Argatroban in combination with rt-PA in ischemic stroke

描述(由申请人提供)： 背景：阿加曲班是一种人工合成的直接凝血酶抑制物，来源于L-精氨酸。阿加曲班的化学名称为1-[5-[(氨基亚氨甲基)氨基]-1-氧代-2[[(1，2，3，4-四氢-3-甲基-8-喹啉)磺酰]氨基]戊基]-4-甲基-2-哌啶甲酸，一水合物。阿加曲班有4个 不对称碳。其中一个不对称碳具有R构型(立体异构体类型I)和S构型(立体异构体类型II)。阿加曲班的分子式为C23H36N605S*H20。其相对分子质量为526.66。阿加曲班由R和S立体异构体的混合物组成，比例约为65：35(+/-2%)。 作用机制：阿加曲班对凝血酶具有很高的选择性，抑制常数(K；)为0.04 mM。在治疗浓度下，阿加曲班对相关丝氨酸蛋白酶(胰酶、Xa因子、纤溶酶和激肽释放酶)没有或几乎没有影响。众所周知，凝血酶在血栓形成中起着关键作用。阿加曲班能够抑制游离型和凝血型凝血酶的作用。在大鼠大脑中动脉闭塞模型中，Matsuo等人报道在梗死区和半影区观察到微血栓。使用相同的模型，Kawai等人证明了阿加曲班可以显著减少梗塞的范围和微血栓的数量。田中等人的研究结果表明，阿加曲班直接抑制缺血性中风急性期继发性微血栓的形成。Tamao和Kikumoto将阿加曲班在脑血栓形成中的作用模式描述为抑制缺血组织损伤所形成的局部凝血酶。阻断这种局部凝血酶会抑制纤维蛋白的形成和血小板的聚集，从而导致在缺血核心区及其周围的微循环中形成血栓。通过防止微循环中随后的血栓形成，假设是改善了 血流到缺血周围/半暗带将挽救处于危险中的神经细胞 由于局部凝血酶抑制作用可阻止并可能逆转微血栓闭塞，因此阿加曲班有可能被证明在治疗大动脉粥样硬化、急性心源性血栓和小动脉闭塞(腔隙梗塞)等中风方面是有益的。

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).?