Deferiprone

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Fernando Tricta - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of Deferiprone for pantothenate kinase associated neurodegeneration a randomised double blind controlled trial and an open label extension study
    Lancet Neurology, 2019
    Co-Authors: Fernando Tricta, Caroline Fradette, Thomas Klopstock, Lynne Neumayr, Ivan Karin, Giovanna Zorzi, Tomasz Kmiec, B Buchner, Hannah E Steele
    Abstract:

    Summary Background Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder characterised by progressive generalised dystonia and brain iron accumulation. We assessed whether the iron chelator Deferiprone can reduce brain iron and slow disease progression. Methods We did an 18-month, randomised, double-blind, placebo-controlled trial (TIRCON2012V1), followed by a pre-planned 18-month, open-label extension study, in patients with PKAN in four hospitals in Germany, Italy, England, and the USA. Patients aged 4 years or older with a genetically confirmed diagnosis of PKAN, a total score of at least 3 points on the Barry-Albright Dystonia (BAD) scale, and no evidence of iron deficiency, neutropenia, or abnormal hepatic or renal function, were randomly allocated (2:1) to receive an oral solution of either Deferiprone (30 mg/kg per day divided into two equal doses) or placebo for 18 months. Randomisation was done with a centralised computer random number generator and with stratification based on age group at onset of symptoms. Patients were allocated to groups by a randomisation team not masked for study intervention that was independent of the study. Patients, caregivers, and investigators were masked to treatment allocation. Co-primary endpoints were the change from baseline to month 18 in the total score on the BAD scale (which measures severity of dystonia in eight body regions) and the score at month 18 on the Patient Global Impression of Improvement (PGI-I) scale, which is a patient-reported interpretation of symptom improvement. Efficacy analyses were done on all patients who received at least one dose of the study drug and who provided a baseline and at least one post-baseline efficacy assessment. Safety analyses were done for all patients who received at least one dose of the study drug. Patients who completed the randomised trial were eligible to enrol in a single-arm, open-label extension study of another 18 months, in which all participants received Deferiprone with the same regimen as the main study. The trial was registered on ClinicalTrials.gov , number NCT01741532 , and EudraCT, number 2012-000845-11. Findings Following a screening of 100 prospective patients, 88 were randomly assigned to the Deferiprone group (n=58) or placebo group (n=30) between Dec 13, 2012, and April 21, 2015. Of these, 76 patients completed the study (49 in the Deferiprone group and 27 in the placebo group). After 18 months, the BAD score worsened by a mean of 2·48 points (SE 0·63) in patients in the Deferiprone group versus 3·99 points (0·82) for patients in the control group (difference −1·51 points, 95% CI −3·19 to 0·16, p=0·076). No subjective change was detected as assessed by the PGI-I scale: mean scores at month 18 were 4·6 points (SE 0·3) for patients in the Deferiprone group versus 4·7 points (0·4) for those in the placebo group (p=0·728). In the extension study, patients continuing Deferiprone retained a similar rate of disease progression as assessed by the BAD scale (1·9 points [0·5] in the first 18 months vs 1·4 points [0·4] in the second 18 months, p=0·268), whereas progression in patients switching from placebo to Deferiprone seemed to slow (4·4 points [1·1] vs 1·4 points [0·9], p=0·021). Patients did not detect a change in their condition after the additional 18 months of treatment as assessed by the PGI-I scale, with mean scores of 4·1 points [0·2] in the Deferiprone–Deferiprone group and of 4·7 points [0·3] in the placebo–Deferiprone group. Deferiprone was well tolerated and adverse events were similar between the treatment groups, except for anaemia, which was seen in 12 (21%) of 58 patients in the Deferiprone group, but was not seen in any patients in the placebo group. No patient discontinued therapy because of anaemia, and three discontinued because of moderate neutropenia. There was one death in each group of the extension study and both were secondary to aspiration. Neither of these events was considered related to Deferiprone use. Interpretation Deferiprone was well tolerated, achieved target engagement (lowering of iron in the basal ganglia), and seemed to somewhat slow disease progression at 18 months, although not significantly, as assessed by the BAD scale. These findings were corroborated by the results of an additional 18 months of treatment in the extension study. The subjective PGI-I scale was largely unchanged during both study periods, indicating that might not be an adequate tool for assessment of disease progression in patients with PKAN. Our trial provides the first indication of a decrease in disease progression in patients with neurodegeneration with brain iron accumulation. The extensive information collected and long follow-up of patients in the trial will improve the definition of appropriate endpoints, increase the understanding of the natural history, and thus help to shape the design of future trials in this ultra-orphan disease. Funding European Commission, US Food and Drug Administration, and ApoPharma Inc.

