Did Clinical Trials in Which Erythropoietin Failed to Reduce Acute Myocardial Infarct Size Miss a Narrow Therapeutic Window 英文参考文献.docVIP

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Did Clinical Trials in Which Erythropoietin Failed to Reduce Acute Myocardial Infarct Size Miss a Narrow Therapeutic Window 英文参考文献.doc

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Did Clinical Trials in Which Erythropoietin Failed to Reduce Acute Myocardial Infarct Size Miss a Narrow Therapeutic Window 英文参考文献

DidClinicalTrialsinWhichErythropoietinFailedto ReduceAcuteMyocardialInfarctSizeMissaNarrow TherapeuticWindow? MarkI.Talan*,IsmayilAhmet,EdwardG.Lakatta Laboratory of Cardiovascular Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America Abstract Background: To test a hypothesis that in negative clinical trials of erythropoietin in patients with acute myocardial infarction (MI) the erythropoietin (rhEPO) could be administered outside narrow therapeutic window. Despite overwhelming evidence of cardioprotective properties of rhEPO in animal studies, the outcomes of recently concluded phaseIIclinicaltrialshavefailedtodemonstratetheefficacyofrhEPOinpatientswithacuteMI.However,thetimebetween symptomsonsetandrhEPOadministrationinnegativeclinicaltrialswasmuchlongerthatinsuccessfulanimalexperiments. Methodology/PrincipalFindings:MIwasinducedinratseitherbyapermanentligationofadescendingcoronaryarteryor by a 2-hr occlusion followed by a reperfusion. rhEPO, 3000IU/kg, was administered intraperitoneally at the time of reperfusion,4hrsafterbeginningofreperfusion,or6hrsafterpermanentocclusion.MIsizewasmeasuredhistologically 24hrsaftercoronaryocclusion.Theareaofmyocardiumatriskwassimilaramonggroups.TheMIsizeinuntreatedrats averaged,42%ofareaatrisk,or,24%ofleftventricle,andwasreducedbymorethan50%(p,0.001)inratstreatedwith rhEPOatthetimeofreperfusion.TheMIsizewasnotaffectedbytreatmentadministered4hrsafterreperfusionor6hrs after permanent coronary occlusion. Therefore, our study in a rat experimental model of MI demonstrates that rhEPO administeredwithin2hrsofacoronaryocclusioneffectivelyreducesMIsize,butwhenrhEPOwasadministeredfollowinga delaysimilartothatencounteredinclinicaltrials,ithadnoeffectonMIsize. Conclusions/Significance:TheclinicaltrialsthatfailedtodemonstraterhEPOefficacyinpatientswithMImayhavemisseda narrowtherapeuticwindowdefinedinanimalexperiments. Citation:TalanMI,AhmetI,Lakat