Eriksson M, Basu S, Larsson A, Mattsson C, Eriksson O, Kiiski R, Nordgren A
Department of Intensive Care, University Hospital of Uppsala, S-751 85 Uppsala, Sweden.
Expert Opin Investig Drugs. 2000 May;9(5):1129-37. doi: 10.1517/13543784.9.5.1129.
Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.
脓毒症和内毒素血症会引发凝血酶的生成，凝血酶负责将纤维蛋白原转化为纤维蛋白、使血小板聚集，并作为一种炎症介质影响多种类型的细胞，包括心肌细胞、平滑肌细胞和内皮细胞。人类革兰氏阴性菌败血症性休克在重症监护病房中很常见，是一种死亡率很高的病症。这种病症可以在内毒素血症猪身上复制。由于脓毒症的许多毒性作用都归因于凝血酶的生成，因此利用这种猪实验性败血症性休克模型来研究抑制凝血酶是否可以减轻内毒素血症的影响就很有意义。为此，使用了美拉加群，一种分子量为429道尔顿的直接合成凝血酶抑制剂。美拉加群除了与凝血酶外，不会与凝血级联中的任何其他酶或纤溶酶发生显著相互作用。此外，美拉加群的抗凝血酶作用不需要抗凝血酶或肝素辅因子II等内源性辅因子，这一点很重要，因为这些抑制剂在脓毒症患者中经常会被消耗。我们已经表明，在实验性败血症性休克期间，通过血浆肌酐和尿量评估，美拉加群对肾功能有有益作用。这些作用在实验期后期最为明显，即在停止输注美拉加群之后。肾内凝血的预防可能归因于这一发现。此外，美拉加群对内毒素血症猪的全身血流动力学（左心室每搏功指数、肺毛细血管楔压和全身血管阻力指数）有有益作用。这一结果可以用美拉加群抑制凝血酶的能力来解释，从而抵消凝血酶的细胞效应。因此，利用这种败血症性休克实验模型可以看出，美拉加群可能有助于减轻内毒素血症的一些破坏性影响，不过还需要更多研究来进一步验证这一点。