  • Deferiprone pharmacokinetics with and without iron overload and in special patient populations
    Blood, 2015
    Co-Authors: Michael Spino, John T Connelly, Yuchung Tsang, Caroline Fradette, Fernando Tricta
    Abstract:

    Background: The value of understanding Deferiprone9s comparative pharmacokinetics (PK) in differing indications and human subpopulations derives from its potential versatility in treating, not only transfusional iron overload, but also conditions in which iron mishandling is localized. While some PK on Deferiprone in patients with thalassemia has been published, little is known for patients without systemic iron overload, or for those requiring special consideration (e.g., children, patients with hepatic or renal impairment). Reporting of characteristics such as Deferiprone9s rapid absorption, extensive glucuronidation, and principally urinary excretion has been consistent, but some publications have followed false trails, and lack of IV data and the dearth of PK information in non-iron-overloaded patients have limited the overall picture. Availability of a comprehensive integration of Deferiprone human PK would address misconceptions and help in predicting doses for patients with various indications currently being investigated, as well as in special populations. Objective: To provide data on the PK of Deferiprone generated from currently unpublished studies, to enable dosing guidance for Deferiprone use in conditions beyond adult patients with thalassemia. Methods: Data from PK studies, conducted as part of our development programme with Deferiprone in thalassemia, sickle cell disease, and conditions without systemic iron overload, as well as in children and subjects with impaired renal function or impaired hepatic function are presented. Results: The absolute (oral vs IV) bioavailability of Deferiprone was 72% (Studies were conducted with Ferriprox™ 500 mg tablets). Following an oral dose of 1,500 mg (20 mg/kg), the mean maximum serum Deferiprone concentration (Cmax) in the fasting state in non-iron-loaded healthy subjects was 20 mcg/mL, and the mean total area under the concentration-time curve (AUC) was 53 mcg·h/mL. Cmax of Deferiprone occurs approximately 1 hour after a single dose in fasted subjects, but may be delayed to 2 hours in the fed state. Food decreases the Cmax of Ferriprox tablets by about a third and the AUC by 10%. Steady state is achieved on the first day of dosing and cross-study comparisons indicate dose proportionality. Protein binding of Deferiprone in human plasma is ≤20%. Metabolism is predominantly UGT 1A6-mediated conjugation to form a 3-O -glucuronide, which is rapidly cleared by renal excretion (Tmax 2-4 hours in fasting subjects) and lacks iron binding capability. There is no evidence of genetic polymorphism. Most of a dose of Deferiprone is rapidly eliminated from plasma, with a t½ of about 2 hours, and is excreted primarily into the urine as the glucuronide. Dose adjustment is not necessary in patients with renal impairment, as confirmed by similar total body clearance to healthy controls. Subjects with mild or moderate hepatic impairment retain sufficient capacity for glucuronidation to also not require dose adjustment. The clearance of Deferiprone in children is comparable to that in adults. The pharmacokinetics in patients with Friedreich Ataxia, PKAN and Parkinson9s disease, conditions in which Deferiprone is currently being evaluated by various investigators, is expected to be comparable to PK in healthy volunteers. Conclusions: Comparative IV and oral dosing of Deferiprone reveals that it is extensively and rapidly absorbed from the gut. The PK of Deferiprone in patients without systemic iron overload is predicted to be similar to the PK in healthy subjects. Studies in special populations demonstrate that dose adjustment in children or in patients with renal or moderate hepatic impairment is not necessary. Disclosures Spino:ApoPharma Inc.: Employment. Off Label Use: Deferiprone is approved for the treatment of iron overload in thalassemia syndromes. Connelly:ApoPharma Inc.: Employment. Tsang:ApoPharma Inc.: Employment. Fradette:ApoPharma Inc.: Employment. Tricta:ApoPharma Inc.: Employment.

