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At least 19 recordsLinked to original sources

PubMed2003

Benefits and risks of deferiprone in iron overload in Thalassaemia and other conditions: comparison of epidemiological and therapeutic aspects with deferoxamine.

Deferiprone is the only orally active iron-chelating drug to be used therapeutically in conditions of transfusional iron overload. It is an orphan drug designed and developed primarily by academic initiatives for the treatment of iron overload in thalassaemia, which is endemic in the Mediterranean, Middle East and South East Asia and is considered an orphan disease in the European Union and North America. Deferiprone has been used in several other iron or other metal imbalance conditions and has prospects of wider clinical applications. Deferiprone has high affinity for iron and interacts with almost all the iron pools at the molecular, cellular, tissue and organ levels. Doses of 50-120 mg/kg/day appear to be effective in bringing patients to negative iron balance. It increases urinary iron excretion, which mainly depends on the iron load of patients and the dose of the drug. It decreases serum ferritin levels and reduces the liver and heart iron content in the majority of chronically transfused iron loaded patients at doses >80 mg/kg/day. It is metabolised to a glucuronide conjugate and cleared through the urine in the metabolised and a non-metabolised form, usually of a 3 deferiprone: 1 iron complex, which gives the characteristic red colour urine. Peak serum levels of deferiprone are observed within 1 hour of its oral administration and clearance from blood is within 6 hours. There is variation among patients in iron excretion, the metabolism and pharmacokinetics of deferiprone. Deferiprone has been used in more than 7500 patients aged from 2-85 years in >50 countries, in some cases daily for >14 years. All the adverse effects of deferiprone are considered reversible, controllable and manageable. These include agranulocytosis with frequency of about 0.6%, neutropenia 6%, musculoskeletal and joint pains 15%, gastrointestinal complains 6% and zinc deficiency 1%. Discontinuation of the drug is recommended for patients developing agranulocytosis. Deferiprone is of similar therapeutic index to subcutaneous deferoxamine but is more effective in iron removal from the heart, which is the target organ of iron toxicity and mortality in iron-loaded thalassaemia patients. Deferiprone is much less expensive to produce than deferoxamine. Combination therapy of deferoxamine and deferiprone has been used in patients not complying with subcutaneous deferoxamine or experiencing toxicity or not excreting sufficient amounts of iron with use of either drug alone. New oral iron-chelating drugs are being developed, but even if successful these are likely to be more expensive than deferiprone and are not likely to become available in the next 5-8 years. About 25% of treated thalassaemia patients in Europe and more than 50% in India are using deferiprone. For most thalassaemia patients worldwide who are not at present receiving any form of chelation therapy the choice is between deferiprone and fatal iron toxicity.

Deferoxamine↗

PubMed1998

Combined therapy with deferiprone and desferrioxamine.

In a proportion of transfusion-dependent patients iron chelation with daily doses of deferiprone of 75 mg/kg body weight (b.w.) is inadequate. The effects on iron status of increasing the daily oral dose of deferiprone and/or combining deferiprone therapy with subcutaneous infusions of desferrioxamine have been studied in 13 transfusion-dependent patients. Raising the daily dose of deferiprone in nine patients from 75 mg/kg to 83-100 mg/kg resulted in a fall in serum ferritin in all nine patients (t test for paired samples, P = 0.0022). Combined therapy of daily deferiprone with subcutaneous desferrioxamine on 2-6 d each week in five patients (with an increased dose of deferiprone in three patients) resulted in a fall in serum ferritin in all five patients studied after 7-15 months (P=0.0791). No toxic side-effects attributable to either drug occurred in these five patients or in the nine patients in whom the dose of deferiprone was increased. The effects of the drugs given on the same day on urine iron excretion were additive. These results suggest that increasing the dose of deferiprone or combining subcutaneous desferrioxamine with deferiprone therapy are two methods by which efficacy of iron chelation with deferiprone can be improved in patients inadequately chelated by a daily dose of deferiprone of 75 mg/kg b.w. More extensive trials including full metabolic balance studies are needed to establish the safety and efficacy of long-term combined therapy.

Adolescent↗

PubMed1995

Changes in transferrin saturation after treatment with the oral iron chelator deferiprone in patients with iron overload.

