Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Deferiprone”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed2006

Effects of combined deferiprone and desferrioxamine iron chelating therapy in beta-thalassemia major end-stage heart failure: a case report.

Despite usual iron chelating therapy based on desferrioxamine, patients affected by beta-thalassemia major (beta-TM) often develop progressive heart failure caused by myocardial iron overload, which is the leading cause of mortality within the third decade of life. Heart transplantation is a limited therapeutic option, as very often these patients have multi-organ iron deposits and infective complications (particularly hepatitis C), secondary to frequent blood transfusions. We report the case of a 26-year-old male affected by beta-TM with end-stage heart failure, who showed a dramatic improvement in symptoms and myocardial function when a new oral iron chelating agent, deferiprone, was added to standard therapy with desferrioxamine.

Adult↗
PubMed1998

Antiproliferative effect of deferiprone on the Hep G2 cell line.

Iron is an essential element in cellular metabolism and the growth of all living species, and is involved in DNA replication. The risk of hepatocellular carcinoma development is associated with an increase in iron availability. The aim of the present work was to investigate the effect of an oral iron chelator, deferiprone (CP20), on HepG2 cell-line proliferation in culture. HepG2 cell cultures were maintained in the absence of fetal calf serum (FCS) and in the presence or not (control cultures) of CP20 at the concentrations of 50 or 100 microM; deferoxamine (DFO) was used as an iron chelator reference. Cell proliferation was investigated by the analysis of DNA synthesis using [3H] methyl-thymidine incorporation and of the cell cycle by flow cytometry. Iron chelation efficiency in the culture model was studied by analyzing the effect of CP20 on radioactive iron uptake, intracellular ferritin level, and transferrin receptor expression. CP20, at the concentration of 50 or 100 microM, inhibited DNA synthesis after 48 hr of incubation and induced an accumulation of the cells in the S phase of the cell cycle. Iron chelators inhibited cellular iron uptake, decreased intracellular ferritin level, and increased transferrin receptor protein and mRNA levels. Our results show that CP20 as well as deferoxamine inhibit HepG2 cell proliferation and block cell cycle in the S phase.

Cell Cycle↗
PubMed1999

Cardioprotective effect of alpha-tocopherol, ascorbate, deferoxamine, and deferiprone: mitochondrial function in cultured, iron-loaded heart cells.

Because mitochondrial inner membrane respiratory complexes are important targets of iron toxicity, we used iron-loaded rat heart cells in culture to study the beneficial effect on mitochondrial enzymes of the iron chelators deferoxamine (DFO) and deferiprone (L1) and of antioxidants and reducing agents (ascorbate and alpha-tocopherol). Reduced nicotinamide adenine dinucleotide-cytochrome c oxidoreductase (complex I-III) and succinate dehydrogenase were the most-sensitive indicators of iron toxicity and cardioprotective effect. Although at concentrations below 0.3 mmol/L the iron-mobilizing effect of L1 was less than that of DFO, both were equally effective in protecting or restoring mitochondrial respiratory enzyme activity. At 1.0 mmol/L, L1 toxicity was manifested in respiratory enzyme inhibition, whereas DFO had no such effect. Ascorbate (0.057 to 5.7 mmol/L) had a mild cardioprotective effect at the highest concentration only, in association with decreased cellular iron uptake. By contrast, alpha-tocopherol (0.023 mmol/L) completely inhibited mitochondrial iron toxicity without affecting iron uptake or release, and irrespective of whether it was used before, during, or after in vitro iron loading. These observations illustrate the usefulness and limitations of iron chelators and other agents used for preventing iron toxicity to the heart and other vital organs, and they underline the need for exploring in more detail the effects of these agents in the clinical setting.

Animals↗
PubMed2002

Reduction of copper and metallothionein in toxic milk mice by tetrathiomolybdate, but not deferiprone.

