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PubMed2003

Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis.

BACKGROUND AND OBJECTIVES: Iron-induced cardiac disease remains the main cause of death in patients with thalassemia major, despite chelation therapy with deferoxamine. Deferiprone is an iron chelator that has the potential to be more effective than deferoxamine in removing intracellular iron from the heart. However, to date, no study has been designed to examine the frequency of cardiac complications and survival as the primary outcomes of a comparative study between these two chelators. This retrospective study assessed the survival and the occurrence of cardiac disease in all patients with thalassemia major treated for at least 4 years with deferiprone or deferoxamine at a single center. DESIGN AND METHODS: The patients were, on average, 18.4 years old at the start of the review period and were followed up, on average, for 6 years. At baseline there was no significant difference in the percentage of patients with cardiac disease in the two therapy groups. RESULTS: At the end of the study, cardiac dysfunction, expressed as worsening of pre-existing cardiac abnormality or development of new cardiac disease, was diagnosed in 2 (4%) of the 54 deferiprone-treated patients and in 15 (20%) of the 75 deferoxamine-treated patients, from the first to the last measurement (p = 0.007). The Kaplan Meier analysis of cardiac disease-free survival over the 5-year period was significantly more favorable in the deferiprone group (p = 0.003). INTERPRETATION AND CONCLUSIONS: None of the patients treated with deferiprone died, while 3 of the patients treated with deferoxamine died because of irreversible worsening of their cardiac condition during the study period. Findings from this study suggest that long-term therapy with deferiprone provides a greater cardio-protective effect against the toxicity of iron overload than does subcutaneous deferoxamine. Formal prospective studies are warranted to confirm this effect.

Adolescent↗
PubMed2000

Evaluation of the protective activity of deferiprone, an aluminum chelator, on aluminum-induced developmental toxicity in mice.

BACKGROUND: Since deferiprone can be an effective chelating agent for the treatment of aluminum (Al) overload, in the present study we investigated whether this chelator could protect against Al-induced maternal and developmental toxicity in mice. METHODS: A single oral dose of Al nitrate nonahydrate (1,327 mg/kg) was given on gestation day 12, the most sensitive time for Al-induced maternal and developmental toxic effects in mice. At 2, 24, 48, and 72 hr thereafter, deferiprone was given by gavage at 0 and 24 mg/kg. Cesarean sections were performed on day 18 of gestation and fetuses were examined for malformations and variations. RESULTS: Aluminum-induced maternal toxicity was evidenced by significant reductions in body weight gain, corrected body weight change, and food consumption. Developmental toxicity was evidenced by a significant decrease in fetal weight per litter and an increase in the total number of fetuses and litters showing bone retardation. No beneficial effects of deferiprone on these adverse effects could be observed. By contrast, a more pronounced decrease in maternal weight gain and corrected body weight change, as well as a higher number of litters with fetuses showing skeletal variations was noted in the group exposed to Al nitrate and treated with deferiprone at 24 mg/kg. CONCLUSIONS: According to the current results, deferiprone would not be effective to prevent Al-induced maternal and embryo/fetal toxicity in mice.

Abnormalities, Drug-Induced↗
PubMed1996

Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial.

We performed an open, nonrandomized, multicenter phase-II trial to evaluate the efficacy and toxicity of 1 year of treatment with the oral iron chelator deferiprone in 38 mainly nonthalassemic patients with transfusional iron overload. Initial serum ferritin varied between 996 and 11.644 micrograms/l. Patients were treated with 3-6 g of deferiprone daily. Mean urinary iron excretion (UIE) in 36 evaluable patients was 21.0 mg/24 h and was significantly higher in the patients with thalassemia than in those with myelodysplasia. Negative iron balance was achieved in 20 patients (56%). The median duration of treatment was 10 months; due to side effects and other causes only 20 patients completed 1 year of treatment. Mean serum ferritin levels decreased from 3563 micrograms/l at the start of the trial to 2767 micrograms/l at 6 months (26 patients, p < 0.004) and to 2186 micrograms/l at 12 months (20 patients, p < 0.005). Serum ferritin levels normalized in two patients who were no longer transfusion dependent. Deferiprone was clearly not effective in three patients (two with myelofibrosis, one with myelodysplasia). One patient with myelodysplasia developed agranulocytosis after 12 months of treatment; this was rapidly reversible after stopping deferiprone. Three patients had a mild and transient decrease in white blood cell count. Other side effects leading to withdrawal from the trial consisted mainly of nausea (3 patients), arthralgia (2), and skin rash (1). No clinical signs of zinc deficiency were seen, although zinc excretion was increased in three patients. No changes were seen in liver enzymes, creatinine, antinuclear factor, T-cell subsets, cardiac function, visual acuity, and audiogram. Although our results confirm deferiprone as an effective iron chelator in patients with thalassemia and in some patients with other forms of iron overload, there is still some concern about the safety of this drug, which therefore, at this time, should be used exclusively in well-controlled clinical trials.

