Keck T, Balcom J H, Antoniu B A, Lewandrowski K, Warshaw A L, Fernández-del Castillo C F
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.
Surgery. 2001 Aug;130(2):175-81. doi: 10.1067/msy.2001.115827.
We evaluated the effect of the novel protease inhibitor nafamostat on rat necrotizing pancreatitis through different routes of administration.
Three hours after the induction of severe pancreatitis, the rats received intravenous gabexate or intravenous or local mesenteric intra-arterial nafamostat. At 9 hours, ascites and bronchoalveolar lavage fluid were collected for the evaluation of capillary leakage (Evans blue extravasation). Pancreas and lung were excised for histologic features, myeloperoxidase, and trypsinogen activation peptide. Twenty-four hour survival was evaluated.
Only the intravenous infusion of nafamostat significantly reduced myeloperoxidase (11.7 +/- 2.3 vs 18.3 +/- 1.8 mU/mg; P <.05) and capillary leakage in lungs (Evans blue dye, 1.6 +/- 0.3 vs 2.6 +/- 0.3; P <.05). Only intra-arterial infusion of nafamostat significantly diminished capillary peritoneal leakage (Evans blue dye, 3.6 +/- 0.9 vs 9.4 +/- 0.4; P <.01). Typsinogen activation peptide levels were significantly reduced in all groups, but only intra-arterial infusion did so to baseline. Histologic inflammation in the pancreas was most significantly reduced after intra-arterial infusion (0.92 +/- 0.08 vs 2.91 +/- 0.06; P <.05). No form of protease inhibition reduced mortality rates.
The effects of protease inhibition depend on the route of administration. Nafamostat has maximal effects on the pancreas and peritoneal capillary leakage when delivered by way of local intra-arterial infusion, and shows a greater reduction of lung leukocyte infiltration and capillary leakage by the intravenous route. Nafamostat is more effective than gabexate.
我们通过不同给药途径评估了新型蛋白酶抑制剂那法莫司对大鼠坏死性胰腺炎的影响。
在诱导严重胰腺炎3小时后，大鼠接受静脉注射加贝酯或静脉注射或局部肠系膜动脉内注射那法莫司。9小时时，收集腹水和支气管肺泡灌洗液以评估毛细血管渗漏（伊文思蓝外渗）。切除胰腺和肺以观察组织学特征、髓过氧化物酶和胰蛋白酶原激活肽。评估24小时生存率。
仅静脉输注那法莫司能显著降低髓过氧化物酶水平（11.7±2.3对18.3±1.8 mU/mg；P<.05）以及肺内的毛细血管渗漏（伊文思蓝染料，1.6±0.3对2.6±0.3；P<.05）。仅动脉内输注那法莫司能显著减少腹膜毛细血管渗漏（伊文思蓝染料，3.6±0.9对9.4±0.4；P<.01）。所有组的胰蛋白酶原激活肽水平均显著降低，但只有动脉内输注使其降至基线水平。动脉内输注后胰腺的组织学炎症减轻最为显著（0.92±0.08对2.91±0.06；P<.05）。任何形式的蛋白酶抑制均未降低死亡率。
蛋白酶抑制的效果取决于给药途径。那法莫司通过局部动脉内输注时对胰腺和腹膜毛细血管渗漏的作用最大，通过静脉途径对肺白细胞浸润和毛细血管渗漏的减少作用更大。那法莫司比加贝酯更有效。