AIMS: To evaluate the changes in transferrin saturation in patients with iron overload following the oral administration of the iron chelator deferiprone; to assess the correlation between the degree of transferrin desaturation, the deferiprone dose, and urinary iron excretion. METHODS: Serum samples were obtained from 16 patients with iron overload at different time intervals following the oral administration of deferiprone (50 mg/kg). These samples were analysed using 6M urea/polyacrylamide gel electrophoresis (UPAGE). This method is able to resolve serum transferrin into four different forms (free iron, two forms of monoferric, and diferric). The deferiprone concentration in these samples was estimated using high pressure liquid chromatography (HPLC). Zero time samples (t0) from 10 patients were incubated with 150 microM deferiprone or normal saline either at room temperature or at 37 degrees C for 30 minutes and 24 hours, and also at -20 degrees C for six weeks. Samples were then analysed using UPAGE. RESULTS: A maximum decrease in transferrin saturation from (mean (SD)) 93.0 (10.6)% to 54.5 (17.2)% was observed 72.5 (50.0) minutes after deferiprone administration and in most of the patients coincided with peak deferiprone concentration. This was associated with a maximum rise in the percentage of iron free transferrin (apotransferrin) from 2.9 (7.0)% to 27.3 (17.8)%. The total amount of iron estimated to be removed from transferrin constituted 21.3 (20.2)% of the 24 hour urinary iron excretion measured during the study. When deferiprone (150 mumol/l) was incubated in vitro with t0 samples from 10 patients for 30 minutes and 24 hours at room temperature, 37 degrees C, and at -20 degrees C for six weeks, deferiprone was more efficient at removing iron from transferrin at 37 degrees C, with maximum transferrin desaturation accomplished within 30 minutes compared with 24 hours at room temperature. CONCLUSIONS: The results confirm that deferiprone can remove iron from transferrin when administered orally to patients with iron overload and that transferrin bound iron may, therefore, be a significant source of the iron chelated by deferiprone in vivo.

Administration, Oral↗

PubMed1999

Deferiprone: a review of its clinical potential in iron overload in beta-thalassaemia major and other transfusion-dependent diseases.

UNLABELLED: Patients with beta-thalassaemia and other transfusion-dependent diseases develop iron overload from chronic blood transfusions and require regular iron chelation to prevent potentially fatal iron-related complications. The only iron chelator currently widely available is deferoxamine, which is expensive and requires prolonged subcutaneous infusion 3 to 7 times per week or daily intramuscular injections. Moreover, some patients are unable to tolerate deferoxamine and compliance with the drug is poor in many patients. Deferiprone is the most extensively studied oral iron chelator to date. Non-comparative clinical studies mostly in patients with beta-thalassaemia have demonstrated that deferiprone 75 to 100 mg/kg/day can reduce iron burden in regularly transfused iron-overloaded patients. Serum ferritin levels are generally reduced in patients with very high pretreatment levels and are frequently maintained within an acceptable range in those who are already adequately chelated. Deferiprone is not effective in all patients (some of whom show increases in serum ferritin and/or liver iron content, particularly during long term therapy). This may reflect factors such as suboptimal dosage and/or severe degree of iron overload at baseline in some instances. Although few long term comparative data are available, deferiprone at the recommended dosage of 75 mg/kg/day appears to be less effective than deferoxamine; however, compliance is superior with deferiprone, which may partly compensate for this. Deferiprone has additive, or possibly synergistic, effects on iron excretion when combined with deferoxamine. The optimum dosage and long term efficacy of deferiprone, and its effects on survival and progression of iron-related organ damage, remain to be established. The most important adverse effects in deferiprone-treated patients are arthropathy and neutropenia/agranulocytosis. Other adverse events include gastrointestinal disturbances, ALT elevation, development of antinuclear antibodies and zinc deficiency. With deferiprone, adverse effects occur mostly in heavily iron-loaded patients, whereas with deferoxamine adverse effects occur predominantly when body iron burden is lower. CONCLUSION: Deferiprone is the most promising oral iron chelator under development at present. Further studies are required to determine the best way to use this new drug. Although it appears to be less effective than deferoxamine at the recommended dosage and there are concerns regarding its tolerability, it may nevertheless offer a therapeutic alternative in the management of patients unable or unwilling to receive the latter drug. Deferipone also shows promise as an adjunct to deferoxamine therapy in patients with insufficient response and may prove useful as a maintenance treatment to interpose between treatments.