  • the safety tolerability and efficacy of a liquid formulation of Deferiprone in young children with transfusional iron overload
    Journal of Pediatric Hematology Oncology, 2010
    Co-Authors: Mohsen Saleh El-alfy, Teny Tjitra Sari, Fernando Tricta, Amal Elbeshlawy
    Abstract:

    Limited data are available on the use of Deferiprone in children younger than 10 years of age. This study evaluated the safety and efficacy of a new liquid formulation of Deferiprone for the treatment of transfusional iron overload in children 1-10 years old. One hundred children (91 thalassemia maj

  • The Tolerability, Safety and Efficacy of a New Oral Solution of Deferiprone in Children with Transfusional Iron Overload
    Blood, 2008
    Co-Authors: Mohsen Saleh El-alfy, Teny Tjitra Sari, Lee Lee Chan, Fernando Tricta, Amal El-beshlawy
    Abstract:

    Abstract Although there are 20 yr of clinical experience with Deferiprone in treating transfusional iron overload, limited data exist on the safety and efficacy of Deferiprone in very young children. Difficulties in swallowing the tablet formulation of Deferiprone (Ferriprox®, ApoPharma, Canada), is a limiting factor in the administration of Deferiprone in young children. The current study evaluated the tolerability, safety and efficacy of a new liquid formulation of Deferiprone (Ferriprox® Oral Solution) in iron-overloaded pediatric patients with transfusion-dependent anemias (≥ 8 transfusions/year). The study also assessed the daily neutrophil count in patients who continued Deferiprone therapy during episodes of mild neutropenia. The study was approved by the relevant regulatory authorities and ethics review boards. Informed consent was obtained from the patients’ legal representatives. One-hundred children [91Thal major, 8 HbE, 1 Sickle Cell disease; 46 female and 54 male; 76 Caucasian (Egyptian), 24 Asian (9 Chinese, 13 Indonesian, 2 Malay)] ranging from 1 to 10 yr of age (median 5.0 yr) were enrolled. At enrollment, 51 children were being treated with deferoxamine (mean duration 1.82 ± 1.95 years; range 0.1–7.3 yr), 20 with Deferiprone (mean duration 0.5 ± 0.6 yr; range 0. 04–2 yr), 8 patients with deferasirox (mean duration 0.4 ± 0.5 yr; range 0.1–1.6 yr) and 21 patients were naïve to chelation therapy. Deferiprone therapy was initiated at 50 mg/kg/day, divided in 3 doses, for the first 2 weeks, and then increased to 75 mg/kg/day. The dose was further increased to 100 mg/kg/day for those patients with ferritin > 2500 μg/L at baseline. Ninety-five children completed 6 months of therapy. One patient was lost to follow-up, 2 patients voluntarily withdrew consent (1 patient disliked the taste, 1 patient did not comply with weekly visits), and 2 were withdrawn due to adverse events. Therapy with the oral solution of Deferiprone was not associated with unexpected adverse reactions. The incidence of gastrointestinal adverse reactions was lower than observed for the tablet formulation in older patients (Table). Oral solution in children ≤ 10 yr old Tablet formulation in children > 6 yr old and adults Adverse Reaction (AR) % Patients with AR % Patients with AR Nausea 1% 16% Abdominal Pain 6% 14% Vomiting 6% 12% Arthralgia 4% 11% Neutropenia (0.5 × 109/L ≤ ANC < 1.5 × 109/L) 6% 6% Agranulocytosis (0.5 < ANC) 2% 1% Five patients experienced single episodes of mild neutropenia [absolute neutrophil count (ANC) 1.5 × 109/L but not less than 1.0 × 109/L], which resolved and did not recur, despite continuous Deferiprone use. Another patient experienced 2 transient episodes of mild neutropenia and a third episode that progressed to agranulocytosis (ANC < 0.5 × 109/L). Deferiprone was discontinued and the patient was treated with G-CSF. The event resolved (ANC > 1.5 × 109/L) within 9 days upon discontinuation of Deferiprone. Another patient experienced a single episode of agranulocytosis, which resolved within 9 days upon discontinuation of Deferiprone and therapy with G-CSF. During the 6-month therapy, there was a significant decrease in serum ferritin from a mean baseline value of 2532 ± 1463 to 2176 ± 1144 μg/L (p< 0.0005). The new oral solution of Deferiprone was well tolerated and effective in lowering serum ferritin in young children with transfusion dependent anemias and exhibited a safety profile similar or better to that reported for the tablet formulation in older patients. The results also suggest that not all episodes of mild neutropenia progress to agranulocytosis with continued Deferiprone therapy, and that further studies are warranted to differentiate those patients from those at risk of developing Deferiprone-induced agranulocytosis following neutropenia. This study includes the first report of patients using Deferiprone as their first iron chelator.

