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Effect of the iron chelator deferoxamine on Trichomonas vaginalis in vitro.

The effect of 10 microMol, 15 microMol, 30 microMol, and 60 microMol concentrations of deferoxamine (DFO), a clinically approved iron chelator, was determined on viability and multiplication of Trichomonas vaginalis grown in TYM axenic culture medium at 24 hours interval. DFO killed all T. vaginalis isolates with a minimum lethal concentration of 30 microMol after 48 hours culture incubation with the drug. A potent and persistent inhibitory effect of DFO on the parasite viability and multiplication was recorded throughout the study till its end, in a drug concentration and time exposure-dependent manner. Furthermore, the present work studied the proteinase activity of T. vaginalis grown for 48 hours in DFO inoculated TYM medium, and recorded a significant decrease by all drug concentrations applied in the work. Different possible mechanisms of action of DFO against T. vaginalis and its possible use for treatment of trichomoniasis are discussed.

Animals↗

Effect of deferoxamine alone and combined with pyrimethamine on acute toxoplasmosis in mice.

The standard regimen of treatment for toxoplasmosis is pyrimethamine with sulfadiazine. However, it is not suitable in some conditions, and nontolerable in AIDS patients. Deferoxamine (DFO), an iron chelator, is well tolerated clinically in transfusion induced - iron overload. The present study had shown that DFO is a promising drug against acute toxoplasmosis in mice. Three doses of 200, 300 and 400 mg/kg DFO were used either alone or in combination with pyrimethamine. Alone, it was effective in a dose- related response with the resultant of 70% protection of infected mice. When DFO was combined with a low minimally effective dose of pyrimethamine, a 100% protection was recorded with the prolongation in duration of survival of mice. Different possible mechanisms of action of DFO against Toxoplasma gondii were discussed.

Acute Disease↗

Deferoxamine effect on selenite-induced cataract formation in rats.

A single subcutaneous dose of 30 nmol of sodium selenite per gram of body weight in 13-day-old rats resulted in posterior subcapsular cataract (PSC) after 24 hr and bilateral nuclear cataracts at 72-96 hr. Within 24 hr of treatment, a 60% decrease in lens glutathione was seen. A loss of calcium homeostasis observed by 48 hr resulted in increased lens calcium (4 mumol/g dry weight), which accompanied nuclear opacification. The iron chelator, deferoxamine (DF), was evaluated as a potential protective agent against these selenite-induced changes. Three doses each consisting of 1.1 mumol DF/g body weight were administered during the initial 24 hr of selenite exposure. Within 96 hr, all lenses from animals treated only with DF remained transparent, but 50% of these lenses showed cortical cataract at 3 wk postinjection. Concurrent administration of DF and selenite protected 80% of rats against PSC after 48 hr and 25% against nuclear cataract after 96 hr. No elevation in lens calcium occurred in the protected lenses. An additional 20% of animals were not protected fully but showed substantially less nuclear opacity than with selenite alone. They had a significant but moderate increase in lens calcium. After 3 wk (animal age, 35-40 d), cataract appeared in these "protected" lenses involving both the nucleus and cortex and loss of ion homeostasis. The glutathione content remained lower in lenses from animals treated with both selenite and DF compared with those from selenite-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Deferoxamine (Desferal) improves the content of oxygen in myocardial tissues during recovery after hypoxia in isolated rabbit heart.

On isolated working right heart from rabbit tissue oxygen content as an indicator of function of oxygen transport and storage was observed by moderate hypoxia, hypoxia with deferoxamine (1) and iron infusion. In addition water content of myocardium as an indicator of metabolic damage was evaluated and the copper depletion was established. During the recovery the results presented a beneficial effect on the content of tissue oxygen which is due to 1. But the copper depletion was not changed. Possible connections are discussed.

Animals↗

[Effect of combination of Ginkgo leaf extract and deferoxamine in preventing and treating ototoxicity of cisplatin].

