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

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

Myelodysplastický syndrom je heterogenní skupina onemocnění, jejichž typickým projevem je neefektivní krvetvorba a závislost na krevních transfuzích. Chelátory železa v současné době představují důležitou léčebnou modalitu u těch pacientů s myelodysplastickým syndromem, u kterých v důsledku přítomnosti anémie a opakovaných krevních transfuzí dochází k hromadění toxického železa v orgánech. Bylo prokázáno, že chelatační terapie u pacientů s mye-lodysplastickým syndromem významně prodlužuje celkové přežití a oddaluje leukemickou transformaci. Kromě vlastní chelatace iontů železa bylo u těchto chelatačních látek prokázáno i výrazné antiproliferační a proapoptotické působení na nádorové buňky. Předpokládanými mechanismy protinádorových účinků chelátorů železa jsou inhibice progrese buněčného cyklu, vyvolání stresu endoplazmatického retikula, akumulace poškozené DNA specificky u nádorových buněk i modulace protinádorové imunitní odpovědi. Přesný mechanismus působení chelatačních látek na nádorové buňky však prozatím není zcela objasněn a i naše výsledky naznačují, že bude velmi komplexní.

Myelodysplastic syndrome represents a heterogeneous group of diseases, typically characterised by ineffective haematopoiesis and transfusion dependency. Iron chelators currently represent an important treatment modality in patients with myelodysplastic syndrome (MDS), who given the presence of anaemia, are dependent on repeated blood transfusions leading to the accumulation of toxic iron in organs. It has been shown that chelation therapy significantly improves overall survival and leukaemia-free survival in patients with MDS. Besides iron chelation, iron chelators also exhibit significant antiproliferative and pro-apoptotic effects on cancer cells. The suggested mechanisms of antitumor effects of iron chelators include inhibition of cell cycle progression, induction of endoplasmic reticulum stress, accumulation of DNA damage specifically in cancer cells and modulation of antitumor immune response. The exact mechanism of action of chelating agents on cancer cells is not yet fully understood and even our data suggest that it is likely to be very complex.

• Keywords
• deferoxamin mesylát, ionty železa,
• MeSH
• Apoptosis drug effects   MeSH
• Immunity, Cellular drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Iron Chelating Agents * pharmacology   metabolism   therapeutic use   MeSH
• Deferasirox MeSH
• Deferiprone MeSH
• Deferoxamine therapeutic use   MeSH
• Ions MeSH
• Humans MeSH
• Myelodysplastic Syndromes * drug therapy   metabolism   MeSH
• Iron Overload drug therapy   prevention & control   MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Signal Transduction drug effects   MeSH
• Endoplasmic Reticulum Stress drug effects   MeSH
• Iron metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Autoři předkládají případ 60letého pacienta s náhodně zjištěnou výraznou makrocytovou anémií a trombocytózou. Za pomoci paraklinických vyšetření je diagnostikován myelodysplastický syndrom (MDS) typu 5q- syndromu. Pacient je od počátku závislý na transfuzích erytrocytů, zprvu úspěšná chelatace selhává zejména pro neochotu pacienta spolupracovat. V době, kdy je u pacienta jednoznačně indikován lenalidomid, nedaří se pro něj tento preparát získat. Po 53 měsících od diagnózy choroba progreduje do MDS typu RAEB. Aniž by došlo k rozvoji akutní leukemie, umírá pacient pod obrazem hepatorenálního selhání. Na příčině smrti se podílí těžká sideróza orgánů, především jater a srdce. Součástí sdělení je pitevní zpráva a fotodokumentace histologických preparátů post mortem, které dokládají jak hemosiderózu životně důležitých orgánů, tak i patologicko-anatomické změny vedoucí k jejich selhání. Práce ukazuje těžké poškození orgánů, ke kterému dochází u neléčených pacientů při přetížení železem. Dnes však může hematolog u dlouhodobě transfundovaných nemocných s MDS předejít fatálnímu poškození orgánů včas indikovanou a důsledně dodržovanou terapií chelátory železa a pokusit se odstranit závislost na transfuzích podáním erytopoetinu, případně při neúspěchu této léčby podat lenalidomid.

The authors present a case of a 60-year-old patient with incidentally uncovered significant macrocytic anaemia and thrombocytosis. Myelodysplastic syndrome, namely 5q- syndrome was diagnosed. From the beginning, the patient was dependent on red blood cell transfusions. Chelation was initially successful, but later it failed especially due to the patient's non compliance. At the time when treatment with lenalidomide was clearly indicated, it was not possible to obtain this medication. At 53 months from diagnosis, the disease progressed to RAEB. The patient died of liver and renal failure without developing acute leukaemia. Severe hemosiderosis of the organs, especially the liver and heart, was one of the causes of death. The article includes the autopsy report and photographs of the relevant histological slides, showing hemosiderosis of the vital organs and pathological-anatomical changes that led to their failure. The paper shows severe organ damage that occurs in patients with untreated iron overload. However, haematologists can currently prevent fatal organ damage in long-term transfused patients suffering from myelodysplastic syndrome with the aid of timely and consistent iron chelator therapy and by attempting to elimi-nate the dependence on transfusions using erythropoietin or in case of its failure by administering lenalidomide.

