05) compared to control animals. Infusion of 50 mg/kg/hr deferoxamine also protected renal function after ischemia (inulin clearance: 624 +/- 116 vs. 285 +/- 90 microliter/min; P less than 0.05) and resulted in less histologic injury. Iron-saturated deferoxamine had no protective effect. Conversely, infusion of the iron complex EDTA-FeCl3 during reperfusion exacerbated postischemic renal dysfunction and lipid peroxidation. Following renal ischemia there was no detectable increase in "free" iron in arterial or renal venous plasma. However, urinary "free" iron increased 10- to 20-fold following reperfusion. Iron chelators which underwent filtration and gained access to this free iron in the urine (free deferoxamine or inulin-conjugated deferoxamine) provided protection, whereas a chelator confined to the vascular space (dextran-conjugated deferoxamine) did not.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