新型合成丝氨酸蛋白酶抑制剂 CU-2010 可剂量依赖性减少犬心脏手术后的出血量，并改善术后缺血恢复。

The novel synthetic serine protease inhibitor CU-2010 dose-dependently reduces postoperative blood loss and improves postischemic recovery after cardiac surgery in a canine model.

机构信息

Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.

出版信息

J Thorac Cardiovasc Surg. 2010 Mar;139(3):732-40. doi: 10.1016/j.jtcvs.2009.10.059.

DOI:10.1016/j.jtcvs.2009.10.059

PMID:20176215

Abstract

BACKGROUND

Serine protease inhibitors such as aprotinin reduce perioperative blood loss and may improve postpump cardiac performance owing to their anti-inflammatory properties. After the "aprotinin era," we investigated the efficacy of the novel synthetic serine protease inhibitors CU-2010 with improved coagulatory and anti-inflammatory profile on blood loss and reperfusion injury in a canine model.

METHODS

Thirty-six dogs were divided into 6 groups: control, aprotinin (n = 8; Hammersmith scheme), and CU-2010 (0.5, 0.83, 1.25, and 1.66 mg/kg). All animals underwent 90 minutes of cardiopulmonary bypass with 60 minutes of hypothermic cardioplegic arrest. End points were blood loss during the first 2 hours after application of protamine, as well as recovery of myocardial contractility (slope of the end-systolic pressure-volume relationship, coronary blood flow, and vascular reactivity.

RESULTS

CU-2010 dose-dependently reduced blood loss to a degree comparable with that of aprotinin at lower doses and even further improved at higher doses (control/aprotinin/CU-2010 in increasing doses: 142 +/- 13, 66 +/- 17, 95 +/- 16, 57 +/- 17, 46 +/- 3, and 13 +/- 4 mL; P < .05). Whereas aprotinin did not influence myocardial function, CU-2010 improved the recovery of end-systolic pressure-volume relationship (control 60 +/- 6 mg kg vs aprotinin 73 +/- 7 mg/kg vs CU-2010 1.66 mg/kg; 102% +/- 8%; P < .05). Coronary blood flow (52 +/- 4 vs 88 +/- 7 vs 96 +/- 7; P < .05) and response to acetylcholine (44% +/- 6% vs 77% +/- 7% vs 81% +/- 6%; P < .05) were improved by both aprotinin and CU-2010.

CONCLUSIONS

The novel serine protease inhibitor CU-2010 significantly reduced blood loss after cardiac surgery comparable with aprotinin. Furthermore, an additionally improved anti-inflammatory profile led to a significantly improved postischemic recovery of myocardial and endothelial function.

摘要

背景

丝氨酸蛋白酶抑制剂如抑肽酶可减少围手术期失血，并可能改善心脏术后心功能，这归因于其抗炎特性。在“抑肽酶时代”之后，我们研究了新型合成丝氨酸蛋白酶抑制剂 CU-2010 的疗效，其具有改善的凝血和抗炎特性，可减少犬模型中的失血和再灌注损伤。

方法

36 只狗分为 6 组：对照组、抑肽酶（n = 8；Hammersmith 方案）和 CU-2010（0.5、0.83、1.25 和 1.66mg/kg）。所有动物均接受 90 分钟心肺转流，60 分钟低温停搏。终点为应用鱼精蛋白后 2 小时内的失血量，以及心肌收缩力的恢复（收缩末期压力-容积关系斜率、冠状动脉血流和血管反应性）。

结果

CU-2010 剂量依赖性地降低失血量，程度与低剂量的抑肽酶相当，甚至在高剂量时进一步改善（对照组/抑肽酶/CU-2010 剂量递增：142±13、66±17、95±16、57±17、46±3 和 13±4ml；P<0.05）。虽然抑肽酶不影响心肌功能，但 CU-2010 改善了收缩末期压力-容积关系的恢复（对照组 60±6mg/kg 对抑肽酶 73±7mg/kg 对 CU-2010 1.66mg/kg；102%±8%；P<0.05）。冠状动脉血流（52±4 对 88±7 对 96±7；P<0.05）和对乙酰胆碱的反应（44%±6%对 77%±7%对 81%±6%；P<0.05）均被抑肽酶和 CU-2010 改善。