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Deferoxamine-fibrin accelerates angiogenesis in a rabbit model of peripheral ischemia.

The intramuscular (i.m.) injection of a modified fibrin meshwork plus deferoxamine was tested in a rabbit model of acute hind-limb ischemia. After excision of the left external iliac and femoral arteries, 12 rabbits at the Milwaukee Heart Institute were divided into two groups: control and fibrin meshwork plus deferoxamine (FDEF) i.m. The rabbits underwent angiography before surgery, immediately after, and 1 month postoperatively. These data were compiled through counting by means of a grid overlay. Another 12 rabbits at the Vakhidov Center of Surgery, which did not undergo angiography, underwent lower limb-calf blood pressure (L-CBP) measurements made immediately after surgery and at postoperative days 10, 20 and 30. Biopsies from thigh skeletal muscles of rabbits that had L-CBP measurements underwent alkaline phosphatase staining on day 30 to determine the percentage of biopsied area that was occupied by capillaries. The number of arteries and arterioles crossing 71 grid intersections immediately post-surgery decreased from 30.2 +/- 2.3 to 18.0 +/- 2.0 (p < 0.05). One month postsurgery this number increased to 29.2 +/- 2.4 in controls (p < 0.05 vs immediately post-surgery) and to 59.6 +/- 3.2 in the FDEF group (p < 0.001 vs immediately post-surgery). By day 30 the L-CBP ratio improved in the FDEF group (0.8 +/- 0.02) vs controls (0.3 +/- 0.04). By day 30 the capillary density increased from that of normal muscle tissue (198.6 +/- 12.9/mm2) to 292 +/- 12.4/mm2 in the FDEF group (p < 0.05), but decreased in the control group to 98.7 +/- 7.7/mm2. I.m. injection of FDEF considerably accelerated angiogenesis in severely ischemic hind-limb tissue in this model, making it a viable treatment method for clinical use in patients who have critical limb ischemia.

Animals↗

The formation of alveoli in rat lung during the third and fourth postnatal weeks: effect of hyperoxia, dexamethasone, and deferoxamine.

Terminal gas-exchange units in the lung of many species are, at birth, relatively large structures termed saccules. Saccules septate postnatally forming smaller units that constitute the final alveoli. In the rat, septation occurs intensively during the first 2 postnatal wk after which it has been considered to stop. Treatment with dexamethasone or exposure to hyperoxia during the first 2 postnatal wk markedly inhibits septation as evidenced by the formation of fewer and bigger alveoli than in normally developed rats. Deferoxamine, an iron chelator, has been reported to protect the lung from the effects of exposure to hyperoxia in early postnatal life. In this study, we investigated the effects of these treatments during the 3rd and 4th postnatal wk, that is, after the early period of rapid alveolarization. Our results show that treatment with dexamethasone no longer had any inhibitory effect on alveoli formation; that exposure to hyperoxia continued to inhibit the formation of new alveoli, resulting in bigger and less numerous alveoli; that treatment of animals exposed to hyperoxia with deferoxamine still protected their lungs against hyperoxic inhibition; and that elastin fiber length density in the lung was significantly reduced in hyperoxic-exposed animals. These results suggest that septation continues beyond the 2nd postnatal wk and does not stop abruptly at age 14 d in air-breathing rats and that hyperoxic inhibition of alveolarization during the 3rd and 4th postnatal wk is due to the inhibition of septation of existing or newly generated gas-exchange units during that period of lung development.

Age Factors↗

The prevention of oxyhemoglobin-induced endothelial and smooth muscle cytoskeletal injury by deferoxamine.

The oxidized breakdown products of hemoglobin are important in the pathogenesis of cerebral vasospasm because of their effects on the endothelium and the smooth muscle of the arterial wall. Cytoskeletal changes in cultured vascular cells are sensitive indicators of oxidative injury. Cultured endothelial cells and smooth muscle cells showed a dose-related disruption of the cytoskeleton, particularly the F-actin and vimentin filaments, when exposed to 10(-5) M oxyhemoglobin. The cytoskeletal injury was prevented by the addition of 10(-3) M deferoxamine or 1% albumin. These experiments support a role for deferoxamine in the pharmacological treatment of vasospasm. Furthermore, cytoskeletal studies of cultured arterial endothelial and smooth muscle cells provide a novel in vitro approach by which to study the cellular mechanisms of oxidant injury initiated by the breakdown products of hemoglobin.

Actins↗

Inhibitory effect of deferoxamine on Paracoccidioides brasiliensis survival in human monocytes: reversal by holotransferrin not by apotransferrin.

