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The New England Journal of Medicine Dec 2022Iron 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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.).
Topics: Humans; Deferiprone; Iron; Levodopa; Neutropenia; Parkinson Disease; Iron Chelating Agents; Substantia Nigra; Disease Progression; Double-Blind Method; Administration, Oral; Brain; Brain Chemistry; Dopamine Agents; Antiparkinson Agents
PubMed: 36449420
DOI: 10.1056/NEJMoa2209254 -
The New England Journal of Medicine Nov 2018
Review
Topics: Anemia, Sickle Cell; Chelation Therapy; Deferiprone; Deferoxamine; Drug Therapy, Combination; Erythrocyte Transfusion; Humans; Iron Chelating Agents; Iron Overload; Thalassemia
PubMed: 30485781
DOI: 10.1056/NEJMra1800219 -
International Journal of Molecular... Jun 2022The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the... (Review)
Review
The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a "magic bullet" drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.
Topics: Adult; Deferiprone; Humans; Iron; Iron Chelating Agents; Iron Overload; Pyridones; COVID-19 Drug Treatment
PubMed: 35743183
DOI: 10.3390/ijms23126735 -
Annals of the New York Academy of... Aug 2010Deferiprone (DFP) has been evaluated in a wide range of disorders, but most data come from transfusion-dependent thalassemia. The safety and tolerability profile...
Deferiprone (DFP) has been evaluated in a wide range of disorders, but most data come from transfusion-dependent thalassemia. The safety and tolerability profile includes gastrointestinal complaints, liver enzymes elevation, weight gain, arthropathy, neutropenia, and agranulocytosis. The last requires close monitoring of blood count and precludes the use of DFP in conditions with bone marrow abnormalities. The efficacy profile is similar among the three available chelators. For DFP, the choice of dosage is crucial to optimize the effect on liver iron concentration, according to the iron load degree and transfusional iron input. Growing evidence indicates that DFP, alone or in combination with deferoxamine, is effective in removing cardiac iron and preventing cardiac iron load. The available data consolidate an important role of DFP in the management of iron overload. There is a need to compare directly the relative value of the available chelators in the long-term prevention of iron toxicity by well-designed randomized controlled trials.
Topics: Deferiprone; Deferoxamine; Humans; Iron; Iron Chelating Agents; Liver; Pyridones; Randomized Controlled Trials as Topic; Thalassemia; Transfusion Reaction
PubMed: 20712776
DOI: 10.1111/j.1749-6632.2010.05586.x -
Journal of Neurochemistry Aug 2013Friedreich's ataxia (FRDA) is a neurological disease related to a deficiency of the protein frataxin involved in iron-sulfur (Fe-S) cluster biogenesis. This leads to an... (Review)
Review
Friedreich's ataxia (FRDA) is a neurological disease related to a deficiency of the protein frataxin involved in iron-sulfur (Fe-S) cluster biogenesis. This leads to an increased cellular iron uptake accumulating in mitochondria, and a subsequently disturbed iron homeostasis. The detailed mechanism of iron regulation of frataxin expression is yet unknown. Deferiprone, an iron chelator that may cross the blood-brain barrier, was shown to shuttle iron between subcellular compartments. It could also transfer iron from iron-overloaded cells to extracellular apotransferrin and pre-erythroid cells for heme synthesis. Here, clinical studies on Deferiprone are reviewed in the context of alternative agents such as desferoxamine, with specific regard to its mechanistic and clinical implications.
Topics: Animals; Clinical Trials as Topic; Deferiprone; Drug Evaluation, Preclinical; Friedreich Ataxia; Humans; Iron; Iron Chelating Agents; Iron-Binding Proteins; Pyridones; Sulfur; Frataxin
PubMed: 23859349
DOI: 10.1111/jnc.12300 -
International Journal of Molecular... Mar 2023The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40... (Review)
Review
The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol-iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world's population. Detailed insights into different aspects of drug development associated with L1 and the maltol-iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.
Topics: Humans; Iron; Deferiprone; Iron Chelating Agents; Iron Overload; Drug Design; Pyridones
PubMed: 36902402
DOI: 10.3390/ijms24054970 -
The Cochrane Database of Systematic... Aug 2013Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine.
