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PubMed1999

Deferoxamine treatment during pregnancy: is it harmful?

The use of the iron chelator, Deferoxamine (DFO), in pregnant thalassemia women with iron overload has been generally avoided due to fear of its potential teratogenicity. We describe a case of a pregnant thalassemia major patient with iron overload, who received DFO throughout her second and third trimesters and gave birth to a healthy infant, who had no findings of DFO toxicity at birth and at a later follow-up. Review of the literature discloses over 40 other cases in which DFO was given in various periods of gestation without evidence of teratogenic effect. Sufficient documentation exists, therefore, to suggest that DFO can be considered for use in cases of pregnant women who need iron chelation treatment.

Abnormalities, Drug-Induced↗

PubMed1992

Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice.

BACKGROUND: Iron is essential for the growth of all living cells. One of the important intracellular roles for iron is in the activation of ribonucleotide reductase, the enzyme that catalyzes the first step in DNA synthesis. Thus, the intracellular iron level may serve as a regulator of cell growth. The authors tested the hypothesis that lowering body iron concentration inhibits the growth of human-derived hepatocellular carcinoma (HCC) cells by depleting these cells of iron. Deferoxamine (DFO), an iron-chelating agent, was used to lower intracellular iron level. METHODS: HCC cells, PLC/PRF/5 (7 x 10(6) cells/mouse), were transplanted subcutaneously into athymic nude mice. When tumors reached 200-300 microliters in size, mice with comparable tumor sizes were paired; one was treated with DFO (300 mg/kg body weight/day, 5 days/week) intraperitoneally while the other received no treatment. RESULTS: Eight pairs of mice with HCC were observed for 5-18 weeks. Mean tumor growth rates (TGR) (mean +/- standard error) for the untreated and treated mice were 30.5 +/- 3.7 microliters/week and 11.9 +/- 1.5 microliters/week. The difference was significant (P < 0.02). In the second set of studies, DFO treatment was begun when the tumor size was smaller (100-200 microliters). Four pairs of mice were observed for 4-15 weeks; mean TGR for the four untreated mice was 18.1 +/- 5.1 microliters/week. In two mice treated with DFO, tumors regressed completely by the seventh week after initiation of treatment. The two remaining mice on DFO therapy had much slower growing tumors, with a mean TGR of 1.8 +/- 0.5 microliters/week. CONCLUSIONS: Thus, our results suggest that (1) reduction of intracellular iron concentration by DFO may be useful as antitumor therapy in HCC and (2) the favorable effects of DFO treatment are best seen when treatment is begun when the tumor is small.

Animals↗

PubMed2000

The effects of conjugated deferoxamine in porcine skin flaps.

BACKGROUND: The free radical scavenger, deferoxamine (DFO) has been shown to reduce skin flap necrosis; however, its shortcomings are its toxicity and short plasma half-life. METHODS: This study investigates the effects of the less toxic, longer acting conjugated form, DFO-Hespan (DFO-H), to ischemic porcine skin flaps. During the study, DFO-H plasma concentrations and flap viability were evaluated over 10 days. RESULTS: Steady DFO serum levels were maintained with no evidence of systemic side effects. However, DFO-H was not effective in increasing porcine skin flap viability. Mean treated flap viability (n = 18) was 36.2% +/- 1.7% (mean +/- SE ) vs control (n = 16) 35.8% +/- 2.6%, p =.9. CONCLUSION: DFO-H conjugation increases its half-life and its systemic tolerance for DFO. However, this conjugation may also reduce DFO's effectiveness to preserve flap survival probably by decreasing its ability to reach the intracellular oxygen free radicals. In addition, further studies are needed to investigate whether longer DFO administration given postoperatively can be more effective in reducing ischemic injury.

Animals↗

PubMed1988

Rapid excretion of gallium-67 isotope in an iron-overloaded patient receiving high-dose intravenous deferoxamine.

