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PubMed2000

Treatment with deferiprone (L1) in a thalassemic patient with bone lesions due to desferrioxamine.

A male thalassemia major patient who developed bone and cartilage abnormalities with a standard dose of desferrioxamine (DFX) given subcutaneously from the age of 4 years was treated with the oral iron chelator deferiprone (L1). During L1 treatment an improvement of genu valgum, evidence of healing and filling in of bone at the periphery of knee metaphysis and improvement in growth velocity were observed. However, the sitting height had decreased further, confirming the irreversibility of platyspondylosis, so affecting the near final standing height (156.8 cm) which was below the mid-parental height (168 cm). Prospective studies are warranted to determine the effect of different iron chelators on the bone metabolism of patients with thalassemia.

Body Height↗
PubMed2004

Radiographic and MRI features of deferiprone-related arthropathy of the knees in patients with beta-thalassemia.

OBJECTIVE: This study was undertaken to describe the radiographic and MRI appearances of arthropathy of the knees in 14 patients with beta-thalassemia major undergoing chelation therapy with deferiprone (L1). MATERIALS AND METHODS: All available radiographs and MRI studies of the knees in 14 beta-thalassemia major patients (mean age, 16.3 years; age range, 7-33 years) undergoing chelation therapy with L1 were retrospectively assessed for changes in the synovium, cartilage, and bone. Imaging findings and signs of knee arthropathy were correlated with chelation therapy and average serum ferritin concentration. RESULTS: Nine (64%) of the 14 patients developed arthralgia of the knees during treatment with L1. Abnormal imaging findings were present in all symptomatic and two asymptomatic patients (12/14, 86%) and included joint effusion, subchondral bone irregularity, and patellar beaks. Additional MRI findings were thickening and enhancement of the synovium; hypointense bands in the synovium; irregularly thickened epiphyseal and articular cartilage overlying subchondral bone defects; and, on T2-weighted sequences, hyperintense articular cartilage lesions. The degree of knee symptoms at the time of imaging did not reflect the severity of cartilage and subchondral bone changes. CONCLUSION: Radiologic changes can be seen in L1-related arthropathy and should be recognized. MRI of the knees should be considered in symptomatic children and young adults with thalassemia undergoing L1 chelation therapy for iron overload.

Adolescent↗
PubMedDate not supplied

Efficacy and adverse effects of oral iron chelator deferiprone (l1, 1,2- dimethyl-3-hydroxypyrid-4-one) in patients with beta thalassaemia major in Pakistan.

BACKGROUND: Deferiprone (DFP,L1) is a bidentate oral iron chelator which binds to iron in a 3:1 ratio. It has the potential advantage of reduced cost and increased compliance. We conducted a study in order to determine the efficacy and adverse effects of DFP in Pakistani thalassaemic patients. METHODS: A group of 26 thalassaemic patients entered the study during the period Jan 1999 to Aug 2002. DFP supplied by Lipomed, Switzerland was given at a daily dose of 75 mg/kg/day (range 50-75 mg/kg/day). After giving informed written consent all the patients were subjected to clinical examination and investigations for monitoring the response. Blood complete picture, liver function tests, blood urea & creatinine, antinuclear factor antibodies (ANF) were tested in all cases before starting DFP treatment. RESULTS: The patients ages ranged from 11 to 27 years, 16 were male and 10 were female. Initial serum ferritin level ranged from 3100-8800 microg/l, mean serum ferritin level was 7129 +/- 1467 microg/l (95% CI 6536 - 7721 microg/l). ECG and Echocardiography was performed in all cases and in 11 cases Cardiac Multigated acquisition (MUGA) Scan was also performed and six patients with impaired left ventricular function were identified. Four patients were lost to follow up and one patient died due to cardiomyopathy. Among the remaining 21 patients serum ferritin levels dropped to 1900 microg/l to 5600 microg/l with mean level of 4288 microg/l (95%CI 3874 - 4702 microg/l), SD 911 microg/l. Significance of difference was (p < 0.001) by Paired samples 't' test. Six patients had gastrointestinal symptoms along with two having arthropathy. ANF positivity was not detected in any patient while on DFP treatment. Similarly, agranulocytosis was not detected in any patient. CONCLUSION: Mean serum ferritin level estimated at the start of trial was 7129 microg/l. This shows that Pakistani thalassaemic patients are quite iron overloaded due to socioeconomic reasons that are peculiar to our setup. In this study DFP was well tolerated and caused fewer side effects. It had much better patient compliance and was effective in lowering serum ferritin level in previously most poorly chelated patients.

Adolescent↗
PubMed2006

Successful recovery of acute hemosiderotic heart failure in beta-thalassemia major treated with a combined regimen of desferrioxamine and deferiprone.

