82e54469a0aecaae0adcb3521d7c9f76 pmc_34439518.pdf 16815e7bde9fd4c56e742282546d0601142360e6 pmc_34439518.pdf 9fd358272f2499013d27decb4aaef48647d1c40caf1859e019bf627e69d86f28 pmc_34439518.pdf Title: Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial Subject: 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. Keywords: iron; deferoxamine; antioxidant; ferroptosis; neuroprotection; outcome Author: Mònica Millán, Núria DeGregorio-Rocasolano, Natàlia Pérez de la Ossa, Sílvia Reverté, Joan Costa, Pilar Giner, Yolanda Silva, Tomás Sobrino, Manuel Rodríguez-Yáñez, Florentino Nombela, Francisco Campos, Joaquín Serena, José Vivancos, Octavi Martí-Sistac, Jordi Cortés, Antoni Dávalos and Teresa Gasull Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Aug 10 10:17:39 2021 CEST ModDate: Tue Aug 10 10:23:23 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1748550 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 10 0 SVOWDU+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 ZDJKPU+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 KCSWRZ+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 WGUMXD+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 KUDXZB+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 58 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 62 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 66 0 LXNYTO+CMSY10 Type 1 Builtin yes yes no 78 0 JDIIHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 92 0 JDIIHP+PalatinoLinotype TrueType WinAnsi yes yes no 95 0 JDIIJB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 98 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 107 0 ZXDKIP+EURM10 Type 1 Builtin yes yes no 114 0 JDINJG+Arial,Bold CID TrueType Identity-H yes yes yes 132 0 JDINKI+Arial,Italic TrueType WinAnsi yes yes no 138 0 JDINLI+SimSun CID TrueType Identity-H yes yes yes 141 0 JDIIHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 147 0 JDIIHO+PalatinoLinotype CID TrueType Identity-H yes yes yes 150 0 JDIIHP+PalatinoLinotype TrueType WinAnsi yes yes no 156 0 JDIIJB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 159 0 JDINIF+Arial CID TrueType Identity-H yes yes yes 162 0 JDIIHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 175 0 JDIIHO+PalatinoLinotype CID TrueType Identity-H yes yes yes 178 0 JDIIHP+PalatinoLinotype TrueType WinAnsi yes yes no 184 0 JDIIJB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 187 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 02:41:43 CEST RepresentationInformation: pmc_34439518.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:14:54 CEST Size: 1748550 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 408 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Subject Clinical Characteristics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Safety Data Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Hemodynamic Vital Signs and Routine Clinical Laboratory Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Ferritin, DFO Pharmacokinetics, and Effects on TSAT Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Clinical Outcome Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Info: Title: Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial Author: Mònica Millán, Núria DeGregorio-Rocasolano, Natàlia Pérez de la Ossa, Sílvia Reverté, Joan Costa, Pilar Giner, Yolanda Silva, Tomás Sobrino, Manuel Rodríguez-Yáñez, Florentino Nombela, Francisco Campos, Joaquín Serena, José Vivancos, Octavi Martí-Sistac, Jordi Cortés, Antoni Dávalos and Teresa Gasull Subject: 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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