Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial

Department of Neurosciences, Hospital Germans Trias i Pujol, 08916 Badalona, Barcelona, Spain. Cellular and Molecular Neurobiology Research Group, Department of Neurosciences, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Barcelona, Spain. Department of Clinical Pharmacology, Hospital Germans Trias i Pujol, 08916 Badalona, Barcelona, Spain. Department of Pharmacy, Hospital Germans Trias i Pujol, 08916 Badalona, Barcelona, Spain. Department of Neurology, Hospital Dr. Josep Trueta, 17007 Girona, Spain. Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela, Hospital Clínico Universitario, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain. Department of Neurology, Hospital Clínico Universitario, 15706 Santiago de Compostela, Spain. Department of Neurology, Hospital La Princesa, 28006 Madrid, Spain. Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain. Department of Statistics and Operations Research, Universitat Politècnica de Catalunya (UPC), 08028 Barcelona, Spain.

Antioxidants (Basel, Switzerland). 2021;10(8)
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Abstract
A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40-60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40-60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50-58% of the 40-60 mg/Kg/day DFO-treated patients.
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Language : eng
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