Schenk J F, Glusa E, Radziwon P, Butti A, Markwardt F, Breddin H K
International Institute of Thrombosis and Vascular Diseases, Frankfurt am Main, Germany.
Haemostasis. 1996 May-Jun;26(3):140-9. doi: 10.1159/000217199.
The pharmacodynamic effects of different intravenous and subcutaneous doses of a recombinant hirudin (r-hirudin; IK-HIR02) on clotting parameters and bleeding time were investigated in 24 healthy volunteers in a bicenter study. Single intravenous bolus injections of 0.1, 0.2 and 0.3 mg/ kg IK-HIR02 caused a prolongation of thrombin time (TT) and aPTT in a dose-dependent manner and led to an increase in hirudin plasma levels > 6 micrograms/ml. The plasma half-life of IK-HIR02 was calculated as 1.3 h. A continuous infusion of 0.03 mg/kg/h of IK-HIR02 for 4 h significantly prolonged TT and aPTT. At the end of the hirudin infusion, a mean plasma level of 0.19 +/- 0.13 microgram/ml was measured. Single subcutaneous doses of 0.1, 0.25 and 0.5 mg/kg markedly prolonged the coagulation tests. The highest increase in hirudin plasma levels was found 2 h after injection. At this time the aPTT was doubled after 0.5 mg/kg. After repeat subcutaneous injections of 0.3 mg/kg b.i.d., aPTT was doubled, and TT increased to about 200 s, 2 h after the injections. At this time the mean plasma level was 0.5-0.6 microgram/ml. There was no cumulative effect after multiple injections. Bleeding time was not changed after the 4-hour intravenous infusion and after repeat subcutaneous injections of 0.3 mg/kg IK-HIR02. Bleeding time was moderately but significantly prolonged after the highest single intravenous and subcutaneous hirudin doses tested. Other than very minor local bleeding in some volunteers, IK-HIR02 was well tolerated. Biochemical blood and urine parameters did not change. In conclusion, r-hirudin (IK-HIR02) obtained by a new technique was well tolerated in healthy volunteers after single intravenous and subcutaneous injections, after repeat subcutaneous doses and during continuous intravenous infusion. Measurement of aPTT and anti-IIa activity, using a chromogenic substrate test, can be used to monitor hirudin effects if doses similar to those tested here are administered.
在一项双中心研究中，对24名健康志愿者研究了不同静脉注射和皮下注射剂量的重组水蛭素（r - 水蛭素；IK - HIR02）对凝血参数和出血时间的药效学作用。单次静脉推注0.1、0.2和0.3 mg/kg的IK - HIR02可使凝血酶时间（TT）和活化部分凝血活酶时间（aPTT）呈剂量依赖性延长，并导致水蛭素血浆水平升高至>6微克/毫升。IK - HIR02的血浆半衰期计算为1.3小时。以0.03 mg/kg/h的速度持续输注IK - HIR02 4小时可显著延长TT和aPTT。在水蛭素输注结束时，测得平均血浆水平为0.19±0.13微克/毫升。单次皮下注射0.1、0.25和0.5 mg/kg可显著延长凝血试验时间。注射后2小时水蛭素血浆水平升高最高。此时，0.5 mg/kg剂量后aPTT加倍。在0.3 mg/kg bid重复皮下注射后，注射后2小时aPTT加倍，TT增加至约200秒。此时平均血浆水平为0.5 - 0.6微克/毫升。多次注射后无累积效应。4小时静脉输注以及0.3 mg/kg IK - HIR02重复皮下注射后出血时间未改变。在测试的最高单次静脉和皮下水蛭素剂量后，出血时间有中度但显著的延长。除了一些志愿者出现非常轻微的局部出血外，IK - HIR02耐受性良好。血液和尿液生化参数未改变。总之，通过新技术获得的r - 水蛭素（IK - HIR02）在健康志愿者单次静脉和皮下注射、重复皮下给药以及持续静脉输注后耐受性良好。如果给予与此处测试剂量相似的剂量，使用发色底物试验测定aPTT和抗IIa活性可用于监测水蛭素的作用。