The mechanisms used by Paracoccidioides brasiliensis to survive into phagocytic cells are not clear. Cellular iron metabolism is of critical importance to the growth of several intracellular pathogens whose capacity to multiply in mononuclear phagocytes is dependent on the availability of intracellular iron. Thus, the objective of this paper was to investigate the role of intracellular iron in regulating the capacity of P. brasiliensis yeast cells to survive within human monocytes. Treatment of monocytes with deferoxamine, an iron chelator, suppressed the survival of yeasts in a concentration-dependent manner. The effect of deferoxamine was reversed by iron-saturated transferrin (holotransferrin) but not by nonsaturated transferrin (apotransferrin). These results strongly suggest that P. brasiliensis survival in human monocytes is iron dependent.

Apoproteins↗

Acute bone marrow aplasia associated with intravenous administration of deferoxamine (desferrioxamine).

The authors report the clinical course and fatal outcome of a case of acute bone marrow aplasia, after intravenous administration of deferoxamine (desferrioxamine) to a 16-year-old girl with homozygous beta-thalassaemia. The type of aplasia was mainly that of a megakaryocytic thrombocytopenia, but the 2 other haemopoetic series were also involved. The absence of any other toxic factors and the quite rapid onset of the bone marrow failure after this type of treatment strongly suggest that intravenous administration of high doses of deferoxamine was the potential toxic factor.

Adolescent↗

Correlation between the depth of inverted T waves and the serum level of ferritin in a deferoxamine-treated patient with primary hemochromatosis and hyperthyroidism.

A 74-year-old female having primary hemochromatosis and hyperthyroidism is described. The initial ECG showed sinus rhythm, and depression of ST segment and inversion of T waves in I, II, III, aVF, and V4-6. By deferoxamine and propylthiouracil, the serum level of ferritin was decreased from 4,500 ng/ml to 440 ng/ml in a period of 6 months. The thyroid function was also returned to normal. After cessation of both drugs, the serum ferritin level increased gradually reaching a level of 3,100 ng/ml in the next 15 months but the thyroid function remained normal. During and after the deferoxamine administration, the depth of inverted T waves became more shallow and gradually deeper again, respectively. There seemed to be a correlation between the depth of inverted T waves and the serum level of ferritin. It was, however, unlikely that toxic iron may have induced the hyperfunction of the thyroid gland.

Aged↗

Deferoxamine-induced bone dysplasia in the distal femur and patella of pediatric patients and young adults: MR imaging appearance.

OBJECTIVE: We investigated the MR imaging appearance of deferoxamine-induced bone dysplasia in the distal femur and patella in patients with thalassemia major. MATERIALS AND METHODS: Thirty-five patients with homozygous ss-thalassemia major who were undergoing regular transfusions and chelation therapy underwent coronal T1-weighted MR imaging of the femur, including the femoral head and the distal femoral epiphysis. Additional coronal fat-saturated dual-echo and sagittal T1-weighted images of the distal femur and patella were obtained in 11 patients who were suspected of having distal femoral lesions on the basis of the coronal T1-weighted images of the entire femur. RESULTS: No dysplastic change was detected in the proximal femur on coronal T1-weighted images. In 22 distal femurs of 11 patients, the following abnormalities were detected on MR imaging: blurred physeal-metaphyseal junction (n = 22), distal metaphyseal areas of hyperintensity (n = 21), physeal widening (n = 18), metadiaphyseal lesions (n = 11), epiphyseal lesions (n = 10), and patellar lesions (n = 2). Physeal widening and distal metaphyseal hyperintense areas were all more pronounced peripherally. Of the 21 distal metaphyseal hyperintensities, lateral abnormalities were larger than medial abnormalities in 16. Of the 18 distal femurs in which physeal widening was detected, the lateral widening was more marked than the medial widening in 12. Patients with MR imaging evidence of bone dysplasia have a significantly (p = 0.003) greater height reduction than patients without such evidence of bone dysplasia. CONCLUSION: Deferoxamine-induced bone dysplasia in the distal femur and patella is represented by a spectrum of morphologic changes in the epiphysis, physis, metaphysis, and metadiaphysis on MR imaging.

Adolescent↗

Citric, malic and succinic acids as possible alternatives to deferoxamine in aluminum toxicity.

The effect of repeated intraperitoneal administration of deferoxamine, citric, malic and succinic acids on the distribution and excretion of aluminum was determined in male Swiss mice which had previously received aluminum nitrate intraperitoneally at a daily dose of 0.27 mmol/kg for five weeks. Chelating agents were administered for two weeks at doses approximately equal to one-fourth of their respective LD50. Treatment with DFOA, citric, malic or succinic acids significantly increased the fecal and urinary excretion of aluminum and reduced the concentration of aluminum found in various organs and tissues, with citric acid being the most effective. In sight of these results, citric, malic or succinic acids may be considered as alternatives to deferoxamine in aluminum toxicity. However, further investigations are required previous to the possible use of these compounds in human aluminum poisoning.