  • safety and effectiveness of long term therapy with the oral iron chelator Deferiprone
    Blood, 2003
    Co-Authors: Alan R. Cohen, Renzo Galanello, Antonio Piga, Vincenzo De Sanctis, Fernando Tricta
    Abstract:

    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 × 109/L) and milder forms of neutropenia (ANC, 500-1500 × 109/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.

Antonio Piga - One of the best experts on this subject based on the ideXlab platform.

  • effect of Deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload
    Journal of Cardiovascular Magnetic Resonance, 2011
    Co-Authors: Gillian C Smith, Antonio Piga, Vasili Berdoukas, Markissia Karagiorga, Vasili Ladis, Athanassios Aessopos, Francisco Alpendurada, John Paul Carpenter, Mohammed H Alam, Efstathios D Gotsis
    Abstract:

    Background: Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs. Methods: In the RCT, 61 TM patients were randomised to receive either Deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment. Results: From baseline to 12 months, Deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p = 0.014), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p = 0.001). This was associated with a 27% increase in T2* (p < 0.001) and 3.1% increase in LVEF (p < 0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p = 0.38), or RVEF (70.0 to 69.9%, p = 0.93) whereas the T2* increased by 13% (p < 0.001), but with no change in LVEF (0.32%; p = 0.66). Analysis of between drugs treatment effects, showed significant improvements favouring Deferiprone with a mean effect on RVESV of -1.82 mL (p = 0.013) and 1.16% for RVEF (p = 0.008). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p < 0.001), with a significant difference in RVEF of 3.5% favouring Deferiprone over deferoxamine (p = 0.012). Conclusion: In this retrospective analysis of a prospective RCT, Deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with Deferiprone.

  • cardiac morbidity and mortality in deferoxamine or Deferiprone treated patients with thalassemia major
    Blood, 2006
    Co-Authors: Caterina Borgnapignatti, Maria Domenica Cappellini, Piero De Stefano, Giovanni Carlo Del Vecchio, Gian Luca Forni, Maria Rita Gamberini, Roberta Ghilardi, Antonio Piga, M A Romeo, Huaqing Zhao
    Abstract:

    Deferoxamine (DFO) therapy has been associated with improved survival of thalassemia patients. However, cardiac disease remains the main cause of death in those patients. In 1995, the oral chelator Deferiprone became available for clinical use. We compared the occurrence of cardiac disease in patients treated only with DFO and in those whose therapy was switched to Deferiprone during the period of observation, from January 31, 1995, to December 31, 2003. All patients with thalassemia major treated in 7 Italian centers who were born between 1970 and 1993 and who had not experienced a cardiac event prior to January 1995 were included. DFO only was given to 359 patients, and 157 patients received Deferiprone for part of the time. A total of 3610 patient-years were observed on DFO and 750 on Deferiprone. At baseline, the 2 groups were comparable for age and sex, while ferritin levels were significantly higher in patients switched to Deferiprone. Fifty-two cardiac events, including 10 cardiac deaths, occurred during therapy with DFO. No cardiac events occurred during Deferiprone therapy or within at least 18 months after the end of it. In the setting of a natural history study, Deferiprone therapy was associated with significantly greater cardiac protection than deferoxamine in patients with thalassemia major.