OBJECTIVE: To observe the effect of combined use of jinnaduo (an injection made by extract of Ginkgo leaf, EGb) and Deferoxamine (DFO, a chelating agent) in antagonizing the ototoxicity of cisplatin (CDDP). METHODS: Guinea pigs were randomly divided into the CDDP group, the EGb group, the DFO group, the combined treated group (EGb + DFO) and the control group. Changes of auditory brain-stem response (ABR), serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) content, as well as light and scanning electronic microscopic (SEM) figures were observed before and after treatment. RESULTS: The threshold of ABR was significantly higher in the CDDP group than that in the other groups (P<0.01), but was insignificantly different among the latter groups (P>0.05). Serum SOD activity was lower and MDA content was higher in the CDDP group than those in the control group (P<0.01), but in comparison of the two parameters between control and other groups, the difference was insignificant (P>0.05). SEM examination on cochlea showed that the damage of hair cells was milder in the DFO group and the combined treated group than that in the CDDP group, which was slightly milder in the EGb group than that in the CDDP group. CONCLUSION: Combined use of EGb and DFO could effectively reduce the ototoxicity of CDDP, its effect is better than using EGb singly, and similar to that of using DFO alone. The combination could also prevent the side-effect of CDDP in bone marrow inhibition. The Fe ion participated free radical response could be one of the mechanisms of CDDP in damaging hearing.

Animals↗

A comparison of the iron-clearing properties of 1,2-dimethyl-3-hydroxypyrid-4-one, 1,2-diethyl-3-hydroxypyrid-4-one, and deferoxamine.

A comparative study of the iron-clearing properties of subcutaneously (SC) administered deferoxamine (DFO) with those of orally administered 1,2-dimethyl-3-hydroxypyrid-4-one (CP20) and 1,2-diethyl-3-hydroxypyrid-4-one (CP94) is presented. The studies were performed in both a non-iron-overloaded, bile duct-cannulated rat model and an iron-loaded Cebus monkey model. All three drugs performed well in the rodent, promoting the excretion of iron in both the urine and the bile, with total iron output efficiencies of 2.8%, 1.2%, and 7.1%, respectively. The efficiency of DFO increased slightly in the Cebus model, while that of the hydroxypyridones was essentially the same in the monkey, with total iron output efficiencies of 5.5%, 2.1%, and 7.4%, respectively. Iron balance studies showed that both DFO and CP94 were able to maintain the animals in a negative iron balance, while CP20 had little impact.

Animals↗

[Ototoxicity of deferoxamine].

Deferoxamine or desferrioxamine (DFO) is a chelating agent, largely used in patients with chronic renal failure, although it has many side effects, being ototoxicity one of them. In this paper we studied the eventually adverse otologic effects of DFO in 20 patients receiving haemodialysis. A complete audiological evaluation, including pure-tone audiometry, brainstem auditory evoked potentials and high-frequency audiometry, was performed. The results showed a sensorineural hearing loss of retrocochlear origin in 3/20 cases (15%). We can accept that ototoxic effects of DFO are minimal, but no inexistent. Because of these we considered highly recommendable an accurate control of hearing in patients with renal disease receiving DFO.

Adult↗

Subcutaneous bolus injection of deferoxamine is an alternative method to subcutaneous continuous infusion.

The objective of this study was to compare the short- and long-term efficacy of deferoxamine (DFO) given by subcutaneous (SC) continuous infusion over 10 hours via a pump (n = 10) versus a twice-daily subcutaneous bolus injection of the same overall dose (n = 10) in 20 thalassemic children. Urinary iron excretion was measured in 24-hour urine samples after DFO treatment in the 20 patients. The patients were randomized to two groups: 10 patients continued SC continuous infusion with a pump and the remaining 10 received the same overall dose of DFO by twice-daily SC bolus injection for a year. Serum ferritin levels and T1-weighted spin-echo and T2-weighted fast spin-echo signal intensities of liver and paraspinal muscle were determined at initiation and 1 year after initiation of the therapy. In 12 patients, six from each group, liver biopsies were performed and hepatic iron concentration was determined at initiation of therapy and 1 year after treatment. A similar and significant decrease in ferritin levels and improvement in signal intensities of the liver were observed in response to chelation therapy with DFO in both groups (P < 0.01, within each group). Hepatic iron concentration decreased in all patients in the SC bolus injection group (P < 0.05) and in four patients in the SC continuous infusion group (P > 0.05). Hepatic iron concentration was noted to be slightly increased in two patients in the SC continuous infusion group, which may be due to poor compliance. Based on these results, twice-daily SC bolus injection of DFO is as effective as administration via SC continuous infusion using a pump. Subcutaneous bolus injection, being more convenient for the patient, may be a more preferable method of DFO administration.

Adolescent↗

[Deferoxamine induces apoptosis of HL-60 cells by activating caspase-3].