A 23 year-old black male with homozygous sickle cell disease (Hb SS disease) and transfusional iron overload was admitted for evaluation of response to intravenous deferoxamine (DFO) therapy. Soon after admission, the patient suffered an intraventricular hemorrhage and during his subsequent hospitalization developed a persistent fever of undetermined origin (f.u.o.). Included in the diagnostic evaluation of fever was a gallium 67 scan (Ga-67), which was initially nondiagnostic because of Ga-67 citrate's preferential chelation by DFO. After DFO was discontinued, a repeat scan demonstrated a lesion above the left kidney. To our knowledge the unusual interaction in vivo of DFO with Ga-67 citrate has not been reported in the clinical literature. With the anticipated increased use of chelation therapy for patients with transfusional iron overload, this interaction may be encountered more frequently. DFO should be discontinued before the use of Ga-67 scanning in this clinical situation, or an alternative isotopic scan, such as indium-labelled white cells, should be considered.

Adult↗

PubMed1992

Reduction in tissue iron stores with a new regimen of continuous ambulatory intravenous deferoxamine.

A new regimen of 24-hr ambulatory continuous intravenous infusion of deferoxamine (CIV DFO) through central venous ports was instituted in nine patients aged (mean +/- SD) 22.4 +/- 5.8 years over a period of 15.7 +/- 7.3 months. Central venous infusion sites were changed weekly in the clinic, eliminating the necessity for reconstitution of DFO and needle insertion at home. Because CIV DFO could be interrupted only by medical personnel, patient compliance was documented accurately; patients administered 93.0% +/- 3.2% of CIV DFO prescribed. Mean urinary iron excretion on CIV DFO (66.8 +/- 50.4 mg/24 hr) was significantly greater than that quantitated during 12-hr equivalent-dose subcutaneous DFO infusions (23.4 +/- 18.3 mg/24 hr; P less than 0.025). Mean serum ferritin declined by 71% over the treatment period (P less than 0.005). This regimen confers the advantages of uninterrupted exposure to DFO, is associated with excellent patient compliance, and should be considered in any patient with severe iron overload and erratic compliance with DFO.

Adolescent↗

PubMed1991

Inhibition of human hepatocellular carcinoma and hepatoblastoma cell lines by deferoxamine.

Inhibition of human hepatocellular carcinoma (PLC/PRF/5 and Hep3B) or hepatoblastoma (Hep G2) cell lines by inclusion of deferoxamine mesylate (desferrioxamine) (DFX) in the culture medium was evaluated. When PLC/PRF/5 cells were maintained for 7 days in 30 or 60 microM DFX, the cell number was decreased by 30-60%, little or no alpha-fetoprotein (AFP) was produced, and supernatant endpoint dilution titers of hepatitis B surface antigen (HBsAg) were reduced 1-2 logs. PLC/PRF/5 cells maintained for 7 days without DFX (simultaneous controls) grew to confluence, produced AFP that reached 10-60 ng/ml in the supernate, and the HBsAg titer remained constant or increased 1 log. Similar effects were observed in Hep3B and Hep G2 cells maintained in DFX (except that Hep G2 cells do not produce HBsAg), compared to simultaneous control cells grown in the absence of DFX. The growth of a human embryonic lung fibroblast cell line (Wl 38) was not significantly inhibited by DFX, although it grew at a slower rate than simultaneous control cells grown without DFX. Subsequent growth in FeSO4 of PLC/PRF/5, Hep3B, and Hep G2 cells that previously had been maintained in DFX did not reverse the effects of DFX. PLC/PRF/5 cells were also inhibited when maintained in medium containing equimolar concentrations of DFX and FeCl3 and in medium containing equimolar concentrations of DFX and FeSO4. PLC/PRF/5 cells were not inhibited by maintenance in up to 60 microM of another chelating agent that has a similar affinity for iron, calcium disodium versenate (EDTA). These studies show that DFX inhibits the growth of human hepatocellular carcinoma and hepatoblastoma cell lines regardless of the presence (PLC/PRF/5, Hep3B) or absence (Hep G2) of integrated hepatitis B virus DNA. The findings also suggest that the inhibition may have been due to mechanisms other than iron chelation.

Carcinoma, Hepatocellular↗

PubMed2005

Barriers to adherence of deferoxamine usage in sickle cell disease.