  • randomized controlled trial of Deferiprone or deferoxamine in beta thalassemia major patients with asymptomatic myocardial siderosis
    Blood, 2006
    Co-Authors: Dudley J Pennell, Antonio Piga, Vasili Berdoukas, Markissia Karagiorga, Vasili Ladis, Athanassios Aessopos, Efstathios D Gotsis, Mark A Tanner, Gill Smith, Mark Westwood
    Abstract:

    Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2*) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral Deferiprone monotherapy. The dose of Deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% ± 5.3% and 93% ± 9.7% ( P = .81), respectively. The improvement in myocardial T2* was significantly greater for Deferiprone than deferoxamine (27% vs 13%; P = .023). Left ventricular ejection fraction increased significantly more in the Deferiprone-treated group (3.1% vs 0.3% absolute units; P = .003). The changes in liver iron level (-0.93 mg/g dry weight vs -1.54 mg/g dry weight; P = .40) and serum ferritin level (-181 μg/L vs -466 μg/L; P = .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for Deferiprone-treated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major.

  • safety and effectiveness of long term therapy with the oral iron chelator Deferiprone
    Blood, 2003
    Co-Authors: Alan R. Cohen, Renzo Galanello, Antonio Piga, Vincenzo De Sanctis, Fernando Tricta
    Abstract:

    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 × 109/L) and milder forms of neutropenia (ANC, 500-1500 × 109/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.

  • comparative effects of Deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major a retrospective analysis
    Haematologica, 2003
    Co-Authors: Antonio Piga, Carmen Maria Gaglioti, Eugenia Fogliacco, Fernando Tricta
    Abstract:

    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.

Renzo Galanello - One of the best experts on this subject based on the ideXlab platform.

  • a pilot trial of Deferiprone for neurodegeneration with brain iron accumulation
    Haematologica, 2011
    Co-Authors: Giovanni Abbruzzese, Renzo Galanello, Giovanni Cossu, Manuela Balocco, Roberta Marchese, Daniela Murgia, Maurizio Melis, Susanna Barella, Gildo Matta, Uberto Ruffinengo
    Abstract:

    Deferiprone was shown to reverse iron deposition in Friedreich’s ataxia. This multi-center, unblinded, single-arm pilot study evaluated safety and efficacy of Deferiprone for reducing cerebral iron accumulation in neurodegeneration with brain iron accumulation. Four patients with genetically-confirmed pantothenate kinase-associated neurodegeneration, and 2 with parkinsonism and focal dystonia, but inconclusive genetic tests, received 15 mg/kg Deferiprone bid. Magnetic resonance imaging and neurological examinations were conducted at baseline, six and 12 months. Chelation treatment caused no apparent hematologic or neurological side effects. Magnetic resonance imaging revealed decreased iron accumulation in the globus pallidus of 2 patients (one with pantothenate kinase-associated neurodegeneration). Clinical rating scales and blinded video rating evaluations documented mild-to-moderate motor improvement in 3 patients (2 with pantothenate kinase-associated neurodegeneration). These results underline the safety and tolerability of Deferiprone, and suggest that chelating treatment might be effective in improving neurological manifestations associated with iron accumulation.

  • Deferiprone in the treatment of transfusion dependent thalassemia a review and perspective
    Therapeutics and Clinical Risk Management, 2007
    Co-Authors: Renzo Galanello
    Abstract:

    Deferiprone is an orally active iron chelator which has emerged from an extensive search for new treatment of iron overload. Comparative studies have shown that at comparable doses Deferiprone may be as effective as deferoxamine in removing body iron. Retrospective and prospective studies have shown that Deferiprone monotherapy is significantly more effective than deferoxamine in improving myocardial siderosis in thalassemia major. Agranulocytosis is the most serious side effect associated with the use of Deferiprone, occurring in about 1% of the patients. More common but less serious side effects are gastrointestinal symptoms, arthralgia, zinc deficiency, and fluctuating transaminases levels. Deferiprone can be used in combination with desferrioxamine. This regimen of chelation is tolerable and attractive for patients unable to comply with standard deferoxamine infusions or with inadequate response to Deferiprone alone. Combination therapy has been effectively used in the management of severe cardiac siderosis.

