Effect Of Desferrioxamine Research Articles

EFFECT OF DIFFERENT VEHICLES ON HEPATO- PROTECTIVE EFFICIENCY OF DESFERRIOXAMNE IN RADIATED CARBON TETRACHLORIDE TREATED MICE

The effect of desferrioxamine (DFO) in different vehicle ( Aqueous and oily) against hepatotoxicity induced by carbon tetrachloride (CC14) in irradiated mice and irradiated carbon tetrachloride (IR-CCI4) in normal mice was investigated. A single dose of CC14 and IR-CCI4 (20 @/kg, i.p.) in irradiated mice (IR-mice) and normal mice induced hepatotoxicrty, manifested biochemically by significant elevation of serum enzyme activities, such as alanine trarsaminase (ALT, EC:2.6.1.2 ) and aspartate transaminase (AST, EC:2.6.1.1). Hepatotoxiaty was further evidenced by significant decrease of total sulfttydryl (-SH) content, and catalase (EC: 1.1 1.1.6) activrty in hepatic tissues and significant increase in hepatic lipid peroxidation measured as malondialdhyde (MDA). Pretreatment of normal mice and IR-mice with DFO (200 mg/kg i.p dissolved either in water or arachis oil vehicle) 1 h before CC14 or IR-CC14 injection ameliorated the hepatotoxicrty as evidenced by a significant reduction in the elevated levels of serum enzymes as well as a significant decrease in the hepatic MDA content and a significant increase in the total sulfhydryl content 24 h after CC14 or IR-CCI4 administration.. These results indicated that both of oily and watery DFO can effectively ameliorated the hepatotoxicity induced by CC14 in IR-mice or IR-CC14 in normal mice. Although, the efficiency of the hepatoprotective effect of DFO in oily vehicle was higher than that DFO in aqueous vehicle. The hepatoprotective effect of DFO possibly through inhibition of the production of oxygen free radicals that cause lipid peroxidation.

Effects of iron and iron chelation in vitro on mucosal oxidant activity in ulcerative colitis.

Reactive oxygen species may be pathogenic in ulcerative colitis. Oral iron supplements anecdotally exacerbate inflammatory bowel disease and iron levels are elevated in the inflamed mucosa. Mucosal iron may enhance hydroxyl ion production via Fenton chemistry. Conversely, the iron chelator, desferrioxamine, is reportedly beneficial in Crohn's disease. To assess the in vitro effects of exogenous iron and of iron chelators on the production of reactive oxygen species by colonic biopsies from normal control subjects and patients with ulcerative colitis. Luminol-amplified chemiluminescence was used to measure mucosal reactive oxygen species production both before and after addition in vitro of ferric citrate (100 microM), desferrioxamine (1 mM) and 1,10-phenanthroline (1 mM). Ferric citrate had no effect on the chemiluminescence produced by human colonic mucosa. However, desferrioxamine and phenanthroline reduced chemiluminescence by 47% (n=7, P=0.018) and by 26% (n=10, P=0.005), respectively, in inactive ulcerative colitis, and by 44% (n=9, P=0. 008) and 42% (n=11, P=0.006) in active disease. The lack of effect of ferric citrate suggests that sufficient free iron is already present in inflamed biopsies to drive the Fenton reaction maximally. The effects of desferrioxamine and 1,10-phenanthroline on the chemiluminescence of biopsies from patients with ulcerative colitis suggest that a clinical trial of topical iron chelation in active disease is indicated.

Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans

In cell culture, hypoxia stabilizes a transcriptional complex called hypoxia-inducible factor-1 (HIF-1) that increases erythropoietin (Epo) formation. One hallmark of HIF-1 responses is that they can be induced by iron chelation. The first aim of this study was to examine whether an infusion of desferrioxamine (DFO) increased serum Epo in humans. If so, this might provide a paradigm for identifying other HIF-1 responses in humans. Consequently a second aim was to determine whether an infusion of DFO would mimic prolonged hypoxia and increase the acute hypoxic ventilatory response (AHVR). Sixteen volunteers undertook two protocols: 1) continuous infusion of DFO over 8 h and 2) control. Epo and AHVR were measured at fixed times during and after the protocols. The results show that 1) compared with control, Epo increased in most subjects at 8 h [52.8 +/- 57.7 vs. 6.9 +/- 2.5 (SD) mIU/ml, for DFO = 4 g/70 kg body wt, P < 0.05] and 12 h (63.7 +/- 76.3 vs. 7.3 +/- 2.5 mIU/ml, P < 0.001) after the start of DFO administration and 2) DFO had no significant effect on AHVR. We conclude that, whereas infusions of DFO mimic hypoxia by increasing Epo, they do not mimic prolonged hypoxia by augmenting AHVR.