• Keywords
• 5q-syndrom, chelatace železa,
• MeSH
• Iron Chelating Agents * adverse effects   therapeutic use   MeSH
• Kidney Failure, Chronic etiology   MeSH
• Deferiprone MeSH
• Fatal Outcome MeSH
• Ferritins blood   MeSH
• Hemosiderosis etiology   pathology   MeSH
• Liver Cirrhosis etiology   MeSH
• Lenalidomide MeSH
• Middle Aged MeSH
• Humans MeSH
• Iron Overload * etiology   drug therapy   prevention & control   MeSH
• Disease Progression MeSH
• Pyridones administration & dosage   adverse effects   MeSH
• Anemia, Refractory, with Excess of Blasts * diagnosis   pathology   therapy   MeSH
• Liver Failure etiology   MeSH
• Thalidomide analogs & derivatives   MeSH
• Erythrocyte Transfusion adverse effects   MeSH
• Thrombocytopenia blood   MeSH
• Patient Dropouts MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

V současné době je věnována velká pozornost diagnostice, prognostickému významu a léčbě stavů spojených s přetížením železem. Přetížení železem je způsobeno primárním onemocněním, tj. vrozenou hemochromatózou, ale i sekundárními příčinami, např. nadměrným přívodem železa u polytransfundovaných nemocných. Nerovnováha mezi přívodem a eliminací železa vede k jeho hromadění v organismu, a tím k toxickému poškození srdce, jater, endokrinních orgánů, případně dalších tkání, které může vyústit i v život ohrožující stavy. Hledají se proto cesty, jak tomuto poškození předejít. V případě vrozené hemochromatózy je touto možností provádění venepunkcí, u polytransfundovaných pacientů jsou k dispozici léky chelatující železo (desferioxamin, deferiprone, deferasirox), obvykle podávané v monoterapii. Předmětem sdělení je kazuistika pacienta s vrozenou hemochromatózou komplikovanou dysplastickým postižením kostní dřeně, u kterého bylo nutno řešit anémii a známky orgánového přetížení železem (hepatopatie, kardiopatie, diabetes mellitus). Teprve až použitím kombinované chelatační léčby (desferioxamin + deferiprone) bylo dosaženo požadovaného terapeutického efektu při zachování uspokojivé kvality života pacienta, plně ambulantně vedenou terapií.

There is currently great interest in the diagnosis and treatment of iron overload syndromes. These syndro-mes are classified as primary (hereditary), for example hereditary hemochromatosis, or secondary (acqui-red), for example transfusional iron overload. An imbalance between iron uptake and iron elimination leads to its accumulation in the body and the toxic effect of iron overload causes tissue damage (heart, liver, endoc-rine organs) and can lead to end-organ failure. Therefore, research has focused on means of preventing iron-related morbidity and mortality. Therapeutic management of hereditary hemochromatosis involves vene-section, while for transfusion iron overload, iron chelation therapy is useful (deferoxamine, deferiprone or deferasirox) mainly given as monotherapy. We report a complicated čase of a patient with hereditary hemochromatosis and simultaneous myelodysplastic syndrome, when venesection was not indicated. In this situation it was necessary to solve anemia and systemic iron overload (hepatopathy, cardiomyopathy, diabetes mellitus) at the same time. This case report demonstrates that combined chelation therapy with deferoxamine and deferiprone was successful, improved patient quality of life and was performed completely in the outpatient clinic.

• Keywords
• Ferriprox, Desferal,
• MeSH
• Chelation Therapy methods   utilization   MeSH
• Deferoxamine therapeutic use   MeSH
• Diabetes Mellitus etiology   MeSH
• Ferritins diagnostic use   physiology   MeSH
• Hemochromatosis diagnosis   therapy   congenital   MeSH
• Drug Therapy, Combination MeSH
• Myelodysplastic Syndromes diagnosis   complications   therapy   MeSH
• Pyridones therapeutic use   MeSH
• Publication type
• Case Reports 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
• beta-Thalassemia drug therapy   MeSH
• Chelation Therapy * MeSH
• Deferiprone administration & dosage   MeSH
• Deferoxamine administration & dosage   MeSH
• Child MeSH
• Adult MeSH
• Liver MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Magnetic Resonance Imaging instrumentation   MeSH
• Adolescent MeSH
• Liver Diseases prevention & control   MeSH
• Heart Diseases prevention & control   MeSH
• Iron Overload * MeSH
• Heart MeSH
• Statistics as Topic MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Randomized Controlled Trial 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