Ferres H
Beecham Pharmaceuticals Research Division, Great Burgh, Epsom.
Drugs. 1987;33 Suppl 3:33-50. doi: 10.2165/00003495-198700333-00005.
An ideal thrombolytic (or fibrinolytic) agent is one which would generate the formation of plasmin only where it is required, i.e. bound to fibrin within the thrombus. However, the capacity of even the newer thrombolytic agents to achieve localised plasmin generation within the thrombus is relative and depends on the concentration of the agent administered. For all available activators, the concentration required for effective clinical thrombolysis is also capable of converting plasminogen to plasmin within the circulation (plasminaemia). Since the action of plasmin is not specific to fibrin, plasminaemia results in dissolution not only of fibrin but also of several other clotting factors. For example, plasmin can degrade fibrinogen and cause impaired haemostasis. The plasminogen activators which are available, or have been developed to date, include streptokinase, urokinase, pro-urokinase, anisoylated plasminogen-streptokinase activator complex (APSAC) and tissue plasminogen activator (t-PA). All of these agents have the same biochemical mechanism of action, cleaving an arginine-valine bond in the plasminogen molecule to form plasmin, but they differ with regard to other important properties. The first property to be considered is clot specificity; the ability to dissolve fibrin as opposed to fibrinogen, and also to dissolve the clot as opposed to a haemostatic plug. Unfortunately, fibrin specificity does not equate entirely with thrombus specificity, and all currently developed plasminogen activators, by dissolving fibrin, will induce the destruction of haemostatic extravascular plugs as well as intravascular thrombi. Thus, no agent is thrombus-specific in this respect. The degree of fibrinogenolysis does vary between plasminogen activators. Those which have the least effect on haemostasis or clotting capability would seem, at first, to be preferable. However, a short term reduction in fibrinogen could also be beneficial, since it may reduce the incidence of early reocclusion and, by reducing blood viscosity, improve microcirculation to the infarct zone. The intrinsic efficiency of the plasminogen activators is a second important property. In vitro, under conditions pertaining to the circulation, urokinase is about 10 times more efficient than t-PA at converting glu-plasminogen to plasmin (on the basis of the Vmax to Km ratio), while streptokinase-plasmin is 20 times more efficient. The efficiency of these activators is increased in the presence of fibrin and lys-plasminogen, 1800-fold for t-PA, 8-fold for urokinase and 180-fold for streptokinase-plasmin.(ABSTRACT TRUNCATED AT 400 WORDS)
理想的溶栓剂（或纤维蛋白溶解剂）是一种仅在需要的地方，即与血栓内的纤维蛋白结合时，才会促使纤溶酶形成的药物。然而，即使是新型溶栓剂，在血栓内实现局部纤溶酶生成的能力也是相对的，并且取决于所给药的药物浓度。对于所有可用的激活剂，有效临床溶栓所需的浓度也能够在循环中（血浆纤溶酶血症）将纤溶酶原转化为纤溶酶。由于纤溶酶的作用并非纤维蛋白特异性的，血浆纤溶酶血症不仅会导致纤维蛋白溶解，还会导致其他几种凝血因子的溶解。例如，纤溶酶可降解纤维蛋白原并导致止血功能受损。目前可用的或已开发的纤溶酶原激活剂包括链激酶、尿激酶、前尿激酶、茴香酰化纤溶酶原 - 链激酶激活剂复合物（APSAC）和组织纤溶酶原激活剂（t - PA）。所有这些药物具有相同的生化作用机制，即切割纤溶酶原分子中的精氨酸 - 缬氨酸键以形成纤溶酶，但它们在其他重要特性方面存在差异。首先要考虑的特性是凝块特异性；即溶解纤维蛋白而非纤维蛋白原的能力，以及溶解血栓而非止血栓子的能力。不幸的是，纤维蛋白特异性并不完全等同于血栓特异性，并且所有目前开发的纤溶酶原激活剂通过溶解纤维蛋白，都会导致血管外止血栓子以及血管内血栓的破坏。因此，在这方面没有一种药物是血栓特异性的。不同纤溶酶原激活剂引起的纤维蛋白原溶解程度有所不同。那些对止血或凝血能力影响最小的药物，乍一看似乎更可取。然而，纤维蛋白原的短期减少也可能是有益的，因为它可能降低早期再闭塞的发生率，并且通过降低血液粘度，改善梗死区域的微循环。纤溶酶原激活剂的内在效率是第二个重要特性。在体外，在与循环相关的条件下，尿激酶在将谷氨酰胺纤溶酶原转化为纤溶酶方面的效率比t - PA高约10倍（基于Vmax与Km的比值），而链激酶 - 纤溶酶的效率高20倍。在存在纤维蛋白和赖氨酸纤溶酶原的情况下，这些激活剂的效率会提高，t - PA提高1800倍，尿激酶提高8倍，链激酶 - 纤溶酶提高180倍。（摘要截取自400字）