Copper is both essential for life and toxic. Aberrant regulation of copper at the level of intracellular transport has been associated with inherited diseases, including Wilson's disease (WND) in humans. WND results in accumulation of copper and the copper and zinc-binding protein metallothionein (MT) in liver and other tissues, liver degeneration, and neurological dysfunction. The toxic milk (TX) mutation in mice results in a phenotype that mimics human WND, and TX has been proposed to be a model of the disease. We characterized TX mice as a model of altered metal ion and MT levels during development, and after treatment with the metal ion chelators tetrathiomolybdate (TTM) and deferiprone (L1). We report that hepatic, renal and brain copper and MT are elevated in TX mice at 3 and 12 months of age. Zinc was significantly higher in TX mouse liver, but not brain and kidney, at both time points. Nodules appeared spontaneously in TX mouse livers at 8-12 months that maintained high copper levels, but with more normal morphology and decreased MT levels. Treatment of TX mice with TTM significantly reduced elevated hepatic copper and MT. Transient increases in blood and kidney copper accompanied TTM treatment and indicated that renal excretion was a significant route of removal. Treatment with L1, on the other hand, had no effect on liver or kidney copper and MT, but resulted in increased brain copper and MT levels. These data indicate that TTM, but not L1, may be useful in treating diseases of copper overload including WND.

Animals↗
PubMed2000

Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1).

Iron is essential for all living organisms. Under normal conditions there is no regulatory and rapid iron excretion in humans and body iron levels are mainly regulated from the absorption of iron from the gut. Regular blood transfusions in thalassaemia and other chronic refractory anaemias can result in excessive iron deposition in tissues and organs. This excess iron is toxic, resulting in tissue and organ damage and unless it is removed it can be fatal to those chronically transfused. Iron removal in transfusional iron overload is achieved using chelation therapy with the chelating drugs deferoxamine (DF) and deferiprone (L1). Effective chelation therapy in chronically transfused patients can only be achieved if iron chelators can remove sufficient amounts of iron, equivalent to those accumulated in the body from transfusions, maintaining body iron load at a non-toxic level. In order to maintain a negative iron balance, both chelating drugs have to be administered almost daily and at high doses. This form of administration also requires that a chelator has low toxicity, good compliance and low cost. DF has been a life-saving drug for thousands of patients in the last 40 years. It is mostly administered by subcutaneous infusion (40-60 mg/kg, 8-12 h, 5 days per week), is effective in iron removal and has low toxicity. However, less than 10% of the patients requiring iron chelation therapy worldwide are able to receive DF because of its high cost, low compliance and in some cases toxicity. In the last 10 years we have witnessed the emergence of oral chelation therapy, which could potentially change the prognosis of all transfusional iron-loaded patients. The only clinically available oral iron chelator is L1, which has so far been taken by over 6000 patients worldwide, in some cases daily for over 10 years, with very promising results. L1 was able to bring patients to a negative iron balance at doses of 50-120 mg/kg/day. It increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in the majority of chronically transfused iron-loaded patients. Despite earlier concerns of possible increased risk of toxicity, all the toxic side effects of L1 are currently considered reversible, controllable and manageable. These include agranulocytosis (0.6%), musculoskeletal and joint pains (15%), gastrointestinal complaints (6%) and zinc deficiency (1%). The incidence of these toxic side effects could in general be reduced by using lower doses of L1 or combination therapy with DF. Combination therapy could also benefit patients experiencing toxicity with DF and those not responding to either chelator alone. The overall efficacy and toxicity of L1 is comparable to that of DF in both animals and humans. Despite the steady progress in iron chelation therapy with DF and L1, further investigations are required for optimising their use in patients by selecting improved dose protocols, by minimising their toxicity and by identifying new applications in other diseases of iron imbalance.

Deferiprone↗
PubMed1997

Liver iron depletion and toxicity of the iron chelator deferiprone (L1, CP20) in the guinea pig.