  • combined therapy with Deferiprone and desferrioxamine in thalassemia major
    Haematologica, 2005
    Co-Authors: Raffaella Origa, Patrizio Bina, Annalisa Agus, Gabriella Crobu, Elisabetta Defraia, Carlo Dessi, Giovanbattista Leoni, Pier Paolo Muroni, Renzo Galanello
    Abstract:

    BACKGROUND AND OBJECTIVES: Effective and convenient iron chelation remains one of the main targets of clinical management of thalassemia major. The combined treatment with desferrioxamine and Deferiprone could have an increased chelation efficacy and sometimes allow drug doses and toxicity to be reduced and the number of days of desferrioxamine infusion to be decreased, improving compliance and quality of life. DESIGN AND METHODS: We used combined therapy with desferrioxamine and Deferiprone to treat 79 patients with severe iron overload (serum ferritin higher than 3000 ng/mL) who had low compliance with subcutaneous desferrioxamine. RESULTS: Total therapy exposure was 201 patient-years. Three patients developed agranulocytosis and seven mild neutropenia. Other adverse effects were nausea, vomiting, abdominal pain, increased concentrations of liver transaminases and joint pain. The efficacy of combined therapy was evaluated in 64 patients treated for at least 12 months. Ferritin decreased from 5243+/-2345 to 3439+/-2446 ng/mL, p<0.001). Mean urinary iron excretion during combined therapy was double that with desferrioxamine or Deferiprone monotherapy. In 20 patients receiving heart therapy at baseline, left ventricular ejection fraction increased from 48.6+/-9% to 57+/-6% (p=0.0001) over 12 to 57 months, without modifying the cardiac treatment. INTERPRETATION AND CONCLUSIONS: Continuous Deferiprone treatment with intermittent administration of subcutaneous desferrioxamine is a practical and effective procedure to decrease severe iron overload in patients with thalassemia major. This study also shows that the combined therapy is associated with an improvement in heart function.

  • safety and effectiveness of long term therapy with the oral iron chelator Deferiprone
    Blood, 2003
    Co-Authors: Alan R. Cohen, Renzo Galanello, Antonio Piga, Vincenzo De Sanctis, Fernando Tricta
    Abstract:

    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 × 109/L) and milder forms of neutropenia (ANC, 500-1500 × 109/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.

  • lack of progressive hepatic fibrosis during long term therapy with Deferiprone in subjects with transfusion dependent beta thalassemia
    Blood, 2002
    Co-Authors: Ian R Wanless, Renzo Galanello, Antonio Piga, G D Sweeney, Amar P Dhillon, Maria Guido, Rita M Gamberini, Elias Schwartz, Alan R. Cohen
    Abstract:

    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.

George J Kontoghiorghes - One of the best experts on this subject based on the ideXlab platform.

  • Effective inhibition of copper-catalyzed production of hydroxyl radicals by Deferiprone
    Journal of Biological Inorganic Chemistry, 2019
    Co-Authors: V.a. Timoshnikov, T.v. Kobzeva, O. Y. Selyutina, N.e. Polyakov, George J Kontoghiorghes
    Abstract:

    Copper ions can catalyze the production of free oxygen radicals (•OH and •OOH) similar to iron ions. The capacity to initiate oxidative damage is most commonly attributed to Cu-induced toxicity in copper-related diseases where there is an increase in copper levels and also when Cu homeostasis and regulation are disrupted. An antioxidant/chelator inhibiting Cu-induced oxidative damage could play a significant role in the treatment of such Cu-related diseases. Deferiprone has high affinity for copper binding and can be considered for the potential treatment of copper toxicity and overloading conditions, such as Wilson’s disease. In the present study, the ability of Deferiprone to inhibit the production of hydroxyl radicals catalyzed by copper ions was elucidated using an Electron Paramagnetic Resonance (EPR) spin trapping technique. The values of g-factors and hyperfine splitting constants were calculated for Cu(II)-Deferiprone 1:1 complex: (a = 58.5 G, g = 2.1667) and 1:2 complex: (a = 73.0 G, g = 2.1378). The TMIO spin trap (2,2,4-trimethyl-2H-imidazole-1-oxide) was used for the detection of free radicals formed in Fenton-like copper-catalyzed reactions. It was demonstrated that the interaction of Deferiprone with Cu2+ ions completely inhibited hydroxyl radical (•OH) production in the presence of hydrogen peroxide. It was found also that Deferiprone inhibits Cu-induced oxidation of linoleic acid in micellar solution. In addition to existing data for water solutions, the affinity of Deferiprone for copper binding in non-aqueous environment has been elucidated.

