Comparative Study of a Mutant Tissue-type Plasminogen Activator, YM866, with a Tissue-type Plasminogen Activator in a Canine Model of Femoral Arterial Thrombosis

3区 · 医学

Article

作者: Sakai, Y ; Kawasaki, T ; Takenaka, T ; Kaku, S

AbstractBecause tissue-type plasminogen activator (tPA), used to treat myocardial infarction, has several disadvantages thought to be connected with its low half-life, mutants of tPA have been prepared with longer half-lives. We have compared the thrombolytic effect of such a mutant, YM866, with that of tPA in copper-coil-induced femoral arterial thrombosis in dogs.One hour after thrombus formation, YM866 was administered by intravenous bolus injection, while tPA was given by the same method or by 60-min infusion under adequate heparinization. Both agents exhibited dose-dependent thrombolysis without systemic fibrinogenolysis. The recanalization rate and recanalization time of YM866 by bolus at 0.2 mg kg−1 were, however, equivalent to those of tPA by infusion at 0.4 mg kg−1 (total dose), whereas the recanalization rate of tPA by bolus was low (0.4 mg kg−1). No significant difference in reocclusion rate, reocclusion time, or patency status after successful thrombolysis was seen.These results suggest that YM866 administered at a lower dose by intravenous bolus injection exerted a thrombolytic effect equivalent to that of tPA by infusion, and that heparin could not prevent reocclusion after successful thrombolysis even under adequate anticoagulation.

2010-02-18·Journal of Pharmacy and Pharmacology3区 · 医学

Ventricular Function and Cardiac Hypertrophy after Coronary Thrombolysis with Tissue-type Plasminogen Activator (t-PA) in Dogs with Coronary Artery Thrombi

3区 · 医学

Article

作者: Suzuki, Masanori ; Kimoto, Aishi ; Usuda, Shinji ; Tanaka, Hideyuki ; Asano, Hironobu

AbstractSubacute prognosis of cardiac function after thrombolysis with a modified tissue-type plasminogen activator (t-PA) YM866 was determined in dogs with coronary artery thromboses induced by injection of a thrombin, fibrinogen and autogenous blood mixture.The left ventricular ejection fraction (LVEF) decreased 30 min after occlusion and had not improved 1 week later. Examination after sacrifice revealed myocardial infarction as well as increases in both the left ventricular myocardial area and heart mass. Occluded coronary arteries reperfused by YM866 (0.1 mg kg−1 i.v.) treatment 30 min after occlusion, by contrast, had improved LVEF and inhibited myocardial infarction development. In addition, the left ventricular myocardial area and heart mass were significantly reduced compared with the vehicle control group 1 week after administration. Although occluded coronary arteries reperfused by YM866 (0.1 mg kg−1 i.v.) treatment 3 h after occlusion did not show an improvement in the LVEF or inhibition of myocardial infarction development, the left ventricular myocardial area and heart mass decreased significantly compared with the vehicle control group 1 week after administration.In conclusion, early reperfusion by t-PA treatment 30 min after occlusion improved the ventricular function and cardiac hypertrophy, whereas late reperfusion by t-PA treatment 3 h after occlusion did not improve the ventricular function but did inhibit hypertrophy in dogs with coronary artery thrombi.

2008-07-01·Cardiovascular & Hematological Agents in Medicinal Chemistry

Fibrin Binding and the Regulation of Plasminogen Activators during Thrombolytic Therapy

Review

作者: Thelwell, C. ; Williams, S. ; Longstaff, C.

First generation thrombolytics (streptokinase and urokinase) had no fibrin binding capabilities and caused systemic plasminogen activation with concomitant destruction of haemostatic proteins. A primary driving force behind the development of the second generation plasminogen activator tissue plasminogen activator (tPA or alteplase) was its ability to bind to fibrin and target thrombolysis. Although in vitro assays highlighted advantages of fibrin binding, clinical trials were disappointing, showing only small benefits in mortality with tPA versus streptokinase, but also with some increase in haemorrhagic stroke. Third generation thrombolytic agents (reteplase, tenecteplase and pamiteplase) are variants of tPA engineered to have improved structure/function, such as longer half life and resistance to inhibitors. However, clear therapeutic advantages of third generation thrombolytics in clinical trials have also been difficult to demonstrate. Although fibrin binding is critical in regulating the activity of tPA, it is not clear how important it is for thrombolytic treatment. Advances are needed in our understanding of the relationship between structure/binding and activity of PAs in vivo under normal conditions and when administered in pharmacological doses. Clearly the impact of fibrin structure and the other components in fibrin clots must also be considered. Ultimately these studies may lead to better engineered therapeutics or optimised mixtures of molecules. With a more detailed understanding of the regulation of plasminogen activation and fibrinolysis it might be possible to tailor thrombolytic therapy to different situations such as myocardial or cerebrovascular treatment or to the patient's age and sex and other characteristics.

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KEGG	Wiki	ATC	Drug Bank
D05410	-	B01AD	-

研发状态

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10 条最早获批的记录,

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适应症	国家/地区	公司	日期
急性心肌梗塞	日本	-	1998-01-01

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适应症	最高研发状态	国家/地区	公司	日期
血栓形成	临床1期	日本	Yamanouchi Pharmaceutical Co., Ltd.	1994-06-01
急性心肌梗塞	临床前	日本	Yamanouchi Pharmaceutical Co., Ltd.	1993-01-01
冠状动脉血栓形成	临床前	日本	Yamanouchi Pharmaceutical Co., Ltd.	1993-01-01