Argatroban, (2R,4R)-4-methyl-1-(N2 [(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfonyl]-L-arginyl)-2-pi peridinecarboxylic
acid, a selective and competitive
thrombin inhibitor, was examined for effectiveness in three different experimental models of
cerebral thrombosis in rats, namely, the four-vessel occlusion model, the
middle cerebral artery occlusion model, and the distal
middle cerebral artery occlusion model.
Argatroban was demonstrated to be effective in these experimental models of
thrombosis. Among these models, the distal
middle cerebral artery occlusion model was the most similar to clinical
cerebral thrombosis with respect to restriction of the
infarction to the cerebral cortex and the accompanying stable
neurologic deficits. In this model, the
thrombus was generated at the Y-shaped bifurcation of the middle cerebral artery by green light irradiation through a cranial window after administration of
rose bengal.
Argatroban given after
thrombus formation by intraperitoneal implantation of an osmotic pressure pump was shown to reduce
infarct size and
neurologic deficits on day 3 and microthrombi generation on day 1, and to raise the regional cerebral blood flow on day 1, at a plasma level of 0.2 to 0.6 microM supporting its clinical usefulness in the treatment of acute-phase
cerebral thrombosis.
Argatroban was considered to exert its effects by salvaging neuronal cells in the ischemic penumbra and suppressing extension of the
infarction into the penumbra by keeping blood vessels patent, mainly through the inhibition of microthrombogenesis.