Effect of Desferrioxamine on Silica-Induced Pulmonary Reaction

Surface iron on a mineral particle may be a major mediator of mineral-dust-induced toxicity, because iron on the surface of the particle acts as a Fenton catalyst to produce hydroxyl radical from hydrogen peroxide. Desferrioxamine (DF), an iron chelator, might inhibit the process of silica-induced pulmonary reaction. To test this assumption, we investigated the protective effect of DF on lipid peroxidation of cell membrane, production of inflammatory cytokine, and fibroblast proliferation by crystalline silica for an in vitro model. The Fenton activity of silica was decreased by preincubation with DF. Marked decreases in malondialde-hyde (MDA) levels were seen in the DF-treated silica group compared with the untreated group. DF inhibited not only silica-induced release of tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) from A549, but also fibroblast proliferation. The therapeutic effect of DF on experimental silicosis in rat was also studied using total cell count with differential percentage in bronchoaiveoiar lavage fluid, the amount of hydroxyproline in lung, and examination of a histologic section. DF significantly reduced inflammation and fibrosis compared with the untreated control. From these results, we concluded that DF might play a role in the inhibition of silica-induced pulmonary reaction.

Effect of desferrioxamine on urinary copper and zinc excretion in β-thalassemia major patients

Effect of desferrioxamine on urinary copper and zinc excretion in β-thalassemia major patients

Effect of desferrioxamine on urinary copper and zinc excretion in ?-thalassemia major patients

Twenty-one β-thalassemia major patients were included to study urinary zinc and copper excretion before and after high dose desferrioxamine (DF). The mean basal zinc excretion (1193.72 ± 1079.64 μg/24 hr) was higher than the mean zinc excretion observed in controls (427.6 ± 74.37 μg/24 hr) (P < 0.001). There was no significant difference between urinary copper levels of patients (185.48 ± 175.45 μg/dl) and the control group (150.0 ± 37 μg/dl) (P > 0.05). No significant difference was observed between the mean basal zinc levels and zinc levels after treatment (1751.06 ± 1462.72 μg/24 hr) (P > 0.05). Although the mean copper excretion was decreased following DF treatment (164.16 ± 117.8 μg/dl), the difference was not significant (P > 0.1). There was a significant interaction for urinary copper and zinc excretion (r = 0.413; P < 0.05). J. Trace Elem. Exp. Med. 13:195–198, 2000. © 2000 Wiley-Liss, Inc.

Effect of desferrioxamine (DFO) and calcium trinatrium diethylenetriaminepentaacetic acid (DTPA) on rat cytomegalovirus replication in vitro and in vivo

Cytomegalovirus (CMV) infection is a major problem in the immunosuppressed patient. It is thought that besides direct CMV induced cell lysis, immunological damage is part of CMV pathogenesis. New antiviral drugs, which combine immunomodulating and antiviral qualities, could be beneficial. Recently, it has been described that desferrioxamine (DFO) and calcium trinatrium diethylenetriaminepentaacetic acid (DTPA) exhibit both properties. In this report the antiviral effects of both compounds against rat CMV (RCMV) are described in vitro and in vivo using a generalised and local infection model. In vitro , both compounds exhibited a significant antiviral effect, DTPA being more potent than DFO. However, in the generalised infection model no effect was seen on mortality, morbidity or presence of virus in internal organs. In rats infected subcutaneously in the hind paw, no effect was seen locally on paw thickness, presence of viral antigens and inflammatory response. In addition, these rats suffered from a generalised infection of low magnitude at 15 days post infection, although both DFO and DTPA were able to lower the level of viral replication. In conclusion, our data indicate that despite in vitro activity, in vivo usage of DFO or DTPA for acute CMV infection is not warranted.

Effect of Desferrioxamine in Acute Haemolytic Anaemia of Glucose-6-Phosphate Dehydrogenase Deficiency

The effectiveness of desferrioxamine (DFO) in ameliorating the severity of the acute haemolysis of glucose-6-phosphate dehydrogenase (G6PD) deficiency was studied in 167 children with G6PD deficiency during an acute haemolytic crisis. All patients received packed cell transfusion on admission if their Hb levels were <8 g/dl, which was repeated as needed. Eighty patients also received a single dose of DFO 30–40 mg/kg by slow intravenous infusion (DFO group). The remaining 87 children did not receive DFO (control group). The need for more than one transfusion was less frequent in the DFO group as compared to the control group (p = 0.01). The need for late transfusion (transfusion after 36 h of admission) was also less in the DFO group (7%) compared to 21% in the control group (p = 0.02). On average, children in the DFO group needed less packed red blood cells (16.5 ml/kg body weight) than the control group (22.8 ml/kg body weight) and the difference was highly significant (p = 0.0001). We conclude from this study that DFO in a small dose is effective in the treatment of acute haemolytic crises of G6PD deficiency. It shortens the duration of the crisis and decreases the amount of blood transfusion needed.