The use of the iron chelator deferiprone (L1, CP20, 1,2-dimethyl-3-hydroxypyrid-4-one) for the treatment of diseases of iron overload and other disorders is problematic and requires further evaluation. In this study the efficacy, toxicity and mechanism of action of orally administered L1 were investigated in the guinea pig using the carbonyl iron model of iron overload. In an acute trial, depletion of liver non-heme iron in drug-treated guinea pigs (normal iron status) was maximal (approximately 50% of control) after a single oral dose of L1 of 200 mg kg-1, suggesting a limited chelatable pool in normal tissue. There was no apparent toxicity up to 600 mg kg-1. In each of two sub-acute trials, normal and iron-loaded animals were fed L1 (300 mg kg-1 day-1) or placebo for six days. Final mortalities were 12/20 (L1) and 0/20 (placebo). Symptoms included weakness, weight loss and eye discharge. Iron-loaded as well as normal guinea pigs were affected, indicating that at this drug level iron loading was not protective. In a chronic trial guinea pigs received L1 (50 mg kg-1 day-1) or placebo for six days per week over eight months. Liver non-heme iron was reduced in animals iron-loaded prior to the trial. The increase in a wave latency (electroretinogram), the foci of hepatic, myocardial and musculo-skeletal necrosis, and the decrease in white blood cells in the drug--treated/normal diet group even at the low dose of 50 mg kg-1 day-1 suggests that L1 may be unsuitable for the treatment of diseases which do not involve Fe overload. However, the low level of pathology in animals treated with iron prior to the trial suggests that even a small degree of iron overload (two-fold after eight months) is protective at this drug level. We conclude that the relationship between drug dose and iron status is critical in avoiding toxicity and must be monitored rigorously as cellular iron is depleted.

Administration, Oral↗
PubMed2001

Comparison between deferoxamine and deferiprone (L1) in iron-loaded thalassemia patients.

INTRODUCTION: Iron-chelating therapy with deferoxamine in patients with thalassemia major has dramatically improved the prognosis of this disease. However, the limitations of this treatment have stimulated the design of alternative orally active iron chelators. OBJECTIVE: To compare the effectiveness and safety of, and compliance with, oral deferiprone (L1), and deferoxamine, in thalassemia major patients. METHODS: All patients were followed up in one center in Lebanon. Sixteen patients were on L1 (75 mg/kg/d), and 40 patients on subcutaneous deferoxamine (20-50 mg/kg/d). Serum ferritin level, urinary iron excretion (UIE) and side effects were monitored over a two year period. RESULTS: Patients on L1 had an initial serum ferritin concentration of 3663+/-566 microg/l (mean+/-SEM), that dropped to 2599+/-314 at 6 months (p<0.02; paired t-test), and stabilised at that level over the 24 months follow up. Patients on deferoxamine had an initial mean serum ferritin concentration of 3480+/-417 (NS compared to the L1 group), which dropped gradually to 3143+/-417 (p<0.05) and 2819+/-292 (p<0.02) at 6 and 24 months, respectively. The most common adverse reactions associated with L1 were arthralgia and nausea, but they did not necessitate stopping the drug. CONCLUSION: L1 had comparable efficacy as deferoxamine with minimal side effects and better compliance. Provided long term side effects are not encountered, L1 seems to be a valuable alternative iron chelator for patients unable or unwilling to use deferoxamine effectively.

Administration, Oral↗
PubMed2004

Effectiveness and safety of combined iron-chelation therapy with deferoxamine and deferiprone.

INTRODUCTION: The purpose of our study was to evaluate the effectiveness and safety of combined therapy with deferoxamine (DFO) and deferiprone (DFP) in patients with beta-thalassemia major and increased serum ferritin. PATIENTS AND METHODS: Our study was performed in 36 patients with beta-thalassemia major. DFP was administered orally in a total daily dose of 60 mg/kg for 6 days per week and DFO was administered subcutaneously in a total daily dose of 40-50 mg/kg for 4-6 days per week. The efficacy of combined treatment was assessed by measurements of serum ferritin and 24-h urine iron excretion levels. RESULTS: Out of the 36 patients, 11 discontinued DFO after a mean of 4 months; however, 25 patients, who continued to receive the combined therapy showed a very satisfactory compliance. After a mean of 13.5 months, their mean serum ferritin levels reduced from 2637 + 1292 to 1580 + 1024 ng/ml (P = 0.002) and their mean urinary iron excretion elevated from 0.41 + 0.27 to 0.76 +0.49 mg/24h (P = 0.003). The observed side effects were gastrointestinal disorders,elevations in liver enzymes, mild neutropenia, joint symptoms, taste disorders, dizziness and fatigue. CONCLUSIONS: The results of this study show that combined iron-chelation therapy with DFO and DFP results in satisfactory reduction of serum ferritin with no significant toxicity.

