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Systematical (retro- and prospective) investigation of the long-term safety (toxicity assessment according to CTCAE v3.0) and efficacy of deferiprone either given alone or in combination with desferrioxamine
Patients with refractory anemias requiring regular blood transfusions accumulate iron at the rate of approximately 0.5 mg/kg/day, which may lead to serious organ toxicity, e.g. to the heart, liver and endocrine organs. The human body has no active mechanism for the excretion of excess iron. Therefore multiply transfused patients will develop a secondary hemosiderosis, if excess iron is not excreted by a chelating agent. Symptoms of iron-overload occur when body iron stores reach 10-20 g 2. At higher levels severe, even fatal complications, particularly cardiac failure, may develop.
Desferrioxamine (DFO, Desferal) is the established and commonly used iron-chelating drug, but is expensive and must be given by slow subcutaneous or intravenous infusion for 8-12 hours a day during 5-7 days weekly at a dosage of 40-50 mg/kg body weight/day. This often leads to failure of compliance of the patient and therefore to inefficient iron chelation. Further, some patients are hypersensitive to desferrioxamine and others suffer from toxicity, e.g. to the ears or eyes.
Deferiprone (L1; CP20; 1,2 dimethyl-3-hydroxypyrid-4-one) is an orally active iron chelator investigated in various clinical trials since 1987. Dosages of 75 - 100 mg/kg body weight/day of L1 have been considered effective to maintain stable iron balance (urinary iron excretion of 0.5 mg/kg/day) and to reduce serum ferritin levels between 6% and 25% within one year of treatment in iron-overloaded thalassemic patients. There exists long-term experience with patients who have received deferiprone continuously for more than 10 years so far. The main side effects encountered during a deferiprone therapy are arthropathy, gastrointestinal symptoms, headache, and mild zinc deficiency. These adverse reactions are usually reversed on reducing the dose or discontinuing the drug. Except for severe joint symptoms in few patients, most of the subjects in different clinical trials have been able to continue with L1 therapy for a long term. The most severe, but rare complication following administration of deferiprone is agranulocytosis or neutropenia.
A new treatment regimen combining deferiprone with desferrioxamine is currently being investigated in many countries. Preliminary data have demonstrated that the combined use of both drugs is highly active showing an additive or even synergistic effect (significant decrease of serum ferritin and hepatic iron content, increase of urinary iron excretion). This synergism could be explained by the different mode of action of the two drugs. It could be demonstrated that patients who were not sufficiently chelated with desferrioxamine or deferiprone, could achieve a negative iron balance with the combination treatment of both drugs. The combined regimen was generally well tolerated. It has been speculated that the individual toxicity profile of both drugs can be positively influenced by the simultaneous administration of L1 and DFO. The daily treatment with L1 tablets combined with at least twice a week administration of parenteral desferrioxamine is more patient-convenient and therefore may enhance the patient's compliance.
The primary aim of this study is to systematically investigate the long-term safety (toxicity assessment according to CTCAE v3.0) of deferiprone either given alone or in combination with desferrioxamine. Further, in patients agreeing to perform annual SQUID analysis of the liver, the annual change of liver iron concentration (LIC) will be examined for four years.
Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Deferiprone (L1), Desferrioxamine
Private children clinic
Active, not recruiting
Published on BioPortfolio: 2014-08-27T03:43:37-0400
Comparison of efficacy and toxicity of the combination treatment of deferiprone and desferrioxamine with the single agent treatment of either drug
The purpose of this study is to look at the pharmacokinetics of a new formulation of deferiprone (deferiprone delayed release tablets) under fed and fasting conditions.
The primary objective of this study is to evaluate the long-term safety and tolerability of deferiprone in subjects with Friedreich's ataxia (FRDA). The secondary objective is to evaluate...
This study is looking at the effects of giving early treatment of deferiprone to young children with beta thalassemia who have started receiving regular blood transfusions but have not yet...
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The Actinobacterium Gordonia rubripertincta CWB2 (DSM 46758) produces hydroxamate-type siderophores (188 mg L) under iron limitation. Analytical reversed-phase HPLC allowed determining a single peak o...
We report a self-assembly-based approach for improved iron chelation of small chelators. A model chelator, deferiprone (DFP) is covalently linked to amphiphilic poly(ethylene glycol)-polypeptide block...
Hereditary hemochromatosis (HH) is an autosomal recessive disorder that occurs in approximately 1 in 200-250 individuals. Mutations in the HFE gene leads to excess iron absorption. Excess iron in the ...
A disorder due to the deposition of hemosiderin in the parenchymal cells, causing tissue damage and dysfunction of the liver, pancreas, heart, and pituitary. Full development of the disease in women is restricted by menstruation, pregnancy, and lower dietary intake of iron. Acquired hemochromatosis may be the result of blood transfusions, excessive dietary iron, or secondary to other disease. Idiopathic or genetic hemochromatosis is an autosomal recessive disorder of metabolism associated with a gene tightly linked to the A locus of the HLA complex on chromosome 6. (From Dorland, 27th ed)
A membrane protein and MHC class I antigen. It contains an IMMUNOGLOBULIN C1-SET DOMAIN and interacts with BETA 2-MICROGLOBULIN. It may also regulate the interaction of TRANSFERRIN with the TRANSFERRIN RECEPTOR. Mutations in the HFE gene are associated with cases of FAMILIAL HEMOCHROMATOSIS.
Human histocompatibility (HLA) surface antigen encoded by the A locus on chromosome 6. The allele occurs with increased frequency in individuals with idiopathic hemochromatosis. HLA-A3 is in linkage disequilibrium with HLA-B7 and HLA-DR2.
The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda.
Human histocompatibility (HLA) surface antigen encoded by the B locus on chromosome 6. There is a weak association between the presence of the HLA-B7 antigen and the diseases of narcolepsy and idiopathic hemochromatosis. HLA-B7 is in linkage disequilibrium with HLA-A3 and HLA-DR2.
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