Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis
Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis
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DOI：
10.1001/archsurg.141.7.670
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发表时间：
2006-07-01
影响因子：
--
通讯作者：
Fernandez-del Castillo, Carlos
中科院分区：
文献类型：
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作者：
Alsfasser, Guido;Warshaw, Andrew L.;Fernandez-del Castillo, Carlos
假设：活化蛋白C的药理学形式、美国食品和药物管理局（fda）批准的第一种治疗严重败血症的药物Drotrecogin α（活化）对实验性急性胰腺炎（AP）有益。设计：动物实验。实验对象：雄性sd大鼠。实验对象：雄性sd大鼠。干预措施：诱导72只大鼠轻度（静脉注射蓝蛋白）或重度（静脉注射蓝蛋白加导管内糖脱氧胆酸）AP，并评估凝血情况。严重AP大鼠随机分为甲羟孕酮α（活化）、100 μ g/kg / h或等渗氯化钠治疗。主要观察指标：胰腺坏死的组织学评分、胰腺和肺的炎症（通过髓过氧化物酶浓度测量）、凝血指标和24小时生存率。结果：在重度AP诱导6小时后观察到严重的消耗性凝血功能障碍、血液浓缩和白细胞增多，而在轻度AP诱导6小时后观察到严重的消耗性凝血功能障碍、血液浓缩和白细胞增多。尽管治疗和未治疗的严重AP动物的胰腺坏死程度相当，但曲曲霉素显著降低了胰腺（P= 0.009）和肺部（P= 0.03）的髓过氧化物酶水平。使用原曲素治疗的动物的严重AP 24小时生存率明显提高（86% vs 38%； P= 0.05）。结论：严重AP的动物有严重的消耗性凝血功能障碍，但给药100 μ g/kg / h的原曲素α（活化）不会加重凝血功能异常。曲曲高金治疗可减少胰腺和肺部的炎症，显著提高生存率。这些结果鼓励临床研究曲曲霉素治疗严重AP。
Hypothesis: Drotrecogin alfa (activated), the pharmacologic form of activated protein C and the first Food and Drug Administration-approved drug for treatment of severe sepsis, is beneficial in experimental acute pancreatitis (AP).Design: Animal study.Setting: Laboratory Subjects: Male Sprague-Dawley rats.Subjects: Male Sprague-Dawley rats.Interventions: Mild (intravenous cerulein) or severe (intravenous cerulein plus intraductal glycodeoxycholic acid) AP was induced in 72 rats, and coagulation evaluated. Rats with severe AP were randomized to treatment with drotrecogin alfa (activated), 100 mu g/kg per hour, or isotonic sodium chloride.Main Outcome Measures: Histologic scoring of pancreatic necrosis, inflammation of the pancreas and lung (measured by myeloperoxidase concentration), coagulation measures, and 24-hour survival.Results: Severe consumptive coagulopathy, hemoconcentration, and leukocytosis were observed 6 hours after induction of severe AP, but not in mild AP. Treatment of AP with drotrecogin did not worsen coagulation measures. Although the degree of pancreatic necrosis was comparable in treated and untreated animals with severe AP, drotrecogin significantly reduced myeloperoxidase levels in the pancreas (P=.009) and lungs (P=.03). The 24-hour survival in severe AP was markedly improved in animals treated with drotrecogin (86% vs 38%; P=.05).Conclusions: Animals with severe AP have severe consumptive coagulopathy, but administration of drotrecogin alfa (activated), 100 mu g/kg per hour, does not worsen coagulation abnormalities. Drotrecogin treatment reduces inflammation in the pancreas and lungs and significantly improves survival. These results encourage clinical investigation of drotrecogin in the treatment of severe AP.