%0 Journal Article
%T Safety evaluation of a recombinant plasmin derivative lacking kringles 2-5 and rt-PA in a rat model of transient ischemic stroke
%A R Crumrine
%A Victor J Marder
%A G Taylor
%A Joseph C LaManna
%A Constantinos P Tsipis
%A Valery Novokhatny
%A Philip Scuderi
%A Stephen R Petteway
%A Vikram Arora
%J Experimental & Translational Stroke Medicine
%D 2012
%I BioMed Central
%R 10.1186/2040-7378-4-10
%X Male spontaneously hypertensive rats were subjected to 6 hours middle cerebral artery occlusion followed by 18 hours reflow. Beginning 1 minute before reflow, they were dosed with saline, vehicle, ¦¤(K2-K5) plasmin (0.15, 0.5, 1.5, and 5£¿mg/kg) or recombinant tissue-type plasminogen activator (10 and 30£¿mg/kg) by local intra-arterial infusion lasting 10 to 60 minutes. The rats were assessed for bleeding score, infarct volume, modified Bederson score and general behavioral score. In a parallel study, temporal progression of infarct volume was determined. In an in vitro study, whole blood clots from humans, canines and rats were exposed to ¦¤(K2-K5). Clot lysis was monitored by absorbance at 280£¿nm.The main focus of this study was intracranial hemorrhage safety. ¦¤(K2-K5) plasmin treatment at the highest dose caused no more intracranial hemorrhage than the lowest dose of recombinant tissue type plasminogen activator, but showed at least a 5-fold superior safety margin. Secondary results include: temporal infarct volume progression shows that the greatest expansion of infarct volume occurs within 2¨C3 hours of middle cerebral artery occlusion in the spontaneously hypertensive rat. A spike in infarct volume was observed at 6 hours ischemia with reflow. ¦¤(K2-K5) plasmin tended to reduce infarct volume and improve behavior compared to controls. In vitro data suggests that ¦¤(K2-K5) plasmin is equally effective at lysing clots from humans, canines and rats.The superior intracranial hemorrhage safety profile of the direct-acting thrombolytic ¦¤(K2-K5) plasmin compared with recombinant tissue type plasminogen activator makes this agent a good candidate for clinical evaluation in the treatment of acute ischemic stroke.Recanalization is an effective treatment for acute ischemic stroke [1]. Currently, recombinant tissue-type plasminogen activator (rt-PA) is the only FDA-approved pharmacological thrombolytic agent for recanalization therapy. Although effective, a major drawback of rt-
%K Ischemic stroke
%K ¦¤(K2-K5) plasmin
%K Intracranial hemorrhage
%K Spontaneously hypertensive rat model
%K Recombinant tissue-type plasminogen activator (rt-PA)
%K Middle cerebral artery occlusion (MCAo)
%U http://www.etsmjournal.com/content/4/1/10