Multicenter preclinical analysis of tenecteplase versus alteplase

Abstract Recombinant tissue plasminogen activator (rtPA/Alteplase) remains the gold standard thrombolytic drug for acute ischemic stroke. However, new rtPA-derived molecules such as Tenecteplase (TNK) with longer plasmatic half-life, practical delivery advantages as a fast, single bolus and increased fibrin binding have been developed. In spite of the recommendations on the bi-directionality of the basic/clinical research relationship, TNK is being tested in clinical trials without a preclinical basis on its toxicity and efficacy. In this study, toxicities of rtPA and TNK were evaluated on endothelial, astrocytes and neuronal culture; and efficacy was independently tested by two research centres in a thromboembolic model of ischemic stroke in mice. Both therapies were tested after early (20 and 30 min) and late administration (4 and 4.5 h) of ischemia onset. rtPA and TNK did not affect the viability of the endothelial cells or astrocytes. In neuronal cultures, rtPA, but not TNK, increased cell death at 24 h by itself. A single bolus dose of TNK showed an infarct volume reduction similar to that obtained after the perfusion of rtPA. TNK has a therapeutic window similar to rtPA and loses its beneficial effect when administered late. Early administration of TNK decreases the risk of haemorrhagic transformations compared to rtPA, but not when it is administered as a late treatment. These two independent preclinical studies support the use of TNK as a promising reperfusion alternative to rtPA treatment, mainly due to lower neurotoxicity and risk of haemorrhagic transformation when administered early after stroke onset.