We report the case of a 25-years-old male with beta-thalassemia major who developed acute heart failure, with severe systolic dysfunction, resulting from iron overload. Combined iron chelation with desferrioxamine and deferiprone together with standard cardiological treatment induced prompt and complete restoration of the cardiac function.

Adult↗
PubMed2006

A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassemia.

We compared the safety and efficacy of alternating deferoxamine and deferiprone with that of deferoxamine monotherapy. Sixty transfusion-dependent thalassemia patients regularly treated with deferoxamine were randomized to continue deferoxamine alone or to receive an alternating therapy for one year. Both arms resulted in equivalent decreases of serum ferritin and liver iron concentration. There was no significant difference in the proportion of patients with adverse events in the two therapy groups although the nature of the adverse events differed according to the chelation regimen.

Adolescent↗
PubMed1995

Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo.

Red blood cell (RBC) membranes from patients with the thalassemic and sickle hemoglobinopathies carry abnormal deposits of iron presumed to mediate a variety of oxidative-induced membrane dysfunctions. We hypothesized that the oral iron chelator deferiprone (L1), which has an enhanced capacity to permeate cell membranes, might be useful in chelating these pathologic iron deposits from intact RBCs. We tested this hypothesis in vitro by incubating L1 with RBCs from 15 patients with thalassemia intermedia and 6 patients with sickle cell anemia. We found that removal of RBC membrane free iron by L1 increased both as a function of time of incubation and L1 concentration. Thus, increasing the time of incubation of thalassemic RBCs with 0.5 mmol/L L1 from 0.5 to 6 hours, enhanced removal of their membrane free iron from 18% +/- 9% to 96% +/- 4%. Dose-response studies showed that incubating thalassemic RBC for 2 hours with L1 concentrations ranging from 0.125 to 0.5 mmol/L resulted in removal of membrane free iron from 28% +/- 15% to 68% +/- 11%. Parallel studies with sickle RBCs showed a similar pattern in time and dose responses. Deferoxamine (DFO), on the other hand, was ineffective in chelating membrane free iron from either thalassemic or sickle RBCs regardless of dose (maximum, 0.333 mmol/L) or time of incubation (maximum, 24 hours). In vivo efficacy of L1 was shown in six thalassemic patients whose RBC membrane free iron decreased by 50% +/- 29% following a 2-week course of L1 at a daily dose of 25 mg/kg. As the dose of L1 was increased to 50 mg/kg/d (n = 5), and then to 75 mg/kg/d (n = 4), 67% +/- 14% and 79% +/- 11%, respectively, of their RBC membrane free iron was removed. L1 therapy--both in vitro and in vivo--also significantly attenuated the malondialdehyde response of thalassemic RBC membranes to in vitro stimulation with peroxide. Remarkably, the heme content of RBC membranes from L1-treated thalassemic patients decreased by 28% +/- 10% during the 3-month study period. These results indicate that L1 can remove pathologic deposits of chelatable iron from thalassemic and sickle RBC membranes, a therapeutic potential not shared by DFO. Furthermore, membrane defects possibly mediated by catalytic iron, such as lipid peroxidation and hemichrome formation, may also be alleviated, at least in part, by L1.

Anemia, Sickle Cell↗
PubMed1995

Oral iron chelation therapy with deferiprone. Monitoring of biochemical, drug and iron excretion changes.

The oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone, CAS 30652-11-0) has been given daily for 3-11 months to 6 transfusion dependent iron loaded patients (myelodysplasia (MDS) 2, Diamond-Blackfan anaemia 1, thalassaemia intermedia 1, thalassaemia major 2). Daily doses of 3 g, 2 x 2 g and 3 x 2 g were administered for the first 2-7 months. Daily doses of 2 x 3 g were also used for periods up to 4 months. Urine iron excretion following 3 g of L1 was found to be related to the number of previous transfusions but not to serum ferritin or the amount of L1 excreted. In each case 24 h urinary iron excretion in response to 3 g L1 ranged from 5-21 mg in MDS, 13-25 mg in a thalassaemia intermedia and a Diamond-Blackfan patient and 16-110 mg in thalassaemia major patients. Further increases of urinary iron were observed in all the patients when the daily dose was increased. Serum ferritin levels have fluctuated but overall have remained unchanged. Biochemical assessment did not show any major abnormalities ascribed to L1 except from subnormal serum zinc levels in two patients and white blood cell absorbate in another. In a separate study we have compared urinary L1 and iron excretions in 7 transfusional iron loaded patients. In all the cases the concentration of L1 was in excess of iron and higher than the level required for 100% iron binding. There was no other apparent correlation between the concentrations of L1 and iron in the urines studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Treatment of iron overload states with oral administration of the chelator agent, L1 (Deferiprone)].