Aluminum↗

Growth of Escherichia coli in whole and skim milk from endotoxin-induced mastitic quarters: in vitro effects of deferoxamine, zinc, and iron supplementation.

A marked growth inhibition of Escherichia coli 0101 K99 F41 was observed in whole and skim milk collected from inflamed quarters 18 and 36 h after intramammary administration of .1 mg E. coli lipopolysaccharide. Individual cow variation in the ability of milk from endotoxin-infused quarters to inhibit growth of E. coli was found. Growth inhibition of E. coli was observed in milk from endotoxin-infused quarters and was most pronounced in skim milk sampled at postinfusion h 18, and incubated at 38 degrees C. The mechanism by which bacterial growth was depressed was probably of noncellular origin. Addition of Fe (45.5 micrograms/ml) and Zn (2.7 micrograms/ml) to whole and skim milk sampled from inflamed quarters at 18 h after endotoxin infusion resulted in a growth-promoting effect. Addition of deferoxamine (6 mg/ml) depressed bacterial growth. Effects of Fe, Zn, and deferoxamine on bacterial growth did not differ in whole and skim milk. No clear relationship was observed between reduction in Zn concentrations in skim milk from inflamed quarters at 18 h after endotoxin infusion and growth inhibition of E. coli in the same samples.

Animals↗

[Experimental research on the use of deferoxamine in the prevention of renal damage from acute ischemia].

Oxygen free-radical reperfusion products play a critical role in postischemic tissues injury. In this study we used deferoxamine, an iron ligand that seems to inhibit hydroxyl radicals production, in renal normothermic acute ischemia in the rat. Our results demonstrated a significant protective effect of deferoxamine on kidneys subjected to normothermic acute ischemia.

Acute Disease↗

Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload.

We compared 48-hour urinary iron excretion after a twice-daily subcutaneous bolus injection of deferoxamine and after 12 hours of subcutaneous continuous infusion of the drug in 27 patients with iron overload (mean age, 55.7 years). In most patients, the iron overload was due to multiple transfusions administered during chemotherapy or as part of supportive care for a hematologic or oncologic disorder. One patient had sickle cell anemia and 1 had hereditary hemochromatosis and spherocytosis. Similar urinary iron excretion was observed with the 2 methods of administration; mean +/- SD values were 6935.3 +/- 3832.3 microg/48 hours with subcutaneous bolus injection and 6630.4 +/- 3606.9 microg/48 hours with subcutaneous continuous infusion (P =.3). Twenty-six patients (96.3%) chose to continue therapy with bolus injection. The long-term efficacy of bolus injection was evaluated by measuring the serum ferritin concentration at regular intervals for a follow-up time of 20.1 +/- 4.5 months. Ferritin concentration decreased to below 1000 microg/L in 73% of the patients and to below 500 microg/L in 42% and became normal in 26%. Best results were obtained in patients who were no longer receiving blood transfusions when chelation therapy was initiated. Three of 26 patients (11.5%) had mild, transient side effects after bolus injection. Larger prospective, randomized studies must be conducted before deferoxamine bolus injection can be routinely recommended for patients with iron overload. (Blood. 2000;95:2776-2779)

Adult↗

[Deferoxamine protects against gentamicin ototoxicity].

OBJECTIVE: To study the prevention of gentamicin(GM) ototoxicity by deferoxamine(DFO) in the guinea pig. METHODS: Guinea pigs were randomly assigned to three experimental groups (GM-treated alone, DFO-treated alone, GM and DFO in combination) and one control group. Acoustic brainstem response (ABR), the surface preparation and transmission electron microscopy were utilized to evaluate the hearing thresholds and the cochlear morphology. To explore the mechanism associated with deferoxamine protection, serum levels of GM, BUN and Cr, together with concentration of MDA, SOD and iron in cochlear and renal tissues were measured. RESULTS: The GM group developed up to 40-60 dB of the threshold shifts at 8 kHz while the GM + DFO group developed only 15-25 dB of the threshold shifts (P < 0.05). Moorphological changes were consistent with functional changes. DFO did not alter serum levels of GM. Renal function of GM group was damaged obviously. However, changes of MDA, SOD and iron were not significant (P > 0.05). MDA and iron concentrations in cochlear tissue of the GM + DFO group were significantly lower than those in the GM group (P < 0.05) while SOD level was much higher than that in GM group. CONCLUSION: This study suggests that free radical and iron involve in GM ototoxicity and DFO may become a promising therapeutic agent that can be used to reduce gentamicin ototoxicity.

Animals↗

Gallium-labeled deferoxamine-galactosyl-neoglycoalbumin: a radiopharmaceutical for regional measurement of hepatic receptor biochemistry.