Adult↗
PubMed2005

The efficacy of deferiprone on tissues aluminum removal and copper, zinc, manganese level in rabbits.

The effect of 1,2-dimethyl-3-hydroxypyrid-4-one [deferiprone (DE)] on aluminum mobilization and elimination from tissues and serum as well as the influence on the excretion of trace elements, copper, zinc and manganese in rabbits was investigated. Sixteen New Zealand rabbits were randomly divided into three groups: control, Al-only and Al+DE. The Al-only and Al+DE animals received injections of Al2(SO43.18H2O 600 micromol Al/kg 5 days per week for 3 weeks. One week after the last Al injection the Al+DE rabbits were given deferiprone 750 micromol/kg/day intragastrically for 2 weeks. At the 42nd day the animals were sacrificed and the organs were taken and digested. Blood was taken from the ear artery three times (at the initiation of the experiment, before and after deferiprone administration). The aluminum and copper, zinc, manganese were determined by atomic absorption spectrophotometry. Our results showed that deferiprone could highly mobilize aluminum stores from tissues. At the end of experiment the aluminum contents of bone, kidney, liver and brain in Al+DE were significantly lower than that in Al-only rabbits. The copper, zinc, manganese contents were not affected by deferiprone administration.

Aluminum↗
PubMed1998

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.

Alkaline Phosphatase↗
PubMed2005

Safety of oral iron chelator deferiprone in young thalassaemics.

UNLABELLED: Deferiprone is now widely used for iron chelation in patients with thalassaemia. Studies on its efficacy and safety have largely included older children and adults. OBJECTIVE: To assess the safety of deferiprone in children <6 yr of age. METHODS: The study is based on scrutiny of follow-up data of 44 patients of age <6 yr receiving deferiprone for a variable period of time. Occurrence of various side effects including gastrointestinal, osteoarticular were noticed and complete blood counts were performed every 2-4 wk. RESULTS: Nausea and vomiting were noticed in 12 (27.2%), joint symptoms were reported by four (9.1%) and neutropenia was observed in only two patients (4.5%). None of the patient had agranulocytosis. Thrombocytopenia was observed in 20 patients (45.45%), which occurred 3 months to 1 yr after deferiprone therapy. Interruption of deferiprone for 2-4 wk led to reversal of symptoms in all but two patients. CONCLUSION: Thrombocytopenia is one of the major side effects in young thalassaemics and necessitates frequent close monitoring of blood counts but its resolution after discontinuation and absence of clinical evidence of bleeding does not preclude its use.

Blood Cell Count↗
PubMed2006

Peripheral blood haematopoietic progenitor cells in patients with beta thalassaemia major receiving desferrioxamine or deferiprone as chelation therapy.

OBJECTIVES: The main adverse effect of deferiprone is the development of neutropenia, which occurs via an unknown mechanism. We aimed to gain insight into the pathogenesis of deferiprone-induced neutropenia by assessing the peripheral blood haematopoietic progenitor cells. METHODS: Sixteen patients with beta thalassaemia were studied; nine (Group A) were receiving desferrioxamine and seven (Group B) deferiprone. Ten healthy individuals comprised the control group (Group C). RESULTS: Granulocyte-erythrocyte-monocyte-megakaryocyte colony forming units were significantly more in Groups A and B compared with Group C. Granulocyte-macrophage colony forming units (CFU-GM) were significantly more in Group B compared with Group C. Macrophage colony forming units were significantly less in Group B compared with Group C. Granulocyte colony forming units (CFU-G) were significantly more in Group A compared with Group C. We found a trend in the difference in the number of CFU-G between patients' groups (P = 0.123). Adding serum from patients receiving deferiprone to cultures of controls resulted in a maturation arrest of the granulocytic lineage. CONCLUSION: Our findings point to a maturation arrest at the level of CFU-GM as a potential mechanism of deferiprone-induced neutropenia.