BACKGROUND: We hypothesized that child cognitive disability would be a significant risk factor for non-adherence with home deferoxamine (DFO) administration and that a factor that would contribute to improved adherence would be sharing of responsibilities for chelation between parents and patients. We explored the influences on adherence of behavioral and psychological adjustment; family stress; perceived convenience of and satisfaction with the DFO regimen; and parent and patient knowledge about DFO. PROCEDURE: Fifteen pediatric patients with sickle cell disease (SCD) who had evidence of excessive iron stores, and their parents, were interviewed about adherence and responsibility for chelation therapy. A neuropsychological assessment battery was administered to the patients. Family stress, the child's emotional and behavioral status, knowledge about chelation and iron overload were explored. Adherence was rated objectively using pharmacy refill patterns and observable signs of chelation. RESULTS: Sharing of responsibilities for chelation between parents and children was related to better adherence while neuropsychological status bore a complex relation to adherence. Of the exploratory variables, low family stress were related to better adherence while satisfaction with the home care regimen and convenience ratings were not useful in predicting adherence. No one element of adherence, even objective measures, was capable of classifying adherence, while a multifactorial scheme categorizing adherent, partially adherent and non-adherent groups demonstrated good face validity. CONCLUSIONS: Supporting developmentally appropriate sharing of responsibilities for self-care is critical, taking patient neurocognitive status into consideration. Clinicians should evaluate adherence using a multifactorial model that highlights the most salient targets for intervention.

Adolescent↗

PubMed1993

Failure of deferoxamine to reduce myocardial infarct size in a primate model of ischemia-reperfusion injury.

Baboons were subjected to treatment with deferoxamine (DF), a strong iron-chelating agent, to inhibit the iron-dependent production of hydroxyl radicals. Studies were then done to determine if this would result in a reduction in the size of myocardial infarct. Baboons underwent occlusion of the left anterior descending coronary artery for 2 hr followed by reperfusion for the next 22 hr. A treated group (n = 4) received a 2-hr preischemic intravenous infusion of DF (10 mg/kg/hr). This infusion continued throughout the ischemic phase and 2 hr into the reperfusion phase. A control group (n = 8) underwent the identical protocol minus the DF infusion. At the end of the reperfusion period, the hearts were sectioned and stained for histological examination. The treated animals had a 22% larger volume of infarct compared with those of the controls (P = 0.06). There was no statistically significant difference (P > 0.05) in hemodynamic or epicardial ST segment measurements between the two groups. In this primate model, there was no myocardial protection afforded by DF. Baboons are similar to humans in that both have minimal collateral circulation. In the literature, DF has been noted to actually contribute to the production of free radicals in certain circumstances. This experiment appears to indicate that caution should be exercised in the use of DF in the treatment of ischemia-reperfusion injury of the heart.

Animals↗

PubMed1994

Deferoxamine given at reperfusion improves function of the cold-stored rat heart.

In this study deferoxamine (DF), a strong iron chelator, was administered either before storage or during reperfusion, in an attempt to inhibit the iron-dependent hydroxyl radical production and improve the functional recovery of the cold-stored/reperfused cardiac explant. Excised rat hearts were flushed with Krebs-Henseleit buffer (KHB), arrested with a cardioplegic solution, CP11-EB, with or without DF, and immersion stored in CP11-EB at 0 degree C for 16 hr. To assess function, the stored hearts were reperfused in the working mode with KHB for 30 min. Experimental groups included: (i) DF treatment during prestorage flush [CP11-EB + 0.01 mM (n = 5), 0.05 mM (n = 13), 0.1 mM (n = 5), 0.2 mM (n = 5), or 0.75 mM DF (n = 5)]; (ii) DF treatment during reperfusion [KHB + 0.3 mM (n = 5), 0.6 mM (n = 7), 0.75 mM (n = 11), 1.0 mM (n = 6), 1.5 mM (n = 4), or 2.5 mM DF (n = 7)]; and (iii) untreated group (n = 8) received no DF during flush or reperfusion. Function of unstored hearts (n = 7) including aortic flow (AF, 54.6 +/ 2.6 ml/min); cardiac output (CO, 76.5 +/- 3.3 ml/min), systolic pressure (SP, 135.7 +/- 1 mm Hg), diastolic pressure (DP, 70.7 +/- 3.8 mm Hg), and work (96.7 +/- 6.4 g-meter/min) served as controls. Functional recovery of the untreated group was AF, 59%; CO, 58%; SP, 71%; DP, 73%; work, 41% of control values. DF treatment at any dose during the initial flush did not improve functional recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats.