OBJECTIVES
To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone with desferrioxamine for thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic fibrosis and Genetic Disorders Group's Haemoglobinopathies trials Register and MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus registers of ongoing trials and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). We also contacted the manufacturers of deferiprone and desferrioxamine.All searches were updated to 05 March 2013.
SELECTION CRITERIA
Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules or doses of deferiprone, in people with transfusion-dependent thalassaemia.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trials for risk of bias and extracted data. Missing data were requested from the original investigators.
MAIN RESULTS
A total of 17 trials involving 1061 participants (range 13 to 213 participants per trial) were included. Of these, 16 trials compared either deferiprone alone with desferrioxamine alone, or a combined therapy of deferiprone and desferrioxamine with either deferiprone alone or desferrioxamine alone; one compared different schedules of deferiprone. There was little consistency between outcomes and limited information to fully assess the risk of bias of most of the included trials.Four trials reported mortality; each reported the death of one individual receiving deferiprone with or without desferrioxamine. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage.Earlier trials measuring the cardiac iron load indirectly by magnetic resonance imaging (MRI) T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, a meta-analysis of two trials suggested that left ventricular ejection fraction was significantly reduced in patients who received desferrioxamine alone compared with combination therapy. One trial, which planned five years of follow up, was stopped early due to the beneficial effects of combined treatment compared with deferiprone alone in terms of serum ferritin levels reduction.The results of this and three other trials suggest an advantage of combined therapy over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no conclusive or consistent evidence for the improved efficacy of combined deferiprone and desferrioxamine therapy over monotherapy from direct or indirect measures of liver iron. Both deferiprone and desferrioxamine produce a significant reduction in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised controlled trials to suggest that either has a greater reduction of clinically significant end organ damage.Evidence of adverse events were observed in all treatment groups. Occurrence of any adverse event was significantly more likely with deferiprone than desferrioxamine in one trial, RR 2.24 (95% CI 1.19 to 4.23). Meta-analysis of a further two trials showed a significant increased risk of adverse events associated with combined deferiprone and desferrioxamine compared with desferrioxamine alone, RR 3.04 (95% CI 1.18 to 7.83). The most commonly reported adverse event was joint pain, which occurred significantly more frequently in patients receiving deferiprone than desferrioxamine, RR 2.64 (95% CI 1.21 to 5.77). Other common adverse events included gastrointestinal disturbances as well as neutropenia or leucopenia, or both.
AUTHORS' CONCLUSIONS
In the absence of data from randomised controlled trials, there is no evidence to suggest the need for a change in current treatment recommendations; namely that deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. Intensified desferrioxamine treatment (by either subcutaneous or intravenous route) or use of other oral iron chelators, or both, remains the established treatment to reverse cardiac dysfunction due to iron overload. Indeed, the US Food and Drug Administration (FDA) recently only gave support for deferiprone to be used as a last resort for treating iron overload in thalassaemia, myelodysplasia and sickle cell disease. However, there is evidence that adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.
Topics: Administration, Oral; Chelation Therapy; Deferiprone; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Randomized Controlled Trials as Topic; Thalassemia; Treatment Outcome
PubMed: 23966105
DOI: 10.1002/14651858.CD004839.pub3 -
The Cochrane Database of Systematic... Jul 2007Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red blood cells. Repeated transfusions result in excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine.
OBJECTIVES
To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone for thalassaemia with desferrioxamine.
SEARCH STRATEGY
We searched the Group's Haemoglobinopathies Trials Register, MEDLINE, EMBASE, Biological Abstracts, ZETOC, Current Controlled Trials and bibliographies of relevant publications. We contacted the manufacturers of deferiprone and desferrioxamine. Most recent searches: June 2006.
SELECTION CRITERIA
Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules of deferiprone, in people with transfusion-dependent thalassaemia.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial quality and extracted data. Missing data were requested from the original investigators.
