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Background: Ongoing clinical trials are testing the effect of fluoxetine delivered post-stroke where a majority of patients are taking statins. This study determined the influence of the timing of administration of fluoxetine and statin on the final infarct volume and the risk of secondary bleeding in an animal model of ischemic stroke.

Methods and findings: Ischemic strokes were induced by endothelin-1 injection into two cortical sites of 10-12 month old female rats, targeting the forelimb motor cortex. Combined medications (5 mg/kg fluoxetine and 1 mg/kg simvastatin) were orally administered either beginning 6-12 hours or 20-26 hours after stroke induction and continued daily for 90 days. Infarct volumes were assessed at poststroke day 91 using Nissl stained coronal brain sections.

Control animals typically had 5-13 mm3 infarct volumes following endothelin-1 induced stroke. Animals that received fluoxetine and simvastatin (FS) beginning 20- 26 hours after stroke induction showed a strong trend of reduced infarct volume (3±0.3447 mm3 SEM, P=0.0563). Earlier drug delivery (6-12 hours after stroke) resulted in significantly larger infarct volumes (15.44.260 mm3 SEM, P=0.0157) when the drug groups were directly compared. Examination of the infarcts showed that earlier drug delivery induced secondary hemorrhagic infarcts, while later delivery did not (P=0.0427; Fisher’s exact test).

Conclusion: There is a danger of secondary bleeding if fluoxetine and simvastatin are combined within 6-12 hours of ischemic stroke induction in rats resulting in larger infarct volumes. Delaying fluoxetine and simvastatin delivery to 20-26 hours after stroke induction in rats, however, reduces infarct volume and significantly lowers the risk of secondary hemorrhagic infarcts.


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