Effect of Desferrioxamine on Silica-Induced Cytotoxicity of A549 and Fibroblast Proliferation

Effect of Desferrioxamine on Silica-Induced Cytotoxicity of A549 and Fibroblast Proliferation

Effect of desferrioxamine and deferiprone (L1) on the proliferation of MG-63 bone cells and on phosphatase alkaline activity.

In the present work, we studied: (i) the effect of different doses of desferrioxamine and deferiprone on the proliferation of osteoblasts and the possible role of iron in this; and (ii) the effect of both chelators on the metabolic activity of these cells, using the quantification of alkaline phosphatase as an enzymatic marker of cellular activity or differentiation. Cellular proliferation was investigated at different concentrations of deferiprone and desferrioxamine, and the effect of the addition of iron citrate on this proliferation was measured. The production of alkaline phosphatase after incubation with deferiprone (150 and 300 microM) and desferrioxamine (20 and 100 microM) was also studied. Cellular proliferation was completely inhibited with 100 microM of desferrioxamine and 300 microM of deferiprone. In both cases, this effect was corrected by means of co-incubation with iron citrate. In the second phase, using the same dose that inhibited the proliferation, it was observed that after 24 h, both chelators slightly decreased alkaline phosphatase activity, while at 48 and 96 h they increased alkaline phosphatase activity. These results demonstrate that both desferrioxamine and deferiprone inhibit the proliferation of the osteoblast-like cell line MG-63; the effect seems to be related to the chelation of some fraction of available iron. In spite of the effect on bone cell proliferation, the chelators do not impair cellular activity.

The effect of desferrioxamine on the development of renal dysfunction in streptozotocin-induced diabetes.

The effect of desferrioxamine on the development of renal dysfunction in streptozotocin-induced diabetes.

Growth, puberty and endocrine function in beta-thalassaemia major.

Although delay in onset of puberty is a common cause of growth failure in adolescent thalassaemic patients, growth retardation could also be due to iron overload, the toxic effects of desferrioxamine, or the development of other endocrinopathies such as GH insufficiency or primary hypothyroidism. Abnormal body proportions with truncal shortening are commonly seen and could be due to the disease itself, iron toxicity, delay in puberty or the toxic effects of desferrioxamine. The absence of a pubertal growth spurt during spontaneous or induced puberty is detrimental to the achievement of a normal final adult height. Low serum IGF-I and normal GH reserve in short thalassaemic children imply that a state of relative GH resistance exists. The rise in IGF-I and improvement in growth with GH therapy suggest that this GH resistance is only partial. Although the results of short-term GH therapy are encouraging, the impact of treatment on final height of non-GH deficient short thalassaemic children remains uncertain. Multiple endocrinopathies, including hypogonadism, hypothyroidism and diabetes mellitus, occur mainly in older patients who tend to have high serum ferritin levels. Prognosis for survival is greatly improved if the serum ferritin is kept below 2000 micrograms/l by regular chelation. Chelation therapy initiated early before the accumulation of a significant iron burden or dosages of desferrioxamine in excess of 50 mg/kg/day should be avoided. Serum ferritin should be checked regularly and the "toxicity index" should be used to monitor chelation therapy. In cases of delayed puberty, sexual development should be induced at an appropriate age.

P-750 - Effect of desferrioxamine(DFX) on Ca2+-ATPase activity of Skeletal muscle sarcoplasmic reticuium: DFX radical and enzyme activity

P-750 - Effect of desferrioxamine(DFX) on Ca2+-ATPase activity of Skeletal muscle sarcoplasmic reticuium: DFX radical and enzyme activity

Effects of desferrioxamine on human cytomegalovirus replication and expression of HLA antigens and adhesion molecules in human vascular endothelial cells