Adult↗
PubMed2002

Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia.

Patients with thalassemia major require lifelong chelation therapy to prevent iron-induced organ damage. The orally active chelator deferiprone has been proposed as an alternative for patients unable or unwilling to use deferoxamine. One report has concluded that deferiprone may worsen hepatic fibrosis in patients with thalassemia, whereas others have found no detrimental effect. A panel of 3 pathologists evaluated 112 coded liver biopsies obtained from 56 patients before and after deferiprone therapy. Fibrosis was scored with the Laennec and Ishak systems. The mean interval between liver biopsies was 3.1 years (range, 1.2-4.9 years). In 11 patients seronegative for hepatitis C, fibrosis scores before and after therapy were 1.12 +/- 1.07 and 0.97 +/- 0.84 (P =.42) with the use of the Ishak system, and 0.71 +/- 0.65 and 0.70 +/- 0.53 (P =.91) with the Laennec system. Among 45 patients seropositive for hepatitis C, fibrosis scores before and after therapy were 1.91 +/- 1.13 and 2.04 +/- 1.30 (P =.43) with the use of the Ishak system and 1.26 +/- 0.73 and 1.35 +/- 0.90 (P =.41) with the Laennec system. When the data set was limited to biopsies that each contained 6 or more portal tracts (31 patients), analysis still showed no significant change in fibrosis with time. With the use of the Laennec system, the fibrosis score did not increase by more than one level in any patients without hepatitis C; it increased by more than one level in 1 patient with hepatitis C; and it did not decrease by more than one level in any of the 56 patients. This analysis of the largest collection of liver biopsies reported to date in patients receiving deferiprone demonstrates no evidence of deferiprone-induced progression of hepatic fibrosis during long-term therapy.

Adolescent↗
PubMed2003

Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone.

The identification of a safe, orally active iron chelator is critically important for the prevention of morbidity and early death in patients receiving regular red cell transfusions. Based on our findings in a 1-year multicenter, prospective study of the safety and efficacy of deferiprone in patients with thalassemia major, we have extended the treatment period to 4 years. The mean dose of the chelator was 73 mg/kg per day during 531 patient-years. The rates of agranulocytosis (absolute neutrophil count [ANC] < 500 x 10(9)/L) and milder forms of neutropenia (ANC, 500-1500 x 10(9)/L) were 0.2 and 2.8 per 100 patient-years, respectively. Neutropenia occurred significantly more commonly in patients with intact spleens. Gastrointestinal and joint symptoms decreased significantly after the first year of therapy, and led to discontinuation of deferiprone in only one patient in years 2 to 4. The mean alanine aminotransferase (ALT) value of 71 U/L after 4 years of therapy was significantly higher than the baseline value of 61 U/L. Trend analysis showed no increase in the ALT levels or the percentage of patients with ALT levels greater than twice the upper limit of the reference range. Ferritin levels did not change significantly from the values at the time of change from deferoxamine to deferiprone in either the intention-to-treat analysis or in the 84 patients who completed 4 years of therapy. Because of concerns regarding the effectiveness of the studied dose of deferiprone, 47 patients discontinued therapy, whereas 15 patients interrupted therapy because of concerns regarding low iron levels. The results of this study help to define the safety and effectiveness of long-term therapy with deferiprone.

Administration, Oral↗
PubMed1998

Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients.

Fifty-one transfusion-dependent iron-loaded adult patients (38 with thalassemia major) were treated with the orally active iron chelator deferiprone (1,2 dimethyl-3-hydroxypyrid-4-one, L1) at a dose of 75 mg/kg/d (range, 50 to 79). Twenty patients discontinued the drug and five died after a mean of 18.7 months (range, 4 to 35). Of the 20, 5 had arthropathy, 5 had gastrointestinal symptoms, 4 had a rising serum ferritin, 3 had agranulocytosis or neutropenia, 1 had tachycardia, 1 had renal failure, and 1 went abroad. Twenty-six patients continued deferiprone for a mean of 39.4 months (range, 12 to 49). Among these patients, there was no overall significant change in serum ferritin (initial mean, 2,937 microg/L; range, 980 to 5,970; final mean, 2,323 microg/L; range, 825 to 5,970) or in urine iron excretion (initial mean, 31.2 mg/24 h; range, 16.3 to 58. 2; final mean, 32.1 mg/24 h; range, 9.4 to 75.8), implying no overall change in iron stores. When the patients who had received deferiprone for longer than 3 years were considered separately, there was also no significant change in serum ferritin or urinary iron excretion. The initial serum ferritin levels in the 26 patients who continued deferiprone treatment were significantly lower than in those who discontinued the drug (P < .01). The liver iron content in 17 patients who had received deferiprone for 24 to 48 months ranged from 5.9 to 41.2 mg/g dry weight, 50% having levels above 15.0 mg, a level associated with a high risk of cardiac disease due to iron overload. In this study the drug caused fewer side effects and was more effective at maintaining iron status among patients previously well chelated and with lower initial serum ferritin levels.

