Argatroban in combination with rt-PA in ischemic stroke

描述（由申请人提供）： 背景：阿加曲班是一种合成的直接凝血酶抑制剂，来源于L-精氨酸。阿加曲班的化学名称为1-[5-[（氨基亚氨基甲基）氨基]-1-氧代-2 [[（1，2，3，4-四氢-3-甲基-8-喹啉基）磺酰基]氨基]戊基]-4-甲基-2-哌啶羧酸，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（I型立体异构体）和S构型（II型立体异构体）。阿加曲班的分子式为C23 H36 N6 O 5S * H2O。其分子量为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高度选择性，抑制常数（Ki）为0.04 MM。在治疗浓度下，阿加曲班对相关丝氨酸蛋白酶（胰蛋白酶、因子Xa、纤溶酶和激肽释放酶）没有影响或影响极小。2.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凝血酶和凝块相关凝血酶的作用。在大鼠大脑中动脉闭塞模型中，Matsuo等人报告了在梗死和半暗区观察到微血栓。使用相同的模型，Kawai等人证明阿加曲班可以显著减少梗死的大小和微血栓的数量。Tanaka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的继发性微血栓形成。Tamao和Kikumoto提供的解释描述了阿加曲班在脑血栓形成中的作用模式，即抑制由于缺血性组织损伤而形成的局部凝血酶。阻断这种局部凝血酶可抑制纤维蛋白形成和血小板聚集，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，该假设是改善了 流向缺血周围/半暗带的血流将挽救处于危险中的神经元细胞 由于局部凝血酶抑制作用可以阻止并可能逆转微血栓闭塞，阿加曲班可能被证明在治疗分类为大动脉粥样硬化、急性心源性栓塞和小动脉闭塞（腔隙性梗死）的中风中有益。

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).?