Clinical Trials as Topic↗

PubMed1996

The pharmacokinetics and pharmacodynamics of the oral iron chelator deferiprone (L1) in relation to hemoglobin levels.

Recently, we demonstrated that administration of the orally active iron chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron excretion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of whom had received a packed red cell transfusion of 15 cc/kg. 72 hours prior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical practice however, thalassemia patients, suppression of endogenous erythropoiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to transfusion. We hypothesized that hemoglobin levels will affect the ability of deferiprone to chelate iron. Ten regularly transfused patients with homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, were treated with deferiprone 75 mg/kg/day, administered every 6 hours (or every 12 hours) for 72 hours immediately prior to a blood transfusion in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion. The deferiprone-induced 24-hour urinary iron excretion was similar during both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given every 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 hours (p = 0.79). However, the calculated 24-hour area under the plasma concentration-time curve (AUC0-24) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 +/- 1,601.6 mg*min/l), than that observed when deferiprone was administered every 12 hours (8,250.1 +/- 1,235.7 mg*min/l) (p = 0.04). The pharmacokinetics of deferiprone when administered immediately prior to transfusions are different from those following transfusions. More studies assessing total body iron excretion are needed to determine the contribution of the fecal route in iron excretion.

Adolescent↗

PubMed1996

Efficacy of deferiprone in the treatment of acute iron intoxication in rats.

BACKGROUND: Deferiprone [(1,2-dimethyl-3-hydroxypyrid-4-one) (L1)], is the first orally active iron chelating agent to reach clinical trials in patients with chronic iron overload. Its efficacy in preventing morbidity and mortality in acute iron poisoning has not been tested. OBJECTIVE: To determine whether deferiprone can reduce the mortality of rats following toxic oral doses of iron. METHODS: Rats were administered 612 mg/kg elemental iron by gavage, corresponding to the LD58. A parallel group received the same oral dose of iron followed by deferiprone intraperitoneally at 400 mg/kg (loading dose), followed by additional intraperitoneal injections of 200 mg/kg, 100 mg/kg and 100 mg/kg of deferiprone at one hour intervals. RESULTS: Coadministering deferiprone with the iron decreased mortality from 58% (11/19) to 15% (3/20) (p = 0.013). The administration of deferiprone was associated with urinary excretion of iron (which did not occur with iron alone) and the production of the red deferiprone-iron complex. On histological examination there appeared to be less iron in the liver and gastrointestinal tract. CONCLUSION: The coadministration of deferiprone can decrease morbidity and mortality caused by acute iron overdose. Deferiprone holds promise for the treatment of iron poisoning but additional study is required.

Animals↗

PubMed2001

Iron complexes of deferiprone and dietary plant catechols as cytoprotective superoxide radical scavengers(1).

Superoxide radicals have been implicated in the pathogenesis of aging, cataract, ischemia-reperfusion, cancer and inflammatory diseases. In the present work, we found that deferiprone (L1), an iron-chelating drug, and dietary dihydroxycinnamic acids (catechols) were much more effective at protecting isolated rat hepatocytes against hypoxia-reoxygenation injury if complexed with Fe(3+). Furthermore, the 2:1 catechol-metal complexes with Cu(2+), Fe(2+), and Fe(3+) were also more effective than uncomplexed catechols in scavenging superoxide radicals generated enzymically (xanthine oxidase/hypoxanthine). The 2:1 deferiprone:Fe(3+) complex was less effective at scavenging enzymically generated superoxide radicals even though it was effective at preventing hepatocyte hypoxia-reoxygenation injury. On the other hand, the 1:1 deferoxamine:Fe(3+) complex, another iron-chelating drug, did not prevent hepatocyte hypoxia-reoxygenation injury and did not scavenge enzymically generated superoxide radicals. Furthermore, hepatocytes readily reduced the 2:1 deferiprone:Fe(3+) complex but not the deferoxamine:Fe(3+) complex. These results suggest that the initial step in superoxide radical scavenging (SRS) activity is the formation of a redox complex between Fe(3+) and deferiprone or catechols. The [deferiprone:Fe(3+)] complex was more cytoprotective than would be expected from its SRS activity. This suggests that [deferiprone:Fe(3+)] complex is reduced by a ferrireductase present on the hepatocyte membrane to form [deferiprone:Fe(2+)] complex, which then scavenges superoxide radicals. Therefore, the clinically used deferiprone (L1) may have therapeutic advantages over deferoxamine in having a double role therapeutically: (a) it chelates iron to alleviate iron overload pathology, and (b) the readily formed iron complex protects hepatocytes from superoxide radical-mediated hypoxia-reoxygenation injury.