Nine iron overloaded patients were treated with L1--Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) in daily dose 3 g (40-50 mg/kg) for 12 weeks. In 7 patients the efficiency of L 1 treatment was compared to the therapeutic effect of the same dose of desferrioxamine (Desferal). A significant increase in urinary iron excretion was observed after administration of both chelating agents. Iron excretion after L 1 treatment was approximately 65% of that obtained with Desferal. The amount of excreted iron correlated with the amount of iron stores before chelation. A significant decrease in transferrin saturation, serum and red cell ferritin was observed after treatment with Desferal, L 1 administration caused a significant decrease only in serum ferritin level. However, all the parameters reflecting iron stores remained increased when compared to normal values after 12 weeks of chelation therapy. An incomplete absorption from gut and some reutilization of chelated iron may be responsible for less potent iron chelation by L 1 in comparison to Desferal. A low tolerance of the drug together with repeated nausea and vomiting were the most frequent adverse effects observed in the course of L1 administration. L 1 treatment had to be discontinued due to repeated vomiting in one patient and due to progressive granulocytopenia and thrombocytopenia in another patient. Because of the side effects more clinical studies with L 1 are needed before its introduction in wide clinical practice.

Administration, Oral↗
PubMed1993

Competition between deferiprone, desferrioxamine and other chelators for iron and the effect of other metals.

Competition for iron between the leading oral iron chelator deferiprone (L1, 1,2-dimethyl-3-hydroxypyrid-4-one) and desferrioxamine (DF), and the effect of other metals has been studied. Visible spectroscopy was used to estimate the displacement of iron from DF-iron(III) and L1-iron(III) complexes, respectively, by varying quantities of up to 100 molar equivalent of a competing metal ion M+ (Mg2+, Al3+, Ca2+, Mn2+, Co2+, Cu2+, Zn2+ and Pb2+) at physiological pH. Copper and aluminium showed the greatest competition against iron, while magnesium, calcium and manganese had little or no effect and the other metals an intermediate effect. DF showed greater selectivity for iron than L1 under these conditions. An analogous series of experiments carried out using a competing chelator of up to 50 molar equivalent in a place of a competing metal ion showed that 8-hydroxyquinoline, diethylenetriamine-pentaacetic acid (DTPA) and tropolone were more effective at displacing iron from DF-Fe and (L1)3Fe complexes than maltol or omadine. Desferrioxamine was the most efficient competitor against L1. Stoichiometric studies of the L1 complexes of aluminium and copper at pH 7.4 using Job Plots, suggested the formation of (L1)3Al and (L1)2Cu complexes, respectively.

Aluminum↗
PubMed1995

Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassemia and hemoglobin E-beta thalassemia.

OBJECTIVES: To assess efficacy and safety of oral iron chelating agent deferiprone (DFP) in patients with beta thalassemia and hemoglobin E-beta thalassemia. DESIGN: Non-randomized study. SETTING: Hematology Out-Patient Department. SUBJECTS: Forty-one patients of beta thalassemia and hemoglobin E-beta thalassemia. INTERVENTIONS: DFP was given to 20 patients, 10 patients of beta thalassemia and 10 with hemoglobin E-beta thalassemia; the rest were taken as controls. RESULTS: A significant fall in serum ferritin was observed in the study group along with rise in urinary iron excretion (p < 0.05). Adverse effects of DFP were nausea and vomiting (30%), significant arthropathy requiring stopping of the drug (30%), and reversible neutropenia in one patient. All these complications could be managed easily with medical supervision and no death or permanent disability was seen. CONCLUSIONS: DFP is an effective and fairly well tolerated oral iron chelating agent. The side effects that occur can be tackled easily if monitored properly.

Administration, Oral↗
PubMed1998

Oral iron chelating therapy. A single center interim report on deferiprone (L1) in thalassemia.