Administration, Oral↗
PubMed1997

Agranulocytosis, arthritis and systemic vasculitis in a patient receiving the oral iron chelator L1 (deferiprone).

A thalassaemic girl presented with agranulocytosis, arthritis of both ankles and clinical and laboratory features consistent with the diagnosis of systemic vasculitis, during oral iron chelator L1 (deferiprone) treatment. Changes in the humoral and cell-mediated immune function. including antinuclear antibodies (ANA), anti-DNA and extractable-nuclear antigens (ENA) antibodies positivity, increased immunoglobulin values, decreased T suppressor and the presence of circulating immune complexes, suggest a cause-and-effect relationship with the observed clinical manifestations. A careful monitoring of the immune function is recommended in patients who are receiving the oral iron chelator L1.

Adult↗
PubMed1999

Transport of 14C-deferiprone in normal, thalassaemic and sickle red blood cells.

The transport of deferiprone (L1) in normal (N), sickle (S) and thalassaemic (T) red blood cells (RBC) was determined by incubation with 14C-L1 at 37 degrees C. Following incubation with 0.5 mM 14C-L1 for 4 h, the intracellular concentration of L1 in T RBC was 3 times higher than was found extracellularly. In contrast, no concentration gradient across N and S RBC membranes was detected. Efflux studies showed that T RBC released only 17 +/- 2% of 14C-L1 into the extracellular space. We hypothesize that L1 accumulation in T RBC results from their high content of chelatable iron and formation of large, hydrophilic L1-Fe(III) complexes trapped within the cytosol.

Adult↗
PubMed2001

Molecular factors affecting the complex formation between deferiprone (L1) and Cu(II). Possible implications on efficacy and toxicity.

Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, L1, CAS 30652-11-0) is a new chelating drug used worldwide for the treatment of iron overloading conditions. Spectrophotometric and potentiometric measurements were carried out to investigate the interaction of L1 with Cu(II) ions under different conditions. The complexation of Cu(II) ions with L1 in aqueous solution leads predominantly to the formation of the Cu(L1)2 species at a pH range of 4-9. The experimental results indicate that L1 has high affinity for Cu(II) with stability constants log beta 11 = 10.3 +/- 0.9 and log beta 12 = 19.2 +/- 0.6. The effect of Cu(II) ions on the affinity of L1 for Fe(III) ions by competition reactions in vitro indicate displacement of Fe(III) in a concentration dependent manner by Cu(II). Similarly, the presence of different buffers at various pH values resulted in the formation of different stoichiometry L1 complexes with Cu(II) and of mixed complexes with buffer anions. The strong interaction of L1 with Cu(II) may have implications on the therapeutic and toxicological properties of this chelating drug. In particular, L1 may be used in the treatment of copper overloading conditions, such as Wilson's disease or other conditions where copper toxicity is implicated.

Algorithms↗
PubMed2001

Exploring the "iron shuttle" hypothesis in chelation therapy: effects of combined deferoxamine and deferiprone treatment in hypertransfused rats with labeled iron stores and in iron-loaded rat heart cells in culture.

Although iron chelation therapy results in a significant improvement in well-being and life expectancy of thalassemic patients with transfusional iron overload, failure to achieve these goals in a substantial proportion of patients underlines the need for improved methods of treatment. In the present studies we used selective radioactive iron probes of hepatocellular and reticuloendothelial (RE) iron stores in hypertransfused rats and iron-loaded heart cells to compare the source of iron chelated in vivo by deferoxamine (DFO) or by deferiprone (L1) and its mode of excretion, to examine the ability of DFO and L1 to remove iron directly from iron-loaded myocardial cells, and to examine the mechanism of their combined interaction through a possible additive or synergistic effect. Our results indicate that L1 given orally is 1.6 to 1.9 times more effective in rats, on a weight-per-weight basis, than parenteral DFO in promoting the excretion of storage iron from parenchymal iron stores but shows no advantage over DFO in promoting RE iron excretion. Simultaneous administration of DFO and L1 results in an increase in chelating effect that is additive but not synergistic. The magnitude of this additive effect is identical to an increase in the equivalent (weight or molar) dose of DFO alone rather than the sum of the separate effects of L1 and DFO. This finding is most probably the result of a transfer of chelated iron from L1 to DFO. These observations may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload.

