Safety Concerns With the Clinical Use of Erythropoietin in Acute Ischemic Stroke
2010; Lippincott Williams & Wilkins; Volume: 41; Issue: 7 Linguagem: Inglês
10.1161/strokeaha.110.585943
ISSN1524-4628
AutoresAbdullah Kumral, Şermin Genç, Kürşad Kutluk, Hasan Özkan,
Tópico(s)Pharmacological Effects and Toxicity Studies
ResumoHomeStrokeVol. 41, No. 7Safety Concerns With the Clinical Use of Erythropoietin in Acute Ischemic Stroke Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBSafety Concerns With the Clinical Use of Erythropoietin in Acute Ischemic Stroke Abdullah Kumral, MD Sermin Genc, MD, PhD Kursad Kutluk, MD Hasan Ozkan, MD Abdullah KumralAbdullah Kumral Department of Pediatrics, School of Medicine, Dokuz Eylul University, Izmir, Turkey Sermin GencSermin Genc Research Laboratory, School of Medicine, Dokuz Eylul University, Izmir, Turkey Kursad KutlukKursad Kutluk Stroke Unit, Department of Neurology, School of Medicine, Dokuz Eylul University, Izmir, Turkey Hasan OzkanHasan Ozkan Department of Pediatrics, School of Medicine, Dokuz Eylul University, Izmir, Turkey Originally published13 May 2010https://doi.org/10.1161/STROKEAHA.110.585943Stroke. 2010;41:e469Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 13, 2010: Previous Version 1 To the Editor:In their study published in Stroke, Ehrenreich et al report serious side effects after erythropoietin (EPO) therapy in acute ischemic stroke. These results call attention to the importance of meta-analysis of preclinical studies as a potential guidance of clinical stroke trials.1 Actually, 2 recent meta-analysis studies evaluating the efficacy of EPO in animal stroke models have concluded that preclinical safety studies for the combination of EPO with thrombolytic therapy and the efficacy of EPO in animals with comorbidity such as hypertension and diabetes are needed.2,3 Such studies are warranted before the design of further clinical stroke trials. For instance, activated protein C, which is another neuroprotectant molecule being tested in an ongoing stroke trial, minimizes side effects due to recombinant tissue-type plasminogen activator that was approved for acute stroke therapy.4–7Since the first in vivo evidence of the protection by EPO in neonatal brain injury in 2003, numerous preclinical studies have confirmed the efficiency of EPO in neonatal hypoxic–ischemic encephalopathy and neonatal stroke in rodents.8,9 Finally, a recent clinical trial has shown that EPO reduces the risk of disability in newborns with hypoxic–ischemic encephalopathy without apparent side effects.10 Clinical trials in neonatal stroke are still ongoing.7 It will be interesting to compare the results and to know the differences between the responses of adult and developing brain to exogenous EPO administration in stroke.Because EPO has also a tissue repair capacity promoting neuroregeneration, repeated administration of the drug might also be beneficial both in adult and developing brain injury.9,10 In this context, use of nonerythropoietic EPO derivatives such as carbamylated EPO may provide avoidance of side effects reported in acute stroke trial.1,11 The results of ongoing clinical trial with carbamylated EPO in acute stroke are still awaited.7 However, a safety concern with the repeated administration of EPO is immunogenicity of recombinant protein therapeutics.12 Furthermore, modified derivatives of recombinant proteins, especially in the form of prolonged therapy, may elicit epitope spreading and induce the immune responses that could trigger thrombotic complications.13Conclusively, all safety concerns should be evaluated in preclinical stroke studies with EPO and its derivatives and analogs.DisclosuresNone.1 Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jähnig P, Herrmann M, Knauth M, Bähr M, Heide W, Wagner A, Schwab S, Reichmann H, Schwendemann G, Dengler R, Kastrup A, Bartels C. EPO Stroke Trial Group. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009; 40: 647–656.LinkGoogle Scholar2 Jerndal M, Forsberg K, Sena ES, Macleod MR, O'Collins VE, Linden T, Nilsson M, Howells DW. A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab. 2010; 30: 961–968.CrossrefMedlineGoogle Scholar3 Minnerup J, Heidrich J, Rogalewski A, Schäbitz WR, Wellmann J. The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis. Stroke. 2009; 40: 3113–3120.LinkGoogle Scholar4 Yepes M, Roussel BD, Ali C, Vivien D. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci. 2009; 32: 48–55.CrossrefMedlineGoogle Scholar5 Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D, Maggirwar SB, Deane R, Fernández JA, LaRue B, Griffin JH, Chopp M, Zlokovic BV. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med. 2006; 12: 1278–1285.CrossrefMedlineGoogle Scholar6 Liu D, Cheng T, Guo H, Fernández JA, Griffin JH, Song X, Zlokovic BV. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med. 2004; 10: 1379–1383.CrossrefMedlineGoogle Scholar7 Available at: http://clinicaltrials.gov/. Accessed May 4, 2010.Google Scholar8 Kumral A, Ozer E, Yilmaz O, Akhisaroglu M, Gokmen N, Duman N, Ulukus C, Genc S, Ozkan H. Neuroprotective effect of erythropoietin on hypoxic–ischemic brain injury in neonatal rats. Biol Neonate. 2003; 83: 224–228.CrossrefMedlineGoogle Scholar9 McPherson RJ, Juul SE. Erythropoietin for infants with hypoxic–ischemic encephalopathy. Curr Opin Pediatr. 2010; 22: 139–145.CrossrefMedlineGoogle Scholar10 Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G, Blomgren K, Wang X. Erythropoietin improved neurologic outcomes in newborns with hypoxic–ischemic encephalopathy. Pediatrics. 2009; 124: 218–226.CrossrefMedlineGoogle Scholar11 Coleman TR, Westenfelder C, Tögel FE, Yang Y, Hu Z, Swenson L, Leuvenink HG, Ploeg RJ, d'Uscio LV, Katusic ZS, Ghezzi P, Zanetti A, Kaushansky K, Fox NE, Cerami A, Brines M. Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci U S A. 2006; 103: 5965–5970.CrossrefMedlineGoogle Scholar12 Sauerborn M, Brinks V, Jiskoot W, Schellekens H. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci. 2010; 31: 53–59.CrossrefMedlineGoogle Scholar13 Esmon CT, Glass JD. The APCs of neuroprotection. J Clin Invest. 2009; 119: 3205–3207.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Shah B, Jagtap P, Sarmah D, Datta A, Raut S, Sarkar A, Bohra M, Singh U, Baidya F, Kalia K, Borah A, Dave K, Yavagal D and Bhattacharya P (2020) Cerebro‐renal interaction and stroke, European Journal of Neuroscience, 10.1111/ejn.14983, 53:4, (1279-1299), Online publication date: 1-Feb-2021. Schneider Gasser E, Elliot-Portal E, Arias-Reyes C, Losantos-Ramos K, Khalid K, Ogunshola O and Soliz J (2019) Developmental expression patterns of erythropoietin and its receptor in mouse brainstem respiratory regions, Respiratory Physiology & Neurobiology, 10.1016/j.resp.2019.05.012, 267, (12-19), Online publication date: 1-Sep-2019. July 2010Vol 41, Issue 7 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.110.585943PMID: 20466989 Originally publishedMay 13, 2010 PDF download Advertisement
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