This study was purposed to observe the changes of caspase-3 activity during apoptosis of HL-60 cells induced by an iron chelator, DFO (deferoxamine), and to explore the mechanism underlying apoptosis in HL-60 cells. The HL-60 cells treated with DFO were examined by light microscopy, flow cytometry (FCM) and DNA agarose gel electrophoresis; the activity of caspase-3 was determined by cellular immunohistochemistry; the transcription of the apoptotic gene of bax was detected by hybridization in situ. The results showed that the typical morphological character of apoptosis cells, DNA ladder and FCM assay confirmed that DFO could induce the apoptosis in HL-60 cells. The apoptotic rate increased in dose-and time-dependent manner. When cells had been cultivated with 100 micromol DFO for 12 hours, a few caspase-3 positive cells were found. In the process of time, the rate of caspase-3 positive cells was progressively higher than that in control (P < 0.05), while the level of bax transcription was also higher than that in the control. It is concluded the activation of caspase-3 and gene bax may be involved in the apoptosis of HL-60 cells induced by DFO.

Apoptosis↗

Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload.

BACKGROUND AND OBJECTIVES: Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferoxamine (Desferal, DFO) reduces morbidity and mortality although the administration schedule of slow, parenteral infusions several days each week limits compliance and negatively affects long-term outcome. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. In a phase II study, the tolerability and efficacy of deferasirox were compared with those of DFO in 71 adults with transfusional hemosiderosis. DESIGN AND METHODS: Patients were randomized to receive once-daily deferasirox (10 or 20 mg/kg; n=24 in both groups) or DFO (40 mg/kg, 5 days/week; n=23) for 48 weeks. Results. Both treatments were well tolerated and no patient discontinued deferasirox due to drug-related adverse events. The reported frequency of transient, mild to moderate gastrointestinal disturbances was higher in the deferasirox group than in the DFO group, but these disturbances settled spontaneously without dose interruption in all patients. Decreases in liver iron concentration (LIC) were comparable in the deferasirox 20 mg/kg/day and DFO groups; baseline values of 8.5 and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw, respectively, by week 48. Deferasirox showed a plasma elimination half-life of 8-16 hours, supporting its once-daily administration. INTERPRETATION AND CONCLUSIONS: Deferasirox at daily doses of 10 or 20 mg/kg was well tolerated and, at 20 mg/kg, showed similar efficacy to DFO 40 mg/kg in terms of decreases in LIC.

Adolescent↗

The effects of subcutaneous deferoxamine administration on renal function in thalassemia major.

To assess the effects of deferoxamine (DFO) on the kidneys, we studied 27 patients with thalassemia major on chronic subcutaneous (s.c.) DFO therapy. In 41% of the patients glomerular filtration rate (GFR) values were above the normal range. In a previous study similar findings were reported for thalassemia patients who did not receive DFO. The subcutaneous administration of DFO was associated with a clinically significant decrease in GFR in 40% of the patients and in a mild decrease in another 40%. In all cases of severe decreases in GFR, it tended to return to baseline values upon discontinuation of DFO. There was a significant increase in urine volume during DFO therapy. These changes are consistent with our previous observation in humans and dogs receiving high dose i.v. DFO, albeit milder.

Adolescent↗

The antibacterial activity of a siderophore. 2. The influence of deferoxamine alone and combined with ascorbic acid on the activity of antibiotics against Staphylococcus aureus.

The in vitro activity of deferoxamine (DFO) combined with cephalothin, gentamicin, cefotaxime, vancomycin, and fusidic acid, in the presence or absence of the reductant ascorbic acid (AA) was investigated against Staphylococcus aureus by a macrobroth dilution technique and killing curve kinetics. DFO and in particular DFO + AA lowered the MICs of cephalothin, gentamicin, cefotaxime, and fusidic acid for most of the strains and in some instances also the MICs of vancomycin. To characterize the interaction between DFO or DFO + AA and antimicrobials we applied the growth constants of logarithmic growth phase. Generally DFO acted synergistically with cephalothin, gentamicin, vancomycin, and fusidic acid, particularly in the presence of AA, and in some cases synergy was demonstrated with cefotaxime, too.

Anti-Bacterial Agents↗

Comparative iron mobilizing actions of deferoxamine, 1,2-dimethyl-3-hydroxypyrid-4-one, and pyridoxal isonicotinoyl hydrazone in iron hydroxamate-loaded mice.

A comparison was made of the actions of deferoxamine (DFX), 1,2-dimethyl-3-hydroxypyrid-4-one (L1), and pyridoxal isonicotinoyl hydrazone (PINH) in mobilizing and promoting excretion of iron in mice loaded with iron-acetohydroxamic acid complex. DFX was given ip, while L1 and PINH were given po. Each was given daily for four days at 300 mg/kg/day, and total excreta were collected 24 hr after each administration. Total iron excreted over the 4-day period, expressed as micrograms/mouse, were: Controls, 26; PINH-treated, 31; DFX-treated, 162; and L1-treated, 208. Measurements of iron in selected organs 96 hr after the last administration of each compound revealed that treatment with L1 and DFX induced significant reductions of iron concentrations in kidneys (16% and 17%, respectively) and in pancreas (18% and 19%, respectively). In addition, L1 treatment led to a significant reduction in the liver iron burden (11%), an action not seen after treatment with DFX. None of the compounds reduced iron concentrations in heart, the most critical organ for toxicity of transfusional siderosis. The synthetic routes for preparation of L1 and PINH are described in detail.