Animals↗
PubMed2002

The iron-loaded gerbil model revisited: effects of deferoxamine and deferiprone treatment.

Although the beneficial effects of deferoxamine (DFO) on iron-associated morbidity and mortality are well documented, the role of deferiprone (L1) in the management of transfusional iron overload is controversial. This debate involves not only the question of efficacy but also of safety, with particular emphasis on the risk of a paradoxical aggravation of iron toxicity by L1. We used the iron-loaded gerbil model introduced by Carthew et al to compare the chelating efficacy of L1, DFO, or both in two gerbil strains treated by means of weekly iron-dextran injections: Psammomys obesus and pathogen-free Mongolian gerbils (Meriones unguiculatus). The difference between the high mortality and advanced hepatocellular necrosis observed in iron-loaded P obesus and the absence of mortality and limited morbidity encountered in pathogen-free Mongolian gerbils is most likely explained by the prevention of coincidental laboratory infections in the latter group. Iron-chelating treatment in all experimental groups resulted in a significant decrease in hepatic iron concentrations and normalization of mitochondrial respiratory enzyme activities, with combined L1 and DFO treatment being the most efficient, followed, in decreasing order, by DFO and L1 as single-drug treatments. Judged by tissue iron concentrations, mitochondrial enzyme activity, and hepatic histology, we could find no evidence of a paradoxical aggravation of iron toxicity by L1 in either of the two series of studies. Although these data appear to be reassuring, the present controversy related to the role of L1 in the development of hepatic cirrhosis should be eventually settled by clinical studies evaluating the effects of long-term iron-chelating treatment.

Animals↗
PubMed2006

Deferiprone or deferoxamine vs. combination therapy in patients with beta-thalassemia major: a case study in Taiwan.

Deferiprone (L1) has been recommended as an effective oral chelation therapy for patients with beta-thalassemia major (TM). From 1999 to 2004, 114 patients with TM from five treatment centers were enrolled in this program: iron (Fe) was chelated with L1 in 57 patients, deferoxamine (DFO) in 26, and combined L1/DFO therapy in 31. We found that serum ferritin (SF) was significantly lower in nine patients receiving L1 for more than 5 years (p = 0.04), 22 patients receiving L1 for 1-2 years (p < 0.01) and 31 receiving the combined therapy (p = 0.01), yet significantly higher in those receiving DFO only (p < 0.01). One patient showed transient neutropenia; arthropathy in one patient and gastrointestinal upset in two were noted, with no significant change in alanine aminotransferase (ALT) level. Of 17 patients who were submitted to a liver biopsy, 15 showed no significant change in hepatic fibrosis scores after therapy with L1. None of the 88 patients, including 31 who received the combined therapy, have abandoned oral L1 treatment due to adverse effects. Results of this study proved that L1 or combined therapy with L1 and DFO is effective in reducing SP; incidence of adverse events was low in patients with TM.

Adolescent↗
PubMed2006

Radiation protection by deferiprone in animal models.

The effectiveness of deferiprone (L1) in removing depleted uranium (DU) and protecting animals from radiation exposure was examined. Rats that had received 2 mg/kg DU via intramuscular injection were orally administered 100, 200 or 400 mg/kg L1 for 3 days. In all of the groups, significant increases in urinary DU excretion and decreases in DU concentration in the injected muscle were observed, indicating that L1 combined with DU and DU was excreted in the urine. No significant increase in the amount of DU in the excreta or decrease in DU concentration in organs other than the muscles was found. As a preliminary test, the effectiveness of L1 in reducing radiation damage was examined in mice injected with 400 mg/kg L1 and rats administered orally with 200 and 400 mg/kg L1 before and just after x-ray exposure. The results were inconclusive.

