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Neuroprotection through the blockade of proteolytic activation of t-PA SuperGen were developing LEX-032, a recombinant form of the endogenous protease inhibitor, serpin. This molecule has a unique spectrum of activities, including the ability to inhibit binding of neutrophils to the vascular surface. In addition, this drug inhibits free radical production by neutrophils, and inhibits the activity of released serine proteases. This profile is consistent with the use in the treatment of myocardial infarction, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation. In the "Focus on CardioVascular disease" section of this edition of TherapeuticAdvances we highlight studies by University of Zurich researchers who report that inhibition of proteolytic activation of t-PA can lead to neuroprotection. Likewise, University of Pennsylvania researchers have recently shown that LEX-032 can speed the recovery of somatosensory evoked potentials in murine models of stroke. Moreover, LEX-032 treatment improved neurologic performance and caused a 55% reduction in brain injury 24 h after ischemia. Finally, leukocyte infiltration was also lower in the LEX-032-treated animals. About 600,000 Americans suffer ischemic stroke each year, 8% of which die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke us therefore immense. Neuroprotective agents are required since the window of opportunity for the use of thrombolytics is very short and LEX-032 offers hope in this respect. The development status of this molecule is unclear. LEX-032 was originally indicated for the treatment of acute pulmonary inflammation, pancreatitis, reperfusion injury, psoriasis and disseminated intravascular coagulation, however development appears to have been ceased. Data reported in the current publication could signal the reemergence of LEX-032 as a treatment of stroke but if not it offers proof of concept for the development of similar molecules for this indication. Link to journal abstract:
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