Animals↗

An approach for immunoradiometric assay with metallic radionuclides: gallium-67-deferoxamine-dialdehyde starch-IgG.

Radiogallium (Ga) labeling of an immunoglobulin-G-deferoxamine conjugate (DF-IgG) to a high-specific radioactivity was performed to allow the development of a radiometallic immunoradiometric assay (IRMA) system. To increase the specific radioactivity of Ga-DF-IgG, we used dialdehyde starch (DAS) as a multi-site spacer for the binding of DF to IgG. Six DF molecules bound to each IgG molecule after DAS conjugation. DF-DAS-IgG was then labeled with the previously reported 67Ga labeling solution, producing labeled IgG with a specific radioactivity of 11,766 MBq/mg IgG. Using this method, we labeled an anti-CA125 tumor-associated antigen monoclonal antibody (130-22), allowing the first application of 67Ga-DF-DAS-IgG to an IRMA system. With this system, a higher sensitivity could be obtained than with 125I IRMA. In addition, a very high correlation (r = 0.995) was obtained between serum CA125 levels as determined by 67Ga IRMA and 125I IRMA. Gallium-67-labeled antibodies with a high-specific radioactivity appear to hold promise for use in highly sensitive radioassay systems.

Antigens, Tumor-Associated, Carbohydrate↗

Correction of haemodialysis-associated anaemia by deferoxamine. Effects on serum aluminum and iron overload.

Aluminium and iron overload is often seen among long-term haemodialysis patients. Untreated non-de-aluminized dialysis water or the intake of large amounts of aluminium hydroxide as phosphate binders are the most common reasons for hyper-aluminaemia. Iron overload is mainly a result of multiple blood transfusions given to correct renal anaemia. In chronic dialysis patients, hypochromic anaemia is one of the clinical manifestations of a long-term overload of aluminium and perhaps of other metals, e.g. iron. We used deferoxamine (DFO) to chelate aluminium and excessive iron in 17 patients on chronic haemodialysis. Two grams of DFO was administered weekly in the form of an i.v. infusion during the last hour of the dialysis session. The mean serum aluminum concentration decreased from 407.3 micrograms/l to 184.2 micrograms/l within 3 years of treatment, the mean serum ferritin concentration from 1,563 micrograms/l to 487 micrograms/l within 2 years. Anaemia was corrected concomitantly with an increase in the haemoglobin level, which rose from 71.7 g/l to 80.8 g/l. The mean corpuscular volume increased from 83.8 fl to 91.3 fl. The need for blood transfusion also decreased significantly in all patients after the institution of DFO therapy. The clinical manifestations of aluminium and iron overload disappeared and the quality of life improved. No major side-effects were observed.

Adult↗

Mucorales and deferoxamine: from saprophytic to pathogenic state.

Rhinocerebral mucormycosis can be a rapidly fatal course disease if the institution of treatment is delayed. We describe a case of a long-term dialysis patient in which the role of a siderophore such as Deferoxamine in promoting mucormycosis is discussed. The frequent lack of early diagnosis, itself subsequent to a break away from the standard diagnostic tools (apart from biopsy and culture) makes the survival prognosis particularly critical.

Deferoxamine↗

Failure of deferoxamine to improve iron overload in chronic hemodialysis patients.

We prospectively studied the in vivo dialytic clearance of iron after deferoxamine (DFO) administration in four stable iron-overloaded chronic hemodialysis patients by quantifying iron concentration in blood entering and leaving the dialyzer and in dialysate after infusions of DFO. No significant arteriovenous iron differences were demonstrated. The mean ratio of venous to arterial iron approached identity at 1.005. All dialysate concentrates used contained large amounts of iron (300-610 micrograms/dl). No changes in efferent versus afferent dialysate iron concentration could be demonstrated. We conclude (a) iron removal during dialysis with DFO was not demonstrated; (b) the dialysate concentrate tested contained large amounts of iron; (c) in view of potentially significant toxicity, and lack of demonstrable therapeutic benefit, caution in prescribing DFO chelation therapy for iron overload is recommended.

Deferoxamine↗