Administration, Oral↗
PubMed2006

Effect of deferiprone on liver iron overload and fibrosis in hepatitis-C-virus-infected thalassemia.

To assess the effects of liver iron overload and fibrosis after treatment with a chelating agent in hepatitis C virus (HCV)-infected thalassemia, from April 1999 to July 2004, 45 patients with thalassemia major (age range 9-33 years, mean 19.3) received daily deferiprone (L1) for 23-60 months (75 mg/kg). The patients were divided into two groups on the basis of their hepatitis status (27 with, 18 without). Their serum was analyzed for alanine aminotransferase (GPT), aspartate aminotransferase (GOT), bilirubin (total/direct), r-glutamyl transpeptidase (r-GT), alkaline phosphatase (Alk-P), and ferritin. Liver iron overload and fibrosis were defined by a senior pathologist. No significant differences were demonstrated in serum levels of GPT, GOT, bilirubin, r-GT, Alk-P or ferritin; comparison was made for each group before and after L1 treatment. Iron scores were 2.3 +/- 0.9 and 2.8 +/- 0.9 for the hepatitis C negative and positive groups, respectively (p = 0.07), with liver fibrosis scores of 1.0 +/- 0.5 and 0.4 +/- 0.52 (p = 0.56). The two scores were not higher for the positive group. There was no evidence of: 1) greater iron overload and fibrosis in the HCV-infected thalassemic patients; 2) L1 inducing progressive hepatic fibrosis or worsening iron overload in HCV-infected thalassemic patients after long-term therapy; 3) further damage to liver cells associated with L1 treatment.

Adolescent↗
PubMed2006

Liver fibrosis and iron levels during long-term deferiprone treatment of thalassemia major patients.

Deferiprone (L1) is an orally active iron-chelation agent that is being evaluated as a treatment for iron overload in thalassemia major. Although some reports have concluded that LI may exacerbate hepatic fibrosis and the deterioration of liver function in thalassemia patients, other studies have reported no detrimental effects. In view of these serious concerns regarding the hepatic toxicity of LI, a Taiwanese group of beta-thalassemia (thal) patients with the longest known duration of LI therapy and who had provided liver biopsies, were enrolled in this study. From April 1999 to July 2004, the 17 enrolled thalassemia major patients had been on L1 therapy for as long as 19 to 60 months. Two liver biopsies from each of the 17 patients were received at the China Medical University Hospital, Taichung, Taiwan. Serum alanine aminotransferase (ALT), viral serological studies for hepatitis B and hepatitis C, iron scores and fibrosis scores were available at the beginning of the study and at the time of the second biopsy. Overall, the 17 patients received L1 therapy continuously for a mean period of 3.3 years. With the exception of two patients, fibrosis scores decreased in all patients after LI therapy. Three patients had increased iron scores after therapy of L1 and 11 patients had increased ALT levels; increased ALT levels occurred more frequently in hepatitis C positive patients. In this study, most thalassemia major patients had no progression of hepatic fibrosis or increased liver iron stores during long-term LI therapy.

Adolescent↗
PubMed2006

Regression of myocardial dysfunction after switching from desferrioxamine to deferiprone therapy in beta-thalassemia major patients.

This study tries to compare the cardioprotective effects of the desferrioxamine (DFO) and deferiprone (L1) therapies on thalassemia major patients. We enrolled nine patients with thalassemia major complicated by some degree of myocardial dysfunction. These patients, recipients of >10 years of DFO injection therapy, were switched from DFO to L1. Echocardiographic measures of left ventricular systolic, diastolic and global functions, were assessed regularly every 6 months. Mean values of each parameter for the DFO and L1 treatment periods were compared using paired t-test and Wilcoxon signed-rank test. Global cardiac function improved significantly. Myocardial dysfunction in patients with thalassemia major can be reversed by regular use of the oral iron chelator L1.

Adolescent↗