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GR Thomas, H Thibodeaux, WF Bennett, CJ Refino, JM Badillo, CJ Errett and JA Zivin
Department of Cardiovascular Research, Genentech Inc., South San Francisco, California.
The dose-dependent effects of tissue-type plasminogen activator (t-PA) on the kinetics of cerebral clot lysis in a rabbit model of middle cerebral artery embolic stroke were investigated. The clots were formed in vitro and tagged with 99Tc for gamma-scintigraphic imaging. After embolization, groups of animals were treated with t-PA. Dose-response curves for the t-PA were generated, and in addition, long and short dosing schedules were assessed. The optimal doses for frequency and rate of cerebral clot lysis in this model are approximately 6.3 mg/kg given over 2 hr or 3.3 mg/kg given over 30 min. These dosing regimens for t-PA were accompanied by approximately 50% consumption of plasma plasminogen, fibrinogen and alpha 2-antiplasmin. Doses of t-PA on either side of this optimum caused attenuation in both the frequency and rate of cerebral clot lysis. Treatment with t-PA under either dosing regimen did not augment the frequency of hemorrhagic transformation, but the size of the resultant hemorrhage in those animals where intracranial bleeding occurred was reduced by 3.3 mg/kg t- PA given over 30 min.
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