BACKGROUND AND OBJECTIVE: Deferiprone (L1) is a largely studied oral chelator in clinical setting, however, no definite conclusions concerning efficacy and toxicity still could be drawn. In an ongoing prospective trial with L1, we evaluated the efficacy and tolerance-toxicity in patients with thalassemia major previously treated by desferrioxamine (DFO); the specific aim of the study is to demonstrate that L1 could be an alternative to DFO in some patients with an acceptable toxicity. DESIGN AND METHODS: Sixty-nine patients over 13 years of age with poor compliance to DFO were considered for the study. The design included a liver biopsy before starting L1 in all patients in order to define liver siderosis either by histologic grading or by hepatic iron concentration (HIC); only patients with a minimum HIC of 4 mg/g dry weight entered the study. A repetition of the liver biopsy after one year of L1 was planned; further evaluations included serum ferritin, plasma iron, transferrin TIBC and iron urine excretion. L1 was given at 70 mg/kg/day in three divided doses. Toxicity was monitored either clinically or by controlling liver, kidney and marrow function by specific tests. Concerning clinical characteristics 52 patients showed hypogonadism (78%), 39 growth retardation (58%), 6 diabetes (9%), 4 cardiomyopathy (6%), 9 hypothyroidism (12%); 45 patients had chronic liver damage (65%). RESULTS: We focus this report on data collected in a group of 29 patients with a minimum follow-up of one year (14-33 months). The mean ferritin value was 3748 ng/mL (range: 200-10,000) and 2550 ng/mL (range: 80-14,500), before and while on L1 therapy, respectively (p = 0.001); the mean sideruria changed from 17.25 mg/dL (range: 5.4-50) to 20.98 mg/dL (range: 10-40), on DFO and L1, respectively (p = 0.078); the ratio between plasma iron (sideremia) and transferrin TIBC changed from 0.96 with DFO to 0.86 with L1 (0.014). A correlation with grade of liver siderosis and serum ferritin (p = 0.069) and iron urine excretion (p = 0.008) was recorded. The judgement of efficacy showed that L1 was effective (EF) in 9 patients, no assessable (UN) in 11 patients, not effective (NE) in 2 patients and with no advantages with respect to DFO in 7 patients. Liver biopsy was repeated in 20 patients showing a reduction of grade of liver siderosis and iron content in 7 patients. Clinical toxic effects of L1 were gastric intolerance (one patient), joint pain (three patients) and mild and temporary neutropenia (one patient). INTERPRETATION AND CONCLUSIONS: This preliminary experience shows that L1 is effective in several patients with thalassemia with poor compliance to DFO and to improve iron burden and iron excretion with generally minor side effects. L1 could be an alternative to DFO in some patients, however the recognition of neutropenia warrants a careful evaluation of patients and efforts finalized to early recognition of those to be addressed with this new and still experimental therapy.

Adolescent↗
PubMed1999

Erythropoiesis: Comparison of Cytotoxic Aldehyde Generation in Beta-Thalassemia Patients Chelated with Deferoxamine or Deferiprone (L1) Versus NO Chelation.

The mechanism of iron-induced organ failure in iron overload disorders is not known, but it is conjectured that excess iron-catalyzed free radical generation contributes to organ damage. We hypothesized that free radical generation, quantified by the presence of 20 separate cytotoxic aldehydes in plasma, would be significantly increased in non-chelated beta-thalassemia major patients, in comparison to those chelated with either deferiprone (L1) or deferoxamine (desferal). We also report on red cell glutathione peroxidase activity in these patient groups, an enzyme involved in averting the damaging effects of free radicals. Ten patients were chelated with nightly subcutaneous infusions of desferal and 10 received the experimental oral chelator L1. Body iron burden was assessed by serum ferritin and hepatic iron concentrations. In comparison to non-chelated controls, significant decreases of 62% and 64% in total cytotoxic aldehyde concentrations were observed in patients chelated with desferal and L1, respectively (p < 0.001). Significantly lower red cell glutathione peroxidase activity was also observed in non-chelated controls, in comparison to those chelated with either desferal or L1 (p < 0.001). This is the first report on the concentrations of cytotoxic aldehydes in non-chelated beta-thalassemia major patients, and the first to report on the effects of L1 against cytotoxic aldehyde formation in plasma of patients with iron-overload.

Journal Article↗
PubMed2004

Combined therapy with desferrioxamine and deferiprone: a new protocol for iron chelation in thalassemia.

Deferiprone (DFO) at the standard daily dose of 75 mg/kg was given to 13 transfusion-dependent patients with thalassemia in whom conventional desferrioxamine (DFX) therapy had proven ineffective and caused adverse side effects. In six patients, serum ferritin and alanine aminotransferase levels decreased significantly and urinary iron excretion increased. In seven patients in whom DFO administration alone was ineffectual, DFX was added at a daily dose of 40 to 50 mg/kg given subcutaneously for 7 to 10 days following transfusion. All patients exhibited a significant decrease in serum ferritin levels and an increase in urinary iron excretion, with alanine aminotransferase levels decreased in four patients. The combined DFX and DFO therapy could represent an effective alternative to conventional DFX therapy not only in nonresponding patients with thalassemia but also, by lowering to less than 25% the DFX dosage, in patients who exhibit important DFX-related side effects.

Adolescent↗