Effect of a Selective Thrombin Inhibitor MCI-9038 on Fibrinolysis In Vitro and In Vivo

Abstract

SummaryThe effect of a selective thrombin inhibitor, (2R, 4R)-4-methyl-1- [N2- [(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfo-nyl]-L-arginyl]-2-piperidinecarboxylic acid (MCI-9038), on the fibrinolysis induced by t-PA and u-PA was studied in vitro and in vivo. MCI-9038 remarkably reduced the lysis time of the plasma clot generated by the addition of calcium chloride to the plasma at the concentration ranging from 0.01 to 0.3 μM. Heparin also reduced the plasma clot lysis time with a lower effect than MCI-9038. The fibrin crosslinkage in the plasma clot was inhibited by MCI-9038 or heparin. MCI-9038 potently inhibited the factor XIIIa generation from factor XIII by thrombin.The effect on the in vivo thrombolysis was studied on the arterial thrombosis generated by the endothelial cell injury of the rabbit carotid artery by acetic acid. t-PA dissolved the thrombi with the infusion at 0.96 mg/kg over 2 h without a significant activation of a systemic fibrinolysis. u-PA dissolved the thrombi with the infusion at 180,000 and 360,000 IU/kg over 2 h. At a dose of 0.48 mg/kg t-PA or 90,000 IU/kg u-PA, the thrombi were not dissolved, but the combined use of MCI-9038 at 1.2 mg/kg over 2 h effectively dissolved the thrombi. Thus, combination of MCI-9038 with plasminogen activators accelerated thrombolysis of an experimental thrombosis in rabbits.

Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator.

“…Furthermore, the accelerated reperfusion was not due to an alteration in plasma t-PA. These data are consistent with a previous study, which reported that MCI9038 enhanced thrombolysis by t-PA in a rabbit model of carotid thrombosis (41), and demonstrate that thrombin delays coronary reperfusion induced by t-PA.…”

Antithrombotic actions of argatroban in rat models of venous, ‘mixed’ and arterial thrombosis, and its effects on the tail transection bleeding time

“…Nevertheless, the present results with heparin suggest that the two compounds are acting primarily on fibrin formation at the doses used, since Peters et al (1991) have shown that the reduction in the platelet content of such shunts is only achieved at doses of thrombin inhibitor (in this case recombinant Bush, 1991) to the extent that Jang et al (1990) used a dose of lOO1gkg-'min-' argatroban to prevent arterial occlusion in 9 out of 13 animals in their rabbit femoral arterial eversion model, which is resistant to heparin. Given the high specificity of argatroban towards both the amidolytic and platelet-aggregating actions of thrombin (Kikumoto et al, 1984;Hara et al, 1986;Tamao et al, 1986b), this reinforces the hypothesis that more thrombin is activated in platelet-rich thrombi, and that thrombin is a central mediator of arterial thrombosis, based on similar results obtained with the hirudins (see Talbot et al, 1991, for review) and the tripeptide irreversible thrombin inhibitor PPACK (Hanson & Harker, 1988). The degree of systemic anticoagulation (thrombin time and APTT prolongation) in the arterial thrombosis model required to inhibit thrombus formation is much lower for argatroban than for heparin.…”

Effect of Argatroban on Microthrombi Formation and Brain Damage in the Rat Middle Cerebral Artery Thrombosis Model

“…It is therefore suggested that impaired microvascular perfusion due to thrombin-induced microthrombi in the area surrounding the ischemic core contributes to the progression of ischemic lesions. Argatroban, a synthetic thrombin inhibitor (11,12), has been shown to prevent platelet-rich arterial thrombosis (13)(14)(15)(16)(17)(18).…”