Adult↗
PubMed2000

Deferiprone: new preparation. Poorly assessed.

Deferiprone, an oral iron chelator, has been licensed in Europe for the treatment of iron overload in patients with beta thalassaemia who cannot be treated with deferoxamine because of adverse effects or the difficult administration schedule. (2) The clinical dossier is thin and methodologically mediocre. Even the preclinical assessment dossier is insufficient (there are no studies of carcinogenicity or hepatotoxicity). (3) The only available comparative trial, involving a small number of patients, suggests that deferiprone is less effective than deferoxamine in reducing ferritin levels and hepatic iron stores. (4) A non comparative trial suggests that long-term deferiprone therapy would not only fail, but would also increase the risk of liver fibrosis in some patients. This doubt is not dispelled by the other available non-comparative trials. (5) Deferiprone carries a risk of agranulocytosis in an estimated 1.2% of patients. (6) Deferiprone is teratogenic in two animal species.

Agranulocytosis↗
PubMed1996

Pharmaceutical analysis of the oral iron chelator deferiprone (DMHP,L1).

The oral iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyrid-4-one, DMHP, LT or CP20) can be a useful drug in patients with transfusional hemosiderosis. From 1987 about 1000 patients in 16 countries have taken this drug on the base of clinical trials or compassionate use. Since this compound is only available as a raw substance, it is important to ascertain its purity before bringing the drug into a pharmaceutical formulation. Because deferiprone is administered chronically and in high doses, intake of potential toxic impurities can be substantial. In this article a proposal for the quality control of deferiprone is presented in the form of a pharmaceutical monograph. This includes the analytical methods required for identification, purity checking and assay. Furthermore the way we synthesized the drug to get hold of it in a pure form is described. This synthesis is also used in manufacturing the drug commercially. The monograph can be used as a guideline for standardization of the quality of deferiprone to be used for further study and treatment.

Administration, Oral↗
PubMed2004

Deferiprone, efficacy and safety.

OBJECTIVE: Deferiprone (L1), the new oral iron chelator has been studied in several countries for its efficacy and toxicity with some conflicting observations. Toxicity involving joints has been reported more frequently in Indian patients. The authors planned to include larger number of Indian thalassemics in studying safety and efficacy of Deferiprone. METHODS: Seventy five thalassemic children (4-14 yr) were studied for one year with various investigations done periodically. Thirty patients (group A) received 50 mg/kg dose and 21 others (group B) received 75 mg/kg dose of Deferiprone. Rest of the patients were followed up without any chelator. RESULTS: The serum ferritin levels reduced significantly in both groups (P < 0.01 each); more in 75 mg/kg than the 50 mg/kg group. Arthropathy appeared in 15 (50%) patients in Group A and 6 (28.6%) of Group B after 1-12 (mean 6) months of L1 treatment; however, only one patient needed withdrawal of L1. Eleven patients needed indomethacin for pain relief. Seropositivity for antinuclear factor and rheumatoid factor had no relation to dose or duration of L1 therapy, arthropathy or the serum ferritin level. Twelve patients developed leucopenia (< 3.0 x 10(9)/L) and neutropenia (0-1.8 x 10(9)/L) after 2-11 months of L1 therapy and was not related to the dose or duration of therapy. The drug was restarted in 10 patients and only one of them developed a second episode of neutropenia. CONCLUSION: Deferiprone is an effective iron chelator, but arthropathy and neutropenia are very frequent side effects and need strict monitoring during therapy. Most of the neutropenia are neither very severe nor recur with re-challenge with the drug. Similarly, arthropathy does not need withdrawal of drug in majority of patients.

Adolescent↗
PubMed2005

Deferiprone as an oral iron chelator in sickle cell disease.