  • Prevention of Iron Overload and Long Term Maintenance of Normal Iron Stores in Thalassaemia Major Patients using Deferiprone or Deferiprone Deferoxamine Combination.
    Drug research, 2017
    Co-Authors: Annita Kolnagou, Christina N Kontoghiorghe, George J Kontoghiorghes
    Abstract:

    Decrease in mortality and morbidity is observed in thalassaemia major patients with reduced iron load in comparison to heavy iron loaded patients. Effective and complete treatment of transfusional iron overload can be achieved by chelation protocols that can eliminate excess iron and maintain normal iron stores (NIS). The maintenance of NIS, i. e., serum ferritin (350 μg/L >), MRI T2* cardiac (>20 ms) and liver (>6.3 ms) relaxation time levels was monitored in 16 thalassaemia major patients (32-53 years, 12 splenectomized, 10 male, erythrocyte transfusions 120-323 ml/kg/year) for about 90 patient years. The patients were treated with individualised tailor-made Deferiprone or Deferiprone/deferoxamine combination protocols. In 8 patients Deferiprone (50-100 mg/kg/day) was sufficient for maintaining NIS and withdrawal of Deferiprone for 28 months in total was necessary in 4 patients for preventing iron deficiency. In 3 other patients intermittent deferoxamine (50-75 mg/kg/8-30 h, 1-4 days/week) in combination with Deferiprone (75-100 mg/kg/day) was sufficient for maintaining NIS. In the remaining 5 patients Deferiprone (75-100 mg/kg/day) and deferoxamine (50-60 mg/kg/8-15 h, 1-7 days/week) combination was used for maintaining NIS, as a result of increased transfusions which were caused mainly by splenomegaly and infections. No toxic side effects were detected during the study. Lower chelation doses were used for the maintenance of NIS in comparison to iron loaded categories of patients. The safe maintenance of NIS using Deferiprone and Deferiprone/deferoxamine combinations should be considered as an optimum therapy for the complete treatment of iron overload in the majority of thalassaemia patients.

  • reduction of body iron stores to normal range levels in thalassaemia by using a Deferiprone deferoxamine combination and their maintenance thereafter by Deferiprone monotherapy
    European Journal of Haematology, 2010
    Co-Authors: Annita Kolnagou, Marios Kleanthous, George J Kontoghiorghes
    Abstract:

    Background:  Iron overload and toxicity is the major cause of morbidity and mortality in thalassaemia patients. New chelating drug protocols are necessary to treat completely transfusional iron overload and eliminate associated toxicity. Appropriate Deferiprone/deferoxamine combinations could achieve this goal. Methods:  A single-centre, single-armed, proof-of-concept study of the combination of Deferiprone (75–100 mg/kg/d) and deferoxamine (40–60 mg/kg, at least 3 d per week) was carried out in eight patients with thalassaemia major (four men and four women) for 21–68 months. The patients were previously treated with deferoxamine and had variable serum ferritin [geometric (G) mean ± SD = 1446 ± 1035 μg/L] and magnetic resonance imaging relaxation times T2* cardiac (Gmean ± SD = 10.32 ± 6.72 ms) and liver (G mean ± SD = 3.77 ± 4.69 ms). The use of Deferiprone (80–100 mg/kg/d) continued for 7–26 months in seven of the eight patients following the combination therapy. Organ function, blood and other biochemical parameters were monitored for toxicity. Results:  The Deferiprone/deferoxamine combination caused an absolute value increase in cardiac (G mean ± SD = 29.6 ± 6.6 ms, P < 0.00076) and liver (G mean ± SD = 25.9 ± 8.07 ms, P < 0.00075) T2* and reduction in serum ferritin (G mean ± SD = 114.7 ± 139.8 μg/L, P < 0.0052) to within the normal body iron store range levels. In two cases, normalisation was achieved within a year. Deferiprone monotherapy was sufficient thereafter in maintaining normal range cardiac (G mean ± SD = 31.4 ± 5.25 ms, P < 0.79) and liver (G mean ± SD = 26.2 ± 12.4 ms, P < 0.58) T2* and normal serum ferritin (G mean ± SD = 150.7 ± 159.1, μg/L, P < 0.17) in five of the seven patients. No serious toxicity was observed. Conclusion:  Transfusional iron overload in patients with thalassaemia could be reduced to normal body iron range levels using effective Deferiprone/deferoxamine combinations. These levels could be maintained using Deferiprone monotherapy.

