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The effects of a new tissue plasminogen activator analogue, Fb-Fb-CF, on cerebral reperfusion in a rabbit embolic
D A Phillips1, M Fisher, T W Smith
1Department of Radiology, University of Massachusetts Medical School, Worcester.
Abstract:
Early fibrinolytic therapy with full molecular tissue plasminogen activator (t-PA) has been observed to be both angiographically and clinically effective when employed in animal stroke models. Preliminary clinical trials with t-PA are in progress. It is possible to refine t-PA by developing fragments or analogues of the drug. Using recombinant DNA technology in the Escherichia coli system, a t-PA analogue consisting of the catalytic fragment of t-PA and a dimer of the B fragment of staphylococcal protein A (Fb-Fb-CF) has been produced. Because this analogue has a long serum half-life of 90 minutes, we employed Fb-Fb-CF in a rabbit cerebral embolic stroke model to assess its efficacy as a reperfusion agent. When given as a bolus to 10 animals 15 minutes after embolization, Fb-Fb-CF produced angiographic cerebral reperfusion in 48 +/- 21 minutes (+/- SD), while in 8 saline-treated controls, reperfusion was not observed at 180 minutes in any animal (p less than 0.01). In another experiment reperfusion was demonstrated at 66 +/- 32 minutes in 11 animals treated with Fb-Fb-CF 90 minutes after embolization as compared with 100 +/- 25 minutes in 12 saline-treated controls (p less than 0.01). A small macroscopic hemorrhage within an infarct was seen in 1 Fb-Fb-CF-treated animal in the 15-minute experiment and in none of the controls. In the 90-minute experiment, macroscopic hemorrhagic infarction was seen in 4 Fb-Fb-CF-treated animals and in 3 controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
A novel tissue plasminogen activator (t-PA) analogue, Fb-Fb-CF, effectively restored blood flow in a rabbit stroke model. This engineered fibrinolytic agent shows promise for treating ischemic stroke.
Area of Science:
- Biochemistry
- Pharmacology
- Neurology
Background:
- Early fibrinolytic therapy using full molecular tissue plasminogen activator (t-PA) demonstrates efficacy in animal stroke models.
- Refining t-PA through fragments or analogues is a potential therapeutic strategy.
- Recombinant DNA technology in Escherichia coli enables the production of t-PA analogues.
Purpose of the Study:
- To assess the efficacy of a novel t-PA analogue, Fb-Fb-CF, as a cerebral reperfusion agent.
- To evaluate the reperfusion potential of Fb-Fb-CF in a rabbit cerebral embolic stroke model.
- To investigate the safety profile of Fb-Fb-CF concerning hemorrhage.
Main Methods:
- Production of Fb-Fb-CF using recombinant DNA technology in E. coli.
- Administration of Fb-Fb-CF as a bolus in a rabbit cerebral embolic stroke model at 15 and 90 minutes post-embolization.
- Assessment of angiographic cerebral reperfusion times and incidence of hemorrhage compared to saline controls.
Main Results:
- Fb-Fb-CF significantly reduced reperfusion time when administered 15 minutes after embolization (48 +/- 21 min vs. no reperfusion in controls).
- Reperfusion was also achieved at 66 +/- 32 minutes when Fb-Fb-CF was given 90 minutes post-embolization, compared to 100 +/- 25 minutes in controls.
- Hemorrhagic complications were observed in a small number of Fb-Fb-CF treated animals and controls.
Conclusions:
- The engineered t-PA analogue, Fb-Fb-CF, is an effective reperfusion agent in a rabbit stroke model.
- Fb-Fb-CF demonstrates potential as a therapeutic agent for ischemic stroke, warranting further investigation.
- The long serum half-life of Fb-Fb-CF may enhance its therapeutic utility.