Desferrioxamine (DFO), commonly used in therapy as a chelator of ferric ion in disorders of iron overload, is a potent inhibitor of human cytomegalovirus (HCMV) replication in cultured fibroblast cells. Moreover, DFO has immunomodulatory activity both in vitro and in vivo. We studied DFO effects on HCMV replication in cultured human endothelial cells and on the expression of several cell surface molecules, which mediate interactions of endothelial cells with other cell types in the immune system. The concentrations of DFO required for 50% reduction in the number of endothelial cells expressing HCMV late antigen, ranged for several HCMV strains from 5.2 to 8.8 μM. DFO concentrations ranging from 5 to 40 μM inhibited cellular DNA synthesis in a dose-dependent manner without any significant effects on the cell viability. DFO at 10 μM concentration suppressed expression of intercellular adhesion molecule-1 (ICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1), while it had no significant effect on the expression of vascular cell adhesion molecule-1 (VCAM-1). Expression of HLA class I and class II was not influenced by DFO treatment. The results showed that DFO is both effective in inhibition of HCMV replication and expression of ICAM-1 and ELAM-1 in endothelial cells, a combination that warrants attention to its potential use to prevent HCMV-induced allograft rejection in transplant recipients.

Inhibition of iron toxicity in rat and human hepatocyte cultures by the hydroxypyridin-4-ones CP20 and CP94

The protective effect of the hydroxypyridin-4-ones (CP20 and CP94) was studied on iron-loaded rat and human hepatocytes; desferrioxamine B was used as a chelator reference. Iron load was achieved by addition of 5 up to 50 μM iron citrate to the culture medium. One day after iron treatment, an increase in lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and malondialdehyde extracellular concentrations was measured in rat and human hepatocyte cultures. This enzyme release and the increase in free extracellular malondialdehyde were observed with 5 μM iron and high levels were obtained with 50 μM. The bidentate chelators CP20 and CP94 (150 μM) appeared to be as effective as the hexadentate chelator desferrioxamine (50 μM) in the protection of rat and human hepatocytes against the toxic effect of iron load achieved by culturing the cells for 1 day in the presence of 50 μM iron citrate. In rat and human hepatocytes cultured for 1 day in the pesence of 1 μM 55Fe-50 μM iron citrate plus CP20, CP94 or desferrioxamine B, a decrease of iron uptake by the cells was observed. When the hepatocytes were cultured for 1 day in the presence of 1 μM 55Fe-50 μM iron citrate and then for a further day in the presence of CP20, CP94 or desferrioxamine B but not iron, the chelators decreased the intracellular iron level, indicating their iron releasing effect from the loaded cells. The observed effects of the hydroxypyridin-4-ones CP20 and CP94 were as potent as the effect of desferrioxamine B.This study presents new data favoring the potential clinical interest of this new class of chelating agents in the treatment of human iron overload.

The effects of desferrioxamine and ascorbate on oxidative stress in the streptozotocin diabetic rat

Oxidative stress and protein glycation are closely related processes that may contribute to the development of complications in diabetes mellitus. Treatment with antioxidants could protect against these processes at a biochemical level, and we have therefore investigated the effects of ascorbate and desferrioxamine treatment in the streptozotocin diabetic rat. Diabetic animals were given ascorbate 1 g/l in drinking water or desferrioxamine 6 mg/kg/day by subcutaneous injection and were killed after 6 weeks. In diabetic animals, oxidative stress was increased as shown by increased levels of conjugated dienes (CD) in plasma and malondialdehyde (MDA) in plasma, erythrocyte membranes, and urine. In addition, there was depletion of the nutritional antioxidants ascorbate, alpha-tocopherol, and retinol. Insulin treatment returned all of these parameters to normal. Ascorbate supplementation or desferrioxamine treatment alone failed to reduce oxidative stress, but a combination of both interventions restored MDA, CD, and antioxidant vitamins to control values. Both ascorbate and desferrioxamine also reduced HbAlc and glycated albumin levels. Treatment with antioxidants can reduce both oxidative stress and protein glycation and may help to reduce the risk of developing diabetic complications. However, ascorbate can have both prooxidant and antioxidant effects in vivo, and its use in pharmacological doses should be approached with caution.

Effects of desferrioxamine on human cytomegalovirus replication and expression of HLA antigens and adhesion molecules in human vascular endothelial cells

Effects of desferrioxamine on human cytomegalovirus replication and expression of HLA antigens and adhesion molecules in human vascular endothelial cells

Effect of desferrioxamine on cisplatin-induced nephrotoxicity in normal rats.