Animals↗

PubMed1998

Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major.

BACKGROUND: Deferiprone is an orally active iron-chelating agent that is being evaluated as a treatment for iron overload in thalassemia major. Studies in an animal model showed that prolonged treatment is associated with a decline in the effectiveness of deferiprone and exacerbation of hepatic fibrosis. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens, magnetic susceptometry, or both. Three hepatopathologists who were unaware of the patients' clinical status, the time at which the specimens were obtained, and the iron content of the specimens examined 72 biopsy specimens from 19 patients treated with deferiprone for more than one year. For comparison, 48 liver-biopsy specimens obtained from 20 patients treated with parenteral deferoxamine for more than one year were similarly reviewed. RESULTS: Of the 19 patients treated with deferiprone, 18 had received the drug continuously for a mean (+/-SE) of 4.6+/-0.3 years. At the final analysis, 7 of the 18 had hepatic iron concentrations of at least 80 micromol per gram of liver, wet weight (the value above which there is an increased risk of cardiac disease and early death in patients with thalassemia major). Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could be evaluated for progression of hepatic fibrosis; of the 20 deferoxamine-treated patients, 12 could be evaluated for progression. Five deferiprone-treated patients had progression of fibrosis, as compared with none of those given deferoxamine (P=0.04). By the life-table method, we estimated that the median time to progression of fibrosis was 3.2 years in deferiprone-treated patients. After adjustment for the initial hepatic iron concentration, the estimated odds of progression of fibrosis increased by a factor of 5.8 (95 percent confidence interval, 1.1 to 29.6) with each additional year of deferiprone treatment. CONCLUSIONS: Deferiprone does not adequately control body iron burden in patients with thalassemia and may worsen hepatic fibrosis.

Adolescent↗

PubMed2003

Chromosomal aberration frequencies in patients with thalassaemia major undergoing therapy with deferiprone and deferoxamine in a comparative crossover study.

Measurements of chromosomal aberrations were made in 10 thalassaemia major patients treated long-term with deferiprone (at least 5 years) and compared with an equal number of patients matched for age, sex and iron overload, treated long-term with deferoxamine. Two blood samples were collected from each patient, 7 and 20 days after a transfusion episode, and the frequency of chromosomal aberrations (gaps, breaks and exchanges) in the patients' circulating lymphocytes analysed in both samples using standard cytogenetic staining techniques. The frequency of reciprocal translocations was also analysed using fluorescence in situ hybridization. Relatively low frequencies of cells with stable and unstable aberrations were seen at both sampling times in all patients, with no statistically significant differences between sexes. Chromosomal aberrations were less frequent in patients treated long-term with deferiprone than in patients treated with deferoxamine, although the difference did not reach statistical significance. After the second blood sample had been collected, all patients had their iron chelation therapy switched to the other chelator. Patients treated long-term with deferiprone had their therapy switched to deferoxamine and patients treated long-term with deferoxamine had their therapy switched to deferiprone. After the switch, two further blood samples were collected 7 and 20 days after transfusion for each of the next two transfusion cycles in all patients. Analysis of the post-switch samples also revealed a slightly higher frequency of chromosomal aberrations during therapy with deferoxamine than with deferiprone at all time points. A small, but statistically significant, increase in cells with aberrations was observed at the first post-switch assessment in the group of patients whose therapy was switched from deferiprone to deferoxamine, whereas the switch from deferoxamine to deferiprone was associated with a decrease in the frequency of chromosomal aberrations. The results of the study demonstrate that, in a clinical setting, deferiprone has no greater clastogenic activity than that of deferoxamine.

Adolescent↗

PubMed1999

An investigation into variability in the therapeutic response to deferiprone in patients with thalassemia major.