The iron chelating activity of deferoxamine (DFO) has been exploited to obtain protection against the peroxidative damage in rat heart which was induced by the administration of an acute dose of doxorubicin (DXR, 25 mg x kg(-1), i.v.). The peroxidative lesions were evaluated both biochemically and histopathologically, 48 h after DXR administration. Abnormal biochemical changes including a marked increase in the levels of serum creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH), as well as elevated serum creatinine, blood urea nitrogen and transaminases (ALT and AST) levels were observed. Myocardial tissue from DXR treated rats showed a marked increase in malondialdehyde (MDA) production and depletion of reduced glutathione (GSH) contents. Similar results were also observed in both kidney and liver tissues. Pretreatment of rats with DFO, given i.p. 30 min prior to DXR injection, substantially reduced the peroxidative damage in the myocardium, hepatic and renal tissues and markedly lowered the serum CK-MB, LDH and the other biochemical variables. The protective effects obtained by DFO administration, however, were not complete and did not reach those of the control group. The significant protection against DXR-induced cardiomyopathy by DFO was evident from the histopathological findings observed by light microscopy. DFO at a dosing level equivalent to 10-fold of that of DXR was useful to obtain protective effects. Higher DFO dosing levels did not, however, show more improvement in the DXR-induced cardiotoxicity and at the same time exhibited hepatoxicity which was confirmed by microscopical examination. These results strongly suggest that DFO protects against acute DXR-induced cardiotoxicity in a dose-dependent manner with recognizing the presence of mild DFO-related biochemical and cytological hepatic toxicity.

Analysis of Variance↗

PubMed1993

Pulmonary toxicity of deferoxamine in iron-poisoned mice.

Previously we have shown that a group of patients treated for iron overdose with prolonged deferoxamine (DFO) infusion died of adult respiratory distress syndrome (ARDS). We now describe a model to investigate the mechanism of this pulmonary toxicity. Mice treated with 1 oral dose of iron (Fe) and then multiple injections of DFO, or with the chelated product ferrioxamine alone, did not develop lung lesions, even at doses which induced mortality. To potentiate any possible free radical reaction, other groups of mice were treated similarly while exposed to 75-80% O2 over a 4-day period. Ten of 12 mice receiving 0.75 mg Fe and then DFO (10 mg, 4 times/day for 4 days) with hyperoxia died suddenly. At autopsy the lungs were dark red and solid; sections showed hyaline membranes and alveolar exudates of edema, fibrin, and PMN. Electron microscopy showed massive destruction of the alveolar epithelium; using cerium chloride, a free radical reaction product was demonstrated at the alveolar surface. Lung lavage fluid contained 10-12 x normal levels of protein when the Fe-DFO-O2 group was compared to air or O2 controls. Mice receiving DFO or Fe, plus O2, showed only slight injury and a small increase in alveolar protein. The results indicate that Fe plus DFO generates free radicals in the lung, a reaction potentiated by hyperoxia to produce an ARDS-like picture. This suggests that the pulmonary toxicity of DFO in iron-poisoned patients is due to its prooxidant activity resulting in free radical destruction of the airblood barrier.

Animals↗

PubMed1982

Deferoxamine mesylate enhancement of 67Ga tumor-to-blood ratios and tumor imaging.