Biochemical and histological evaluations of the effects of the iron chelator desferrioxamine on the nephrotoxicity induced by cisplatin in normal rats were carried out. A single dose of cisplatin (7.5 mg/kg, intravenously) caused nephrotoxicity that manifested biochemically as an elevation of blood urea nitrogen, serum creatinine and an increase in the kidney weight as a percent of body weight. Moreover, severe decreases in serum calcium and albumin were observed. Histopathological examination of kidney tissue revealed tubular necrosis with sloughing of tubular epithelium. Desferrioxamine treatment (250 mg/kg, intraperitoneally) 30 min before cisplatin administration does not protect the kidney from the damaging effects of cisplatin. A greater increase in blood urea nitrogen, serum creatinine and kidney weight was observed with significant tubular necrosis and a mild lymphocytic infiltrate. Desferrioxamine pretreatment decreased the lipid peroxidation induced by cisplatin but at the same time increased nonprotein sulfhydryl (-SH) concentrations in the kidney tissue. The findings of this study suggest that lipid peroxidation is not the main cause of cisplatin-induced nephrotoxicity and that desferrioxamine which was useful for prevention of cardiac and hematological damage induced by doxorubicin, aggrevated the cisplatin-induced nephrotoxicity. More investigations are needed to establish a definite assessment of its selectivity.

11 Control of disease by selective iron depletion: a novel therapeutic strategy utilizing iron chelators

Recognition of the central role of iron in the generation of toxic, oxygen-derived species through the Haber-Weiss reaction, the ability of desferrioxamine (DFX) to prevent the damage associated with free radical generation in reperfusion injury, and its inhibitory effect on cell proliferation by inactivation of the iron dependent enzyme ribonucleotide reductase, resulted in an increasing number of studies exploring the novel therapeutic applications of iron chelating drugs: (a) Animal models of reperfusion injury have shown that DFX is able to decrease post-anoxic damage to the brain and heart as manifested in decreased infarct size and improved functional recovery. Iron chelators may be particularly useful in improving the preservation of organs intended for transplantation such as the heart, lung or kidney. (b) Anthracycline cardiotoxicity is aggravated by iron and inhibited by iron chelators. Because the mechanism of its antineoplastic effect differs from its cardiotoxic effect, it is possible to inhibit anthracycline cardiotoxicity without interfering with therapeutic efficacy. In vivo and in vitro animal studies have yielded encouraging results but much additional experimental work is still required before iron chelating therapy may be advocated for use in patients on anthracycline therapy. (c) Cell proliferation can be inhibited by iron chelators through the reversible inhibition of ribonucleotide reductase, a rate-limiting enzyme in DNA synthesis. This may be exploited for the treatment of malignant disease, and preliminary studies have already shown that DFX in combination with multidrug chemotherapy is effective in controlling neuroblastoma and other tumours. However, the contribution of DF to the overall clinical effect is unclear. Prospective controlled clinical studies are required in order to establish whether the antiproliferative, or cell synchronizing properties of DFX may be of practical usefulness in the control of malignant disease. (d) Control of protozoal infection: Experimental in vivo and in vitro models have shown that malarial infection may be inhibited by iron chelating therapy. This useful effect of DFX and other iron chelators is most probably related to ribonucleotide reductase inhibition. Clinical studies of asymptomatic P. falciparum malaria and of cerebral malaria have shown both an accelerated rate of parasite clearance and earlier recovery from coma. These observations lend new meaning to the term 'nutritional immunity' and open new channels for exploring the possibility of controlling infection by means of selective intracellular iron deprivation. Experimental models for studying the effect of iron chelators on other intracellular pathogens such as Toxoplasma gondii, Chlamydia psittaci, or Mycobacterium tuberculosis should be established.(ABSTRACT TRUNCATED AT 400 WORDS)

The protective effect of desferrioxamine on paraquat‐treated pea (Pisum sativum)

Paraquat, a widely used herbicide, is photoreduced by photosystem I to the monovalent cation radical, which in turn, can react quickly and efficiently with molecular oxygen to produce superoxide anion radicals. In the presence of redox‐active iron (or copper) superoxide radicals can serve as a source for the more active species such as hydroxyl radicals. The present sludv investigated the possible mediatory role of iron in paraquat to xicity. The results demonstrate that desferrioxamme (0–150μM) a highiy specific iron chelator, reduces the loss of proteins (by 34–69%) and lipid peroxidation (by 31–96%) in paraquat treated leaf cuts. Dcsferrioxamine also protects malate dehydrogenase (61–70%) hydroxvpyruvate reductase (54–100%), and Ca2+‐dependent ATPase (25–34%) against the paraquat‐induced loss of their activity. It also induces an increase in glutathione reductase activity (by 188%). These results, together with those from other experiments concerning the effect of desferrioxamine on paraquat uptake by the leaf cuts, suggest that the protection by desferrioxamine arises from its specific iron chelanon properties, and lead to the conclusion that nan‐protein‐bound and redoxactive forms of iron pluy a role in the manifestation of paraquat toxicity in plants.