Data suggest a large variability in the effectiveness of the orally active iron chelator, deferiprone, in inducing a sustained decrease in body iron to concentrations compatible with the avoidance of complications from iron overload. We analyzed 19 patients with thalassemia major who were undergoing long-term therapy with deferiprone (75 mg/kg/day every 8 hours). In seven of the 19 patients, hepatic iron concentration had been reduced or maintained at less than 7 mg/g of dry weight liver tissue, associated with no evidence of iron-induced toxicity (group A). In the remaining 12, hepatic iron concentration had either stabilized at higher than 7 mg/g of dry weight liver tissue, or increased to such concentrations during therapy with deferiprone (group B). We studied in these patients determinants that may explain such variability, including initial hepatic iron concentrations, compliance, transfusion index, pharmacokinetic characteristics of deferiprone, and plasma vitamin C status. Patients in group B showed significantly decreased plasma vitamin C concentrations compared with those in group A, who demonstrated normal levels (0.04 mg/dl [0.04-0.19 mg/dl] and 0.62 mg/day [0.44-1.05 mg/day], respectively; p = 0.02). A significant difference in apparent volume of distribution (Vd/F) had developed between the groups over time, with a higher Vd/F in group B (1.66 [0.681, group A] and 3.16 [0.811, group B]; p = 0.006). Group B had started with hepatic iron concentrations that were significantly higher than those of group A, a difference that became more pronounced over time. In the initial analysis, serum ferritin concentrations were also higher in group B. The two groups did not differ in the remaining factors. The initial hepatic iron concentrations predicted the slope of change in this value. Regression analysis suggested that patients with initial hepatic iron concentration of less than or equal to 7.22 mg/g of dry weight liver tissue are unlikely to further decrease while taking deferiprone 75 mg/kg/day. Vitamin C deficiency developed in patients in group B over time. Vitamin C is an important biologic cofactor that plays a role in the distribution of iron. The trend of increase in Vd/F of deferiprone over time may imply a compartment shift of iron stores to one less accessed by deferiprone. This study confirmed the effectiveness of deferiprone in heavily iron-loaded patients and provided evidence that its effectiveness decreases in proportion to liver iron load.

Adult↗

PubMed2000

A trial of deferiprone in transfusion-dependent iron overloaded children.

OBJECTIVE: To determine the efficacy and safety of deferiprone. DESIGN: Prospective study. SETTING: 5 paediatric medical units at the Lady Ridgeway Hospital for Children (LRHC), Colombo. PATIENTS: Transfusion-dependent iron overloaded children in the age group 2 to 15 years. INTERVENTION: Patients were given a total daily dose of 75 mg/kg of deferiprone orally in divided doses. MEASUREMENTS: Efficacy of deferiprone therapy was assessed by 4-monthly serum ferritin assays using the ELISA technique. Safety of deferiprone therapy was assessed by 4-weekly white cell counts, platelet counts and serum transaminase levels. The Z-test was used to assess the significance of the difference between the mean initial serum ferritin level and the mean subsequent serum ferritin level. RESULTS: 54 patients received deferiprone therapy for a mean duration of 9 +/- 3 months. Initial serum ferritin levels ranged from 1500 to 10,700 ng/ml with a mean of 5743. Subsequent serum ferritin levels, obtained in 48 patients ranged from 740 to 7300 ng/ml with a mean of 3558 (p < 0.001). In 47 of the 48 patients subsequent serum ferritin levels were lower than initial levels. One child developed severe neutropaenia, which reverted to normal on discontinuation of treatment. 11 children developed arthropathy, which responded to ibuprofen therapy combined in some cases with a reduction of the dose of deferiprone to 50 mg/kg/day. Serum transaminase levels were raised in 5 patients but reverted to pretreatment values or lower despite continuation of deferiprone therapy. CONCLUSIONS: Deferiprone is a safe and effective oral iron-chelating agent which can be used, under strict supervision, in transfusion-dependent iron overloaded children.

Adolescent↗

PubMedDate not supplied

Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial.

Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major. To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups. Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.

Adolescent↗

PubMed2000

The efficacy of oral deferiprone in acute iron poisoning.

