Argatroban in combination with rt-PA in ischemic stroke

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DESCRIPTION (provided by the applicant): Background: Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine. The chemical name for Argatroban is 1-[5-[(aminoiminomethyl) amino]-1-oxo-2 [[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl] amino] pentyl]-4-methyl-2piperidinecarboxylic acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). The molecular formula of Argatroban is C23H36N605S*H20. Its molecular weight is 526.66.' Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35 (+/- 2%). Mechanism of Action: Argatroban is highly selective for thrombin with an inhibitory constant (K;) of 0.04 MM. At therapeutic concentrations, Argatroban has no or minimal effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). 2 It is well known that thrombin plays a pivotal role in thrombosis. Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. In rat middle cerebral artery occlusion models, Matsuo, et al, reported observation of microthrombi in the infarcted and penumbral areas. Using the same model, Kawai, et al, demonstrated that Argatroban could significantly reduce the size of an infarct and the number of microthrombi. Results of studies by Tanaka, et al, suggest that Argatroban directly inhibits secondary microthrombus formation in acute stages of ischemic strokes An explanation offered by Tamao and Kikumoto describes the mode of action of Argatroban in cerebral thrombosis as an inhibition of the local thrombin formed due to ischemic tissue damage. Blocking of this local thrombin inhibits fibrin formation and platelet aggregation that lead to formation of thrombi in the microcirculation in and around the core zone of ischemia. By preventing subsequent thrombus formation in the microcirculation, the hypothesis is that improved blood flow to the peri-ischemic/penumbra would rescue neuronal cells at risks Because the action of local thrombin inhibition halts and possibly reverses microthrombi occlusion, Argatroban could potentially prove to be of benefit in the treatment of strokes classified as large-artery atherosclerotic, acute cardioembolic, and small-artery occlusion (lacunar infarcts).?