Iron overload is not uncommon in sickle cell disease (SCD) and requires regular chelation therapy in several instances. The present study evaluates the effect of deferiprone in 15 adult patients with SCD (ten beta(s)/beta(0)thalassemia and five beta(s)/beta(s)) and iron overload. Deferiprone was given at a dose of 75 mg/kg daily for 12 months. The evaluation considered pre- and post-treatment values of serum ferritin, urinary iron excretion, and T2 values of liver and heart obtained by magnetic resonance imaging (MRI). Eleven patients had a liver biopsy prior to starting therapy to evaluate iron concentration (LIC). Twelve patients completed the study with satisfactory compliance. In ten of them (83.3%) the serum ferritin levels decreased significantly at the end of the trial; in eight patients (66.6%) the reduction of serum ferritin was accompanied by a significant increase of their liver T2 values. All patients had a significant increase of urinary iron excretion in response to the drug. Ferritin levels and liver T2 values correlated with liver iron concentration; on the contrary, ferritin levels and liver T2 values failed to show any correlation with heart T2 values. Heart T2 values did not also show any correlation with left ventricular ejection fraction. Deferiprone was well tolerated and did not cause any significant adverse effects. These results suggest that deferiprone may effectively decrease the iron deposition in patients with SCD; moreover, T2 MRI proves to be a reliable and rapid, noninvasive method for assessing the liver iron load in patients with SCD.

Administration, Oral↗
PubMed1994

Binding of aluminium to plasma proteins: comparative effect of desferrioxamine and deferiprone (L1).

Ultramicrofiltration techniques were used to study both the binding of aluminium to high molecular weight proteins in the presence of different concentrations of desferrioxamine and deferiprone (L1) and the kinetics of aluminium release from human serum proteins. Human serum from healthy volunteers was used in all studies. The serum was spiked with aluminium (100 micrograms/l) and different concentrations of chelators. Ultramicrofiltration was performed with Amicon YMT membranes which had a nominal cut-off of 30,000 Da. Aluminium was measured by graphite furnace atomic absorption spectrometry in total serum and ultrafiltered fluid. Deferiprone shows a higher capability to displace aluminium from serum proteins (80%) than desferrioxamine (60%) at equivalent concentrations of the chelators. The kinetics of the release were also faster for deferiprone, taking 20 min to achieve its maximum effect, whereas, desferrioxamine achieved only 80% of its maximum effect after 2 h. Thus, deferiprone could be an attractive alternative to desferrioxamine, as an aluminium chelator agent.

Aluminum↗
PubMed1994

Arthropathy in thalassaemia patients receiving deferiprone.

The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.

Adolescent↗
PubMed1997

Immune function in patients with beta thalassaemia receiving the orally active iron-chelating agent deferiprone.

Short-term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immuno-suppression or immunodeficiency are observed during deferiprone therapy.

Adolescent↗
PubMed2000

Safety profile of the oral iron chelator deferiprone: a multicentre study.

In previous trials, the orally active iron chelator deferiprone (L1) has been associated with sporadic agranulocytosis, milder forms of neutropenia and other side-effects. To determine the incidence of these events, we performed a multicentre prospective study of the chelator. Blood counts were performed weekly, and confirmed neutropenia mandated discontinuation of therapy. Among 187 patients with thalassaemia major, the incidence of agranulocytosis (neutrophils < 0.5 x 109/l) was 0.6/100 patient-years, and the incidence of milder forms of neutropenia (neutrophils 0.5-1.5 x 109/l) was 5.4/100 patient-years. All cases of neutropenia resolved after interruption of therapy. Neutropenia occurred predominantly in non-splenectomized patients. Nausea and/or vomiting occurred early in therapy, was usually transient and caused discontinuation of deferiprone in three patients. Mild to moderate joint pain and/or swelling did not require permanent cessation of deferiprone and occurred more commonly in patients with higher ferritin levels. Mean alanine transaminase (ALT) levels rose during therapy. Increased ALT levels were generally transient and occurred more commonly in patients with hepatitis C. Persistent changes in immunological studies were infrequent, although sporadic abnormalities occurred commonly. Mean zinc levels decreased during therapy. Ferritin levels did not change in the overall group but decreased in those patients with baseline levels > 2500 microgram/l. This study characterized the safety profile of deferiprone, and, under the specific conditions of monitoring, demonstrated that agranulocytosis is less common than previously predicted.

Agranulocytosis↗