Due to its high cost and need for parenteral administration, the standard iron chelator deferoxamine is not used in many individuals with acute and chronic iron poisoning worldwide. Deferiprone is the first oral iron chelator to be shown to be effective in chronically iron overloaded thalassemia patients. Its efficacy, by oral administration, in acute iron poisoning has not been tested. Our objective was to determine whether orally administered deferiprone can reduce the mortality of rats following acute, toxic, oral doses of iron. Rats were administered 612 mg/kg elemental iron orally, corresponding to LD50 in the species tested. Two other groups received the same oral dose of iron followed by oral deferiprone: 800 mg/kg and 800 mg/kg, followed by another dose of 800 mg/kg 2 hours later. Coadministration of 800 mg/kg deferiprone with the iron decreased mortality from 30% to 6.6% after 2 hours (P = .02), from 40% to 16.6% after 12 hours (P = .04), and from 53.3% to 20% after 24 hours (P = 0.007). Mortality was also significantly decreased among animals coadministrated 2 repeated doses of deferiprone of 800 mg/kg with iron, to 0%, 9%, and 18%, and 2, 12, and 24 hours postdrug administration, respectively (P = .04, .05, .04, respectively). Histologically, there was a dose-dependent decrease in iron accumulation in the gastrointestinal tract. Orally administered deferiprone can decrease morbidity and mortality caused by acute iron overdose in rats. Oral deferiprone holds promise in the treatment of iron poisoning in humans.

Acute Disease↗

PubMed2002

Deferiprone protects against doxorubicin-induced myocyte cytotoxicity.

The iron chelating hydroxypyridinone deferiprone (CP20, L1) and the clinically approved cardioprotective agent dexrazoxane (ICRF-187) were examined for their ability to protect neonatal rat cardiac myocytes from doxorubicin-induced damage. Doxorubicin is thought to induce oxidative stress on the heart muscle, both through reductive activation to its semiquinone form, and by the production of hydroxyl radicals mediated by its complex with iron. The results of this study showed that both deferiprone and dexrazoxane were able to protect myocytes from doxorubicin-induced lactate dehydrogenase release. Deferiprone quickly and efficiently removed iron(III) from its complex with doxorubicin. In addition, this study also showed that deferiprone rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex, suggesting that in the myocyte, deferiprone should also be able to displace iron from its complex with doxorubicin. It was shown by electron paramagnetic resonance spectroscopy that under hypoxic conditions myocytes were able to reduce doxorubicin to its semiquinone free radical. Deferiprone also greatly reduced hydroxyl radical production by the iron(III)-doxorubicin complex in the xanthine oxidase/xanthine superoxide generating system. Together these results suggest that deferiprone may protect against doxorubicin-induced damage to myocytes by displacing iron bound to doxorubicin, or chelating free or loosely bound iron, thus preventing site-specific iron-based oxygen radical damage.

Animals↗

PubMed2001

The controversial role of deferiprone in the treatment of thalassemia.

The role of the orally active iron (Fe) chelator deferiprone in the treatment of beta-thalassemia remains a controversial subject. Despite initial studies showing high Fe chelation efficacy in vitro and also in animals and human subjects, several latter studies have not been so successful. In fact, it has been reported in several clinical trials that deferiprone after long-term treatment had either little effect or actually increased hepatic Fe loading. In addition, an increase in liver fibrosis was noted in one study. However, more recently, results by other investigators have suggested that the drug may be used under some circumstances without marked toxicity. In particular, it has been demonstrated that the combination of deferoxamine (DFO) and deferiprone results in more Fe excretion than when either chelator is used alone. Moreover, a combination of both drugs led to a decrease in deferiprone-mediated toxicity. Other studies performed in patients for up to 10 years showed no progressive fibrosis after deferiprone therapy, while a possible trend toward increasing fibrosis was noted in another investigation. Additional studies using larger numbers of deferiprone-treated patients are essential to determine the efficacy and safety of this drug, particularly in relation to the development of fibrosis. The present review discusses the possible role of deferiprone in the treatment of Fe overload.

Agranulocytosis↗

PubMed1997

Systemic administration of the iron chelator deferiprone attenuates subarachnoid hemorrhage-induced cerebral vasospasm in the rabbit.