  • Reduction of body iron stores to normal range levels in thalassaemia by using a Deferiprone/deferoxamine combination and their maintenance thereafter by Deferiprone monotherapy
    European Journal of Haematology, 2010
    Co-Authors: Annita Kolnagou, Marios Kleanthous, George J Kontoghiorghes
    Abstract:

    Background:  Iron overload and toxicity is the major cause of morbidity and mortality in thalassaemia patients. New chelating drug protocols are necessary to treat completely transfusional iron overload and eliminate associated toxicity. Appropriate Deferiprone/deferoxamine combinations could achieve this goal. Methods:  A single-centre, single-armed, proof-of-concept study of the combination of Deferiprone (75–100 mg/kg/d) and deferoxamine (40–60 mg/kg, at least 3 d per week) was carried out in eight patients with thalassaemia major (four men and four women) for 21–68 months. The patients were previously treated with deferoxamine and had variable serum ferritin [geometric (G) mean ± SD = 1446 ± 1035 μg/L] and magnetic resonance imaging relaxation times T2* cardiac (Gmean ± SD = 10.32 ± 6.72 ms) and liver (G mean ± SD = 3.77 ± 4.69 ms). The use of Deferiprone (80–100 mg/kg/d) continued for 7–26 months in seven of the eight patients following the combination therapy. Organ function, blood and other biochemical parameters were monitored for toxicity. Results:  The Deferiprone/deferoxamine combination caused an absolute value increase in cardiac (G mean ± SD = 29.6 ± 6.6 ms, P 

  • benefits and risks of Deferiprone in iron overload in thalassaemia and other conditions comparison of epidemiological and therapeutic aspects with deferoxamine
    Drug Safety, 2003
    Co-Authors: George J Kontoghiorghes, Katia Neocleous, Annita Kolnagou
    Abstract:

    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.

Alan R. Cohen - One of the best experts on this subject based on the ideXlab platform.

  • safety and effectiveness of long term therapy with the oral iron chelator Deferiprone
    Blood, 2003
    Co-Authors: Alan R. Cohen, Renzo Galanello, Antonio Piga, Vincenzo De Sanctis, Fernando Tricta
    Abstract:

    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 × 109/L) and milder forms of neutropenia (ANC, 500-1500 × 109/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.

  • lack of progressive hepatic fibrosis during long term therapy with Deferiprone in subjects with transfusion dependent beta thalassemia
    Blood, 2002
    Co-Authors: Ian R Wanless, Renzo Galanello, Antonio Piga, G D Sweeney, Amar P Dhillon, Maria Guido, Rita M Gamberini, Elias Schwartz, Alan R. Cohen
    Abstract:

    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.

  • safety profile of the oral iron chelator Deferiprone a multicentre study
    British Journal of Haematology, 2000
    Co-Authors: Alan R. Cohen, Renzo Galanello, Antonio Piga, Calogero Vullo, A Dipalma, Fernando Tricta
    Abstract:

    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  2500 μg/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.

  • A Multi‐Center Safety Trial of the Oral Iron Chelator Deferiprone
    Annals of the New York Academy of Sciences, 1998
    Co-Authors: Alan R. Cohen, Renzo Galanello, Antonio Piga, Calogero Vullo, Fernando Tricta
    Abstract:

    Abstract: 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

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