To improve the tumor-to-blood ratio in 67Ga tumor imaging, the effect of administration of deferoxamine mesylate (DFO) was evaluated. DFO improved 67Ga tumor-to-blood ratios in tumor-bearing rats. Administration of DFO 12 h after 67Ga injection did not decrease the concentration of radioactivity in the tumor of rats, but administration of DFO 4 h after 67Ga decreased the concentration of radioactivity in the tumor. Serum unsaturated iron binding capacity in rats was transiently increased by DFO administration, but when DFO was administered before 67Ga injection the tumor uptake showed rather decreased levels. In human studies, DFO accelerated the excretion of 67Ga from the blood, but tumor images were not necessarily improved.

Animals↗

PubMedDate not supplied

Effects of deferoxamine on H2O2-induced oxidative stress in isolated rat heart.

During myocardial reperfusion injury, iron has been implicated in the Fenton based generation of hydroxyl radical, .OH, leading to further organ injury. Although previous studies have investigated the protective effect of iron chelators including deferoxamine (DFX) in myocardial reperfusion injury, there is little information regarding the role of iron chelation during oxidative stress produced by H2O2 on the heart. Isolated hearts from male Sprague-Dawley rats were retrograde-perfused with Krebs-Henseleit solution at 5 ml/min. After a 60-min equilibration, oxyradical challenge was instituted by the addition of H2O2 (200-600 microM) to the perfusate for 60 min. A subgroup of animals received DFX (400 microM) in the perfusate prior to challenge with 400 microM H2O2. Contractility was continuously monitored; perfusate samples for glutathione (GSH) and lactate dehydrogenase (LDH) estimations were collected at 30-min intervals. Headspace ethane, an indicator of lipid peroxidation, was estimated at 30-min intervals by gas chromatography. Control hearts maintained contractility during the perfusion period. H2O2 perfusion caused a dose dependent decrease in myocardial contractility; DFX pretreatment was partially protective. Headspace ethane slowly accumulated in control hearts; perfusion with H2O2 caused dose dependent increase in ethane accumulation indicative of enhanced lipid peroxidation. GSH and LDH in the perfusate remained low in control hearts. In contrast, H2O2 treated hearts had a dose dependent increase in the efflux of GSH and LDH which was markedly increased by perfusion with 600 microM H2O2. Pretreatment with DFX did not significantly reduce GSH or LDH efflux from hearts perfused with peroxide. While H2O2 perfusion causes a dose dependent decrease in myocardial contractility with a corresponding increase in headspace ethane release with GSH & LDH efflux indicative of oxidative stress, concurrent treatment with DFX reduces myocardial dysfunction and ethane generation. However, sublethal damage of plasma membrane still continues as reflected by continuous enhancement of LDH efflux, possibly indicating involvement of other reactive species besides hydroxyl radical.

Animals↗

PubMed1989

Fatal fungal peritonitis in an adolescent on continuous ambulatory peritoneal dialysis: association with deferoxamine.

An unusual case of Rhizopus microsporus (mucormycosis) fungal infection in a teenage boy on continuous ambulatory peritoneal dialysis is presented. Premortem cultures were negative and the patient developed a rapidly disseminated fatal infection. The patient was being treated with deferoxamine (DFO) for iron and aluminum overload. An argument is made for a probable association between DFO and this fatal fungal infection in patients with end-stage renal disease.

Adolescent↗

PubMed1996

Aluminium-induced bone disease in uremic rats: effect of deferoxamine.