OBJECTIVE: Iron catalyzed generation of injurious free radicals has been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). The present study assessed the effects of the iron chelator deferiprone on cerebral vasospasm in an in vivo rabbit model of SAH. METHODS: Twenty-four rabbits were assigned to three groups as follows: SAH plus placebo (n = 8), SAH plus deferiprone (n = 8), or control plus placebo (n = 8). Deferiprone was administered to an additional group of three rabbits that were not subjected to SAH. Drug administration was initiated 8 hours after SAH was induced and was repeated at 8-hour intervals. The animals were killed using perfusion-fixation 48 hours after SAH. Cross-sectional areas of basilar artery histological sections were measured by an investigator blinded to the treatment groups. RESULTS: In placebo-treated animals, the average luminal cross-sectional area of the basilar artery was reduced by 54% after SAH compared to controls (i.e., from 0.272 to 0.125 mm2). The vasospastic response after SAH was attenuated significantly in animals treated with deferiprone (0.208 mm2, representing a 24% reduction). CONCLUSION: Previous experimental studies suggested that iron chelation can be effective in attenuating cerebral vasospasm after SAH. Deferiprone is a recently developed iron chelator that has been extensively evaluated for the treatment of patients requiring chronic blood transfusions. The present study demonstrates that deferiprone is effective in attenuating experimental cerebral vasospasm. Because of its stability, lipophilicity, and ability to penetrate the blood-brain barrier, deferiprone represents an attractive candidate for the treatment of cerebral vasospasm.

Animals↗

PubMed1998

A multi-center safety trial of the oral iron chelator deferiprone.

Deferiprone, also known as L1, is an orally active iron chelator that has been studied extensively in clinical trials. The sporadic occurrence of agranulocytosis in association with deferiprone and the highly variable frequency of other possible side effects such as arthralgia have created uncertainty about the true incidence of deferiprone-related complications. A multi-center, 1-year trial was initiated to determine the safety profile of deferiprone. Using the Apotex formulation of deferiprone, 187 patients with thalassemia who were unable or unwilling to use deferoxamine were enrolled in four centers; 162 patients completed one year of therapy. Agranulocytosis (ANC < 500/mm3) occurred in one patient after 15 weeks of treatment, was not accompanied by infection and resolved following treatment with G-CSF. Nine other subjects developed less severe neutropenia (ANC 500-1500/mm3) with the lowest absolute neutrophil count reaching 500-1250/mm3. The neutropenia in these patients developed after 1-50 weeks of therapy, frequently accompanied febrile illnesses, and occurred predominantly in non-splenectomized patients. Reasons other than neutropenia for discontinuing use of deferiprone included nausea (4), voluntary withdrawal (3), high ALT (2), platelet count < 100,000/mm3 (2), low but unconfirmed ANC (1), protocol violation (1) fatigue (1), and depression (1). Mean ALT levels rose within three months of therapy and stabilized thereafter. Arthralgia and nausea and/or vomiting occurred in 6% and 24% of subjects, respectively. In this multi-center trial with weekly monitoring of blood counts, the incidence of agranulocytosis was 0.58 per 100 patient-years, and the frequency of agranulocytosis after one year was 0.5%. These findings support the safety of this formulation of deferiprone, using the careful monitoring system employed in this trial.

Administration, Oral↗

PubMed2003

[Effect of desferrioxamine and deferiprone on osteocalcin secretion in osteoblast-type cells].

Desferrioxamine and deferiprone are both metal-chelating drugs often used in aluminum-overloaded dialysis patients. In these patients, desferrioxamine produces an improvement on bone mineralisation without a relevant decrease in bone aluminum. Thus, desferrioxamine might have a direct effect on bone cells. The aim of this study was to assess the effect of desferrioxamine and deferiprone on 1,25(OH)2D3-stimulated osteocalcin secretion in osteoblast--like cells. The study was carried out in MG-63 cell cultures. Cells were seeded at a density of 15,000 cel/cm2 and grown to confluence for 72 hours in DMEM supplemented with 10% FCS. The medium was then replaced by another medium containing 1% BSA, 10(-9) M 1,25(OH)2D3 and desferrioxamine 5, 10, 20, 40, 60, 80 microM or deferiprone 15, 30, 60, 120, 180, 240 microM. Tris-HCl at pH 7.4 was used as control. After 48 hours, supernatants were collected for the measurement of secreted osteocalcin. Desferrioxamine and deferiprone, at high doses (desferrioxamine: 60 microM, 80 microM; deferiprone: 180 microM, 240 microM), inhibited the 1,25(OH)2D3-induced osteocalcin secretion. On the contrary, at lower doses (desferrioxamine 5 microM; deferiprone 15 microM) stimulated the secretion. In summary, these results suggest that desferrioxamine and deferiprone exert a direct effect on bone cell metabolism that might be independent from their metal-chelating properties.

Aluminum↗