天普洛安剂量及安全性探讨2003

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。,KEN-ICHIRO INOUE，et al: Protective Role of Urinary Trypsin Inhibitor in Acute Lung Injury Induced by Lipopolysaccharide, Exp Biol Med 230:281287, 2005Ken-Ichiro Inoue, et al: Urinary Trypsin Inhibitor Protects against SystemicInflammation Induced by Lipopolysaccharide, Mol Pharmacol 67:673680, 2005,机体内缺失乌司他丁会?,Closed symbols : UTI(-/-) miceOpen symbols: WT miceAnimals 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,kidney,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 Lipopolysaccharide, 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 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 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 preincubatedwith UTI (1,000 U/ml) for 30 min and then stimulated 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 Heart 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 & Therapeutics (1999) 12, 16,天普洛安对LPS肺损伤的保护作用具有剂量相关性,Effects of UTI on LPS-induced changes in the concentration of interleukin-8 in bronchoalveolar lavage fluid (BALF) and wet/dry weight (W/D) ratio. BALF and lung lobe were collected 6 h after the start of the saline or LPS infusion. Each value represents meanSD from seven rabbits. *P0.05 versus group Saline-Only, P0.05 vs. group LPS-Only, P0.01 vs. group LPS-Only.,Effects of Urinary Trypsin Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury in Rabbits Inflammation 2011,Effects of UTI on lung tissue damage in rabbits at 6 h after the start of saline or LPS infusion. Representative hotomicrographies showing hematoxylin and eosin staining samples with median values in a group Saline-Only, b group LPS-Only, and c group pre-UTI-High. Original print magnifications 200. Lung injury score d: lung injury was scored from 0 (no damage) to 4+ (severe damage) according to the criteria described in MATERIALS AND METHODS. Bars represent median values from seven rabbits. *P0.05 vs. group Saline-Only. P0.05 vs. group LPS-Only.,乌司他丁对LPS肺损伤的保护作用具有剂量相关性,乌司他丁疗效存在剂量依赖关系-烧伤休克,乌司他丁疗效存在剂量依赖关系-内毒素性休克,乌司他丁疗效存在剂量依赖关系-创伤性休克,乌司他丁疗效存在剂量依赖关系-失血性休克,Effect of urinary trypsin inhibitor (UTI) on the change in mean aortic blood pressure, mean aortic blood flow induced by hemorrhagic shock in anesthetized dogs.Each value represents the meanstandard error.Saline; UTI 30,000 U/kg, i.v.; UTI 50,000 U/kg, i.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4dA1: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; P2:UTI 20万U /kg/d, 辐射前治疗3d，辐射后治疗4dA1: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 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