- MeSH
- Iron Chelating Agents administration & dosage pharmacology MeSH
- Chelation Therapy * trends MeSH
- Deferasirox administration & dosage pharmacology MeSH
- Deferiprone administration & dosage pharmacology MeSH
- Deferoxamine administration & dosage pharmacology MeSH
- Drug Therapy, Combination MeSH
- Humans MeSH
- Thalassemia drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
Chelatační léčba je nezbytnou součástí terapie hematologických pacientů s chronickou transfuzní léčbou, kteří jsou ohroženi přetížením železem (Fe) nebo již vykazují jeho známky. V našich podmínkách jsou opakované dlouhodobé krevní převody u dospělých pacientů se selháním krvetvorby nejčastěji nutné u nemocných s myelodysplastickým syndromem (MDS), méně u nemocných s myelofibrózou dřeně, paroxysmální noční hemoglobinurií (PNH) a poměrně vzácnou chronickou aplastickou anemií (AA). Mnohem vzácnější jsou pak anemie ze skupiny vrozených anemií, jako jsou vrozené AA, dyserytropoetické anemie, talasemie a poruchy enzymů (tabulka 1).
- Keywords
- Exjade, Ferriprox, Desferal,
- MeSH
- Anemia classification complications therapy MeSH
- Benzoates adverse effects therapeutic use MeSH
- Iron Chelating Agents therapeutic use MeSH
- Deferasirox MeSH
- Deferiprone MeSH
- Deferoxamine adverse effects therapeutic use MeSH
- Blood Transfusion utilization MeSH
- Humans MeSH
- Myelodysplastic Syndromes complications therapy MeSH
- Transfusion Reaction MeSH
- Iron Overload drug therapy MeSH
- Pyridones adverse effects therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Practice Guideline MeSH
- MeSH
- Chelation Therapy MeSH
- Deferiprone administration & dosage MeSH
- Deferoxamine administration & dosage MeSH
- Phlebotomy MeSH
- Drug Therapy, Combination MeSH
- Humans MeSH
- Young Adult MeSH
- Iron Overload drug therapy MeSH
- Anemia, Sideroblastic * drug therapy therapy MeSH
- Bone Marrow Transplantation MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Deferiprone administration & dosage MeSH
- Deferoxamine administration & dosage MeSH
- Ferritins analysis MeSH
- Hemosiderosis diagnosis MeSH
- Liver MeSH
- Humans MeSH
- Magnetic Resonance Imaging * MeSH
- Iron Overload MeSH
- Heart MeSH
- Thalassemia * diagnosis drug therapy MeSH
- Iron analysis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Comparative Study MeSH
- MeSH
- Apoptosis * drug effects MeSH
- Chelation Therapy MeSH
- Deferiprone administration & dosage pharmacology MeSH
- Deferoxamine administration & dosage pharmacology MeSH
- Adult MeSH
- Heme Oxygenase-1 analysis drug effects MeSH
- Immunohistochemistry methods MeSH
- Caspases analysis drug effects MeSH
- Humans MeSH
- Thalassemia * drug therapy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).
- MeSH
- Antiparkinson Agents * administration & dosage adverse effects pharmacology therapeutic use MeSH
- Administration, Oral MeSH
- Iron Chelating Agents * administration & dosage adverse effects pharmacology therapeutic use MeSH
- Deferiprone * administration & dosage adverse effects pharmacology therapeutic use MeSH
- Dopamine Agents administration & dosage adverse effects pharmacology therapeutic use MeSH
- Double-Blind Method MeSH
- Levodopa therapeutic use MeSH
- Humans MeSH
- Brain Chemistry MeSH
- Brain diagnostic imaging MeSH
- Neutropenia chemically induced MeSH
- Parkinson Disease * drug therapy metabolism physiopathology MeSH
- Disease Progression MeSH
- Substantia Nigra * chemistry diagnostic imaging drug effects metabolism MeSH
- Iron * analysis metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
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.
- MeSH
- Iron Chelating Agents adverse effects therapeutic use MeSH
- Deferiprone adverse effects therapeutic use MeSH
- Child MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Pantothenate Kinase-Associated Neurodegeneration drug therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Child, Preschool MeSH
- Disease Progression MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
Labile redox-active iron ions have been implicated in various neurodegenerative disorders, including the Parkinson's disease (PD). Iron chelation has been successfully used in clinical practice to manage iron overload in diseases such as thalassemia major; however, the use of conventional iron chelators in pathological states without systemic iron overload remains at the preclinical investigative level and is complicated by the risk of adverse outcomes due to systemic iron depletion. In this study, we examined three clinically-used chelators, namely, desferrioxamine, deferiprone and deferasirox and compared them with experimental agent salicylaldehyde isonicotinoyl hydrazone (SIH) and its boronate-masked prochelator BSIH for protection of differentiated PC12 cells against the toxicity of catecholamines 6-hydroxydopamine and dopamine and their oxidation products. All the assayed chelating agents were able to significantly reduce the catecholamine toxicity in a dose-dependent manner. Whereas hydrophilic chelator desferrioxamine exerted protection only at high and clinically unachievable concentrations, deferiprone and deferasirox significantly reduced the catecholamine neurotoxicity at concentrations that are within their plasma levels following standard dosage. SIH was the most effective iron chelator to protect the cells with the lowest own toxicity of all the assayed conventional chelators. This favorable feature was even more pronounced in prochelator BSIH that does not chelate iron unless its protective group is cleaved in disease-specific oxidative stress conditions. Hence, this study demonstrated that while iron chelation may have general neuroprotective potential against catecholamine auto-oxidation and toxicity, SIH and BSIH represent promising lead molecules and warrant further studies in more complex animal models.
- MeSH
- PC12 Cells MeSH
- Iron Chelating Agents * pharmacology MeSH
- Deferasirox pharmacology MeSH
- Deferiprone pharmacology MeSH
- Deferoxamine pharmacology MeSH
- Dopamine pharmacology MeSH
- Catecholamines pharmacology MeSH
- Rats MeSH
- Oxidative Stress MeSH
- Oxidopamine pharmacology MeSH
- Iron Overload * MeSH
- Iron pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