MAIN RESULTS
Ten trials involving 398 people (range 10 to 144 people) were included. Nine trials compared deferiprone with desferrioxamine or a combination of deferiprone and desferrioxamine and one compared different schedules of deferiprone. There was little consistency between outcomes and little information to fully assess the methodological quality of most of the included trials. No trial reported long-term outcomes (mortality and end organ damage). There was no consistent effect on reduction of iron overload between all treatment comparisons, with the exception of urinary iron excretion in comparisons of deferiprone with desferrioxamine. An increase in iron excretion levels favoured deferiprone in one trial and desferrioxamine in three trials, even though measurement of urinary iron excretion underestimates total iron excretion by desferrioxamine.Adverse events were recorded in trials comparing deferiprone with desferrioxamine. There was evidence of adverse events in all treatment groups. Adverse events in one trial were significantly more likely with deferiprone than desferrioxamine, relative risk 2.24 (95% confidence interval 1.19 to 4.23).
AUTHORS' CONCLUSIONS
We found no reason to change current treatment recommendations, namely deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. However, there is an urgent need for adequately-powered, high quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.
Topics: Chelation Therapy; Deferiprone; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Randomized Controlled Trials as Topic; Thalassemia; Treatment Outcome
PubMed: 17636775
DOI: 10.1002/14651858.CD004839.pub2 -
Aesthetic Surgery Journal Mar 2021Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In...
BACKGROUND
Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In addition to absence of oxygen, sequestration of iron also stimulates HIF-1α. Therefore, we analyzed the efficacy of the iron-chelator deferiprone (DFP) at stimulating dermal fibroblasts.
OBJECTIVES
The main objective of this study was to quantify the DFP concentrations capable of stimulating dermal fibroblasts in vitro and to correlate the effective DFP concentrations with the ability of DFP to penetrate the epidermis, reach the dermis, and activate HIF-1α in vivo.
METHODS
We measured cell proliferation, metabolic activity, HIF-1α expression, and lactate dehydrogenase levels of both young and aged fibroblasts after a 24-hour in vitro preconditioning with DFP. In addition, we evaluated cell survival rates and morphology with different cellular stainings. Finally, we performed a transdermal permeation study with a 1% DFP topical formulation to quantify the concentration required to reach the dermis.
RESULTS
In vitro administration of iron-chelation therapy (156-312.5 µg/mL DFP ) on aged fibroblasts resulted in activation of various antiaging processes. The concentration required to reach the dermis within 24 hours was 1.5% (0.15 mg/mL), which corresponds well with the effective doses of our laboratory analyses.
CONCLUSIONS
The activation of HIF-1α by DFP enhances cell metabolism, proliferation, and survival of fibroblasts while reducing lactate dehydrogenase levels. Modulation of HIF-1α is linked to activation of key regeneration enzymes and proteins, and by proxy, antiaging. Therefore, the antiaging properties of DFP and its satisfactory dermal penetration make it a promising regenerative agent.
Topics: Cell Proliferation; Deferiprone; Epidermis; Fibroblasts; Gene Expression Regulation
PubMed: 32479616
DOI: 10.1093/asj/sjaa142 -
British Journal of Pharmacology Jan 2023Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has...
BACKGROUND AND PURPOSE
Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest as iron deposition has been detected in the injured brain in the weeks to months post-TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity; and whether this is a cause or consequence of the long-term effects of TBI remains unknown.
EXPERIMENTAL APPROACH
We investigated the role of iron and the effect of therapeutic intervention using a brain-permeable iron chelator, deferiprone, in a controlled cortical impact mouse model of TBI. An extensive assessment of cognitive, motor and anxiety/depressive outcome measures were examined, and neuropathological and biochemical changes, over a 3-month period post-TBI.
KEY RESULTS
Lesion volume was significantly reduced at 3 months, which was preceded by a reduction in astrogliosis, microglia/macrophages and preservation of neurons in the injured brain at 2 weeks and/or 1 month post-TBI in mice receiving oral deferiprone. Deferiprone treatment showed significant improvements in neurological severity scores, locomotor/gait performance and cognitive function, and attenuated anxiety-like symptoms post-TBI. Deferiprone reduced iron levels, lipid peroxidation/oxidative stress and altered expression of neurotrophins in the injured brain over this period.
CONCLUSION AND IMPLICATIONS
Our findings support a detrimental role of iron in the injured brain and suggest that deferiprone (or similar iron chelators) may be promising therapeutic approaches to improve survival, functional outcomes and quality of life following TBI.
Topics: Animals; Mice; Deferiprone; Quality of Life; Mice, Inbred C57BL; Brain Injuries, Traumatic; Iron
PubMed: 36102035
DOI: 10.1111/bph.15950