We have previously established a rat model of chronic uremia, which is suitable to investigate the effect of various treatment modalities on renal osteodystrophy [1]. After four months subsequent to 5/6 nephrectomy, some animals were treated by gavage for 9 weeks with tap water (controls), or with aluminium (Al-citrate) 3 x 25 mg/week/kg b.wt +/- subsequent deferoxamine (DFO) 3 x 50 mg/week/kg b.wt. for 4 weeks. At termination of the study, serum clinical chemistry, femoral chemical composition and mechanical properties, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC) and phospholipase C (PLC) activities, cross-sectional femoral area, as well as bone histomorphometry, were analyzed. Animals given Al displayed moderately enhanced serum Al and bone Al accumulation, however, DFO-treatment did not fully alleviate bone Al retainment. A small increase in serum PTH was seen in all animals rendered uremic. Furthermore, a marked fall in serum alkaline phosphatase (ALP) below normal controls was observed in Al +/- DFO-treated animals compared with uremic controls. The uremic condition led to reduced femoral ratios of hydroxyproline (HYP) over Ca(2+) and phosphate (P(i)), while Al-intoxication alone enhanced femoral Hyp contents above values seen for normal controls. The protracted ureamia caused a deterioration of long bone resilience and brittleness, however, Al +/- DFO-treatment seemed to normalize the latter. Contrastingly, Al +/- DFO-gavage enhanced time to fracture. Uremic rats intoxicated with Al showed a complete loss of calvarial PTH-sensitive AC and PLC activities. DFO-treatment normalized PTH-elicited PLC, while PTH-susceptible AC remained super-normal. Al apparently exerts a long term down-regulation of both PTH-sensitive signaling systems as evidenced by studies of rat UMR 106 osteosarcoma cells in culture. The uremic condition enhanced endosteal bone resorption as shown by femoral shaft dimension analysis, while Al +/- DFO-treatment insignificantly reversed the condition. Finally, histomorphometrical analyses showed that DFO-administration tended to normalize aberrant trabecular bone volume, while rectifying both bone resorption and degree of mineralization. In conclusion, we assert that Al-intoxication hampers both processes (i.e. formation and resorption) of bone turnover, and that DFO-treatment to a certain extent prevents the uremia- and Al-induced bone disease in rats.

Adenylyl Cyclases↗

PubMed1993

MR imaging of deferoxamine-induced bone dysplasia in an 8-year-old female with thalassemia major.

Bone changes in thalassemic patients receiving deferoxamine therapy for iron chelation include metaphyseal and growth plate irregularities. We present a case of an 8-year-old female with thalassemia major, who had magnetic resonance imaging after plain radiographs had shown metaphyseal changes in the distal femur. The signal characteristics of these abnormalities were consistent with hyaline cartilage; the surrounding marrow showed no evidence of iron overload.

Bone Diseases, Developmental↗

PubMed1993

Spinal deformities in deferoxamine-treated homozygous beta-thalassemia major patients.

A new constellation of spinal changes are observed in homozygous beta-thalassemia major (HBT) patients receiving deferoxamine (DF), an iron-chelating drug used in combination with transfusion therapy in certain anemic syndromes. In a retrospective study of 22 HBT patients who were receiving DF therapy, morphological deformities (decreased spinal height, increased thoracic kyphosis, vertebral flattening and elongation anteriorly, and disk calcification) were found in 16 of 22 patients. These changes are believed to be caused by interference with spinal growth-plate development. Investigation of DF-dose correlation supports the conclusion that the spinal changes were DF-induced. Spinal changes observed in DF-treated patients differ both morphologically and pathogenetically from earlier reports of vertebral deformities occurring as a sequel to compensatory marrow hyperplasia in poorly transfused patients.

Adolescent↗

PubMed1995

Assessment of the developmental toxicity of deferoxamine in mice.

Deferoxamine (DFO), an efficient chelating agent available for the treatment of iron and aluminium overload, was evaluated for developmental toxicity in Swiss mice. Intraperitoneal injections of DFO were given to pregnant animals at 0, 44, 88, 176, and 352 mg/kg per day on gestational days 6 through 15. Maternal clinical status was monitored daily during and after treatment. Fetal parameters, including external, visceral, and skeletal malformations and variations, were assessed. Mice were killed on day 18. No maternal mortality was observed, but dams exhibited reduced body weight gain during treatment at 88, 176, and 352 mg/kg per day. Body weight at termination, corrected body weight, and food consumption were reduced in all groups. In contrast, the only significant treatment-related embryo/fetal effect was a decrease in the number of live fetuses per litter at 352 mg/kg per day. The no-observable-adverse-effect level (NOAEL) for maternal toxicity of DFO was < 44 mg/kg per day, whereas the NOAEL for developmental toxicity was 176 mg/kg per day. In summary, intraperitoneal administration of DFO to mice during organogenesis produced developmental toxicity in the presence of maternal toxicity. Because of the remarkable maternal toxicity of DFO, extreme caution in the use of this drug is recommended during pregnancy.

Animals↗