天普洛安剂量及安全性探讨-2003.ppt

1、危重症患者乌司他丁临床应用剂量探讨,天普洛安（乌司他丁）剂量及安全性探讨,内容提要,体内乌司他丁与疾病或炎症反应的关系 天普洛安（乌司他丁）的量效关系 天普洛安（乌司他丁）的安全性,Ken-ichiro Inoue.et al, J. Clin. Biochem. Nutr., 43, 139142, November 2008,炎症反应促进Bikunin和乌司他丁大量释放，从而抑制蛋白酶活性,这是一项用乌司他丁天然缺失（-/-）与正常表达两种基因型小鼠所进行的对比性研究。 分别在这两种基因型的小鼠腹腔内注射1mg/kg内毒素以诱导全身炎症反应。 然后对比这两种动物血液学和组织学的变化。,KE

2、N-ICHIRO INOUE，et al: Protective Role of Urinary Trypsin Inhibitor in Acute Lung Injury Induced by Lipopolysaccharide, Exp Biol Med 230:281287, 2005 Ken-Ichiro Inoue, et al: Urinary Trypsin Inhibitor Protects against Systemic Inflammation Induced by Lipopolysaccharide, Mol Pharmacol 67:673680, 2005,

3、机体内缺失乌司他丁会?,Closed symbols : UTI(-/-) mice Open symbols: WT mice Animals were harvested72 h after i.p. injection of vehicle or LPS * P 0.05 versus vehicle-treated mice *P 0.01 versus vehicle-treated mice # P 0.05 versus LPS-treated WT mice #P 0.01 versus LPS-treated WT mice,在乌司他丁缺陷动物，大量白细胞被羁押在各器官,ki

4、dney,liver,lung,乌司他丁缺陷动物，各器官细胞损伤明显加重,UTI null (-/-) mice injected with LPS; WT mice injected with LPS (C) UTI null (-/-) mice injected with vehicle; (D) WT mice injected with vehicle,Ken-Ichiro Inoue, et al: Urinary Trypsin Inhibitor Protects against Systemic Inflammation Induced by Lipopolysacchari

5、de, Mol Pharmacol 67:673680, 2005,天普洛安前体浓度与疾病严重程度及死亡率相关,The Journal of Infectious Diseases 2003, 188:91926,病情越严重，血浆和尿液中乌司他丁水平越低,SHI DE LIN,et al.Journal of Gastroenterology and Hepatology (2004)19,327332,Child-Push C级患者的血浆和尿液UTI水平显著低于A级和B级患者,严重疾病患者乌司他丁水平不足以消除被激活的酶,Insufficient production of urinary

6、trypsin inhibitor for neutrophil elastase release after cardiac arrest.SHOCK 2008,29(5):549-552,Control group: 8位健康志愿者 Short cardiac arrest: 11位心脏骤停后30分钟内复苏患者 Long cardiac arrest:25位心脏骤停后超过30分钟复苏患者 NE:粒细胞弹性蛋白酶,ARDS患者肺泡中乌司他丁浓度不足以灭活PMNE,ARDS group (n=8) Control group(n=8),In conclusion, PMNE activity

7、in the BALF of post-surgerical ARDS is not inhibited by the small amount of UTI that is present in the BALF,Surg Today,Jpn J Surg(1999)29:1030-33,乌司他丁是保护机体免受炎性损害的重要机制 当疾病进展到一定程度，体内乌司他丁水平严重不足,小 结,乌司他丁抑制炎症的效果与其浓度有密切依赖关系,Human monocytes were preincubated with UTI (1,000 U/ml) for 30 min and then stimul

8、ated with LPS (100 ng/ml). control; UTI without LPS; LPS; , LPS+UTI. *P 0.01 vs. control; P 0.01vs. LPS.,Human monocytes were preincubated with various concentrations of UTI for 30 min and then stimulated with LPS (100 ng/ml). Four hours after stimulation,Perenlei Molor-Erdene, et al. Am J Physiol H

9、eart Circ Physiol 288: H1265H1271, 2005.,高浓度的乌司他丁对溶酶体膜稳定作用更明显,Effects of ulinastatin (UT; U/ml) on N-acetyl-b-D-glucosaminidase (NAG) release from L2 cells after treatment with 2 uM antimycin A (A2). *P0.05 vs. A2; *P0.05 vs. control.,Pulmonary Pharmacology UTI 30,000 U/kg, i.v.; UTI 50,000 U/kg, i.

10、v.,大剂量乌司他丁预防辐射引起的小鼠肺损伤,20,R: 对照组 P1:UTI 40万U /kg/d, 辐射前治疗3d，辐射后治疗4d; P2:UTI 20万U /kg/d, 辐射前治疗3d，辐射后治疗4d A1:UTI 40万U /kg/d, 辐射后治疗7d; A2:UTI 20万U /kg/d, 辐射后治疗7d,Pengtao Bao, et al. European Journal of Pharmacology 603 (2009) 114119,21,大剂量乌司他丁预防辐射引起的小鼠肺损伤,21,R: 对照组 P1:UTI 40万U /kg/d, 辐射前治疗3d，辐射后治疗4d; P

11、2:UTI 20万U /kg/d, 辐射前治疗3d，辐射后治疗4d A1:UTI 40万U /kg/d, 辐射后治疗7d; A2:UTI 20万U /kg/d, 辐射后治疗7d,Pengtao Bao, et al. European Journal of Pharmacology 603 (2009) 114119,大剂量乌司他丁颈内静脉推注治疗难治性间质性肺炎,颈内静脉推注UTI 30万U，共3次，其间间隔5h *P0.01,1个月后影像学改变,结论： UT inhibitor bolus infusion therapy could show anti-inflammatory and

12、anti-oxidant effects without serious adverse effects. UT inhibitor bolus infusion therapy could be useful as an alternative therapy for refractory IP.,乌司他丁对重症脓毒症患者炎性反应的影响及疗效评价,重症脓毒症患者63例 随机分成对照组( 组, n = 21) UTI 1万U/kg/d组( 组, n = 21) UTI 2万U/kg/d组( 组, n = 21) 治疗前及治疗后5d分别采外周血检测TNF -、IL - 1、IL - 10、MDA和SOD水平 并进行APACHE评分。记录28 d病死率,倪红英，方强等.中国急救医学2008年4月第28卷第4期,乌司他丁具有可靠的安全性,乌司他丁半衰期很短。健康男性30万U/10ml静脉注射给药后，清除半衰期为40分钟 日本乌司他丁上市后研究数据显示：总病例8710例中，74例（0.8%）出现副作用。主要为AST/ALT上升（0.4%），白细胞