Galactosyl-neoglycoalbumin (NGA) is a synthetic ligand to the hepatocyte-specific receptor, hepatic binding protein. In-vitro and in-vivo characterization of a chelation-based derivative of NGA, deferoxamine-galactosyl-neoglycoalbumin (DF-NGA), is described. A two-step glutaraldehyde method was used to covalently couple deferoxamine (DF) to NGA. Products with an average DF-to-NGA ratio of less than 2 contained less than 3% polymeric DF-NGA. All products retained the chelator after 12 mo of storage at 4 degrees C. Gallium labeling of DF-NGA-41 (41 galactose units per HSA) with an average of 1.1 DF per NGA was quantitative within 15 min after the addition of 67Ga-citrate. The labeled product was stable for at least 24 hr. Scatchard and reverse-binding assays of 67Ga-DF-NGA-41 revealed a forward binding rate constant kb similar to that of 125I-NGA-44. The %ID of 67Ga-DF-NGA-41 in rabbit liver was approximately 90% at 10 min after injection of 1.2 x 10(-9) mole DF-NGA per kilogram of body weight. This value decreased to 40% at a scaled molar dose of 1.2 x 10(-7) mol/kg. Biodistribution data of 67Ga-DF-NGA in rabbits was similar to 99mTc-NGA. High tissue specificity and facile labeling will make 68Ga-labeled neoglycoalbumin an ideal agent for regional measurements of receptor biochemistry in the investigational and clinical setting.

Albumins↗

Toxic effects of high-dose deferoxamine treatment in patients with iron overload: an electrophysiological study of cerebral and visual function.

BACKGROUND AND METHODS: It is well known that deferoxamine (DFO) treatment in thalassemia major can produce ocular toxicity. In one experience, Visual evoked potentials (VEPS) to pattern reversal were formed to be altered in 4 out of 10 patients under conventional treatment with DFO, before supplementary high-dose i.v. deferoxamine. In all 4 cases the alterations consisted of bilaterally delayed P100 latency, always obtained by stimulation with high spatial frequency (15' checks) and associated in three cases with low spatial frequency (55'). Computerized EEG (cEEG) studies showed a generalized increase of slowing activity. All patients underwent high-dose DFO treatment. RESULTS: At the control performed at the end of treatment in all 4 cases with previous VEP alterations, a further delay in P100 latency was observed bilaterally while two of the six patients, without previous involvement, showed delayed responses when using checks of 15'. The EEG slowing activity was not modified. Three weeks after terminating i.v. DFO therapy, the patients were still under subcutaneous treatment (50 mg/kg/day); a more evident VEP recovery towards the initial values was observed in those patients without initial alterations. No significant changes were found between electrophysiological parameters and serum ferritin levels. CONCLUSIONS: Our results indicate that high-dose DFO therapy in patients with iron overload induces reversible visual impairment without significant changes in brain electrical activity. The employment of VEP in intensive chelation programs in thalassemia major is discussed.

Adolescent↗

In vivo effects of repeated exposure of human neuroblastoma cell lines to deferoxamine.

Using an in vitro cytotoxicity assay method we examined the effects of three repeated exposures to 33 microM Deferoxamine on human neuroblastoma cell lines SK-N-DZ and VA-N-BR. There were no changes in cytolytic or cytostatic sensitivities in either cell line when compared to first time exposure. We conclude that tumor cell sensitivity may not be altered during repetitive spaced courses of deferoxamine in the clinical setting.

Cell Division↗

[The possible therapeutic effect of deferoxamine in experimental infections of mice by Plasmodium berghei].

Deferoxamine is a compound with iron chelating properties. Body depletion of this mineral, according to some authors, might influence the metabolism of plasmodia that thrive in the erythrocytes. In order to verify this possibility, we administered daily doses of 300 or 1.000 mg/kg of the compound, for five days and again 15 days, to mice infected with Plasmodium berghei. The parameters used to check the activity of deferoxamine were mortality of the animals and the count of blood parasites. The results showed a progressive increase of mortality and of the parasitemia in all animals, without differences in relation to the controls. So, at least on hand of the present study, the mentioned substance cannot be considered useful for the treatment of malaria.

Animals↗

[Intravenous administration of deferoxamine in over-night hospitalization: efficacy and good psychological tolerance in thalassemic children].

Daily subcutaneous infusion of deferoxamine in thalassemia and other transfusion dependent-patients can successfully treat iron overload, but most patients, mainly young children and teenagers may not comply with this method. Experience with nightly intravenous infusion of deferoxamine (8 g) through a subcutaneous-port over 5 out of 21 days, is reported in 4 children with dramatic improvement in clinical status, ferritin levels and quality of life.

Adolescent↗